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Competing Interests: The authors declare that they have no conflict of interest.

Purpose: A high-risk patent foramen ovale (PFO) could be the cause of cryptogenic stroke, and an atrial septal aneurysm (ASA) increases the risk of stroke recurrence in cryptogenic stroke patients with a patent foramen ovale (PFO). Factors related to stroke recurrence according to PFO characteristics have not been fully evaluated., Methods: Data from a multicenter, observational registry of ischemic stroke patients undergoing transesophageal echocardiography were used for this study. Patients were classified into three groups: high-risk PFO, PFO with large shunt (≥20 microbubbles) or ASA; right-to-left shunt (RLS), RLS including PFO with <20 microbubbles or without ASA, or pulmonary arteriovenous fistula; and negative RLS. Cox proportional hazards regression analysis was used to explore the factors related to stroke recurrence in these three groups., Results: In total, 586 patients (185 females; 65.5±13.2 years) were analyzed. In cryptogenic stroke (329 patients) with median follow-up of 4.2 (interquartile range, 1.0-6.1) years, 55 patients had stroke recurrence. The negative RLS, RLS, and high-risk PFO groups included 179, 90, and 60 patients, in which stroke recurrence occurred in 5.3%, 2.5%, and 4.6% per person-year, respectively. In patients with high-risk PFO, the National Institutes of Health stroke scale score (hazard ratio [HR] 1.257 [1.034-1.530]) and periventricular hyperintensity (HR 3.369 [1.103-10.294]) were predictors of stroke recurrence on multivariable Cox hazards analysis, but no factors were related to stroke recurrence in the RLS and negative RLS groups., Conclusion: Periventricular hyperintensity was shown to predict recurrent stroke in patients with a high-risk PFO., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Yuji Ueno reports financial support was provided by Bristol-Myers Squibb. Yuji Ueno reports a relationship with Ohara Pharmaceutical Co Ltd that includes: speaking and lecture fees. Nobukazu Miyamoto reports a relationship with Ohara Pharmaceutical Co Ltd that includes: speaking and lecture fees. Kazuo Yamashiro reports a relationship with Nestle Japan Ltd Tokyo Commercial Office that includes: funding grants. Takao Urabe reports a relationship with Daiichi Sankyo Inc that includes: speaking and lecture fees. Takao Urabe reports a relationship with Boehringer Ingelheim Ltd that includes: speaking and lecture fees. Takao Urabe reports a relationship with Otsuka Pharmaceutical Co Ltd that includes: speaking and lecture fees. Takao Urabe reports a relationship with Bayshore Pharmaceuticals LLC that includes: speaking and lecture fees. Takao Urabe reports a relationship with AstraZeneca that includes: speaking and lecture fees. Takao Urabe reports a relationship with Otsuka Pharmaceutical Co Ltd that includes: funding grants. Takao Urabe reports a relationship with AbbVie Ltd. that includes: funding grants. Nobutaka Hattori reports a relationship with Asahi Kasei Medical Co Ltd that includes: funding grants. Nobutaka Hattori reports a relationship with Shin Nippon Biomedical Laboratories Ltd that includes: funding grants. Nobutaka Hattori reports a relationship with FP Pharmaceutical Corporation that includes: funding grants. Nobutaka Hattori reports a relationship with Eisai Co Ltd that includes: funding grants. Nobutaka Hattori reports a relationship with CellSource that includes: funding grants. Nobutaka Hattori reports a relationship with MJFF that includes: funding grants. Nobutaka Hattori reports a relationship with Mds Pharma Services that includes: funding grants. Nobutaka Hattori reports a relationship with Meiji Seika Pharma Co Ltd that includes: speaking and lecture fees. Nobutaka Hattori reports a relationship with Sumitomo Pharma Co Ltd that includes: speaking and lecture fees. Nobutaka Hattori reports a relationship with Ono Pharmaceutical Co Ltd that includes: funding grants. Nobutaka Hattori reports a relationship with Otsuka Pharmaceutical Co Ltd that includes: speaking and lecture fees. Nobutaka Hattori reports a relationship with Takeda Pharmaceutical Co Ltd Tokyo Headquarters that includes: speaking and lecture fees. Nobutaka Hattori reports a relationship with Kyowa Kirin Co Ltd that includes: speaking and lecture fees. Nobutaka Hattori reports a relationship with FP Pharmaceutical Corporation that includes: speaking and lecture fees. Nobutaka Hattori reports a relationship with Eisai Co Ltd that includes: speaking and lecture fees. Nobutaka Hattori reports a relationship with Nihon Medi-Physics Co Ltd that includes: speaking and lecture fees. Nobutaka Hattori reports a relationship with Novartis Pharma that includes: speaking and lecture fees. Nobutaka Hattori reports a relationship with Biogen Japan Ltd that includes: speaking and lecture fees. Nobutaka Hattori reports a relationship with Abbvie GK that includes: speaking and lecture fees. Nobutaka Hattori reports a relationship with Teijin Pharma Limited that includes: speaking and lecture fees. Nobutaka Hattori reports a relationship with Alexion Pharmaceuticals Inc that includes: speaking and lecture fees. Nobutaka Hattori reports a relationship with Daiichi Sankyo Inc that includes: speaking and lecture fees. Nobutaka Hattori reports a relationship with Sumitomo Pharma Co Ltd that includes: funding grants. Nobutaka Hattori reports a relationship with Otsuka Pharmaceutical Co Ltd that includes: funding grants. Nobutaka Hattori reports a relationship with Takeda Pharmaceutical Co Ltd Tokyo Headquarters that includes: funding grants. Nobutaka Hattori reports a relationship with Kyowa Kirin Co Ltd that includes: funding grants. Nobutaka Hattori reports a relationship with SUNWELS that includes: funding grants. Nobutaka Hattori reports a relationship with Eisai Co Ltd that includes: funding grants. Nobutaka Hattori reports a relationship with Nihon Medi-Physics Co Ltd that includes: funding grants. Nobutaka Hattori reports a relationship with Abbott Japan Co Ltd that includes: funding grants. Nobutaka Hattori reports a relationship with Abbvie GK that includes: funding grants. Nobutaka Hattori reports a relationship with Medtronic that includes: funding grants. Nobutaka Hattori reports a relationship with Boston Scientific Japan that includes: funding grants. Nobutaka Hattori reports a relationship with Ono Pharmaceutical Co Ltd that includes: funding grants. Nobutaka Hattori reports a relationship with Mitsubishi Tanabe Pharma Corporation that includes: funding grants. Nobutaka Hattori reports a relationship with Kowa Co Ltd Tokyo Office that includes: funding grants. Nobutaka Hattori reports a relationship with PARKINSON Laboratories Co., Ltd that includes: funding grants. Nobutaka Hattori reports a relationship with Ohara Pharmaceutical Co Ltd that includes: funding grants. If there are other authors, they 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 Inc.)

Competing Interests: The authors declare that they have no conflict of interest.

Competing Interests: The authors declare that they have no conflict of interest.

Macroautophagy/autophagy maintains cellular homeostasis by degrading cytoplasmic components and its disruption is linked to Parkinson disease (PD), which is characterized by dopamine depletion and the accumulation of SNCA/α-synuclein aggregates in neurons. Therefore, activation of autophagy is considered a therapeutic strategy for PD; however, autophagy inducers have not yet been developed as therapeutic drugs because they are involved in a wide range of signaling pathways. Here, we focused on the lysosomal clustering around the microtubule-organizing center (MTOC) that can regulate the process of autophagosome-lysosome fusion, the final step of autophagy, and examined how lysosomal clustering affects protein degradation through autophagy. Our study identified six compounds from a high-content screen of 1,200 clinically approved drugs that induce both lysosomal clustering and autophagy. Notably, albendazole reduced SNCA aggregates in a PD model by lysosomal clustering and autophagy. These findings suggest that targeting lysosomal clustering could offer new therapeutic insights for PD.

Competing Interests: The authors declare that they have no conflict of interest.

Competing Interests: The authors declare that they have no conflict of interest.

SNCA/PARK1 encodes α-synuclein, which is associated with familial Parkinson's disease. Despite its abundance in presynaptic terminals, the aggregation mechanism of α-synuclein and its relationship with Parkinson's disease have not yet been elucidated. Moreover, the ultrastructures of α-synuclein localization sites in neuronal presynaptic terminals remain unclear. Therefore, we herein generated transgenic mice expressing human α-synuclein tagged with mKate2 (hSNCA-mKate2 mice). These mice exhibited normal growth and fertility and had no motor dysfunction relative to their wild-type littermates, even at one year old. α-Synuclein-mKate2 accumulated in presynaptic terminals, particularly between Purkinje cells in the cerebellum and neurons in cerebellar nuclei. α-Synuclein-mKate2 was associated with the presynaptic marker, synaptophysin. In-resin CLEM and immunoelectron or electron microscopy revealed that α-synuclein-mKate2 localized on the surface of synaptic vesicles that were tightly arranged and assembled to form large synaptic pools in the cerebellum with negligible effects on the active zone. These results suggest that α-synuclein-associated ultrastructures in the presynaptic terminals of hSNCA-mKate2 mice reflect the structures of α-synuclein-assembled synaptic vesicle pools, and the size of vesicle pools increased. This transgenic mouse model will be a valuable tool for studying α-synuclein-associated synaptic vesicle pools., Competing Interests: Declaration of competing interest None declared, (Copyright © 2024. Published by Elsevier B.V.)

Competing Interests: The authors declare that they have no conflict of interest.

Competing Interests: The authors declare that they have no conflict of interest.

Competing Interests: The authors declare that they have no conflict of interest.

Competing Interests: The authors declare that they have no conflict of interest.

Competing Interests: The authors declare that they have no conflict of interest.

Objective: We hypothesized that patients with amyotrophic lateral sclerosis (ALS) face a dilemma between motivation to live and difficulty in living, and brain-machine interfaces (BMIs) can reduce this dilemma. This study aimed to investigate the present situation of patients with ALS and their expectations from BMIs., Materials and Methods: Our survey design consisted of an anonymous mail-in questionnaire comprising questions regarding the use of tracheostomy positive pressure ventilation (TPPV), motivation to live, anxiety about the totally locked-in state (TLS), anxiety about caregiver burden, and expectations regarding the use of BMI. Primary outcomes were scores for motivation to live and anxiety about caregiver burden and the TLS. Outcomes were evaluated using the visual analogue scale., Results: Among 460 participants, 286 (62.6%) were already supported by or had decided to use TPPV. The median scores for motivation to live, anxiety about TLS, and anxiety about caregiver burden were 8.0, 9.0, and 7.0, respectively. Overall, 49% of patients intended to use BMI. Among patients who had refused TPPV, 15.9% intended to use BMI and TPPV. Significant factors for the use of BMI were motivation to live ( p = .003), anxiety about TLS ( p < .001), younger age ( p < .001), and advanced disease stage ( p < .001)., Conclusions: These results clearly revealed a serious dilemma among patients with ALS between motivation to live and their anxiety about TLS and caregiver burden. Patients expected BMI to reduce this dilemma. Thus, the development of better BMIs may meet these expectations.

The exact cause of nigral cell death in Parkinson's disease (PD) is still unknown. However, research on MPTP-induced experimental parkinsonism has significantly advanced our understanding. In this model, it is widely accepted that mitochondrial respiratory failure is the primary mechanism of cell death. Studies have shown that a toxic metabolite of MPTP inhibits Complex I and alpha-ketoglutarate dehydrogenase activities in mitochondria. Since then, many research groups have focused on mitochondrial dysfunction in PD, identifying deficiencies in Complex I or III in PD patients' brains, skeletal muscle, and platelets. There is some debate about the decline in mitochondrial function in peripheral organs. However, since α-synuclein, the main component protein of Lewy bodies, accumulates in peripheral organs, it is reasonable to consider PD a systemic disease. Additionally, mutant mitochondrial DNA with a 4,977 base pair deletion has been found in the brains of PD patients, suggesting that age-related accumulation of deleted mtDNA is accelerated in the striatum and may contribute to the pathophysiology of PD. While the cause of PD remains unknown, mitochondrial dysfunction is undoubtedly a factor in cell death in PD. In addition, the causative gene for familial PD, parkin (now PRKN), and PTEN-induced putative kinase 1 (PINK1), both gene products are also involved in mitochondrial quality control. Moreover, we have successfully isolated and identified CHCHD2, which is involved in the mitochondrial electron transfer system. There is no doubt that mitochondrial dysfunction contributes to cell death in PD., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Background: The receptor for advanced glycation end product (RAGE) is a transmembrane receptor accelerating a pro-inflammatory signal. RAGE signalling is promoted by decreased soluble isoform of RAGE (sRAGE), which is a decoy receptor for RAGE ligands, and RAGE SNP rs2070600 minor allele. In Caucasian and Japanese cohorts, low circulatory sRAGE levels and presence of the minor allele are associated with poor survival of idiopathic pulmonary fibrosis (IPF) and increased disease susceptibility to interstitial lung disease, respectively. However, whether sRAGE and RAGE SNP rs2070600 are associated with acute exacerbation of IPF (AE-IPF) is unclear., Methods: This retrospective cohort study evaluated the association between the onset of AE-IPF and serum sRAGE levels in 69 German and 102 Japanese patients with IPF. The association of AE-IPF with RAGE SNP rs2070600 in 51 German and 84 Japanese patients, whose DNA samples were stored, was also investigated., Results: In each cohort, the incidence of AE-IPF was significantly and reproducibly higher in the patients with sRAGE < 467.1 pg/mL. In a pooled exploratory analysis, the incidence of AE-IPF was lowest in the patients with higher sRAGE levels and rs2070600 minor allele, although no significant difference in the incidence was observed between the patients with and without the rs2070600 minor allele., Conclusions: Low sRAGE levels were associated with increased incidence of AE-IPF in two independent cohorts of different ethnicities. The combination of rs2070600 and sRAGE levels may stratify patients with IPF for the risk of AE., Competing Interests: Declarations Ethics approval and consent to participate This study was approved by the Ethics Committees of Ruhrlandklinik (IRB 06-3170) and Hiroshima University Hospital (IRB33 and M326). Consent for publication Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Mammalian wounds leave visible scars, and there are no methods for complete regeneration. However, mouse fetuses regenerate their skin, including epidermal and dermal structures, up to embryonic day (E)13. This regeneration pattern requires the formation of actin cables in the wound margin epithelium; however, the molecular mechanisms are not fully understood. Rac1 alters actin in cells and is involved in the formation of filopodia. We investigated whether actin remodeling and skin regeneration patterns can be reproduced through the regulation of Rac1 signaling. Rac1 expression was downregulated in E13 wounds and upregulated after E15 when scars remained. NSC23766, a Rac1-specific inhibitor, altered actin dynamics at the cell margin from filopodia formation to cable formation and inhibited the migration of mouse epidermal keratinocyte, PAM212, by Rac1 signaling suppression. NSC23766 suppressed Rac1 activity and completely regenerated the fetal mouse wounds, even at E14, by changing actin dynamics. Knocked-out Rac1 transgenic mice experienced delayed epithelialization of wounds with suppressed epidermal migration in adults; however, in fetuses, complete wound regeneration via Rac1 signal suppression was observed. Therefore, Rac1 suppression in the wound epidermis can achieve regenerative wound healing in fetuses and may be a potential candidate for healing scars., (© 2024. The Author(s).)

Rationale: Accurate prognostic awareness (PA) and knowledge of the disease are critical for decision-making regarding treatment options, advance care planning, and end-of-life care. However, they have not been investigated in patients with interstitial lung disease (ILD)., Objectives: To determine the prevalence of patients with ILD who have accurate PA and/or knowledge of acute exacerbation. In addition, to determine whether accurate PA is associated with end-of-life medical interventions and quality of dying and death., Methods: Through a nationwide bereavement survey, we examined the prevalence of accurate PA and knowledge of acute exacerbation (AE) in patients with ILD who died in acute general hospitals between January 2018 and February 2020. Patients' PA and knowledge were assessed from the perspective of the bereaved. We also quantified the quality of dying and death from the perspective of the bereaved using three scales, the Good Death Inventory, the Quality of Dying and Death (QODD) questionnaire, and the single-item QODD overall score, and obtained information on end-of-life interventions from the electronic medical record. We examined the associations of accurate PA with end-of-life interventions and quality of dying and death., Results: A total of 296 patients whose caregivers completed questionnaires were analyzed. One hundred sixty-three patients (55.1%, 95% confidence interval [CI] = 49.2-60.8) who died of ILD had accurate PA and 138 (46.9%, 95% CI = 35.9-47.4) recognized that their disease could have AE. Multivariate regression analysis showed that accurate PA was associated with significantly fewer intensive care unit (ICU) deaths (odds ratio = 0.28, 95% CI = 0.10-0.82, P = 0.02). Patients with accurate PA had better quality of dying and death on all the three scales., Conclusions: Approximately half of the patients who died of ILD did not recognize that their disease could lead to death or AE. The lower number of ICU deaths and better quality of dying and death in patients with accurate PA suggest the potential benefits of obtaining accurate PA in patients with ILD.

Introduction: Immunoadsorption plasmapheresis (IA) has been reported to have immunoregulatory effects, in addition to the removal of autoantibodies. This study aimed to investigate the effects of IA on the proportion of myeloid-derived suppressor cells (MDSCs) that potentially suppress autoimmune responses and regulate immunity., Methods: The study included 21 patients with autoimmune neurological diseases and 8 healthy participants. We measured polymorphonuclear (PMN)-MDSCs (CD14 - CD11b + CD33 + ) and inflammation-related mediators before and after a single session of tryptophan-IA. We also investigated whether an increase in PMN-MDSCs after initial IA was a predictor of clinical efficacy in nine patients with myasthenia gravis based on the Quantitative Myasthenia Gravis score., Results: For a total of 36 times of IA procedures, the number of PMN-MDSCs significantly increased after IA. Interleukin-10, monocyte chemoattractant protein-1 and macrophage inflammatory protein-1β levels showed significant increases after IA. Despite similar severity at admission, the Quantitative Myasthenia Gravis scores at discharge were significantly lower in the group in which IA increased PMN-MDSCs to a level of 20% of peripheral blood mononuclear cells or more., Conclusion: Tryptophan-IA regulates PMN-MDSCs and pro-inflammatory cytokines, possibly leading to suppression of autoimmune responses and tissue damage in neuroimmunological disorders., (© 2024 International Society for Apheresis and Japanese Society for Apheresis.)

In super-aged societies, dementia has become a critical issue, underscoring the urgent need for tools to assess cognitive status effectively in various sectors, including financial and business settings. Facial and speech features have been tried as cost-effective biomarkers of dementia including Alzheimer's disease (AD). We aimed to establish an easy, automatic, and extensive screening tool for AD using a chatbot and artificial intelligence. Smile images and visual and auditory data of natural conversations with a chatbot from 99 healthy controls (HCs) and 93 individuals with AD or mild cognitive impairment due to AD (PwA) were analyzed using machine learning. A subset of 8 facial and 21 sound features successfully distinguished PwA from HCs, with a high area under the receiver operating characteristic curve of 0.94 ± 0.05. Another subset of 8 facial and 20 sound features predicted the cognitive test scores, with a mean absolute error as low as 5.78 ± 0.08. These results were superior to those obtained from face or auditory data alone or from conventional image depiction tasks. Thus, by combining spontaneous sound and facial data obtained through conversations with a chatbot, the proposed model can be put to practical use in real-life scenarios., (© 2024. The Author(s).)

Background/aim: The severe malignancy of pancreatic ductal adenocarcinoma (PDAC) is mainly due to frequent local invasiveness and distant metastasis. As for local invasiveness, we previously reported that cancer-specific molecular alterations detected on resected PDAC specimen surfaces, so-called molecular surgical margin (MSM) positiveness, were significantly associated with postoperative locoregional recurrence and distant metastasis. However, due to anatomical limitations, achieving adequate surgical margins during pancreatic cancer resection is often challenging. Therefore, predicting local invasiveness based on the primary tumor's gene profile is crucial to avoid positive MSM., Materials and Methods: Genome-wide miRNA expression profiles were examined and compared between MSM-positive and negative cases. Candidate miRNAs were evaluated in another validation cohort, and their clinicopathological characteristics were examined. Mimic or inhibitor constructs of the candidate miRNA were transfected to PDAC cell lines to evaluate the miRNA function in the pancreatic cancer cell lines and detect the downstream targets., Results: Among some candidates with highly expressed miRNAs in MSM-positive cases by miRNA expression array, recurrence-free survival (RFS) was significantly shorter in the miR-210-3p high expression group (p=0.015). High miR-210-3p was significantly associated with large tumor diameter (p=0.001), anterior invasion positive (p=0.010), and positive lymph node metastasis (p<0.001). miR-210-3p inhibition in PDAC cell lines resulted in decreased proliferation and invasiveness. The iron-sulfur cluster assembly enzyme (ISCU) gene was identified as a target of miR-210-3p. ISCU reduction was significantly observed in PDAC primary tumors with high levels of miR-210-3p, leading to mitochondrial dysfunction in miR-210-3p-overexpressing PDAC cell lines, as demonstrated by glycolysis stress tests., Conclusion: Highly expressed hypoxia-inducible miR-210-3p in primary PDAC tissues induces locally invasive characteristics through mitochondrial dysfunction by suppressing ISCU expression, which may result in poor postoperative RFS outcomes., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Purpose: Parkinson disease (PD) is a common progressive neurodegenerative disorder in our ageing society. Early-stage PD biomarkers are desired for timely clinical intervention and understanding of pathophysiology. Since one of the characteristics of PD is the progressive loss of dopaminergic neurons in the substantia nigra pars compacta, we propose a feature extraction method for analysing the differences in the substantia nigra between PD and non-PD patients., Method: We propose a feature-extraction method for volumetric images based on a rank-1 tensor decomposition. Furthermore, we apply a feature selection method that excludes common features between PD and non-PD. We collect neuromelanin images of 263 patients: 124 PD and 139 non-PD patients and divide them into training and testing datasets for experiments. We then experimentally evaluate the classification accuracy of the substantia nigra between PD and non-PD patients using the proposed feature extraction method and linear discriminant analysis., Results: The proposed method achieves a sensitivity of 0.72 and a specificity of 0.64 for our testing dataset of 66 non-PD and 42 PD patients. Furthermore, we visualise the important patterns in the substantia nigra by a linear combination of rank-1 tensors with selected features. The visualised patterns include the ventrolateral tier, where the severe loss of neurons can be observed in PD., Conclusions: We develop a new feature-extraction method for the analysis of the substantia nigra towards PD diagnosis. In the experiments, even though the classification accuracy with the proposed feature extraction method and linear discriminant analysis is lower than that of expert physicians, the results suggest the potential of tensorial feature extraction., (© 2024. CARS.)

Background and Aims: Accurately diagnosing biliary strictures is crucial for surgical decisions, and although peroral cholangioscopy (POCS) aids in visual diagnosis, diagnosing malignancies or determining lesion margins via this route remains challenging. Indigo carmine is commonly used to evaluate lesions during GI endoscopy. We aimed to establish the utility of virtual indigo carmine chromoendoscopy (VICI) converted from POCS images using artificial intelligence., Methods: This single-center, retrospective study analyzed 40 patients with biliary strictures who underwent POCS using white-light imaging (WLI) and narrow-band imaging (NBI). A cycle-consistent adversarial network was used to convert the WLI into VICI of POCS images. Three experienced endoscopists evaluated WLI, NBI, and VICI via POCS in all patients. The primary outcome was the visualization quality of surface structures, surface microvessels, and lesion margins. The secondary outcome was diagnostic accuracy., Results: VICI showed superior visualization of the surface structures and lesion margins compared with WLI (P < .001) and NBI (P < .001). The diagnostic accuracies were 72.5%, 87.5%, and 90.0% in WLI alone, WLI and VICI simultaneously, and WLI and NBI simultaneously, respectively. WLI and VICI simultaneously tended to result in higher accuracy than WLI alone (P = .083), and the results were not significantly different from WLI and NBI simultaneously (P = .65)., Conclusions: VICI in POCS proved valuable for visualizing surface structures and lesion margins and contributed to higher diagnostic accuracy comparable to NBI. In addition to NBI, VICI may be a novel supportive modality for POCS., Competing Interests: Disclosure All authors disclosed no financial relationships., (Copyright © 2024 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.)

Background: Non-motor symptoms (NMS) are important factors when selecting treatments for patients with advanced Parkinson's disease (PD). We sought to elucidate the prescribing practices for advanced PD patients with NMS in Japanese clinical practice., Methods: We examined the prescription rates and doses of anti-PD drugs, and the use of non-steroidal anti-inflammatory drugs (NSAIDs) in post hoc analyses of a 52-week observational study of 996 PD patients with wearing-off on levodopa-containing therapy and ≥1 NMS., Results: Dopamine agonists were the most frequently prescribed drugs combined with levodopa-containing drugs, followed by entacapone, zonisamide, istradefylline, selegiline, and amantadine. The daily dose of levodopa-containing drugs, rotigotine, entacapone, istradefylline, and droxidopa, and the levodopa-equivalent dose increased during the observation period. In a subgroup analysis of patients stratified by NMS status (improved/unchanged/deteriorated), the deteriorated group had higher prescription rates of entacapone and istradefylline, whereas the improved group had higher prescription rates of NSAIDs and zonisamide at Week 52. Prescriptions varied by geographical region for anti-PD drugs and by NMS status for NSAIDs., Conclusions: There were significant changes in the prescriptions and dosing of selected anti-PD drugs, especially newer drugs. Anti-PD drug and NSAID prescriptions also varied by changes in NMS status and geographic region., Competing Interests: Masahiro Nomoto reported research funds from Kyowa Kirin in relation to this study; and reported employment by The Social Welfare Organization Imperial Gift Foundation Inc. Saiseikai Imabari Hospital; honoraria from Ehime University, Takeda Pharmaceutical, Kyowa Kirin, Eisai, and Ono Pharmaceutical; consultancies for Kissei Pharmaceutical and SNLD; and has served on advisory boards for the Pharmaceuticals and Medical Devices Agency and Ehime Prefecture. Yoshio Tsuboi reported research funds from Kyowa Kirin in relation to this study; and reported lecture fees from Sumitomo Pharma, Takeda Pharmaceutical, Novartis Pharma, Ono Pharmaceutical, and Eisai; and contributes to courses organized by SUNWELS and Nipro Corporation. Kenichi Kashihara reported research funds from Kyowa Kirin in relation to this study; and reported employment by Okayama Neurology Clinic; and honoraria from Kyowa Kirin, Takeda Pharmaceutical, Ono Pharmaceutical, Sumitomo Pharma, FP Corporation, AbbVie GK, and Eisai. Shih-Wei Chiu reported research funds from Kyowa Kirin in relation to this study. Tetsuya Maeda reported research funds from Kyowa Kirin in relation to this study; and reported lecture fees and scholarship donations from Sumitomo Pharma, Takeda Pharmaceutical Company, Ono Pharmaceutical, Eisai, Otsuka Pharmaceutical, Nippon Boehringer Ingelheim, Daiichi Sankyo, and Japan Medtronic; lecture fees from AbbVie, FP Corporation, Biogen, and Chugai Pharmaceutical; scholarship donations from Bayer Yakuhin, Teijin, and CSL Behring; and consulting fees from Kyowa Kirin and Ono Pharmaceutical. Hidemoto Saiki reported editorial support from Kyowa Kirin in relation to this study; and reported honoraria from Eisai, Sumitomo Pharma, Ono Pharmaceutical, Takeda Pharmaceutical, and Medtronic Japan; and grants from Otsuka Pharmaceutical and PDRadiopharma Inc. Hirohisa Watanabe reported research funds from Kyowa Kirin in relation to this study; and reported honoraria from Takeda Pharmaceutical, AbbVie, Kyowa Kirin, Sumitomo Pharma, Novartis Pharma, Otsuka Pharmaceutical, and FP Corporation. Yasushi Shimo reported honoraria from Takeda Pharmaceutical, Abbott Japan, Otsuka Pharmaceutical, Medtronic Japan, Kyowa Kirin, Eisai, MDS, Boston Scientific Japan, Sumitomo Pharma, Daiichi Sankyo, Nihon Medi-Physics, and EA Pharma; and a grant from Japan Society for the Promotion of Science (JSPS KAKENHI no. 21K07282). Nobutaka Hattori reported research grants, support for attending advisory boards, and support for a joint research department from Kyowa Kirin; and reported research contracts with Sumitomo Pharma and CellSource; consultancy fees from PARKINSON Laboratories; honoraria from Sumitomo Pharma, AbbVie, Otsuka Pharmaceutical, Novartis Pharma, Ono Pharmaceutical, FP Pharmaceutical, Eisai, and Daiichi Sankyo; support for attending advisory boards from Sumitomo Pharma, Novartis Pharma, Ono Pharmaceutical, Teijin Pharma, and Mitsubishi Tanabe Pharma Corporation; support for an endowed department from Nippon Boehringer Ingelheim, FP Pharmaceutical, Teijin Pharma, Fujifilm Wako Pure Chemical Corporation, and Meiji Seika Pharma; support for a joint research department from Kyowa Kirin, Sumitomo Pharma, Parkinson Laboratories, Takeda Pharmaceutical, Otsuka Pharmaceutical, Ono Pharmaceutical, Nihon Medi-Physics, Mitsubishi Tanabe Pharma Corporation, and Sunwels; scholarship donations from FP Pharmaceutical; holds stock in Parkinson Laboratories; honoraria for a team leader role at RIKEN Center for Brain Science; and is a coauthor on patent applications by Juntendo University. Takuhiro Yamaguchi reported grants from Otsuka Pharmaceutical, Solasia Pharma, Japan Tobacco Inc., Daiichi Sankyo, Eisai, and Cordis Corporation; and personal fees from Intellim Corporation, Chugai Pharmaceutical, SONIRE Therapeutics Inc., Merck and Co Inc., EPS Corporation, Japan Tobacco Inc., Ono Pharmaceutical, Kowa Company, Daiichi Sankyo, Eisai, 3H Clinical Trial Inc., and Incyte Biosciences Japan. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2024 Nomoto 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.)

Introduction: Neurolymphomatosis (NL) is a rare condition characterized by the infiltration of malignant lymphoma cells into the peripheral nervous system. The optimal treatment for NL remains unclear, and patients with secondary NL have a poor prognosis. Although early recognition of NL may contribute to successful treatment, the predictive factors for secondary NL are yet to be established., Case Presentation: Here, we present our investigation on the predictive factors for secondary NL, and report two cases of secondary NL with a literature review. We analyzed chromosomal abnormalities in patients with secondary NL and found a common deletion of chromosome 10 and add(11)(p11). The chromosomal abnormalities might be a predictive factor for secondary NL; therefore, confirmation of chromosomal abnormalities can possibly give a hint for early detect of secondary NL. Prompt histopathological examination or imaging techniques can lead to early diagnosis of secondary NL in patients with diffuse large B-cell lymphoma (DLBCL)., Conclusion: When neurological symptoms manifest in patients with DLBCL and there are chromosomal abnormalities, the possible development of secondary NL should be considered., Competing Interests: The authors state that they have no conflict of interest., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Introduction: Studies have shown the antitumor efficacy of immune checkpoint inhibitors (ICI) in patients with non-small cell lung cancer (NSCLC) and brain metastases (BM). However, it is unclear whether the efficacy of ICI is similar between patients with and without BM. It is yet unclear whether the efficacy of ICI in patients with BM increases with higher levels of programmed cell death-ligand 1 (PD-L1) expression, as observed in patients without BM., Methods: We compared the outcomes of ICI treatment between patients with and without BM using a cohort containing 1741 prospectively enrolled patients with lung cancer. We investigated whether there were differences in the outcomes of ICI based on PD-L1 expression levels between these patients., Results: We enrolled 240 patients with NSCLC with or without BM who were treated with ICI or both chemotherapy and ICI. There were no significant differences in overall survival (OS) between all patients with or without BM (p = 0.489). However, OS was significantly shorter in patients with BM than in those without in the PD-L1 ≥ 50% group (16.5 M vs. 30.6 M, p = 0.003) but not in the PD-L1 ≥ 1% or negative group. BM was an independent poor prognostic factor for OS (hazard ratio: [95% confidence interval], 2.045; [1.058-3.953], p = 0.033) in the PD-L1 ≥ 50% group., Conclusion: Our study indicated that the outcomes of patients with or without BM treated with ICI were not significantly different. The efficacy of ICI in patients with PD-L1 expression ≥50% would be lower in patients with BM than in those without., (© 2024 The Author(s). Thoracic Cancer published by John Wiley & Sons Australia, Ltd.)

Most follicular lymphomas (FLs) demonstrate an indolent clinical course with favorable outcomes; however, a fraction of patients experiences progression of disease within 24 months (POD24) and has adverse outcomes. This study aimed to determine the predictive risk factors for POD24 in patients with FL, and the characteristics of the microenvironment in FL with POD24. By multivariate analysis, we revealed that increased Ki-67 expression was associated with POD24 events in patients with FL (hazard ratio [HR]: 6.29, 95% confidence interval [CI]: 1.96-20.22, p = 0.0020). Additionally, patients with FL with POD24 demonstrated immune cell reduction by immunohistochemistry analysis. Our results help better understand the therapeutic strategies for FL with POD24.

Parkinson's disease (PD), the second most prevalent neurodegenerative disorder, was classically attributed to alpha-synuclein aggregation and consequent loss of dopaminergic neurons in the substantia nigra pars compacta. Recently, emerging evidence suggested a broader spectrum of contributing factors, including exosome-mediated intercellular communication, which can potentially serve as biomarkers and therapeutic targets. However, there is a remarkable lack of comprehensive studies that connect the serum exosome microRNA (miRNA) transcriptome with demographic, clinical, and neuroimaging data in PD patients. Here, we present serum exosome miRNA transcriptome data generated from four cohort studies. Two of these studies include 96 PD patients and 80 age- and gender-matched controls, with anonymised demographic, clinical, and neuroimaging data provided for PD patients. The other two studies involve 96 PD patients who were evaluated both before and after one year of treatment with rasagiline, a widely prescribed anti-parkinsonism drug. Together, the datasets provide a valuable source for understanding pathogenesis and discovering biomarkers and therapeutic targets in PD., (© 2024. The Author(s).)

Corticobasal degeneration (CBD) is a major four-repeat tauopathy along with progressive supranuclear palsy (PSP). Although detergent-insoluble 37-40-kDa carboxyl-terminal tau fragments (CTFs) are hallmarks of CBD pathology, the process of their formation is unknown. This study monitored the formation of CBD-type fibrils that exhibit astrocytic plaques, a characteristic CBD pathology, using its biochemical properties different from those of Alzheimer's disease/PSP-type fibrils. Tau fibrils from patients with CBD were amplified in non-astrocytic cultured cells, which maintained CBD-specific biochemical properties. We found that the lysosomal protease Legumain (LGMN) was involved in the generation of CBD-specific 37-40-kDa CTFs. While LGMN cleaved tau fibrils at Asn167 and Asn368 in the brain tissues of patients with Alzheimer's disease and PSP, tau fibrils from patients with CBD were predominantly resistant to cleavage at Asn368 by LGMN, resulting in the generation of CBD-specific CTFs. LGMN preference in tau fibrils was lost upon unraveling the tau fibril fold, suggesting that the CBD-specific tau fibril fold contributes to CBD-specific CTF production. From these findings, we found a way to differentiate astrocytic plaque from tufted astrocyte using the anti-Asn368 LGMN cleavage site-specific antibody. Inoculation of tau fibrils amplified in non-astrocytic cells into the mouse brain reproduced LGMN-resistant tau fibrils and recapitulated anti-Asn368-negative astrocytic plaques, which are characteristic of CBD pathology. This study supports the existence of disease-specific tau fibrils and contribute to further understanding of the tauopathy diagnosis. Our tau propagation mouse model using cellular tau seeds may contribute to uncovering disease mechanisms and screening for potential therapeutic compounds., Competing Interests: Declaration of competing interest All authors declare no conflict of interest., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: There have been only a few cases showing the efficacy of pembrolizumab on granulocyte-colony - stimulating factor (G-CSF)-producing non-small-cell lung cancer (NSCLC) with high programmed cell death ligand 1 (PD-L1) expression. Herein, we report the first case showing the efficacy of pembrolizumab for G-CSF-producing NSCLC with high PD-L1 expression, although the patient had factors indicative of poor pembrolizumab efficacy, such as poor performance status (PS) due to the tumor-induced inflammation and corticosteroids administration., Case Presentation: A 77-year-old woman was diagnosed with G-CSF-producing NSCLC-not otherwise specified, classified as clinical stage IVB, T2N3M1c. She had fever and her PS was 3, and her C-reactive protein (CRP) was 6.47 mg/dL due to inflammation by a G-CSF-producing tumor. Thus, we initiated the administration of dexamethasone (3.3 mg/day). Her fever abated the next day, and CRP dropped to 3.22 mg/dL after 4 days. Driver mutations were negative, and PD-L1, tumor proportion score, was highly expressed at 100%. Thus, pembrolizumab was started. Subsequently, the white blood cell count decreased, and the tumor shrank, indicating a partial response. After three cycles of pembrolizumab therapy, the anorexia improved, and she was discharged. The patient developed sclerosing cholangitis after discharge. Therefore, the pembrolizumab treatment was discontinued. The primary lesion was enlarged, indicating progressive disease. However, the patient and her family did not want additional treatment. Finally, her progression-free survival and overall survival were 6 and 7 months, respectively., Conclusion: Pembrolizumab may be effective against G-CSF-producing NSCLC with high PD-L1 expression. Corticosteroids seemed to inhibit inflammation induced by the tumor, and exert the efficacy of pembrolizumab., Competing Interests: Takeshi Masuda reports personal fee from Daiichi-Sankyo Co., Ltd., Taiho Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., Kyowa Kirin Co., Ltd., Eli Lilly Japan K.K., Ono Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., and AstraZeneca K.K. outside the submitted work. Kakuhiro Yamaguchi reports honoraria from Ono Pharmaceutical Co., Ltd., outside the submitted work. Shinjiro Sakamoto reports honoraria from AstraZeneca K.K., Nippon Boehringer Ingelheim Co., Ltd., Chugai Pharmaceutical Co., Ltd., Kyowa Kirin Co., Ltd., and Novartis Pharma K.K. outside the submitted work. Yasushi Horimasu reports honoraria from Nippon Boehringer Ingelheim Co., Ltd., outside the submitted work. Taku Nakashima reports honoraria from AstraZeneca K.K. and Chugai Pharmaceutical Co., Ltd., outside the submitted work. Noboru Hattori reports honoraria from AstraZeneca K.K., Bristol Myers Squibb, Chugai Pharmaceutical Co., Ltd., and Ono Pharmaceutical Co., Ltd., outside the submitted work. No other disclosures are reported., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

This study aimed to explore the intricate relationship between mitochondrial dysfunction, infection, and neuroinflammation, focusing specifically on the impact of pathogenic epitopes of the Epstein-Barr Virus (EBV) nuclear antigen 1 (EBNA1) in a mouse model of mitochondrial dysfunctions. The investigation included female middle-aged PARK2 -/- and C57BL/6J wild-type mice immunized with EBNA1 386-405 or with active experimental autoimmune encephalomyelitis (EAE) induction by the myelin oligodendrocyte glycoprotein (MOG) 35-55 peptide. The PARK2 -/- mice developed more severe EAE than the wild-type mice. Following immunization with EBNA1 386-405 , only PARK2 -/- exhibited symptoms resembling EAE. During the acute phase, PARK2 -/- mice immunized with either MOG 35-55 or EBNA1 386-405 exhibited a similar infiltration of the T cells and macrophages in the spinal cord and decreased glial fibrillary acidic protein (GFAP) expression in the brain. However, the EBNA1 386-405 -immunized PARK2 -/- mice showed significantly increased frequencies of CD8a + T cells and CD11c + B cells, and distinct cytokine profiles in the periphery compared to the wild-type controls. These findings highlight the role of EBV in exacerbating inflammation, particularly in the context of mitochondrial deficiencies.

Background: Various reduced-intensity conditioning/reduced-toxicity conditioning regimens have been developed for patients receiving allogeneic hematopoietic cell transplantation. The balance between disease relapse and toxicity can be partly dependent on reduced-intensity conditioning/reduced-toxicity conditioning regimens. This retrospective study aimed to compare the nonrelapse mortality, relapse incidence, progression-free survival, and overall survival rates between the fludarabine/melphalan/reduced-dose busulfan (Flu/Mel/Bu2; busulfan at a dose of 6.4 mg/kg intravenously) and fludarabine/melphalan/full-dose busulfan (Flu/Mel/Bu4; busulfan at a dose of 12.8 mg/kg intravenously) regimens in patients receiving umbilical cord blood transplantation., Method: Eighty-seven adult patients who received the Flu/Mel/Bu2 (n = 45) or Flu/Mel/Bu4 (n = 42) regimen as a conditioning regimen before umbilical cord blood transplantation at our institution between January 2013 and December 2022 were included in this study., Results: There were no significant differences in terms of clinical outcomes including nonrelapse mortality, relapse incidence, progression-free survival, and overall survival rates between the two regimens. Further, even in higher-risk patients classified according to the Refined Disease Risk Index, the Flu/Mel/Bu2 regimen was comparable to the Flu/Mel/Bu4 regimen., Conclusion: The novel Flu/Mel/Bu2 regimen could be applied in clinical settings as it can be tolerated and effective in older patients., 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 article., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Neuroimaging databases for neuro-psychiatric disorders enable researchers to implement data-driven research approaches by providing access to rich data that can be used to study disease, build and validate machine learning models, and even redefine disease spectra. The importance of sharing large, multi-center, multi-disorder databases has gradually been recognized in order to truly translate brain imaging knowledge into real-world clinical practice. Here, we review MRI databases that share data globally to serve multiple psychiatric or neurological disorders. We found 42 datasets consisting of 23,293 samples from patients with psychiatry and neurological disorders and healthy controls; 1245 samples from mood disorders (major depressive disorder and bipolar disorder), 2015 samples from developmental disorders (autism spectrum disorder, attention-deficit hyperactivity disorder), 675 samples from schizophrenia, 1194 samples from Parkinson's disease, 5865 samples from dementia (including Alzheimer's disease), We recognize that large, multi-center databases should include governance processes that allow data to be shared across national boundaries. Addressing technical and regulatory issues of existing databases can lead to better design and implementation and improve data access for the research community. The current trend toward the development of shareable MRI databases will contribute to a better understanding of the pathophysiology, diagnosis and assessment, and development of early interventions for neuropsychiatric disorders., (© 2024 The Author(s). Psychiatry and Clinical Neurosciences published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Psychiatry and Neurology.)

A 63-year-old Japanese female presented with fever. Computed tomography showed multiple nodules in both lungs. Corticosteroids and antibiotics were administered to treat suspected organizing and bacterial pneumonia, resulting in no improvement and respiratory failure worsened. Surgical lung biopsy revealed infiltration of CD3, CD56, Granzyme B, and EBV-encoded RNA-ISH-positive atypical lymphocytes. She was diagnosed with primary pulmonary extranodal NK/T-cell lymphoma (ENKL) and died two months after diagnosis with only a temporary effectiveness of chemotherapy. We should consider the possibility of ENKL and perform prompt and appropriate biopsy for early diagnosis in cases where empiric therapy is ineffective for suspected pneumonia., Competing Interests: 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. No conflicts of interest., (© 2024 The Authors.)

Esophageal squamous cell carcinoma (ESCC) is recognized as one of the most aggressive cancers with a poor prognosis. Global expression profiling was conducted on primary ESCC tissues with distant metastases. We investigated the identification of secretogranin V (SCG5) as a promising biomarker for the detection and assessment of ESCC. SCG5 transcription levels were evaluated in 21 ESCC cell lines. Small interfering RNA-mediated knockdown experiments validated SCG5's roles in cell invasion, proliferation, and migration. We utilized a mouse subcutaneous xenograft model to assess tumor growth. SCG5 expression was measured in 164 ESCC tissues by quantitative reverse transcription quantitative polymerase chain reaction, and its association with clinicopathological parameters was investigated. SCG5 protein levels were assessed in surgically resected tissues from 177 patients with ESCC using a tissue microarray. The mRNA expression levels of SCG5 varied widely in ESCC cell lines. The in vitro cell invasion, proliferation, and migration of ESCC cells were suppressed by the knockdown of SCG5. Mouse xenograft models revealed that tumor growth was reduced by small interfering RNA-mediated SCG5 knockdown. Analysis of clinical samples demonstrated that SCG5 mRNA was expressed in ESCC compared to adjacent normal esophageal tissues. High SCG5 mRNA expression was linked to significant decreases in overall and disease-specific survival. Furthermore, SCG5 protein expression was linked to a decrease in disease-specific survival and disease-free survival. The expression of the SCG5 was significantly associated with disease-specific survival, suggesting that SCG5 may play a significant role as a diagnostic and prognostic biomarker for ESCC., (© The Author(s) 2024. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Although bone marrow-derived cells with high aldehyde dehydrogenase activity (ALDH br ) have shown therapeutic potential against various diseases in animal studies, clinical trials have failed to show concurrent findings. We aimed to clarify the optimal conditions for the efficacy of ALDH br cells by using a murine bleomycin-induced pulmonary fibrosis model., Methods: We intravenously transferred male or female donor C57BL/6 mice-derived ALDH br cells into recipient C57BL/6 mice under various conditions, and used mCherry-expressing mice as a donor to trace the transferred ALDH br cells., Results: Pulmonary fibrosis improved significantly when (1) female-derived, not male-derived, and (2) lineage (Lin)-negative, not lineage-positive, ALDH br cells were transferred during the (3) fibrotic, not inflammatory, phase. Consistent with the RNA-sequencing results, female-derived Lin - /ALDH br cells were more resistant to oxidative stress than male-derived cells in vitro, and transferred female-derived Lin - /ALDH br cells were more viable than male-derived cells in the fibrotic lung. The mechanism underlying the antifibrotic effects of Lin - /ALDH br cells was strongly associated with reduction of oxidative stress., Conclusions: Our results indicated that Lin - /ALDH br cell therapy could ameliorate pulmonary fibrosis by reducing oxidative stress and suggested that their efficacy was mediated by sex-related differences. Thus, sex-awareness strategies may be important for clinical application of bone marrow ALDH br cells as a therapeutic tool., (© 2024. The Author(s).)

Background and Aims: Although EUS-guided liver abscess drainage (EUS-LAD) has been developed, only the left hepatic or caudate lobe can traditionally be drained by EUS. However, there is no evidence for the technical feasibility of EUS-LAD for the right hepatic lobe. In this retrospective study, the technical feasibility of EUS-LAD using a novel partially covered self-expandable metal stent (PCSEMS) with an antimigration system was evaluated as a first-line drainage technique for right hepatic lobe abscesses., Methods: This study included consecutive patients with right lobe liver abscesses between December 2020 and February 2024. The primary outcome in this study was the technical success rate of EUS-LAD. Technical success of EUS-LAD was defined as successful stent deployment from the liver abscess to the duodenum. Clinical success, procedure time, duration of hospital stay, recurrence of liver abscess, and adverse events were evaluated as secondary outcomes., Results: Nineteen patients were enrolled in this study. The location of the liver abscesses was mainly at segment 6. The mean size of the liver abscesses was 91.8 mm. The liver abscess could be identified under EUS guidance from the duodenum in 16 patients. Puncture using a 19-gauge needle was attempted, but the needle could not reach the liver abscess in 1 patient. The novel PCSEMS was successfully deployed in all patients. The technical success rate of EUS-LAD was 78.9% (15/19). Adverse events associated with the procedure were observed in 3 patients, but conservative treatment was successful. Clinical success was obtained in 14 patients (93.3%). The median duration of stent placement was 19 days (range, 7-41). The median follow-up period was 556 days, and recurrence of liver abscess was not observed in any patients., Conclusions: EUS-LAD for the right liver lobe using a novel PCSEMS can be feasible and safe., Competing Interests: Disclosure All authors disclosed no financial relationships., (Copyright © 2024 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.)

Background:  Primary analysis of the phase III AGEHA study suggested a favorable benefit-risk profile for emicizumab prophylaxis in patients with acquired hemophilia A (PwAHA); however, only patients undergoing immunosuppressive therapy (IST; Cohort 1) were included., Objectives:  To present final analysis results of AGEHA, including data on IST-ineligible patients (Cohort 2) and on long-term prophylaxis with emicizumab., Methods:  For patients in both Cohorts 1 and 2, emicizumab was administered subcutaneously at 6 mg/kg on Day 1, 3 mg/kg on Day 2, and 1.5 mg/kg once weekly from Day 8 onward., Results:  Twelve patients (Cohort 1) and two patients (Cohort 2) were enrolled. Duration of emicizumab treatment was 8 to 639 days (median: 44.5 days) in Cohort 1 and 64 and 450 days in Cohort 2. In both cohorts, no major bleeds were observed after initial emicizumab administration. Six patients started their first rehabilitation sessions during emicizumab treatment and no rehabilitation-related bleeds occurred. Twenty-three surgeries were performed under emicizumab prophylaxis and there were no bleeds related to surgeries. Although asymptomatic deep vein thrombosis was reported in one patient in the primary analysis, no other thrombotic events occurred thereafter. Two patients developed anti-emicizumab antibodies, one of whom showed accelerated emicizumab clearance. Tailored IST approaches (delayed initiation, no use, or reduced dose) were successfully executed in three patients undergoing emicizumab prophylaxis., Conclusion:  These results suggest that emicizumab prophylaxis has a favorable benefit-risk profile in PwAHA regardless of eligibility for IST., Competing Interests: M. Shima has received research funding from Chugai Pharmaceutical Co., Ltd., CSL Behring, and Takeda; has received honoraria from Bayer, Chugai Pharmaceutical Co., Ltd., CSL Behring, Fujimoto Seiyaku, Sanofi, Novo Nordisk, Pfizer, and Takeda; holds patents with Chugai Pharmaceutical Co., Ltd.; and has participated on a data safety monitoring board or advisory board for Chugai Pharmaceutical Co., Ltd., Fujimoto Seiyaku, KYORIN Pharmaceutical Co., Ltd., Novo Nordisk, and Pfizer. N.S. has received honoraria from Bayer, Chugai Pharmaceutical Co., Ltd., CSL Behring, Japan Blood Products Organization, KM Biologics, Novo Nordisk, Pfizer, Sanofi, and Takeda. K.A. has received research funding from KM Biologics; has received consulting fees from Chugai Pharmaceutical Co., Ltd.; has received honoraria from Bayer, Chugai Pharmaceutical Co., Ltd., CSL Behring, Fujimoto Pharmaceutical Corporation, Japan Blood Products Organization, KM Biologics, Novo Nordisk, Pfizer, Sanofi, and Takeda; has participated on a data safety monitoring board or advisory board for Chugai Pharmaceutical Co., Ltd.; and is belong to endowed chair for CSL Behring. Y.O. has received consulting fees and honoraria from Chugai Pharmaceutical Co., Ltd. R.K. and R.O. are employees of Chugai Pharmaceutical Co., Ltd. K.Y. is an employee of Chugai Pharmaceutical Co., Ltd. and an inventor of patents related to anti-activated FIX/FX bispecific antibodies. N.M. is an employee of Chugai Pharmaceutical Co., Ltd. and has stocks of Chugai Pharmaceutical Co., Ltd. E.S. has received research funding from Eisai; has received honoraria from Janssen, Novartis, Pfizer, Sanofi, and Takeda, and has leadership or fiduciary role in other board, society, committee, or advocacy group (unpaid) for Japan Adult Leukemia Study Group and Japanese Society of Myeloma. S.H. has received research funding from Chugai Pharmaceutical Co., Ltd. and has received honoraria from Bayer, Chugai Pharmaceutical Co., Ltd., CSL Behring, Novo Nordisk, Sanofi, and Takeda. K.N. has received research funding from Bayer, Chugai Pharmaceutical Co., Ltd., CSL Behring, KM Biologics, Novo Nordisk, Sanofi, and Takeda; has received consulting fees from Chugai Pharmaceutical Co., Ltd.; and has received honoraria from Bayer, Chugai Pharmaceutical Co., Ltd., CSL Behring, KM Biologics, Novo Nordisk, Sanofi, and Takeda. The remaining authors have no conflicts of interest to declare., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Intraoperative CT navigation has revolutionized spinal surgery by enhancing precision, particularly in pedicle screw placement. However, the traditional use of bone-fixed dynamic reference frames (DRFs) often necessitates placement on spinous processes, complicating percutaneous pedicle screw (PPS) insertion and requiring additional incisions. This case report presents a novel approach utilizing a skin-fixed DRF in spinal trauma surgery. A 26-year-old female sustained lower limb paralysis, sensory impairment, and bladder-rectal dysfunction after a 15 m fall, resulting in an L1 fracture-dislocation (American Spinal Injury Association score C, Thoracolumbar AOSpine Injury Score score 13). The radiological assessment confirmed dural sac compression. An emergency damage control surgery was conducted using a skin-fixed DRF, secured with sutures and tape near the PPS insertion site. Intraoperative CT navigation guided the insertion of PPS from T11 to L3. The procedure lasted 141 minutes with an estimated blood loss of 256 mL. Postoperative CT verified accurate screw placement. At six months postoperatively, the patient exhibited significant motor recovery and regained independent ambulation. The skin-fixed DRF technique minimizes surgical complexity, obviates the need for additional incisions, and mitigates the challenges associated with bone-fixed DRFs during PPS procedures. This method demonstrates potential as a minimally invasive and effective surgical technique in spinal trauma cases., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. 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, Kishi et al.)

Neutrophils play an important role in innate immunity and produce reactive oxygen species, but they can also cause inflammation and oxidative stress that can damage their own tissues. We have developed neutrophil activity evaluation systems that simultaneously monitors superoxide radicals and hypochlorite ions secreted by stimulated neutrophils in a few microliters of whole blood and have conducted clinical studies in humans. Here, we report normal reference intervals with our systems based on the results of 3,082 persons who underwent comprehensive cancer screening between February 2020 and March 2022. A total of 344 were extracted as reference individuals based on the results of the cancer screening and the reference intervals of the two systems were interim estimated considering gender and age. Reference intervals can be used as a marker of sub-clinical inflam-mation, which is difficult to detect with other blood markers., Competing Interests: TS, TM, and KK are employees of Hamamatsu Photonics K.K. YH and CI were employees of Hamamatsu Photonics K.K. when this research was conducted. KK submitted patent applications on the technologies used in this study. The other authors declare no potential conflicts of interest., (Copyright © 2024 JCBN.)

Peptide-binding motif (PBM) model, a hierarchical clustering of HLA class I based on their binding specificity, was developed to predict immunopeptidome divergence. The effect of PBM mismatches on outcomes is unknown in HLA-haploidentical haematopoietic cell transplantation with post-transplant cyclophosphamide (PTCy-haplo). We therefore conducted a retrospective study using national registry data in PTCy-haplo. Overall, 1352 patients were included in the study. PBM-A bidirectional mismatch was associated with an increased risk of overall mortality in multivariable analysis (hazard ratio, 1.26; 95% confidence interval, 1.06 to 1.50; p = 0.010). None of relapse, non-relapse mortality (NRM) and graft-versus-host disease showed significant differences according to PBM-A bidirectional mismatch status in the entire cohort. The impact of PBM-A bidirectional mismatch on overall survival (OS) was preserved within the HLA-A genotype bidirectional mismatch population, and their lower OS stemmed from higher relapse rate in this population. The worse OS due to high NRM with PBM-A bidirectional mismatch was prominent in lymphoid malignancies receiving reduced-intensity conditioning. The PBM model may predict outcomes more accurately than HLA genotype mismatches. In conclusion, this study demonstrated that the presence of PBM-A bidirectional mismatch elevated the risk of mortality of PTCy-haplo. Avoiding PBM-A bidirectional mismatch might achieve better outcomes in PTCy-haplo., (© 2024 British Society for Haematology and John Wiley & Sons Ltd.)

Background: Esophageal squamous cell carcinoma (ESCC) has a poor prognosis despite advances in multidisciplinary treatments and immune checkpoint inhibitors. We previously reported that neural pentraxin receptor (NPTXR), a transmembrane protein mainly expressed in the brain and involved in synaptic transmission, is implicated in gastric cancer malignancy. This study evaluated the expression and function of NPTXR in ESCC, the therapeutic potential of monoclonal antibody (mAb) against NPTXR, and its prognostic value in ESCC patients., Methods: The study involved analyzing the NPTXR expression in 21 ESCC cell lines and total 371 primary ESCC tissue samples using quantitative reverse-transcription polymerase chain reaction and immunohistochemistry. The impact of NPTXR on the malignant behavior of ESCC was examined using small interfering RNA-mediated knockdown and a subsequent assessment of cell proliferation, apoptosis, and adhesion. This study further investigated the efficacy of anti-NPTXR mAb in vitro and associations between the expression of NPTXR messenger RNA (mRNA) and protein with clinicopathological factors and the prognosis., Results: NPTXR was overexpressed in several ESCC cell lines and primary ESCC tissues. Knockdown of NPTXR in ESCC cells resulted in reduced proliferation, increased apoptosis, and decreased cell adhesion. The mAb against NPTXR significantly inhibited ESCC cell proliferation in vitro. A high NPTXR expression in patient tissues was correlated with a worse overall survival, suggesting its potential as a prognostic biomarker., Conclusions: NPTXR influences the malignant behavior of ESCC cells. Anti-NPTXR mAb may be a promising therapeutic agent, and its expression in ESCC tissues may serve as a prognostic biomarker., (© 2024. Society of Surgical Oncology.)

Leucine-rich repeat kinase 2 (LRRK2) is the most common gene responsible for familial Parkinson's disease (PD). The gene product of LRRK2 contains multiple protein domains, including armadillo repeat, ankyrin repeat, leucine-rich repeat (LRR), Ras-of-complex (ROC), C-terminal of ROC (COR), kinase, and WD40 domains. In this study, we performed genetic screening of LRRK2 in our PD cohort, detecting sixteen LRRK2 rare variants. Among them, we selected seven variants that are likely to be familial and characterized them in terms of LRRK2 protein function, along with clinical information and one pathological analysis. The seven variants were S1120P and N1221K in the LRR domain; I1339M, S1403R, and V1447M in the ROC domain; and I1658F and D1873H in the COR domain. The kinase activity of the LRRK2 variants N1221K, S1403R, V1447M, and I1658F toward Rab10, a well-known phosphorylation substrate, was higher than that of wild-type LRRK2. LRRK2 D1873H showed enhanced self-association activity, whereas LRRK2 S1403R and D1873H showed reduced microtubule-binding activity. Pathological analysis of a patient with the LRRK2 V1447M variant was also performed, which revealed Lewy pathology in the brainstem. No functional alterations in terms of kinase activity, self-association activity, and microtubule-binding activity were detected in LRRK2 S1120P and I1339M variants. However, the patient with PD carrying LRRK2 S1120P variant also had a heterozygous Glucosylceramidase beta 1 (GBA1) L444P variant. In conclusion, we characterized seven LRRK2 variants potentially associated with PD. Five of the seven variants in different LRRK2 domains exhibited altered properties in kinase activity, self-association, and microtubule-binding activity, suggesting that each domain variant may contribute to disease progression in different ways., Competing Interests: Declaration of competing interest None., (Copyright © 2023. Published by Elsevier Inc.)

B cells that produce anti-aquaporin-4 (AQP4) antibodies play a crucial role in neuromyelitis optica spectrum disorder (NMOSD) pathogenesis. We previously reported that naïve B (NB) cells from patients with NMOSD, unlike those from healthy controls, exhibit transcriptional changes suggesting the adoption of an antibody-secreting cell (ASCs) phenotype. CD25 + NB cells, whose numbers are increased in NMOSD patients, have a greater capacity to differentiate into ASCs than do CD25 - NB cells. Here, we attempted to establish novel B cell subset cell lines from patients with NMOSD to enable molecular analysis of their abnormalities. We generated Epstein-Barr virus-immortalized lymphoblastoid cell lines (LCLs) from CD25 + NB, CD25 - NB, and switched memory B (SMB) cells. All LCLs largely maintained the features of the original cell type in terms of cell surface marker expression and could differentiate into ASCs. Notably, CD25 + NB-LCLs derived from patients with NMOSD exhibited a greater capacity to differentiate into SMB-LCLs than did CD25 - NB-LCLs derived from patients with NMOSD, suggesting that the established LCLs maintained the characteristics of cells isolated from patients. The LCLs established in this study are likely to be useful for elucidating the mechanism by which cells that produce anti-AQP4 antibodies develop in NMOSD.

Background and Aims: The difficulty in radiographic confirmation of the presence of stones remains challenging in the treatment of intrahepatic bile duct (IHBD) stones in patients after hepaticojejunostomy (HJ). Peroral direct cholangioscopy (PDCS) enables direct observation of the bile duct and is useful for detecting and removing residual stones; however, its effectiveness is not clearly established in this clinical context., Methods: This single-center, single-arm, prospective study included 44 patients with IHBD who underwent bowel reconstruction with HJ during the study period. Stone removal was performed by using short-type double-balloon enteroscopy. After balloon-occluded cholangiography, the double-balloon enteroscopy was exchanged for an ultra-slim endoscope through the balloon overtube for PDCS. The primary end point was the rate of residual stones detected by PDCS. Secondary end points were success rate of PDCS, residual stone removal with PDCS, procedure time for PDCS, procedure-related adverse events, and stone recurrence rate., Results: PDCS was successful in 39 (89%) of 44 patients, among whom residual stones were detected in 16 (41%) (95% CI, 28%-54%). Twelve patients (75%) had residual stones <5 mm. Stone removal was successful in 15 (94%) patients, and median procedure time for PDCS was 16 minutes (interquartile range, 10-26 minutes). The rate of procedure-related adverse events was 7% (3 of 44); all adverse events improved with conservative treatment. During the median follow-up of 2.1 years (interquartile range, 1.4-3.3 years), the overall probability of recurrence-free status at 1, 2, and 3 years was 100%, 92%, and 86%, respectively., Conclusions: PDCS is a safe and effective procedure for complete stone removal in patients with IHBD stones after HJ., Competing Interests: Disclosure All authors disclosed no financial relationships., (Copyright © 2024 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.)