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The sarcomere is the contractile unit of striated muscle and is composed of actin and myosin filaments. There is increasing evidence to support that actin assembly mediated by Fhod3, a member of the formin family of proteins, is critical for sarcomere formation and maintenance in cardiac muscle. Fhod3, which is abundantly expressed in the heart, localizes to the center of sarcomeres and contributes to the regulation of the cardiac function, as evidenced by the fact that mutations in Fhod3 cause cardiomyopathy. However, the role of Fhod3 in skeletal muscle, another type of striated muscle, is unclear. We herein show that Fhod3 is expressed in the tongue at both mRNA and protein levels, although in smaller amounts than in the heart. To determine the physiological role of Fhod3 expressed in the tongue, we generated embryos lacking Fhod3 in the tongue. The tongue tissue of the Fhod3-depleted embryos did not show any significant structural defects, suggesting that Fhod3 is dispensable for normal development of the mouse tongue. Unexpectedly, the immunostaining analysis revealed the absence of specific sarcomeric signals for Fhod3 in the wild-type tongue when compared to the Fhod3-depleted tongue as a negative control, despite the use of antibodies that had previously been validated by immunostaining of heart tissues. Taken together, although Fhod3 protein is expressed at a significant level in the tongue, Fhod3 in the tongue does not appear to exhibit the same sarcomeric pattern as observed in the heart, suggesting a different role for Fhod3 in the tongue muscles.Key words: actin, formin, sarcomere, striated muscle.

Background/aim: Radiotherapy (RT) for advanced oropharyngeal cancer (OPC) is effective, especially when combined with chemotherapy (CRT). However, its success can vary depending on factors, such as tumor stage, HPV infection (p16 status), and the patient's nutritional and immune status. This study examined the controlling nutritional status (CONUT) score and tumor immunity as predictive factors for treatment outcomes in OPC, aiming to develop a personalized risk score., Patients and Methods: A retrospective analysis was conducted on 84 patients with OPC treated with definitive RT or CRT, and survival outcomes were compared based on various factors, including BMI, CONUT score, CD8 expression, and HLA class II expression., Results: We observed better overall survival (OS) rates in CD8-positive patients and those with higher HLA class II expression. The univariate analysis identified stage, p16 status, BMI, CONUT score, and CD8 expression as significantly associated with OS. In multivariate analysis, stage, BMI, and CONUT score remained significant predictors of OS. A risk scoring system was developed based on stage, p16 status, BMI, CONUT score, and CD8 expression. Patients were categorized into low-risk and high-risk groups, with significantly better survival in the low-risk group., Conclusion: A combined risk score incorporating clinical, nutritional, and immune factors can improve the prediction of treatment outcomes for OPC patients. This risk stratification may enable personalized treatment plans and improve ΟS rates., Competing Interests: The Authors declare that they have no conflicts of interest in relation to this study., (©2024 The Author(s). Published by the International Institute of Anticancer Research.)

Purpose: Root Cause Analysis (RCA) of reported incident reports can lead to measures to prevent the recurrence of accidents. The purpose of this study is to clarify the relationship between the occurrence of cases, causal factors, contributing factors, and the experience years of the reporters classified into three groups: less than 2 years, 3 to less than 5 years, and more than 5 years, for incident reports subject to RCA., Methods: From April 2018 to March 2023, a chi-square test was conducted between each item extracted from 239 cases subject to RCA and the experience years of the reporters, with a significance level of less than 5% considered significant., Results: Regarding the occurrence cases, radiological technologists with longer experience had more misidentified a patient and fewer errors in imaging conditions and range, while radiological technologists with 3 to less than 5 years of experience had more errors in imaging conditions (p<0.001). In terms of occurrence factors, radiological technologists with 3 to less than 5 years of experience had more cases of insufficient confirmation (p<0.05). For contributing factors, there was no significant difference between the experience year groups (p=0.19), with "Impatience" being the most common factor., Conclusion: This survey suggested that in incident reports of radiological technologists, "Impatience" is a contributing factor that can occur regardless of years of experience.

Purpose: Most studies on the performance of first-trimester cardiac screening have concentrated on comparing the detection rate between different protocols and not on the actual reason for false-negative results. Herein, we report the performance of first-trimester congenital heart disease (CHD) screening and factors that may affect the detection rate of CHDs., Methods: This retrospective observational study included patients who underwent first-trimester screening and subsequently gave birth at our facility. We analyzed the performance of first-trimester screening for CHD and major CHD (CHD requiring cardiac surgery or interventional catheterization within 12 months of birth)., Results: Of the 6614 fetuses included, 53 had CHD and 35 had major CHD. For the prenatal diagnosis of CHD, the detection rate, specificity, positive predictive value, negative predictive value, and first-trimester detection rate for CHD were 64.1%, 99.9%, 94.4%, 99.7%, and 82.9%, respectively; the respective values for major CHD were 85.7%, 99.96%, 93.75%, 99.92%, and 85.7%. The detection rate was not significantly different when classified by crown-rump length or number of fetuses. A weak correlation was observed between low detection rate of major CHD and lower maternal body mass index (BMI) (correlation ratio: 0.17). The detection rate was significantly higher when the fetus was scanned with its spine at the 5-7 o'clock position (posterior spine) than at other positions (odds ratio: 3.82, 95% confidence interval: 1.16-12.5, p = 0.02)., Conclusion: Posterior spine contributes to an improved diagnostic rate in first-trimester CHD screening. In addition, sonographers must recognize that low maternal BMI is a risk factor of false-negative results., (© 2024. The Author(s), under exclusive licence to The Japan Society of Ultrasonics in Medicine.)

Purpose: Physician and surgeon involvement in industry has received considerable attention in recent decades. In this study, we outline the perspective of the general US population regarding (1) disclosure, (2) ownership, and (3) compensation between physicians/surgeons and industry. We hypothesize that the general population would be largely supportive of the physician/surgeon-industry relationship., Methods: An online, survey-based, descriptive study was conducted through a crowdsourcing platform, Amazon Mechanical Turk. Survey respondents were presented with a seven-item questionnaire inquiring about the physician/surgeon and industry relationship. An "attention check" question was included; those who failed this question were excluded. Descriptive statistics were used to assess the data and a McNemar chi-squared test for paired, dichotomous data., Results: A total of 993 respondents were included. Survey responses are summarized in Table 1. 70.6% of respondents stated that it was "important" or "extremely important" to disclose that the patient be informed whether implants used in surgery had been developed by the operating surgeon. 71.1% of respondents reported that it was "important" or "extremely important" to disclose partial ownership within industry. Seventy-one percent of respondents stated it was "important" or "extremely important" to disclose royalty payments pertaining to surgical implants. 95.6% of respondents suggested that it was acceptable for surgeons to accept free airfare and lodging, and 95.2% of respondents stated that it was acceptable for the surgeon to be compensated for time away from practice to learn about new equipment., Discussion: In our survey of 993 respondents, we found that relationships with industry are considered acceptable if appropriate disclosure is given to patients. We also found that although respondents suggested that physicians and surgeons may be influenced by a free meal, compensation for trips to try new equipment and time spent away from practice is considered appropriate., Level of Evidence: 2c, Ecological studies., (Copyright © 2024 by the American Academy of Orthopaedic Surgeons.)

γ-Glutamyl-β-cyanoalanylglycine (gEcnAG) is a glutathione analog in which the cysteine moiety in glutathione is replaced with β-cyanoalanine, a known plant cyanide metabolite. Previously, gEcnAG was detected in the liver of rats and chicks exposed to β-cyanoalanine. We reported the detection of gEcnAG in naïve mammalian cells using liquid chromatography coupled with tandem quadrupole time-of-flight mass spectrometry (LC-QTOF-MS). LC-QTOF-MS analysis enabled high-resolution confirmation (exact mass determination and MS/MS fragmentation) of the gEcnAG structure. The detection of gEcnAG in rat pheochromocytoma (PC12) cells that were not exposed to β-cyanoalanine suggests its endogenous production. Furthermore, the inhibition of myeloperoxidase, an enzyme potentially required for endogenous cyanide generation, decreased gEcnAG levels in PC12 cells. This supports the notion that PC12 cells intrinsically produce cyanide, unlike HepG2 cells, which exhibited lower intracellular gEcnAG levels. Notably, β-cyanoalanine was undetectable in PC12 cells. Moreover, depleting glutathione with buthionine sulfoximine reduced intracellular gEcnAG levels, whereas supplementation with glutathione reduced ethyl ester increased them. These observations suggest that endogenous gEcnAG may be generated from glutathione, potentially through its reaction with endogenous cyanide. Our findings implicate gEcnAG as a possible metabolite of endogenous cyanide., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Aim: Echocardiography is necessary for portopulmonary hypertension diagnosis, and identifying patients with cirrhosis who require it is challenging. In this study, we aimed to investigate the utility of the total bile acid (TBA) levels as a screening tool for identifying patients with decompensated cirrhosis who should undergo echocardiography for portopulmonary hypertension diagnosis., Methods: We evaluated 135 patients with decompensated cirrhosis who underwent liver transplantation. Subsequently, factors contributing to tricuspid regurgitation pressure gradient (TRPG) elevation (≥30 mmHg) were analyzed using preoperative data, including the TBA levels., Results: The median age of patients was 58 years (61 women), and 45 and 90 patients had Child-Turcotte-Pugh grades of B and C, respectively. The median TRPG level was 21 mmHg, and 17 patients (12.6%) showed TRPG elevation. Multiple logistic regression analysis revealed that elevated TBA (odds ratio 4.322; p = 0.013) and main pulmonary artery diameter ≥33 mm (odds ratio 4.333; p = 0.016) were significantly associated with TRPG elevation. The TBA cut-off value (167.7 μmol/L) showed a high diagnostic performance, with 70.6% sensitivity and 64.4% specificity. Ursodeoxycholic acid (UDCA) administration increased the TBA levels dose-dependently. Analysis stratified by UDCA use revealed that in patients not taking UDCA (n = 59), elevated TBA levels and younger age significantly contributed to TRPG elevation. However, in those taking UDCA (n = 76), this contribution disappeared, suggesting that UDCA consumption reduced TBA levels' efficiency in diagnosing TRPG elevation., Conclusions: The TBA levels may be a potential screening tool for TRPG elevation; however, caution is warranted when interpreting cases treated with UDCA., (© 2024 Japan Society of Hepatology.)

Objectives: The objective of this study was to examine the effectiveness and drug tolerability of biological DMARD (bDMARD) and Janus kinase inhibitor (JAKi) monotherapy in patients with RA in a multicentre cohort study., Methods: Patients with RA for whom bDMARD/JAKi monotherapy without conventional synthetic DMARDs has been initiated were included. Monotherapy regimens were categorized as IL-6 receptor inhibitors (IL-6Ris), cytotoxic T-lymphocyte-associated protein 4 immunoglobulin (CTLA4Ig), JAKis, or TNF inhibitors (TNFis). Multiple propensity score-based inverse probability weighting (IPW) was used to reduce selection bias. Linear mixed-effect models with IPW were used to examine changes in the DAS in 28 joints using ESR (DAS28)-ESR at 24 weeks, and drug retention was compared between monotherapy groups using IPW Cox proportional hazards models., Results: A total of 849 treatment courses were included, involving 635 patients (IL-6Ris, 218; CTLA4Ig, 183; JAKis, 92; TNFis, 356). The change in DAS28-ESR at week 24 as the primary outcome was -0.93 (95% CI: -1.20 to -0.66) lower in the IL-6Ri group than in the TNFi group, while those of the CTLA4Ig and JAKi groups were similar to that of the TNFi group [-0.20 (-0.48 to 0.08), -0.25 (-0.67 to 0.16), respectively]. IL-6Ri use was associated with significantly lower overall drug discontinuation than that for TNFi use [hazard ratio = 0.55 (0.39-0.78), P = 0.001]. Similar retention rates were identified for the CTLA4Ig and JAKi groups to that of the TNFi group., Conclusion: In the analysis with IPW to reduce selection bias, IL-6Ri monotherapy was superior to TNFi monotherapy in terms of effectiveness and drug retention. No significant differences were identified between CTLA4Ig, JAKi and TNFi monotherapy., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: The Trunk Assessment Scale for Spinal Cord Injury (TASS) and the Trunk Control Test for individuals with a Spinal Cord Injury (TCT-SCI) are highly reliable assessment tools for evaluating the trunk function of individuals with SCIs. However, the potential differences in the validity of these two scales are unclear. Objectives: To evaluate the criterion validity of the TASS and the construct validity of the TASS and TCT-SCI. Participants and Methods: We evaluated 30 individuals with SCIs (age 63.8 ± 10.7 yrs, 17 with tetraplegia). To evaluate criterion validity, we calculated Spearman's rho between the TASS and the gold standard (the TCT-SCI). To determine construct validity, we used the following hypothesis testing approaches: ( i ) calculating Spearman's rho between each scale and the upper and lower extremity motor scores (UEMS, LEMS), the Walking Index for SCI-II (WISCI-II), and the motor score of the Functional Independence Measure (mFIM); and ( ii ) determining the cut-off point for identifying ambulators with SCIs (≥ 3 points on item 12 of Spinal Cord Independent Measure III) by a receiver operating characteristics analysis. Results: A moderate correlation was confirmed between the TASS and the TCT-SCI ( r  = 0.68). Construct validity was supported by six of the eight prior hypotheses. The cut-off points for identifying ambulators with SCIs were 26 points (TASS) and 18 points (TCT-SCI). Conclusion: Our results indicate that the contents of the TASS and the TCT-SCI might reflect the epidemiological characteristics of the populations in which they were developed.

Background: In familial adenomatous polyposis (FAP) patients, fundic gland polyps (FGPs) have been considered a risk factor for gastric neoplasms. We speculated that FGPs in FAP patients spread directionally from the greater to the lesser curvature of the gastric body and investigated the relationship between the distribution of FGPs and gastric neoplasm development., Methods: We extracted 195 FAP patients from two institutions and reviewed their medical records. Gastric polyposis was classified based on the FGP distribution (P0, no FGPs; P1, localized in the fundus or greater curvature of the gastric body; P2, spreading to the anterior or posterior wall; P3, involving the proximal half of the lesser curvature; and P4, spreading from P3 to the anal side of the lesser curvature)., Results: The 195 eligible patients were divided into the neoplasm group (n = 54, 28%) and the non-neoplasm group (n = 141, 72%). Overall, 24% of the patients were Helicobacter pylori (H. pylori)-positive. In the FGP distribution, the rate of patients with gastric neoplasm tended to increase significantly with each step towards an increasingly wide distribution from P0 to P4 in H. pylori-negative patients, but not in H. pylori-positive ones. In addition, in H. pylori-negative patients, the likelihood of neoplasm increased consistently from P0 to P4, with the highest odds ratio (95% confidence interval) at P4 of 14.1 (2.5-154.4). Furthermore, multivariate analysis showed P4 and Spigelman stage ≥III were significantly associated with gastric neoplasm development., Conclusion: FGP distribution was correlated with gastric neoplasm development in FAP patients., (© 2024. The Author(s) under exclusive licence to The International Gastric Cancer Association and The Japanese Gastric Cancer Association.)

Prenatal diagnosis of a true umbilical cord knot is challenging. However, prenatal diagnosis is clinically valuable because it allows preparation for fetal distress during labor. Here, we report a case of prenatal diagnosis of true umbilical cord knot, with a favorable delivery management., (© 2024 Wiley Periodicals LLC.)

Varkud satellite ribozyme (VS ribozyme) is a class of catalytic RNA with self-cleavage activity. The wild-type VS ribozyme has structural modularity with a relatively large catalytic module (H2-H6 elements) and a small substrate module (H1 element). The two modules can be dissected physically, and the substrate H1 RNA is recognized and then cleaved by the rest of the parent ribozyme serving as catalytic RNA. We characterized the catalytic properties of a bimolecular VS ribozyme developed and employed for an in-droplet evolution experiment of the VS ribozyme. We examined the effects of polyamines and several divalent metal ions. The results obtained in this study would be useful for the optimization of laboratory evolution of the VS ribozyme.

Background: Pulmonary nodules in patients with soft tissue sarcomas are likely pulmonary metastases, whereas synchronous primary pulmonary sarcomas are rare. Without surgery, determining whether a solitary pulmonary nodule is a primary or metastatic nodule is difficult. Herein, we report a rare case of a primary pulmonary sarcoma that presented synchronously with a primary dedifferentiated liposarcoma., Case Presentation: A 77-year-old man presented to another hospital with left inguinal swelling and a suspected recurrent inguinal hernia. Computed tomography revealed a left inguinal mass and pure-solid nodule in the left lung and the patient was referred to our hospital for detailed examination and treatment. The inguinal mass was pathologically diagnosed as a dedifferentiated liposarcoma using needle biopsy, whereas bronchoscopic biopsy revealed histological findings suggestive of a sarcoma; however, the primary site could not be determined. Positron emission tomography-computed tomography revealed no high-accumulation lesions except for the two sarcomas. We decided to perform surgery on both sarcomas for diagnostic and curative purposes. The surgical specimens showed that the two sarcomas were different. Based on the immunohistochemical staining findings of MDM2, a left inguinal dedifferentiated liposarcoma and primary pulmonary unclassified sarcoma were diagnosed. The patient displayed no evidence of recurrence 1 year after surgery., Conclusions: We encountered a rare case of synchronous multiple primary sarcomas, one presenting in the lung and the other in the soft tissue. Surgery was required to achieve a definitive diagnosis for the patient, who achieved disease-free survival at 1 year. This case suggests that proactive resection of pulmonary nodules in patients with soft tissue sarcomas may be feasible as a diagnostic treatment if complete resection is achieved., (© 2024. The Author(s).)

Objectives: The prognostic significance of a high visceral fat area (VFA) in metastatic colorectal cancer (mCRC) remains unclear. We evaluated the prognostic impact of high-VFA on the long-term outcomes of patients with mCRC who underwent chemotherapy., Methods: Ninety patients with metastatic CRC who underwent chemotherapy were included. VFA measurement was performed by pre-treatment computed tomography using image analysis system. Overall survival (OS) and progression-free survival (PFS) rates were analyzed using the Cox proportional hazards model and Kaplan-Meier curves with the log-rank test., Results: High-VFA was identified in 39 patients. The OS (2-year OS rates: 51.6% vs 33.3%, p=0.0023) and PFS rates (2-year PFS rates: 18.0% vs 2.7%, p=0.012) were significantly lower in the high-VFA group than in the low-VFA group. In multivariate analysis, the independent significant predictors of OS were carbohydrate antigen 19-9 (CA19-9) ≥37.0 U/mL (HR: 1.99, 95%CI [1.20-3.31], p=0.007), Glasgow prognostic score (GPS) of 1 or 2 (HR: 2.65, 95%CI [1.53-4.58], p<0.001), and high-VFA (HR: 3.09, 95%CI [1.81-5.25], p<0.001). Similarly, the independent significant predictors of PFS were CA19-9 ≥37.0 U/mL (HR: 2.02, 95%CI [1.21-3.38], p=0.007), GPS of 1 or 2 (HR: 1.87, 95%CI [1.17-2.99], p=0.008), and high-VFA (HR: 2.65, 95% CI [1.61-4.35], p<0.001)., Conclusions: We demonstrated that pre-treatment high-VFA and high-GPS were significantly associated with worse OS and PFS rates in patients with mCRC who underwent chemotherapy., Competing Interests: Conflicts of Interest There are no conflicts of interest., (Copyright © 2024 The Japan Society of Coloproctology.)

Sex differences in the development and progression of cardiovascular disease manifest across multiple life stages. These differences are associated with variations in cardiovascular morphology and function between the sexes. Although estrogens and sex hormones are associated with sex differences in cardiovascular diseases in reproductive adults, the molecular mechanisms of cardiovascular sex differences during development are largely unknown. Thus, we investigated sex differences in cardiovascular development. We employed a newly-developed coronary arteriogram system to visualize the morphology of the coronary arteries in murine anterior surface ventricles at embryonic day 17.5 by injecting nano-particle ink at a constant pressure. No sex difference was found in the length of ventricle. Based on the boundary value of the distribution of that length, the hearts were divided into "long" and "short" groups, and the diameters of the left coronary arteries were analyzed. The mean diameter of the coronary arteries was significantly smaller in females than in males only in the group with the longer length of ventricle. This ventricular size-specific sex difference was observed in the presence of vasodilators such as NOC7. When NOC7 was perfused into the left coronary arteries of embryonic day 17.5 mice, females with longer ventricles showed larger left coronary arteries than males. These sex differences in vasodilation capacity suggest that factors related to drug reactivity such as signaling pathways are present at a late embryonic stage. These results indicate that sex differences in the functional morphology of the left coronary arteries exist at a late embryonic stage in mice.

We measured intestinal fatty acid-binding protein (I-FABP) levels, a useful marker of small intestinal mucosal injury, in patients with cirrhosis to determine their relationship with liver function and complications. This cross-sectional study included 71 patients with cirrhosis admitted for treatment of cirrhotic complications or hepatocellular carcinoma (cohort A) and 104 patients with cirrhosis who received direct-acting antiviral therapy for HCV (cohort B). I-FABP levels, measured by ELISA, were evaluated relative to hepatic reserve and compared with non-invasive scoring systems for diagnostic performance in cirrhotic complications. The median I-FABP level in both cohorts were significantly elevated in patients with reduced hepatic reserve (CTP grade A/BC cohort A, 2.33/3.17 ng/mL, p = 0.032; cohort B, 2.46/3.64 ng/mL, p = 0.008) and complications with gastroesophageal varices (GEV; GEV (-)/(+) cohort A, 1.66/3.67 ng/mL, p < 0.001; cohort B, 2.32/3.36 ng/mL; p = 0.003). Further, multiple logistic regression analysis identified I-FABP as the only factor contributing to GEV presence in both cohorts, which outperformed non-invasive scoring systems for GEV diagnosis (sensitivity 84.6%; specificity 84.2%; sensitivity 69.6%; specificity 63.8%, respectively). In conclusion, elevated small-intestinal mucosal injury in patients with cirrhosis was related to reduced hepatic reserve and GEV presence. I-FABP levels reflect portal hypertension and may be useful in cirrhosis management., (© 2024. The Author(s).)

Hemorrhagic shock and resuscitation (HSR) enhances the risk of acute lung injury (ALI). This study investigated the protective effect of carbamazepine (CBZ) on HSR-induced ALI in rats. Male Sprague-Dawley rats were allocated into five distinct groups through randomization: control (SHAM), saline + HSR (HSR), CBZ + HSR (CBZ/HSR), dimethyl sulfoxide (DMSO) + HSR (DMSO/HSR), and CBZ + chloroquine (CQ) + HSR (CBZ/CQ/HSR). Subsequently, HSR models were established. To detect tissue damage, we measured lung histological changes, lung injury scores, and wet/dry weight ratios. We measured neutrophil counts as well as assessed the expression of inflammatory factors using RT-PCR to determine the inflammatory response. We detected autophagy-related proteins LC3II/LC3I, P62, Beclin-1, and Atg12-Atg5 using western blotting. Pretreatment with CBZ improved histopathological changes in the lungs and reduced lung injury scores. The CBZ pretreatment group exhibited significantly reduced lung wet/dry weight ratio, neutrophil aggregation and number, and inflammation factor (TNF-α and iNOS) expression. CBZ changed the expression levels of autophagy-related proteins (LC3II/LC3I, beclin-1, Atg12-Atg5, and P62), suggesting autophagy activation. However, after injecting CQ, an autophagy inhibitor, the beneficial effects of CBZ were reversed. Taken together, CBZ pretreatment improved HSR-induced ALI by suppressing inflammation, at least in part, through activating autophagy. Thus, our study offers a novel perspective for treating HSR-induced ALI., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Li et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

After traumatic events, simple cue-threat associative memories strengthen while episodic memories become incoherent. However, how the brain prioritises cue associations over episodic coding of traumatic events remains unclear. Here, we developed an original episodic threat conditioning paradigm in which participants concurrently form two memory representations: cue associations and episodic cue sequence. We discovered that these two distinct memories compete for physiological fear expression, reorganising overnight from an overgeneralised cue-based to a precise sequence-based expression. With multivariate fMRI, we track inter-area communication of the memory representations to reveal that a rebalancing between hippocampal- and prefrontal control of the fear regulatory circuit governs this memory maturation. Critically, this overnight re-organisation is altered with heightened trait anxiety. Together, we show the brain prioritises generalisable associative memories under recent traumatic stress but resorts to selective episodic memories 24 h later. Time-dependent memory competition may provide a unifying account for memory dysfunctions in post-traumatic stress disorders., (© 2024. The Author(s).)

Importance: There are 2 degree programs for licensed physicians in the US: allopathic medical doctorate (MD) and osteopathic doctorate (DO). However, evidence is limited as to whether outcomes differ between patients treated by MD vs DO surgeons., Objective: To evaluate differences in surgical outcomes and practice patterns by surgeon medical school training (MD vs DO)., Design, Setting, and Participants: This retrospective cohort study used 100% Medicare claims data from inpatient hospitals providing surgical services from January 1, 2016, to December 31, 2019 among Medicare fee-for-service beneficiaries aged 65 to 99 years who underwent 1 of the 14 most common surgical procedures. Data analysis was performed from January 17, 2023, to August 13, 2024., Exposure: Medical school degree (MD vs DO)., Main Outcomes and Measures: The primary outcome was 30-day mortality, and the secondary outcomes were readmissions and length of stay. To assess differences between surgeons by medical school training, a multivariable linear probability model was used, which was adjusted for hospital fixed effects and patient, procedure, and surgeon characteristics., Results: Of the 2 360 108 total surgical procedures analyzed, 2 154 562 (91.3%) were performed by MD surgeons, and 205 546 (8.7%) were performed by DO surgeons. Of 43 651 total surgeons, most surgeons were MDs (39 339 [90.1%]), the median (SD) age was 49.0 (9.8) years, and 6649 surgeons (15.2%) were female. The mean (SD) age of patients undergoing surgical procedures was 74.9 (6.7) years, 1 353 818 of 2 360 108 patients (57.4%) were female, and 2 110 611 patients (89.4%) self-reported as White. DO surgeons were significantly more likely to operate on older patients (DO patient mean [SD] age: 75.3 [7.1] years; MD patient mean [SD] age: 74.8 [6.6]), female patients (DO: 60.2% of patients; MD: 57.1% of patients), and Medicaid dual-eligible patients (DO: 10.3% of patients; MD: 8.6% of patients). DOs performed a lower proportion of elective operations (DO: 74.2% vs MD: 80.2%) and were more likely to work in public hospitals (DO: 10.3%; MD: 9.5%) and nonteaching hospitals (DO: 57.9%; MD: 68.1%). There was no evidence that 30-day mortality differed between MD and DO surgeons (adjusted mortality rate, DO: 1.61%; MD: 1.58%; absolute risk difference [aRD], -0.04 percentage points; 95% CI, -0.11 to 0.04; P = .37). On secondary analyses, no difference was found in 30-day readmissions or length of stay between MD and DO surgeons., Conclusions and Relevance: In this retrospective cohort study using Medicare data, there was no evidence that patient outcomes differed between MD and DO surgeons for common operations after adjusting for patient factors and practice settings.

Artificial intelligence (AI) holds significant potential for enhancing quality of gastrointestinal (GI) endoscopy, but the adoption of AI in clinical practice is hampered by the lack of rigorous standardisation and development methodology ensuring generalisability. The aim of the Quality Assessment of pre-clinical AI studies in Diagnostic Endoscopy (QUAIDE) Explanation and Checklist was to develop recommendations for standardised design and reporting of preclinical AI studies in GI endoscopy.The recommendations were developed based on a formal consensus approach with an international multidisciplinary panel of 32 experts among endoscopists and computer scientists. The Delphi methodology was employed to achieve consensus on statements, with a predetermined threshold of 80% agreement. A maximum three rounds of voting were permitted.Consensus was reached on 18 key recommendations, covering 6 key domains: data acquisition and annotation (6 statements), outcome reporting (3 statements), experimental setup and algorithm architecture (4 statements) and result presentation and interpretation (5 statements). QUAIDE provides recommendations on how to properly design (1. Methods, statements 1-14), present results (2. Results, statements 15-16) and integrate and interpret the obtained results (3. Discussion, statements 17-18).The QUAIDE framework offers practical guidance for authors, readers, editors and reviewers involved in AI preclinical studies in GI endoscopy, aiming at improving design and reporting, thereby promoting research standardisation and accelerating the translation of AI innovations into clinical practice., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: The aim of this article is to update evidence on the efficacy and safety of disease-modifying antirheumatic drugs (DMARDs) and provide information to the taskforce for the 2024 update of the Japan College of Rheumatology clinical practice guidelines for the management of rheumatoid arthritis (RA)., Methods: We searched various databases for randomised controlled trials on RA published until June 2022, with no language restriction. For each of the 15 clinical questions, two independent reviewers screened the articles, evaluated the core outcomes, and performed meta-analyses., Results: Subcutaneous injection of methotrexate (MTX) showed similar efficacy to oral MTX in MTX-naïve RA patients. Ozoralizumab combined with MTX improved drug efficacy compared to the placebo in RA patients with inadequate response (IR) to conventional synthetic DMARD (csDMARD). Rituximab with and without concomitant csDMARDs showed similar efficacy to other biological DMARDs (bDMARDs) in bDMARD-IR RA patients. Combined Janus kinase inhibitors and MTX achieved similar clinical responses and equal safety during a 4-year period compared to tumour necrosis factor inhibitors in MTX-IR RA patients. Biosimilars showed efficacy equivalent to that of the original bDMARDs in csDMARD-IR and bDMARD-IR RA patients., Conclusions: This systematic review provides latest evidence for the 2024 update of the Japan College of Rheumatology clinical practice guidelines for RA management., (© Japan College of Rheumatology 2024. Published by Oxford University Press.)

Objective: Infections are a critical concern for patients with microscopic polyangiitis (MPA). This study aimed to identify the risk factors associated with serious infections (SIs) and infection-related mortality in patients with MPA, as well as the effect of glucocorticoid (GC) dose tapering on these outcomes., Methods: This multicentre, retrospective, and observational study utilised data from a cohort of patients with MPA in Japan [Registry of Vasculitis Patients to Establish REAL World Evidence (REVEAL) cohort]. Patients were categorised based on the occurrence of SIs or infection-related deaths, and various characteristics were compared among the groups., Results: Among 182 patients, 66 (36.2%) experienced 129 SIs and 27 (14.8%) developed infection-related deaths. Advanced age, elevated C-reactive protein (CRP) levels, and higher ratio of the GC dose at 3 months to the initial dose were identified as independent risk factors for SIs. Older age was also associated with infection-related deaths. Furthermore, the cumulative incidence of infection-related deaths was significantly higher in patients with a higher ratio of the GC dose at 24 months to the initial dose., Conclusion: Older age, elevated CRP levels, and slower GC dose tapering predispose patients to SIs and infection-related deaths. Strategies, such as rapid GC dose tapering, are anticipated to mitigate the risk of infections., (© Japan College of Rheumatology 2024. Published by Oxford University Press.)

Monoclonal antibody drugs (mAb) are widely used to treat various diseases. Keeping quality of mAbs is crucial to maximize efficacy and minimize adverse effects. To this end, mAb content in the drug product must be precisely quantified. As methods for the determination of mAbs, absorbance measurement at 280 nm, the ligand binding assay based on ELISA, or the LC-MS/MS method based on the surrogate peptide approach is usually used. However, these methods have drawbacks in terms of selectivity, reliability, and cost, respectively. The present method is based on the surrogate peptide approach where a peptide specific to the mAb is determined by a post-column derivatization LC system with fluorescence detection and the König reaction, which is usually used for the detection of cyanide and its derivatives. The detection mechanism was the production of cyanide from the surrogate peptide by chloramine T and the generated cyanide was detected by the König reaction. In this study, adalimumab was used as a model target protein. The calculated LOD and LOQ of the present method were 0.31 μg/mL and 0.94 μg/mL, respectively. The intra-day accuracies and precisions were 127.1 % and 2.94 % for 5 μg of adalimumab and 101.6 % and 10.2 % for 50 μg of adalimumab, respectively. The inter-day accuracies and precisions were 121.8 % and 5.71 % for 5 μg of adalimumab and 101.8 % and 6.98 % for 50 μg of adalimumab, respectively. Our quantitatively determined amount of adalimumab in Humira® was in good agreement with the specified value. This method only requires a conventional LC system, not an LC-MS/MS system. By extending the application of the König reaction, we open the door to a new surrogate peptide approach for the determination of proteins including monoclonal antibody drugs., 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: The JCOG0802/WJOG4607L trial revealed superior overall survival in segmentectomy compared with lobectomy for small-peripheral NSCLC. Nevertheless, locoregional relapse (LR) is a major issue for segmentectomy. An ad hoc supplementary analysis aimed to determine the risk factors for LR and the degree of advantages of segmentectomy on the basis of primary tumor sites., Methods: Participants in multi-institutional and intergroup, open-label, phase 3 randomized controlled trial in Japan were enrolled from August 10, 2009, to October 21, 2014. Risk factors for LR after segmentectomy and clinical features following the primary tumor site were investigated., Results: Of 1105 patients, 576 and 529 underwent lobectomy and segmentectomy, respectively. The primary tumor site for segmentectomy was the left upper division, left lingular segment, left S6, left basal segment, right upper lobe, right S6, or right basal segment. Multivariable analysis in the segmentectomy group revealed that pure-solid appearance on thin-section computed tomography (OR = 3.230; 95% confidence interval [CI]: 1.559-6.690; p = 0.0016), margin distance less than the tumor size (OR = 2.682; 95% CI: 1.350-5.331; p = 0.0049), and male sex (OR = 2.089; 95% CI: 1.047-4.169; p = 0.0366) were significantly associated with LR. Patients with left lingular segment tumors (OR = 4.815; 95% CI: 1.580-14.672) tended to experience LR more frequently than those with left upper division tumors, although primary tumor sites were not statistically significant., Conclusions: Thin-section computed tomography findings and margin distance are important factors to avoid LR in segmentectomy., Competing Interests: Disclosure The authors declare no conflict of interest., (Copyright © 2024 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

This study aimed to address the diagnostic challenges in distinguishing between alcohol-related liver disease (ALD) and metabolic dysfunction-associated steatotic liver disease (MASLD). We utilized whole-slide imaging technology to conduct a comprehensive digital analysis of liver specimens collected from patients undergoing transplantation. This study included 36 and 17 patients with ALD and MASLD cirrhosis, respectively, who underwent transplantation at our institution. Digital slides were analyzed for fibrosis patterns using FibroNest™. Patient background characteristics were comparable between ALD (n = 36) and MASLD (n = 17) groups, except for sex. The ALD group exhibited thicker collagen per strand, longer and more flexural fibrosis, and a more heterogeneous distribution than the MASLD group. In patients with ALD and concomitant metabolic dysfunction, fiber distribution became relatively uniform, resembling MASLD. Application of the phenotypic fibrosis composite score achieved 100% sensitivity and specificity for ALD/MASLD diagnosis. Digital pathological analysis of the fibrosis patterns showed morphological differences between ALD and MASLD. This approach holds promise for histological differentiation, providing valuable insights beyond the current definitions based solely on alcohol intake. This study emphasizes the potential of digital pathology in refining the diagnostic criteria for hepatic disorders., (© 2024. The Author(s).)

Allogeneic hematopoietic stem cell transplantation from a female donor to a male recipient (female-to-male allo-HCT) is a well-established risk factor for chronic graft-versus-host disease (GVHD) and non-relapse mortality (NRM). The inferior outcomes of female-to-male allo-HCT are considered to be due to allo-immunity against H-Y antigens. However, the influence of minor histocompatibility antigens in haplo-identical allo-HCT remains to be elucidated. We investigated the impact of female-to-male allo-HCT according to the haplo-HCT subtype. In the post-transplant cyclophosphamide (PTCY) cohort (n = 660), a female-to-male sex-mismatch was significantly associated with a decreased risk of relapse (HR: 0.70 [95% CI: 0.49-0.99], P = 0.045), but not with overall survival (OS) or NRM (HR: OS 0.89 [95% CI: 0.68-1.16], P = 0.40; NRM 0.98 [95% CI: 0.68-1.41], P = 0.90). On the other hand, in the non-PTCY cohort (n = 219), a female-to-male sex-mismatch was associated with inferior risks of OS and NRM, but was not associated with relapse. These results suggested that the survival impact of the haplo-HCT subtype differed according to the presence of a sex-mismatch. PTCY might be feasible for overcoming the inferiority of female-to-male allo-HCT and might preserve a GVL effect against H-Y antigens., Competing Interests: Declaration of competing interest M.Tamaki received honoraria from Astella Pharma. H.Nakasone. received subsidies from JCR Pharmaceuticals, Kyowa Kirin, Terumo, Santen Pharmaceutical, Taiho Pharma, and honoraria from Takeda Pharmaceutical, Otsuka Pharmaceutical, Bristol-Myers Squibb, Pfizer, Novartis, Janssen Pharmaceutical, Eisai, Chugai Pharmaceutical, Meiji Seika Pharma, and Nippon Shinyaku., (Copyright © 2024 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.)

Background: Mepolizumab (MPZ) has demonstrated efficacy in clinical trials for eosinophilic granulomatosis with polyangiitis (EGPA); however, few studies compare the disease course between patients treated with MPZ (MPZ group) and those who were not treated with MPZ (non-MPZ group) in real-world settings., Objectives: This study aimed to compare the disease course and outcomes between the two groups and assess the long-term efficacy of MPZ in a multicenter cohort in Japan. Methods: We enrolled 113 EGPA patients registered in the cohort until June 2023. Data on clinical characteristics, disease activity, organ damage, treatments, and outcomes were retrospectively collected. To minimize potential confounding factors, we conducted propensity score matching (PSM)., Results: After PSM, 37 pairs of matched patients were identified. Clinical characteristics, including age at disease onset, sex, disease duration at last observation, antineutrophil cytoplasmic antibody positivity at disease onset, Birmingham Vasculitis Activity Score (BVAS) at disease onset, and Five-factor score at disease onset, were comparable between the groups. The median BVAS at the last observation was 0 in both groups; however, more cases in the non-MPZ group exhibited elevated BVAS, resulting in a significantly higher BVAS in the non-MPZ group at the last observation (median; MPZ group: 0, non-MPZ group: 0, p=0.028). The MPZ group had significantly lower glucocorticoid (GC) doses at the last observation (median; MPZ group: 4 mg/day, non-MPZ group: 5 mg/day, p=0.011), with a higher proportion achieving a GC dose ≤ 4 mg/day at the last observation (MPZ group: 51.4%, non-MPZ group: 24.2%, p=0.027). Three models of multivariable logistic regression analyses were performed to identify factors associated with GC doses ≤ 4 mg/day at the last observation. In all models, achieving a GC dose ≤ 4 mg/day was positively associated with MPZ administration and inversely associated with asthma at disease onset. Finally, we evaluated the survival rates between the groups, and the 5-year survival rates were significantly higher in the MPZ group compared to the non-MPZ group (MPZ group: 100%, non-MPZ group: 81.3%, p=0.012)., Conclusion: Mepolizumab not only contributes to disease activity control but also reduces the GC dose, which may lead to improved survival in EGPA patients., Competing Interests: RW received speaker fees from AbbVie, Asahi Kasei, Chugai, Eli Lilly, GSK, and UCB Japan, and research grants from AbbVie. SM received speaker fees from AbbVie, and research grants from Japan Intractable Diseases Research Foundation. TK received speaker fees from AbbVie, Bristol-Myers Squibb, Chugai, Eisai, Eli Lilly, and Pfizer. RH received speaker fees from AbbVie, Asahi Kasei, Bristol-Myers, Daiichi Sankyo, Eisai, Eli Lilly, GSK, Kissei, Pfizer, Tanabe Mitsubishi, and UCB Japan, and research grants from GSK. MH received speaker fees from Bristol Meyers, Chugai, Eisai, Eli Lilly, and Tanabe Mitsubishi, and research grants from AbbVie, Asahi Kasei, Astellas, Bristol Meyers, Eisai, Daiichi Sankyo, Eli Lilly, Novartis Pharma, and Taisho Toyama. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest., (Copyright © 2024 Shiomi, Watanabe, Matsuda, Kotani, Okazaki, Masuda, Yoshida, Shoji, Tsuge, Kadoba, Hiwa, Yamamoto, Takeda, Itoh and Hashimoto.)

Voltage-gated sodium channels, including Na V 1.7, Na V 1.8, and Na V 1.9, play important roles in pain transmission and chronic pain development. However, the specific mechanisms of their action remain unclear, highlighting the need for in vivo stimulation studies of these channels. Optogenetics, a novel technique for targeting the activation or inhibition of specific neural circuits using light, offers a promising solution. In our previous study, we used optogenetics to selectively excite Na V 1.7-expressing neurons in the dorsal root ganglion of mice to induce nocifensive behavior. Here, we further characterize the impact of nocifensive behavior by activation of Na V 1.7, Na V 1.8, or Na V 1.9-expressing neurons. Using CRISPR/Cas9-mediated homologous recombination, Na V 1.7-iCre, Na V 1.8-iCre, or Na V 1.9-iCre mice expressing iCre recombinase under the control of the endogenous Na V 1.7, Na V 1.8, or Na V 1.9 gene promoter were produced. These mice were then bred with channelrhodopsin-2 (ChR2) Cre-reporter Ai32 mice to obtain Na V 1.7-ChR2, Na V 1.8-ChR2, or Na V 1.9-ChR2 mice. Blue light exposure triggered paw withdrawal in all mice, with the strongest response in Na V 1.8-ChR2 mice. These light sensitivity differences observed across Na V 1.x-ChR2 mice may be dependent on ChR2 expression or reflect the inherent disparities in their pain transmission roles. In conclusion, we have generated noninvasive pain models, with optically activated peripheral nociceptors. We believe that studies using optogenetics will further elucidate the role of sodium channel subtypes in pain transmission., (© 2024 The Author(s). Journal of Neuroscience Research published by Wiley Periodicals LLC.)

Robot-assisted surgery for congenital biliary dilatation has been evolving primarily with the da Vinci® Surgical System. The hinotori™ Surgical Robot System, developed in Japan, received approval for gastroenterological surgery in 2022. We present the inaugural case of congenital biliary dilatation surgery utilizing the hinotori™ system. A 57-year-old woman was referred to our institution for evaluation and treatment of common bile duct dilatation classified under Todani Type Ia congenital biliary dilatation. Robotic resection of the extrahepatic bile duct and hepaticojejunostomy with Roux-en-Y were performed. The operation lasted 292 min with minimal blood loss (10 mL). The patient had an uneventful postoperative course and was discharged 10 days after surgery. Robotic surgery using the hinotori™ system for congenital biliary dilatation can be safely performed., (© 2024 Asia Endosurgery Task Force and Japan Society of Endoscopic Surgery and John Wiley & Sons Australia, Ltd.)

Damaged mitochondria are selectively eliminated in a process called mitophagy. PINK1 and Parkin amplify ubiquitin signals on damaged mitochondria, which are then recognized by autophagy adaptors to induce local autophagosome formation. NDP52 and OPTN, two essential mitophagy adaptors, facilitate de novo synthesis of pre-autophagosomal membranes near damaged mitochondria by linking ubiquitinated mitochondria and ATG8 family proteins and by recruiting core autophagy initiation components. The multifunctional serine/threonine kinase TBK1 also plays an important role in mitophagy. OPTN directly binds TBK1 to form a positive feedback loop for isolation membrane expansion. TBK1 is also thought to indirectly interact with NDP52; however, its role in NDP52-driven mitophagy remains largely unknown. Here, we focused on two TBK1 adaptors, AZI2/NAP1 and TBKBP1/SINTBAD, that are thought to mediate the TBK1-NDP52 interaction. We found that both AZI2 and TBKBP1 are recruited to damaged mitochondria during Parkin-mediated mitophagy. Further, a series of AZI2 and TBKBP1 knockout constructs combined with an OPTN knockout showed that AZI2, but not TBKBP1, impacts NDP52-driven mitophagy. In addition, we found that AZI2 at S318 is phosphorylated during mitophagy, the impairment of which slightly inhibits mitochondrial degradation. These results suggest that AZI2, in concert with TBK1, plays an important role in NDP52-driven mitophagy., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: There are often discrepancies in the evaluation of disease activity between patients and physicians in systemic lupus erythematosus (SLE). In this study, we examined the factors that affect those evaluations., Methods: Physician visual analogue scale (Ph-VAS), patient VAS (Pt-VAS), Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2k), glucocorticoid (GC) usage and dose, age, Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index, and three patient-reported outcomes (SLE symptom checklist [SSC], short-form 36 questionnaire [SF-36], and LupusPRO) were obtained from a study performed in 2019 using 225 SLE outpatients of the Kyoto Lupus Cohort at Kyoto University Hospital. Correlations among Ph-VAS, Pt-VAS, or dif (Pt-VAS-Ph-VAS) (Pt-VAS minus Ph-VAS) and other factors were examined., Results: We found a significant discrepancy between Pt-VAS (median 38.0 mm) and Ph-VAS (median 18.7 mm) scores ( p < 0.001). SSC score showed a significant correlation with Pt-VAS and dif (Pt-VAS-Ph-VAS) ( p < 0.001). Among SSC items, fatigue showed the most significant correlation with dif (Pt-VAS-Ph-VAS). We also showed that higher dif (Pt-VAS-Ph-VAS) was associated with lower quality of life (QOL) evaluated by SF-36 and LupusPRO., Conclusions: Pt-VAS scores tended to be higher than Ph-VAS scores, and the discrepancy was influenced mainly by fatigue. Higher dif (Pt-VAS-Ph-VAS) was associated with lower patient QOL., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: MH received research grants and/or speaker fee from Abbvie, Asahi Kasei, Astellas, Brystol Meyers, Chugai, EA Pharma, Eisai, Daiichi Sankyo, Eli Lilly, Novartis Pharma, Taisho Toyama, Tanabe Mitsubishi. K.U. received a research and/or speaker fee from Sumitomo Pharma, outside the submitted work. A.O. received a research and/or speaker fee from Daiichi-Sankyo, AbbVie G.K., Chugai Pharmaceutical Co. Ltd, Eli Lilly Japan, GSK, Mitsubishi Tanabe, Asahi Kasei Pharma and Pfizer Inc. R.W. received a research grant from AbbVie and speaker’s fee from Asahi Kasei, Chugai, Eli Lilly, and GSK. K.K. received a research and/or speaker fee from GSK K. K. R.N received a research and/or speaker fee from Takeda and Medical & Biological Laboratories Co. Ltd, Bristol-Myers Squibb, Astellas Pharma, Boehringer Ingelheim, Actelion Pharmaceuticals, and Mitsubishi Tanabe Pharma, outside the submitted work. H.Y. has received a research grant from GSK and honoraria from Chugai, unrelated to this work. R.U. received personal fees from Eisai, Sawai Pharmaceutical, Statcom, SAS Institute Japan, and EPS Corporation, outside the submitted work. M.T. received a research and/or speaker fee from AbbVie G.K., Asahi Kasei Pharma Corp., Astellas Pharma Inc., Ayumi Pharmaceutical Corp., Bristol-Myers Squibb, Chugai Pharmaceutical Co. Ltd, Eisai Co., Ltd, Eli Lilly Japan K. K., Pfizer Inc., UCB Japan Co. Ltd, Janssen Pharmaceutical K. K., Mitsubishi Tanabe Pharma Corp., Novartis Pharma K. K., Taisho Pharma Co. Ltd. K.O. received research grants and/or speaker’s fees from AbbVie, Actelion, Asahikasei Pharma, Astellas, AYUMI, Bristol-Myers Squibb, Chugai, Daiichi-Sankyo, Eisai, Eli Lilly, GSK, Janssen, JB, Mitsubishi Tanabe, Nippon Kayaku, Nippon Shinyaku, Novartis, Sanofi, and Takeda while the present study was being performed. A.M. received research grants and/or speaker’s fees from Eli Lilly Japan K.K., Ono Pharmaceutical Co., Pfizer Inc., UCB Japan, AbbVie G.K., Asahi Kasei Pharma., and Chugai Pharmaceutical Co. Ltd. M.T. and M.H. and A. O are in the endowed chair and are funded by two local governments in Japan (Nagahama City, Shiga and Toyooka City, Hyogo) and five pharmaceutical companies (Mitsubishi Tanabe Pharma Corp., Chugai Pharmaceutical Co. Ltd, Ayumi Pharmaceutical Corp., Asahi Kasei Pharma Corp., and UCB Japan Co. Ltd). H.D., Y.T., R.I., T.K., T.Y., T.I., M.T., M.T., Y.T., M.S., H.O., H.T., S.A., K.M., W.Y., and T.I. declared no conflicts of interest. The sponsors were not involved in the study design; the collection, analysis, and interpretation of data; writing this manuscript; or the decision to submit the article for publication. The authors, their immediate families, and any research foundations with which they are affiliated have not received any financial payment or other benefits from any commercial entity related to the subject of this article.

Aim: The association between out-of-hospital cardiac arrest (OHCA) and the appropriate provision of public access defibrillation (PAD) remains unclear. This study aimed to evaluate the factors associated with whether or not PAD was provided., Methods: This retrospective cohort study utilized the All-Japan Utstein and Emergency Transport Registries in 2021. We included OHCA patients who were applied to automated external defibrillators (AEDs) by bystanders and were deemed eligible for defibrillation by an AED. We defined PAD provided or no PAD provided based on bystander defibrillation. Multivariable logistic regression analysis with the Firth bias adjustment method was employed to estimate the adjusted odds ratios (AORs) and 95% confidence intervals (CIs) for the exploratory evaluation of factors associated with PAD provided., Results: 1949 patients were eligible for analysis (PAD provided, n = 1696 [87.0%]; no PAD provided, n = 253 [13.0%]). Factors positively associated with PAD provided were male (AOR [95% CI], 1.61 [1.17-2.21]; vs. female), other public place incidence (AOR [95% CI], 10.65 [1.40-1367.54]; vs. public place), non-family member witnessed (AOR [95% CI], 2.51 [1.86-3.42]; vs. unwitnessed) and conventional cardiopulmonary resuscitation (CPR), (AOR [95% CI], 1.75 [1.17-2.67]; vs. hands-only CPR). Conversely, factors negatively associated with no PAD provided were over 65 years old (AOR [95% CI], 0.48 [0.28-0.80]; vs. 19-64 yr), night-time onset (AOR [95% CI], 0.61 [0.45-0.83]; vs. daytime), non-cardiogenic (AOR [95% CI], 0.43 [0.31-0.61]; vs. cardiogenic), home setting (AOR [95% CI], 0.33 [0.14-0.83]; vs. public place), healthcare facility setting (AOR [95% CI], 0.40 [0.23-0.66]; vs. public place), no bystander CPR (AOR [95% CI], 0.31 [0.14-0.71]; vs. hands-only CPR), and dispatcher-assistance (AOR [95% CI], 0.72 [0.53-0.97]; vs. no dispatcher-assistance)., Conclusion: Male patients, other public place onset, witnessed by non-family and conventional CPR were associated with PAD provide. Therefore, training skilled first responders to use AEDs appropriately is necessary., 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.)

Aim: Peripheral artery disease (PAD) severely impairs patient prognosis and quality of life (QOL). Although lipoprotein apheresis (LA) has been applied to patients with PAD and elevated serum atherogenic lipoproteins, we hypothesized that LA can be effective for treating PAD even in patients with controlled serum lipoproteins through pleiotropic anti-atherosclerotic effects beyond lipoprotein removal. This study aimed to evaluate the efficacy of LA in patients with treatment-resistant PAD and controlled serum lipoproteins focusing on QOL., Methods: In a single-arm prospective study, 30 patients with refractory PAD who had controlled serum lipoproteins underwent sequential LA sessions using dextran sulfate adsorption columns, aiming to complete 10 sessions. The ankle-brachial pressure index (ABI) and vascular QOL (VascuQOL) score were evaluated as the primary outcomes. Secondary outcomes included reactive hyperemia index (RHI) and biological antioxidant potential (BAP) as an endothelial function test and serum antioxidative-capacity evaluation, respectively., Results: ABI significantly increased after LA sessions (pre-treatment 0.60±0.09 vs. post-treatment 0.65±0.13, p=0.023). Total VascuQOL score (3.7±1.1 vs 4.6±1.1, p＜0.001) and RHI (1.70±0.74 vs 2.34±1.76, p=0.023) significantly improved after the LA sessions. BAP tended to increase after the LA sessions, and the change reached statistical significance 3 months after treatment., Conclusion: ABI and QOL improved after a series of LA sessions in conventional treatment-resistant PAD patients with controlled serum lipoprotein levels. Increased antioxidative capacity and ameliorated endothelial function were observed after the LA treatment.

Background: Endoscopic resection (ER) is a minimally invasive treatment for esophageal cancer that sometimes causes complications. To understand the real-world incidence and risk factors for these complications, a nationwide survey was conducted across Japan., Methods: This retrospective multicenter study included patients who underwent ER for esophageal cancer from April 2017 to March 2018 (2017 complication analysis) and April 2021 to March 2022 (2021 complication analysis). The study assessed the complication rates and conducted risk factor analyses for endoscopic submucosal dissection (ESD) using data for these patients, with exclusions based on specific criteria to ensure data accuracy., Results: In the 2021 complication analysis, there were two mortalities highly likely attributable (0.03%) to ER and one mortality possibly attributable (0.01%) to ER. Intraoperative perforation, delayed bleeding, and pneumonia occurred in 137 cases (1.8%), 44 cases (0.6%), and 130 cases (1.7%), respectively. In the multivariate analysis for complications after ESD, low ER volume of the facility was an independent risk factor for perforation, while lesion location in the cervical or upper thoracic esophagus was an independent factor for reduced risk of perforation. Age ≥ 80 years was a risk factor for pneumonia, while use of traction techniques was a factor for reduced risk of pneumonia. Lesions located in the middle thoracic esophagus had a lower risk of stricture, and the risk of stricture increased as the circumferential extent of the lesion increased., Conclusions: This large-scale study provided detailed insights into the complications associated with esophageal ER and identified significant risk factors., (© 2024. The Author(s) under exclusive licence to The Japan Esophageal Society.)

A 74-year-old Japanese male with lung squamous cell carcinoma received his first dose of immune checkpoint inhibitors (ICIs): ipilimumab and nivolumab. He developed acute kidney injury (AKI) and was admitted to our department. We diagnosed kidney immune-related adverse effects (irAE), and a kidney biopsy revealed acute tubulointerstitial nephritis. We started oral prednisolone (PSL) and his AKI immediately improved. The patient maintained stable findings after PSL was tapered off. However, seven months after the ICI administration, he developed rapid progressive glomerular nephritis and was admitted to our department again. The second kidney biopsy showed findings consistent with anti-glomerular basement membrane glomerulonephritis. Although the patient was treated with pulse methylprednisolone followed by oral PSL and plasma exchange, he became dependent on maintenance hemodialysis. To our knowledge, no case report has described two different types of biopsy-proven nephritis. In cases of suspected relapsing kidney irAEs, both a relapse of previous nephritis and the development of another type of nephritis should be considered., (© 2024. The Author(s), under exclusive licence to Japanese Society of Nephrology.)

Objectives: To elucidate the association between genetic variants and the risk of GCA via large-scale genome-wide association studies (GWAS). In addition, to assess the causal effect of a specific molecule by employing the obtained GWAS results as genetic epidemiological tools., Methods: We applied additional variant quality control to the publicly available GWAS results from the biobanks of the UK (UKBB) and Finland (FinnGen), which comprised 532 cases vs 408 565 controls and 884 cases vs 332 115 controls, respectively. We further meta-analysed these two sets of results. We performed two-sample Mendelian randomization (MR) to test the causal effect of low-density lipoprotein (LDL) cholesterol on the risk of GCA., Results: The MHC class II region showed significant associations in UKBB, FinnGen and the meta-analysis. The VLDLR region was associated with GCA risk in the meta-analysis. The T allele of rs7044155 increased the expression of VLDLR, decreased the LDL cholesterol level and decreased the disease risk. The subsequent MR results indicated that a 1 s.d. increase in LDL cholesterol was associated with an increased risk of GCA (odds ratio 1.21, 95% CI 1.01-1.45; P = 0.04)., Conclusions: Our study identified associations between GCA risk and the MHC class II and VLDLR regions. Moreover, LDL cholesterol was suggested to have a causal effect on the risk of developing GCA., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Epigenetic alterations critically affect tumor development. Polycomb-group complexes constitute an evolutionarily conserved epigenetic machinery that regulates stem cell fate and development. They are implicated in tumorigenesis, primarily via histone modification. Polycomb repressive complex 1 (PRC1) complexes 1-6 (PRC1.1-6) mediate the ubiquitination of histone H2A on lysine 119 (H2AK119ub). Here, we studied the functional roles of a PRC1.6 molecule, L3MBTL2, in neuroblastoma (NB) cells. L3MBTL2-knockout and knockdown revealed that L3MBTL2 depletion suppressed NB cell proliferation via cell-cycle arrest and gamma-H2A.X upregulation. L3MBTL2-knockout profoundly suppressed xenograft tumor formation. Transcriptome analysis revealed suppressed cell-cycle-related and activated differentiation-related pathways. Break repair meiotic recombinase recruitment factor 1 (BRME1) and nuclear receptor interacting protein 3 (NRIP3) were notably de-repressed by L3MBTL2-knockout. The deletion of L3MBTL2 reduced enrichment of H2AK119ub and PCGF6 at transcriptional start site proximal regions of the targets. Add-back studies unveiled the importance of L3MBTL2-BRME1 and -NRIP3 axes for NB cell proliferation. We further manifested the association of MYCN with de-repression of NRIP3 in an L3MBTL2-deficient context. Therefore, this study first revealed the significance of L3MBTL2-mediated gene silencing in MYCN-amplified NB cells., (© 2024 Molecular Biology Society of Japan and John Wiley & Sons Australia, Ltd.)

Objective: Segmentectomy and mediastinal lymph node dissection (LND) may increasingly be used for non-small cell lung cancer (NSCLC). Lymph node metastasis (LNM) distribution varies by lower lobe segments; however, its segment-specific spread to the lower zone (#8, 9) (LZ) in lower lobe NSCLC is seldom reported., Methods: In total, 352 patients with clinical T1 lower lobe NSCLC who underwent lobectomy with systematic or lobe-specific LND were included for analysis between January 2006 and December 2018., Results: Fifty-eight (16.2%) patients had LNM (pN1: 24, pN2: 34), and nine (2.6%) had LZ metastasis. LZ metastasis was significantly more frequent in tumors with diameter > 2 cm, tumors without ground-glass opacity on radiological findings, left lung cancer, and basal segment lung cancer (respectively, p = 0.039, 0.006, 0.0177, 0.0024). None of the S6 NSCLC patients had LZ metastasis. Two patients with right basal segment NSCLC had LZ metastases (tumor on S10) as well as N1 lymph node and subcarinal zone metastasis. Seven (8.4%) patients with left basal segment NSCLC had LZ metastasis (tumor on S8: 3, tumor on S10: 4). Of them, three patients with left basal NSCLC had isolated LZ metastasis., Conclusions: The LND of the LZ can be omitted for clinical T1 patients with S6 NSCLC. In addition, the LND of the LZ may be omitted in right basal NSCLC if intraoperative confirmation of negative N1 and subcarinal zone lymph nodes is obtained; however, it is necessary for left basal segment NSCLC., (© 2024. The Author(s), under exclusive licence to The Japanese Association for Thoracic Surgery.)

Introduction There are several postoperative evaluation methods for anterior cruciate ligament reconstruction (ACLR), and patient-reported outcome measurement (PROM) is one of the most important for evaluating postoperative clinical results. However, conventional PROMs have a high risk of a ceiling effect at one and two years postoperatively and do not accurately reflect functional improvement over time. Therefore, a longitudinal evaluation using PROM with a low risk of ceiling effect is necessary. The forgotten joint score-12 (FJS) was developed for clinical evaluation after arthroplasty. It is considered an evaluation method after arthroplasty with a low risk of demonstrating a ceiling effect. However, few studies have used the FJS as an evaluation method after ACLR, particularly those tracking changes over time. This study aimed to longitudinally evaluate FJS at one and two years after ACLR. Methods This is a retrospective observational study of postoperative patients using existing data and a questionnaire-based survey. This study included patients who underwent primary double-bundle ACLR between August 2017 and August 2021. We compared the FJS, knee injury and osteoarthritis outcome score (KOOS), and Lysholm knee scale (LKS) scores at one and two years post-surgery using the Wilcoxon signed-rank test. The ceiling effect for each PROM was calculated at one and two years post-surgery. A ceiling was defined as obtaining a perfect score in PROMs, and the risk of demonstrating a ceiling effect was the percentage of perfect scores among all cases. The risk of demonstrating a ceiling effect for each PROM was compared using the McNemar test. To identify factors influencing FJS one-year post-ACLR across all cases, multivariate linear regression analysis was conducted for the FJS.  Results Finally, 87 patients were included in this study. Fifty-six participants were women, and 31 were men, with an average age of 28.5 ± 11.8 years at the time of surgery and a BMI of 23.2 ± 3.7 kg/m 2 . Fifty-eight patients with meniscus injuries requiring treatment were observed. A total of 54 patients were used to compare the results at one and two years, while 87 patients were included in the multivariate analysis for FJS at one year. The median of FJS at one and two years post-surgery were 90.6 and 95.8, respectively. The FJS showed a statistically significant improvement from one to two years (p = 0.033). Question #12 in FJS showed a significant improvement from the first to the second year postoperatively (1.74 ± 1.46 vs 1.15 ± 1.25 at one year vs two years, respectively; p = 0.0016). FJS had a lower risk of demonstrating a ceiling effect than KOOS ADL at one and two years (FJS vs KOOS ADL; at first year: 20.4% and 48.1%, p < 0.001; at second year: 33.3% and 63.0%, p = 0.0013). There was no difference compared to the other PROMs. According to the multivariate linear regression analysis, predictive factors for higher FJS scores at one year post-surgery were younger age and limb symmetry index of single-leg hop test(SLH-LSI) on the affected side that was close to that of the healthy side (SLH-LSI > 0.9). Conclusions The FJS continued to improve over two years after ACLR. The FJS post-ACLR was higher in younger individuals and those with SLH-LSI of 0.9 or higher., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. The Institutional Review Board of Chiba University issued approval M10379. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Sakamoto et al.)

Objective Patients undergoing maintenance dialysis are at a higher risk of morbidity and mortality due to severe coronavirus disease 2019 (COVID-19) than the general population. However, longitudinal data regarding this subpopulation of patients are lacking. We therefore examined the prognosis of patients with COVID-19 undergoing maintenance dialysis between 2020 and 2023. In addition, we explored the factors correlated with COVID-19 severity, focusing on the transition thereof throughout the observational period. Methods The primary outcome was the progression to severe or fatal COVID-19. We evaluated the correlation between the primary outcome and baseline demographic and clinical characteristics of patients. Patients undergoing maintenance dialysis who were hospitalized for mild-to-moderate COVID-19 between February 2020 and April 2023 were enrolled at four institutions in Kanagawa, Japan. Results Of the 173 patients, 7 (4.0%) developed severe COVID-19, and 12 (6.9%) died. The severe/death cohort was significantly older, with a higher percentage of unvaccinated patients than the non-severe cohort (58.2% and 25.0%, respectively; p=0.016). Thymus and activation-regulated chemokine levels on admission were lower in the severe/death cohort than in the non-severe cohort, albeit not to a statistically significant degree (148±84 mg/dL and 342±657 pg/mL, respectively; p=0.082). A multivariate logistic regression analysis revealed that the odds ratio for severe morbidity or death was 0.23 (95% confidence interval: 0.07-0.75) for vaccinated patients. Conclusion In patients undergoing maintenance dialysis, the severity rate of COVID-19 is approximately 10%. Vaccination was correlated with a reduced risk of severe COVID-19.

Background Artificial intelligence (AI) has made remarkable progress in image recognition using deep learning systems and has been used to detect esophageal squamous cell carcinoma (ESCC). However, all previous reports were not investigated in clinical settings, but in a retrospective design. Therefore, we conducted this trial to determine how AI can help endoscopists detect ESCC in clinical settings. Methods This was a prospective, single-center, exploratory, and randomized controlled trial. High-risk patients with ESCC undergoing screening or surveillance esophagogastroduodenoscopy were enrolled and randomly assigned to either the AI or control group. In the AI group, the endoscopists watched both the AI monitor detecting ESCC with annotation and the normal monitor simultaneously, whereas in the control group, the endoscopists watched only the normal monitor. In both groups, the endoscopists observed the esophagus using white-light imaging (WLI), followed by narrow-band imaging (NBI) and iodine staining. The primary endpoint was the enhanced detection rate of ESCC by non-experts using AI. The detection rate was defined as the ratio of WLI/NBI-detected ESCCs to all ESCCs detected by iodine staining. Results A total of 320 patients were included in this analysis. The detection rate of ESCC in non-experts was 47% in the AI group and 45% in the control group (p=0.93), with no significant difference, was similar to that in experts (87% vs. 57%, p=0.20) and all endoscopists (57% vs. 50%, p=0.70). Conclusions This study could not demonstrate an improvement in the esophageal cancer detection rate using the AI diagnostic support system for ESCC., Competing Interests: Toshiaki Hirasawa has received a honoraria for lecture from AI Medical Service Inc. out of this study. Tomohiro Tada is a shareholder in AI Medical Service Inc. Other authors do not have any conflict of interest relevant to this study., (Thieme. All rights reserved.)

Background: The practice of endoscopic diagnosis of esophageal squamous cell carcinoma (ESCC) often diverges from evidence-based standards due to various factors, including inadequate dissemination of evidence or a mismatch between evidence and real-world contexts. This survey aimed to identify discrepancies between evidence-based standard practices and community standard practices for ESCC among endoscopists., Methods: An online survey targeting endoscopists who perform upper gastrointestinal endoscopy at least weekly was conducted to collect data on clinical practices related to ESCC diagnosis. The survey, comprising 20 questions, was disseminated through multiple professional networks. Descriptive statistical analysis and logistic regression were performed to analyze the data., Results: Data from 819 endoscopists were included in the analyses. Notably, a significant proportion employed narrow-band imaging/blue-laser imaging over iodine staining, and preferences varied based on risk assessment for ESCC. In total, 64.0% of endoscopists primarily used iodine solution at a concentration of 1% or less, while 96.5% of endoscopists performed an observation of the oral cavity and the pharynx when conducting upper gastrointestinal endoscopies on individuals at high risk of ESCC. The surveillance interval for metachronous multiple ESCCs was most commonly every 6 months, followed by every 12 months. In addition, most physicians conducted surveillance of metastatic recurrence at 6-month intervals., Conclusions: This survey highlights significant gaps between evidence-based and community standard practices in the endoscopic diagnosis of ESCC. These findings underscore the need for enhanced dissemination of evidence-based guidelines and consideration of real-world clinical contexts to bridge these gaps and optimize patient care., (© 2024. The Author(s) under exclusive licence to The Japan Esophageal Society.)

Introduction: The risk of post-traumatic osteoarthritis remains high even after anterior cruciate ligament reconstruction (ACLR). Medial meniscal extrusion (MME) is a valuable clinical sign as an early morphological change. This study aimed to analyze MME before and after ACLR and investigate the factors affecting postoperative MME., Materials and Methods: This study included patients who underwent anatomical double-bundle ACLR between January 2016 and July 2021. MME was measured using MRI preoperatively and one year postoperatively. The medial meniscus (MM) treatments were categorized into three groups: no MM injury and no repair (no injury/no repair (N/N)), MM injury but no repair (injury/no repair (I/N)), and MM injury and repair (injury/repair (I/R)). We investigated the factors influencing MME after ACLR using multiple linear regression analysis and compared MME before and after ACLR using paired t-tests., Results: This study included 133 patients, of whom 90 (37 males and 53 females) were analyzed. The mean age of the patients at surgery was 27.5 years, and 41, 27, and 22 patients were assigned into N/N, I/N, and I/R groups, respectively. Preoperative MME (p<0.001) and I/R (p<0.001) had significant effects on postoperative MME in a regression analysis. Postoperative MME had greater effects than the preoperative MME in all cases (1.16 and 1.53 mm (p<0.01)) and in every MM treatment group (N/N: 1.02 and 1.32 mm (p<0.01), I/N: 1.16 and 1.44 mm (p<0.01), and I/R: 1.42 and 2.05 mm (p<0.001))., Conclusions: Larger preoperative MME and receiving MM repair were significantly associated with a larger MME after ACLR. Postoperative MME in ACLR patients was significantly greater than preoperative MME., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Research Ethics Committee of the Graduate School of Medicine, Chiba University issued approval M10436. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Ito et al.)

The EML4-ALK oncogene is a fusion of the EML4 and ALK genes and is found in approximately 5-6% of the cases of non-small cell lung cancer (NSCLC). Herein, we present a unique case of lung adenocarcinoma with metastases to the bilateral ovaries harboring a rare EML4-ALK fusion gene variant in a 52-year-old patient. The patient had initially received a diagnosis of ovarian cancer, then had undergone neo-adjuvant chemotherapy followed by a surgical resection. Despite two cycles of adjuvant chemotherapy consisting of carboplatin and gemcitabine, CT revealed that the pleural effusion had increased from it before chemotherapy, and the shortness of breath worsened. Molecular profiling revealed an EML4-ALK rearrangement containing ALK -EML4 and ALK -NPR2 fusion genes. The diagnosis was changed to primary lung adenocarcinoma with metastases to the bilateral ovaries based on a pathological reevaluation. Treatment with alectinib, a second-generation ALK-tyrosine kinase inhibitor, led to a partial response of 18 months' duration, and the shortness of breath improved. No adverse events related to the alectinib therapy occurred. To assess the unique structure of the fusion genes, RNA sequencing was performed. An intronic sequence from both ALK and EML4 was found between ALK and EML4 exon, possibly because of an unusual insertion of a gene fragment derived from NRP2 , indicated by the panel sequencing results. Variations in the drug response among EML4-ALK fusion variants highlight the importance of understanding their molecular structure. Further investigation is warranted to refine fusion gene detection methods and assess the therapeutic implications of rare fusion variants., Competing Interests: M.Y. received honoraria (lecture fee) from AstraZeneca, Takeda, MSD, Chugai Pharmaceutical, Ono Pharmaceutical, and Bristol-Myers Squibb. M.K. received honoraria (lecture fee) from AstraZeneca and Chugai Pharmaceutical. Y. H. received honoraria (lecture fee) from AstraZeneca, Eli Lilly Japan, Taiho Pharmaceutical, Chugai Pharmaceutical, Ono Pharmaceutical, Bristol-Myers Squibb, Kyowa Kirin, Nippon Kayaku, Takeda, Eisai, Novartis, Pfizer and MSD. The other authors declare that they have no conflicts of interest., (© 2024 Maruta et al.)