Search

Aim: Recently, substantial studies have been accumulated to indicate the important role of gut microbiota in diabetic kidney disease (DKD). The abnormal change of bacterial-derived products could imply specific injuries or play beneficial or harmful roles in DKD progression. In this study, we examined the presence and contribution of the Klebsiella oxytoca gene in the circulation of patients with DKD., Method: We enrolled a total of 16 healthy participants, 17 patients with DKD, 5 patients with DKD requiring haemodialysis (HD), and 7 patients with CKD without diabetes. Bacterial-derived DNA (16S rDNA and a specific K. oxytoca gene) in the blood was detected using droplet digital PCR, then investigated the relationship with clinical characteristics., Results: We identified an increase in K. oxytoca genes in the blood of DKD patients. Interestingly, blood K. oxytoca copies and K. oxytoca/ 16S DNA ratio correlated with higher blood creatinine and BUN levels together with lower eGFR in DKD patients. K. oxytoca levels were also associated with higher neutrophil percentage, lower lymphocyte frequency, and increased neutrophil-to-lymphocyte ratio., Conclusion: Collectively, the presence of the K. oxytoca gene in the circulation could serve as a biomarker reflecting reduced renal function in DKD patients., (© 2024 Asian Pacific Society of Nephrology.)

Background: Cancer patients are more susceptible to an aggressive course of COVID-19. Developing biomarkers identifying cancer patients at high risk of COVID-19-related death could help determine who needs early clinical intervention. The miRNAs hosted in the genomic regions associated with the risk of aggressive COVID-19 could represent potential biomarkers for clinical outcomes., Patients and Methods: Plasma samples were collected at The University of Texas MD Anderson Cancer Center from cancer patients (N = 128) affected by COVID-19. Serum samples were collected from vaccinated healthy individuals (n = 23) at the Municipal Clinical Emergency Teaching Hospital in Timisoara, Romania. An in silico positional cloning approach was used to identify the presence of miRNAs at COVID-19 risk-associated genomic regions: CORSAIRs (COvid-19 RiSk AssocIated genomic Regions). The miRNA levels were measured by RT-qPCR., Results: We found that miRNAs were enriched in CORSAIR. Low plasma levels of hsa-miR-150-5p and hsa-miR-93-5p were associated with higher COVID-19-related death. The levels of hsa-miR-92b-3p were associated with SARS-CoV-2 test positivity. Peripheral blood mononuclear cells (PBMC) increased secretion of hsa-miR-150-5p, hsa-miR-93-5p, and hsa-miR-92b-3p after in vitro TLR7/8- and T cell receptor (TCR)-mediated activation. Increased levels of these three miRNAs were measured in the serum samples of healthy individuals between one and nine months after the second dose of the Pfizer-BioNTech COVID-19 vaccine. SARS-CoV-2 infection of human airway epithelial cells influenced the miRNA levels inside their secreted extracellular vesicles., Conclusions: MiRNAs are enriched at CORSAIR. Plasma miRNA levels can represent a potential blood biomarker for predicting COVID-19-related death in cancer patients., (© 2024. The Author(s).)

In mammalian cells, protein condensates underlie diverse cell functions. Intensive synthetic biological research has been devoted to fabricating liquid droplets using de novo peptides/proteins designed from scratch in test tubes or bacterial cells. However, the development of de novo sequences for synthetic droplets forming in eukaryotes is challenging. Here, we report YK peptides, comprising 9-15 residues of alternating repeats of tyrosine and lysine, which form reversible amyloid-like fibrils accompanied by binding with poly-anion species such as ATP. By genetically tagging the YK peptide, superfolder GFPs assemble into artificial liquid-like droplets in living cells. Rational design of the YK system allows fine-tuning of the fluidity and construction of multi-component droplets. The YK system not only facilitates intracellular reconstitution of simplified models for natural protein condensates, but it also provides a toolbox for the systematic creation of droplets with different dynamics and composition for in situ evaluation., (© 2024. The Author(s).)

Hepatocellular carcinoma (HCC) rupture is a severe complication, yet there is limited literature on cases complicated by subsequent non-occlusive mesenteric ischemia (NOMI). A 77-year-old man presented to our hospital with abdominal pain and shock. Arterial phase computed tomography (CT) hepatic arteriography revealed a 77-mm HCC in the left lobe with active extravasation, and the feeding artery was embolized. Although the abdominal pain initially subsided after the procedure, it recurred the next day. A contrast-enhanced CT scan revealed pneumatosis intestinalis and decreased enhancement of the small intestinal wall. The patient underwent resection of the affected segment of the small intestine and was ultimately diagnosed with NOMI based on pathological findings. This is the first reported case of NOMI following HCC rupture. Given the high mortality associated with these conditions, clinicians should be aware of this rare complication and ensure comprehensive evaluation and timely intervention to improve patient outcomes., (© 2024. Japanese Society of Gastroenterology.)

The size of the ovarian reserve, an indicator of the number of primordial follicles, varies widely among individuals, and declines with age. However, the association between the ovarian reserve and fertility remains unclear. Therefore, in the present study, we analyzed the relationship between plasma concentrations of anti-Müllerian hormone (AMH), a marker of ovarian reserve, and reproductive outcomes in Japanese Black cattle. AMH level quartiles were positively associated with pregnancy following artificial insemination (AI), and the median number of days to pregnancy in Q4 (13 days, 95% confidence interval [CI] = 7-18 days) was significantly shorter than that in Q1 (21 days, 95% CI = 15-46 days). The odds ratio for the predicted pregnancy rate by logistic regression analysis in Q4 (4.06, 95% CI = 1.54-10.67) was also significantly higher than that in Q1. Plasma AMH concentrations were significantly higher in summer (June-August) than in winter (December-February). Furthermore, a strong correlation (r = 0.829, P < 0.001) was observed between plasma AMH concentrations at 2 and 14 months of age. Calves with plasma AMH concentrations of > 700 pg/ml at 2 months old showed a transient increase and maximum AMH concentration within 5 months of birth. Overall, the results of this study indicate that the plasma AMH concentration serves as a predictive marker for the probability of conception following AI in Japanese Black cattle. The current findings contribute to the reliable assessment of AMH production and the early prediction of reproductive performance in sexually mature heifers.

Insulin-like growth factor binding proteins (IGFBP) regulate insulin-like growth factor (IGF) signaling, but IGFBP-specific functions are not well characterized in fishes. A line of rainbow trout ( Oncorhynchus mykiss ) lacking a functional IGFBP-2b was produced using gene editing and subsequent breeding to an F2 generation. This loss-of-function model (2bKO) was subjected to either continuous feeding or feed deprivation (3 wk) followed by refeeding (1 wk). During continuous feeding, the 2bKO line displayed faster specific growth rate for both body weight and fork length, higher feed intake, and reduced feed conversion ratio compared to a wild type (WT) line. However, loss of IGFBP-2b did not affect the feed deprivation or refeeding response in terms of weight loss or weight gain, respectively. Several components of the IGF/IGFBP system were affected by loss of IGFBP2b. Total serum IGF-1 in the 2bKO line was reduced to 0.5 - 0.8-fold of the WT line although the concentration of free serum IGF-1 was not affected. Gene expression differences include reduced abundance of igfbp1a1 , igfbp1b2 , igfbp5b2 , and igfbp6b1 transcripts, and elevated igf2 and igfbp6b2 transcripts in liver of the 2bKO line. Collectively, these findings suggest that although IGFBP-2b is a carrier of circulating IGF-1 in salmonids, the presence of IGFBP-2a and compensatory responses of other IGF/IGFBP system components support an anabolic response that improved growth performance in the loss-of-function model.

Objectives: A preference for eveningness - one's perception of being most alert later in the day - is associated with negative developmental outcomes in adolescence. Sleep onset consistency is protective against such outcomes. Toward a more nuanced understanding of relations between sleep-wake processes and adolescent development, we examined weeknight sleep onset consistency as a moderator of relations between eveningness and multiple indicators of development., Method: A sample of 272 high-school students ( M age  = 17 years, SD = 9.12 months; n  = 133 identified as female; 41% non-Hispanic Black/African-American, 59% non-Hispanic White/European-American) participated in a week of at-home sleep actigraphy assessment in 2017-2018. Adolescents reported their morningness - eveningness, internalizing symptoms (depression, anxiety), positive affect (optimism and subjective happiness), and physical health, and mothers reported on youths' behavior problems. Relations were examined between morningness - eveningness and each indicator of development; sleep onset consistency was examined as a moderator of these associations., Results: On average, adolescents with a preference for eveningness had higher levels of externalizing behaviors and internalizing symptoms and lower levels of positive affect and physical health compared to peers with a preference for morningness ( B s = -0.27*-0.12***). Each association was moderated by weeknight sleep onset consistency. Across all indicators of development, evening-preferring youth with more consistent weeknight sleep onset had 0.49-0.72 SD better outcomes on average than evening-preferring youth with less consistent weeknight sleep onset., Conclusions: Falling asleep at roughly the same time each night can protect adolescent night owls from behavior problems and internalizing symptoms and can promote their positive affect and physical health.

Background: Recent advancements in generative artificial intelligence (AI) for image generation have presented significant opportunities for medical imaging, offering a promising way to generate realistic virtual medical images while ensuring patient privacy. The generation of a large number of virtual medical images through AI has the potential to augment training datasets for discriminative AI models, particularly in fields with limited data availability, such as neuroimaging. Current studies on generative AI in neuroimaging have mainly focused on disease discrimination; however, its potential for simulating complex phenomena in psychiatric disorders remains unknown. In this study, as examples of a simulation, we aimed to present a novel generative AI model that transforms magnetic resonance imaging (MRI) images of healthy individuals into images that resemble those of patients with schizophrenia (SZ) and explore its application., Methods: We used anonymized public datasets from the Center for Biomedical Research Excellence (SZ, 71 patients; healthy subjects [HSs], 71 patients) and the Autism Brain Imaging Data Exchange (autism spectrum disorder [ASD], 79 subjects; HSs, 105 subjects). We developed a model to transform MRI images of HSs into MRI images of SZ using cycle generative adversarial networks. The efficacy of the transformation was evaluated using voxel-based morphometry to assess the differences in brain region volumes and the accuracy of age prediction pre- and post-transformation. In addition, the model was examined for its applicability in simulating disease comorbidities and disease progression., Results: The model successfully transformed HS images into SZ images and identified brain volume changes consistent with existing case-control studies. We also applied this model to ASD MRI images, where simulations comparing SZ with and without ASD backgrounds highlighted the differences in brain structures due to comorbidities. Furthermore, simulating disease progression while preserving individual characteristics showcased the model's ability to reflect realistic disease trajectories., Discussion: The results suggest that our generative AI model can capture subtle changes in brain structures associated with SZ, providing a novel tool for visualizing brain changes in different diseases. The potential of this model extends beyond clinical diagnosis to advances in the simulation of disease mechanisms, which may ultimately contribute to the refinement of therapeutic strategies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Yamaguchi, Sugihara, Shimizu and Yamashita.)

Background: Implantable cardioverter defibrillators (ICDs) reduce mortality associated with ventricular arrhythmia in high-risk patients with cardiovascular disease. Machine learning (ML) approaches are promising tools in arrhythmia research; however, their application in predicting ventricular arrhythmias in patients with ICDs remains unexplored. We aimed to predict and stratify ventricular arrhythmias requiring ICD therapy using 12-lead electrocardiograms (ECGs) in patients with an ICD., Methods and Results: This retrospective analysis included 200 adult patients who underwent ICD implantation at a single center. Patient demographics, clinical features, and 12-lead ECG data were collected. Unsupervised learning techniques, including K-means and hierarchical clustering, were used to stratify patients based on 12-lead ECG features. Dimensionality reduction methods were also used to optimize clustering accuracy. The silhouette coefficient was used to determine the optimal method and number of clusters. Of the 200 patients, 59 (29.5%) received appropriate therapy. The mean age of patients was 62.3 years, and 81.0% were male. The mean follow-up period was 2,953 days, with no significant intergroup differences. Hierarchical clustering into 3 clusters proved to be the most accurate (silhouette coefficient=0.585). Kaplan-Meier curves for these 3 clusters revealed significant differences (P=0.026)., Conclusions: We highlight the potential of ML-based clustering using 12-lead ECGs to help in the risk stratification of ventricular arrhythmia. Future research in a larger multicenter setting may provide further insights and refine ICD indications.

Aim: The chronic lack of obstetrics-gynecology (Ob/Gyn) doctors is a serious problem to be tackled in Japan. To address this issue, it is necessary for medical students to be interested in working as an Ob/Gyn doctor and more junior residents need to specialize in Ob/Gyn. This study aims to identify the preferences concerning working conditions among students and discusses what information should be provided and what conditions should be changed., Methods: A questionnaire survey was conducted among participants in the Summer School 2023 of the Japanese Society of Obstetrics and Gynecology. The respondents were medical students and junior residents interested in Ob/Gyn. Ob/Gyn specialists contributing to the summer school were also asked the same questions for comparison. The resulting data focused on important working conditions, concerns about future work, and expected future working conditions., Results: Responses from 132 medical students (97.8%, N = 135), 122 residents (99.2%, N = 123), and 76 specialists (95.0%, N = 80) were obtained. There were three main findings. First, large gaps between students/residents and specialists were observed in terms of preferences. Second, differences between male and female students/residents were not negligible, although the difference was relatively small in specialists. Third, students/residents were more concerned about risks related to medical malpractice than specialists., Conclusions: Gaps in preferences and perceptions regarding working conditions between students/residents and specialists should be narrowed through sufficient information provision. Working conditions should become gender-inclusive rather than focus on female persons., (© 2024 Japan Society of Obstetrics and Gynecology.)

In pulmonary disease patients since oxygen desaturation during 6-min walk test (6MWT) affects walk distance (6MWD), some novel indices such as desaturation/distance ratio [DDR, oxygen desaturation area (DAO 2 )/6MWD] and distance-saturation product [DSP, 6MWD × minimum peripheral oxygen saturation (SpO 2 )] are evaluated. However, there has been no study examining these indices that consider exercise-induced desaturation (EID) in patients with cardiovascular disease. In 94 cardiovascular disease patients without pulmonary complications, 6MWT and echocardiography were performed at the entry of cardiac rehabilitation. SpO 2 was measured during 6MWT using a continuously monitorable pulse oximeter, and DSP and DDR were calculated using minimum SpO 2 and DAO 2 [sum of (100-SpO 2 ) per second during 6MWT], respectively. EID was defined as SpO 2 decrease of ≥ 4% or minimum SpO 2 of < 90% during 6MWT. DSP was slightly lower and DDR was markedly higher in patients with EID than in those without. When examining correlations of DSP and DDR with their components, DSP was correlated with 6MWD much closely than minimum SpO 2 , while DDR was correlated as closely with DAO 2 as 6MWD. Furthermore, DAO 2 , but not minimum SpO 2 , had a direct correlation with 6MWD. As for associations with cardiac function, DSP was correlated with several cardiac parameters, but DDR was not correlated with any of these parameters. Our findings suggest that oxygen desaturation during 6MWT affects walking distance in cardiovascular disease patients even without pulmonary complications and that DDR is more appropriate than DSP as an index of walking performance that takes EID into consideration, independently of cardiac function., (© 2024. Springer Nature Japan KK, part of Springer Nature.)

Backgrounds & Aims: This study aimed to investigate the association between vitamin D deficiency and covert hepatic encephalopathy (CHE), overt hepatic encephalopathy (OHE) occurrence, and mortality in patients with cirrhosis., Methods: This retrospective study reviewed 679 patients with cirrhosis. Vitamin D deficiency was defined as serum 25-hydorxyvitamin D (25-OHD) levels < 20 ng/mL. The associations between 25-OHD and CHE, OHE occurrence, and mortality were assessed using logistic regression, Fine-Gray competing risk regression, and Cox proportional hazards regression models, respectively., Results: Of 428 eligible patients, 75% had vitamin D deficiency and 23% had CHE. The prevalence of CHE was higher in patients with vitamin D deficiency than in those without vitamin D deficiency (28% vs. 13%, p = 0.002). During the median follow-up period of 2.3 years, 14% of the patients developed OHE and 27% died. Patients with vitamin D deficiency had a higher incidence of OHE (p = 0.002) and mortality (p = 0.006) than those without vitamin D deficiency. After adjustment for potential covariates, multivariate analyses showed that 25-OHE was associated with CHE (odds ratio, 0.95; 95% confidence interval [CI], 0.91-0.99; p = 0.023), OHE occurrence (sub-distribution hazard ratio, 0.92; 95% CI, 0.86-0.98; p = 0.013) and mortality (hazard ratio, 0.96; 95% CI, 0.93-0.99; p = 0.020) in patients with cirrhosis., Conclusions: Vitamin D deficiency is highly prevalent and is associated with CHE, OHE, and mortality in patients with cirrhosis. Evaluation of vitamin D is essential to predict the outcomes of patients with cirrhosis., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Neuroimaging databases for neuro-psychiatric disorders enable researchers to implement data-driven research approaches by providing access to rich data that can be used to study disease, build and validate machine learning models, and even redefine disease spectra. The importance of sharing large, multi-center, multi-disorder databases has gradually been recognized in order to truly translate brain imaging knowledge into real-world clinical practice. Here, we review MRI databases that share data globally to serve multiple psychiatric or neurological disorders. We found 42 datasets consisting of 23,293 samples from patients with psychiatry and neurological disorders and healthy controls; 1245 samples from mood disorders (major depressive disorder and bipolar disorder), 2015 samples from developmental disorders (autism spectrum disorder, attention-deficit hyperactivity disorder), 675 samples from schizophrenia, 1194 samples from Parkinson's disease, 5865 samples from dementia (including Alzheimer's disease), We recognize that large, multi-center databases should include governance processes that allow data to be shared across national boundaries. Addressing technical and regulatory issues of existing databases can lead to better design and implementation and improve data access for the research community. The current trend toward the development of shareable MRI databases will contribute to a better understanding of the pathophysiology, diagnosis and assessment, and development of early interventions for neuropsychiatric disorders., (© 2024 The Author(s). Psychiatry and Clinical Neurosciences published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Psychiatry and Neurology.)

Objectives: The placement of plastic stents (PS), including intraductal PS (IS), is useful in patients with unresectable malignant hilar biliary obstruction (UMHBO) because of patency and ease of endoscopic reintervention (ERI). However, the optimal stent replacement method for PS remains unclear., Methods: This retrospective study included 322 patients with UMHBO. Among them, 146 received PS placement as initial drainage (across-the-papilla PS [aPS], 54; IS, 92), whereas 75 required ERI. Eight bilateral aPS, 21 bilateral IS, and 17 bilateral self-expandable metallic stent (SEMS) placements met the inclusion criteria. Rates of technical and clinical success, adverse events, recurrent biliary obstruction (RBO), time to RBO (TRBO), overall survival, and secondary ERI were compared., Results: There were no significant intergroup differences in rates of technical or clinical success, adverse events, RBO occurrence, or overall survival. The median TRBO was significantly shorter in the aPS group (47 days) than IS (91 days; P = 0.0196) and SEMS (143 days; P < 0.01) groups. Median TRBO did not differ significantly between the IS and SEMS groups (P = 0.44). On Cox multivariate analysis, the aPS group had the shortest stent patency (hazard ratio 2.67 [95% confidence interval 1.05-6.76], P = 0.038). For secondary ERI, the median endoscopic procedure time was significantly shorter in the IS (22 min) vs. SEMS (40 min) group (P = 0.034)., Conclusions: Bilateral IS and SEMS placement featured prolonged patency after first ERI. Because bilateral IS placement is faster than SEMS placement and IS can be removed during secondary ERI, it may be a good option for first ERI., (© 2024 Japan Gastroenterological Endoscopy Society.)

Background: Rapid skeletal muscle loss adversely affects the clinical outcomes of liver cirrhosis. However, the relationships between the annual changes in skeletal muscle area (ΔSMA/year) and the etiology of cirrhosis, factors associated with muscle loss, and risk of mortality remains unclear., Methods: A total of 384 patients who underwent multiple computed tomography (CT) scans between March 2004 and June 2021 were enrolled in this study (median age, 67 years; 64% men; median model for end-stage liver disease score, 9). Body composition and ΔSMA/year were estimated using a 3D image analysis system and data from at least two distinct CT scans. Differences in ΔSMA/year among different etiologies of cirrhosis, factors associated with rapid muscle loss (defined as ΔSMA/year ≤  - 3.1%), and the association between ΔSMA/year and mortality were examined., Results: Patients with alcohol-associated liver disease (ALD) cirrhosis experienced more rapid muscle loss (ΔSMA/year, - 5.7%) than those with hepatitis B (ΔSMA/year, - 2.8%) and hepatitis C cirrhosis (ΔSMA/year, - 3.1%). ALD cirrhosis was independently associated with ΔSMA/year ≤  - 3.1% after adjusting for age, sex, and liver functional reserve. Over a median follow-up period of 3.8 years, ALD cirrhosis, ΔSMA/year ≤  - 3.1%, and low subcutaneous adipose tissue level were found to be significantly associated with reduced survival. ALD cirrhosis (hazard ratio [HR], 2.43; 95% confidence interval [CI] 1.12-5.28) and ΔSMA/year ≤  - 3.1% (HR, 3.68; 95% CI 2.46-5.52) were also predictive of mortality., Conclusions: These results suggest that ALD cirrhosis increases the risk of rapid muscle loss and mortality in affected patients., (© 2024. The Author(s).)

Objective: Recently, the Pediatric Rheumatology International Trials Organization (PRINTO) has proposed revisions to the current International League of Associations for Rheumatology (ILAR) criteria for systemic juvenile idiopathic arthritis (s-JIA). Interleukin (IL)-18 overproduction plays a significant role in the pathogenesis of s-JIA. This study aimed to evaluate the performance of the PRINTO criteria compared with the ILAR criteria and determine whether serum IL-18 levels improve their diagnostic performances., Methods: Overall, 90 patients with s-JIA and 27 patients with other febrile disease controls presenting with a prolonged fever of > 14 days and arthritis and/or erythematous rash were enrolled. The ILAR and PRINTO classification criteria were applied to all patients and examined with expert diagnoses. Enzyme-linked immunosorbent assay was used for measuring serum IL-18 levels., Results: The PRINTO criteria had higher sensitivity but lower specificity than the ILAR criteria (sensitivity: PRINTO 0.856, ILAR 0.533; specificity: PRINTO 0.259, ILAR 0.851). With the addition of serum IL-18 levels ≥ 4,800 pg/mL, the sensitivity of the ILAR criteria and specificity of the PRINTO criteria were improved to 1.000 and 1.000, respectively. PRINTO plus serum IL-18 levels ≥ 4,800 pg/mL showed the highest value in Youden's index (sensitivity - [1 - specificity])., Conclusion: Serum IL-18 levels could improve the diagnostic performance of the PRINTO and ILAR criteria for s-JIA. The PRINTO criteria plus serum IL-18 levels ≥ 4,800 pg/mL could be the best diagnostic performance for s-JIA., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Drug oxygenation is mainly mediated by cytochromes P450 (P450s, CYPs) and flavin-containing monooxygenases (FMOs). Polymorphic variants of P450s and FMOs are known to influence drug metabolism.　Species differences exist in terms of drug metabolism and can be important when determining the contributions of individual enzymes. The success of research into drug-metabolizing enzymes and their impacts on drug discovery and development has been remarkable. Dogs and pigs are often used as preclinical animal models. This research update provides information on P450 and FMO enzymes in dogs and pigs and makes comparisons with their human enzymes. Newly identified dog CYP3A98, a testosterone 6β- and estradiol 16α-hydroxylase, is abundantly expressed in small intestine and is likely the major CYP3A enzyme in small intestine, whereas dog CYP3A12 is the major CYP3A enzyme in liver. The roles of recently identified dog CYP2J2 and pig CYP2J33/34/35 were investigated. FMOs have been characterized in humans and several other species including dogs and pigs. P450 and FMO family members have been characterized also in cynomolgus macaques and common marmosets. P450s have industrial applications and have been the focus of attention of many pharmaceutical companies. The techniques used to investigate the roles of P450/FMO enzymes in drug oxidation and clinical treatments have not yet reached maturity and require further development. The findings summarized here provide a foundation for understanding individual pharmacokinetic and toxicological results in dogs and pigs as preclinical models and will help to further support understanding of the molecular mechanisms of human P450/FMO functionality., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Oxidative stress is a risk factor for distal sensorimotor polyneuropathy (DSPN). Selenoprotein P is a protein with antioxidant properties but has not been investigated in the context of DSPN. This study aimed to assess the associations between selenoprotein P and DSPN in people without and with type 2 diabetes (T2D)., Methods: Cross-sectional and prospective analyses were based on 1053 (including 217 with T2D) and 513 participants (including 79 with T2D), respectively, aged 61-82 years from the population-based KORA F4 survey. DSPN at baseline (KORA F4) and in the follow-up survey KORA FF4 was defined based on the Michigan Neuropathy Screening Instrument. Serum levels of full-length selenoprotein P were quantified by ELISA. Associations between selenoprotein P and prevalent or incident DSPN were estimated using logistic regression analysis adjusting for multiple confounders., Results: Selenoprotein P levels were not associated with prevalent DSPN in the total sample. However, there was a significant interaction by diabetes status. Higher levels of selenoprotein P were associated with lower odds of prevalent DSPN in individuals without T2D (fully adjusted model: OR 0.825 [95 % CI 0.682, 0.998], p = 0.0476), but not in those with T2D (OR [95 % CI] 1.098 [0.829, 1.454], p = 0.5132; p interaction  = 0.0488). Selenoprotein P levels were not associated with incident DSPN over a follow-up of 6.5 years., Conclusion: In individuals without T2D from the older general population, lower selenoprotein P levels were associated with a higher prevalence of DSPN. Whether the antioxidant properties of selenoprotein P are responsible for the observed associations remains to be elucidated in future research., Competing Interests: Declaration of competing interest All authors declare that there are no conflicts of interest in connection with this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Combined hepatocellular cholangiocarcinoma is a rare and challenging primary liver malignancy that lacks any established standard treatments for unresectable cases. We herein present the first known case of a 49-year-old woman diagnosed with unresectable combined hepatocellular-cholangiocarcinoma, who underwent novel chemotherapy involving durvalumab plus tremelimumab combination therapy. The treatment was temporarily discontinued owing to immune-related adverse events, such as rash, and the patient was subsequently managed with systemic steroid therapy; however, the disease progressed after two courses of this treatment. Further studies are needed to validate the efficacy and safety of immune checkpoint inhibitors such as durvalumab and tremelimumab for the treatment of unresectable combined hepatocellular cholangiocarcinoma.

The presence of prolonged symptoms after COVID infection worsens the workability and quality of life. 200 adults with long COVID syndrome were enrolled after medical, physical, and mental screening, and were divided into two groups based on their performance. The intervention group (n = 100) received supervised rehabilitation at Department of Pulmonology, Semmelweis University with the registration number 160/2021 between 01/APR/2021-31/DEC/2022, while an age-matched control group (n = 100) received a single check-up. To evaluate the long-term effects of the rehabilitation, the intervention group was involved in a 2- and 3-month follow-up, carrying out cardiopulmonary exercise test. Our study contributes understanding long COVID rehabilitation, emphasizing the potential benefits of structured cardiopulmonary rehabilitation in enhancing patient outcomes and well-being. Significant difference was found between intervention group and control group at baseline visit in pulmonary parameters, as forced vital capacity, forced expiratory volume, forced expiratory volume, transfer factor for carbon monoxide, transfer coefficient for carbon monoxide, and oxygen saturation (all p < 0.05). Our follow-up study proved that a 2-week long, patient-centered pulmonary rehabilitation program has a positive long-term effect on people with symptomatic long COVID syndrome. Our data showed significant improvement between two and three months in maximal oxygen consumption (p < 0.05). Multidisciplinary, individualized approach may be a key element of a successful cardiopulmonary rehabilitation in long COVID conditions, which improves workload, quality of life, respiratory function, and status of patients with long COVID syndrome., (© 2024. The Author(s).)

Implantation cyst is often reported to be a delayed complication after colorectal surgery. This report presents a 70-year-old man undergoing gastrectomy 33 years earlier for an acute gastric ulcer. His endoscopic finding showed a submucosal tumor about 20 mm in diameter at the gastro-jejunal anastomosis. Endoscopic ultrasonography showed that the tumor was a cystic mass that was continuous from the third layer, but there were no existences of internal substantial nodules, indicating that the tumor was diagnosed as implantation cyst. This is the first report showing that implantation cyst can occur at gastro-jejunal anastomosis. We should take into account the occurrence of implantation cyst, when we encounter a submucosal tumor at gastro-jejunal anastomosis after surgery even if a long period has passed., (© 2024. Japanese Society of Gastroenterology.)

Competing Interests: The authors declare no conflict of interest.

Introduction: Peritoneal equilibration test (PET) has been used to monitor peritoneal function. A more convenient marker would be useful in clinical situations including home medical care. Autotaxin is known to leak into the interstitium as vascular permeability increases during the progression of tissue fibrosis. Therefore, we hypothesized that autotaxin concentrations in peritoneal dialysis (PD) effluent might reflect peritoneal function., Methods: This study enrolled 45 patients undergoing PD from 2016 to 2021. Autotaxin concentrations measured in PD effluent were evaluated for their associations with markers obtained from PET., Results: Mean age was 69 years, and 33 patients were men. Univariate and multivariate analyses revealed that autotaxin concentrations are associated with dialysate/plasma creatinine ratio, end/start dialysate glucose ratio, and the dip in the dialysate sodium concentration, a marker of ultrafiltration capacity, at baseline (all p < 0.05)., Conclusions: Autotaxin concentrations in PD effluent might be an adjunct marker that reflects peritoneal function., (© 2024 International Society for Apheresis and Japanese Society for Apheresis.)

We evaluated the utility of the Hospital Frailty Risk Score (HFRS) as a predictor of adverse events post-hospitalization in a retrospective analysis of patients undergoing neurosurgical procedures due to aneurysmal subarachnoid hemorrhage (SAH). This historical cohort study analyzed the data of patients hospitalized with aneurysmal SAH (n = 1,343) between April 2014 and August 2020 who were registered in the JMDC database. We used HFRS to classify the patients into the low-frailty risk group (HFRS < 5) and high-frailty risk group (HFRS ≥ 5). The primary outcome was a modified Rankin Scale (mRS) score of 0-2 points at discharge. Of 1,343 patients, 1,001 (74.5%) and 342 (25.5%) were in the low- and high-frailty risk groups, respectively. A high-frailty risk was negatively associated with a mRS score of 0-2 at discharge (high-frailty risk group: odds ratio 0.4; 95% confidence interval [CI]: 0.3-0.6) and home discharge (high-frailty risk group: odds ratio 0.5; 95% CI: 0.4-0.7). A high-frailty risk was negatively associated with Barthel Index gain (high-frailty risk group: coefficient -10.4, 95% CI: -14.7 to -6.2) and had a longer length of stay (high-frailty risk group: coefficient 8.4, 95% CI: 5.1-11.7). HFRS could predict adverse outcomes during hospitalization of aneurysmal SAH patients.

Objective: In open repair for descending thoracic aortic aneurysm (DTAA) or thoracoabdominal aortic aneurysm (TAAA), the influence of re-interventions on spinal cord injury (SCI) remains unclear. This study evaluated the relationships between re-interventions, atherosclerosis, and SCI. Methods: We retrospectively reviewed 78 patients who underwent open surgical repair for DTAA or TAAA between April 2011 and May 2023. The associations of SCI with (i) re-interventions with a history of endovascular therapy and graft replacement and (ii) atherosclerotic factors, including monocyte count, triglyceride levels (TG), and intra-aortic plaques, were examined. Results: The rates of SCI complications and 30-day mortality were both 3.8% (3/78). There was no significant difference between the incidence of SCI in the re-intervention and first-time intervention groups (p >0.90). However, patients with protruding plaque on computed tomography (CT) were more affected by SCI than those without (13.3% vs. 1.6%, p = 0.034). Univariate analysis revealed that SCI was associated with increased monocyte count, TG, protruding plaques on CT, and intraoperative blood loss. Conclusion: Re-interventions for DTAA and TAAA showed no association with the development of SCI under appropriate protective measures. The implicated risk factors may be atherosclerosis factors such as elevated monocyte count, TG, and protruding plaques on CT., (@ 2024 The Editorial Committee of Annals of Vascular Diseases.)

We recently reported a method for recovering and quantifying residual proteins bound to surfaces of various medical instruments via thermal coagulation under neutral pH and room temperature. The method effectively recovered and solubilised coagulated proteins at high temperatures in dry and humid conditions, with a protein recovery rate of > 90%. This study validated the previous method by comparing residual protein recovery from test samples using a conventional extraction solution (1% SDS, [pH 11.0]) and proposed solution (1% SDS, 10 mM TCEP, and 10 mM HEPES [pH 7.0]). To mimic soiled medical equipment, pseudo-blood-contaminated stainless steel plates were prepared. Residual protein was recovered using conventional and proposed solutions under varying temperature and humidity conditions. Quantitative protein recovery limits were determined at nine facilities. Compared with the conventional solution, the proposed solution recovered proteins more effectively from samples processed at temperatures > 60 °C. However, low recovery rates were observed for samples processed at 95 °C, possibly owing to differences in protein adhesion due to sample and plate-surface properties. Our findings present a method for quantifying residual proteins on medical instruments exposed to high temperatures during use or disinfection. Further studies should standardise test soiling conditions, materials, and solutions to evaluate cleaning methods., (© 2024. The Author(s).)

A dosimeter should ideally be calibrated in a reference field with similar energy and doserate to that which the dosimeter is being used to measure. Environments around nuclear reactors and radiation therapy facilities have high-energy photons with energies exceeding that of 60 Co gamma rays, and controlling exposure to these photons is important. The Japan Atomic Energy Agency and National Metrology Institute of Japan have high-energy reference fields with energies above several megaelectronvolts for different types of accelerators. Their reference fields have different fluence-energy distributions. In this study, the energy dependencies of the two-cavity ionization chambers, which are often used by secondary standard laboratories, were experimentally and computationally evaluated for each high-energy field. These results agreed well within the relative expanded uncertainties ( k = 2), and their capabilities for air kerma measurements in each high-energy reference field were confirmed. Therefore, the capabilities of the air-kerma measurements were verified in the two high-energy reference fields., (© 2024 Society for Radiological Protection. Published on behalf of SRP by IOP Publishing Limited. All rights, including for text and data mining, AI training, and similar technologies, are reserved.)

Background: As the number of revision total knee arthroplasty (TKA) continues to rise, close attention has been paid to factors influencing postoperative length of stay (LOS). The aim of this study is to develop generalizable machine learning (ML) algorithms to predict extended LOS following revision TKA using data from a national database., Methods: 23,656 patients undergoing revision TKA between 2013 and 2020 were identified using the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database. Patients with missing data and those undergoing re-revision or conversion from unicompartmental knee arthroplasty were excluded. Four ML algorithms were applied and evaluated based on their (1) ability to distinguish between at-risk and not-at-risk patients, (2) accuracy, (3) calibration, and (4) clinical utility., Results: All four ML predictive algorithms demonstrated good accuracy, calibration, clinical utility, and discrimination, with all models achieving a similar area under the curve (AUC) (AUC LR =AUC RF =AUC HGB =0.75, AUC ANN =0.74). The most important predictors of prolonged LOS were found to be operative time, preoperative diagnosis of sepsis, and body mass index (BMI)., Conclusions: ML models developed in this study demonstrated good performance in predicting extended LOS in patients undergoing revision TKA. Our findings highlight the importance of utilizing nationally representative patient data for model development. Prolonged operative time, preoperative sepsis, BMI, and elevated preoperative serum creatinine and BUN were noted to be significant predictors of prolonged LOS. Knowledge of these associations may aid with patient-specific preoperative planning, discharge planning, patient counseling, and cost containment with revision TKA., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Introduction: Infection is among the most common reasons for revision after a total joint arthroplasty (TJA) and is associated with notable morbidity and mortality rates. As the demand for TJA increases, a concurrent increase in the prevalence of periprosthetic joint infection (PJI) is also expected to rise. While previous studies have explored differences in postoperative outcomes between general and spinal anesthesia, there is limited data on the use of regional blocks in patients undergoing revision joint arthroplasty for PJI. This study evaluated the postoperative outcomes of patients undergoing revision TJA for PJI using regional blocks., Methods: Data from 518 patients were retrospectively collected. Patients included in the study had undergone revision TJA for PJI from January 2004 to January 2023 at a single institution. Patients undergoing same-day bilateral revisions, above-knee amputations, and aseptic revisions were excluded. Postoperative complications investigated included local complications, postoperative transfusion, wound complication, readmission, sepsis, systemic infection, spinal infection, death, persistent PJI, periprosthetic fracture, and unplanned revision surgery. Chi-square analysis was used to compare postoperative complications between procedures that used spinal or general anesthesia with regional blocks and those with spinal or general anesthesia without regional blocks., Results: Of the 518 patients who underwent revision TJA, 63 (12.2%) used a regional block. After surgery, 12.7% (n = 8) of patients with regional block and 23.5% (n = 107) of patients without regional block experienced persistent PJI (P = 0.076). No significant differences in wound complication (P = 0.333), readmission (P = 0.998), revision surgery (P = 0.783), and death (P = 0.588) were found between those with and without regional block use. Sepsis (P = 0.224), systemic infection (P = 0.220), and spinal infection (P = 0.998) rates within 1 year after revision TJA for PJI surgery were comparable between the two groups. No local infections were observed at the block site. A subanalysis comparing spinal and general anesthesia demonstrated comparable persistent PJI postoperatively and complication rates; however, spinal anesthesia use was associated with shorter length of stay (P = 0.003) and lower transfusion rates (P = 0.002)., Conclusion: The results of this study suggest that the use of regional block is not associated with an increased probability of postoperative persistent PJI, local wound complication, readmission, spinal/systemic/other infections, death, or revision surgery. Surgeons can comfortably choose regional block as a safe option for revision surgery for PJI. Consistent with previous research, patients who received spinal anesthesia had shorter hospital stays and lower transfusion rates when compared with those who received general anesthesia., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Orthopaedic Surgeons.)

To assess the impact of adverse event (AE) severity, caused by targeted therapy, on overall survival (OS) and progression-free survival (PFS) in patients with unresectable hepatocellular carcinoma (HCC), a total of 183 patients with HCC treated with atezolizumab plus bevacizumab (40), lenvatinib (57), sorafenib (79), cabozantinib (3), ramucirumab (3), and regorafenib (1) were included in this study. Age-, AFP-, and ALBI score-adjusted hazard ratios (HRs) of AE grades 1 to 3 versus grade 0 for OS and PFS were calculated using Cox proportional hazards models. The linear trend of the HRs was assessed by calculating the p values for this trend. The most common AEs were appetite loss (AE grade 0/1/2/3 = 97/23/55/12), general fatigue (102/31/44/6), hypertension (120/6/40/17), hand-foot syndrome (HFS) (135/21/24/3), proteinuria (140/13/16/14), and hypothyroidism (148/12/23/0). The adjusted HRs for OS of these AEs were 0.532-1.450-2.361 ( p for trend 0.037), 1.057-1.691-3.364 ( p for trend 0.004), 1.176-0.686-0.281 ( p for trend 0.002), 0.639-0.759-1.820 ( p for trend 0.462), 1.030-0.959-0.147 ( p for trend 0.011), and 0.697-0.609 ( p for trend 0.119), respectively. Those for PFS of the corresponding AEs were 0.592-1.073-2.811 ( p for trend 0.255), 1.161-1.282-4.324 ( p for trend 0.03), 0.965-0.781-0.655 ( p for trend 0.095), 0.737-0.623-2.147 ( p for trend 0.153), 1.061-0.832-0.800 ( p for trend 0.391), and 1.412-0.560 ( p for trend 0.081), respectively. Appetite loss and general fatigue negatively affected clinical outcomes, whereas hypertension, HFS, proteinuria, and hypothyroidism had positive effects.

Objective: The genetic basis underlying the pathophysiology of quasi-moyamoya disease (qMMD) is unclear. Herein, the authors aimed to comprehensively analyze genetic variants in qMMD and investigate their association with clinical phenotypes, focusing on RNF213 and other moyamoya angiopathy (MMA)-related genes., Methods: The authors evaluated 14 consecutive cases of qMMD, whose underlying conditions included autoimmune disease, head irradiation, meningitis/pachymeningitis, and Turner syndrome, and 9 cases of hyperthyroidism-associated MMD (hMMD). The frequencies of RNF213 p.Arg4810Lys in qMMD and hMMD were each compared to those in healthy controls and in patients with MMD. Whole-exome sequencing was performed, and rare variants (RVs) or damaging variants were analyzed in RNF213 and 36 MMA-related genes., Results: The frequencies of p.Arg4810Lys were significantly higher in patients with qMMD (28.6%) and hMMD (33.3%) than in controls (1.1%; p < 0.001) and lower in the two former groups than in the MMD group (67.6%; p = 0.003 and 0.065, respectively). In qMMD, no significant clinical differences were observed based on the presence of p.Arg4810Lys. A novel RNF213 RV was identified in four cases with qMMD. These same cases also presented with significant worsening of intracranial main artery stenosis, which suggests a possible association between RNF213 RVs and the severe progression of qMMD. Among the 36 MMA-related genes, no variants correlated with specific phenotypes., Conclusions: While the clinical implications of p.Arg4810Lys in cases with qMMD were not identified, the study findings suggest a potential association between RNF213 RVs and the significant progression of intracranial artery stenosis. Genetic analysis should not focus solely on p.Arg4810Lys but instead consider a comprehensive analysis of RNF213 for more accurate clinical prognostication of qMMD.

Evidence demonstrates efficacy of maxillomandibular advancement (MMA) treatment of obstructive sleep apnea (OSA) and airway expansion. Patient studies are limited to pre/post-surgery comparisons. This cadaveric study evaluated intra-individual relationships between magnitudes of MMA advancement and airway changes. MMA with distraction osteogenesis devices and incremental advancement of the maxillomandibular complex, was performed on cadavers (n = 5). Computed tomography at each 2-mm advancement was used to measure volume and dimension of the oropharyngeal airway. Three-dimensional shape analysis visualized magnitudes and locations of changes. Incremental advancements caused volume, anteroposterior, and lateral dimensions to increase progressively, while length decreased. Changes were significant at lower advancements. Comparisons of MMA indicate alterations in airway volume from 4 to 6 mm and 6 to 8 mm were relatively greater than the changes from 8 to 10 mm (P = 0.044, P = 0.028, respectively), 10 to 12 mm (P = 0.024, P = 0.023), and 12 to 14 mm (P = 0.021, P = 0.019). These results may expand MMA application suggesting 6-8 mm advancements provide substantial increases in airway volume. MMA may be an OSA treatment option when large advancements are not possible. Lower magnitudes of advancement decrease risks of unfavorable facial esthetics from excess protrusion., Competing Interests: Competing interests None., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Obscure gastrointestinal bleeding (OGIB), defined in 2010, involves bleeding from the GI tract that remains unexplained after standard diagnostic procedures. OGIB, which accounts for about 5% of all GI bleeds, poses diagnostic and management challenges, particularly due to the anatomical features of the small intestine. Advances in capsule endoscopy (CE) and balloon-assisted endoscopy have improved the diagnostic and therapeutic landscape for small intestinal lesions., Objective: To determine the recurrence rate and identify risk factors for recurrence following diagnostic and therapeutic interventions using CE and balloon-assisted endoscopy in patients with OGIB., Methods: A retrospective cohort study at Gifu University Hospital analyzed CE procedures for patients with OGIB from 2008 to 2022. Patients underwent CE with subsequent treatments based on the findings. Statistical analyses, including Kaplan-Meier and Cox proportional hazards models, were used to estimate cumulative recurrence rates and identify recurrence risk factors., Results: Out of 417 patients, 65.2% had positive CE findings, leading to therapeutic interventions in 16.3% of cases. The cumulative recurrence rates at 12, 24, and 36 months were 4.3%, 9.0%, and 13.9%, respectively. Liver cirrhosis (hazard rate: 4.15, 95% confidence interval 1.88-9.18, p < 0.01) was identified as a significant risk factor for recurrence., Conclusions: A significant recurrence rate in OGIB patients, with liver cirrhosis being a major risk factor. Despite diagnostic and therapeutic advances, a comprehensive approach including careful follow-up and consideration of risk factors is essential for management., Competing Interests: None., (© 2024 The Author(s). DEN Open published by John Wiley & Sons Australia, Ltd on behalf of Japan Gastroenterological Endoscopy Society.)

Purpose: To investigate whether Leukotriene B4 receptor 2 (BLT-2), an upstream regulator of tight junction protein (TJP) Claudin-4, and TJPs could be etiologic factors in Hirschsprung-associated enterocolitis (HAEC) after pull-through (PT) for Hirschsprung disease (HD)., Methods: Normoganglionic colon (HD-N) and aganglionic rectum (HD-A) specimens from rectal/rectosigmoid (R/RS) or descending/transverse (D/T) HD were assessed using quantitative polymerase chain reaction (qPCR) for Occludin, TJP-1, TJP-2, Junctional adhesion molecule (JAM)-1, JAM-2, Claudin-1, Claudin-3, Claudin-4, and BLT-2 and immunoblotting for Claudin-4 using fresh specimens obtained intraoperatively (2021-2024; n = 17; R/RS = 15 and D/T = 2). Claudin-4 immunohistochemistry was also evaluated quantitatively using preserved (n = 29; R/RS = 20 and D/T = 9; 2009-2021) and fresh HD specimens for comparison with anorectal malformation patients having colostomy closure as controls (n = 42) and between HD-A versus HD-N, R/RS versus D/T, and HAEC (+) versus HAEC (-). Technically inadequate or transitional zone PT were excluded., Results: Subjects were 123 PT cases. Mean ages at PT/colostomy closure (years) were R/RS: 2.7 ± 2.9, D/T: 1.6 ± 2.2, and controls: 1.4 ± 0.7. Postoperative HAEC occurred 18 times in 14 PT cases (grade I = 5, grade II = 13). Post-PT HAEC was significantly more frequent in D/T (50.0% versus 6.4%; p < 0.001); Claudin-4 was significantly lower in HD-N from post-PT HAEC cases, especially D/T (p < 0.05) on immunohistochemistry. Claudin-4 was significantly lower in HD-N/HD-A compared with controls on immunoblotting (p < 0.05) and immunohistochemistry (p < 0.001). qPCR showed TJP-1, TJP-2, JAM-1, JAM-2, Claudin-4, and BLT-2 were significantly lower in HD-N/HD-A compared with controls., Conclusions: Lower Claudin-4 and BLT2 in post-PT HAEC HD-N (especially D/T) suggests generalized epithelial barrier derangement with possible etiologic implications for HAEC., Level of Evidence: Ⅱ., Competing Interests: Conflicts of interest The authors declare they have no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Rationale: Cytokine release syndrome (CRS) is a common adverse event of chimeric antigen receptor T (CAR-T) cell therapy. CRS is generally a systemic inflammatory reaction, but in rare cases, it can occur in specific body areas and is referred to as "local CRS (L-CRS)." A case of laryngeal edema due to L-CRS that required tracheal intubation because of the lack of response to tocilizumab (TCZ) and dexamethasone (DEX) is reported., Patient Concerns: A 67-year-old woman with relapsed transformed follicular lymphoma was treated with CAR-T cell therapy. Although she had been given TCZ and DEX for CRS, neck swelling appeared on day 4 after infusion., Diagnoses: Laryngoscopy showed severe laryngeal edema, which was presumed to be due to L-CRS, since there were no other apparent triggers based on history, physical examination, and computed tomography., Interventions: Tracheal intubation was performed because of the risk of upper airway obstruction. Ultimately, 4 doses of tocilizumab (8 mg/kg) and 6 doses of dexamethasone (10 mg/body) were required to improve the L-CRS., Outcomes: On day 7, laryngeal edema improved, and the patient could be extubated., Lessons: The lessons from this case are, first, that CAR-T cell therapy may induce laryngeal edema in L-CRS. Second, TCZ alone may be ineffective in cervical L-CRS. Third, TCZ, as well as DEX, may be inadequate. In such cases, we should recognize L-CRS and manage it early because it may eventually progress to laryngeal edema that requires securing the airway., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

A 73-year-old man presented with left hypochondral pain. Dynamic computed tomography (CT) revealed abnormal vessels surrounding the pancreas, leading to a suspected diagnosis of pancreatic arteriovenous malformation (PAVM). At the time of the initial examination, dynamic CT revealed mild acute pancreatitis, and PAVM was diagnosed based on the findings of dynamic CT. Although repeated abdominal pain was observed after the improvement of pancreatitis, distal pancreatectomy was performed. At >1 year after surgery, no recurrence of PAVM was observed. Surgical resection should be considered in patients with symptomatic PAVM.

Purpose: To evaluate prolonged esomeprazole use in Japanese pediatric patients for reflux esophagitis (RE) maintenance therapy and prevention of gastric (GU) and/or duodenal ulcers (DU) while using non-steroidal anti-inflammatory drugs (NSAIDs) or low-dose aspirin (LDA)., Methods: This multicenter, open-label, parallel-group, phase III study (NCT03553563) included patients who were administered esomeprazole according to body weight (10 mg/day [Groups 1 and 3] and up to 20 mg/day [Groups 2 and 4] for patients weighing 10-20 kg and ≥20 kg, respectively). Efficacy outcomes for Groups 1 and 2 (maintenance therapy for healed RE) and Groups 3 and 4 (prevention of long-term NSAID/LDA use-associated GU/DU) were the presence/absence of RE relapse and GU/DU recurrence, respectively., Results: Esomeprazole as maintenance therapy was associated with a low RE recurrence rate, independent of body weight or dosage. Recurrence rates of RE were 0.0% and 5.3% for Groups 1 and 2, respectively. In patients previously diagnosed with GU and/or DU due to long-term NSAID/LDA use, the recurrence rates of GU/DU during weeks 0-32 were 11.1% and 0.0% in Groups 3 and 4, respectively., Conclusion: Long-term use of 10- or 20-mg, once-daily esomeprazole demonstrated a favorable benefit-risk balance in preventing RE and suppressing recurrence of GU and/or DU secondary to NSAID or LDA therapy in Japanese pediatric patients. No new safety concerns were identified. Esomeprazole may be a viable option for managing RE and preventing GU and DU in Japanese pediatric patients., Competing Interests: Conflict of Interest: The authors have no financial conflicts of interest., (Copyright © 2024 by The Korean Society of Pediatric Gastroenterology, Hepatology and Nutrition.)

We investigated long-term changes in the megabenthic community in Tokyo Bay, Japan, using data from fisheries-independent trawl surveys conducted from 1977 to 2023. In addition, we examined the potential relationship between changes in biotic communities and environmental conditions. The total abundance and biomass exhibited an increasing trend until 1987, followed by a substantial decline from the late 1980s to the 1990s due to a decrease in small to medium-sized fish and crustacean species. Meanwhile, a marked increase in the number of large fish (including elasmobranchs), mollusks, and echinoids, was observed in the 2000s. These shifts in the megabenthic community structure were correlated with an increase in water temperature and a decrease in nutrient concentrations and copepod densities. Cumulative evidence suggests that a remarkable shift in the megabenthic community structure occurred between the 1970s and the 2020s, which was possibly associated with variations in the environmental conditions in Tokyo Bay., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Benign choledochojejunal anastomotic stricture (CJS) is a complication of pancreaticoduodenectomy and choledochojejunostomy. Typically managed with endoscopic balloon dilatation, CJS has a high recurrence rate. Covered metallic stent (CMS) placement is a potential alternative; however, a comprehensive evaluation is lacking., Objectives: The aim of this study was to evaluate the treatment outcomes of CMS placement in patients with CJS., Methods: We retrospectively analyzed patients who underwent balloon dilation via endoscopic retrograde cholangiopancreatography using a double-balloon endoscope for CJS between October 2010 and October 2023. The study outcomes included technical and clinical success rates, adverse event rates, choledochojejunal anastomotic stricture recurrence rates, and time to recurrence for balloon dilation and CMS treatment for CJS., Results: There were 43 patients, 55 procedures (40 balloon dilation and 15 CMS placement). The technical and clinical success rates were 100% for both treatments. Recurrence of CJS was observed in 35% (14/40) of the patients in the balloon dilation group. The recurrence rate was significantly higher in the balloon dilation group than in the CMS group (35% vs. 0%, p = 0.006). The time to CJS recurrence was significantly shorter in the balloon dilation group than in the covered metallic stent group (NR vs. NR, p = 0.03)., Conclusion: Placement of CMS for treating patients with CJS was demonstrated to be an effective and safe method with a lower recurrence rate than balloon dilation., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background/aim: There are only a few studies on dosimetry with ultrahigh-dose-rate (uHDR) scanned carbon-ion beams. This study investigated the characteristics of four types of ionization chambers for the uHDR beam., Materials and Methods: We employed a newly developed large-plane parallel chamber to monitor a 208.3-MeV/u uHDR scanned carbon-ion beam with a 110-Gy/s average dose rate. The ionization chambers used were the Advanced Markus chamber (AMC), PinPoint 3D chamber (PPC), Farmer chamber (FC), and large-plane parallel chamber (StingRay). The AMC and StingRay surfaces and the PPC and FC geometric centers were aligned to the radiation isocenter using treatment room lasers. Using the voltage range stated in the instruction manuals, we obtained the saturation curves of the chambers. From these curves, we obtained the ion recombination correction factors using the two-voltage and three-voltage linear methods. The dose linearity was evaluated using five measurement points, and the chamber repeatability was verified by conducting repeated measurements for different dose values., Results: Although all chambers, except for AMC, reached saturation when specified voltages were applied, they exhibited excellent linearity for different dose values. The ion recombination correction factors of the AMC obtained using the aforementioned linear methods were nearly 1. Additionally, all chambers exhibited excellent repeatability. Although the standard deviation of the PPC for the lowest dose was ~1.5%, those of all the other chambers were <1.0%., Conclusion: All ionization chambers can be used for measuring the relative dose, and absolute dose can be conveniently measured using the AMC with an uHDR carbon-ion scanned beam., (Copyright © 2024, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Aim: This study aimed to establish the shear wave measurement (SWM) cut-off value for each fibrosis stage using magnetic resonance (MR) elastography values as a reference standard., Methods: We prospectively analyzed 594 patients with chronic liver disease who underwent SWM and MR elastography. Correlation coefficients (were analyzed, and the diagnostic value was evaluated by the area under the receiver operating characteristic curve. Liver stiffness was categorized by MR elastography as F0 (<2.61 kPa), F1 (≥2.61 kPa, <2.97 kPa, any fibrosis), F2 (≥2.97 kPa, <3.62 kPa, significant fibrosis), F3 (≥3.62 kPa, <4.62 kPa, advanced fibrosis), or F4 (≥4.62 kPa, cirrhosis)., Results: The median SWM values increased significantly with increasing fibrosis stage (p < 0.001). The correlation coefficient between SWM and MR elastography values was 0.793 (95% confidence interval 0.761-0.821). The correlation coefficients between SWM and MR elastography values significantly decreased with increasing body mass index and skin-capsular distance; skin-capsular distance values were associated with significant differences in sensitivity, specificity, accuracy, or positive predictive value, whereas body mass index values were not. The best cut-off values for any fibrosis, significant fibrosis, advanced fibrosis, and cirrhosis were 6.18, 7.09, 8.05, and 10.89 kPa, respectively., Conclusions: This multicenter study in a large number of patients established SWM cut-off values for different degrees of fibrosis in chronic liver diseases using MR elastography as a reference standard. It is expected that these cut-off values will be applied to liver diseases in the future., (© 2024 The Authors. Hepatology Research published by John Wiley & Sons Australia, Ltd on behalf of Japan Society of Hepatology.)

Background: Acute kidney injury (AKI) is a serious complication of cirrhosis. This study analyzed the prognostic effect of AKI in patients with cirrhosis and its risk factors, particularly in relation to amino acid imbalance., Methods: This retrospective study reviewed 808 inpatients with cirrhosis at two institutes in Gifu, Japan. AKI was diagnosed according to the recommendations of the International Club of Ascites. Amino acid imbalance was assessed by measuring serum branched-chain amino acid (BCAA) levels, tyrosine levels, and the BCAA-to-tyrosine ratio (BTR). Factors associated with mortality and AKI development were assessed using the Cox proportional hazards regression model with AKI as a time-dependent covariate and the Fine-Gray competing risk regression model, respectively., Results: Of the 567 eligible patients without AKI at baseline, 27% developed AKI and 25% died during a median follow-up period of 4.7 years. Using a time-dependent covariate, AKI development (hazard ratio [HR], 6.25; 95% confidence interval [CI], 3.98-9.80; p < 0.001) was associated with mortality in patients with cirrhosis independent of potential covariates. In addition, alcohol-associated/-related liver disease, metabolic dysfunction-associated steatohepatitis, Child-Pugh score, and BTR (subdistribution HR 0.78; 95% CI 0.63-0.96; p = 0.022) were independently associated with AKI development in patients with cirrhosis. Similar results were obtained in the multivariate model that included BCAA and tyrosine levels instead of BTR., Conclusions: AKI is common and associated with mortality in Japanese patients with cirrhosis. An amino acid imbalance is strongly associated with the development of AKI in patients with cirrhosis., (© 2024. The Author(s).)

Background/aim: We and others have previously shown that cell fusion plays an important role in cancer metastasis. Color coding of cancer and stromal cells with spectrally-distinct fluorescent proteins is a powerful tool, as pioneered by our laboratory to detect cell fusion. We have previously reported color-coded cell fusion between cancer cells and stromal cells in metastatic sites by using color-coded EL4 murine lymphoma cells and host mice expressing spectrally-distinct fluorescent proteins. Cell fusion occurred between cancer cells or, between cancer cells and normal cells, such as macrophages, fibroblasts, and mesenchymal stem cells. In the present study, the aim was to morphologically classify the fusion-hybrid cells observed in the primary tumor and multiple metastases EL4 formed from cells expressing red fluorescent protein (RFP) in transgenic mice expressing green fluorescent protein (GFP), in a syngeneic model., Materials and Methods: RFP-expressing EL4 murine lymphoma cells were cultured in vitro. EL4-RFP cells were harvested and injected intraperitoneally into immunocompetent transgenic C57/BL6-GFP mice to establish a syngeneic model. Two weeks later, mice were sacrificed and each organ was harvested, cultured, and observed using confocal microscopy., Results: EL4 intraperitoneal tumors (primary) and metastases in the lung, liver, blood, and bone marrow were formed. All tumors were harvested and cultured. In all specimens, RFP-EL4 cells, GFP-stromal cells, and fused yellow-fluorescent hybrid cells were observed. The fused hybrid cells showed various morphologies. Immune cell-like round-shaped yellow-fluorescent fused cells had a tendency to decrease with time in liver metastases and circulating blood. In contrast fibroblast-like spindle-shaped yellow-fluorescent fused cells increased in the intraperitoneal primary tumor, lung metastases, and bone marrow., Conclusion: Cell fusion between EL4-RFP cells and GFP stromal cells occurred in primary tumors and all metastatic sites. The morphology of the fused hybrid cells varied in the primary and metastatic sites. The present results suggest that fused cancer and stromal hybrid cells of varying morphology may play an important role in cancer progression., (Copyright © 2024, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Increasing evidence suggests that, in addition to a loss of tolerance, bile acid (BA) modulates the natural history of primary biliary cholangitis (PBC). We focused on the impacts of dietary changes on the immunopathology of PBC, along with alterations in BA composition and gut microbiota. In this study, we have taken advantage of our unique PBC model, a Cyp2c70/Cyp2a12 double knockout (DKO), which includes a human-like BA composition, and develops progressive cholangitis following immunization with the PDC-E2 mimic, 2-octynoic acid (2OA). We compared the effects of a ten-week high-fat diet (HFD) (60 % kcal from fat) and a normal diet (ND) on 2OA-treated DKO mice. Importantly, we report that 2OA-treated DKO mice fed HFD had significantly exacerbated cholangitis, leading to cirrhosis, with increased hepatic expression of Th1 cytokines/chemokines and hepatic fibrotic markers. Serum lithocholic acid (LCA) levels and the ratio of chenodeoxycholic acid (CDCA)-derived BAs to cholic acid-derived BAs were significantly increased by HFD. This was also associated with downregulated expression of key regulators of BA synthesis, including Cyp8b1, Cyp3a11, and Sult2a1. In addition, there were increases in the relative abundances of Acetatifactor and Lactococcus and decreases in Desulfovibrio and Lachnospiraceae&#95;NK4A136&#95;group, which corresponded to the abundances of CDCA and LCA. In conclusion, HFD and HFD-induced alterations in the gut microbiota modulate BA composition and nuclear receptor activation, leading to cirrhotic change in this murine PBC model. These findings have significant implications for understanding the progression of human PBC., Competing Interests: Declaration of competing interest None., (Copyright © 2024. Published by Elsevier Ltd.)

Necroptosis, necrosis characterized by RIPK3-MLKL activation, has been proposed as a mechanism of doxorubicin (DOX)-induced cardiomyopathy. We showed that rapamycin, an mTORC1 inhibitor, attenuates cardiomyocyte necroptosis. Here we examined role of MLKL in DOX-induced myocardial damage and protective effects of rapamycin. Cardiomyopathy was induced in mice by intraperitoneal injections of DOX (10 mg/kg, every other day) and followed for 7 days. DOX-treated mice showed a significant decline in LVEF assessed by cardiac MRI (45.5 ± 5.1% vs. 65.4 ± 4.2%), reduction in overall survival rates, and increases in myocardial RIPK3 and MLKL expression compared with those in vehicle-treated mice, and those changes were prevented by administration of rapamycin (0.25 mg/kg) before DOX injection. In immunohistochemical analyses, p-MLKL signals were detected in the cardiomyocytes of DOX-treated mice, and the signals were reduced by rapamycin. Mlkl +/- and Mlkl -/- mice were similarly resistant to DOX-induced cardiac dysfunction, indicating that a modest reduction in MLKL level is sufficient to prevent the development of DOX-induced cardiomyopathy. However, evidence of cardiomyocyte necrosis assessed by C9 immunostaining, presence of replacement fibrosis, and electron microscopic analyses was negligible in the myocardium of DOX-treated mice. Thus, MLKL-mediated signaling contributes to DOX-induced cardiac dysfunction primarily by a necrosis-independent mechanism, which is inhibitable by rapamycin., (Copyright © 2024 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

Purpose: Histiocytic necrotizing lymphadenitis (HNL) is an inflammatory disease of unknown etiology clinically characterized by painful lymphadenopathy. This study aimed to investigate the role of interferon (IFN)-α in the pathogenesis of HNL and the clinical significance of serum IFN-α levels for the diagnosis and monitoring of HNL disease activity., Methods: This study enrolled 47 patients with HNL and 43 patients with other inflammatory diseases that require HNL differentiation including malignant lymphoma (ML), bacterial lymphadenitis, and Kawasaki disease. Expression of IFN-stimulated genes (ISGs) and MX1 in the lymph nodes was measured by real-time quantitative reverse transcription polymerase chain reaction and immunofluorescence staining, respectively. Enzyme-linked immunosorbent assay was used to quantify serum cytokine levels. The results were compared with the clinical features and disease course of HNL., Results: Patients with HNL had a significantly elevated ISG expression in the lymph nodes compared with those with ML. MX1 and CD123, a specific marker of plasmacytoid dendritic cells (pDCs), were colocalized. In patients with HNL, serum IFN-α levels were significantly elevated and positively correlated with disease activity. The serum IFN-α level cutoff value for differentiating HNL from other diseases was 11.5 pg/mL., Conclusion: IFN-α overproduction from pDCs may play a critical role in HNL pathogenesis. The serum IFN-α level may be a valuable biomarker for the diagnosis and monitoring of disease activity in patients with HNL., Competing Interests: Declaration of competing interest All the authors declare that they have no relevant conflicts of interest., (Copyright © 2024. Published by Elsevier Inc.)