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We report on electron ratchet transport’s manifestation in the optical rectification (OR) of an asymmetric grating. The photon-drag enabled effect is magnified by asymmetric photon scatterings and the induced optical nonlinearity associated with the surface plasmon polariton (SPP) via its near-field and gradient intensifications. The measured OR efficiency is increased multi-fold, over the prior art, which is attributable to its operating in a higher-order diffraction and nonlinearity regime and to a minimized coupling loss to a potential SPP mode at the lower interface.

We fabricated magnetic tunnel junctions with a 3d-transition material(X)-doped MgO (Mg-X-O) barrier, and evaluated the effect of the doping on magnetoresistance (MR) and microstructure. Among the variations of X (X = Fe, Co, Ni, Cr, Mn, Ti, V, and Zn), X = Fe and Mn showed a high MR ratio of more than 100%, even at a low resistance-area product of 3 Ωμm2. The microstructure analysis revealed that (001) textured orientation formed for X = Fe and Mn despite substantial doping (about 10 at%). The elemental mappings indicated that Fe atoms in the Mg-Fe-O barrier were segregated at the interfaces, while Mn atoms were evenly involved in the Mg-Mn-O barrier. This suggests that MgO has high adaptability for Fe and Mn dopants in terms of high MR ratio.

Scientific research on forest therapy's preventive medical and mental health effects has advanced, but the need for clear evidence for practical applications remains. We conducted an unblinded randomized controlled trial involving healthy men aged 40-70 to compare the physiological and psychological effects of forest and urban walking. Eighty-four participants were randomly assigned to either the forest or urban group, with 78 completing 90-min walks and analysis. The primary outcome measured was the change in saliva-secreted immunoglobulin A (sIgA) levels. Evaluating researchers were blinded to the groups, but participants and on-site staff were not. Here, we demonstrate a significant increase in saliva-secreted immunoglobulin A (sIgA) levels in the forest group. Furthermore, forest walking resulted in improved mood, including a reduction in stress hormone levels. In conclusion, mindful forest walking has the potential to enhance immunity and promote health. Clinical trial registration: University Hospital Medical Information Network. Trail registration number: UMIN000045851. Approval date: 25/10/2021., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Ethical approval: The National Hospital Organization Tokyo Medical Center’s Ethics Committee approved this study (Issue no. R21-046, approval date: July 19, 2021). Informed consent: All participants provided written informed consent for this study following the Consolidated Standards of Reporting Trials 2010 guidelines. Consent to publish: All participants provided written informed consent for the photo publication., (© 2025. The Author(s).)

Aims: In patients undergoing transcatheter aortic valve implantation (TAVI) for severe aortic stenosis (AS), data on the differences in subsequent cardiac structure and function among stratified groups with flow gradient patterns through the aortic valve are insufficient., Methods and Results: In this large multicenter study, 4523 patients undergoing TAVI for severe AS between 2013 and 2019 were divided into three groups according to the following criteria: (i) high-gradient AS (HG-AS) [mean pressure gradient (MPG) ≥ 40 mmHg], (ii) classical low-flow low-gradient AS (cLFLG-AS) [MPG < 40 mmHg, left ventricular (LV) ejection fraction (LVEF) <50%], and (iii) paradoxical low-flow low-gradient AS (pLFLG-AS) [MPG < 40 mmHg, LVEF ≥ 50% but stroke volume index (SVi) <35 mL/m2]. Echocardiography was performed at baseline, post-procedure, and 1 year post-TAVI. 3697, 507, and 319 patients had HG-AS, cLFLG-AS, and pLFLG-AS, respectively. After adjusting for clinical factors, cLFLG-AS and pLFLG-AS had an ∼1.5-fold higher 2-year all-cause mortality compared with HG-AS. During 1 year following TAVI, compared with HG-AS, cLFLG-AS showed greater reduction of LV systolic diameter (LVDs) and LV diastolic diameter (LVDd) and greater increase of LVEF (P < 0.001 for all), and changes in LV mass index (LVMi) and SVi were comparable (P = 0.915 and P = 0.821, respectively). However, pLFLG-AS demonstrated less reduction of LVDs and LVDd (P = 0.039 and P = 0.001, respectively), less improvement of LVEF and LVMi (P = 0.045 and P < 0.001, respectively), and comparable change in SVi (P = 0.364)., Conclusion: During 1 year post-TAVI, compared with HG-AS, cLFLG-AS achieves smaller LV diameters, greater increase in LVEF, and comparable regression of LVMi, whereas pLFLG-AS does not., Competing Interests: Conflict of interest: Dr Izumo is a screening proctor for Edwards Lifesciences. Dr Yashima, Dr Ohno, and Dr Asami are clinical proctors for Medtronic. Dr Takagi, Dr Naganuma, Dr Mizutani, and Dr Ueno are clinical proctors for Edwards Lifesciences and Medtronic. Dr Yamamoto, Dr Shirai, Dr Tada, Dr Watanabe, and Dr Hayashida, are clinical proctors for Edwards Lifesciences, Abbott Medical, and Medtronic. The remaining authors have nothing to disclose., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Objectives: A novel self-assembling peptide gel (SAPG) was recently developed for hemostasis during endoscopic resection (ER) as an alternative for electrocoagulation and clip placement. Therefore, this exploratory study aimed to evaluate the hemostatic effect of SAPG on bleeding during ER of the duodenum., Methods: Patients with superficial duodenal epithelial tumors who underwent endoscopic submucosal dissection (ESD) or cold-snare polypectomy (CSP) between June 2022 and October 2023 were enrolled in the study. SAPG was used for hemostasis of the intraprocedural bleeding when spontaneous hemostasis was essential for the continuation of ESD or was not achieved within 30 s after CSP. The primary outcome was a successful hemostatic rate using SAPG., Results: Among the included patients, 15 and 8 underwent ESD and CSP, respectively. Forty-two points of intraoperative bleeding were noted during ESD, of which 39 (92.9%) and 3 (7.1%) were oozing and nonspurting bleedings, respectively. Successful hemostatic rates were 84.6% and 0% in the oozing and nonspurting bleedings, respectively. All nonspurting bleedings were weakened after SAPG use. Of the 70 CSPs, 60 were oozing bleedings (85.7%), which were successfully stopped with SAPG. The median time to hemostasis from SAPG application was 30 s (interquartile range [IQR] 17-40 s) and 25 s (IQR 10-33 s) during ESD and CSP, respectively. No adverse event was observed in any of the cases during the perioperative period., Conclusion: Self-assembling peptide gel has an acceptable effect of successful hemostasis for intraoperative oozing bleeding during duodenal ESD and CSP., (© 2024 Japan Gastroenterological Endoscopy Society.)

Background: Evidence regarding the incidence of prosthesis-patient mismatch (PPM) and long-term mortality after transcatheter aortic valve replacement (TAVR) in patients with bicuspid aortic valve stenosis (AS) is scarce., Objectives: This study sought to assess the incidence and prognostic impact of PPM after TAVR for bicuspid AS compared with that for tricuspid AS., Methods: In total, 7,393 patients who underwent TAVR were prospectively enrolled in the OCEAN-TAVI (Optimized Catheter Valvular Intervention Transcatheter Aortic Valve Implantation) registry, an ongoing Japanese, multicenter registry. We analyzed 7,051 patients (median age = 85 years, 68.4% women) and identified 503 (7.1%) with bicuspid AS. We compared the incidence of PPM and long-term mortality in 497 patients with and 497 without bicuspid AS after one-to-one propensity score matching analysis., Results: Among the 7,051 patients, moderate and severe PPM were observed in 756 (10.7%) and 92 (1.3%) patients, respectively. Upon Kaplan-Meier curve analysis of the overall cohort, severe PPM appeared to be associated with long-term mortality (log-rank test, P = 0.065). After propensity score matching analysis, moderate and severe PPM were more frequently observed among patients with tricuspid AS than patients with bicuspid AS (moderate PPM, 11.7% vs 4.4%; severe PPM, 1.4% vs 1.0%; P = 0.0001)., Conclusions: Severe PPM appeared to be associated with all-cause mortality. Moderate and severe PPM were more frequently observed in patients with tricuspid AS than patients with bicuspid AS., Competing Interests: Funding Support and Author Disclosures The OCEAN-TAVI registry is supported by Edwards Lifesciences, Medtronic, Boston Scientific, Abbott Medical, and Daiichi-Sankyo Company. Dr Yashima is a clinical proctor for Medtronic. Dr Ohno is a clinical proctor for Medtronic. Dr Izumo is a screening proctor for Edwards Lifesciences. Dr Asami is a clinical proctor for Medtronic. Dr Naganuma is a clinical proctor for Edwards Lifesciences and Medtronic. Dr Takagi is a clinical proctor for Edwards Lifesciences and Medtronic. Dr Mizutani is a clinical proctor for Edwards Lifesciences and Medtronic. Dr Tada is a clinical proctor for Edwards Lifesciences, Abbott Medical, and Medtronic. Dr Shirai is a clinical proctor for Edwards Lifesciences, Abbott Medical, and Medtronic. Dr Ueno is a clinical proctor for Edwards Lifesciences and Medtronic. Dr Watanabe is a clinical proctor for Edwards Lifesciences, Abbott Medical, and Medtronic. Dr Yamamoto is a clinical proctor for Edwards Lifesciences, Abbott Medical, and Medtronic. Dr Hayashida is a clinical proctor for Edwards Lifesciences, Abbott Medical, and Medtronic. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2025 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: In patients with adult congenital heart disease (ACHD), significant atrioventricular valve regurgitation is an important risk factor for poor outcomes, such as heart failure. However, in many cases, transcatheter intervention may reduce the risk profile to avoid a high surgical risk., Case Summary: A 44-year-old man with complex ACHD in the form of a double-inlet left ventricle, congenitally corrected transposition of the great arteries, pulmonary atresia, atrial septal defect, and patent ductus arteriosus was referred for the treatment of severe tricuspid regurgitation. He received an aortopulmonary shunt and a left-sided modified Blalock-Taussig shunt during childhood. Because of the patient's high surgical risk due to seroma formation around the two shunts and intra-mediastinal collateral vessels, the heart team opted for transcatheter edge-to-edge repair (TEER) using a MitraClip (Abbott Vascular, Santa Clara, CA, USA). Tricuspid TEER was successfully performed using the MitraClip G4 system. The postoperative course was uneventful, with significant improvements in the New York Heart Association functional class., Discussion: Our case demonstrates that tricuspid TEER can be an alternative option for patients with complex ACHD who are at high risk for conventional surgeries; however, careful assessment with multimodality imaging and a heart team approach, including a cardiologist, ACHD specialist, cardiac surgeon, anthologist, and intensivist, should be considered., Competing Interests: Conflict of interest: T.M. and S.M. are clinical proctors of transcatheter edge-to-edge repair at Abbott Medical Japan. All other authors declare no conflict of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Objectives: Patients with myeloproliferative neoplasms (MPNs) are at higher risk of developing secondary malignancies. In this study, we focused on patients with MPNs that complicated lymphoid neoplasms. To analyze the real-world status of lymphoid neoplasm treatment in patients with pre-existing MPNs in Japan, we conducted a multicenter retrospective study., Methods: Questionnaires were sent to collect the data on patients who were first diagnosed with either polycythemia vera, essential thrombocythemia or myelofibrosis and who later were complicated with lymphoid neoplasms defined as malignant lymphoma, multiple myeloma, or chronic lymphocytic leukemia/small cell lymphoma., Results: Twenty-four patients with MPNs complicated by lymphoid neoplasms were enrolled (polycythemia vera, n  = 8; essential thrombocythemia, n  = 14; and primary myelofibrosis, n  = 2). Among these, diffuse large B-cell lymphoma (DLBCL) was the most frequently observed ( n  = 13, 54.1%). Twelve (92.3%) of the patients with DLBCL received conventional chemotherapy. Among these 12 patients, regarding cytoreductive therapy for MPNs, 8 patients stopped treatment, one continued treatment, and two received a reduced dose. Consequently, most patients were able to receive conventional chemotherapy for DLBCL with a slightly higher dose of granulocyte colony-stimulating factor support than usual without worse outcomes. All 3 patients with multiple myeloma received a standard dose of chemotherapy., Conclusion: Our data indicate that if aggressive lymphoid neoplasms develop during the course of treatment in patients with MPNs, it is acceptable to prioritize chemotherapy for lymphoma.

Objectives: Hemorrhagic events are a rare but potentially fatal complication in patients with polycythemia vera (PV)., Methods: We analyzed the characteristics of hemorrhagic events in 267 patients with PV., Results: A median follow-up of 4.8 years revealed that 23 (8.6%) hemorrhagic events occurred. Significantly more hemorrhagic events occurred in younger patients aged below 60 years (n = 72) than in older patients aged 60 years or above (n = 191) (n = 12 [16.7%] vs. n = 11 [5.8%], respectively, P  = 0.012). In univariate analysis among the younger patients, white blood cell (WBC) count ≥ 15 × 10 9 /L (hazard ratio [HR] = 7.746, 95% confidence interval [CI] 2.082-28.830, P  = 0.002), palpable splenomegaly (HR = 5.629, 95% CI 1.193-26.550, P  = 0.029), and JAK2 V617F allele burden ≥ 80% (HR = 22.850, 95% CI 2.885-181.00, P  = 0.003) were associated with an increased risk of hemorrhagic events. In multivariate analysis, JAK2 V617F allele burden ≥ 80% (HR = 9.394, 95% CI 1.046-84.380, P  = 0.046) was a significant risk factor., Conclusions: There is an increased risk of hemorrhagic events after diagnosis in younger PV patients with a high JAK2 V617F allele burden, high WBC count or palpable splenomegaly. It is important to consider treatment options that aim to avoid hemorrhagic events by reducing the JAK2 V617F allele burden in younger PV patients.

We report a rare case of an infracardiac-type total anomalous pulmonary venous connection with nonconfluent bilateral pulmonary veins in a patient diagnosed with heterotaxy syndrome with right atrial isomerism, mitral valve atresia, a single atrium, and double-outlet right ventricle. On the fourth day of life, the patient underwent successful repair using a sutureless technique. Two years after the surgery, the patient remained well without any signs of pulmonary venous obstruction., Competing Interests: Data availability statementsThe data underlying this article are available for this article. Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

The study investigates the effect of biotin concentration on the role of anaplerotic reactions catalysed by pyruvate carboxylase (PC) and phosphoenolpyruvate carboxylase (PEPC) in glutamic acid production by Corynebacterium glutamicum. C. glutamicum requires biotin for its growth, and its glutamic acid production can be induced by the addition of Tween 40 or penicillin or by biotin limitation. The biotin enzyme PC and the non-biotin enzyme PEPC catalyse two anaplerotic reactions to supply oxaloacetic acid to the TCA cycle in C. glutamicum . Therefore, they are crucial for glutamic acid production in this bacterium. In this study, we investigated the contribution of each anaplerotic reaction to Tween 40- and penicillin-induced glutamic acid production using disruptants of PEPC and PC. In the presence of 20 µg l -1 biotin, which is sufficient for growth, the PEPC-catalysed anaplerotic reaction mainly contributed to Tween 40- and penicillin-induced glutamic acid production. However, when increasing biotin concentration 10-fold (i.e. 200 µg l -1 ), both PC- and PEPC-catalysed reactions could function in glutamic acid production. Western blotting revealed that the amount of biotin-bound PC was reduced by the addition of Tween 40 and penicillin in the presence of 20 µg l -1 . However, these induction treatments did not change the amount of biotin-bound PC in the presence of 200 µg l -1 biotin. These results indicate that both anaplerotic reactions are functional during glutamic acid production in C. glutamicum and that biotin concentration mainly affects which anaplerotic reactions function during glutamic acid production.

Intracholecystic papillary neoplasm (ICPN) is a rare preinvasive neoplasm of the gallbladder. The lesion typically appears as a polypoid lesion or gallbladder wall thickening. We report a case involving a 40-year-old man with an ICPN that lacked typical polypoid lesions and was difficult to differentiate from adenomyomatosis because of the presence of intramural cysts. Initial contrast-enhanced computed tomography and magnetic resonance imaging showed edematous gallbladder wall thickening. The lumen was constricted and surrounded by a cluster of small cysts that were suspected to be Rokitansky-Aschoff sinuses (RAS). There were also large cysts within the gallbladder wall. No mucosal irregularities or polypoid lesions were observed, and the mucosal continuity was preserved. After antimicrobial therapy, follow-up computed tomography revealed improvement in the thickening of the gallbladder wall; however, the cysts persisted and some had enlarged. The patient underwent laparoscopic cholecystectomy. Pathologically, a tubulopapillary lesion with atypical epithelial cells was observed in the lumen of the gallbladder, extending continuously into the RAS and cysts within the gallbladder wall. High-grade dysplasia was occasionally found, and microscopic foci of invasion were present. ICPN with associated invasive carcinoma was diagnosed. In conclusion, ICPN may not exhibit polypoid lesions or significant wall thickening on imaging. ICPN may present with secondary RAS dilatation, and the presence of large intramural cysts may be helpful in the diagnosis., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: During total arch replacement (TAR) using frozen elephant trunk (FET) technique with Frozenix for true thoracic aortic aneurysm (tTAA), oversized FET tends to be chosen similar to the endovascular devise selection. However, the oversized FET is considered a risk factor for intimal injury. The appropriate size selection of FET remains insufficiently understood., Methods: Between October 2014 and March 2022, a total of 49 patients underwent TAR using Frozenix for tTAA. Out of 49 patients, four patients planned to staged surgery were excluded, 19 patients were operated on with an undersized Frozenix compared with the descending aorta (undersized FET group) and in 26 patients an equal or oversized Frozenix was used (oversized FET group). Clinical outcomes and postoperative diameter changes were investigated., Results: In-hospital mortality was 0%. The mean diameter of Frozenix and the descending aorta was 30.7 mm and 28.8 mm, respectively, in the oversized FET group, and 26.7 mm and 30.1 mm in the undersized FET group. Postoperative computed tomography (CT) demonstrated no endoleaks not only in the oversized FET group but also in the undersized FET group. CT also revealed that undersized FET had expanded more than the original diameter in all cases except for two, with an average of 2.47 ± 1.53 mm. Additionally, the descending aorta covered with Frozenix shrank in 10 patients (53%). Postoperative adverse aortic events were not observed., Conclusions: Undersized Frozenix tightly fit the descending aorta and resulted in complete sealing without endoleaks. Oversized FET is not strictly necessary considering the size-related adverse complications., (© 2024. The Author(s), under exclusive licence to The Japanese Association for Thoracic Surgery.)

Objective: Endoscopic submucosal dissection (ESD) is a specific procedure that uses an electrosurgical knife for en-bloc resectioning large tumors. However, no study has examined the effect of ESD on the defecation function of patients with rectal tumors. We aimed to investigate the potential effects caused by ESD by analyzing changes in the morphology and movement of the anorectum pre- and post-ESD., Methods: This prospective observational study included 11 patients with anorectal tumors who underwent ESD between April 2020 and February 2022. Pre-ESD assessments included anorectal manometry and defecography. Post-ESD assessments were conducted 2 months later, including anorectal manometry, defecography, and proctoscopy for ulcer and stenosis evaluation., Results: The median patient age was 73 years, including seven males and four females. Eight patients (73%) had a tumor in the lower rectum, and the extent of resection was less than 50% of the rectal lumen. Resection reached the dentate line in six cases (55%). In the patients with post-ESD mucosal defects involving the dentate line, the median of functional anal canal length significantly decreased from (3.4 cm pre-ESD to 2.8 cm post-ESD, p  = 0.04). Defecography revealed one case with incomplete evacuation (<50%) and incontinence post-ESD. Interestingly, patients with pre-existing rectoceles noted resolution of lesions post-ESD. None of the patients reported daily constipation or fecal incontinence., Conclusions: While rectal ESD is unlikely to cause significant real-world defecation difficulties, alterations in rectal and anal canal morphology and function may occur if the dentate line is involved in the resection range.

Objectives: We aimed to conduct a systematic review and meta-analysis to assess the value of image-enhanced endoscopy including blue laser imaging (BLI), linked color imaging, narrow-band imaging (NBI), and texture and color enhancement imaging to detect and diagnose gastric cancer (GC) compared to that of white-light imaging (WLI)., Methods: Studies meeting the inclusion criteria were identified through PubMed, Cochrane Library, and Japan Medical Abstracts Society databases searches. The pooled risk ratio for dichotomous variables was calculated using the random-effects model to assess the GC detection between WLI and image-enhanced endoscopy. A random-effects model was used to calculate the overall diagnostic performance of WLI and magnifying image-enhanced endoscopy for GC., Results: Sixteen studies met the inclusion criteria. The detection rate of GC was significantly improved in linked color imaging compared with that in WLI (risk ratio, 2.20; 95% confidence interval [CI], 1.39-3.25; p < 0.01) with mild heterogeneity. Magnifying endoscopy with NBI (ME-NBI) obtained a pooled sensitivity, specificity, and area under the summary receiver operating curve of 0.84 (95 % CI, 0.80-0.88), 0.96 (95 % CI, 0.94-0.97), and 0.92, respectively. Similarly, ME-BLI showed a pooled sensitivity, specificity, and area under the curve of 0.81 (95 % CI, 0.77-0.85), 0.85 (95 % CI, 0.82-0.88), and 0.95, respectively. The diagnostic efficacy of ME-NBI/BLI for GC was evidently high compared to that of WLI, However, significant heterogeneity among the NBI studies still existed., Conclusions: Our meta-analysis showed a high detection rate for linked color imaging and a high diagnostic performance of ME-NBI/BLI for GC compared to that with WLI., Competing Interests: Osamu Dohi received research funding from Fujifilm Co., Ltd. Naohisa Yoshida received research funds and lecture fees from Fujifilm Co., Ltd. The other authors declare no conflict of interest., (© 2024 The Author(s). DEN Open published by John Wiley & Sons Australia, Ltd on behalf of Japan Gastroenterological Endoscopy Society.)

Background: Systemic sclerosis presents with a variety of cardiac manifestations, while myocarditis is usually a rare finding. Furthermore, there are no reports on the use of mitral transcatheter edge-to-edge repair (M-TEER) for the treatment of severe ventricular functional mitral regurgitation (vFMR) secondary to scleroderma myocarditis., Case Summary: A-79-year-old male was admitted to our hospital because of fever and fatigue. His physical examination revealed thickening of the fingertips' skin, Raynaud phenomenon, and mild pedal oedema. Positive anti-centromere antibodies indicated a diagnosis of a limited cutaneous systemic sclerosis. He presented with symptoms of heart failure, and moderate to severe lymphocytic infiltration was evident in his endomyocardial biopsy. He responded well to medical therapy and was discharged. However, one month after hospital discharge, he was readmitted to our institution because of worsening heart failure. Transthoracic echocardiography showed a decrease in left ventricular systolic function and progression of left ventricular remodelling, which caused severe vFMR. Endomyocardial biopsy revealed decreased lymphocytic infiltration and mild myocardial interstitial fibrosis, indicative of scleroderma myocarditis. As he was unable to be weaned off inotropes, we performed M-TEER for severe vFMR, which led to a significant reduction in MR volume and improvement of heart failure symptoms. A week after procedure, immunosuppressive therapy was initiated and the patient was discharged home in stable condition., Discussion: Scleroderma myocarditis may manifest as heart failure with reduced ejection fraction with severe vFMR. Mitral transcatheter edge-to-edge repair for severe vFMR in the context of myocarditis can be one of the therapeutic options for haemodynamic stabilization., Competing Interests: Conflict of interest: T.M. has received honoraria for lectures from Abbott Vascular. S.M. has received honoraria for lectures from Abbott Vascular. The other authors do not have any potential conflict of interest to declare., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Objectives: Sepsis is a systemic inflammatory disorder characterized by life-threateningorgan dysfunction resulting from a dysregulated host response to infection. Prostacyclin (PGI 2 ) is a bioactive lipid produced by PGI synthase (PGIS) and is known to play important roles in inflammatory reactions as well as cardiovascular regulation. However, little is known about the roles of PGIS and PGI 2 in systemic inflammatory responses such as septic shock., Methodology: Systemic inflammation was induced by intraperitoneal injection of 5 mg/kg lipopolysaccharide (LPS) in wild type (WT) or PGIS knockout (KO) mice. Selexipag, a selective PGI 2 receptor (IP) agonist, was administered 2 h before LPS injection and again given every 12 h for 3 days., Results: Intraperitoneal injection of LPS induced diarrhea, shivering and hypothermia. These symptoms were more severe in PGIS KO mice than in WT micqe. The expression of Tnf and Il6 genes was notably increased in PGIS KO mice. In contrast, over 95% of WT mice survived 72 h after the administration of LPS, whereas all of the PGIS KO mice had succumbed by that time. The mortality rate of LPS-administrated PGIS KO mice was improved by selexipag administration., Conclusion: Our study suggests that PGIS-derived PGI 2 negatively regulates LPS-induced symptoms via the IP receptor. PGIS-derived PGI 2 -IP signaling axis may be a new drug target for systemic inflammation in septic shock., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Single-cell transcriptome sequencing (scRNA-seq) has revolutionized our understanding of cellular processes by enabling the analysis of expression profiles at an individual cell level. This technology has shown promise in uncovering new cell types, gene functions, cell differentiation, and trajectory inference through the study of various biological processes, such as hematopoiesis. Recent scRNA-seq analysis of mouse bone marrow cells has provided a network model of hematopoietic lineage. However, all data analyses have predicted undirected network maps for the associated cell trajectories. Moreover, the debate regarding the origin of basophil cells still persists. In this work, we apply the Volatility Constrained (VC) correlation method to predict not only the network structure but also the causality or directionality between the cell types present in the hematopoietic process. Our findings suggest a dual origin of basophils, from both granulocyte/macrophage and erythrocyte progenitors, the latter being a trajectory less explored in previous research. The proposed approach and predictions may assist in developing a complete hematopoietic process map, impacting our understanding of hematopoiesis and providing a robust directional network framework for further biomedical research., Competing Interests: Declaration of competing interest none, (Copyright © 2024 Elsevier B.V. All rights reserved.)

The uncertainty of true labels in medical images hinders diagnosis owing to the variability across professionals when applying deep learning models. We used deep learning to obtain an optimal convolutional neural network (CNN) by adequately annotating data for oral exfoliative cytology considering labels from multiple oral pathologists. Six whole-slide images were processed using QuPath for segmenting them into tiles. The images were labeled by three oral pathologists, resulting in 14,535 images with the corresponding pathologists' annotations. Data from three pathologists who provided the same diagnosis were labeled as ground truth (GT) and used for testing. We investigated six models trained using the annotations of (1) pathologist A, (2) pathologist B, (3) pathologist C, (4) GT, (5) majority voting, and (6) a probabilistic model. We divided the test by cross-validation per slide dataset and examined the classification performance of the CNN with a ResNet50 baseline. Statistical evaluation was performed repeatedly and independently using every slide 10 times as test data. For the area under the curve, three cases showed the highest values (0.861, 0.955, and 0.991) for the probabilistic model. Regarding accuracy, two cases showed the highest values (0.988 and 0.967). For the models using the pathologists and GT annotations, many slides showed very low accuracy and large variations across tests. Hence, the classifier trained with probabilistic labels provided the optimal CNN for oral exfoliative cytology considering diagnoses from multiple pathologists. These results may lead to trusted medical artificial intelligence solutions that reflect diverse diagnoses of various professionals., (© 2024. The Author(s).)

Background: This study aims to explore novel microRNAs in urine for screening and predicting clinical characteristics in pancreatic cancer (PC) patients using a microRNA array-based approach., Methods: We used the Toray ® 3D-Gene microRNA array-based approach to compare urinary levels between PC patients and healthy volunteers., Results: (1) Four oncogenic microRNAs (miR-744-5p, miR-572, miR-210-3p, and miR-575) that were highly upregulated in the urine of PC patients compared to healthy individuals were identified by comprehensive microRNA array analysis. (2) Test-scale analysis by quantitative RT-PCR for each group of 20 cases showed that miR-210-3p was significantly upregulated in the urine of PC patients compared to healthy individuals (P = 0.009). (3) Validation analysis (58 PC patients and 35 healthy individuals) confirmed that miR-210-3p was significantly upregulated in the urine of PC patients compared to healthy individuals (P < 0.001, area under the receiver operating characteristic curve = 0.79, sensitivity: 0.828, specificity: 0.743). We differentiated PC patients into invasive ductal carcinoma (IDCa) and intraductal papillary mucinous carcinoma (IPMC) groups. In addition to urinary miR-210-3p levels being upregulated in IDCa over healthy individuals (P = 0.009), urinary miR-210-3p levels were also elevated in IPMC over healthy individuals (P = 0.0018). Urinary miR-210-3p can differentiate IPMC from healthy individuals by a cutoff of 8.02 with an AUC value of 0.762, sensitivity of 94%, and specificity of 63%. (4) To test whether urinary miR210-3p levels reflected plasma miR-210-3p levels, we examined the correlation between urinary and plasma levels. Spearman's correlation analysis showed a moderate positive correlation (ρ = 0.64, P = 0.005) between miR-210-3p expression in plasma and urine., Conclusions: Urinary miR-210-3p is a promising, non-invasive diagnostic biomarker of PC, including IPMC., Trial Registration: Not applicable., (© 2024. The Author(s).)

Background: Clinical outcomes of Chiari pelvic osteotomy for acetabular dysplasia, including conversion to total hip arthroplasty (THA), have not been adequately explored. The purpose of this study was to examine the long-term results and clinical outcomes of Chiari pelvic osteotomy as the primary outcome and to analyze its prognostic factors as the second outcome., Methods: This study was a multicenter, retrospective cohort study. Ninety-seven patients underwent Chiari pelvic osteotomy at three hospitals between March 1975 and October 1997. The long-term clinical outcomes of Chiari pelvic osteotomy, including conversion to THA and hip pain, were analyzed using the Kaplan-Meier method. In addition, the prognostic factors for conversion to THA after Chiari pelvic osteotomy were evaluated with clinical variables and radiographic parameters., Results: The study included 51 hips in 45 patients (4 men and 41 women) with long-term follow-up. The survival rates assessed by Kaplan-Meier analysis with conversion to THA as an endpoint, were 90.2% (95% confidence interval (CI) 82.0-98.4%) at 20 years and 73.5% (95% CI 61.1-86.0%) at 30 years. In contrast, the Kaplan-Meier survival rates with the Japanese Orthopaedic Association hip score for pain ≤20 as an endpoint, were 86.3% (95% CI 76.8-95.7%) at 20 years and 65.6% (95% CI 52.3-79.0%) at 30 years. Only older age at osteotomy was the significantly poor prognostic factor for conversion to THA, with a hazard ratio of 1.11/year, 95% CI 1.06 to 1.18, (p < 0.01)., Conclusion: Chiari pelvic osteotomy may still be a good alternative to bony reconstructive surgery for acetabular dysplasia especially in young patients. Only older age at the osteotomy was related to the poor prognosis of preserving hip function., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest., (Copyright © 2023 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.)

Background: Aggressive mature T-cell lymphoma (TCL) is a disease that carries a poor prognosis. Methods: We analyzed the expression of 22 tumor cell functional proteins in 16 randomly selected patients with TCL. Immunohistochemistry was performed in paraffin-embedded tumor tissue sections to determine the protein expression statuses in tumor cells. Results: Glucose-regulated protein 94 (GRP94), a protein that serves as a pro-survival component under endoplasmic reticulum (ER) stress in the tumor microenvironment, was significantly associated with a shortened survival. Furthermore, significant differences were observed when GRP94 was combined with six other factors. The six factors were (1) programmed cell death-ligand 1 (PD-L1); (2) programmed cell death 1 (PD-1); (3) aldo-keto reductase family 1 member C3 (AKR1C3); (4) P53, a tumor suppressor; (5) glucose-regulated protein 78 (GRP78), an ER stress protein; and (6) thymidine phosphorylase (TP). Based on the combination of GRP94 and the six other factors expressed in the tumors, we propose a new prognostic classification system for TCL (TCL Urayasu classification). Group 1 (relatively good prognosis): GRP94-negative ( n = 6; median OS, 88 months; p < 0.01); Group 2 (poor prognosis): GRP94-positive, plus expression of two of the six factors mentioned above ( n = 5; median OS, 25 months; p > 0.05); and Group 3 (very poor prognosis): GRP94-positive, plus expression of at least three of the six factors mentioned above ( n = 5; median OS, 10 months; p < 0.01). Conclusions: Thus, the TCL Urayasu prognostic classification may be a simple, useful, and innovative classification that also explains the mechanism of resistance to treatment for each functional protein. If validated in a larger number of patients, the TCL Urayasu classification will enable a targeted treatment using selected inhibitors acting on the abnormal protein found in each patient.

Background/purpose: Although the impact of predicted prosthesis-patient mismatch (PPM P ) on outcomes after surgical aortic valve replacement is well established, studies on PPM P in transcatheter aortic valve replacement (TAVR) are limited. This study investigated the effects of PPM p on haemodynamic and 5-year clinical outcomes after TAVR., Methods/materials: We analysed 1733 patients who underwent TAVR. PPM p was defined using two different methods: 1) normal reference values of the effective orifice area for each valve type and size indexed to body surface area (PPM p1 ; n = 1733) and 2) reference values for aortic annulus area or perimeter assessed with pre-procedural computed tomography indexed to body surface area (PPM p2 ; n = 1227). The primary endpoint was the composite of all-cause death and/or rehospitalisation for heart failure at 5 years., Results: The incidence of PPM p1 was 11.7 % and 0.8 % in moderate and severe cases, respectively. PPM p2 was classified as either moderate (3.8 %) or severe (0 %). Rates of residual mean aortic gradient ≥20 mmHg significantly increased depending on PPM p1 severity (no PPM p1 : 3.1 % vs. moderate PPM p1 : 26.8 % vs. severe PPM p1 : 53.9 %, p < 0.0001) and PPM p2 (no PPM p2 : 4.1 % vs. moderate PPM p2 : 12.8 %, p = 0.0049). Neither of PPM P methods were associated with the composite outcome in total cohort; however, PPM P1 was significantly related to worse clinical outcomes at 5 years among patients with reduced left ventricular ejection fraction (LVEF) in multivariate analysis (HR: 1.87; 95 % CI: 1.02-3.43)., Conclusions: The impact of PPM P on TAVR clinical outcomes may not be negligible in patients with low LVEF., Competing Interests: Declaration of competing interest T.O. has received honoraria for lectures from Medtronic. K.S. has received honoraria for lectures from Medtronic. M.J. has received honoraria for lectures from Edwards Lifesciences and Medtronic. T.V. is a clinical proctor of Edwards Lifesciences (SAPIEN). M.L. reports receiving non-regulatory research grants from Teleflex and consultant fees from Boston Scientific, Edwards Lifesciences, and Medtronic. S.S is a clinical proctor of Edwards Lifesciences (SAPIEN), Medtronic (CoreValve) and Abbott (Navitor). N.M. has received honoraria for lectures from Abbott, Edwards Lifesciences, and Medtronic. And N.M. is a clinical proctor of Edwards Lifesciences (SAPIEN) and Boston Scientific (ACURATE neo), and received a research grant from the Japanese Circulation Society. The other authors have no potential conflicts of interest to declare., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Progression of chronic liver fibrosis and related increased fibrotic markers are associated with functional liver reserves or patient prognosis as well as tumor factors in hepatocellular carcinoma (HCC) patients. The aim of this study was to newly clarify the relationship between fibrotic markers and HCC malignant behaviors or its long-term postoperative prognosis by the retrospective cohort study., Methods: We examined the relationship between tumor-related factors or six liver fibrosis-associated parameters, including platelet count, hyaluronic acid (HA), Mac-2 binding protein glycosylation isomer (M2BPGi), type IV collagen 7S (T4C7), aspartate aminotransferase-to-platelet ratio index (APRI), fibrosis-4 (Fib-4) index, and clinicopathological parameters, surgical records, and postoperative prognosis in 130 HCC who underwent curative hepatectomy., Results: Histological fibrosis stage 4 as cirrhosis was in 31%. The platelet count significantly decreased in stage 4 fibrosis and correlated with grade B liver damage (P<0.01). HA levels were significantly increased in multiple HCC, stage 4 fibrosis, and grade B liver damage (P<0.01). T4C7 was significantly increased in patients with post-hepatectomy tumor recurrence compared to those without (P<0.01). Additionally, M2BPGi was significantly higher in stage 4 fibrosis and liver damage grade B, and was significantly associated with poor prognosis (P<0.05). Fib-4 index was significantly higher in patients with liver damage B (P<0.05), and T4C7 alone did not correlate with other five fibrosis markers. Stage 4 fibrosis, higher T4C7, higher M2BPGi, and increased tumor size were significantly associated with shorter cancer-free, overall, and cancer-specific survivals. Higher T4C7, non-met Milan criteria, liver damage B, blood transfusion, and curability C were independently associated with cancer-specific survivals (P<0.05)., Conclusions: Type IV collagen 7S (T4C7) may reflect not only impaired liver function but also HCC malignant behaviors and patient survivals., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-24-94/coif). The authors have no conflicts of interest to declare., (2024 Translational Cancer Research. All rights reserved.)

Selective dorsal rhizotomy (SDR) has been used to treat children with spastic cerebral palsy (CP), and its beneficial effect on quality of life and ambulation has been confirmed in long-term follow-up studies. However, the role of SDR in the treatment of spasticity in patients with hereditary spastic paraplegia (HSP) and related disorders is not well-established. Here, we report the first patient with the ZC4H2 variant who underwent SDR to treat spastic paraplegia. Abnormal gait was discovered during a regular checkup at the age of 3 years and 9 months, and she was diagnosed with spastic paraplegia. She was heterozygous for the ZC4H2 variant and underwent SDR at the age of 5 years and 11 months, which alleviated the spasticity. The patient underwent inpatient postoperative rehabilitation for 4 months and continued outpatient physiotherapy after discharge. The Gross Motor Function Measure-88 score and maximum walking speed decreased transiently 1 month postoperatively, but gradually recovered, and continuously improved 6 months postoperatively. SDR and postoperative intensive rehabilitation were effective in improving motor and walking functions up to 6 months after surgery, although long-term follow-up is needed to draw conclusions.

Background and Aims: This retrospective study aimed to compare the short- and long-term outcomes of endoscopic submucosal dissection and laparoscopic and endoscopic cooperative surgery in patients with superficial non-ampullary duodenal epithelial tumors., Patients and Methods: We investigated consecutive patients with SNADETs > 10 mm in size who underwent ESD (ESD group) or LECS (LECS group) between January 2015 and March 2021. The data was used to analyze the clinical course, management, survival status, and recurrence between the two groups., Results: A total of 113 patients (100 and 13 in the ESD and LECS groups, respectively) were investigated. The rates of en bloc resection and curative resection were 100% vs. 100% and 93.0% vs. 77.0% in the ESD and LECS groups, respectively, with no significant difference. The ESD group had shorter resection and suturing times than the LECS group, but there were no significant difference after propensity score matching. There were also no differences in the rates of postoperative adverse event (7.0% vs. 23.1%; P = 0.161). The 3-year overall survival (OS) rate was high in both the ESD and LECS groups (97.6% vs. 100%; P = 0.334). One patient in the ESD group experienced recurrence due to liver metastasis; however, no deaths related to SNADETs were observed., Conclusion: ESD and LECS are both acceptable treatments for SNADETs in terms of a high OS rate and a low long-term recurrence rate, thereby achieving a comparable high rate of curative resection. Further studies are necessary to compare the outcomes of ESD and LECS for SNADETs once both techniques are developed further., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

We propose a simple scheme of degenerate spontaneous parametric down-conversion (SPDC) in nonlinear metasurfaces or photonic crystal slabs with quasi-guided modes. It employs a band crossing between even- and odd-parity quasi-guided mode bands inside the light cone (above the light line) and a selection rule in the conversion efficiency of the SPDC. The efficiency can be evaluated fully classically via the inverse process of noncollinear second-harmonic generation (SHG). As a toy model, we study the SPDC and SHG in a monolayer of noncentrosymmetric spheres and confirm that the scenario works well to enhance the SPDC.

Competing Interests: Funding Support and Author Disclosures Dr Ochiai has received honoraria for lectures from Edwards Lifesciences and Medtronic. Dr Moriyama has received honoraria for lectures from Edwards Lifesciences and Medtronic; and has been a clinical proctor for Edwards Lifesciences and Boston Scientific. Dr Shishido has received honoraria for lectures from Abbott Vascular and Medtronic. Dr Saito is a clinical proctor for Edwards Lifesciences, Medtronic, and Abbott Vascular. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Background: Transcatheter aortic valve implantation (TAVI) is an established treatment for severe aortic stenosis (AS), but despite estimates of life expectancy after TAVI being essential in heart team discussion, these data are scarce. Therefore, the current study sought to assess long-term survival and its trends in relation to chronological age, surgical risk, and treatment period., Methods and results: We included 2,414 consecutive patients who underwent TAVI for severe symptomatic AS between 2008 and 2021 at 2 international centers. For the analysis, long-term survival was evaluated according to age, surgical risk, and treatment period categorized into 3 groups, respectively. The longest follow-up was 13.5 years. Overall survival was 67.6% at 5 years and 26.9% at 10 years. Younger patients, lower surgical risk, and later treatment period showed better survival (log-rank P<0.001, respectively). In the multivariate analysis, age <75years, lower surgical risk, and later time period were significantly associated with better survival. The incidence of paravalvular leakage ≥moderate, red blood cell transfusion, and acute kidney injury were independently associated with increasing risk of 5-year death., Conclusions: In a real-world registry, survival was substantial following TAVI, especially in younger and lower surgical-risk patients, with improving outcomes over time. This should be considered in heart team discussions of life-long management for AS patients after TAVI.

Purpose: Chemotherapy for the hemodialysis (HD) patient is a challenging situation because it requires special considerations including dose modifications and timing of drug administration in relation with HD sessions. Polaltuzumab vedotin (PV), an antibody-drug conjugate in which monomethyl auristatin E (MMAE) is linked to an anti-CD79b monoclonal antibody, is an extremely promising therapeutic for treating diffuse large B cell lymphoma (DLBCL), but the pharmacokinetics are unknown in HD patients., Methods: We carried out pharmacokinetic studies of PV when administered at 1.2 mg/kg to a DLBCL patient on HD, and compared the results with that of non-HD patients. PV was administered in conjunction with bendamustine and rituximab., Results: Serum concentration-time curves of both antibodyconjugated and unconjugated MMAE in the presented HD patient were similar compared to that of non-HD patients. We also demonstrate that elimination of both antibody-conjugated and unconjugated MMAE through HD is limited. PV administration at 1.2 mg/kg to an HD patient was also clinically feasible, and no signs of peripheral neuropathy were observed., Conclusions: PV therapy may be a relatively safe treatment method for DLBCL patients on HD., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Sodium-glucose cotransporter-2 inhibitors (SGLT2is) are widely used in cardiology and are effective in treating acute coronary syndrome (ACS). Their effects on unstable plaque in patients with ACS remains unclear. This study aimed to examine the effectiveness of SGLT2is in coronary plaque based on optical coherence tomography (OCT) images and the prognosis of ACS with type 2 diabetes mellitus. This retrospective study included 109 patients in the total cohort and 29 patients in the OCT cohort. Based on SGLT2i administration after ACS, the total cohort was categorized into non-SGLT2i (n = 69) and SGLT2i (n = 40) groups. The OCT cohort had 15 and 14 patients in the non-SGLT2i and SGLT2i groups, respectively. The OCT images of unstable plaque were analyzed in nonstented lesions during ACS catheterization and at the 6-month follow-up. The total cohort was assessed after 1 year for major adverse cardiovascular events, including all-cause mortality, revascularization, cerebrovascular disease, and heart failure hospitalization. SGLT2is improved unstable lesions with a significantly thicker fibrous cap (48 ± 15 μm vs 26 ± 24 μm, p = 0.005), reduced lipid arc (-29 ± 12° vs -18 ± 14°, p = 0.028), higher % decrease in total lipid arc (-35 ± 13% vs -19 ± 18%, p = 0.01), and lower major adverse cardiovascular event incidence (log-rank p = 0.023, hazard ratio 4.72 [1.08 to 20.63]) and revascularization rate (adjusted hazard ratio 6.77 [1.08 to 42.52]) than the non-SGLT2i group. In conclusion, SGLT2is can improve the markers of plaque stability and may improve the prognosis in patients with type 2 diabetes mellitus., Competing Interests: Declaration of competing interest The authors have no competing interest to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Preexisting right bundle branch block (RBBB) is the strongest predictor for permanent pacemaker implantation (PPI) after transcatheter aortic valve implantation (TAVI). However, the risk assessment for new PPI and effective procedural strategy for preventing new PPI in patients with preexisting RBBB are still unclear. This study stratified the new PPI risk after TAVI and investigated the impact of implantation strategy in a preexisting RBBB cohort. We analyzed 237 patients with preexisting RBBB who underwent TAVI. The primary endpoint was the incidence of new PPI. Multivariate analyses investigating predictors for new PPI were performed. The overall PPI rate was 33.3%. Significant baseline predictors for new PPI were combination of RBBB, left anterior or posterior fascicular block, and first-degree atrioventricular block (odds ratio [OR] 2.55, 95% confidence interval [CI] 1.09 to 5.04), high calcium volume of noncoronary cusp (OR 2.08, 95% CI 1.05 to 4.10), and membranous septum (MS) length <2 mm (OR 2.02, 95% CI 1.09 to 3.75) in the univariate analysis and MS length <2 mm (OR 2.25, 95% CI 1.06 to 4.82) in the multivariate analysis. On the multivariate analysis including procedural variables, predilatation (OR 2.41, 95% CI 1.01 to 5.83), self-expanding valves (Corevalve, Evolut R, and Evolut Pro/Pro+; Medtronic Inc., Minneapolis, Minnesota) or mechanical expanding valves (Lotus/Lotus Edge; Boston Scientifics, Marlborough, Massachusetts) (OR 3.00, 95% CI 1.31 to 6.91), and implantation depth > MS length (OR 4.27, 95% CI 1.81 to 10.08) were significantly associated with new PPI. The incidence of new PPI increased according to the number of baseline predictors (0: 20.9%, 1: 34.3%, and ≥2: 52.0%) and procedural predictors (0: 3.7%, 1: 20.9%, 2: 40.5%, and 3: 60.0%). New PPI risk in a preexisting RBBB subset could be stratified by baseline factors. Device selection and implantation strategy considering MS length could prevent new PPI even in these high-risk population., Competing Interests: Declaration of competing interest Dr. Moriyama reports financial support was provided by the Japanese Circulation Society. Dr. Ochiai reports a relation with Medtronic Inc that includes: speaking and lecture fees. Dr. Shishido reports a relation with Medtronic Inc that includes: speaking and lecture fees. Dr. Laine reports a relation with Teleflex Inc that includes: funding grants. Dr. Laine reports a relation with Boston Scientific Corp that includes: consulting or advisory. Dr. Laine reports a relation with Edwards Lifesciences Corporation that includes: consulting or advisory. Dr. Laine reports a relation with Medtronic Inc that includes: consulting or advisory. Dr. Moriyama reports a relation with Abbott that includes: speaking and lecture fees. Dr. Moriyama reports a relation with Edwards Lifesciences Corporation that includes: speaking and lecture fees. Dr. Moriyama reports a relation with Medtronic Inc that includes: speaking and lecture fees. Coauthors are clinical proctors of Edwards Lifesciences (SAPIEN) – Drs. Vähäsilta, Saito, and Moriyama. Co-author is a clinical proctor of Medtronic (CoreValve) – Dr. Saito. Co-author is a clinical proctor of Abbott (Navitor) – Dr. Saito Co-author is a clinical proctor of Boston Scientific (ACURATE neo) – Dr. Moriyama. The remaining authors have no competing interests to declare., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Stress fractures of the proximal phalanx of the great toe are primarily attributed to repetitive shear forces, with the vertical ground reaction forces exerting several times the body weight. In the initial stages of injury, conservative management anticipates bone healing within approximately five weeks, followed by a gradual return to sports activities over an additional five weeks. Athletes presenting with pain in this region warrant a thorough evaluation for stress fractures to initiate timely conservative care. In instances of delayed healing or non-union, surgical intervention is indicated. However, literature on the management and optimal timing of surgery, particularly in adolescent athletes, remains sparse. This case report, complemented by a literature review, offers insights into management based on the patient's clinical course., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Sakakibara et al.)

Hyperplastic dental follicles (HDFs) represent odontogenic hamartomatous lesions originating from the pericoronal tissues and are often associated with impacted or embedded teeth. These lesions may occasionally feature unique calcifying bodies, known as calcifying whorled nodules (CWNs), characterized by stromal cells arranged in a whorled or spiral fashion. CWNs are typically observed in multiple calcifying hyperplastic dental follicles or regional odontodysplasia. In our study, we examined 40 cases of HDFs, including nine instances with characteristics of CWNs, referred to as calcifying hyperplastic dental follicles (CHDFs), which are infrequently accompanied by odontodysplasia. The median ages of the HDFs and CHDFs were 16 (ranging from 3 to 66) and 15 (ranging from 11 to 50) years, respectively. The lower third molars were the most frequently affected by HDSFs and CHDFs, followed by the upper canines. A histological examination was conducted on all 40 cases, with an immunohistochemical analysis performed on 21 of them. Among the cases with CWN, nine affected a single embedded tooth, with one exception. CWNs exhibited diverse calcifications featuring sparse or entirely deposited psammoma bodies, and some displayed dentinoid formation. Immunohistochemically, the stromal cells of HDFs were frequently positive for CD56 and nestin. By contrast, CWNs were negative for CD56 but positive for nestin as well as hairy and enhancer split 1 (HES1), with a few dentin sialoprotein (DSP)-positive calcified bodies. Our results revealed that hamartomatous CHDFs can impact multiple and single-embedded teeth. CWNs composed of nestin and HES1-positive ectomesenchymal cells demonstrated the potential to differentiate into odontoblasts and contribute to dentin matrix formation under the influence of HES1. This study is the first report documenting odontoblastic differentiation in HDFs. The rare occurrence of HDFs and CHDFs contributes to limited comprehension. To prevent misdiagnosis, a better understanding of these conditions is necessary.

We aimed to clarify the long-term outcomes and prognosis of vocal cord paralysis (VCP) after cardiothoracic surgery in infants as well as the usefulness of laryngeal ultrasound (LUS) as screening for VCP. Overall, 967 infants aged 1-year-old or younger who underwent cardiothoracic surgery between 2008 and 2022 were included in this study. We divided the patients into two groups based on the period on whether they underwent screening without or with LUS and compared the incidence of VCP between the groups. There were no differences in the patients' preoperative characteristics between the two periods, whereas the incidence of VCP was significantly higher in period 2 than in period 1 (11.0% vs. 3.2%, p < 0.0001). The incidence of VCP among the procedures, including aortic arch repair, was > 50% and significantly increased from period 1 to period 2. The sensitivity and specificity of LUS was 87% and 90%, respectively. Symptoms of VCP improved in 92% of patients. Repeated flexible laryngoscopy revealed that the residual rate of VCP was 68%, 52%, and 48% at 6, 12, and 24 months, respectively. In conclusion, symptoms of postoperative VCP improved in most cases; however, paralysis persisted in half of the patients. As a screening method, LUS is useful for evaluating postoperative VCP. A more accurate understanding of VCP is needed to improve postoperative outcomes., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Risk-adapted therapy is recommended to prevent major clinical complications, such as thrombo-haemorrhagic events, in patients with essential thrombocythaemia (ET). In this study, we analysed the association between non-driver gene mutations and thrombo-haemorrhagic events in 579 patients with ET. ASXL1 and TP53 mutations were frequently identified in patients with ET complicated by thrombosis (22.7% and 23.1%, respectively), and the DNMT3A mutation was frequently identified in patients who experienced haemorrhage (15.2%). Multivariate analyses of thrombosis-free survival (TFS) revealed that ASXL1 and TP53 mutations are associated with thrombosis (hazard ratio [HR] = 3.140 and 3.752 respectively). Patients harbouring the ASXL1 or TP53 mutation had significantly worse TFS rates than those without mutation (p = 0.002 and p < 0.001 respectively). Furthermore, JAK2V617F-mutated patients with accompanying ASXL1 mutations showed significantly shorter TFS compared with those without ASXL1 mutations (p = 0.003). Multivariate analyses of haemorrhage-free survival (HFS) revealed that the DNMT3A mutation (HR = 2.784) is associated with haemorrhage. DNMT3A-mutated patients showed significantly shorter HFS than those without the mutation (p = 0.026). Non-driver gene mutations should be considered in treatment strategies and may provide important information for personalised treatment approaches., (© 2023 British Society for Haematology and John Wiley & Sons Ltd.)

Background: Conduction disturbances and the need for permanent pacemaker (PPM) implantation remains a common complication for transcatheter aortic valve replacement (TAVR), particularly when self-expanding (SE) valves are used., Aims: We compared in-hospital and 30-day rates of new PPM implantation between patients undergoing TAVR with SE valves using the conventional three-cusp coplanar implantation technique and the cusp-overlap technique., Methods: We retrospectively compared patients without a pre-existing PPM who underwent a TAVR procedure with SE Evolut R or PRO valves using the cusp-overlap technique from July 2018 to September 2020 (n = 519) to patients who underwent TAVR using standard three-cusp technique from April 2016 to March 2017 (n = 128) in two high volume Canadian centers., Results: There was no significant difference in baseline RBBB between the groups (10.4% vs. 13.2; p = 0.35). The rate of in-hospital new complete heart block (9.4% vs. 23.4%; p ≤ 0.001) and PPM implantation (8% vs. 21%; p ≤ 0.001) were significantly reduced when using the cusp-overlap technique. The incidence of new LBBB (30.4% vs. 29%; p = 0.73) was similar. At 30 days, the rates of new complete heart block (11% vs. 23%; p ≤ 0.001) and PPM implantation (10% vs. 21%, p ≤ 0.001) remained significantly lower in the cusp-overlap group, while the rate of new LBBB (35% vs. 30%; p = 0.73) was similar., Conclusion: Cusp-overlap approach offers several potential technical advantages compared to standard three-cusp view, and may result in lower PPM rates in TAVR with SE Evolut valve., (© 2023 The Authors. Catheterization and Cardiovascular Interventions published by Wiley Periodicals LLC.)

Introduction: Esophagogastroduodenoscopy is the most important tool to detect gastric cancer (GC). In this study, we developed a computer-aided detection (CADe) system to detect GC with white light imaging (WLI) and linked color imaging (LCI) modes and aimed to compare the performance of CADe with that of endoscopists., Methods: The system was developed based on the deep learning framework from 9,021 images in 385 patients between 2017 and 2020. A total of 116 LCI and WLI videos from 110 patients between 2017 and 2023 were used to evaluate per-case sensitivity and per-frame specificity., Results: The per-case sensitivity and per-frame specificity of CADe with a confidence level of 0.5 in detecting GC were 78.6% and 93.4% for WLI and 94.0% and 93.3% for LCI, respectively (p < 0.001). The per-case sensitivities of nonexpert endoscopists for WLI and LCI were 45.8% and 80.4%, whereas those of expert endoscopists were 66.7% and 90.6%, respectively. Regarding detectability between CADe and endoscopists, the per-case sensitivities for WLI and LCI were 78.6% and 94.0% in CADe, respectively, which were significantly higher than those for LCI in experts (90.6%, p = 0.004) and those for WLI and LCI in nonexperts (45.8% and 80.4%, respectively, p < 0.001); however, no significant difference for WLI was observed between CADe and experts (p = 0.134)., Conclusions: Our CADe system showed significantly better sensitivity in detecting GC when used in LCI compared with WLI mode. Moreover, the sensitivity of CADe using LCI is significantly higher than those of expert endoscopists using LCI to detect GC., (© 2024 S. Karger AG, Basel.)

Understanding the genetic mechanisms that underlie innate fear behavior is essential for improving the management and performance of the poultry industry. This study aimed to map QTL associated with innate fear responses in open field (OF) and tonic immobility (TI) tests, using an F2 chicken intercross population between 2 behaviorally distinct breeds: the aggressive Japanese Oh-Shamo (OSM) and the docile White Leghorn T-line (WL-T). Genome-wide QTL analysis for the OF and TI traits was conducted using 2,109 single nucleotide polymorphism (SNP) markers obtained through restriction site-associated DNA sequencing (RAD-seq). While several suggestive QTL were identified for TI and OF traits at genome-wide 20% significance threshold levels, the analysis revealed 2 significant QTL for 2 OF traits (total distance and maximum speed) at genome-wide 5% significance threshold levels. These significant QTL were located between 12.34 and 30.49 megabase (Mb) on chromosome 1 and between 40.02 and 63.38 Mb on chromosome 2, explaining 6.75 to 7.40% of the total variances. These findings provide valuable insights for the poultry industry, particularly in refining chicken management strategies and informing targeted breeding efforts., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

After endoscopic treatment for esophageal cancer, a 65-year-old male underwent surveillance esophagogastroduodenoscopy. A 12-mm discolored flat lesion was noted on the greater curvature of the middle gastric body. Magnifying endoscopy with blue laser imaging demonstrated an irregular papillary surface. Biopsy revealed atypical cells with mucus and irregularly distributed nuclei. The lesion was diagnosed as a gastric-type neoplasm with low atypia. Thereafter, endoscopic submucosal dissection (ESD) was conducted and specimen was sent for biopsy. The ESD specimen suggested a signet-ring cell carcinoma with MUC5AC-positive phenotype and adenocarcinoma of the fundic gland type, with MUC6 positivity and pepsinogen I positivity in the shallow and deeper layers, respectively. Moreover, the cervical region of fundic glands demonstrated a transformation zone of the signet-ring cell carcinoma into an adenocarcinoma of the fundic gland type. Herein, we report this rare case along with a literature review.

Objectives: Since MPL mutation is a rare driver gene mutation found in a small number of essential thrombocythemia (ET) patients, the clinical characteristics of patients with MPL mutations and their association with thrombotic events have not yet been elucidated in Japan., Methods: We enrolled 579 Japanese ET patients based on the diagnostic criteria of the WHO classification 2017 and compared clinical characteristics of MPL -mutated patients ( n  = 22; 3.8%) to JAK2 V617F-mutated ( n  = 299; 51.6%), CALR -mutated ( n  = 144; 24.9%), and triple-negative (TN) ( n  = 114; 19.7%) patients., Results: Thrombosis during follow up was observed in 4 out of 22 (18.2%) in the MPL -mutated group, which was the highest among all driver gene mutation groups ( JAK2 V617F-mutated, 8.7%; CALR -mutated, 3.5%; TN,1.8%). The MPL- and JAK2 V617F-mutated groups had worse thrombosis-free survival (TFS) than the CALR -mutated ( p  = 0.043) and TN groups ( p  = 0.006). Univariable analysis revealed that a history of thrombosis was a possible risk factor for thrombosis among MPL -mutated patients (hazard ratio: 9.572, p  = 0.032)., Conclusions: MPL -mutated ET patients should require more intensive management to prevent recurrence of thrombosis.

Long-chain acyl-CoA synthetase 4 (ACSL4) converts free highly unsaturated fatty acids (HUFAs) into their acyl-CoA esters and is important for HUFA utilization. HUFA-containing phospholipids produced via ACSL4-dependent reactions are involved in pathophysiological events such as inflammatory responses and ferroptosis as a source for lipid mediators and/or a target of oxidative stress, respectively. However, the in vivo role of ACSL4 in inflammatory responses is not fully understood. This study sought to define the effects of ACSL4 deficiency on lipopolysaccharide (LPS)-induced systemic inflammatory responses using global Acsl4 knockout (Acsl4 KO) mice. Intraperitoneal injection of LPS-induced more severe symptoms, including diarrhea, hypothermia, and higher mortality, in Acsl4 KO mice within 24 h compared with symptoms in wild-type (WT) mice. Intestinal permeability induced 3 h after LPS challenge was also enhanced in Acsl4 KO mice compared with that in WT mice. In addition, plasma levels of some eicosanoids in Acsl4 KO mice 6 h post-LPS injection were 2- to 9-fold higher than those in WT mice. The increased mortality observed in LPS-treated Acsl4 KO mice was significantly improved by treatment with the general cyclooxygenase inhibitor indomethacin with a partial reduction in the severity of illness index for hypothermia, diarrhea score, and intestinal permeability. These results suggest that ACSL4 deficiency enhances susceptibility to endotoxin at least partly through the overproduction of cyclooxygenase-derived eicosanoids., (© 2023 Federation of American Societies for Experimental Biology.)

Polphylipoprotein (PLP) is a recently developed nanoparticle with high biocompatibility and tumor selectivity, and which has demonstrated unprecedentedly high performance photosensitizer in photodynamic therapy (PDT) and photodynamic diagnosis. On the basis of these discoveries, PLP is anticipated to have a very high potential for PDT. However, the mechanism by which PLP kills cancer cells effectively has not been sufficiently clarified. To comprehensively understand the PLP-induced PDT processes, we conduct multifaceted experiments using both normal cells and cancer cells originating from the same sources, namely, RGM1, a rat gastric epithelial cell line, and RGK1, a rat gastric mucosa-derived cancer-like mutant. We reveal that PLP enables highly effective cancer treatment through PDT by employing a unique mechanism that utilizes the process of autophagy. The dynamics of PLP-accumulated phagosomes immediately after light irradiation are found to be completely different between normal cells and cancer cells, and it becomes clear that this difference results in the manifestation of the characteristic effect of PDT when using PLP. Since PLP is originally developed as a drug delivery agent, this study also suggests the potential for intracellular drug delivery processes through PLP-induced autophagy., (© 2023. The Author(s).)

Background: Black esophagus, or acute esophageal necrosis (AEN), is a rare disease with a poor prognosis in which the esophageal mucosa is black in color. We report a case of esophageal perforation due to AEN that was successfully treated., Case Presentation: An 88-year-old woman presented to her local hospital with the chief complaint of abdominal pain. Endoscopic and radiological examinations revealed esophageal perforation due to AEN and duodenal perforation. Omental patch repair was performed for the esophageal perforation, and the duodenal ulcer perforation was treated by simple closure and gastrojejunostomy at the local hospital. Following refractory esophageal and duodenal perforations after the initial surgery, the patient was transferred to our hospital where emergent surgery was performed, comprising thoracoscopic esophagectomy, cervical esophagostomy, T-tube drainage, and omentopexy for duodenal perforation, as well as thoracic and abdominal drainage. Mucosal regeneration of the esophagostomy was confirmed endoscopically on postoperative day 19., Conclusions: Appropriate surgical intervention may be an optimal option in patients with esophageal perforation due to AEN., (© 2023. The Author(s).)

The structural diversity of chemical libraries, which are systematic collections of compounds that have potential to bind to biomolecules, can be represented by chemical latent space. A chemical latent space is a projection of a compound structure into a mathematical space based on several molecular features, and it can express structural diversity within a compound library in order to explore a broader chemical space and generate novel compound structures for drug candidates. In this study, we developed a deep-learning method, called NP-VAE (Natural Product-oriented Variational Autoencoder), based on variational autoencoder for managing hard-to-analyze datasets from DrugBank and large molecular structures such as natural compounds with chirality, an essential factor in the 3D complexity of compounds. NP-VAE was successful in constructing the chemical latent space from large-sized compounds that were unable to be handled in existing methods, achieving higher reconstruction accuracy, and demonstrating stable performance as a generative model across various indices. Furthermore, by exploring the acquired latent space, we succeeded in comprehensively analyzing a compound library containing natural compounds and generating novel compound structures with optimized functions., (© 2023. The Author(s).)

The optimal percent oversizing (%OS) using the SAPIEN3 Ultra (S3U) weighing the incidence of paravalvular regurgitation (PVR) ≥ mild against the risk of conduction disturbance (CD) is not known. This study sought to define an optimal extent of the annulus area %OS suitable for transcatheter aortic valve implantation with the S3U compared with the SAPIEN3 (S3). A total of 350 patients with the S3U were compared with 606 patients with the S3. Patients were categorized depending on the degree of %OS. PVR ≥ mild was observed in 8.9% of patients with the S3U and in 21.8% of those with the S3 (p <0.001). The S3U demonstrated a sustainably lower incidence of PVR ≥ mild than the S3 in any extent of %OS. There was an inverse proportional relation between the extent of %OS and frequency of PVR ≥ mild in the S3, whereas the S3U group provided little change. The incidences of PVR ≥ mild were steady >5%OS in the S3 (5% to 10%OS: 13.3%, and >10%OS: 12.1%) and >0%OS in the S3U (0% to 5%OS: 5.9%, 5% to 10%OS: 6.0%, and >10%OS: 6.1%). An increasing %OS was independently associated with the occurrence of CD (<0%OS: 9.8%, 0% to 5%OS: 13.1%, 5% to 10%OS: 16.6%, and >10%OS: 19.2%, p = 0.012). The incidence of PVR ≥ mild and/or CD was the lowest (10.1%) in the 0% to 5%OS in patients with the S3U. In conclusion, the HomoSAPIEN2 study suggests that the S3U tolerates a lesser degree of %OS for mitigating PVR ≥ mild than the S3. Minimal %OS, ranging from 0% to 5%, may be optimal for the S3U with balancing the risk of PVR and CD. Trial Identifier: UMIN000040413/URL: https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr&#95;view.cgi?recptno=R000046115., Competing Interests: Declaration of Competing Interest Dr. Moriyama has received honoraria for lectures from Abbott, Edwards Lifesciences, and Medtronic, is a clinical proctor of Edwards Lifesciences (SAPIEN) and Boston Scientific (ACURATE neo), and received a research grant from the Japanese Circulation Society. Dr. Ochiai has received honoraria for lectures from Medtronic. Dr. Shishido has received honoraria for lectures from Medtronic. Dr. Vähäsilta is a clinical proctor of Edwards Lifesciences (SAPIEN). Dr. Laine reports receiving nonregulatory research grants from Teleflex and consultant fees from Boston Scientific, Edwards Lifesciences, and Medtronic. Dr. Saito is a clinical proctor of Edwards Lifesciences (SAPIEN), Medtronic (CoreValve), and Abbott (Navitor). The remaining authors have no competing interests to declare., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

The insulin/IGF-1 signaling (IIS) regulates a wide range of biological processes, including aging and lifespan, and has also been implicated in the pathogenesis of Alzheimer's disease (AD). We and others have reported that reduced signaling by genetic ablation of the molecules involved in IIS (e.g., insulin receptor substrate 2 [IRS-2]) markedly mitigates amyloid plaque formation in the brains of mouse models of AD, although the molecular underpinnings of the amelioration remain unsolved. Here, we revealed, by a transcriptomic analysis of the male murine cerebral cortices, that the expression of genes encoding extracellular matrix (ECM) was significantly upregulated by the loss of IRS-2. Insulin signaling activity negatively regulated the phosphorylation of Smad2 and Smad3 in the brain, and suppressed TGF-β/Smad-dependent expression of a subset of ECM genes in brain-derived cells. The ECM proteins inhibited Aβ fibril formation in vitro , and IRS-2 deficiency suppressed the aggregation process of Aβ in the brains of male APP transgenic mice as revealed by injection of aggregation seeds in vivo Our results propose a novel mechanism in AD pathophysiology whereby IIS modifies Aβ aggregation and amyloid pathology by altering the expression of ECM genes in the brain. SIGNIFICANCE STATEMENT The insulin/IGF-1 signaling (IIS) has been recognized as a regulator of aging, a leading risk factor for the onset of Alzheimer's disease (AD). In AD mouse models, genetic deletion of key IIS molecules markedly reduces the amyloid plaque formation in the brain, although the molecular underpinnings of this amelioration remain elusive. We found that the deficiency of insulin receptor substrate 2 leads to an increase in the expression of various extracellular matrices (ECMs) in the brain, potentially through TGF-β/Smad signaling. Furthermore, some of those ECMs exhibited the potential to inhibit amyloid plaque accumulation by disrupting the formation of Aβ fibrils. This study presents a novel mechanism by which IIS regulates Aβ accumulation, which may involve altered brain ECM expression., (Copyright © 2023 the authors.)

Background: Odontogenic keratocysts constitute 10%-20% of odontogenic cysts and exhibit a distinctive corrugated parakeratinized lining epithelium. Considering that cornified envelope formation is an important phenomenon during keratinocyte differentiation, this study aimed to clarify the characteristics of cornified envelope formation in odontogenic keratocysts., Methods: We investigated the cellular distribution of cornified envelope-related proteins (transglutaminases and their substrates), as well as the upstream regulatory protein c-Fos, by immunohistochemical analysis of the lining epithelium of 20 odontogenic keratocysts. We examined the corresponding mRNA levels by quantitative polymerase chain reaction. Ten dentigerous cysts served as control non-keratinized cysts., Results: The distributions of transglutaminase and their substrates except loricrin and small protein-rich protein 1a significantly differed between odontogenic keratocysts and dentigerous cysts. There was no significant difference in c-Fos expression between odontogenic keratocysts and dentigerous cysts. The mRNA levels of transglutaminases and their substrates were significantly higher in odontogenic keratocysts than in dentigerous cysts. However, c-Fos mRNA levels did not significantly differ between groups., Conclusion: Surprisingly, the overall appearance of cornified envelope-related proteins of odontogenic keratocysts was consistent with the characteristics of non-keratinized oral mucosa identified in previous studies. These findings indicate that the contribution of cornified envelope-related molecules in odontogenic keratocysts is similar to that in non-keratinized oral epithelium, rather than keratinized oral epithelium, suggesting that odontogenic keratocysts are not genuine keratinized cysts. The upregulation of cornified envelope-related genes in odontogenic epithelium could be an important pathognomonic event during odontogenic keratocyst development., (© 2023 The Authors. Journal of Oral Pathology & Medicine published by John Wiley & Sons Ltd.)