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Abstract Background Bone marrow lesion (BML) is an important magnetic resonance finding (MRI) finding that predicts knee osteoarthritis. The purpose of this study was to investigate the influence of proximal tibial morphology on BML, including the spreading root sign (SRS), in women without radiographic knee osteoarthritis (OA). It was hypothesized that varus alignment and a greater posterior tibial slopes (PTS) are associated with BML. Materials and methods A total of 359 female volunteers without knee OA who were participants in the Iwaki Health Promotion Project in 2017 or 2019 were enrolled. Participants were divided into the non-OA and early knee OA (EKOA) groups based on the Luyten’s classification criteria. The presence of pathological cartilage lesions, BMLs, attritions, meniscal lesions and effusions was scored on T2-weighted fat-suppressed magnetic resonance imaging (MRI) according to the Whole-Organ MRI Scoring system. The medial proximal tibial angle (MPTA) and medial and lateral PTS (MPTS and LPTS, respectively) were measured. Regression and receiver operating characteristic (ROC) analyses were performed to reveal the relationship between BMLs and proximal tibial morphological parameters. Results Of the 359 participants, 54 (15%) were classified as having EKOA. The prevalence of cartilage lesions, BMLs, attritions, meniscal lesions and effusions was higher in the EKOA group than in the non-OA group. The two groups had no significant difference in the proximal tibial parameters. Regression analysis revealed that age and a smaller MPTA were associated with BML in both groups. Attrition (p = 0.029) and the MPTS (p = 0.025) were positively associated with BML in the EKOA group. Conclusion The prevalence of BMLs was higher in women with EKOA and correlated with the varus and greater posterior slopes in those without radiographic knee OA. Level of evidence Level III, retrospective case–control study.

Abstract Japanese Hayabusa2 spacecraft has successfully carried out an impact experiment using a small carry-on impactor (SCI) on an asteroid (162173) Ryugu. We examine the size distribution of particles inside and outside an artificial impact crater (the SCI crater) based on the images taken by the optical navigation camera onboard the Hayabusa2 spacecraft. The circumferential variation in particle size distribution inside the SCI crater is recognized and we interpret that major circumferential variation is caused by the large boulders inside the SCI crater that existed prior to the impact. The size distribution inside the SCI crater also shows that the subsurface layer beneath the SCI impact site had a large number of particles with a characteristic size of – 9 cm, which is consistent with the previous evaluations. On the other hand, the size distribution outside the SCI crater exhibits the radial variation, implying that the deposition of ejecta from the SCI crater is involved. The slope of the size distribution outside the crater at small sizes differs from the slope of the size distribution on the surface of Ryugu by approximately 1 or slightly less. This is consistent with the claim that some particles are buried in fine particles of the subsurface origin included in ejecta from the SCI crater. Thus, the particle size distributions inside and outside the SCI crater reveal that the subsurface layer beneath the SCI impact site is rich in fine particles with – 9 cm in size while the particles on the surface have a size distribution of a power-law form with shallower slopes at small sizes due to the deposition of fine ejecta from the subsurface layer. Finally, we discuss a process responsible for this difference in particle size distribution between the surface and the subsurface layers. The occurrence of segregation in the gravitational flow of particles on the surface of Ryugu is plausible. Graphical Abstract

Objectives: This study aimed to determine whether texture analysis of positron emission tomography (PET) images from patients with oral squamous cell carcinoma (OSCC) can accurately diagnose cervical lymph node (LN) metastases. Methods: We conducted a retrospective chart review of 166 patients with newly pathologically diagnosed OSCC. The patient inclusion criteria were LNs exhibiting high 18F-fluorodeoxyglucose uptake [maximum standardised uptake value (SUVmax) ≥2.5] and/or LNs diagnosed as metastatic cervical LNs by a board-certified nuclear medicine physician, irrespective of the SUVmax value. The patient exclusion criteria were LNs with a metabolic tumour volume (MTV) of ≤1.0 cm3. The primary predictor variables were 31 textural indices, SUVmax and MTV. The diagnostic performance was evaluated by receiver operating characteristic (ROC) curve analysis. Results: Analyses of 91 cervical LNs (48 positives, 43 negatives) indicated that long-run emphasis (LRE) could demonstrate the highest area under the ROC curve (AUC) of 0.809. Comparison of the AUCs between SUVmax and LRE indicated that the AUC of LRE was marginally higher than that of SUVmax (p = 0.067). Furthermore, the diagnostic performance of the combination of SUVmax and LRE was more accurate than that of SUVmax alone (p = 0.04). Conclusions: The combination of SUVmax and LRE may improve the diagnostic accuracy of determining cervical LN metastases.

We evaluated whether texture analysis of positron emission tomography (PET) scans could predict the response to induction chemotherapy (ICT) in patients with oral squamous cell carcinoma (OSCC). Our retrospective cohort study included 21 patients with OSCC who underwent ICT. We extracted 31 textural indices from pretreatment PET scans and performed receiver operating characteristic curve (ROC) analysis to evaluate these indices’ efficacy in predicting ICT response. The area under the ROC curve was statistically significant for one texture index: short-zone emphasis (SZE; p = 0.041).

A material weakly linking two superconductors may itself exhibit superconductivity whilst its material properties strongly influence the nature of the supercurrent. Here, the authors identify a supercurrent with p-wave symmetry in such a Josephson junction made of topologically non-trivial material.

Frequency analysis of the rf emission of oscillating Josephson supercurrent is a powerful passive way of probing properties of topological Josephson junctions. In particular, measurements of the Josephson emission enable the detection of topological gapless Andreev bound states that give rise to emission at half the Josephson frequency f_{J} rather than conventional emission at f_{J}. Here, we report direct measurement of rf emission spectra on Josephson junctions made of HgTe-based gate-tunable topological weak links. The emission spectra exhibit a clear signal at half the Josephson frequency f_{J}/2. The linewidths of emission lines indicate a coherence time of 0.3–4 ns for the f_{J}/2 line, much shorter than for the f_{J} line (3–4 ns). These observations strongly point towards the presence of topological gapless Andreev bound states and pave the way for a future HgTe-based platform for topological quantum computation.

Japan's combination of high seismicity and a long history has produced copious written records of historical earthquakes. Systematic collection and investigation of such historical documents began late in the 19th century. Now, almost all of Japan's known historical materials on earthquakes have been transcribed into 25 printed volumes. The collections include records of about 400 destructive earthquakes from A.D. 599 to 1872. Epicentral coordinates and magnitudes have been estimated for about half these events and details of earthquake and tsunami disasters have been summarized in catalogues. The space-time pattern of great Tokai and Nankai earthquakes is a good example of revealed earthquake history. The existing collections of historical sources, however, contain low-quality records that produce errors and fictitious (fake) earthquakes, and are difficult of full utilization because of volumes. Moreover, there are peculiar problems to Japan's historical times such as calendar and time of day. Systematic ways of estimating seismic intensities, epicenters, focal depths and magnitudes have not yet been established. Therefore, historical earthquake catalogues are yet incomplete. Constructing a reliable database of the whole historical documents in collaboration with historians to give wide-ranging researchers easy and full utilization of old earthquake records is urgent task. Revision of earthquake catalogues and construction of a seismic intensity database with international standard are also necessary.

Abstract. Objective:  Curdlan, an extracellular bacterial polysaccharide, is a linear β-1,3-glucan. Previously, we developed Curdlan-oligo (CRDO). We investigated its effect on the production of cytokines in leukocytes from mice, and compared its activity with that of SCG, a 6-branched 1,3-β-glucan. Methods:  Splenocytes from DBA/2 mice were cultured with CRDO or SCG (0, 1, 10 or 100 μg/ml) in vitro, and then the supernatants were collected to measure cytokines. Bone marrow-derived dendritic cells (BMDCs) were cultured with CRDO (0, 1, 10 or 100 ng/ml) in vitro, and then the supernatant was collected to measure cytokines. Results:  SCG stimulated splenocytes in DBA/2 mice to produce GM-CSF, IFN-γ and TNF-α. CRDO induced production of GM-CSF and IFN-γ, but not TNF-α. The amounts of GM-CSF and IFN-γ were small compared with those produced in response to SCG. The effect of SCG on TNF-α production was partially inhibited by CRDO. In bone marrow-derived dendritic cells, CRDO induced production of TNF-α and IL-6. Conclusion:  Taken together, these results suggest that CRDO stimulated mouse leukocytes to induce the production of cytokines, and the mechanism of the effect of CRDO on leukocytes is different from that of SCG. [ABSTRACT FROM AUTHOR]

Magnetic transport of holes in Ge/Si core/shell nanowires (NWs) is investigated under the control of dual electrical gating. The strength of the spin–orbit interaction (SOI) is analyzed from the weak-antilocalization (WAL) of the magnetoconductance (MC) as a function of a perpendicular magnetic field. By superimposing a small alternating signal on the voltage offset of both gates the universal conductance fluctuations are largely removed from the averaged MC traces, enabling a good fitting to WAL theory models. The tuning of both spin lifetime and the SOI strength is observed in the NWs with dual gating while the carrier density is kept constant. We observe an enhancement of spin lifetime with the mean free path due to the effect of geometrical confinement. The measured SOI energy of 1–6 meV may arise from the dipole coupled Rashba SOI, which is predicted to be one order of magnitude larger than the conventional Rashba coefficient in the Ge/Si core/shell NW system. A clear electrostatic modulation of SOI strength by a factor of up to three implies that Ge/Si NWs are a promising platform for the study of helical states, Majorana fermions and spin–orbit qubits. [ABSTRACT FROM AUTHOR]

We have formed tunnel barriers in individual multi-wall carbon nanotubes using the Ga focused ion beam irradiation. The barrier height was estimated by the temperature dependence of the current (Arrhenius plot) and the current–voltage curves (Fowler–Nordheim plot). It is shown that the barrier height has a strong correlation with the barrier resistance that is controlled by the dose. Possible origins for the variation in observed barrier characteristics are discussed. Finally, the single electron transistor with two barriers is demonstrated. [ABSTRACT FROM AUTHOR]

We have fabricated Nb nanogap electrodes using a combination of molecular lithography and electron beam lithography. Au nano-particles with anchor molecules were placed in the gap, the width of which could be controlled on a molecular scale ([?]2 nm). Three different anchor molecules which connect the Au nano-particles and the electrodes were tested to investigate their contact resistance, and a local gate was fabricated underneath the Au nano-particles. The electrical transport measurements at liquid helium temperatures indicated single electron transistor (SET) characteristics with a charging energy of about [?] 5 meV, and a clear indication of the effect of superconducting electrodes was not observed, possibly due to the large tunnel resistance. [ABSTRACT FROM AUTHOR]

We combine spectroscopic ellipsometry (SE), Fourier transform infrared spectroscopy (FT-IR), kinetic Monte Carlo simulations (KMC) and convex corner undercutting analysis in order to characterize and explain the effect of the addition of small amounts of surfactant in alkaline aqueous solutions, such as Triton X-100 in tetra methyl ammonium hydroxide (TMAH). We propose that the surfactant is adsorbed at the silicon-etchant interface as a thin layer, acting as a filter that moderates the surface reactivity by reducing the amount of reactant molecules that reach the surface. According to the SE and FT-IR measurements, the thickness of the adsorbed layer is an orientation- and concentration-dependent quantity, mostly due to the orientation dependence of the surface density of H-terminations and the concentration dependence of the relative rates of the underlying oxidation and etching reactions, which have a direct impact on the number of OH terminations. For partial OH coverage of the surface, the hydration of the OH group effectively acts as an anchoring location for the hydration shell of a surfactant molecule, thus enabling the formation of hydration bridges that amplify the adsorption density of the surfactant. At high concentration, the model explains the large reduction in the etch rate of the exact and vicinal Si{1 1 0} surfaces, and the small changes in the etch rates for the exact and vicinal Si{1 0 0} surfaces. At low concentration, it explains how the etch rate for both families is significantly reduced. The orientation and concentration dependence of the surfactant adsorption explains the dramatic differences in the micron-scale wet-etched patterns obtained using TMAH and TMAH亸궢 for microelectromechanical systems applications. [ABSTRACT FROM AUTHOR]

Background: Little is known about the survival impacts of mitochondrial status in esophageal squamous cell carcinoma (ESCC) patients who undergo neoadjuvant chemotherapy (NAC) followed by surgery., Methods: In total, 260 pre-NAC samples from ESCC patients were analyzed. Mitochondrial status was estimated employing an objective, immunohistochemistry-based system (Mito-score). Mito-scores were dichotomized according to the median value of our cohort. We also evaluated the immune microenvironment (CD4, CD8, Foxp3, HLA class-1, Ki-67 and programmed death ligand-1) on pre-NAC specimens. Multivariate Cox hazards models were applied to determine independent predictors of poor overall survival (OS)., Results: Patients with cT3-4 tumors had higher Mito-scores than those with cT1-2 tumors (p = 0.06), and good responders to NAC had significantly higher Mito-scores than poor responders to NAC (p = 0.04). CD8 cells and Ki-67 expression were significantly higher in Mito-high than Mito-low tumors (p = 0.017 and p < 0.001, respectively). Patients with low Mito-scores had significantly poorer OS than those with high Mito-scores (3-year OS: 57.6% vs. 68.2%; p = 0.03). A survival difference by Mito-score was evident in cStage III-IV patients (3-year OS: low 50.6% vs. high 66.1%; p = 0.006). Multivariable analysis revealed that a low Mito-score (hazard ratio 1.59, 95% confidence interval 1.12-2.24; p = 0.009) as well as pT3-4 disease (p < 0.001) and pN2-3 disease (p < 0.001) were independently associated with poor OS outcomes., Conclusions: A low Mito-score before NAC had a significant survival impact in ESCC patients, especially in those with advanced disease. Mitochondrial status might be associated with tumor aggressiveness and responsiveness to NAC, thereby possibly affecting the survival outcomes of ESCC patients., Competing Interests: Disclosure: Kotaro Sugawara, Shingo Sakashita, Takashi Fukuda, Chiaki Murakami, Daiji Oka, Gulanbar Amori, Kumiko Ishibashi, Yasuhito Kobayashi, Hiroaki Kanda, and Noriko Motoi have no conflicts of interest to declare that may be relevant to the contents of this study. Human and Animal Rights: All procedures were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964 and later versions. Informed Consent: Informed consent was obtained from all individual participants in the form of opt-out on the website. Those who rejected participation, were excluded., (© 2024. The Author(s).)

Background: This study aimed to investigate whether arithmetic hip-knee-ankle angle (aHKA) can be a surrogate for valgus stress radiography (VSR). Furthermore, we investigated the optimal cutoff values for preoperative radiographic parameters, thereby validating the appropriate inclusion criteria for prearthritic/kinematic unicompartmental knee arthroplasty (prearthritic-UKA)., Methods: We retrospectively analyzed 123 patients who underwent medial UKA. We measured the HKA on VSR, termed sHKA. The aHKA was calculated by subtracting the lateral distal femoral angle from the medial proximal tibial angle. Prearthritic-UKA was defined as a postoperative HKA angle within 3° of the aHKA. We divided the patients into the prearthritic-UKA and non-prearthritic-UKA groups. To assess whether the aHKA serves as a surrogate for VSR, Spearman's rank correlations were performed among the radiographic parameters. These radiographic parameters calculated the proper criteria for prearthritic-UKA using receiver operating characteristic (ROC) curve analysis and logistic regression analysis., Results: Overall, 59 patients were classified into the prearthritic-UKA group. The aHKA was larger than the sHKA and exhibited no significant correlation with the sHKA. ROC analysis revealed that the cutoff values of aHKA for detecting overcorrected UKA (i.e., postoperative HKA - aHKA >3°) was -5.0°. Similarly, the cutoff values for detecting undercorrected UKA (i.e., postoperative HKA - aHKA <-3°) were -3°. Logistic regression analysis revealed that the aHKA was significantly associated with prearthritic-UKA., Conclusion: The aHKA was not identified as a surrogate for the sHKA. Comprehensive preoperative radiographic assessment, including both aHKA and VSR, is crucial for optimizing UKA outcomes and minimizing risks of misalignment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Conventional plant gene editing requires laborious tissue-culture-mediated transformation, which restricts the range of applicable plant species. In this study, we developed a heritable and tissue-culture-free gene editing method in Nicotiana benthamiana using tobacco ringspot virus (TRSV) as a vector for in planta delivery of Cas9 and single-guide RNA (sgRNA) to shoot apical meristems. Agrobacterium-mediated inoculation of the TRSV vector induced systemic and heritable gene editing in Nicotiana benthamiana PHYTOENE DESATURASE. Transient downregulation of RNA silencing enhanced gene editing efficiency, resulting in an order of magnitude increase (0.8-13.2%) in the frequency of transgenerational gene editing. While the TRSV system had a preference for certain sgRNA sequences, co-inoculation of a TRSV vector carrying only Cas9 and a tobacco rattle virus vector carrying sgRNA successfully introduced systemic mutations with all five tested sgRNAs. Extensively gene-edited lateral shoots occasionally grew from plants inoculated with the virus vectors, the transgenerational gene editing frequency of which ranged up to 100%. This virus-mediated heritable gene editing method makes plant gene editing easy, requiring only the inoculation of non-transgenic plants with a virus vector(s) to obtain gene-edited individuals., (© The Author(s) 2024. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists.)

Quality control of translation is crucial for maintaining cellular and organismal homeostasis. Obstacles in translation elongation induce ribosome collision, which is monitored by multiple sensor mechanisms in eukaryotes. The E3 ubiquitin ligase Znf598 recognizes collided ribosomes, triggering ribosome-associated quality control (RQC) to rescue stalled ribosomes and no-go decay (NGD) to degrade stall-prone mRNAs. However, the impact of RQC and NGD on maintaining the translational homeostasis of endogenous mRNAs has remained unclear. In this study, we investigated the endogenous substrate mRNAs of NGD during the maternal-to-zygotic transition (MZT) of zebrafish development. RNA-Seq analysis of zebrafish znf598 mutant embryos revealed that Znf598 down-regulates mRNAs encoding the C2H2-type zinc finger domain (C2H2-ZF) during the MZT. Reporter assays and disome profiling indicated that ribosomes stall and collide while translating tandem C2H2-ZFs, leading to mRNA degradation by Znf598. Our results suggest that NGD maintains the quality of the translatome by mitigating the risk of ribosome collision at the abundantly present C2H2-ZF sequences in the vertebrate genome., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Ishibashi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective : Previous studies of topographical disorientation have focused on cerebrovascular diseases. However, a detailed assessment of patients with neurodegenerative diseases may aid our understanding of spatial navigation. We report the case of a patient with right temporal variant frontotemporal dementia (rtvFTD) initially presenting with heading disorientation, a distinct category of topographical disorientation. Method : The patient was a 71-year-old woman with gradually increasing episodes of getting lost in a familiar environment. Detailed neuropsychological assessment, magnetic resonance imaging (MRI), and positron emission tomography (PET) studies were performed. Results : Topographical disorientation was conspicuous in the patients' cognitive dysfunction despite preserved general cognition. She could not dictate a route or draw a map from her nearest train station to her home, although she recognized environmental landmarks relatively well. Neuropsychological assessments, including the card-placing test, suggested heading disorientation. The MRI and PET abnormalities were large but confined to the right hemisphere and involved the retrosplenial region, an area associated with heading disorientation in cerebrovascular diseases, and the cortical areas that comprise a network together with the retrosplenial region. Amyloid PET was negative, ruling out Alzheimer's disease. Her topographical symptoms gradually worsened. Behavioral symptoms and loss of empathy gradually became apparent fulfilling the criteria for rtvFTD. Conclusions : Neuropsychological assessment revealed heading disorientation in the initial stage of rtvFTD. Based on previous studies, heading disorientation was likely attributed to neurodegeneration in the right hemispheric network centered in the retrosplenial region. The gradual progression of topographical symptoms contrasted with previous reports of heading disorientation due to cerebrovascular diseases.

Abstract: 18 F-labeled THK5351 PET can visualize ongoing astrogliosis by estimating monoamine oxidase B levels and can be used as a neuroinflammation marker for identifying inflammatory lesions by imaging astrogliosis. Assessment of its performance is of interest, especially when compared with conventional MRI. Here, we present 2 cases of neurosyphilis, in which 18 F-THK5351 PET identified inflammatory lesions by imaging astrogliosis, whereas MRI had difficulty detecting the lesions. Hence, this study suggests that 18 F-THK5351 PET is superior to conventional MRI in identifying inflammatory lesions and that this feature of 18 F-THK5351 can provide insights into the pathophysiology of neurosyphilis in living patients., Competing Interests: Conflicts of interest and sources of funding: This study was supported by JSPS KAKENHI grant number JP23K06957 (to K.I.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Imaging of type 1 metabotropic glutamate receptor (mGluR1), which is predominantly expressed in Purkinje cells, is currently possible using positron emission tomography (PET). We have previously shown that cerebellar mGluR1 availability decreases in patients with cerebellar ataxia and that the degree of ataxia is related to the magnitude of cerebellar mGluR1 availability. This study presents the longitudinal changes in cerebellar mGluR1 availability after an interval of years in patients with spinocerebellar ataxia type 6 (SCA6)., Methods: Three patients with SCA6 underwent baseline and follow-up mGluR1 PET and magnetic resonance imaging (MRI) at intervals of 2-6 years. The volume-of-interest was placed on the cerebellum. The binding potential (BP ND ) was calculated to estimate the mGluR1 availability using a simplified reference tissue model. Cerebellar volume was measured using MRI. The degree of ataxia was scored with the Scale for the Assessment and Rating of Ataxia (SARA)., Results: The cerebellar BP ND values, cerebellar volume, and SARA scores changed by 2.73-7.49 %, 0.60-1.75 %, and 0.5-3, respectively, from baseline to follow-up assessments. The rates of reduction in cerebellar mGluR1 availability were higher than those in cerebellar volume., Conclusions: This study shows that cerebellar mGluR1 availability decreases with disease progression in SCA6, and that mGluR1 imaging is likely superior to MRI in identifying small changes in the cerebellum. Therefore, mGluR1 imaging can be used as a specific biomarker for monitoring cerebellar function., 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.)

Background: Although the MADIT-ICD benefit score (MBS) helps select suitable implantable cardioverter defibrillator (ICD) candidates, optimal indicators for cardiac resynchronization therapy (CRT) remain uncertain. Evaluating the applicability of the MBS in Japanese CRT patients is imperative., Methods and Results: This multicenter study assessed the cumulative incidence of ventricular tachycardia/fibrillation (VT/VF) and non-arrhythmic mortality (AM) in CRT patients grouped according to potential benefit (lowest, highest, and intermediate). Among 400 primary prevention patients (mean age 65 years, 76% male), VT/VF occurred in 4 (7%), 68 (24%), and 14 (23%) patients in the lowest-, intermediate-, and highest-benefit groups, respectively (P=0.027), over a median follow-up of 34 months. Non-arrhythmic death was observed in 15 (25%), 91 (33%), and 9 (15%) patients in the lowest-, intermediate-, and highest-benefit groups, respectively (P=0.025). Multivariate analysis identified VT/VF score ≥7 (hazard ratio [HR] 2.14; 95% confidence interval [CI] 1.09-4.19; P=0.027) as a significant VT/VF predictor. The presence of left bundle branch block (HR 0.51; 95% CI 0.29-0.92; P=0.025) was associated with a reduced risk of VT/VF events. Non-AM score ≥3 (HR 1.70; 95% CI 1.01-2.88; P=0.047), systolic blood pressure <100 mmHg (HR 1.84; 95% CI 1.25-2.70; P=0.002), and estimated glomerular filtration rate <30 mL/min/1.73 m 2 (HR 1.98; 95% CI 1.23-3.20; P=0.005) were significant predictors of non-arrhythmic death., Conclusions: The MBS can identify suitable candidates for CRT-D among Japanese individuals.

The globalization and rapid advancements in medical technologies necessitate the harmonization of international regulatory frameworks to ensure the efficient and timely clinical application of medical products, including pharmaceuticals and medical devices. Regulatory reliance, a critical component of this harmonization process, is a powerful tool that provides efficient access for economic entities and regulatory authorities, promoting predictable decision-making and accelerating approvals. The Medical Device Single Audit Program (MDSAP) serves as a regulatory reliance framework for medical device inspections. Implemented by countries including Japan, the United States, Canada, Australia, and Brazil, MDSAP allows third-party certification bodies, recognized by these regulatory authorities, to conduct audits on medical device manufacturers. The outcomes of these audits are shared with the regulatory authorities, who use them for regulatory assessments and decision-making. Since transitioning to its implementation phase in 2017, MDSAP has been widely utilized in various countries. This review provides an overview of the adoption and utilization of MDSAP in major countries, exploring the program's impact on regulatory processes and its potential as a method of regulatory reliance to facilitate timely access to effective and safe medical devices., (© 2024. The Author(s), under exclusive licence to The Drug Information Association, Inc.)

Objectives: Although some studies have evaluated the effectiveness of comprehensive genomic profiling (CGP) in solid tumors, the effectiveness of CGP in metastatic colorectal cancer (mCRC) has not been evaluated using detailed real-world long-outcome data., Methods: This was part of a single institutional non-comparative prospective observational study that observed all patients with solid tumors who underwent CGP at Saitama Medical Center, Saitama Medical University. We enrolled patients with mCRC between June 4, 2020, and March 31, 2023. The primary endpoint was the proportion of patients who received CGP-based therapy., Results: There were 43 patients with mCRC. Of these, six patients (14.0%) received CGP-based therapy. The median overall survival from CGP testing in patients who received CGP-based therapy was 9.7 months. The progression free survival (PFS) ratio of CGP-based therapy and immediate previous therapy ranged from 0.04 to 2.0. The PFS ratio >1.5 was 14.3% (one out of seven treatments). One patient exhibited an exceptional response to pembrolizumab. Before CGP testing, the patient's cancer was classified as non-microsatellite instability-high, although the CGP test revealed a high tumor mutational burden. In Japan, patients with this subtype cannot undergo pembrolizumab without testing for CGP., Conclusions: This prospective observational study's findings provide an overview of CGP testing outcomes in patients with refractory mCRC., Competing Interests: Conflicts of Interest Hideyuki Ishida is funded by Taiho Pharmaceutical Co Ltd. No other disclosures were reported., (Copyright © 2024 The Japan Society of Coloproctology.)

Abstract: 18 F-labeled THK5351 PET can visualize ongoing astrogliosis by estimating monoamine oxidase B levels and can be used as an adjunct for diagnosing neurodegenerative disorders. Little has been reported on multiple system atrophy (MSA) in the differential diagnosis of parkinsonian syndromes. Here, we present 18 F-THK5351 images in typical cases of MSA-P (parkinsonian type) and MSA-C (cerebellar type), showing intense 18 F-THK5351 uptake in the lateral-posterior part of the putamen (MSA-P) and in the pons and middle cerebellar peduncles (MSA-C). Hence, this study illustrates the possible utility of 18 F-THK5351 PET as an adjunct for diagnosing MSA-P and MSA-C by imaging ongoing astrogliosis., Competing Interests: Conflicts of interest and sources of funding: none declared. This study was supported by JSPS KAKENHI grant JP23K06957 (to K. Ishibashi). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: An adaptive cardiac resynchronization therapy (aCRT) algorithm allows continuous adjustments of pacing timings of atrioventricular delays by periodic automatic evaluation of electrical conduction. This applies to patients with an atrioventricular block and is effective in cardiac resynchronization therapy (CRT) devices; however, whether this algorithm benefits patients with pacemaker dependency is uncertain., Methods: This study examined the clinical impact of an aCRT algorithm in patients diagnosed with heart failure with reduced ejection fraction and pacemaker dependency. A total of 359 patients underwent CRT between January 2016 and December 2022. Patients undergoing pacemaker-dependent CRT with the aCRT algorithm function were selected. Sixty-four patients with pacemaker dependency (31 with aCRT algorithm and 33 without) were included. Pacemaker dependency was defined as the absence of spontaneous ventricular activity during the sensing test at VVI 30 bpm or prolonged atrioventricular delay (> 300 ms). The primary endpoint was the composite clinical outcome of all-cause death or hospitalization for heart failure., Results: No significant differences were observed in baseline characteristics between groups. During a median follow-up of 1,067 days (interquartile range 553-1,776 days), aCRT reduced the risk of composite clinical outcomes in patients with pacemaker dependency (log-rank P = 0.028). In addition, using the aCRT algorithm was an independent predictor of the composite clinical outcomes in the multivariate analysis (hazard ratio 0.34, 95% confidence interval: 0.12-0.94, P = 0.038)., Conclusion: The aCRT algorithm significantly reduced the risk of adverse clinical outcomes in patients with pacemaker dependency. This algorithm may be an important tool for managing such patients., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Acrylamide polymers with zwitterionic carboxybetaine (CB) side groups have attracted attention as stealth polymers that do not induce antibodies when conjugated to proteins. However, they induce antibodies when modified onto liposomes. We hypothesized that antibodies are produced against polymer backbones rather than CB side groups. Objectives: In this study, we designed and synthesized a polymer employing CB in its main chain, poly( N -acetic acid- N -methyl-propyleneimine) (PAMPI), and evaluated the blood retention of PAMPI-modified liposomes in mice. Results: The non-fouling nature of PAMPI-modified liposomes estimated from serum protein adsorption was found to be not inferior to PCB- and PEG-modified liposomes. However, to our surprise, the PAMPI-modified liposomes showed an instantaneous clearance less than 1 h post-injection, comparable to the naked liposomes. Conclusions: The extent of the blood retention of polymer-modified liposomes cannot be predicted by their susceptibility to serum protein adsorption and semi-flexible conformation.

Background/objectives: Colorectal neoplasia developing from ulcerative colitis mucosa (CRNUC) can be divided into ulcerative colitis-associated neoplasia (UCAN) and non-UCAN; however, it is often difficult to distinguish UCAN from non-UCAN during a biopsy diagnosis. We investigated whether a genomic analysis could improve the diagnostic accuracy of UCAN using biopsy specimens., Methods: In step 1, 14 CRNUCs were used to examine whether the genomic landscape of biopsy and resection specimens matched. In step 2, we investigated the relationship between the genomic landscapes and the pathological diagnosis of 26 CRNUCs. The cancer genome was analyzed by deep sequencing using a custom panel of 27 genes found to be mutated in our previous CRNUC analysis., Results: In step 1, of the 27 candidate genes, 14 were mutated. The concordance rate of the pathogenic mutations in these 14 genes between the biopsy and resection specimens was 29% (4/14), while that of the pathogenic mutations in TP53 and KRAS was 79% (11/14). In step 2, the pathological diagnosis of biopsy specimens using only hematoxylin and eosin (HE) staining had a sensitivity of 33% and an accuracy of 38% for UCAN diagnosis. On the other hand, the combination of the HE pathology and p53 immunohistochemical staining had a sensitivity of 73% and an accuracy of 85% for UCAN diagnosis, while the combination of HE staining and a TP53 mutation had a sensitivity of 87% and an accuracy of 88% for UCAN diagnosis., Conclusions: An evaluation of TP53 mutations in biopsy specimens may be useful for diagnosing UCAN. However, further studies with larger sample sizes are required before this can be applied in clinical practice.

Dengue fever is a febrile viral disease transmitted by mosquitoes. The symptoms of dengue fever are numerous and varied; however, cardiac tamponade is a particularly rare and atypical complication. This study describes a case of a 30-year-old male who presented with acute respiratory distress and chest pain on the ninth day after diagnosis of dengue fever. On admission, a computed tomography scan revealed a large pericardial effusion. The patient went into shock and was urgently treated with pericardial drainage, which resulted in rapid improvement of his symptoms. Emergent management of this rare but potentially fatal complication of dengue fever resulted in a favorable outcome in this case., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Ship International Hospital Ethics Committee issued approval #1001. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Ishibashi et al.)

A 73-year-old woman with posterior cortical atrophy (PCA) presented with progressive apperceptive visual agnosia, alexia, agraphia, ventral simultanagnosia, prosopagnosia, and allocentric (stimulus-centered) left-sided hemispatial neglect. All of these symptoms were attributed to damage to the bilateral occipito-temporal cortices, consistent with ventral variant PCA. While the Pittsburgh compound B uptake was extensively distributed throughout the occipito-parietal (dorsal) and occipito-temporal (ventral) areas, the THK5351 (ligand binding to tau aggregates/astrocyte gliosis) accumulation was limited to the ventral area. These findings suggest that local accumulation of tau proteins and/or astrocyte gliosis over the occipito-temporal cortices can result in ventral variant PCA.

Background: Patients who achieve improved left ventricular ejection fraction (LVEF >35%) with cardiac resynchronization therapy (CRT) are at a lower risk of ventricular arrhythmia (VA). Little is known about the significance of the B-type natriuretic peptide (BNP) level for the risk of VA. This study investigated the risk factors for VA in CRT and the risk stratification of VA with BNP in CRT with improved LVEF., Methods and Results: This study evaluated 352 CRT patients from 2012 to 2020. Patients were categorized into 2 groups: improved LVEF (impEF; LVEF >35%), and low LVEF (lowEF; LVEF ≤35%). The serum BNP levels 6 months after CRT device implantation were measured. The primary endpoint was defined as VA requiring treatment with anti-tachycardia pacing or shock or persisting for ≥30 s. Overall, 102 patients had improved LVEF. The impEF group had a significantly lower VA risk than the lowEF group. Patients with low BNP had a lower VA risk than those with high BNP; however, no significant difference was observed between patients with high BNP and those in the lowEF group. Univariate analysis revealed that high BNP was a predictor of VA in the impEF group., Conclusions: The VA risk is reduced with improved LVEF after CRT but not with high BNP levels. The post-BNP level after CRT implantation is a useful marker for predicting VA in patients with improved LVEF., Competing Interests: N.U. received honoraria from Medtronic Japan Co., Ltd for providing lectures. K.I. has received honoraria for teaching lectures from BIOTRONIK Japan and Medtronic Japan Co., Ltd. T.N. has received honoraria for lectures from Medtronic Japan Co., Ltd and BIOTRONIK Japan, Inc., and belongs to a department endowed by BIOTRONIK Japan. S.N. is affiliated with a department endowed by Japan Medtronic, Inc. K.K. has received honoraria from BIOTRONIK Japan and Medtronic Japan, and research grants from Medtronic Japan. However, none of the sponsors/honoraria were involved in the study design, the collection, analysis, and interpretation of data, the writing of the report, or the decision to submit the article for publication. This study was supported by the Intramural Research Program Fund (25-4-7; K.K.) for cardiovascular diseases of the National Cerebral and Cardiovascular Center., (Copyright © 2024, THE JAPANESE CIRCULATION SOCIETY.)

Objectives: Endoscopic treatment of superficial pharyngeal carcinomas includes endoscopic submucosal dissection (ESD; usually performed by endoscopists), and endoscopic laryngo-pharyngeal surgery (ELPS; primarily performed by otolaryngologists). Few studies have compared the efficacy of the two techniques in treating superficial pharyngeal carcinomas. In this study, we compared the outcomes of these two techniques to determine the advantages., Methods: We retrospectively examined the short- and long-term outcomes of 93 consecutive patients with superficial pharyngeal carcinoma who either underwent an ESD or ELPS between August 2008 and December 2021., Results: There were 35 lesions among 29 patients and 93 lesions among 71 patients in the ESD and ELPS groups, respectively. The ELPS group had a significantly shorter procedure time (121.2 ± 97.4 min vs. 54.7 ± 40.2 min, p<0.01), greater procedure speed (0.10 ± 0.06 min/min vs. 0.30 ± 0.23 min/min, p<0.01), and less laryngeal edema than that of the ESD group. There were no significant differences in the 3-year overall, relapse-free, or disease-specific survival rates between the two groups. Intervention with ESD during ELPS was most commonly required when it was difficult to secure the visual field., Conclusions: There were no differences in batch resection rates or long-term prognoses between the two groups; nevertheless, the ELPS group had a shorter treatment time and less laryngeal edema than the ESD group. However, the treatment of narrow areas, such as the esophageal inlet patch, is a technical limitation of ELPS; thus, ELPS should be combined with ESD techniques., Competing Interests: None., (© 2024 The Author(s). DEN Open published by John Wiley & Sons Australia, Ltd on behalf of Japan Gastroenterological Endoscopy Society.)

Because virus vectors can spread systemically autonomously, they are powerful vehicles with which to deliver genome-editing tools into plant cells. Indeed, a vector based on a positive-strand RNA virus, potato virus X (PVX), harboring SpCas9 and its single guide RNA (sgRNA), achieved targeted mutagenesis in inoculated leaves of Nicotiana benthamiana . However, the large size of the SpCas9 gene makes it unstable in the PVX vector, hampering the introduction of mutations in systemic leaves. Smaller Cas variants are promising tools for virus vector-mediated genome editing; however, they exhibit far lower nuclease activity than SpCas9. Recently, AsCas12f, one of the smallest known Cas proteins so far (one-third the size of SpCas9), was engineered to improve genome-editing activity dramatically. Here, we first confirmed that engineered AsCas12f variants including I123Y/D195K/D208R/V232A exhibited enhanced genome-editing frequencies in rice. Then, a PVX vector harboring this AsCas12f variant was inoculated into N. benthamiana leaves by agroinfiltration. Remarkably, and unlike with PVX-SpCas9, highly efficient genome editing was achieved, not only in PVX-AsCas12f-inoculated leaves but also in leaves above the inoculated leaf (fourth to sixth upper leaves). Moreover, genome-edited shoots regenerated from systemic leaves were obtained at a rate of >60%, enabling foreign DNA-free genome editing. Taken together, our results demonstrate that AsCas12f is small enough to be maintained in the PVX vector during systemic infection in N. benthamiana and that engineered AsCas12f offers advantages over SpCas9 for plant genome editing using virus vectors., Competing Interests: KI, ON, HS, and ST have filed a patent application related to this work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Ishibashi, Sukegawa, Endo, Hara, Nureki, Saika and Toki.)

Chirality-controlled synthesis of carbon nanotubes (CNTs) is one of the ultimate goals in the field of nanotube synthesis. At present, direct synthesis achieving a purity of over 90%, which can be called single-chirality synthesis, has been achieved for only two types of chiralities: (14,4) and (12,6) CNTs. Here, we realized an ultrahigh-purity (∼95.8%) synthesis of (6,5) CNTs with a trimetallic catalyst NiSnFe. Partial formation of Ni 3 Sn crystals was found within the NiSnFe nanoparticles. The activation energy for the selective growth of (6,5) CNTs decreased owing to the formation of Ni 3 Sn crystals, resulting in the high-purity synthesis of (6,5) CNTs. Transmission electron microscopy (TEM) reveals that one-dimensional (1D) crystals of periodic strip lines with 8.8 Å spacing are formed within the as-grown ultrahigh-purity (6,5) CNTs, which are well-matched with the simulated TEM image of closely packed 37 (6,5) CNTs with 2.8 Å intertube distance, indicating the direct formation of chirality-pure (6,5)-CNT bundle structures. The photoluminescence (PL) lifetime increases more than 20 times by the formation of chirality-pure bundle structures of (6,5) CNTs compared to that of isolated (6,5) CNTs. This can be explained by exciton delocalization or intertube excitons within bundle structures of chirality-pure (6,5) CNTs.

Cancer brain metastasis has a poor prognosis, is commonly observed in clinical practice, and the number of cases is increasing as overall cancer survival improves. However, experiments in mouse models have shown that brain metastasis itself is an inefficient process. One reason for this inefficiency is the brain microenvironment, which differs significantly from that of other organs, making it difficult for cancer cells to adapt. The brain microenvironment consists of unique resident cell types such as neurons, oligodendrocytes, astrocytes, and microglia. Accumulating evidence over the past decades suggests that the interactions between cancer cells and glial cells can positively or negatively influence the development of brain metastasis. Nevertheless, elucidating the complex interactions between cancer cells and glial cells remains challenging, in part due to the limitations of existing experimental models for glial cell culture. In this review, we first provide an overview of glial cell culture methods and then examine recent discoveries regarding the interactions between brain metastatic cancer cells and the surrounding glial cells, with a special focus on astrocytes and microglia. Finally, we discuss future perspectives for understanding the multifaceted interactions between cancer cells and glial cells for the treatment of metastatic brain tumors., (© 2024 The Author(s). Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: The adaptive cardiac resynchronization therapy (aCRT) algorithm enables synchronized left ventricular pacing (sLVP) to achieve fusion with intrinsic right ventricular activation. Although sLVP presents benefits over biventricular pacing, the adequate sLVP rate for better clinical outcomes remains unclear. We aimed to assess the association between sLVP rates and clinical outcomes., Methods: Our study cohort included 271 consecutive patients, who underwent CRT implantation between April 2016 and August 2021., Results: We evaluated 63 patients on whom we applied the aCRT algorithm [48 men, mean age: 64 ± 14 years; median follow-up period: 316 days (interquartile range: 212-809 days)]. At the 6-month follow-up after CRT implantation, the frequency of CRT responders was 71 % (n = 45). The sLVP rate was significantly higher in responders than in non-responders (75 ± 30 % vs. 47 ± 40 %, p = 0.003). Receiver operating characteristics curve analysis revealed that the optimal cut-off value during the sLVP rate was 59.4 % for the prediction of CRT responders (area under the curve, 0.70; sensitivity, 80 %; specificity, 61 %; positive predictive value, 84 %; and negative predictive value, 55 %). Kaplan-Meier analysis demonstrated that the higher-sLVP group (sLVP ≧59.4 %, n = 43) had a better prognosis (cardiac death and heart failure hospitalization) than the lower-sLVP group (sLVP <59.4 %, n = 20) (log-rank p < 0.001). Multivariate Cox hazard analysis revealed that a higher sLVP rate was associated with a good prognosis (p < 0.001)., Conclusions: sLVP was associated with CRT response, and a higher sLVP rate (≧59.4 %) was important for good prognosis in patients with aCRT., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: This study compared the stability of the Medtronic Attain Stability Quad (ASQ), a novel quadripolar active fixation left ventricular (LV) lead with a side helix, to that of conventional quadripolar leads with passive fixation (non-ASQ) and evaluated their LV lead performance., Methods and Results: In all, 183 consecutive patients (69 ASQ, 114 non-ASQ) who underwent cardiac resynchronization therapy (CRT) between January 2018 and June 2021 were enrolled. Complications, including elevated pacing capture threshold (PCT) levels, phrenic nerve stimulation (PNS), and LV lead dislodgement, were analyzed during the postimplantation period until the first outpatient visit after discharge. The frequency of LV lead-related complications was significantly lower in the ASQ than non-ASQ group (14% vs. 30%, respectively; P=0.019). Specifically, LV lead dislodgement occurred only in the non-ASQ group, and elevated PCT levels were significantly lower in the ASQ group (7% vs. 23%; P=0.007). Kaplan-Meier analysis confirmed a significantly lower incidence of LV lead-related complications in the ASQ group (log-rank P=0.005). Cox multivariable regression analysis showed a significant reduction in lead-related complications associated with ASQ (hazard ratio 0.44; 95% confidence interval 0.23-0.83; P=0.011)., Conclusions: The ASQ group exhibited fewer LV lead-related complications requiring reintervention and setting changes than the non-ASQ group. Thus, the ASQ may be a favorable choice for CRT device implantation.

Background: The SMART Pass algorithm for subcutaneous implantable cardioverter-defibrillator prevents inappropriate shocks due to oversensing. The mechanisms and significance of SMART Pass deactivation remain unclear., Objective: The objective of this study was to assess whether SMART Pass deactivation is associated with inappropriate shocks and to elucidate the underlying mechanism., Methods: We retrospectively investigated 115 patients who underwent subcutaneous implantable cardioverter-defibrillator implantation between 2016 and 2021. SMART Pass deactivation and inappropriate shocks during follow-up were assessed. The QRS amplitudes of the subcutaneous (S-ECG) and 12-lead electrocardiogram (ECG) at the time of implantation (pre) and SMART Pass deactivation (post) were measured. The patients were divided into the SP-ON group with SMART Pass consistently on and the SP-OFF group with the experience of SMART Pass deactivation., Results: Three of 12 patients in the SP-OFF group experienced inappropriate shocks during a median follow-up of 1094 (interquartile range, 887-1502) days compared with 4 of 87 patients in the SP-ON group. Pre- and post-S-ECG QRS amplitudes were significantly lower in the SP-OFF group than in the SP-ON group (both P < .05), despite similar 12-lead ECG QRS amplitude in both groups. A significant temporary drop in the QRS amplitude of the S-ECG led to SMART Pass deactivation (pre-QRS amplitude vs amplitude at deactivation, P = .015; 95% CI, 0.3-1.9)., Conclusion: The rate of inappropriate shocks was numerically higher after SMART Pass deactivation. A low QRS amplitude in S-ECG was a potential risk factor for SMART Pass deactivation. Careful follow-up and suitable management are required for managing patients with risks of SMART Pass deactivation., Competing Interests: Disclosures Dr Ueda received honoraria from Medtronic Japan Co, Ltd for providing lectures. Dr Ishibashi received honoraria from Biotronik Japan and Medtronic Japan Co, Ltd for lectures. Dr Satoshi Nagase is affiliated with a department endowed by Japan Medtronic Inc. Dr Kusano received honoraria from Biotronik, Japan and Medtronic Japan as well as research grants from Medtronic Japan. None of the authors have any conflicts of interest associated with this study., (Copyright © 2024 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Purpose: Rathke cleft cysts are commonly encountered sellar lesions, and their inflammation induces symptoms and recurrence. Cyst wall enhancement is related to inflammation; however, its range and frequency have not yet been investigated. This study aimed to investigate the clinical and radiological differences between inflammatory and non-inflammatory Rathke cleft cysts., Methods: Forty-one patients who underwent cyst decompression surgery for Rathke's cleft cysts between January 2008 and July 2022 were retrospectively analyzed. Based on the pathological reports, patients were divided into inflammatory and non-inflammatory groups. Clinical assessments, endocrinological evaluations, cyst content analysis, and imaging metrics (mean computed tomographic value, maximum diameter, mean apparent diffusion coefficient [ADC] value, and qualitative features) were analyzed. Receiver operating characteristic curve analysis was performed, to determine ADC cutoff values, for differentiating inflammatory group from non-inflammatory group., Results: Totally, 21 and 20 cases were categorized into the inflammatory and non-inflammatory groups, respectively. The inflammatory group displayed a higher incidence of central diabetes insipidus (arginine vasopressin deficiency) (p = 0.04), turbid cyst content (p = 0.03), significantly lower mean ADC values (p = 0.04), and more extensive circumferential wall enhancement on magnetic resonance imaging (MRI) (p < 0.001). In the inflammatory group, all cases revealed circumferential wall enhancement, with some exhibiting thick wall enhancement. There were no significant differences in other radiological features. The ADC cutoff value for differentiating the two groups was 1.57 × 10 -3  mm 2 /s, showing a sensitivity of 81.3% and specificity of 66.7% CONCLUSION: Inflammatory Rathke cleft cysts tended to show a higher incidence of central diabetes insipidus and turbid cyst content. Radiologically, they exhibited lower mean ADC values and greater circumferential wall enhancement on MRI., (© 2024. The Author(s).)

With the advent of immune checkpoint inhibitors (ICIs), a better understanding of tumor microenvironment (TME) is becoming crucial in managing esophageal squamous cell carcinoma (ESCC) patients. We investigated the survival impact of TME status and changes in patients with ESCC who underwent neoadjuvant chemotherapy (NAC) followed by surgery (n = 264). We examined immunohistochemical status (CD4 + , CD8 + , CD20 + , Foxp3 + , HLA class-1 + , CD204 + , and programmed death ligand-1 [PD-L1 + ]) on 264 pre-NAC and 204 paired post-NAC specimens. Patients were classified by their pre- and post-NAC immune cell status and their changes following NAC. Our findings showed that pre-NAC TME status was not significantly associated with survival outcomes. In contrast, post-NAC TME status, such as low level of T cells, CD4 + T cells, and high PD-L1 combined positive score (CPS), were significantly associated with poor overall survival (OS). Notably, TME changes through NAC exerted significant survival impacts; patients with consistently low levels of T cells, low levels of CD4 + T cells, or high levels of PD-L1 (CPS) had very poor OS (3-year OS: 35.5%, 40.2%, and 33.3%, respectively). Tumor microenvironment changes of consistently low T cells, low CD4 + T cells, and high PD-L1 were independent predictors of poor OS in multivariate Cox hazards analyses, while factors indicating post-NAC status (T cells, CD4 + , and PD-L1 [CPS]) alone were not. Therefore, we suggest that the consistently low T/high PD-L1 group could benefit from additional therapies, such as ICIs, and the importance of stratification by the TME, which has recently been recognized., (© 2024 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Abstract: Currently, monoamine oxidase B is recognized as the primary target of 18F-THK5351, although 18F-THK5351 was initially developed to target neurofibrillary tangles (NFTs) in Alzheimer disease. When clinically applying 18F-THK5351 PET to visualize ongoing astrogliosis via estimating monoamine oxidase B levels, a crucial concern is how much degree 18F-THK5351 uptake reflects NFTs in in vivo images. To unravel this concern, a head-to-head comparison between 18F-THK5351 and 18F-MK-6240 (estimating NFT) images in the NFT lesion ideally without accompanying astrogliosis is essential. Here, we present such a case suggesting that 18F-THK5351 uptake may not estimate NFTs in in vivo images., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

This study aims to elucidate the clinical and molecular characteristics, treatment outcomes and prognostic factors of patients with histone H3 K27-mutant diffuse midline glioma. We retrospectively analyzed 93 patients with diffuse midline glioma (47 thalamus, 24 brainstem, 12 spinal cord and 10 other midline locations) treated at 24 affiliated hospitals in the Kansai Molecular Diagnosis Network for CNS Tumors. Considering the term "midline" areas, which had been confused in previous reports, we classified four midline locations based on previous reports and anatomical findings. Clinical and molecular characteristics of the study cohort included: age 4-78 years, female sex (41%), lower-grade histology (56%), preoperative Karnofsky performance status (KPS) scores ≥ 80 (49%), resection (36%), adjuvant radiation plus chemotherapy (83%), temozolomide therapy (76%), bevacizumab therapy (42%), HIST1H3B p.K27M mutation (2%), TERT promoter mutation (3%), MGMT promoter methylation (9%), BRAF p.V600E mutation (1%), FGFR1 mutation (14%) and EGFR mutation (3%). Median progression-free and overall survival time was 9.9 ± 1.0 (7.9-11.9, 95% CI) and 16.6 ± 1.4 (13.9-19.3, 95% CI) months, respectively. Female sex, preoperative KPS score ≥ 80, adjuvant radiation + temozolomide and radiation ≥ 50 Gy were associated with favorable prognosis. Female sex and preoperative KPS score ≥ 80 were identified as independent good prognostic factors. This study demonstrated the current state of clinical practice for patients with diffuse midline glioma and molecular analyses of diffuse midline glioma in real-world settings. Further investigation in a larger population would contribute to better understanding of the pathology of diffuse midline glioma., (© 2024. The Author(s).)

Patients with Guillain-Barré syndrome (GBS) occasionally have residual gait disturbance one year after disease onset. We hypothesized that providing hip joint movement assistance can improve gait in patients with GBS and residual gait disturbance. A 78-year-old man with GBS showed improvement in gait following conventional rehabilitation and gait training using GAIT TRAINER HWA-01 (HWA-01; Honda Motor Co., Ltd., Tokyo, Japan), which is a hip-wearable exoskeleton robot. Initially, he presented with gastrointestinal symptoms, subsequently flaccid quadriplegia, and respiratory muscle paralysis. He was diagnosed with acute motor axonal neuropathy and was transferred to our hospital on day 185 after the disease onset. Seven months after rehabilitation, his walking ability plateaued. On day 382, a single-case study with ABABA design intervention, with conventional gait training in phase A and gait training using HWA-01 in phase B, was conducted. The primary outcomes included a comfortable walking speed, stride length, and cadence. Comfortable walking speed, stride length, and cadence statistically improved after gait training using HWA-01. Furthermore, improvement in exercise capacity and activities of daily living exceeded the minimal clinically important difference for the intervention. The use of the HWA-01 gait trainer potentially improves gait in patients with GBS who have residual gait disturbance., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Ethics Committee of Ibaraki Prefectural University of Health Sciences issued approval e204. Written informed consent was obtained from the patient for participation in and publication of this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: This work was supported by the Japan Society for the Promotion of Science (KAKENHI) (grant number: JP22H04408 and JP22H04417), and Grant-in-Aid for Project Research from the Ibaraki Prefectural University of Health Sciences (grant number: 2266-3). Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Yabuki et al.)

Mesenchymal stem cells (MSCs) and macrophages collaboratively contribute to bone regeneration after injury. However, detailed mechanisms underlying the interaction between MSCs and inflammatory macrophages (M1) remain unclear. A macrophage-depleted tooth extraction model was generated in 5-wk-old female C57BL/6J mice using clodronate liposome (12.5 mg/kg/mouse, intraperitoneally) or saline injection (control) before maxillary first molar extraction. Mice were sacrificed on days 1, 3, 5, 7, and 10 after tooth extraction ( n  = 4). Regenerated bone volume evaluation of tooth extraction socket (TES) and histochemical analysis of CD80 + M1, CD206 + M2 (anti-inflammatory macrophages), PDGFRα + MSC, and TNF-α + cells were performed. In vitro, isolated MSCs with or without TNF-α stimulation (10 ng/mL, 24 h, n  = 3) were bulk RNA-sequenced (RNA-Seq) to identify TNF-α stimulation-specific MSC transcriptomes. Day 7 micro-CT and HE staining revealed significantly lower mean bone volume (clodronate vs control: 0.01 mm 3 vs 0.02 mm 3 , p <.0001) and mean percentage of regenerated bone area per total TES in clodronate group (41.97% vs 54.03%, p <.0001). Clodronate group showed significant reduction in mean number of CD80 + , TNF-α + , PDGFRα + , and CD80 + TNF-α + cells on day 5 (306.5 vs 558.8, p <.0001; 280.5 vs 543.8, p <.0001; 365.0 vs 633.0, p <.0001, 29.0 vs 42.5, p <.0001), while these cells recovered significantly on day 7 (493.3 vs 396.0, p =.0004; 479.3 vs 384.5, p =.0008; 593.0 vs 473.0, p =.0010, 41.0 vs 32.5, p =.0003). RNA-Seq analysis showed that 15 genes (|log2FC| > 5.0, log2TPM > 5) after TNF-α stimulation were candidates for regulating MSC's immunomodulatory capacity. In vivo, Clec4e and Gbp6 are involved in inflammation and bone formation. Clec4e , Gbp6 , and Cxcl10 knockdown increased osteogenic differentiation of MSCs in vitro. Temporal reduction followed by apparent recovery of TNF-α-producing M1 macrophages and MSCs after temporal macrophage depletion suggests that TNF-α activated MSCs during TES healing. In vitro mimicking the effect of TNF-α on MSCs indicated that there are 15 candidate MSC genes for regulation of immunomodulatory capacity., Competing Interests: The authors declare no conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research.)