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Abstract Background Surgical resection is standard treatment for invasive intraductal papillary mucinous carcinoma (IPMC); however, impact of multidisciplinary treatment on survival including postoperative adjuvant therapy (AT), neoadjuvant therapy (NAT), and treatment for recurrent lesions is unclear. We investigated the effectiveness of multidisciplinary treatment in prolonging survival of patients with invasive IPMC. Methods This retrospective multi‐institutional study included 1183 patients with invasive IPMC undergoing surgery at 40 academic institutions. We analyzed the effects of AT, NAT, and treatment for recurrence on survival of patients with invasive IPMC. Results Completion of the planned postoperative AT for 6 months improved the overall survival (OS), disease‐specific survival (DSS), and recurrence‐free survival (RFS) of patients with stage IIB and stage III resected invasive IPMC, elevated preoperative carbohydrate antigen 19–9 level, lymphovascular invasion, perineural invasion, serosal invasion, and lymph node metastasis on un‐matched and matched analyses. Of the patients with borderline resectable (BR) invasive IPMC, the OS (p = 0.001), DSS (p = 0.001), and RFS (p = 0.001) of patients undergoing NAT was longer than that of those without on the matched analysis. Of the 484 invasive IPMC patients (40.9%) who developed recurrence after surgery, the OS of 365 patients who received any treatment for recurrence was longer than that of those without treatment (40.6 vs. 22.4 months, p

Abstract Aims The incidence and prognosis of symptomatic heart failure following acute myocardial infarction (AMI) in the primary percutaneous coronary intervention era have rarely been reported in the literature. This study aimed to (i) determine the incidence of heart failure admission among AMI survivors, (ii) compare 1 year outcomes between patients with heart failure admission and those without, and (iii) identify the independent risk factors associated with heart failure admission. Methods and results The Japan Acute Myocardial Infarction Registry is a prospective multicentre registry from which data on consecutively enrolled patients with AMI from 50 institutions between 2015 and 2017 were obtained. Among the 3411 patients enrolled, 3226 who survived until discharge were included in this study. The primary endpoint was all‐cause mortality. The secondary endpoints were major adverse cardiovascular events (defined as cardiovascular mortality, non‐fatal myocardial infarction, or non‐fatal cerebral infarction) and major bleeding events corresponding to Bleeding Academic Research Consortium Type 3 or 5. Clinical outcomes were compared between the patients who were and were not admitted for heart failure. Over a median follow‐up of 12 months, 124 patients (3.8%) were admitted due to heart failure. Independent risk factors for heart failure admission included older age, female sex, Killip class ≥2 on admission, left ventricular ejection fraction

Introduction Few studies have reported on administering enfortumab vedotin to patients with metastatic urothelial carcinoma and end‐stage renal disease requiring hemodialysis. Case presentation Case 1: An 85‐year‐old man underwent hemodialysis for progressive renal failure 4 months after right laparoscopic radical nephroureterectomy. Case 2: A 73‐year‐old man underwent hemodialysis after two laparoscopic radical nephroureterectomies for recurrent urothelial carcinoma. In both cases, enfortumab vedotin was administered due to postoperative recurrence and progression despite platinum‐based chemotherapy and pembrolizumab. Partial response and disease progression were observed in cases 1 and 2, respectively. Adverse events included a mild skin rash in both patients and neutropenia in Case 1, both of which resolved with symptomatic treatment. Conclusion The efficacy and safety of enfortumab vedotin in patients with metastatic urothelial carcinoma, and end‐stage renal disease undergoing hemodialysis, were confirmed.

Abstract Introduction This study evaluated the clinical outcomes of stereotactic body radiotherapy (SBRT) for both pathologically diagnosed (PD) and clinically diagnosed (CD) early‐stage non‐small cell lung cancer (NSCLC) and explored the significance of accurate expert computed tomography (CT) interpretation. Methods We retrospectively analyzed 95 patients with early‐stage NSCLC who received SBRT at our institution. Patients were classified into CD and PD groups. Two chest radiologists retrospectively interpreted the pre‐SBRT CT images to determine the tumor subtype and probability of malignancy (PM). Clinical findings, CT features, and treatment outcomes were compared between the two groups. The survival rate of the CD group was analyzed separately according to the PM grade. Results Median overall survival for the CD and PD groups was 6.0 and 5.4 years (P = 0.57), respectively. Median cause‐specific survival was 10.2 years in the CD group and not reached in the PD group (P = 0.76). In the CD group, lung cancer mortality was lower in the low PM group (25% [1 of 4]) than in the high PM group (47.4% [9 of 19]). Conclusion It may be desirable to evaluate the PM of the nodule using expert CT interpretation to decide whether SBRT is indicated in CD early‐stage NSCLC.

Background Left ventricular noncompaction (LVNC) is a hereditary type of cardiomyopathy characterized by prominent trabeculations. Detailed characteristics of biventricular noncompaction (BiVNC) remain unknown. This study aimed to elucidate the clinical characteristics and genetic landscape of BiVNC. Methods and Results We recruited children with left ventricular noncompaction from Japanese multi‐institutional centers from 2013 to 2021. Left ventricular noncompaction was classified as BiVNC, congenital heart disease, arrhythmia, dilated cardiomyopathy, or normal function. In these patients, cardiomyopathy‐associated genes were screened. A total of 234 patients (127 male; mean age, 4 months [range, 0–6.6 years]) were enrolled in this study, of whom 25 had BiVNC; 55, normal function; 84, dilated cardiomyopathy; 38, congenital heart disease; and 32, arrhythmia. BiVNC was diagnosed during the perinatal period in 10 patients, in whom the prevalence was higher than that in other patients. A total of 14 patients in the group with BiVNC had congenital heart disease, but not necessarily right heart lesions. Left ventricular dyskinesis was frequently observed in the lateral wall (24%) and apex (28%). Eleven pathogenic variants were found in 11 patients with BiVNC (44.0%). The group with BiVNC had a higher ratio of mitochondrial and developmental gene variants than the other groups. Among all groups, the group with BiVNC had the worst survival rate (P=0.0009). Conclusions Pediatric patients with BiVNC had a high rate of ventricular dyskinesis and poor outcome. A comprehensive and careful screening for disease‐causing genes and phenotype may help identify specific patients with left ventricular noncompaction and mortality‐related cardiac phenotypes.

Abstract Background and Aim This study aimed to clarify whether several single‐nucleotide polymorphisms (SNPs)‐related chronic pancreatitis such as carboxypeptidase A1 (CPA1), carboxypeptidase B1 (CPB1), Gamma‐glutamyltransferase 1 (GGT1), G‐protein‐coupled receptor Class C Group 6 Member A (GPRC6A), and serine protease inhibitor, Kazal type 1 (SPINK‐1) genotypes were associated with clinical characteristics of patients with intraductal papillary mucinous neoplasm (IPMN) and worrisome features of IPMN. Methods We enrolled 100 patients with IPMN and 116 patients as a control. Serum p‐amylase, lipase, trypsin, phospholipase A2 (PLA2), and elastase‐1 levels were measured. An Olympus EUS (GF‐UCT 260) was used to perform endosonography in 100 patients with IPMN. Total EUS score was evaluated using endosonography. DNA was isolated from the duodenal tissue using a commercial system and polymerase chain reaction (PCR) was performed on 7500 Fast PCR System. Results There were no associations between glucose tolerances, lipid levels and genotypes of CPA1, GGT1, GPRC6A, and SPINK‐1 in patients with IPMN. CPA1 genotype was significantly associated with the pathophysiology of IPMN. Then, GGT1 genotype was also significantly associated with EUS total score and the size of cyst more than 20 mm and more than 30 mm as one of worrisome features of IPMN. Conclusion Genotypes of carboxypeptidase A1 and gamma‐glutamyltransferase 1 may be useful tools for the diagnosis and the predictor of worrisome features of IPMN.

Abstract Background Cancer cachexia affects more than half of all cancer patients, reducing survival rates. Evidence‐based approaches are urgently needed to optimize treatment. Methods A systematic review and network meta‐analysis were conducted to assess the effectiveness and safety of different pharmacotherapies for cancer cachexia. Three databases (PubMed, Cochrane Library, and Web of Science) were searched for the period from January 1, 2000, to March 20, 2024. The netmeta package in R software was used to calculate the pooled effect, employing a random effects model. Results Seven placebo‐controlled randomized trials involving 1421 patients were analyzed. Pairwise analysis showed that body weight increases were 4.6 kg (95% confidence interval [CI] 0.83–8.37 kg) for olanzapine, 3.82 kg (95% CI 0.73–6.91 kg) for espindolol (20 mg), 2.36 kg (95% CI 1.84–2.89 kg) for anamorelin (100 mg), and 1.31 kg (95% CI 0.42–2.19 kg) for anamorelin (50 mg). In terms of safety profiles, olanzapine demonstrated the lowest odds ratio when compared to placebo, at 0.26 (95% CI 0.07–0.94), followed by anamorelin (50 mg) at 0.86 (95% CI 0.30–2.48), and anamorelin (100 mg) at 0.89 (95% CI 0.42–1.88). However, network meta‐analysis could not confirm the superiority of olanzapine over anamorelin in terms of efficacy and safety. Conclusion Both olanzapine and anamorelin are useful in improving body weight in patients with cancer cachexia. Personalization may be helpful for different patients.

Abstract Background There are two methods of Roux‐en‐Y (RY) reconstruction after gastrectomy: the antecolic route (ACR) and retrocolic route (RCR). There is no evidence to support that the ACR achieves comparable long‐term survival. Methods This was a multi‐center historical cohort study. Patients diagnosed with clinical T3/4a and any N stage who underwent open gastrectomy and R0 resection for gastric adenocarcinoma between January 2006 and December 2012 were enrolled. The primary outcome was the hazard ratio of ACR for overall survival, with adjustment for confounding factors by propensity score matching, and a Cox proportional hazards model. Results A total of 1758 eligible patients were identified from the database. After matching, 410 patients in the ACR and RCR groups were included in the final analysis. The adjusted hazard ratio (95% CI) for ACR was 1.148 (0.870–1.492). The five‐year survival rates in the ACR and RCR groups were 74.3% (69.5–78.4) and 77.3% (72.3–81.2), respectively. The short‐term surgical outcomes of the two groups did not differ to a statistically significant extent. Conclusion The route used to lift the jejunum in RY reconstruction did not affect the incidence of long‐term survival or postoperative complications. The ACR and RCR are both acceptable options for RY reconstruction during gastric cancer surgery.

Abstract Objective To achieve patient‐centricity in metastatic renal cell carcinoma (mRCC) treatment, it is essential to clarify the differences in perspectives between patients and physicians. This cross‐sectional analysis of a web survey aimed to clarify the differences in expectations and concerns between mRCC patients and physicians regarding systemic mRCC therapy in Japan. Methods Surveys from 83 patients and 165 physicians were analyzed. Results The top three most significant differences in expectations of systemic therapy between patients and physicians (patient‐based physician value) were “Chance of achieving treatment‐free status” (−30.1%, p

Introduction There have been reports of surgery for residual ureteral tumors, most of them involved open surgeries. Herein, we report a case of retroperitoneal scopic left ureteral resection and partial cystectomy, performed by placing a fluorescent ureteral catheter in the residual ureter. Case presentation A 79‐year‐old man was admitted to our hospital with a chief complaint of gross hematuria. He had undergone transperitoneal left radical nephrectomy due to angiomyolipoma 20 years ago. Computed tomography and Magnetic resonance imaging revealed a solid tumor in the left residual ureter. Retroperitoneal scopic residual ureterectomy has been performed. During the operation, a fluorescent ureteral catheter proved to be very helpful in detecting the ureter. Conclusion A fluorescent ureteral catheter is considered to be a useful tool in laparoscopic surgery, especially in cases where identification of the ureter is expected to be difficult, such as the residual ureter in this case.

Abstract Spatial population synchrony, defined as spatial covariation in population density fluctuations, exists across different temporal and spatial scales. Determining the degree of spatial synchrony is useful for inferring environmental drivers of population variability in the wake of climate change. In this study, we applied novel statistical methods to detect spatial synchrony patterns of Calanus finmarchicus on the Northeast U.S. Shelf at multiple spatiotemporal scales using unevenly distributed data. Our results reveal that C. finmarchicus subpopulations connected by advection are not necessarily in synchrony, indicating that the degree of synchrony is likely influenced by heterogeneity of local habitats. In addition, regionally synchronous environmental conditions (e.g., sea surface temperature) may not play as significant a role in influencing subregional population dynamics as was previously hypothesized. Overlooking the spatial heterogeneity of synchronous patterns at different time scales could lead to erroneous inferences of potential environmental drivers responsible for C. finmarchicus variability.

Abstract Background During transvenous lead extraction (TLE), a GlideLight laser sheath (Philips) cannot always be advanced over the lead, and crossover to the Evolution system (i.e., an Evolution RL sheath or Evolution Shortie RL sheath [Cook Medical]) is required. We aimed to determine the associated factors and outcomes of such device crossover. Methods This observational study included 112 patients who underwent TLE. The patients were divided into crossover and non‐crossover groups. Outcomes and associated factors of crossover were evaluated. Results Overall, 57 (50.9%) patients required crossover to the Evolution system (crossover group), whereas 55 (49.1%) patients did not require crossover (non‐crossover group). Clinical success rate was similar between the two groups (98.3% vs. 100%; p = 1.00). No major intraprocedural complications related to powered sheaths occurred. Multivariate logistic regression analysis results showed that dwell time of the oldest extracted lead (per year) (odds ratio [OR]: 1.18, 95% confidence interval [CI]: 1.02–1.36; p = .026), number of leads extracted per procedure (OR: 7.23, 95% CI: 1.74–29.99; p = .007), and use of a femoral approach (OR: 21.09, 95% CI: 2.33–190.67; p = .007) were associated factors of crossover. The cutoff for crossover was 7.7 years from the implant (sensitivity 90.5%, specificity 64.9%, area under the curve 0.80). Conclusions Both groups showed a high rate of clinical success. Switching to the Evolution system may facilitate a safe and effective TLE when a laser sheath does not advance despite laser activation.

Abstract Background Anamorelin was approved in Japan in 2021 to treat cancer cachexia associated with non‐small cell lung, gastric, pancreatic, or colorectal cancers. Post‐marketing surveillance is being conducted to evaluate the real‐world safety and effectiveness of anamorelin. Methods This prospective, observational surveillance registered all patients who started treatment with anamorelin after April 21, 2021. Hyperglycemia, hepatic impairment, conduction disorders, and their associated adverse events related to treatment were defined as main safety specifications. Body weight (BW) and appetite were assessed as effectiveness specifications. Results This analysis was based on data as of January 21, 2023. The safety and effectiveness analysis sets included 6016 and 4511 patients, respectively. Treatment‐related adverse events in ≥1% of patients were hyperglycemia (3.9%) and nausea (2.6%). The incidences of hyperglycemia, hepatic impairment, conduction disorders, and their associated adverse events related to treatment were 4.8%, 1.2%, and 1.1%, respectively. The mean changes (standard error [SE]) in BW from baseline to weeks 3, 12, 24, and 52 were 0.64 (0.05) kg, 1.19 (0.12) kg, 1.40 (0.21) kg, and 1.42 (0.39) kg, respectively. The mean changes (SE) in Functional Assessment of Anorexia/Cachexia Treatment 5‐item Anorexia Symptom Scale total scores from baseline to weeks 3, 12, 24, and 52 were 3.2 (0.09), 4.8 (0.18), 5.2 (0.30), and 5.3 (0.47), respectively, exceeding the clinically meaningful improvement score (2.0 points). Conclusion The overall safety of anamorelin raised no new safety concerns, although continued caution may be required for hyperglycemia and nausea. Improvements in BW and appetite were also observed in real‐world clinical settings.

Abstract We developed pulmonary emphysema and a type 2 airway inflammation overlap mouse model. The bronchoalveolar lavage (BAL) interleukin 13 (IL‐13), IL‐4, and IL‐5 levels in the overlap model were higher than in the pulmonary emphysema model and lower than in the type 2 airway inflammation model, but IL‐33 level in the lung was higher than in other models. IL‐33 and interferon‐γ (IFNγ) in lungs may control the severity of a type 2 airway inflammation in lung.

Abstract Gastroesophageal submucosal hematoma is a disease in which blood vessels in the gastroesophageal submucosa rupture and form a hematoma. In this report, we describe a case of gastroesophageal submucosal hematoma that developed due to vomiting in a patient with no history of bleeding and resolved with conservative treatment. A 69‐year‐old man presented with precordial pain and hematemesis after vomiting. A diagnosis of idiopathic gastroesophageal submucosal hematoma was made by computed tomography scan, magnetic resonance imaging, and esophagogastroduodenoscopy. Healing was achieved by conservative treatment with fasting, rehydration, and acid suppression. When a patient presents with sudden chest pain, hematemesis, and dysphagia, the possibility of this disease should be considered.

Abstract Cronkhite‐Canada syndrome (CCS) is a rare disease characterized by gastrointestinal polyposis, skin pigmentation, alopecia, and abnormal nailfolds. Although colorectal cancer has been reported in patients with CCS, reports are limited regarding the effectiveness of the usage of image‐enhanced endoscopy in CCS lesions. Here, we report a case of CCS in which narrow‐band imaging (NBI) magnifying endoscopy was applied to detect an adenomatous component in multiple hamartomatous polyps. A 79‐year‐old female complained of taste disorder, anorexia, and weight loss over several months. Endoscopic examination revealed multiple reddened polyps in the stomach and colon, leading to a diagnosis of CCS. Narrow‐band imaging magnification showed sparse and dilated round pits on the CCS polyps. Furthermore, 12 out of the numerous colorectal CCS polyps had a coexisting light reddish elevated component with a regular distribution of microvessels and a regular reticular pattern. This pattern satisfied the criteria for Type 2A of the Japan Narrow‐band‐imaging Expert Team classification, indicating adenoma. After resection, these twelve polyps were subject to pathological analysis, which confirmed they were all hamartomatous polyps with low‐grade adenoma on the superficial layer. Immunohistochemical analysis revealed a significant increase in the Ki‐67 index and p53 staining only in the adenomatous lesions. We conclude that narrow‐band imaging magnifying endoscopy would be useful in differentiating adenoma from CCS‐related polyps, which thereby facilitates early detection and treatment of precancerous lesions.

Abstract Dabigatran is a useful and widely used drug for stroke prevention in patients with atrial fibrillation. However, it has been reported to cause esophagitis. Herein, we report the case of a 77‐year‐old man with dabigatran‐induced esophagitis with blue pigmentation, which is known to be a rare adverse effect. The patient presented to our hospital with a tightness of the chest and anorexia. Computed tomography revealed a thickening of the entire esophageal wall, with an upper esophageal predominance. Esophagogastroduodenoscopy was performed, which showed that the cervical and upper thoracic esophagus had blue pigmentation with edematous changes, partial narrowing, and longitudinal sloping. We replaced dabigatran with edoxaban, a similar anticoagulation medication. The patient was closely monitored for 1 month after switching to edoxaban. The follow‐up esophagogastroduodenoscopy showed marked improvements, revealing resolution of the bluish discoloration and edematous changes, and the patient's complaints regarding the tightness of the chest and anorexia were also resolved. It is important to recognize that such side effects can occur with dabigatran, a drug that is frequently used in daily practice. Considering the fact that strong edematous changes can cause indigo carmine pigmentation associated with dabigatran stagnation, we recommend switching to another anticoagulant if esophagitis occurs during dabigatran administration.

Key Clinical Message Distal stent graft‐induced new entry may occur after stent grafting for aortic dissection. Four‐dimensional magnetic resonance imaging is useful for predicting outcomes, showing accelerated flow and increased wall shear stress, indicating further false lumen expansion.

Abstract To improve the forecast accuracy of numerical weather prediction, it is essential to obtain better initial conditions by combining simulations and available observations via data assimilation. It has been known that a part of observations degrade the forecast accuracy. Detecting and discarding such detrimental observations via proactive quality control (PQC) could improve the forecast accuracy. However, conventional methods for diagnosing observation impacts require future observations as a reference state and PQC cannot be real‐time in general. This study proposes using machine learning (ML) trained by a time series of analyses to obtain a reference state without future observations and enable real‐time ML‐based PQC. This study presents proof‐of‐concept using a low‐dimensional dynamical system. The results indicate that ML‐based and model‐based estimates of observation impacts are generally consistent. Furthermore, ML‐based real‐time PQC successfully improves the forecast accuracy compared to a baseline experiment without PQC.

Abstract An 81‐year‐old male with a history of coronary artery disease, hypertension, paroxysmal atrial fibrillation and chronic kidney disease presents with asymptomatic bradycardia. Examination was notable for an early diastolic heart sound. 12‐lead electrocardiogram revealed sinus bradycardia with a markedly prolonged PR interval and second‐degree atrioventricular block, type I Mobitz. We review the differential diagnosis of early diastolic heart sounds and present a case of Wenckebach associated with a variable early diastolic sound on physical exam.

Abstract Single‐molecule enzyme activity assay is a platform that enables the analysis of enzyme activities at single proteoform level. The limitation of the targetable enzymes is the major drawback of the assay, but the general assay platform is reported to study single‐molecule enzyme activities of esterases based on the coupled assay using thioesters as substrate analogues. The coupled assay is realized by developing highly water‐soluble thiol‐reacting probes based on phosphonate‐substituted boron dipyrromethene (BODIPY). The system enables the detection of cholinesterase activities in blood samples at single‐molecule level, and it is shown that the dissecting alterations of single‐molecule esterase activities can serve as an informative platform for activity‐based diagnosis.

Key Clinical Message We present a patient catheterized for prostatic lesions who developed sepsis of urinary origin with a penile cavernosal abscess due to urethral injury caused by catheter ballooning. Urethral injury might lead to a life‐threatening penile abscess.

Abstract Nano‐sized contrast agents (NCAs) hold potential for highly specific tumor contrast enhancement during magnetic resonance imaging. Given the quantity of contrast agents loaded into a single nano‐carrier and the anticipated relaxation effects, the current molecular design approaches its limits. In this study, a novel molecular mechanism to augment the relaxation of NCAs is introduced and demonstrated. NCA formation is driven by the intramolecular self‐folding of a single polymer chain that possesses systematically arranged hydrophilic and hydrophobic segments in water. Utilizing this self‐folding molecular design, the relaxivity value can be elevated with minimal loading of gadolinium complexes, enabling sharp tumor imaging. Furthermore, the study reveals that this NCA can selectively accumulate into tumor tissues, offering effective anti‐tumor results through gadolinium neutron capture therapy. The efficacy and versatility of this self‐folding molecular design underscore its promise for cancer diagnosis and treatment.

Abstract Cells are small, closed spaces filled with various types of macromolecules. Although it is shown that the characteristics of biochemical reactions in vitro are quite different from those in living cells, the role of the co‐existence of various macromolecules in cell‐size space remains still elusive. Here, using a constructive approach, it is demonstrated that the co‐existence of various macromolecules themselves has the ability to tune protein localization for spatiotemporal regulation and a biochemical reaction system in a cell‐size space. Both experimental and theoretical analyses reveal that enhancement of interfacial effects by a large surface‐area‐to‐volume ratio facilitates membrane localization of molecules in the cell‐size space, and the interfacial effects are alleviated by competitive binding to lipid membranes among multiple proteins even if their membrane affinities are weak. These results indicate that competition for membrane binding among various macromolecules in the cell‐size space plays a role in regulating the spatiotemporal molecular organization and biochemical reaction networks. These findings shed light on the importance of surrounding molecules for biochemical reactions using purified elements in small spaces.

Background Pulse wave velocity (PWV) is a noninvasive measure of arterial stiffness and predictor of cardiovascular disease. However, the association between PWV and vascular calcification across different vascular beds has not been fully investigated. This study aimed to quantify the association between PWV and multiterritory calcification and to explore whether PWV can identify individuals with vascular calcification beyond traditional risk factors. Methods and Results Among 1351 older adults (mean age, 79.2 years [SD, 4.1]) from the ARIC (Atherosclerosis Risk in Communities) study, we measured segment‐specific PWVs: heart–carotid, heart–femoral, carotid–femoral, heart–ankle, brachial–ankle, and femoral–ankle. Dependent variables were high calcium score (≥75th percentile of Agatston score) across different vascular beds: coronary arteries, aortic valve ring, aortic valve, mitral valve, ascending aorta, and descending aorta. Quartiles of carotid–femoral, heart–femoral, heart–ankle, and brachial–ankle PWV were significantly associated with coronary artery calcium (eg, adjusted odds ratio [OR] for the highest versus lowest quartile of carotid–femoral PWV, 1.84 [95% CI, 1.24–2.74]). Overall, PWVs were most strongly associated with descending aorta calcification, with significant results for carotid–femoral, heart–femoral, heart–ankle, and brachial–ankle PWV (eg, adjusted OR for the highest versus lowest quartile of carotid–femoral PWV, 3.99 [95% CI, 2.61–6.17]). In contrast, femoral–ankle PWV was inversely associated with descending aorta calcification. Some PWVs improved the discrimination of coronary artery calcium and descending aorta calcification beyond traditional risk factors. Conclusions The associations of PWV with vascular calcification varied substantially across segments, with descending aorta calcification most closely linked to PWVs. Our study suggests that some PWVs, especially carotid–femoral PWV, are helpful to identify individuals with coronary artery calcium and descending aorta calcification.

Abstract Objective To compare the microbiota between cholesteatoma and chronic suppurative otitis media (COM) and to identify potential pathogens that explain the relevant phenotypes of cholesteatoma. Study Design Prospective cohort study. Methods Surgical specimens collected from 20 cholesteatomas and nine COMs were treated to dissolve biofilms and subjected to 16S ribosomal RNA (rRNA) gene sequencing and amplicon sequence variant‐level analysis for microbiota profiling and quantitative comparison. Correlations between the relative abundance of potential pathogens and the volume of the primary resected cholesteatomas were examined. Results Differences in bacterial composition (beta diversity) were observed between cholesteatomas and COM (p = .002), with a higher abundance of Staphylococcus in cholesteatomas than in COM (p = .005). Common genera in the external auditory canal (EAC) flora, such as Staphylococcus, Corynebacterium, and Cutibacterium, were predominant in both cholesteatoma and COM; Staphylococcus aureus and Pseudomonas aeruginosa were increased in both diseases compared with the EAC flora. Furthermore, coagulase‐negative staphylococci (CoNS) were more abundant in cholesteatomas than in COM (p = 0.002). Linear discriminant analysis coupled with effect size measurements (LEfSe) identified four CoNS as potential biomarkers for cholesteatoma. The relative abundance of S. aureus, a potential pathogen, was positively correlated with cholesteatoma volume (r = .60, p = .02). Conclusion The microbiota of cholesteatoma and COM originated from EAC flora, but the bacterial composition was largely altered. Our results suggested that S. aureus infection is involved in cholesteatoma progression. Level of Evidence 3b

Abstract Aims/Introduction We aimed to investigate the association of active commuting (cycling or walking to work), as well as the association of the individual commuting modes, with the risk of diabetes in a prospective cohort of community‐dwelling adults in Japan. Material and Methods A total of 1,270 residents aged 40–79 years were followed up for a median of 14 years. Active commuting was defined as either cycling or walking to work. A Cox proportional hazards model was used to examine the association of active commuting with the risk of diabetes. Associations for different forms of active commuting (cycling, walking and mixed modes of cycling or walking with non‐active components) were also examined. Results During the follow‐up period, 191 participants developed diabetes. Active commuting was associated with a lower risk of diabetes than non‐active commuting after adjustment for potential confounders (hazard ratio [HR] 0.54, 95% confidence interval [CI] 0.31–0.92). With regard to the commuting modes, the risk of diabetes was significantly lower in individuals who commuted by cycling alone (HR 0.46, 95% CI 0.22–0.98), and tended to be lower in individuals who commuted by walking alone (HR 0.14, 95% CI 0.02–1.02) compared with that in individuals with non‐active commuting. Meanwhile, no significant associations were observed for the mixed mode of walking and non‐active commuting (HR 1.69, 95% CI 0.77–3.71). Conclusions Active commuting, particularly that consisting exclusively of cycling or walking, was associated with a reduced risk of diabetes. Our findings support a public health policy that promotes the choice of active commuting for the prevention of diabetes.

Abstract Objective This retrospective study was designed to observe differences in ictal movements of epileptic spasm (ES) before and after corpus callosotomy (CC). We hypothesized that asymmetric expression of ES is more clarified after CC and would be a good indicator for the epileptic hemisphere. Methods We selected 16 patients with intractable ES in West syndrome who were seizure‐free after CC and subsequent resection or disconnective surgery of the unilateral hemisphere. We retrospectively reviewed their behavioral ES recorded at video‐electroencephalography monitoring before and after CC. Asymmetric neck flexion (NF) and involuntary muscular contraction of the upper and lower extremities (MCU and MCL, respectively) were primarily described correlating their laterality and the responsible hemisphere proved by surgical resection. Results Asymmetric NF, MCU, and MCL could be found both before and after CC. However, the percentage of those movements to the total number of ES increased after CC; asymmetric NF, 82.9% vs. 20.1%; unilaterally predominant MCU, 81% vs. 39.3%; and unilaterally predominant MCL, 77.6% vs. 29.9%. Regarding asymmetric NF, the direction in which the neck flexed or the head turned was significantly ipsilateral to the responsible hemisphere in 9 of 12 patients after CC (75%). The predominant side of MCU and MCL were significantly contralateral to the responsible hemisphere in 11 of 11 and 7 of 9 patients (100% and 77.8%, respectively). Significance Asymmetric NF, MCU, and MCL were clarified in patients with ES who were successfully treated with CC and subsequent surgery. Those changes in ictal behaviors after CC may indicate the lateralization of epileptic activity and encourage more curative surgical treatment.

Abstract In this paper, we present the first high‐speed video observation of a cloud‐to‐ground lightning flash and its associated downward‐directed Terrestrial Gamma‐ray Flash (TGF). The optical emission of the event was observed by a high‐speed video camera running at 40,000 frames per second in conjunction with the Telescope Array Surface Detector, Lightning Mapping Array, interferometer, electric‐field fast antenna, and the National Lightning Detection Network. The cloud‐to‐ground flash associated with the observed TGF was formed by a fast downward leader followed by a very intense return stroke peak current of −154 kA. The TGF occurred while the downward leader was below cloud base, and even when it was halfway in its propagation to ground. The suite of gamma‐ray and lightning instruments, timing resolution, and source proximity offer us detailed information and therefore a unique look at the TGF phenomena.

Abstract Hepatoblastoma is the most common pediatric liver tumor, but little research has been done on the role of macrophages in hepatoblastoma. The purpose of this study was to gain insight into potential roles for macrophages in hepatoblastoma. Paraffin‐embedded specimens from 56 patients who underwent surgical resection were examined with immunohistochemical staining for the macrophage‐specific markers, Iba1 and CD163. Significant differences were seen among histological subtypes. Significantly increased numbers of macrophages were detected in embryonal components compared to fetal components in the mixed epithelial type. In vitro studies using human monocyte‐derived macrophages and two hepatoblastoma cell lines (HepG2 and Huh6) were performed. Conditioned medium from these cell lines induced increased CD163 expression in macrophages. Direct co‐culture with macrophages induced tumor cell proliferation via induction of protumor cytokine secretion from macrophages. Direct co‐culture with macrophages also induced interleukin (IL)‐34 overexpression by Huh6 cells via Brd4 signaling. IL‐34 overexpression promoted tumor cell proliferation and chemoresistance. High IL‐34 and Brd4 expression was detected in embryonal components, which have potentially higher proliferation activity than fetal components. In conclusion, IL‐34 expression in embryonal components may induce macrophage chemotaxis in a paracrine manner, and tumor cell proliferation and chemoresistance in an autocrine manner. IL‐34 is a potential therapeutic target for hepatoblastoma.

Abstract Background Acute appendicitis (AA) in older patients can look different from AA in younger patients. Although it is crucial that primary care physicians can recognize AA in patients of any age, few Japanese studies have examined the characteristics of older AA patients. To address this, we evaluated the clinical characteristics of older Japanese patients with AA. Methods We performed a post hoc analysis of the data from a previous Japanese single‐center study. We analyzed the clinical information of both younger (age: 16–64 years) and older patients (age: ≥65 years). Results A cohort of 236 patients consisting of 219 (92.8%) younger patients and 17 (7.2%) older patients was evaluated. The median ages of the younger and older patients were 34 (interquartile range [IR], 24–45) and 78 years (IR, 74–81), respectively. The prevalence of complicated appendicitis (CA) (older: 41.2% vs. younger: 14.2%), comorbidities (70.6% vs. 13.2%), and thrombocytopenia (17.7% vs. 4.1%), along with serum C‐reactive protein (CRP) level (6.7 mg/dl vs. 1.0 mg/dl), was significantly higher in older patients. Significantly fewer older patients had epigastric pain (17.7% vs. 53.0%). Logistic regression evaluating the characteristics of older AA patients showed that CRP >5 mg/dl had a high odds ratio (OR) (5.01; 95% CI, 1.73–14.54), while epigastric pain had a low OR (0.24; 95% CI, 0.06–0.90). Conclusion Our study reveals a higher prevalence of CA and comorbidities in older patients, and suggests that a lack of epigastric pain, thrombocytopenia, and higher serum CRP level are characteristics of older AA patients.

Abstract Background and Aim Liver stiffness measurement (LSM) and spleen stiffness measurement (SSM@50 Hz) using standard vibration‐controlled transient elastography (VCTE) have been studied as a noninvasive test for screening of gastroesophageal varices (GEV) in chronic liver disease (CLD). Recently, a novel spleen‐dedicated VCTE (SSM@100 Hz) has been developed. We evaluated the diagnostic performance of SSM@100 Hz, SSM@50 Hz, LSM, and other noninvasive tests using esophagogastroduodenoscopy (EGD) as the reference as well as the correlation with hepatic venous pressure gradient (HVPG). Methods A total of 123 patients with CLD enrolled in this cross‐sectional study. SSM@100 Hz, SSM@50 Hz, and LSM were determined by VCTE. EGD and HVPG were performed within 12 weeks before or after VCTE. Results GEV were present in 60 patients. Failure or suboptimal SSM were fewer at 100 Hz (4.0%) than at 50 Hz (17.7%). All SSM values obtained at 100 Hz were lower than the 100 kPa ceiling threshold, but 10 patients reached the 75 kPa ceiling threshold for SSM@50 Hz. SSM@100 Hz was most accurate (area under the receiver operating characteristic [AUROC] = 0.944) for the diagnosis of GEV compared to SSM@50 Hz, LSM, and scoring systems. AUROC of SSM@100 Hz for diagnosis of high‐bleeding risk varices (HRV) was 0.941, which was significantly higher than that of SSM@50 Hz (AUROC = 0.842, P = 0.002). SSM@100 Hz showed higher specificity (82.0%) for diagnosis of HRV than SSM@50 Hz (specificity = 67.1%). SSM@100 Hz was significantly correlated with HVPG (r = 0.71, P

Abstract Epigenetic alterations of chromatin structure affect chromatin accessibility and collaborate with genetic alterations in the development of cancer. Lysine demethylase 4B (KDM4B) has been identified as a JmjC domain‐containing epigenetic modifier that possesses histone demethylase activity. Although recent studies have demonstrated that KDM4B positively regulates the pathogenesis of multiple types of solid tumors, the tissue specificity and context dependency have not been fully elucidated. In this study, we investigated gene expression profiles established from clinical samples and found that KDM4B is elevated specifically in acute myeloid leukemia (AML) associated with chromosomal translocation 8;21 [t(8;21)], which results in a fusion of the AML1 and the eight‐twenty‐one (ETO) genes to generate a leukemia oncogene, AML1‐ETO fusion transcription factor. Short hairpin RNA‐mediated KDM4B silencing significantly reduced cell proliferation in t(8;21)‐positive AML cell lines. Meanwhile, KDM4B silencing suppressed the expression of AML1‐ETO‐inducible genes, and consistently perturbed chromatin accessibility of AML1‐ETO‐binding sites involving altered active enhancer marks and functional cis‐regulatory elements. Notably, transduction of murine KDM4B orthologue mutants followed by KDM4B silencing demonstrated a requirement of methylated‐histone binding modules for a proliferative surge. To address the role of KDM4B in leukemia development, we further generated and analyzed Kdm4b conditional knockout mice. As a result, Kdm4b deficiency attenuated clonogenic potential mediated by AML1‐ETO and delayed leukemia progression in vivo. Thus, our results highlight a tumor‐promoting role of KDM4B in AML associated with t(8;21).

Abstract Aims/Introduction Thrombin exerts various pathophysiological functions by activating protease‐activated receptors (PARs). Recent data have shown that PARs influence the development of glomerular diseases including diabetic kidney disease (DKD) by regulating inflammation. Heparin cofactor II (HCII) specifically inactivates thrombin; thus, we hypothesized that low plasma HCII activity correlates with DKD development, as represented by albuminuria. Materials and Methods Plasma HCII activity and spot urine biomarkers, including albumin and liver‐type fatty acid‐binding protein (L‐FABP), were determined as the urine albumin‐to‐creatinine ratio (uACR) and the urine L‐FABP‐to‐creatinine ratio (uL‐FABPCR) in 310 Japanese patients with diabetes mellitus (176 males and 134 females). The relationships between plasma HCII activities and those DKD urine biomarkers were statistically evaluated. In addition, the relationship between plasma HCII activities and annual uACR changes was statistically evaluated for 201/310 patients (115 males and 86 females). Results The mean plasma HCII activity of all participants was 93.8 ± 17.7%. Multivariate‐regression analysis including confounding factors showed that plasma HCII activity independently contributed to the suppression of the uACR and log‐transformed uACR values (P = 0.036 and P = 0.006, respectively) but not uL‐FABPCR (P = 0.541). In addition, plasma HCII activity significantly and inversely correlated with annual uACR and log‐transformed uACR increments after adjusting for confounding factors (P = 0.001 and P = 0.014, respectively). Conclusions The plasma HCII activity was inversely and specifically associated with glomerular injury in patients with diabetes. The results suggest that HCII can serve as a novel predictive factor for early‐stage DKD development, as represented by albuminuria.