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Competing Interests: Competing interests: MN received research funding from Takeda Pharmaceutical Company Limited. The other authors declare no competing financial interests related to this work.

Bacterial intra-kingdom communication involves the secretion of outer membrane vesicles as signaling carriers to the target cells. However, limited research exists on extracellular vesicles (EVs) from Gram-positive gut bacteria, their interactions with enteric pathogens, and potential inhibitory effects. In this study, we characterized the structure, protein content, and inhibitory effects of EVs from three new potential probiotic gut symbionts, Ligilactobacillus salivarius UO.C109, Ligilactobacillus saerimneri UO.C121, and Ligilactobacillus salivarius UO.C249. EVs were isolated and characterized using three different methods (ultracentrifugation, density gradient purification, and size exclusion chromatography). The purity, dose-dependency, structure, and proteome profiles of the purified EVs were evaluated. Antibacterial and anti-virulence activities of EV subpopulations were assessed against Salmonella enterica serovar Typhimurium and Campylobacter jejuni. EVs from Lg. salivarius UO.C109 and Lg. saerimneri UO.C121 showed inhibitory activity against S. Typhimurium, whereas EVs from Lg. salivarius UO.C249 inhibited the growth of C. jejuni. Notably, purified F3 fraction exhibited the highest inhibitory activity and was enriched in lysin motif (LysM)-containing proteins, peptidoglycan hydrolases, peptidoglycan recognition proteins (PGRPs), and metallopeptidases, which have been shown to play a prominent role in antimicrobial activities against pathogens. F3 had the highest concentration (73.8%) in the 80-90 nm size compared to the other fractions. Gene expression analysis revealed that EVs from Lg. salivarius UO.C109 and Lg. saerimneri UO.C121 downregulated adhesion and invasion factors in S. Typhimurium. Likewise, EVs from Lg. salivarius UO.C249 reduced pathogenicity gene expression in C. jejuni. This study highlighted the potential of gut bacterial EVs as therapeutic agents against enteric pathogens., Competing Interests: Declarations. Ethical Approval: Not required. Competing Interests: R.H., S.M., and W.M. are co-inventors and co-applicants with the University of Ottawa on a patent application (US Patent Application Number 63/607,682, filed December 08, 2023) entitled 'LIGILACTOBACILLUS PROBIOTICS, LIGILACTOBACILLUS EXTRACELLULAR VESICLES AND METHODS OF USING SAME, which covers the inhibitory activity of probiotic extracellular vesicles. The remaining authors declare no conflicts of interest., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purposes: The optimal surgical technique and perioperative management to prevent postoperative pancreatic fistula (POPF) formation after pancreaticoduodenectomy have not yet been established. This study examined the perioperative outcomes of pancreaticogastrostomy with endoscopic transgastric drainage., Methods: We performed a retrospective analysis of 191 patients who underwent pancreaticoduodenectomy between 2016 and 2023. They were divided into two groups: pancreaticojejunostomy group (n = 135) and pancreaticogastrostomy group (n = 56). We compared preoperative factors and postoperative outcomes. We performed endoscopic drainage only in the pancreaticogastrostomy group., Results: Preoperative factors were similar between the two groups. Operative time [480 (404-542) vs. 382 (346-458) minutes], blood loss [505 (270-850) vs. 315 (145-535) g], pseudoaneurysm formation (7 % vs. 0 %), and postoperative hospital stay [28 (22-38) vs. 19 (17-24) days] were significantly lower in the pancreaticogastrostomy group. In the analysis of 41 patients with POPF, postoperative hospital stay [40 (23-108) vs. 27 (18-54) days] and hospital stay after POPF diagnosis [30 (10-99) vs. 15 (5-35) days] were significantly shorter in the pancreaticogastrostomy group. Endoscopic transgastric drainage was performed in 77 % of patients in the pancreaticogastrostomy group, and drainage was successfully completed in all patients., Conclusion: Pancreaticogastrostomy with endoscopic transgastric drainage could be effective for the safe management of pancreaticoduodenectomy., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Introduction: Methadone is used to treat intractable cancer pain when other opioid analgesics are ineffective. Methadone tablets may be difficult to administer in cases of gastrointestinal passage obstruction. However, changing the route of methadone tablet administration is possible. Case Description: The patient, diagnosed with esophagogastric junction cancer with multiple metastases, continued to receive methadone tablets even after not being longer able to take oral medication. Method: Methadone tablets were administered using a simple suspension method via gastrostomy. We measured the respiratory rate during sleep daily. We also measured weekly QTc values using a 12-lead electrocardiogram and methadone blood concentration periodically. No side effects were observed. Conclusion: Using a simple suspension method to administer methadone is a safe pain management method when accompanied by careful monitoring. To date, no study has examined the tube administration safety of methadone tablets. Thus, this case report is of important clinical significance.

In this study, we aimed to develop a protective probiotic coculture to inhibit the growth of Salmonella enterica serovar Typhimurium in the simulated chicken gut environment. Bacterial strains were isolated from the digestive mucosa of broilers and screened in vitro against Salmonella Typhimurium ATCC 14028. A biocompatibility coculture test was performed, which identified two biocompatible strains, Ligilactobacillus salivarius UO.C109 and Ligilactobacillus saerimneri UO.C121 with high inhibitory activity against Salmonella. The cell-free supernatant (CFS) of the selected isolates exhibited dose-dependent effects, and the inhibitory agents were confirmed to be proteinaceous by enzymatic and thermal treatments. Proteome and genome analyses revealed the presence of known bacteriocins in the CFS of L. salivarius UO.C109, but unknown for L. saerimneri UO.C121. The addition of these selected probiotic candidates altered the bacterial community structure, increased the diversity of the chicken gut microbiota challenged with Salmonella, and significantly reduced the abundances of Enterobacteriaceae, Parasutterlla, Phascolarctobacterium, Enterococcus, and Megamonas. It also modulated microbiome production of short-chain fatty acids (SCFAs) with increased levels of acetic and propionic acids after 12 and 24 h of incubation compared to the microbiome challenged with S. Typhimurium. Furthermore, the selected probiotic candidates reduced the adhesion and invasion of Salmonella to Caco-2 cells by 37-39% and 51%, respectively, after 3 h of incubation, compared to the control. These results suggest that the developed coculture probiotic strains has protective activity and could be an effective strategy to control Salmonella infections in poultry., Competing Interests: Declarations Conflict of Interest The authors declare no competing interests., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

In recent years, the Japanese population has been aging and the risk of contracting various age-related diseases has increased. Thus, there is a need to analyze components that are characteristic of aging and examine their association with diseases to detect age-related diseases at an early stage. In the present study, microRNAs (miRNAs/miRs) in serum extracellular vesicles (EVs) of 82-102-week-old mice were analyzed to identify miRNAs characteristic of aging. Increased expression of mmu-miR-21a-5p was observed. These miRNAs may be derived from senescent vascular endothelial cells, and RNA-sequencing data (GSE130727) of HUVECs induced to senesce by 4 Gy of radiation revealed that the miRNAs were involved in the cell cycle and DNA repair. Annotations to senescence-related pathways were also identified. Reduced expression of the miR-21-5p target gene, which has an identical sequence in humans and mice, was confirmed. In HUVECs induced to age under similar conditions, increased senescence-associated β-galactosidase activity and increased intracellular miR-21-5p expression were observed. A portion of the miR-21-5p was secreted extracellularly by internalizing tetraspanin-positive EVs, and miR-21-5p was secreted into the extracellular space. The present study also demonstrated that miR-21-5p expression was upregulated and extracellular secretion of miR-21-5p was enhanced during vascular endothelial cell senescence. These findings suggested that increased serum miR-21-5p represents a biomarker for vascular endothelial cell senescence., Competing Interests: The authors declare that they have no competing interests., (Copyright: © 2024 Yamamoto and Chiba.)

Background: Superior outcomes have been obtained for neoadjuvant treatment with immune checkpoint inhibitors (ICI) plus chemotherapy over neoadjuvant chemotherapy alone, especially in patients with high programmed cell death ligand 1 (PD-L1) expression. However, it is not always possible to obtain sufficient tumor specimens for biomarker testing before surgery. In this study, we explored clinical factors that can predict high PD-L1 expression., Methods: We retrospectively enrolled 340 lung cancer patients who received pulmonary resection between 2014 and 2023 and who had PD-L1 expression data. Chi-squared tests and logistic regression analyses were used to identify clinical factors associated with high PD-L1 status., Results: Univariable and multivariable analyses revealed that smoking, high maximum standardized uptake value (SUVmax) of 18F-fluorodeoxyglucose positron emission computed tomography (18F-FDG PET/CT), and high plasma fibrinogen are independent predictors of high PD-L1 expression. A predictive score for high PD-L1 expression (ranging from 0 to 3) was developed based on these parameters. Notably, only 5% of patients with a score of 0 exhibited high PD-L1 expression, whereas this proportion increased to 53% for patients with a score of 3., Conclusion: These results showed that plasma fibrinogen, smoking history, and SUVmax are predictors of high PD-L1 expression, providing a basis for identifying patients expected to benefit from neoadjuvant ICI treatment., (© 2024 The Author(s). Thoracic Cancer published by John Wiley & Sons Australia, Ltd.)

Diet-related cardiometabolic diseases and inflammatory bowel disease, common previously in Western countries, are global problems. We hypothesized that inflammatory bowel disease is a lifestyle disease primarily mediated by the current Western diet. We report here the simultaneous onset of ulcerative colitis and autoimmune pancreatitis, a rare systemic complication of inflammatory bowel disease, 2 months after acute myocardial infarction in a patient with type 2 diabetes. A 67-year-old man with type 2 diabetes was referred to us because of newly diagnosed ulcerative colitis 2 months after acute myocardial infarction. A plant-based diet was provided during hospitalization. An abrupt deterioration in plasma glucose and hemoglobin A1c due to asymptomatic type 2 autoimmune pancreatitis was observed. Prednisolone administration under intensive insulin therapy led to the remission of both diseases. This case was an illustrative one of association between cardiometabolic diseases and inflammatory bowel diseases caused by current unhealthy diets and their shared pathogenesis., Competing Interests: • Conflicts of Interest: No conflict of interest., (© 2024 Journal of Lifestyle Medicine.)

Campylobacter jejuni ( C. jejuni ) is one of the most common causes of foodborne infections worldwide and a major contributor to diarrheal diseases. This study aimed to explore the ability of commensal gut bacteria to control C. jejuni infection. Bacterial strains from the intestinal mucosa of broilers were screened in vitro against C. jejuni ATCC BAA1153. The cell-free supernatant (CFS) of Ligilactobacillus salivarius UO.C249 showed potent dose-dependent antimicrobial activity against the pathogen, likely due to the presence of bacteriocin-like moieties, as confirmed by protease treatment. Genome and exoproteome analyses revealed the presence of known bacteriocins, including Abp118. The genome of Lg. salivarius UO.C249 harbors a 1.8-Mb chromosome and a 203-kb megaplasmid. The strain was susceptible to several antibiotics and had a high survival rate in the simulated chicken gastrointestinal tract (GIT). Post-protease treatment revealed residual inhibitory activity, suggesting alternative antimicrobial mechanisms. Short-chain fatty acid (SCFA) quantification confirmed non-inhibitory levels of acetic (24.4 ± 1.2 mM), isovaleric (34 ± 1.0 µM), and butyric (32 ± 2.5 µM) acids. Interestingly, extracellular vesicles (EVs) isolated from the CFS of Lg. salivarius UO.C249 were found to inhibit C. jejuni ATCC BAA-1153. Proteome profiling of these EVs revealed the presence of unique proteins distinct from bacteriocins identified in CFS. The majority of the identified proteins in EVs are located in the membrane and play roles in transmembrane transport and peptidoglycan degradation, peptidase, proteolysis, and hydrolysis. These findings suggest that although bacteriocins are a primary antimicrobial mechanism, EV production also contributes to the inhibitory activity of Lg. salivarius UO.C249 against C. jejuni ., Importance: Campylobacter jejuni ( C. jejuni ) is a major cause of gastroenteritis and a global public health concern. The increasing antibiotic resistance and lack of effective alternatives in livestock production pose serious challenges for controlling C. jejuni infections. Therefore, alternative strategies are needed to control this pathogen, especially in the poultry industry where it is prevalent and can be transmitted to humans through contaminated food products. In this study, Ligilactobacillus salivarius UO.C249 isolated from broiler intestinal mucosa inhibited C. jejuni and exhibited important probiotic features. Beyond bacteriocins, Lg. salivarius UO.C249 secretes antimicrobial extracellular vesicles (EVs) with a unique protein set distinct from bacteriocins that are involved in transmembrane transport and peptidoglycan degradation. Our findings suggest that beyond bacteriocins, EV production is also a distinct inhibitory signaling mechanism used by Lg. salivarius UO.C249 to control C. jejuni . These findings hold promise for the application of probiotic EVs for pathogen control., Competing Interests: R.H., S.M., and W.M. are co-inventors and co-applicants with the University of Ottawa on a patent application (US Patent Application Number 63/607,682, filed 08 December 2023) entitled "LIGILACTOBACILLUS PROBIOTICS, LIGILACTOBACILLUS EXTRACELLULAR VESICLES AND METHODS OF USING SAME" that covers the inhibitory activity of probiotic extracellular vesicles. The remaining authors declare no competing interests.

Objective: To introduce and evaluate the non-assistant help operation in dual-portal robotic-assisted thoracic surgery (neoDRATS), a novel technique designed to eliminate the need for skilled assistants by using all 4 robotic arms independently during anatomical lung surgery., Methods: Patients were placed in the lateral decubitus position under general anesthesia with single-lung ventilation. The da Vinci Xi Surgical System was used, with specific configurations for right- and left-side operations. The neoDRATS technique used a 4-cm working port and a 1.8-cm secondary port, with detailed guidelines for optimal setup and robotic arm manipulation., Results: The neoDRATS approach demonstrated successful surgical outcomes without the need for a skilled assistant. The use of a 0° camera and careful placement of instruments minimized interference within the thoracic cavity. The technique provided smooth operability and minimized postoperative discomfort. Video demonstrations of right and left upper lobectomies are provided to illustrate the approach., Conclusions: NeoDRATS offers a practical, safe, and minimally invasive alternative to conventional multiportal and uniportal robotic-assisted thoracic surgeries. This technique simplifies the surgical process, particularly in settings with limited availability of skilled assistants, and represents a significant advancement in robotic thoracic surgery. Further refinement and clinical integration of neoDRATS are anticipated as robotic innovations continue to evolve., Competing Interests: The authors reported no conflicts of interest. The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest., (© 2024 The Author(s).)

A 59-year-old woman was diagnosed with a pancreatic neuroendocrine tumor (P-NET; Grade 3, Ki67: 25%) with multiple liver and lymph node metastases and started chemotherapy with streptozosin (500 mg/m 2 /day) in combination with lanreotide acetate (120 mg). After six courses of (daily) streptozosin, the patient had progressive disease, as assessed by computed tomography (CT), and peptide receptor radionuclide therapy (PRRT) was started as second-line treatment. As PRRT was remarkably successful and the tumor shrank, surgery was performed to resect the primary pancreatic tumor, liver metastases, and lymph node metastases. CT evaluation performed six months after the surgery showed a complete response.

In this study, we investigated the invasiveness of Gekko japonicus, a prevalent gecko species in Japan and an ancient non-native species, focusing on its competition with both the undescribed endemic Gekko species (referred to as Nishiyamori in Japanese) and G. hokouensis. These species are co-distributed with G. japonicus, leading us to hypothesize that G. japonicus was invasive upon its initial introduction. We employed niche analysis and population genetics through ddRAD-seq to assess the historical invasiveness of G. japonicus by comparing regions with and without interspecies competition. Our niche analysis across the Goto Islands, Hiradojima Island (colonized by G. japonicus) and the Koshikishima Islands (not colonized by G. japonicus) indicated that endemic Gekko sp. alter their microhabitat usage in response to invasions by other gecko species, despite having similar suitable habitats and microhabitat preferences. Population genetic analysis revealed significant population declines in Gekko sp. within areas of introduced competition, in contrast to stable populations in areas without such competition. These findings suggest a tripartite competitive relationship among the gecko species, with G. japonicus and G. hokouensis invasions restricting the distribution of the endemic Gekko sp. Consequently, G. japonicus may have historically acted as an invasive species. Acknowledging the historical dynamics of current biodiversity is crucial for addressing complex ecological issues and making informed conservation decisions., (© 2024 John Wiley & Sons Ltd.)

Study Design: Retrospective review of prospectively collected data., Objective: This study aimed to accurately map the lower extremity muscles innervated by the lumbar spinal roots by directly stimulating the spinal roots during surgery., Summary of Background Data: Innervation of the spinal roots in the lower extremities has been estimated by clinical studies, anatomic studies, and animal experiments. However, there have been discrepancies between studies. Moreover, there are no studies that have studied the laterality of lower limb innervation., Materials and Methods: In 73 patients with lumbar degenerative disease, a total of 147 spinal roots were electrically stimulated and the electromyographic response was recorded at the vastus medialis (VM), gluteus medius (GM), tibialis anterior (TA), biceps femoris (BF), and gastrocnemius (GC). The asymmetry index (AI) was obtained using the following equation to represent the left-right asymmetry in the compound muscle action potential (CMAP) amplitude. Paired t tests were used to compare CMAP amplitudes on the right and left sides. Differences in the AI among the same spinal root groups were determined using one-way analysis of variance., Results: The frequency of CMAP elicitation in VM, GM, TA, BF, and GC were 100%, 75.0%, 50.0%, 83.3%, and 33.3% in L3 spinal root stimulation, 90.4%, 78.8%, 59.6%, 73.1%, and 59.6% in L4 spinal root stimulation, 32.2%, 78.0%, 93.2%, 69.5%, and 83.1% in L5 spinal root stimulation, and 40.0%, 100%, 80.0%, 70.0%, and 80.0% in S1 spinal root stimulation, respectively. The most frequent muscle with maximum amplitude of the CMAP in L3, L4, L5, and S1 spinal root stimulation was the VM, GM, TA, and GM, respectively. Unilateral innervation occurred at high rates in the TA in L4 root stimulation and the VM in L5 root stimulation in 37.5% and 42.3% of patients, respectively. Even in patients with bilateral innervation, a 20% to 38% AI of CMAP amplitude was observed., Conclusions: The spinal roots innervated a much larger range of muscles than what is indicated in general textbooks. Furthermore, a non-negligible number of patients showed asymmetric innervation of lower limb by the lumbar spinal roots., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Non-alcoholic steatohepatitis (NASH) is a fatty liver disease that is not caused by alcohol consumption and is characterized by fatty degeneration, inflammation and hepatocellular damage. Therefore, predicting future fibrosis is critical in the early stages of NASH to prevent disease progression. The present study examined histological changes in the liver as well as microRNA (miR/miRNA) expression changes in the liver and serum of NASH mice model to identify potential biomarker candidates that could predict early fibrosis. This study used 6-week-old C57BL/6NJcl male mice and fed the control with a standard solid diet (CE-2) for breeding and propagation and NASH groups with a high-fat diet [choline-deficient high-fat and 0.1% (w/v) methionine supplemented diet], respectively. Agilent Technologies miRNA microarray was used to investigate microRNA expression in the liver and serum. Hematoxylin and eosin staining of the livers of the NASH group mice during the second week of feeding revealed fatty degeneration, balloon-like degeneration and inflammatory cell infiltration, confirming that the mice were in a state of NASH. The livers of the NASH group mice at 6 weeks of feeding showed fibrosis. Microarray analysis revealed that miRNAs were upregulated and 47 miRNAs were downregulated in the liver of the NASH group. Pathway analysis using OmicsNet predicted miR-29 to target collagen genes. Furthermore, miR-29 was downregulated in the livers of NASH-induced mice but upregulated in serum. These findings suggested that lower miR-29 expression in NASH-induced liver would increase collagen expression and fibrosis. Early liver fibrosis suggests that miR-29 leaks from the liver into the bloodstream, and elevated serum miR-29 levels may be a predictive biomarker for early liver fibrosis., Competing Interests: The authors declare that they have no competing interests., (Copyright: © 2024 Matsumoto et al.)

Key Clinical Message: Hematopoietic neoplasms can cause adrenal infarction. In cases of thrombosis occurring at uncommon sites, it is necessary to consider evaluating for the JAK2 V617F mutation, even in the absence of notable abnormalities in blood counts., Abstract: Adrenal infarction, a rare ailment, has been sporadically linked to hematopoietic neoplasms. A 46-year-old male encountered left adrenal infarction, which coincided with a progressive rise in platelet counts. Subsequent diagnosis revealed myelodysplastic/myeloproliferative neoplasm-unclassifiable, featuring a JAK2 V617F mutation. Simultaneously, the patient manifested multiple arteriovenous thromboses, necessitating treatment with edoxaban, aspirin, and hydroxyurea. Following thrombosis resolution, he was transferred to a transplantation center. This report delves into the thrombogenicity linked to the JAK2 V617F mutation, while also examining documented instances of adrenal infarction in myeloid neoplasms. We should consider evaluating for JAK2 V617F mutation even in cases of thrombosis at unusual sites, including adrenal infarction, even if there are no considerable abnormalities in blood counts., Competing Interests: The authors have no conflicts of interest relevant to the content of this article., (© 2024 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.)

Abstract: Adult T-cell leukemia/lymphoma (ATLL) is an aggressive T-cell malignancy with a poor prognosis and limited treatment options. Programmed cell death ligand 1(PD-L1) is recognized to be involved in the pathobiology of ATLL. However, what molecules control PD-L1 expression and whether genetic or pharmacological intervention might modify PD-L1 expression in ATLL cells are still unknown. To comprehend the regulatory mechanisms of PD-L1 expression in ATLL cells, we performed unbiased genome-wide clustered regularly interspaced short palindromic repeat (CRISPR) screening in this work. In ATLL cells, we discovered that the neddylation-associated genes NEDD8, NAE1, UBA3, and CUL3 negatively regulated PD-L1 expression, whereas STAT3 positively did so. We verified, in line with the genetic results, that treatment with the JAK1/2 inhibitor ruxolitinib or the neddylation pathway inhibitor pevonedistat resulted in a decrease in PD-L1 expression in ATLL cells or an increase in it, respectively. It is significant that these results held true regardless of whether ATLL cells had the PD-L1 3' structural variant, a known genetic anomaly that promotes PD-L1 overexpression in certain patients with primary ATLL. Pevonedistat alone showed cytotoxicity for ATLL cells, but compared with each single modality, pevonedistat improved the cytotoxic effects of the anti-PD-L1 monoclonal antibody avelumab and chimeric antigen receptor (CAR) T cells targeting PD-L1 in vitro. As a result, our work provided insight into a portion of the complex regulatory mechanisms governing PD-L1 expression in ATLL cells and demonstrated the in vitro preliminary preclinical efficacy of PD-L1-directed immunotherapies by using pevonedistat to upregulate PD-L1 in ATLL cells., (© 2024 American Society of Hematology. Published by Elsevier Inc. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: We assert that the ubiquitous environmental factor in inflammatory bowel disease (IBD) is our westernized diet. Therefore, all of our newly diagnosed patients were admitted to experience a plant-based diet (PBD). In the present study, we investigated the efficacy of a PBD in pregnant women with IBD., Case Description: Included in the study were women with IBD provided with a PBD (lacto-ovo-vegetarian diet) between 2004 and 2020 who were either pregnant or became pregnant. There were 10 pregnancies in eight cases: seven cases of ulcerative colitis (UC) and one case of Crohn's disease (CD). Five active cases during pregnancy were treated. The other five cases experienced the diet before pregnancy. Two cases developed UC either during pregnancy or in the postpartum period. The PBD without medication induced remission in two mild cases of UC. Infliximab and the PBD induced remission in a relapsed case of CD. There were six conceptions during remission without medication in four cases of UC. No case relapsed during pregnancy in these cases. Vaginal, cesarean, and vacuum extraction were undertaken in four, four, and two deliveries, respectively. Three in two cases were preterm deliveries. There were 10 live births in the eight cases. Two neonates from a mother had jaundice. In the median follow-up period of 71 months, all eight cases were in the quiescent phase. PBD scores in their follow-up period, which indicate adherence to the PBD, exceeded the baseline scores., Conclusions: Our case series study indicated that a PBD was effective for pregnant women with IBD., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tgh.amegroups.com/article/view/10.21037/tgh-23-67/coif). The authors have no conflicts of interest to declare., (2024 Translational Gastroenterology and Hepatology. All rights reserved.)

Background: The use of soft coagulation is becoming common in thoracic surgery. Soft coagulation provides rapid hemostasis from small vessels during surgery by dehydrating tissue and denaturing proteins, without burning the tissue., Case Presentation: A 68-year-old man, with a history of right lower lobectomy 3 years prior, underwent a partial resection of the right upper lobe for a pulmonary nodule suspicious for secondary lung cancer. During the surgery, dissection of the adhesion caused a bleeding from the 6th intercostal artery, and hemostasis was achieved using soft coagulation (some degree of tissue carbonization was noticed at later mortality and morbidity conference). He experienced hemoptysis at postoperative day 18 and was transferred to our hospital. Contrast-enhanced CT scan revealed bleeding from the pseudoaneurysm of the 6th intercostal artery. Embolization was performed by angiography to stop the bleeding., Conclusions: We experienced a case of late-onset bleeding from a pseudoaneurysm related to soft coagulation hemostasis. Lessons learned from this patient are that additional hemostasis, such as ligation, would be considered for small arteries after hemostasis has been achieved by soft coagulation, especially when some degree of tissue carbonization is suspected., (© 2024. The Author(s).)

Exposure to high-dose radiation causes life-threatening intestinal damage. Histopathology is the most accurate method of judging the extent of intestinal damage following death. However, it is difficult to predict the extent of intestinal damage. The present study investigated extracellular microRNAs (miRNAs or miRs) in serum and feces using a radiation-induced intestinal injury mouse model. A peak of 25-200 nucleotide small RNAs was detected in mouse serum and feces by bioanalyzer, indicating the presence of miRNAs. Microarray analysis detected four miRNAs expressed in the small intestine and increased by >2-fold in serum and 19 in feces following 10 Gy radiation exposure. Increased miR-375-3p in both serum and feces suggests leakage due to radiation-induced intestinal injury and may be a candidate for high-dose radiation biomarkers., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Chiba et al.)

Serum microRNAs (miRNAs) are considered useful as non-invasive biomarkers for different diseases. However, the optimal method for extracting RNAs from serum is currently unknown. In the present study, several RNA extraction kits were used to examine the optimal kit. RNAs were extracted from the serum of 8-week-old C57BL/6NJcl male mice following the protocol of each RNA extraction kit. The yield of the extracted RNA samples was calculated, and an Agilent Bioanalyzer was used to assess the electrophoretic patterns. An Agilent mouse miRNA microarray was utilized to confirm the expression patterns of the extracted RNA samples. The results revealed significant differences in RNA yields from the miRNeasy Serum/Plasma Advanced kit and mirVana™ PARIS™ RNA and Native Protein Purification Kit compared with almost all other samples. Further, two peaks were determined in the miRNeasy Serum/Plasma Advanced kit using a small RNAs kit of Agilent Bioanalyzer, including one at 20-40 nucleotides (nt) and another at ~40-100 nt, whereas the other reagents had a single peak. This revealed that the extracted RNAs may differ in composition based on the RNA extraction method. Some types of miRNAs were only detected with certain RNA extraction reagents. This suggested that different RNA extraction reagents may cause differences in the types of miRNAs detected. On the other hand, the miRNAs commonly expressed by the three RNA extraction reagents are highly correlated in expression levels., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Yamamoto and Chiba.)

Mild cognitive impairment (MCI) is an early stage that can result in dementia. MCI can be reversed, and diagnosis at an early stage is crucial to control the progression to dementia. Dementia is currently diagnosed based on interviews and screening tests; however, novel biomarkers must be identified to allow early MCI detection. Therefore, the present study aimed to identify novel biomarkers in the form of blood microRNAs (miRNAs/miRs) for the diagnosis of MCI or early dementia. Blood samples were collected from C57BL/6NJcl male mice at four time points, including 4-week-old (4W), 8-week-old (8W), 36-week-old (36W) and 58-week-old (58W), and serum was isolated. Body weight and blood total cholesterol levels were increased, and blood alkaline phosphatase was decreased with aging. The 8W mice exhibited the highest cognitive ability in the Morris water maze test, whereas the 58W mice demonstrated decreased cognitive ability. The serum RNA concentrations of the 4W, 8W, 36W and 58W mice demonstrated no significant differences. Furthermore, small RNA levels were detected in the serum of all mice. miRNA microarray analysis revealed a >1.5-fold increase in the serum expression of two miRNAs (miR-21a-5p and miR-92a-3p) and a >1.5-fold decrease in the serum expression of two other miRNAs (miR-6769b-5p and miR-709) in 58W mice compared with those in 8W mice. In the future, we aim to further analyze aged mice to discover novel MCI biomarkers., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Yamamoto et al.)

Fatty liver is a condition of excessive triglyceride accumulation in hepatocytes. Additionally, hepatocytes exhibit a high degree of fat droplet accumulation during excessive alcohol consumption and metabolic syndrome. However, the molecular mechanisms involved in fat droplet formation remain unknown. The present study used an in vitro fatty liver formation model of the human liver cancer cell line, HepG2, to comprehensively search for fat droplet formation-related genes, and which exhibit changes in expression during fat droplet formation. Microarray analysis with extracted total RNA determined the genes that are involved in fat droplet formation and their expression was confirmed using quantitative polymerase chain reaction following the culture of the HepG2 cells in culture medium containing 0, 50, 200 and 500 µM of oleic acid for 24 h. The results revealed 142 genes demonstrating increased expression levels by >2.0-fold with oleic acid treatment and 426 genes demonstrating decreased expression levels. Perilipin 2 ( PLIN2 ) was estimated as the gene most closely associated with fatty liver. Lipid droplet formation in the HepG2 cells induced by oleic acid led to the upregulation of PLIN2 in a concentration-dependent manner. On the whole, the findings of the present study indicate the involvement of genes in oleic acid-induced lipid droplet formation in HepG2 cells; PLIN2 in particular may play a crucial role in this process., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Chiba et al.)

Background: As methadone can prevent the development of opioid resistance, it has application in alleviating cancer-related pain that proves challenging to manage with other opioids. QT interval prolongation is a serious side effect of methadone treatment, with some reported deaths. In particular, owing to the increased risk of QT interval prolongation, caution should be exercised when using it in combination with drugs that also prolong the QT interval., Case Presentation: This study presents a case in which methadone was introduced to a patient (a man in his 60s) already using levofloxacin, which could prolong the QT interval-a serious side effect of methadone treatment-and whose QTc value tended to increase. Given that levofloxacin can increase the risk of QT interval prolongation, we considered switching to other antibacterial agents before introducing methadone. However, because the neurosurgeon judged that controlling a brain abscess was a priority, low-dose methadone was introduced with continuing levofloxacin. Owing to the risks, we performed frequent electrocardiograms. Consequently, we responded before the QTc increased enough to meet the diagnostic criteria for QT interval prolongation. Consequently, we prevented the occurrence of drug-induced long QT syndrome., Conclusions: When considering the use of methadone for intractable cancer pain, it is important to eliminate possible risk factors for QT interval prolongation. However, as it may be difficult to discontinue concomitant drugs owing to comorbidities, there could be cases in which the risk of QT interval prolongation could increase, even with the introduction of low-dose methadone. In such cases, frequent monitoring, even with simple measurements such as those used in this case, is likely to prevent progression to more serious conditions., (© 2023. The Author(s).)

Objective: Bile duct tumor thrombosis in hepatocellular carcinoma (HCC) is a relatively rare event with a poor prognosis. Furthermore, bile duct tumor thrombus in HCC may be misdiagnosed when only imaging modalities are used. The efficiency of peroral cholangioscopy (POCS) in evaluating bile duct lesions has been reported. Patients: We present three cases of HCC with bile duct strictures in which POCS was performed as a preoperative evaluation. Results: In these three cases, diagnosing whether the lesion was a bile duct tumor thrombus on CT and endoscopic retrograde cholangiopancreatography was difficult. We performed POCS in three cases and were able to diagnose the presence of bile duct tumor thrombus of HCC, including differentiation from extrinsic compression of the bile duct. Conclusion: POCS for HCC with bile duct features is useful for the preoperative diagnosis of bile duct tumor thrombus, especially in cases where the surgical procedure depends on the presence of bile duct tumor thrombus., Competing Interests: The authors have no conflict of interest for this article., (©2023 The Japanese Association of Rural Medicine.)

Introduction: Approximately 10% of mutations in the EGFR gene in NSCLC are in-frame insertions in exon 20 (X20ins). These tumors usually do not respond to conventional EGFR tyrosine kinase inhibitors (TKIs). Several novel EGFR TKIs active for X20ins are in clinical development, including mobocertinib, which was recently approved by the U.S. Food and Drug Administration. However, acquired resistance during treatment with these TKIs still occurs as in the case of EGFR TKIs of earlier generations., Methods: We chronically exposed murine pro-B-cell line cells transduced with the five most common X20ins (A763_Y764insFQEA, V769_D770insASV, D770_N771insSVD, H773_V774insNPH and H773_V774insH) to mobocertinib in the presence of N-ethyl-N-nitrosourea and searched for secondary EGFR mutations. We evaluated the efficacies of several EGFR X20ins inhibitors, including zipalertinib and sunvozertinib, against cells with acquired resistant mutations., Results: All secondary mutations resulting in acquired resistance to mobocertinib were exclusively C797S in insFQEA and insSVD. However, in the case of other X20ins (insASV, insNPH, and insH), T790M or C797S secondary mutations contributed to acquired resistance to mobocertinib. The emergence of T790M was more frequent in cells treated with lower drug concentrations. Sunvozertinib exhibited good activity against resistant cells with T790M. Cells with C797S were refractory to all EGFR TKIs, except for erlotinib, which was active for insFQEA with C797S., Conclusions: T790M or C797S, depending on the original X20ins mutations, conferred acquired resistance to mobocertinib. Sunvozertinib may be the treatment of choice for patients with tumors resistant to mobocertinib because of T790M., (Copyright © 2023 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: Robotic-assisted thoracic surgery (RATS) has gained increasing interest in recent years, with most procedures performed using the conventional multiportal approach. Uniportal RATS (URATS) approaches have recently been reported in the pursuit of minimally invasive procedures. However, URATS requires specific skills. Herein, we introduce dual-portal RATS (DRATS) performed with two incisions., Methods: Data of DRATS procedures performed from December 2022 to May 2023 were retrospectively reviewed. Twenty patients with lung cancer underwent anatomical lung resections via DRATS performed by our group at three institutes., Results: Among 20 cases of planned DRATS for anatomical pulmonary resections, there were no conversions to thoracotomy and no need for extra ports. The mean surgery time was 121±60 minutes and mean console time was 91±47 minutes. The mean intraoperative blood loss volume was 9.6±12.1 g. The mean duration of chest tube drainage and hospital stay were 2±1 and 5±2 days, respectively. The mean numerical rating scale for pain was 2±1 on the first postoperative day, 1±1 on the third day, and 1±1 at discharge. There were no postoperative complications or mortalities., Conclusions: Our primary experience shows that DRATS is safe and feasible for anatomical lung resection. We consider DRATS to be a very good preliminary step in the future transition to URATS., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-23-1141/coif). The authors have no conflicts of interest to declare., (2023 Journal of Thoracic Disease. All rights reserved.)

Senescent cells secrete inflammatory proteins and small extracellular vesicles (sEVs), collectively termed senescence-associated secretory phenotype (SASP), and promote age-related diseases. Epigenetic alteration in senescent cells induces the expression of satellite II (SATII) RNA, non-coding RNA transcribed from pericentromeric repetitive sequences in the genome, leading to the expression of inflammatory SASP genes. SATII RNA is contained in sEVs and functions as an SASP factor in recipient cells. However, the molecular mechanism of SATII RNA loading into sEVs is unclear. In this study, we identified Y-box binding protein 1 (YBX1) as a carrier of SATII RNA via mass spectrometry analysis after RNA pull-down. sEVs containing SATII RNA induced cellular senescence and promoted the expression of inflammatory SASP genes in recipient cells. YBX1 knockdown significantly reduced SATII RNA levels in sEVs and inhibited the propagation of SASP in recipient cells. The analysis of the clinical dataset revealed that YBX1 expression is higher in cancer stroma than in normal stroma of breast and ovarian cancer tissues. Furthermore, high YBX1 expression was correlated with poor prognosis in breast and ovarian cancers. This study demonstrated that SATII RNA loading into sEVs is regulated via YBX1 and that YBX1 is a promising target in novel cancer therapy.

Cancer cachexia is a complex malnutrition syndrome that causes progressive dysfunction. This syndrome is accompanied by protein and energy losses caused by reduced nutrient intake and the development of metabolic disorders. As many as 80% of patients with advanced cancer develop cancer cachexia; however, an effective targeted treatment remains to be developed. In this study, we developed a novel rat model that mimics the human pathology during cancer cachexia to elucidate the mechanism underlying the onset and progression of this syndrome. We subcutaneously transplanted rats with SLC cells, a rat lung adenocarcinoma cell line, and evaluated the rats' pathophysiological characteristics. To ensure that our observations were not attributable to simple starvation, we evaluated the characteristics under tube feeding. We observed that SLC-transplanted rats exhibited severe anorexia, weight loss, muscle atrophy, and weakness. Furthermore, they showed obvious signs of cachexia, such as anemia, inflammation, and low serum albumin. The rats also exhibited weight and muscle losses despite sufficient nutrition delivered by tube feeding. Our novel cancer cachexia rat model is a promising tool to elucidate the pathogenesis of cancer cachexia and to conduct further research on the development of treatments and supportive care for patients with this disease.

The signal intensities of CO2- radicals in teeth can be utilised as an individual indicator of the cumulative external dose for animals. To accurately determine the external dose, it is desirable to analyse the CO2- radical intensity and improve its detection limit. We recently reported a dose-response in the range of 0-200 mGy and estimated the absorbed dose for seven wild Japanese macaques captured in/around the related areas to the Fukushima Daiichi Nuclear Power Plant accident. Herein, for further improvement of this method, we examined the electron spin resonance spectra of the teeth of these seven and an additional four macaques captured in Fukushima by applying two spectrum-decomposition algorithms., (© The Author(s) 2023. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Identification and recognition of the ubiquitous environmental factor are prerequisite for treatment and prevention of the disease. The biggest problem with current practice in inflammatory bowel disease (IBD) is the lack of a widely appreciated ubiquitous environmental factor for the disease. The incidence of IBD is associated with dietary transition from a traditional diet to the current (westernized) diet. Prospective cohort studies and case-control studies indicate that the current diet is a risk factor for IBD. The current diet tends to cause gut microbial dysbiosis resulting in a pro-inflammatory state. Therefore, we regard our current diet as this factor. Even nutritionally balanced meals are unable to suppress relapse, particularly in Crohn's disease (CD). Therefore, we developed a plant-based diet (PBD) (lacto-ovo-semi-vegetarian diet) to counter the current diet. By incorporating the PBD into practice, we achieved far better outcomes in both ulcerative colitis (UC) and CD in both the induction and quiescent phases compared to the current standard therapy. All patients were treated on an inpatient basis and provided with a PBD. CD is far more untenable than UC and is destined to follow a disabling course. Therefore, infliximab was indicated in all patients with CD, but only in severe cases with UC. This infliximab and PBD as first-line (IPF) therapy broke the barrier of primary nonresponders to biologics (around 30%): the remission rate was 96% (44/46) in CD and 76% (13/17) in severe UC. A PBD can induce remission without medication in approximately one-third of mild cases of UC. All patients were advised to adhere PBD after discharge. In CD, a relapse-free outcome was achieved in nearly a half of patients (52%) at 10-year follow-up without biologics or immunosuppressants. Cumulative relapse rates for 51 initial episode cases of UC (18 mild, 30 moderate, 3 severe) at 1 and 5 years were 14% and 27%, respectively. We believe our assertion that the current diet is the ubiquitous environmental factor underlying IBD is correct and a PBD is right diet for the disease., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tgh.amegroups.com/article/view/10.21037/tgh-23-6/coif). The authors have no conflicts of interest to declare., (2023 Translational Gastroenterology and Hepatology. All rights reserved.)

Objectives: Our objective was to evaluate the short- and long-term safety and efficacy of teduglutide treatment in infants and children with short bowel syndrome with intestinal failure (SBS-IF)., Methods: Two open-label phase 3 studies and 1 extension study investigated the short- and long-term safety and efficacy of teduglutide (0.05 mg/kg/day) in infants and children with SBS-IF: NCT03571516, 24-week study of infants who were randomized to receive teduglutide or standard of care (SoC); NCT02980666, 24-week study of infants and children who all received teduglutide; and NCT03268811, 24-week extension study of patients who completed NCT02980666 (patients could receive up to 48 weeks of total treatment)., Results: Twelve infants and 8 children enrolled in the core studies, and 2 infants and 7 children in the extension study. After 24 weeks of treatment, parenteral support (PS) requirements reduced by ≥20% from baseline for 4 infants (57.1%) and 4 children (66.7%) receiving teduglutide and for 2 infants receiving SoC (50.0%). One infant (50.0%) and 4 children (80.0%) receiving teduglutide maintained the ≥20% reduction in PS at 48 weeks of treatment. Two children receiving teduglutide achieved enteral autonomy, after 12 weeks and 28 weeks of treatment, respectively. All adverse events (AEs) were in line with known impacts of SBS-IF and adverse reactions to teduglutide. Only one serious AE (abdominal pain) was considered related to teduglutide., Conclusions: Short- and long-term treatment with teduglutide resulted in clinically meaningful reductions in PS requirements for infants and children with SBS-IF. Teduglutide was well tolerated, and efficacy improved with longer-term treatment., Competing Interests: S.C. is an employee of Takeda Pharmaceutical Company Limited, Cambridge, MA, USA and is a stockholder of Takeda Pharmaceutical Company Limited. S.S. is an employee of Takeda Pharmaceutical Company Limited, Osaka, Japan and is a stockholder of Takeda Pharmaceutical Company Limited. E.U. was an employee of Takeda Pharmaceutical Company Limited, Tokyo, Japan. M.W. received research funding from Shire, a Takeda company. The remaining authors report no conflicts of interest., (Copyright © 2023 The Author(s). Published by Wolters Kluwer on behalf of European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Cellular senescence and senescence-associated secretory phenotype (SASP) in stromal cells within the tumor microenvironment promote cancer progression. Although cellular senescence has been shown to induce changes in the higher-order chromatin structure and abnormal transcription of repetitive elements in the genome, the functional significance of these changes is unclear. In this study, we examined the human satellite II (hSATII) loci in the pericentromere to understand these changes and their functional significance. Our results indicated that the hSATII loci decompact during senescence induction, resulting in new DNA-DNA interactions in distinct genomic regions, which we refer to as DRISR (Distinctive Regions Interacted with Satellite II in Replicative senescent Fibroblasts). Interestingly, decompaction occurs before the expression of hSATII RNA. The DRISR with altered chromatin accessibility was enriched for motifs associated with cellular senescence and inflammatory SASP genes. Moreover, DNA-fluorescence in situ hybridization analysis of the breast cancer tissues revealed hSATII decompaction in cancer and stromal cells. Furthermore, we reanalyzed the single-cell assay for transposase-accessible chromatin with sequencing data and found increased SASP-related gene expression in fibroblasts exhibiting hSATII decompaction in breast cancer tissues. These findings suggest that changes in the higher-order chromatin structure of the pericentromeric repetitive sequences during cellular senescence might directly contribute to the cellular senescence phenotype and cancer progression via inflammatory gene expression.

Introduction: Lung tumor organoids (LTOs) have attracted attention as in vitro preclinical models; however, their clinical and experimental applications have not been fully established., Methods: We attempted to establish LTOs from resected specimens of patients with lung cancer who underwent lung resection. Clinicopathologic characteristics related to the establishment of LTOs were evaluated. Histologic assessment and genetic analysis were conducted for both LTOs and their parental tumors. Organoid-derived xenografts were generated in immunocompetent mice. Drug sensitivity was assessed using cell proliferation assays., Results: We established 53 LTOs from 79 lung cancer samples, including 10 long-term culture models. The establishment rate was significantly lower in squamous cell carcinomas than in other histologic types (48% versus 75%, p  = 0.034). Histologic similarities were confirmed among LTOs, the parental tumors, and organoid-derived xenografts. Seven mutations, including two EGFR L858R and one EGFR exon 20 H773delinsYNPY mutations, were detected in both LTO and parental tumors; the other four mutations were detected in either LTO or parental tumors. The extensive culture ability of LTO (passaged >10 times) correlated with poor patient prognosis. LTO9 cells harboring EGFR H773delinsYNPY were sensitive to osimertinib. The parental patient, who had new metastatic lesions, was treated with osimertinib and exhibited a remarkable response., Conclusions: The establishment and growth rates of LTOs were associated with the histologic subtype and tumor size. LTOs derived from resected specimens have become preclinical models that can be used to predict drug responses and accelerate the development of treatment strategies for patients with rare mutations., (© 2023 The Authors.)

Metallo-beta-lactamases (MBLs) are enzymes that break down carbapenem antibiotics, leading to carbapenem-resistant organisms. Carbapenemase-resistant Enterobacterales (CRE) is one of them. Outbreaks of CRE infection can occur in healthcare facilities and lead to increased deaths, illness, and medical costs. This study was conducted to detect MBLs using non-carbapenem agents and exclude MBLs among CRE isolates. A total of 3776 non-duplicate sequential Enterobacterales isolates from a single facility were screened between January 2019 and December 2022 using non-carbapenem agents, ceftazidime and cefoperazone/sulbactam. Positive 153 isolates (4.0%) were further tested using carbapenemase-confirmation tests and verified through polymerase chain reaction (PCR) testing. Fifteen imipenemase (IMP)-type MBL-producing Enterobacterales (0.4%) including one susceptible to carbapenems were identified. Moreover, 160 isolates (4.2%) meeting the criteria for CRE were directly subjected to PCR testing. All fourteen CRE isolates with MBLs identified through PCR testing were found to be the same strains screened using ceftazidime and cefoperazone/sulbactam. Screening using ceftazidime and cefoperazone/sulbactam can effectively detect MBL-producing Enterobacterales strains. This screening method showed comparable results to screening with meropenem, potentially serving as a supplementary approach and contributing to differentiating between MBL- and non-MBL-producing CRE strains. Our findings support these screening methods, particularly in regions where IMP-type MBLs are prevalent.

Staphylococcus aureus bacteremia results in substantial mortality. Rapid identification and the determination of methicillin susceptibility are crucial for immediate treatment with appropriate antibiotics. In the present study, we aimed to evaluate the basic assay performance of GeneSoC®, a novel rapid quantitative polymerase chain reaction (qPCR) method, for the detection of methicillin-susceptible (MS) or -resistant (MR) S. aureus in blood culture (BC) bottles. qPCR pimers and probes were desinged for femA and mecA genes to diagnose S. aureus and its methicilline-resistance status. GeneSoC® system can detect target genes within 12 min per sample using microfludic thermal cycling. A total of 100 BC-positive samples, showing clusters of gram-positive cocci using microscopy, were tested. The analytical sensitivity was demonstrated for the target sequence of femA and mecA genes at 10 copies/μL, respectively. The detection limit of the MRSA bacterial burden using this system was 10 4 and 10 3  CFU/mL for femA and mecA, respectively. Compared with culture-based identification and susceptibility testing, the sensitivity and specificity for the detection of femA (+)/mecA (+) MRSA using GeneSoC® were 90.9 and 98.9%, respectively, whereas the sensitivity and specificity for detection of femA (+)/mecA (-) MSSA were 96.2% and 97.3%, respectively. In conclusion, although this was a small sample and pilot study, the GeneSoC® system is beneficial for rapid, reliable, and highly sensitive real-time testing of MRSA and MSSA in BC bottles., Competing Interests: Declaration of competing interest This study was funded by Kyorin Pharmaceutical Co., Ltd. The sponsor provided technical support for the GeneSoC® system examination, including system maintenance, during the study period. The sponsor had no control over the interpretation, writing, or publication of this work., (Copyright © 2023 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

Primary cystic duct carcinoma is a rare tumor. The curative treatment of cystic duct carcinoma is complete surgical resection, for which the evaluation of local extension is important. We herein report two cases of cystic duct carcinoma in which a preoperative examination was performed using per-oral cholangioscopy (POCS). Both patients underwent POCS due to suspicion of cystic duct carcinoma based on imaging findings. A visual analysis and biopsy were performed to evaluate local extension, which led to surgery. These cases suggest that POCS is useful for the preoperative assessment of local extension in advanced cystic duct carcinoma.

In previous works, we developed a self-healing organic coating with dispersed spherical capsules for corrosion protection. The capsule consisted of a polyurethane shell and healing agent as the inner. When the coating was damaged physically, the capsules were broken, and the healing agent was released from the broken capsules to the damaged area. The healing agent could react with moisture in the air to form the self-healing structure and cover the damaged area of coating. In the present investigation, a self-healing organic coating with spherical and fibrous capsules was formed on aluminum alloys. The corrosion behavior of the specimen coated with the self-healing coating was examined in a Cu 2+ /Cl - solution after physical damage, and it was found that no corrosion occurred during the corrosion test. This is discussed in terms of the high healing ability of fibrous capsules as a result of the high projected area.

Background and Aims: The need for mastering standard imaging techniques for convex EUS in the biliopancreatic regions has been increasing; however, large variations in the aptitude for achieving EUS competency hinder expert development. Therefore, we investigated the factors influencing the achievement of expert competency in EUS using a new assessment tool for multiple imaging items., Methods: Between January 2018 and February 2022, 3277 consecutive EUS procedures conducted by 5 beginners (EUS procedures <250), 7 intermediate trainees (250-749), and 2 experts (≥750) were prospectively evaluated. Immediately after each EUS procedure, the success or failure of imaging for each item was recorded using a newly developed EUS assessment tool that requires 17 items to be photographed. After correcting for missing values using multiple imputation, learning curves of EUS scores were created, and a competency was set based on expert scores. Finally, a comparative analysis between high and low performers was performed to extract factors influencing EUS scores., Results: Although 3 of 7 intermediates (43%; mean, 317 cases) achieved competency, none of the beginners achieved competency. During a comparative analysis, although no significant difference in the number of EUS procedures performed was observed between the high and low performers, the former had significantly higher scores in the written test (theoretical knowledge)., Conclusions: Our results showed that theoretical knowledge, rather than the number of EUS cases, may be a possible influencing factor for distinguishing high and low performers after treating 250 cases. (Clinical trial registration number: UMIN 000043271.)., (Copyright © 2023 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.)

Enamel is formed by the repetitive secretion of a tooth-specific extracellular matrix and its decomposition. Calcification of the enamel matrix via hydroxyapatite (HAP) maturation requires pH cycling to be tightly regulated through the neutralization of protons released during HAP synthesis. We found that Gpr115, which responds to changes in extracellular pH, plays an important role in enamel formation. Gpr115-deficient mice show partial enamel hypomineralization, suggesting that other pH-responsive molecules may be involved. In this study, we focused on the role of Gpr111/Adgrf2, a duplicate gene of Gpr115, in tooth development. Gpr111 was highly expressed in mature ameloblasts. Gpr111-KO mice showed enamel hypomineralization. Dysplasia of enamel rods and high carbon content seen in Gpr111-deficient mice suggested the presence of residual enamel matrices in enamel. Depletion of Gpr111 in dental epithelial cells induced the expression of ameloblast-specific protease, kallikrein-related peptidase 4 (Klk4), suggesting that Gpr111 may act as a suppressor of Klk4 expression. Moreover, reduction of extracellular pH to 6.8 suppressed the expression of Gpr111, while the converse increased Klk4 expression. Such induction of Klk4 was synergistically enhanced by Gpr111 knockdown, suggesting that proper enamel mineralization may be linked to the modulation of Klk4 expression by Gpr111. Furthermore, our in vitro suppression of Gpr111 and Gpr115 expression indicated that their suppressive effect on calcification was additive. These results suggest that both Gpr111 and Gpr115 respond to extracellular pH, contribute to the expression of proteolytic enzymes, and regulate the pH cycle, thereby playing important roles in enamel formation., (© 2023 Federation of American Societies for Experimental Biology.)

Competing Interests: Conflicts of Interest: The authors declare that there are no relevant conflicts of interest.

There has been no study of the therapeutic effect of a plant-based diet (PBD) in inflammatory bowel disease (IBD) except for our studies in Japan. In this review, we describe the rationale for the requirement of PBD in IBD and the outcomes of our modality incorporating PBD together with a literature review. The biggest problem in current therapy for IBD is the lack of a widely appreciated ubiquitous environmental factor in IBD. Therefore, a radical strategy against IBD has not been established. Japanese data showed an increased incidence of IBD in association with dietary westernization. Current global consumption consists of an excess of unhealthy foods and a shortage of healthy foods recognized as pro-inflammatory. Patients with IBD are no exception. One of the recommended healthy reference diets is PBD recognized as anti-inflammatory. We assert that IBD occurs in susceptible individuals mainly as a result of our omnivorous (westernized) diet. Therefore, we developed and began to provide a PBD, a lacto-ovo-vegetarian diet, for IBD patients in 2003. Infliximab and PBD as first-line (IPF) therapy was administered for all patients with newly developed Crohn's disease (CD) and for severe ulcerative colitis (UC). Our modality broke the barrier of primary nonresponders to biologics, with a remission rate of 96% in CD, and created a new relapse-free course in slightly over half of the patients (52%) with CD. Based on the rationale derived from available evidence and the clinical outcomes, PBD is highly recommended for IBD.

Background: The Japan Surveillance for Infection Prevention and Healthcare Epidemiology (J-SIPHE) system aggregates information related to antimicrobial resistance (AMR) measures in participating medical institutions nationwide and is intended to be used for promotion of AMR measures in participating facilities and their communities. This multicenter study aimed to determine the usefulness of the J-SIPHE system for evaluating the correlation between antibiotic use and antibiotic resistance in Hokkaido, Japan., Methods: Data on antibiotic use and detection rate of major resistant Gram-negative bacteria at 19 hospitals in 2020 were collected from the J-SIPHE system, and data correlations were analyzed using JMP Pro., Results: The detection rate of carbapenem-resistant Pseudomonas aeruginosa was significantly positively correlated with carbapenem use (Spearman's ρ = 0.551; P = .015). There were significant positive correlations between the detection rate of fluoroquinolone-resistant Escherichia coli and the use of piperacillin/tazobactam, carbapenems, and quinolones [ρ = 0.518 (P = .023), ρ = 0.76 (P < .001), and ρ = 0.502 (P = .029), respectively]., Conclusions: This is the first multicenter study to investigate the correlation between antibiotic use and antibiotic resistance using the J-SIPHE system. The results suggest that using this system may be beneficial for promoting AMR measures., (Copyright © 2022 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved.)

Anaplastic large cell lymphoma (ALCL) and classical Hodgkin lymphoma (HL) share a similar cytological and high surface expression of CD30, and novel therapeutic strategies are needed. The EP300 and CREBBP acetyltransferases play essential roles in the pathogenesis of non-Hodgkin B cell lymphoma, but their functions in ALCL and HL are unknown. In the current study, we investigated the physiological roles of EP300 and CREBBP in both ALCL and HL, and exploited the therapeutic potential of EP300/CREBBP small molecule inhibitors that target either the HAT or bromodomain activities. Our studies demonstrated distinct roles for EP300 and CREBBP in supporting the viability of ALCL and HL, which was bolstered by the transcriptome analyses. Specifically, EP300 but not CREBBP directly modulated the expression of oncogenic MYC/IRF4 network, surface receptor CD30, immunoregulatory cytokines IL10 and LTA, and immune checkpoint protein PD-L1. Importantly, EP300/CREBBP HAT inhibitor A-485 and bromodomain inhibitor CPI-637 exhibited strong activities against ALCL and HL in vitro and in xenograft mouse models, and inhibited PD-L1 mediated tumor immune escape. Thus, our studies revealed critical insights into the physiological roles of EP300/CREBBP in these lymphomas, and provided opportunities for developing novel strategies for both targeted and immune therapies., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Senescent cells exhibit several typical features, including the senescence-associated secretory phenotype (SASP), promoting the secretion of various inflammatory proteins and small extracellular vesicles (EVs). SASP factors cause chronic inflammation, leading to age-related diseases. Recently, therapeutic strategies targeting senescent cells, known as senolytics, have gained attention; however, noninvasive methods to detect senescent cells in living organisms have not been established. Therefore, the goal of this study was to identify novel senescent markers using small EVs (sEVs). sEVs were isolated from young and senescent fibroblasts using three different methods, including size-exclusion chromatography, affinity column for phosphatidylserine, and immunoprecipitation using antibodies against tetraspanin proteins, followed by mass spectrometry. Principal component analysis revealed that the protein composition of sEVs released from senescent cells was significantly different from that of young cells. Importantly, we identified ATP6V0D1 and RTN4 as novel markers that are frequently upregulated in sEVs from senescent and progeria cells derived from patients with Werner syndrome. Furthermore, these two proteins were significantly enriched in sEVs from the serum of aged mice. This study supports the potential use of senescent markers from sEVs to detect the presence of senescent cells in vivo.

Background: Cancer treatment has recently evolved due to the advances in comprehensive therapies, including chemotherapy and radiotherapy. The aspect of cancer-related bone metastasis has undergone a paradigm shift with the transformation of orthopedic interventions for spinal metastasis. We performed this retrospective observational study to investigate the changes in patient status and metastatic spine-tumor treatment over the past decade., Methods: We included 186 patients (122 men and 64 women; mean age: 67.6 years) who were referred to our hospital between 2009 and 2018 and were diagnosed and treated for metastatic spinal tumors. We classified the patients into early (81 patients from 2009 to 2013) and late (105 patients from 2014 to 2018) groups. The following components were investigated and compared between the groups: primary tumor, time taken from subjective-symptom onset to hospital visit, primary tumor evaluation during the visit, walking capacity due to lower paralysis during the visit, local treatment details, and post-treatment functional prognosis., Results: Predominant primary tumors with similar trends in both groups included lung cancer, multiple myeloma, and prostate cancer. The percentage of non-ambulatory patients during the consultation was significantly lower in the late group (28% vs. 16%, P = 0.04). Among non-ambulatory patients at the time of hospital visit, the mean time from the primary doctor consultation to our hospital visit was 2.8 and 2.1 days in the early and late groups, respectively. In both groups, surgical procedures were performed promptly on the non-ambulatory patients; however, postoperative lower function did not improve in approximately half of the patients., Conclusions: Our findings demonstrated that in recent years, patients tended to be referred promptly from their previous doctors under a favorable collaboration system. However, the effectiveness of lower paralysis treatment remains limited, and it is important to raise awareness regarding the importance of early consultation among the general public for earlier detection., (© 2023. The Author(s).)