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Sari Mishina,1 Yuichiro Ito,1 Takumi Lee,1 Toshiaki Murofushi,2 Yoshiyuki Uetake,2 Tadao Akizawa3 1Astellas Pharma Inc, Tokyo, Japan; 2INTAGE Healthcare Inc, Tokyo, Japan; 3Division of Nephrology, Department of Medicine, Showa University School of Medicine, Tokyo, JapanCorrespondence: Sari Mishina, Astellas Pharma Inc, 2-5-1, Nihonbashi-Honcho, Chuo-ku, Tokyo, Japan, Tel +81-3-3244-0294, Email sari.mishina@astellas.comBackground: Several treatment options are available for anemia associated with chronic kidney disease (CKD); however, there remains a lack of awareness of physician and patient preferences regarding these treatments. We aimed to explore physicians’ and patients’ perceptions and preferences regarding the management of anemia of CKD in Japan.Methods: A web-based survey, including best-worst scaling (BWS), was conducted with physicians who had treated ≥ 1 patient with anemia of CKD in the preceding year, and with patients with CKD who self-reported a clinical diagnosis of anemia of CKD or low hemoglobin levels. A three-step approach was used comprising cognitive interviews, a pilot survey, and a main survey. The BWS survey results were analyzed using multinomial logit and hierarchical Bayesian models.Results: The survey was completed by 906 participants: 103 patients (average age 60.6 years; 77.7% male) and 803 physicians (166 nephrologists, 214 cardiologists, 137 diabetologists, and 286 general internists). Almost all (96.0%) physicians surveyed considered anemia of CKD to be an important condition to treat. Hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitors had the highest treatment satisfaction among physicians, whereas patients had the highest satisfaction with both erythropoietin-stimulating agent therapy and HIF-PH inhibitors. Approximately one-third (35.9%) of patients surveyed indicated that they were receiving treatment. When comparing the relative importance of attributes and levels, physicians favored efficacy (particularly improvement in hemoglobin levels), whereas patients favored safety (particularly a lower rate of severe adverse events).Conclusion: Although a majority of physicians consider treatment of CKD-related anemia important, differences in the perceptions and usage of medications exist between medical specialties. Preferences for the management of anemia of CKD vary between physicians and patients; therefore, patient involvement in treatment decisions may help optimize outcomes.Keywords: anemia, best-worst scaling, chronic kidney disease, erythropoiesis-stimulating agents, hypoxia-inducible factor prolyl hydroxylase inhibitors, treatment preference

Detecting crustal deformation during transient deformation events at offshore subduction zones remains challenging. The spatiotemporal evolution of slow slip events (SSEs) on the offshore Hikurangi subduction zone, New Zealand, during February–July 2019, is revealed through a time‐dependent inversion of onshore and offshore geodetic data that also accounts for spatially varying elastic crustal properties. Our model is constrained by seafloor pressure time series (as a proxy for vertical seafloor deformation), onshore continuous Global Navigation Satellite System (GNSS) data, and Interferometric Synthetic Aperture Radar displacements. Large GNSS displacements onshore and uplift of the seafloor (10–33 mm) require peak slip during the event of 150 to >200 mm at 6–12 km depth offshore Hawkes Bay and Gisborne, comparable to maximum slip observed during previous seafloor pressure deployments at north Hikurangi. The onshore and offshore data reveal a complex evolution of the SSE, over a period of months. Seafloor pressure data indicates the slow slip may have persisted longer near the trench than suggested by onshore GNSS stations in both the Gisborne and Hawkes Bay regions. Seafloor pressure data also reveal up‐dip migration of SSE slip beneath Hawke Bay occurred over a period of a few weeks. The SSE source region appears to coincide with locations of the March 1947 Mw 7.0–7.1 tsunami earthquake offshore Gisborne and estimated great earthquake rupture sources from paleoseismic investigations offshore Hawkes Bay, suggesting that the shallow megathrust at north and central Hikurangi is capable of both seismic and aseismic rupture. Plain Language Summary: Subduction zones, where one tectonic plate dives beneath another, generate the planet's largest earthquakes. They also host an important mode of fault slip called "slow slip events (SSEs)," which are essentially earthquakes in slow motion. The Hikurangi subduction zone, where the Pacific Plate subducts beneath New Zealand hosts large and frequent SSEs near the trench, where the plate boundary emerges at the seabed, requiring seafloor instrumentation to investigate them. Seafloor pressure measurements can track centimeter‐level up or down movement of the seafloor during slow slip, and reveal offshore displacement during a large 2019 SSE at the Hikurangi subduction zone. The 2019 event involved substantial migration, beginning at ∼15 km depth, and expanding to the trench over a period of several weeks. We also show that the same areas which have ruptured in previous seismic earthquakes (that involved faster slip) can also rupture slowly, in SSEs. This raises the possibility that regions where we currently observe SSEs could also produce seismic events. This result also demands that more work must be done to understand the physical processes that enable the same part of a fault to rupture both fast and slow at different times. Key Points: Central Hikurangi slow slip events (SSEs) propagate up‐dip over a period of weeks to monthsSeafloor geodetic data reveal that shallow SSEs may last longer than onshore Global Navigation Satellite System data suggestThe same portions of a shallow megathrust can host both large seismic and aseismic rupture [ABSTRACT FROM AUTHOR]

Pulsating Aurora (PsA) is one of the major classes of diffuse aurora associated with precipitation of a few to a few tens of keV electrons from the magnetosphere. Recent studies suggested that, during PsA, more energetic (i.e., sub‐relativistic/relativistic) electrons precipitate into the ionosphere at the same time. Those electrons are considered to be scattered at the higher latitude part of the magnetosphere by whistler‐mode chorus waves propagating away from the magnetic equator. However, there have been no actual cases of simultaneous observations of precipitating electrons causing PsA (PsA electrons) and chorus waves propagating toward higher latitudes; thus, we still do not quite well understand under what conditions PsA electrons become harder and precipitate to lower altitudes. To address this question, we have investigated an extended interval of PsA on 12 January 2021, during which simultaneous observations with the Arase satellite, ground‐based all‐sky imagers and the European Incoherent SCATter (EISCAT) radar were conducted. We found that, when the PsA shape became patchy, the PsA electron energy increased and Arase detected intense chorus waves at magnetic latitudes above 20°, indicating the propagation of chorus waves up to higher latitudes along the field line. A direct comparison between the irregularities of the magnetospheric electron density and the emission intensity of PsA patches at the footprint of the satellite suggests that the PsA morphology and the energy of PsA electrons are determined by the presence of "magnetospheric density ducts," which allow chorus waves to travel to higher latitudes and thereby precipitate more energetic electrons. Plain Language Summary: Pulsating Aurora (PsA) is a kind of diffuse aurora associated with periodic precipitation of energetic electrons from the near‐Earth space into the atmosphere. Recent research has shown that, during PsA events, energetic particles at the sub‐relativistic energy range precipitate into the atmosphere. We speculate that such particles are scattered by wave‐particle resonance with natural electromagnetic waves, called chorus waves, at higher magnetic latitude regions. However, there has been no experimental case of PsA during which propagation of the chorus waves to higher magnetic latitudes was confirmed; thus, we still do not fully understand when and why PsA electrons become more energetic. Here, we investigate a PsA event on 12 January 2021, simultaneously observed by the Arase satellite, ground‐based all‐sky imagers and the European Incoherent SCATter (EISCAT) radar. We found that, when the PsA shape was patchy, the energy of precipitating electrons increased and chorus waves were observed at high latitudes in the magnetosphere. Comparing the magnetospheric electron density with the PsA brightness seen from the ground, we suggest that both the PsA shape and the energy of precipitating electrons were influenced by the so‐called magnetospheric ducts, which guide chorus waves to high‐latitudes regions where they interact with more energetic electrons. Key Points: Examined simultaneous observations of Pulsating Aurora (PsA) with the Arase satellite, ground‐based all‐sky imagers, and the EISCAT radarFound a relationship among the patchy PsA, the enhanced energy of PsA electrons, and the chorus wave propagation to high‐latitudes (>20°)Arase observations suggest that the observed relationship can be explained by the ducted propagation of chorus waves [ABSTRACT FROM AUTHOR]

Deprotonation or suppression of the p K a of the amino group of a lysine sidechain is a widely recognized phenomenon whereby the sidechain amino group transiently can act as a nucleophile at the active site of enzymatic reactions. However, a deprotonated lysine and its molecular interactions have not been directly experimentally detected. Here, we demonstrate a deprotonated lysine stably serving as an "acceptor" in a H-bond between the photosensor protein RcaE and its chromophore. Signal splitting and trans-H-bond J coupling observed by NMR spectroscopy provide direct evidence that Lys261 is deprotonated and serves as a H-bond acceptor for the chromophore NH group. Quantum mechanical/molecular mechanical calculations also indicate that this H-bond exists stably. Interestingly, the sidechain amino group of the lysine can act as both donor and acceptor. The remarkable shift in the H-bond characteristics arises from a decrease in solvation, triggered by photoisomerization. Our results provide insights into the dual role of this lysine. This mechanism has broad implications for other biological reactions in which lysine plays a role., Competing Interests: Competing interests statement:The authors declare no competing interest.

Background: Childhood neurodegenerative diseases often pose a challenge to clinicians to diagnose because of the degree of genetic heterogeneity and variable presentations. Here, we present a child with progressive neurodegeneration consisting of spasticity, dystonia, and ataxia in which postmortem pathological analysis led to the diagnosis of interferon regulatory factor 2 binding protein like (IRF2BPL)-related disorder., Methods: Detailed postmortem gross and histological examination was conducted, and findings consistent with dentatorubral-pallidoluysian atrophy (DRPLA) and included polyglutamine (polyQ) inclusions. Follow up testing for the CAG repeat expansion at ATN1 was non-diagnostic., Results: Subsequent exome sequencing reanalysis of the research exome identified a pathogenic de novo IRF2BPL variant. The IRF2BPL c.562C>T, p.(Arg188Ter) variant, distal to the polyQ repeat tract, results in variable mRNA levels depending on the cell type examined with decreased mRNA in the brain, as well as destabilization of the protein product and corresponding downstream molecular abnormalities in patient derived cells., Conclusion: We provide the first detailed pathological description for IRF2BPL-related disorder, termed NEDAMSS (neurodevelopmental disorder with regression, abnormal movements, loss of speech and seizures; Mendelian Inheritance in Man, 618088) and evidence for the inclusion of this condition in the differential diagnosis of spastic-ataxic neurodegenerative conditions, reminiscent of DRPLA. Although the individuals with NEDAMSS do not carry an expansion, the polyQ repeat tract may play a role in the pathological inclusions that would represent a novel disease mechanism for polyQ repeats. © 2024 International Parkinson and Movement Disorder Society., (© 2024 International Parkinson and Movement Disorder Society.)

Background/aim: The liver effectively restores both size and function following partial hepatectomy (PHx). Angiogenesis is crucial for the repair and regeneration of liver tissue post-PHx. Calcitonin gene-related peptide (CGRP) released from sensory nerves and its receptor-receptor activity-modifying protein 1 (RAMP1) are involved in angiogenesis. This study aimed to assess the role of RAMP1 signaling in angiogenesis during liver regeneration following PHx., Materials and Methods: RAMP1 deficient (RAMP1 -/- ) and wild-type (WT) mice were subjected to PHx., Results: RAMP1 -/- mice demonstrated delayed liver regeneration, indicated by lower liver-to-body weight ratios compared to WT mice. This was associated with lower levels of Ki67 + hepatocytes and hepatic trophic growth factors. Additionally, RAMP1 -/- mice exhibited lower levels of endothelial cell markers, including CD31, compared to WT mice. This reduction was associated with reduced levels of vascular endothelial growth factor (VEGF)-C, VEGF-D, and VEGF receptor 3 (VEGFR3). In WT mice with PHx, the administration of a VEGFR3 inhibitor reduced the liver-to-body weight ratio, Ki67 + hepatocytes, and VEGF-C/VEGFR3 expression levels in the liver compared to those in the vehicle-treated group., Conclusion: The deletion of RAMP1 signaling suppresses liver regeneration and angiogenesis through VEGFR3. Specific activation of RAMP1 signaling may represent a potential therapeutic strategy for liver regeneration following PHx., (Copyright © 2024, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

This study aimed to better understand the association between the amount of polyunsaturated fatty acids, namely, linoleic acid (LA) and linolenic acid (LNA), and the increases in the peroxide value that results from storing interesterified fats, which are used as sources of solid fats in edible oil and fat products, at high temperatures. Six interesterified fats with different LA and LNA contents were prepared and oxidized at 50°C, 60°C, 70°C, and 80°C under Rancimat test conditions. The oxidation rate increased with LA and LNA contents and increasing temperature. The oxidation kinetic analysis during the early oxidation stages demonstrated that when LA and LNA exceeded 8% and 2% respectively, the oxidative stability decreased as expected. However, the total LA and LNA contents had a higher correlation with the reaction rate constant [k (meq kg -1 h -1 )] than each amount of LA and LNA contained therein. In other words, the oxidation stability of the interesterified fats used in this study depended on the total LA and LNA contents.

Background: Patients with idiopathic pulmonary fibrosis (IPF) often experience sarcopenia and malnutrition. However, this has not been fully examined through longitudinal surveys. This study investigated whether sarcopenia and malnutrition were associated with 1-year outcomes in IPF., Methods: We evaluated sarcopenia and nutritional status in 64 outpatients with IPF. We assessed the time-to-event for respiratory-related hospitalizations or deaths 12 months after enrollment. Sarcopenia was diagnosed by the criteria of the Asian Working Group for Sarcopenia, 2019. Nutritional status was assessed by serum transthyretin and the Geriatric Nutritional Risk Index (GNRI)., Results: The average age was 73.6 ± 7.9 years, and the percent predicted forced vital capacity (FVC) was 81.9 ± 15.7%. Of the 64 patients, 24 (37.5%) had sarcopenia. The median serum transthyretin level and mean GNRI were 23.8 mg/dL and 102, respectively. Eleven patients (17.2%) experienced respiratory-related hospitalization or death within the first year. Cox regression analysis showed that the % predicted diffusion capacity for carbon monoxide, lowest oxygen saturation in the 6-min walk test, serum transthyretin level, and GNRI were significant predictors of 1-year outcomes. The Kaplan-Meier method, which divided the patients into two groups based on a transthyretin level of 22.6 mg/dL, showed a significant difference (P < 0.001, log-rank test). Sarcopenia and the percent predicted FVC did not predict the 1-year outcomes., Conclusions: This pilot study represents the first longitudinal survey assessing patients with IPF for sarcopenia and malnutrition. Serum transthyretin levels may predict respiratory-related hospitalization or death within 1 year in patients with IPF., (Copyright © 2024 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

The biological heterogeneity of neuroblastoma underscores the need for an in vitro model of each molecularly defined subgroup to investigate tumorigenesis and develop targeted therapies. We have established a permanently growing cell line from a 12-year-old girl who developed a late recurrent stage MS, MDM2-amplified neuroblastoma arising in the liver and performed histological, molecular, cytogenetic, exome, and telomere analyses of the recurrent tumor and the cell line. On histology, the recurrent tumor was immunoreactive for TP53, CDKN1A, and MDM2. A molecular cytogenetic study of the recurrent tumor revealed the amplification of MDM2 but no amplification of MYCN. The established cell line, NBM-SHIM, showed amplification of both MDM2 and MYCN on double-minute chromosomes. A copy number evaluation based on exome data confirmed the finding for MYCN and MDM2 and further identified high ploidy on CDK4 and GLI2 loci in the recurrent tumor and the cell line. The telomere maintenance mechanism on the cell line is unusual in terms of the low expression of TERT despite MYCN amplification and alternative lengthening of telomeres suggested by positive value for C-circle assay and telomere contents quantitative assay. The cell line is unique because it was established from a MYCN-nonamplified, MDM2-amplified, late-relapsed stage MS neuroblastoma, and MYCN amplification was acquired during cell culture. Therefore, the cell line is a valuable tool for investigating neuroblastoma tumorigenesis and new molecular targeted therapies for disrupted ARF-TP53-MDM2 pathway and amplification of MDM2 and CDK4., (© 2024. The Author(s) under exclusive licence to Japan Human Cell Society.)

Background: Viral or atypical bacterial respiratory infections are involved in the new development and the pathogenesis of asthma. Though an association between pertussis and asthma has been expected, few studies have reported it consistently. We assessed the prevalence and clinical relevance of pertussis infection in adult patients with asthma., Methods: In this prospective, cross-sectional study, newly referred, adult patients with asthma (n = 107) and with non-asthmatic subacute/chronic cough (n = 31) were enrolled. The prevalence of pertussis in patients with asthma and in those with non-asthmatic subacute/chronic cough was assessed. Next, the prevalence of newly diagnosed asthma was compared between asthmatic patients with and without pertussis. Finally, demographic characteristics of patients, blood test results, pulmonary function test results, and questionnaire scores were compared between the two patient groups., Results: The prevalence of pertussis infection was significantly higher in patients with asthma than in those with non-asthmatic subacute/chronic cough (36% vs 10%; P = 0.004). The prevalence of newly diagnosed asthma was significantly higher in asthmatic patients with pertussis than in those without (74.4% vs 50.0%; P = 0.014). The physical, psychological, and total scores of the Leicester Cough Questionnaire were significantly lower in asthmatic patients with pertussis than in those without (all P < 0.05). The acid-reflux, dyspeptic, and total scores of the Frequency Scale for Symptoms of Gastroesophageal Reflux Disease (GERD) (FSSG) were significantly higher in asthmatic patients with pertussis than in those without (all P ≤ 0.05). The FSSG acid-reflux score was negatively correlated with the cough-specific quality of life (QOL) score only in asthmatic patients with pertussis (rho = -0.68, P = 0.01)., Conclusions: The prevalence of pertussis infection was significantly higher in adult patients with asthma than in those with non-asthmatic subacute/chronic cough. In patients with asthma, comorbid pertussis infection may play a role in newly diagnosed asthma and may contribute to impaired cough-specific QOL partly due to worsening acid-reflux symptoms of GERD., Competing Interests: Declaration of competing interest The authors have no conflicts of interest., (Copyright © 2024 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

We aimed to determine the impact of air inflow into vacuum-type immobilization devices (VIDs) on setup errors. We assigned 70 patients undergoing radiotherapy for head and neck cancer to groups V (n = 34) or N (n = 36) according to whether the VIDs were deflated weekly or not deflated during treatment, respectively. We calculated systematic errors (Σ) as the standard deviations (SDs) of mean errors, and random errors (σ) as the root mean square of SDs in each patient. We compared overall means (μ), SDs (SD overall ), random errors and systematic errors. We also measured temporary pressure changes in VIDs to determine the influence of pressure changes in VIDs on setup errors. The μ was within 0.20 mm and 0.2° in both groups, whereas SD overall significantly differed between them. The SD overall differed the most in the Roll axes of groups N (0. 87°) and V (0.58°). The Σ and σ values were lower in all axes of group V than in group N. Despite the initial deflation target of - 70 kPa, the pressure in VIDs reached - 5 kPa at the end of treatment. However, weekly deflation apparently maintained pressure at - 20 kPa. Effective pressure control in VIDs can reduce patient-by-patient variation and improve setup reproducibility for individual patients, consequently resulting in small variations among overall setup errors., (© 2024. The Author(s), under exclusive licence to Japanese Society of Radiological Technology and Japan Society of Medical Physics.)

Background: Chlorhexidine gluconate solution is superior to povidone-iodine for prevention of surgical site infection. However, the overall efficacy of chlorhexidine gluconate for surgical site infection prevention in various types of gastroenterological surgery, as well as the optimal concentration of chlorhexidine gluconate, remain unclear. The aim of the present study was to clarify whether subcutaneous wound soaking with chlorhexidine gluconate would reduce the incidence of surgical site infection associated with gastroenterological surgery in patients with wound classes Ⅱ to Ⅳ., Methods: Patients were randomly assigned (1:1) to either wound soaking with chlorhexidine gluconate (chlorhexidine gluconate group) or no chlorhexidine gluconate soaking (control group). After closure of the abdominal fascia, gentle subcutaneous soaking of the wound was performed using gauze fully soaked in aqueous 0.05% chlorhexidine gluconate before skin closure. Incisional surgical site infection was diagnosed using the Centers for Disease Control and Prevention criteria. The primary end point was the occurrence of incisional surgical site infection., Results: Among 363 patients, 245 (67%) underwent laparoscopic surgery. All 363 patients were included-181 in the chlorhexidine gluconate group (49.9%) and 182 (50.1%) in the control group. There were no significant inter-group differences in patient background, the type of procedure, or wound classification. The incidence proportion of incisional surgical site infection was significantly lower in the chlorhexidine gluconate group than in the control group (9.4% vs 19.2%; P = .008)., Conclusion: Subcutaneous wound soaking with chlorhexidine gluconate reduces the incidence of incisional surgical site infection in patients undergoing gastroenterological surgery., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: To assess the feasibility of swept-source optical coherence tomography angiography (SS-OCTA) to differentiate macular diseases, including nonpolypoidal macular neovascularization (MNV), polypoidal choroidal vasculopathy (PCV), type 3 MNV, and chronic central serous chorioretinopathy (CSC) without indocyanine green angiography (ICGA)., Study Design: Retrospective observational study., Methods: This study examined 63 eyes of 63 patients with treatment-naive neovascular age-related macular degeneration (AMD), including 23 eyes with nonpolypoidal MNV, 17 eyes with PCV, and 1 eye with type 3 MNV and 22 eyes with chronic CSC. Two independent retina specialists, blinded to the clinical diagnosis, assessed each case of neovascular AMD and chronic CSC using only B-scan and en face images of SS-OCTA without referring to other examination outcomes., Results: By SS-OCTA alone, 19 eyes were diagnosed with nonpolypoidal MNV, 17 eyes with PCV, 2 eyes with type 3 MNV, and 22 eyes with chronic CSC, indicating high sensitivity (82.6%, 94.1%, 100%, and 100%, respectively) and specificity (100%, 97.8%, 98.4%, and 100%, respectively); however, three eyes could not be diagnosed because of obscure images. The agreement of diagnosis with SS-OCTA alone was high between the two specialists (κ = 0.82)., Conclusion: SS-OCTA showed high sensitivity and specificity in the differentiation of nonpolypoidal MNV, PCV, type 3 MNV, and chronic CSC. The differential criteria based on SS-OCTA could be a substitute for the ICGA-based diagnoses., (© 2024. Japanese Ophthalmological Society.)

Background: We report a rare case of posterior cruciate ligament (PCL) calcification, which has only been reported in two case studies on PubMed., Case Presentation: A 71-year-old man developed left popliteal pain in the morning without any history of trauma and the pain became severe that night. On the following day, he presented to our department. The patient could not flex his left knee at all due to pain and swelling. CT and MRI scans showed calcification behind the PCL with mild osteoarthritic changes and accumulation of synovial fluid in the joint. Synovial fluid analysis did not reveal any crystals. Blood tests at first admission showed inflammation, hyperglycemia, and low blood uric acid levels. Although the patient's knee joint was injected with steroids, his symptoms did not improve. Thus, we performed arthroscopic surgery two days after symptoms had appeared. Intraoperatively, we observed a white, soft tissue in the synovial membrane behind the PCL. Part of this tissue was collected for histological analysis, which revealed sparse fibers with calcium deposits. Immediately after surgery, the patient's symptoms were completely gone. Afterward, the patient remained asymptomatic one month after surgery., Conclusion: This is the first reported case of debridement of PCL calcification and ossification that was performed soon after symptoms appeared. In addition, we demonstrated that early debridement led to complete recovery., (© 2024. The Author(s).)

Fear of cancer recurrence (FCR) is a common and distressing condition among adolescents and young adults (AYAs). This study aims to investigate the efficacy of digital interventions, including distress screening-based information provision and smartphone problem-solving therapy, on common psychological distress, especially FCR, in AYA patients with cancer. Participants will be 224 AYA outpatients with cancer aged 15-39 years who will be randomly assigned to either an 8-week smartphone-based intervention or a waitlist control group. This intervention includes smartphone-based distress screening, information provision, and psychotherapy (problem-solving therapy). The primary endpoint will be the Fear of Cancer Recurrence Inventory-Short Form score at week 8. This study will be conducted as a fully decentralized, randomized, and multicenter trial. The study protocol was approved by the Institutional Review Board of Nagoya City University on 19 April 2024 (ID: 46-23-0005). Trial registration: UMIN-CTR: UMIN000054583., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Pancreatic cancer is often diagnosed at advanced stages, and early-stage diagnosis of pancreatic cancer is difficult because of nonspecific symptoms and lack of available biomarkers., Methods: We performed comprehensive serum miRNA sequencing of 212 pancreatic cancer patient samples from 14 hospitals and 213 non-cancerous healthy control samples. We randomly classified the pancreatic cancer and control samples into two cohorts: a training cohort (N = 185) and a validation cohort (N = 240). We created ensemble models that combined automated machine learning with 100 highly expressed miRNAs and their combination with CA19-9 and validated the performance of the models in the independent validation cohort., Results: The diagnostic model with the combination of the 100 highly expressed miRNAs and CA19-9 could discriminate pancreatic cancer from non-cancer healthy control with high accuracy (area under the curve (AUC), 0.99; sensitivity, 90%; specificity, 98%). We validated high diagnostic accuracy in an independent asymptomatic early-stage (stage 0-I) pancreatic cancer cohort (AUC:0.97; sensitivity, 67%; specificity, 98%)., Conclusions: We demonstrate that the 100 highly expressed miRNAs and their combination with CA19-9 could be biomarkers for the specific and early detection of pancreatic cancer., (© 2024. The Author(s).)

Background and Importance: Flow diverters (FDs) provide curative endovascular treatment for wide-necked sidewall aneurysms. The efficacy of FDs for bifurcation or branching sidewall aneurysms is probably limited. We used anatomical flow diversion (AFD) for intractable large cerebral aneurysms. We report our experiences with AFD., Methods: The concept of AFD is the transformation from the bifurcation or branching sidewall type to the nonbranching sidewall type. Linearization of the parent artery by stenting, intentional branch occlusion, and aneurysmal coil embolization were performed. Furthermore, bypass surgery is performed for patients intolerant to branch occlusions. We evaluated the clinical outcomes of intractable aneurysms treated with AFD., Results: AFD was performed in seven unruptured large aneurysms. Aneurysmal locations were the top of the basilar artery (BA), BA-superior cerebellar artery (SCA), internal carotid artery (IC)-posterior communicating artery (PcomA), and IC terminal. The mean dome diameter was 17.0 ± 4.6 mm. Six patients underwent bypass surgery. The occluded branches were the PCA + SCA, PcomA, and anterior cerebral artery (ACA) A1. An FD was used in three patients and a neck bridge stent in four patients. No intraprocedural complications occurred. Two postprocedural ischemic complications occurred in one patient. Six (86%) patients demonstrated a modified Rankin Scale (mRS) 0 at the 3-month follow-up, and one with an ischemic complication showed an mRS 5. Complete occlusion of all aneurysms was maintained with a median follow-up duration of 60 months., Conclusion: AFD is useful for intractable large cerebral aneurysms with high curability, although safety verification is required., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Introduction: The diagnostic tools of nucleic acid amplification tests and antigen tests have been extensively employed for the detection of Coronavirus disease 2019 (COVID-19). Although the reverse-transcriptase polymerase chain reaction (RT)-PCR test has high sensitivity and specificity, it is a time-consuming and labor-intensive process. On the other hand, antigen tests are simple and prompt, however, their low sensitivity and potential for false positives have been identified as limitations. In light of these factors, the development of novel tests that combine speed and clinical dependability is a promising prospect., Methods: Surface plasmon field-enhanced fluorescence spectroscopy (SPFS) excites chromophores by means of an enhanced electromagnetic field induced on a gold film surface. It enables the highly sensitive measurement of biomarkers in a short and simple 20-min window. In this study, a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) SPFS-based antigen test targeting the SARS-CoV-2 nucleocapsid protein was performed and evaluated in 25 patients with COVID-19 and 10 non-infected controls., Results: A positive correlation was observed between antigen levels determined by SPFS and RNA levels determined via RT-PCR. The sensitivity values were 100 %, 92 %, and 62.5 %; and the specificity values were 100 %, 90 %, and 100 %; for nasopharyngeal swabs, nasal swabs, and saliva specimens when the cutoff values were set to 65.1, 0.2, and 1.5 pg/mL, respectively. No clinically problematic cross-reactivity with analogous coronaviruses was observed., Conclusions: The SARS-CoV-2 SPFS antigen test showed excellent clinical diagnostic accuracy for nasopharyngeal and nasal swabs, with a rapid turnaround., (Copyright © 2024 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

Background: Patients with intermediate-risk papillary thyroid carcinoma (PTC) have a favorable prognosis with standard treatment of total thyroidectomy (TT) and adjuvant radioactive iodine therapy (RAIT). However, the benefits of TT or adjuvant RAIT remain undetermined, and they are often omitted in Japan. We investigated risk factors for life-threatening distant recurrence in patients with intermediate-risk PTC who are optimal candidates for adjuvant RAIT., Patients and Methods: Outcomes without RAIT were retrospectively examined in 4030 intermediate-risk conventional PTC cases underwent initial surgery from 2005 to 22 (IRB approval 20200709-1)., Results: Lobectomy (LT) and TT was performed in 11.5% and 88.5%, respectively. Recurrent laryngeal nerve paralysis and hypoparathyroidism was less commonly observed in LT (1.3% and 0%) than TT (2.4% and 3.5 %). Fifty-six cases (1.4%) had distant recurrence. Recurrence-free survival rates at 10 years was 93.5%. There was no significant difference in recurrence rate between LT and TT. Age ≥55, cN1b, and tumor diameter >30 mm significantly associated with distant recurrence. There was a strong relationship between the number of positive risk factors and recurrence; the distant recurrence rate in cases of 0, 1, 2, and 3 positive factors was 0.3% (4/1203), 1.3% (25/1889), 2.7% (23/830) and 7.1% (4/52) (HR 6.46 (2.34-17.86), Log-rank <0.001)., Conclusion: For intermediate-risk conventional PTC, there is no difference in prognosis even if LT was selectively conducted. However, in patients with risk factors for distant metastatic recurrence, such as age ≥55 years, cN1b, and tumor size >30 mm, adjuvant RAIT was considered eligible., (© 2024 The Author(s). World Journal of Surgery published by John Wiley & Sons Ltd on behalf of International Society of Surgery/Société Internationale de Chirurgie (ISS/SIC).)

Type 2 spinal muscular atrophy with lower extremity dominance (SMALED2) is caused by bicaudal D cargo adaptor 2 (BICD2) variants. However, the SMALED2 genotype and phenotype correlation have not been thoroughly characterized. We identified de novo heterozygous BICD2 missense variants in two fetuses with severe, prenatally diagnosed multiple arthrogryposis congenita. This report provides further insights into the genetics of this rare disease., (© 2024. The Author(s).)

Background and Purpose: Flat-panel cone-beam CT (CBCT) is essential for detecting hemorrhagic complications during neuroendovascular treatments. Despite its superior image quality and trajectory over conventional CBCT (Circular scan), dual-axis butterfly scan incurs a slightly higher radiation dose relative to conventional CBCT. This study evaluates the image quality in dose-reduction mode to uncover the appropriate radiation dose for the butterfly scan., Materials and Methods: We prospectively included patients who scheduled neuroendovascular treatment and performed conventional CBCT and dose-reduction mode of the butterfly scan. Two reduced radiation dose modes were utilized for the butterfly scan: medium-dose butterfly scan (70% of the original dose, 45 mGy) or low-dose butterfly scan (50% of the original dose, 30 mGy). The enrolled patients were assigned alternately to receive either the medium-or low-dose butterfly scan. We evaluated and compared artifacts, contrast, and discrimination of the corticomedullary junction between conventional CBCT and one of the dose-reduction modes of the butterfly scan, with a 5-point scale scoring system., Results: Twenty patients were enrolled in each of the medium-and low-dose groups, totaling 40 patients. Compared to conventional CBCT, the medium-dose butterfly group exhibited reduced artifacts, enhanced contrast, and discriminated corticomedullary junction (except in the occipital lobe). While the low-dose butterfly group exhibited markedly reduced artifacts and improved contrast (except in the occipital lobe), a significant improvement in corticomedullary junction discrimination was unobserved., Conclusions: Even with dose reduction, the specialized trajectory of the butterfly scan enables artifact reduction, contrast improvement, and enhanced corticomedullary junction discrimination. However, the impact of the reduced dose was more noticeable, particularly in the occipital region where susceptibility to bone interference resulted in decreased contrast and compromised corticomedullary junction discrimination., Abbreviations: AVM=arteriovenous malformation, CBCT=cone-beam CT, CAS=carotid artery stenting, CTDI=CT dose index, DAVF=dural arteriovenous fistula, FD=flow diverter,PTAS=percutaneous transluminal angioplasty and stenting., Competing Interests: The authors declare no conflicts of interest related to the content of this article., (© 2024 by American Journal of Neuroradiology.)

The direct one-step hydrogenation of toluene to methylcyclohexane facilitated by a proton-exchange membrane water electrolyzer driven by renewable energy has garnered considerable attention for stable hydrogen storage and safe hydrogen transportation. However, a persistent challenge lies in the crossover of toluene from the cathode to the anode chamber, which deteriorates the anode and decreases its energy efficiency and lifetime. To address this challenge, the catalyst-poisoning mechanism is systematically investigated using IrO2 and high-entropic non-noble-metal alloys as anodes in acidic electrolytes saturated with toluene and toluene-oxidized derivatives, such as benzaldehyde, benzyl alcohol, and benzoic acid. Benzoic acid plays an important role in polymer-like carbon-film formation by blocking the catalytically active sites on the anode surface. Moreover, Nb and the highly entropic state on the surface of the multi-element alloy lower the adsorbing ability of toluene and prevent polymer-like carbon film formation. This study contributes to the design of catalyst-poisoning-resistant anodes for organic hydride technology, advanced fuel cells, and batteries., (© 2024 Wiley‐VCH GmbH.)

We present the identification and characterization of the complete genome of metronidazole (MTZ)-resistant Prevotella bivia strain TOH-2715 [minimum inhibitory concentration (MIC): 8 mg/L], isolated from the urine of an elderly Japanese woman, as well as details of its mobile genetic elements (MGEs) containing antimicrobial resistance (AMR) genes and its relationship with other bacterial species determined using whole-genome sequencing (WGS) data. TOH-2715 possessed two chromosomes with putative MGEs containing AMR genes. Two AMR-related MGE regions were present in chromosome 2. MGE-region 1 (7,821 bp) included Tn 6456 , where nimK was located, and MGE-region 2 (58.8 Kbp) included the integrative and conjugative element (ICE), where tet (Q) and ermF were located. The genetic structure of the ICE of TOH-2715 was similar to that of CTn DOT -family transposons, where ermF and tet (Q) are located. A search of public databases revealed that nimK was present in Prevotella spp., including P. bivia , and was partially composed of a Tn 6456 -like element lacking the efflux transporter gene qacE and the Crp/Fnr family transcriptional regulator gene in some cases. Core ICE gene analysis showed that ICEs similar to that of TOH-2715 were present in Prevotella spp. and Bacteroides spp., suggesting horizontal gene transfer among anaerobes. This is the report of WGS analysis of an MTZ-resistant clinical strain of P. bivia (TOH-2715) with Tn 6456 encoding nimK . Other submitted genomes have described the presence of nimK , but none of them have described MTZ resistance. Additionally, we described putative MGE regions containing the AMR gene within the genus Prevotella and among anaerobes, raising concerns about the future spread of nimK among anaerobes., Importance: Metronidazole (MTZ) is an important antimicrobial agent in anaerobic infections and is widely used in clinical settings. The rate of MTZ resistance in anaerobic bacteria has been increasing in recent years, and the nim gene (nitro-imidazole reductase) is one of the resistance mechanisms. Prevotella bivia is found in humans in the urinary tract and vagina and is known to cause infections in some cases. One of the nim genes, nimK , has recently been discovered in this species of bacteria, but there are no reports of antimicrobial resistance (AMR)-related regions in its whole genome level. In this study, we analyzed the AMR region of nimK -positive P. bivia derived from clinical specimens based on comparisons with other anaerobic genomes. P. bivia was found to be engaged in horizontal gene transfer with other anaerobic bacteria, and the future spread of the nimK gene is a concern.

Background/aims: Serum leucine-rich alpha-2 glycoprotein (LRG) is a potential biomarker of Crohn's disease (CD). This study aimed to evaluate the usefulness of LRG in predicting clinical relapse in patients in remission with CD., Methods: This retrospective observational study assessed the relationships among patient-reported outcome (PRO2), LRG, and other blood markers. The influence of LRG on clinical relapse was assessed in patients in remission with CD., Results: Data of 94 patients tested for LRG between January 2021 and May 2023 were collected. LRG level did not correlate with PRO2 score (ρ = 0.06); however, it strongly correlated with C-reactive protein (CRP) level (r=0.79) and serum albumin level (r=-0.70). Among 69 patients in clinical remission, relapse occurred in 22 patients (31.9%). In the context of predicting relapse, LRG showed the highest area under the curve, followed by CRP level, platelet count, and albumin level. Multivariate analysis revealed that only LRG (P= 0.02) was an independent factor for predicting clinical remission. The cumulative non-relapse rate was significantly higher in patients with LRG < 13.8 μg/mL than in patients in remission with LRG ≥ 13.8 μg/mL and normal CRP level (P= 0.002) or normal albumin level (P= 0.001). Cumulative non-relapse rate was also higher in patients with LRG < 13.8 μg/mL compared to those with LRG ≥ 13.8 μg/mL in patients with L3 or B2+B3 of Montreal calcification., Conclusions: LRG is useful in predicting clinical relapse in patients with CD during biological remission. LRG is a useful biomarker for predicting prognosis, even in patients with intestinal stenosis, or previous/present fistulas.

XELOX therapy, which comprises capecitabine and oxaliplatin, is the standard first-line chemotherapeutic regimen for colorectal cancer. However, its myelosuppressive effects pose challenges for its clinical management. Mathematical modeling combining pharmacokinetics (PK) and toxicodynamics (TD) is a promising approach for optimizing dosing strategies and reducing toxicity. This study aimed to develop a translational PK-TD model using rat data to inform dosing strategies and TD implications in humans. The rats were administered capecitabine, oxaliplatin, or XELOX combination regimen, and PK and TD data were collected. PK parameters were analyzed using sequential compartment analysis, whereas TD responses were assessed using Friberg's semiphysiological model. A toxicity intensity-based nomogram recommends optimal dosing strategies. Translational modeling techniques using the hybrid PK-TD model were employed to predict clinical responses. The PK-TD model successfully predicted the time-course profiles of hematological responses in rats following monotherapy and XELOX combination treatment. Interactive effects on lymphocytopenia were identified with the coadministration of capecitabine and oxaliplatin. A model-based recommended combination of the dose reduction rate for escaping severe lymphocytopenia was proposed as 40% and 60% doses of capecitabine and oxaliplatin, respectively. The current translational model techniques successfully simulated the time-course profiles of blood cell counts with confidence intervals in patients using rat data. Our study provides valuable insights into dose optimization strategies for each individual drug within the XELOX regimen and underscores the potential of translational modeling to improve patient outcomes. In addition to dose determination, these data will lay the groundwork for advancing drug development processes in oncology. SIGNIFICANCE STATEMENT: This study introduced a novel translational modeling approach rooted in a rat PK-TD model to optimize dosing strategies for the XELOX regimen for colorectal cancer treatment. Our findings highlight the interactive effects on lymphocytopenia and suggest a toxicity intensity-based nomogram for dose reduction, thus advancing precision medicine. This translational modeling paradigm enhances our understanding of drug interactions, offering a tool to tailor dosing, minimize hematological toxicity, and improve therapeutic outcomes in patients undergoing XELOX therapy., (Copyright © 2024 by The American Society for Pharmacology and Experimental Therapeutics.)

Background: Blast transformation is a rare but well-recognized event in Philadelphia-negative myeloproliferative neoplasms associated with a poor prognosis. Secondary acute myeloid leukemias evolving from myeloproliferative neoplasms are characterized by a unique set of cytogenetic and molecular features distinct from de novo disease. t(8;21) (q22;q22.1); RUNX1::RUNX1T1, one of the most frequent cytogenetic abnormalities in de novo acute myeloid leukemia, is rarely observed in post-myeloproliferative neoplasm acute myeloid leukemia. Here we report a case of secondary acute myeloid leukemia with t(8;21) evolving from JAK2-mutated essential thrombocythemia., Case Presentation: The patient was a 74-year-old Japanese woman who was referred because of thrombocytosis (platelets 1046 × 10 9 /L). Bone marrow was hypercellular with increase of megakaryocytes. Chromosomal analysis presented normal karyotype and genetic test revealed JAK2 V617F mutation. She was diagnosed with essential thrombocythemia. Thrombocytosis had been well controlled by oral administration of hydroxyurea; 2 years after the initial diagnosis with ET, she presented with leukocytosis (white blood cells 14.0 × 10 9 /L with 82% of blasts), anemia (hemoglobin 91 g/L), and thrombocytopenia (platelets 24 × 10 9 /L). Bone marrow was hypercellular and filled with 80% of myeloperoxidase-positive blasts bearing Auer rods. Chromosomal analysis revealed t(8;21) (q22;q22.1) and flow cytometry presented positivity of CD 13, 19, 34, and 56. Molecular analysis showed the coexistence of RUNX1::RUNX1T1 chimeric transcript and heterozygous JAK2 V617F mutation in leukemic blasts. She was diagnosed with secondary acute myeloid leukemia with t(8;21)(q22;q22.1); RUNX1::RUNX1T1 evolving from essential thrombocythemia. She was treated with combination chemotherapy with venetoclax and azacytidine. After the first cycle of the therapy, blasts disappeared from peripheral blood and decreased to 1.4% in bone marrow. After the chemotherapy, RUNX1::RUNX1T1 chimeric transcript disappeared, whereas mutation of JAK2 V617F was still present in peripheral leukocytes., Conclusions: To our best knowledge, the present case is the first one with JAK2 mutation preceding the acquisition of t(8;21). Our result suggests that t(8;21); RUNX1::RUNX1T1 can be generated as a late event in the progression of JAK2-mutated myeloproliferative neoplasms. The case presented typical morphological and immunophenotypic features associated with t(8;21) acute myeloid leukemia., (© 2024. The Author(s).)

A moment analysis method was developed for the study of solute permeation at the interface of spherical molecular aggregates. At first, new moment equations were developed for determining the partition equilibrium constant (K p ) and permeation rate constants (k in and k out ) of solutes from the first absolute (μ 1A ) and second central (μ 2C ) moments of elution peaks measured by using high-performance liquid chromatography (HPLC). Then, the method was applied to the analysis of mass transfer phenomena of three solutes, i.e., hydroquinone, resorcinol, and catechol, at the interface of sodium dodecylsulfate (SDS) micelles. HPLC data were measured by using an ODS column and an aqueous phosphate buffer solution (pH = 7.0) as the mobile phase solvent. Pulse response experiments were conducted while changing SDS concentration (5 - 20 mmol dm -3 ) in the mobile phase under the conditions that the surface of ODS stationary phase was dynamically coated by SDS monomers. In order to demonstrate the effectiveness of the moment analysis method using HPLC, the values of K p , k in , and k out were determined for the three solutes as 35 - 69, 2.4 × 10 -8 - 1.4 × 10 -6 m s -1 , and 7.0 × 10 -10 - 2.1 × 10 -8 m s -1 , respectively. Their values increase with an increase in the hydrophobicity of the solutes. The method has some advantages for the study of interfacial solute permeation of molecular aggregates. For example, neither immobilization nor chemical modification of both solute molecules and molecular aggregates is required when elution peaks are measured by using HPLC. Interfacial solute permeation takes place in the mobile phase without any chemical reaction or physical action on molecular aggregates. The values of K p , k in , and k out were analytically determined from those of μ 1A and μ 2C by using the moment equations. The results of this study must contribute to the dissemination of an opportunity for studying the interfacial solute permeation of molecular aggregates to many researchers because of extremely high versatility of HPLC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Roseomonas mucosa is difficult to identify using routine analytical techniques. We herein report a case of peritoneal dialysis (PD)-related peritonitis caused by R. mucosa identified using matrix-assisted laser desorption/ionization-time-of-flight (MALDI-TOF) mass spectrometry (MS). A 70-year-old woman was admitted to our hospital with PD-related peritonitis. Blood agar medium of dialysate culture derived colony pale pink in color, and the organism was identified as R. mucosa using MALDI-TOF MS. She was successfully treated with ciprofloxacin and meropenem without catheter removal. To our knowledge, this is the first case of R. mucosa peritonitis in which technique failure has been avoided.