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This study aims to generate test cases for scenario-based assessment of automated driving systems (ADS) when encounter a cut-out maneuver where the lead vehicle having changed lanes, revealing a new lead vehicle that, in some cases, is slower than the original lead (the cutting-out) vehicle. We extracted the cut-out scenarios from an established real-world traffic dataset recorded by instrumented vehicles on Japanese highways and then defined them using vehicle kinematic parameters (velocities and distances). The extracted scenarios were analyzed based on the direct correlation between every two consecutive vehicles: a rear part that describes the correlation between the following vehicle and the cutting-out vehicle; and a frontal part that describes the correlation between the cutting-out vehicle and the preceding vehicle. Parameter ranges were quantified with a regression model and determined based on the risk acceptance threshold applied in the field of Japanese high-speed trains and annual exposure by professional highway drivers to produce a scenario space with a reasonably foreseeable range in which ADS may not produce crashes lest it performs worse than human drivers. A multi-dimensional distribution analytical approach was used to derive a correlation between the following and preceding vehicles considering the initial longitudinal velocities. Results suggest that when the time headway between the following vehicle and the cutting-out vehicle is equal to or more than 2 s, there should not have collision risks between the following vehicle and the preceding vehicle. These findings can help to understand normative driver behavior during cut-out scenarios and to generate accident-free scenario space for which ADS must perform flawlessly.

Verification and validation of automated driving systems’ safety are some of the biggest challenges for the introduction of automated vehicles into the market. Scenario-based safety assessment is an efficient and repeatable method to test the systems’ safety before their deployment in the real world. However, even with limited traffic situations identified as critical to the system behavior, there is still an open range of parameters to describe each situation. Thus, defining specific parameter ranges is crucial to realize the scenario-based safety assessment approach. This study proposes a method to parameterize scenarios extracted from real-world traffic data, analyze their distribution and correlation, and incorporate them into the definition of reasonably foreseeable parameter ranges through the contextualization of resulting ranges with reasonable risk acceptance thresholds from different fields and international environments. Representative values can be selected from these specific parameter ranges to extract specific concrete scenarios applicable for the systems safety assessment. The applicability of the proposed method is demonstrated using parameter ranges obtained to define two sets of 960 cut-in and 6,442 deceleration scenarios extracted from a new set of traffic data collected from Japanese highways under the SAKURA initiative. The outcomes will enable comparisons with traffic data from other countries and inform automated driving system developers, standardization bodies, and policymakers to develop automated vehicle safety assessments applicable internationally.

Abstract Strong magnetic fields, synchrotron emission, and Compton scattering are omnipresent in compact celestial X-ray sources. Emissions in the X-ray energy band are consequently expected to be linearly polarized. X-ray polarimetry provides a unique diagnostic to study the location and fundamental mechanisms behind emission processes. The polarization of emissions from a bright celestial X-ray source, the Crab, is reported here for the first time in the hard X-ray band (~20–160 keV). The Crab is a complex system consisting of a central pulsar, a diffuse pulsar wind nebula, as well as structures in the inner nebula including a jet and torus. Measurements are made by a purpose-built and calibrated polarimeter, PoGO+. The polarization vector is found to be aligned with the spin axis of the pulsar for a polarization fraction, PF = (20.9 ± 5.0)%. This is higher than that of the optical diffuse nebula, implying a more compact emission site, though not as compact as, e.g., the synchrotron knot. Contrary to measurements at higher energies, no significant temporal evolution of phase-integrated polarisation parameters is observed. The polarization parameters for the pulsar itself are measured for the first time in the X-ray energy band and are consistent with observations at optical wavelengths.

In the modern world of wastewater treatment, control of odors has moved from an afterthought to a primary design consideration for most collection and treatment facilities. As development encroaches on our facilities and our new neighbours become less tolerant of nuisance odors, wastewater professionals have found the need to address odor as a primary concern in the design and operation of collection and treatment facilities. When facility odors affect air quality and cause citizen complaints, an investigation of those odors may require that specific odorants be measured and that odorous air be measured using standardized scientific methods. Odour intensity is one of main odour characterization parameters, and remarkably common and important sensory indicator of environmental odours. Odour intensity reflects people’s perception of odours and contributes to effective odour management. The “triangle odors bag method', which has been adopted for the offensive odors control law in Japan, and the dynamic olfactometry defined by EN 13725 has been adopted in Europe. These methods are the worldwide used for as reference methods for the sensorial measurement of odours. On these methods are also based the training of electronic nose (e.Nose). In this study odour samples were collected on municipal wastewater treatment plant located in south Italy at four different treatment units to determine the relationship between odour intensity assessed by Japanese “triangle odors bag method', odour concentration measured with dynamic olfactometry according to European standard EN13725:2003 and with odour concentration measured by a novel prototype of e.Nose patented by University of Salerno. A monthly sampling and relative measurements were carried out for consecutive 12 months at Laboratory of Sanitary Environmental Engineering Division (SEED) at University of Salerno (Italy). Results show when high odours were detected by Japanese standard, the odour concentrations measured according European standard were also high (e.g. emission from sludge line). Concentrations measured by e.Nose are strongly correlated with the measurements carried out by standard methods.

Carrier distributions near n-type epitaxially-grown Ge(100) surfaces with high impurity concentrations (1 × 1020 cm−3) were studied using high resolution electron energy loss spectroscopy (HREELS) upon surface treatments in aqueous solutions of HF and HCl. After surface treatments with HCl and HF, the molecular vibration modes distinctly showed either chloride or hydride terminations of Ge surfaces with negligible oxidation. The free-carrier concentration profile was inferred from the conduction band plasmon measurements as a function of the incident electron energies employing a dielectric theory simulation with a 4-layer structure and an effective electron mass of 0.02m0. A carrier-free layer of 40 and 24 Å were derived for HCl- and HF-treated Ge(100), respectively. The surface band bending was estimated to be 0.32 eV for HF-treated Ge. HCl-treated Ge surfaces showed a band bending of 0.91 eV attributed to the strong effect of the surface Cl-Ge dipole.

Background: Fractional flow reserve (FFR)-guided percutaneous coronary intervention (PCI) for chronic coronary syndromes (CCS) improves outcomes compared with angiography-guided PCI, however cardiac events still occur during long-term follow-up of FFR-negative patients. In the PREVENT study preventive PCI reduced cardiac-events in lesions which were FFR-negative (FFR > 0.80) and had intracoronary imaging defined vulnerable plaque. Coronary computed tomography angiography (CTA)-defined high risk plaque (HRP) is known to predict future cardiac events. We hypothesized that CTA defined HRP would identify which FFR-negative patients were at greatest risk of future cardiac events., Methods and Results: We examined 373 consecutive CCS patients undergoing CTA followed not more than 90 days later by invasive FFR. Cardiac events were defined as cardiac death, non-fatal acute coronary syndromes, and ischemia-driven revascularization. Clinical follow-up was performed in all patients at a median of 32 months. Revascularization was performed in 131 of the 373 patients due to an FFR ≤ 0.80 (Treat group), with the remaining 242 having revascularization deferred (Defer group) due to an FFR > 0.80. In the Treat group the cardiac event rates between patients with and without HRP on CTA were similar (9.4 % versus 10.1 %, p = 0.90), whilst in the Defer group they were higher in patients with HRP (21.1 % versus 4.7 %, Log-rank-p < 0.0001). In multivariate Cox hazard analysis the presence of HRP (Hazard-ratio 12.79, 95 %confidence-intervals: 3.57-45.83, p < 0.0001) was an independent predictor for cardiac events in the Defer group., Conclusions: HRP on CTA was associated with future cardiac events in patients in whom revascularization was deferred due to a negative invasive-FFR (UMIN000054067; CAPTURE)., Competing Interests: Declaration of competing interest All authors did not have any conflict of interest (COI) for this study., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background Aims: Allogeneic hematopoietic stem cell transplantation (HSCT) improves outcomes for myelodysplastic syndrome (MDS) patients, but relapse rates remain high, and postrelapse treatment options are limited. Therefore, this study aimed to identify the factors contributing to the response to donor lymphocyte infusion (DLI) in relapsed MDS patients post-HSCT., Methods: This study included 107 patients with relapsed and DLI-treated MDS who underwent their first HSCT between 2002 and 2022 and were registered in the Transplant Registry Unified Program. Univariate and multivariate survival analyses were conducted using log-rank tests and Cox proportional hazards models. Overall survival (OS) and response rates to DLI were also analyzed., Results: The 1-year OS was 30.0% and univariate analysis identified poor prognostic factors: age ≥58 years (P = 0.003), complex karyotype (P = 0.026), hematologic relapse (P = 0.026) and early relapse (P = 0.004). Azacitidine plus DLI also improved prognosis (P < 0.001). Multivariate analysis confirmed age ≥58 years, hematologic relapse, and early relapse as poor prognostic factors. The adjusted OS for patients aged ≥58 years who relapsed <110 days post-transplant showed that the 1-year OS in patients with cytogenetic/molecular relapse was 43.6%, compared to 9.4% for those with hematologic relapse. Acute graft-versus-host disease (GVHD) occurred in 62.3% of patients, and chronic GVHD in 30.8%, with manageable outcomes., Conclusions: DLI may improve OS in younger patients, those with cytogenetic/molecular relapse, and those with late relapse. Despite the risk of GVHD, its impact on prognosis is minimal. Given the limited treatment options, DLI should be considered for relapsed MDS patients post-HSCT., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2024 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.)

Umbilical cord blood transplantation (CBT) is accepted as an effective treatment for acute myeloid leukemia (AML), and reduced-intensity conditioning (RIC), rather than myeloablative conditioning (MAC) regimens allowed elderly patients to be treated safely. However, appropriate intensities of conditioning regimens are still unclear, especially for middle-aged patients. To compare outcomes after RIC and MAC regimens, we analyzed AML patients aged 16 years or older in the Japanese registry database, who underwent single cord unit CBT between 2010-2019. Median ages of the RIC group (n = 1353) and the MAC group (n = 2101) were 59 and 51 years (P < 0.001), respectively. 5-year overall survival (OS) after MAC was superior to that of RIC (38.3% vs 27.7%, P < 0.001) with lower incidence of relapse (33.9% vs 37.4%, P = 0.029) and better neutrophil engraftment (84.7% vs 75.9%, P < 0.001). Detailed subgroup analysis revealed that age at transplantation is the most important factor affecting 5-year OS in RIC and MAC. This analysis identified a threshold of 55 years, beyond which the superiority of MAC disappeared, irrespective of other factors such as disease status or performance status. In conclusion, RIC may be preferable for patients aged 56 or older in CBT for AML due to higher potential toxicities., Competing Interests: Competing interests: The authors declare no competing interests. Ethical approval: The study was planned by the Adult AML Working Group of the JSTCT, approved by the data management committees of JSTCT and by the Institutional Review Board of Kyoto University Hospital. All methods were performed in accordance with the Helsinki Declaration. Informed consent: Written informed consent was obtained from all patients., (© 2025. The Author(s).)

When nematic liquid crystal elastomers (LCEs) crosslinked at their isotropic phase are quenched to the nematic phase, they show polydomain patterns, in which nematic microdomains with different orientations self-organize into a three-dimensional mosaic with characteristic correlation patterns. The orientational correlation length of the domain, which is usually in the micrometer range, is believed to emerge as a result of a competition between liquid crystalline ordering and frozen network inhomogeneity. Although polydomain patterns show potentials as the basic platform for optical, memory, and mechanical devices, no study exists regarding how they are modulated by experimentally accessible parameters. Here, using confocal polarized fluorescence microscopy, we study the effects of a solid-wall or open boundary on the domain size in conjunction with effects of cross-linking density. The LCE bounded by solid glass shows reduced domain size near the boundary. In contrast, increased domain size appears at the free surface. With increasing cross-linking density, the domain size decreases, also exhibiting the boundary effects. Guided by theoretical considerations, the results are explained by a picture that the effective strength of the inhomogeneity frozen in the polymer network, i.e. , the effective disorder strength, varies depending on the cross-linking density and constrained states at boundaries. The results offer the first experimental approach to global and local modulation of the polydomain pattern in nematic LCEs.

Fludarabine and myeloablative busulfan (FluBu4) in allogeneic hematopoietic stem cell transplantation (HSCT) for older people have not been adequately examined. This retrospective study analyzed data from a large-scale, nationwide database in Japan. Adult patients (> 15 years old, y/o) who received their first HSCT with FluBu4 for hematological malignancies were included. They were categorized into the younger (< 60 y/o, N = 1295) and the older group (≥ 60 y/o, N = 993). The 3-year overall survival (OS) rate after HSCT was significantly worse in the older group than in the other (p < 0.01, 39.9% vs. 48.5%). The 3-year non-relapse mortality (NRM) was significantly higher in the older group than in the other (p < 0.01, 30.9% vs. 23.0%), and the 3-year cumulative incidence of relapse was comparable between them. According to the multivariate analysis, age ≥ 60 years was significantly associated with poor OS and high NRM. In a subgroup analysis of the older group, the use of additional chemotherapeutic drugs to FluBu4 was significantly associated with poor OS and high NRM. Total body irradiation was significantly associated with high NRM and 1-year incidence of sinusoidal obstruction syndrome but not with OS. Thus, FluBu4 should be used with caution in older people., (© 2025 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Patients with adult T-cell leukemia/lymphoma (ATL) are considered to have worse outcomes after allogeneic hematopoietic stem cell transplantation (allo-HSCT) than patients with other hematological malignancies, owing to high risk of relapse and immunocompromised status. However, no studies have compared transplant outcomes between patients with ATL and those with other hematological malignancies using a large-scale database., Objectives: To compare transplant outcomes between patients with ATL and those with other leukemias and to identify factors contributing to worse transplant outcomes in ATL patients., Study Design: Using Japanese registry data, we retrospectively compared transplant outcomes between patients with ATL and those with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). As ATL often develops in patients in their 60s or older, patients with ATL, AML, or ALL aged ≥50 years were included in order to compare patients in the same age group. A total of 7764 patients (ATL, n = 1151; AML, n = 5393; ALL, n = 1220) who underwent their first allo-HSCT between January 1, 2006 and December 31, 2017 were included in this study., Results: Compared with AML, ATL showed significantly worse overall survival (OS) (hazard ratio [HR], 1.24; 95% confidence interval [CI], 1.14 to 1.34; P < .001) and higher risk of relapse (HR, 1.33; 95% CI, 1.2 to 1.47; P < .001), while there were no significant differences between AML and ALL. Among patients in complete remission (CR) at transplantation, ATL showed worse OS (HR, 1.30; 95% CI, 1.08 to 1.56; P = .006), higher risk of relapse (HR, 1.78; 95% CI, 1.48 to 2.14; P < .001), and higher risk of nonrelapse mortality (NRM) (HR, 1.38; 95% CI, 1.14 to 1.33; P = .001) in comparison with AML, whereas there were no significant differences between AML and ALL., Conclusion: We found that ATL patients have poor transplant outcomes compared with AML or ALL patients. In ATL patients, survival is poor, relapse is more frequent, and NRM is significantly higher, especially in cases of CR. These findings suggest that prevention of relapse and transplant-related complications is important for successful allo-HSCT in ATL., (Copyright © 2025. Published by Elsevier Inc.)

Background: The JAVELIN Bladder 100 trial demonstrated improved overall survival (OS) with maintenance avelumab in patients with locally advanced or metastatic urothelial carcinoma UC (la/mUC) who achieved disease control following first-line platinum-based chemotherapy (1 L-PBC). However, real-world data on eligibility, utilization, and outcomes of maintenance avelumab therapy remain limited., Methods: This retrospective study included patients with la/mUC who received 1 L-PBC. Eligibility for maintenance avelumab therapy was determined based on the best overall response to 1 L-PBC, with patients who achieved stable disease or a partial or complete response considered eligible. Survival outcomes were analyzed using the Kaplan-Meier method. Multivariate Cox regression analysis was used to identify prognostic factors among patients with la/mUC who received maintenance avelumab., Results: Of 161 prospective patients, 67.1% were eligible for maintenance avelumab therapy, and 46.3% of eligible patients received the treatment. The median progression-free survival (PFS) following avelumab initiation was 10.2 months, whereas the median OS was not reached. Prognostic factors associated with PFS included the presence of liver metastases, elevated C-reactive protein (> 1.0 g/dL), and administration of more than five cycles of 1 L-PBC. Adverse events occurred in 60% of patients treated with avelumab, with 16% experiencing grade 3-4 adverse events., Conclusion: We emphasize the real-world applicability of maintenance avelumab for Japanese patients with la/mUC. Maintenance avelumab demonstrated favorable survival outcomes, consistent with clinical trial data. Identifying prognostic factors and optimizing treatment sequencing are essential strategies for improving outcomes in this patient population., (© The Author(s) 2025. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The concept of genome-microbiome interactions, in which the microenvironment determined by host genetic polymorphisms regulates the local microbiota, is important in the pathogenesis of human disease. In otolaryngology, the resident bacterial microbiota is reportedly altered in non-infectious ear diseases, such as otitis media pearls and exudative otitis media. We hypothesized that a single-nucleotide polymorphism in the ATP-binding cassette sub-family C member 11 ( ABCC11 ) gene, which determines earwax properties, regulates the ear canal microbiota. We analyzed ABCC11 gene polymorphisms and ear canal microbiota in healthy individuals to understand the relationship between genome-microbiome interactions in the ear canal. The study included 21 subjects who were divided into two groups: 538GA (9) and 538AA (12). Staphylococcus auricularis and Corynebacterium spp. were observed in the 538GA group, whereas Methylocella spp. was observed in the 538AA group. PICRUSt analysis revealed significant enrichment of certain pathways, such as superpathway of N-acetylglucosamine, N-acetylmannosamine and N-acetylneuraminate degradation, chlorosalicylate degradation, mycothiol biosynthesis, and enterobactin biosynthesis in the GA group, whereas allantoin degradation IV (anaerobic), nitrifier denitrification, starch degradation III, L-valine degradation I, and nicotinate degradation I were significantly enriched in the AA group. The ABCC11 gene polymorphism regulates the composition of the ear canal microbiota and its metabolic pathways. This study revealed a genome-microbiome interaction within the resident microbiota of the external auditory canal that may help to elucidate the pathogenesis of ear diseases and develop novel therapies., Importance: The ABCC11 gene polymorphism, which determines earwax characteristics, regulates the composition of the ear canal microbiota and its metabolic pathways. We determined the presence of genome-microbiome interactions in the resident microbiota of the ear canal. Future studies should focus on ABCC11 gene polymorphisms to elucidate the pathogenesis of ear diseases and develop therapeutic methods.

Idiopathic infantile hypercalcemia (IIH) is characterized by hypercalcemia, nephrocalcinosis, vomiting, dehydration, and failure to thrive. It is caused by the presence of biallelic loss-of-function variants in the CYP24A1 locus. Although hypercalcemia has been linked to the consumption of vitamin D-fortified milk, no reports have documented its role in triggering IIH in patients with CYP24A1 variants. Herein, we describe a case of IIH triggered by vitamin D-fortified milk consumption in a 9-mo-old male patient carrying a CYP24A1 variant. After BCG vaccination, the patient developed a facial rash, became anorexic, appeared to be in a bad mood, and began consuming vitamin D-fortified milk instead of baby food. Blood tests showed a marked hypercalcemia (18.5 mg/dL), high 1,25-(OH) 2 D (98.7 pg/dL) levels, and low parathyroid hormone (PTH) (< 4.0 pg/dL) and PTHrP (< 1.0 pg/dL) levels. The calcium levels were successfully normalized after treatment with saline loading, furosemide, pamidronate, and a low-calcium milk diet. After discharge, blood calcium levels remained normal with no recurrence of symptomatic hypercalcemia, but circulating PTH levels were persistently suppressed. Renal ultrasonography at 8 yr of age revealed high medullary echogenicity and diffuse echogenic foci in both kidneys. Trio-based whole-genome sequencing identified the following biallelic pathogenic variants c.[464G>A];[1324C>T], p.[Trp155Ter];[Gln442Ter], in the CYP24A1 (NM&#95;000782.5) locus. Unexplained hypercalcemia in infants should raise suspicions of abnormal vitamin D metabolism and CYP24A1 locus genotypic analysis can be informative in this regard., Competing Interests: Jun Takayama, Gen Tamiya, and Atsuo Kikuchi received a research grant from Astellas Pharma. The other authors have no conflicts of interest to declare., (2025©The Japanese Society for Pediatric Endocrinology.)

This study retrospectively compared outcomes of various allogeneic haematopoietic cell transplantation (allo-HCT) platforms in patients with adult T-cell leukaemia/lymphoma. Platforms included human leukocyte antigen (HLA)-haploidentical-related donors using post-transplant cyclophosphamide (PTCY), HLA-matched related donors (MRD), HLA-matched unrelated donors (MUD) and cord blood transplantation (CBT). Patients who underwent their first allo-HCT between 2016 and 2021 were included. Outcomes analysed were overall survival (OS), relapse and non-relapse mortality (NRM). Seven hundred patients were included (PTCY, n = 121; MRD, n = 91; MUD, n = 160; CBT, n = 328). With a median follow-up of 794 days for survivors, 2-year OS was 48.1% (PTCY), 48.8% (MRD), 48.4% (MUD) and 34.6% (CBT); the respective 2-year cumulative incidence of relapse was 37.1%, 47.5%, 33.9% and 45.1% and that of NRM was 24.2%, 19.8%, 24.7% and 27.3%. PTCY was associated with delayed platelet engraftment relative to MRD and MUD. There was no increase in the incidence of severe acute or chronic graft-versus-host disease. In the PTCY group, poor performance status was a significant predictor of inferior OS, and infused CD34+ cell numbers of less than 5 × 10 6 /kg were associated with delayed neutrophil and platelet engraftment. These results suggest that allo-HCT with PTCY is a safe and effective platform for patients with adult T-cell leukaemia/lymphoma., (© 2024 The Author(s). British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

We retrospectively evaluated the impacts of using granulocyte colony-stimulating factor (G-CSF) and its timing on posttransplant outcomes for 9766 adults with acute myeloid leukemia (AML) between 2013 and 2022 using a Japanese database. We separately evaluated three distinct cohorts based on graft type: 3248 received bone marrow transplantation (BMT), 3066 received peripheral blood stem cell transplantation (PBSCT), and 3452 received single-unit cord blood transplantation (CBT). Multivariate analysis showed that G-CSF administration significantly accelerated neutrophil recovery after BMT, PBSCT, and CBT. However, it was associated with a higher risk of grades II-IV acute graft-versus-host disease (GVHD) across all graft types. Moreover, an increased incidence of overall chronic GVHD was observed with G-CSF administration in BMT and CBT patients, but not in PBSCT patients. G-CSF administration significantly improved overall survival (OS) and leukemia-free survival (LFS) only following CBT. Regarding the timing of G-CSF, in comparison with late initiation of G-CSF (Days 5-10), early initiation (Days 0-4) did not provide benefits for hematopoietic recovery regardless of graft type. In contrast, late initiation was significantly associated with a lower risk of grades II-IV acute GVHD and better OS and LFS in CBT patients. These data demonstrated that G-CSF administration accelerated neutrophil recovery and increased the risk of grades II-IV acute GVHD across all graft types, but significantly improved survival outcomes but only following CBT. Therefore, routine use of G-CSF should be considered for CBT in adult patients with AML., (© 2024 The Author(s). American Journal of Hematology published by Wiley Periodicals LLC.)

Background: De novo chronic myeloid leukemia in blastic phase (CML-BP) showing lymphoid immunophenotype mimics Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL). Although upfront allogeneic hematopoietic cell transplantation (HCT) is considered in both diseases, it is not yet clear whether the transplant outcomes are also similar., Methods: Using a registry database, the transplant outcomes between de novo CML-BP and Ph-positive ALL in negative-minimal residual disease (MRD), positive MRD, and nonremission cohorts were compared, respectively. All of the included patients had received tyrosine kinase inhibitor therapy before HCT and underwent HCT between 2002 and 2021. Regarding Ph-positive ALL, patients with p210 transcripts were excluded because there was concern that this group might include patients with de novo CML-BP., Results: Although most of the outcomes were comparable, in patients with positive MRD at HCT, de novo CML-BP was significantly associated with superior disease-free survival (DFS) (hazard ratio [HR] 0.6, p = .0032), overall survival (HR 0.66, p = .027), and a lower risk of relapse (HR 0.48, p = .0051). In subgroup analyses, BCR::ABL1 mutation status had a significant interaction with the disease (p for interaction = .0027). De novo CML-BP seemed to be associated with superior disease-free survival in a BCR::ABL1 mutation-positive cohort, whereas this association was not observed in a mutation-negative cohort., Conclusions: Considering previous reports that showed inferior outcomes for de novo CML-BP compared to Ph-positive ALL, the data suggested that allogeneic HCT could overcome the poor prognosis of de novo CML-BP. These findings highlight the importance of distinguishing de novo CML-BP from Ph-positive ALL., (© 2024 American Cancer Society.)

An Ott-Antonsen reduced M-population of Kuramoto-Sakaguchi oscillators is investigated, focusing on the influence of the phase-lag parameter α on the collective dynamics. For oscillator populations coupled on a ring, we obtained a wide variety of spatiotemporal patterns, including coherent states, traveling waves, partially synchronized states, modulated states, and incoherent states. Back-and-forth transitions between these states are found, which suggest metastability. Linear stability analysis reveals the stable regions of coherent states with different winding numbers q. Within certain α ranges, the system settles into stable traveling wave solutions despite the coherent states also being linearly stable. For around α≈0.46π, the system displays the most frequent metastable transitions between coherent states and partially synchronized states, while for α closer to π/2, metastable transitions arise between partially synchronized states and modulated states. This model captures metastable dynamics akin to brain activity, offering insights into the synchronization of brain networks., (© 2025 Author(s). Published under an exclusive license by AIP Publishing.)

Background: Utility values of responders and nonresponders are essential inputs in cost-effectiveness studies of radiation therapy for painful bone metastases but, to our knowledge, they have not been reported separately. Objective: We sought to determine the utility values of responders and nonresponders using data from a prospective observational study on bone metastases. Methods: The original prospective observational study was conducted at 26 centers in Japan. Of 232 enrolled patients, 181 whose pain scores at baseline were ≥2 were analyzed. Health-related quality of life (QOL) was measured using the EuroQol 5-dimensions 5-levels (EQ-5D-5L) instrument at baseline and 2- and 6-month follow-up assessments. At follow-up assessments, patients were categorized as responders or nonresponders. Pain response was assessed using the International Consensus Pain Response Endpoints. Results: Of the 181 patients analyzed, 133 (73%) and 84 (46%) were evaluable at the 2- and 6-month follow-up assessment, respectively. The EQ-5D-5L index score (utility) increased from baseline to the 2- and 6-month follow-up assessments; regarding opioid analgesic use, no clear trend was observed during the same period. The mean utility was significantly higher in responders than in nonresponders at both follow-up times. The mean daily oral morphine equivalent dose was significantly lower in responders than in nonresponders at both follow-up times. Conclusion: We determined utility values for responders and nonresponders. Pain response was associated with better QOL and less opioid use. Our utility values according to response status can be used for model input in future cost-effectiveness studies on radiation therapy for bone metastases.

Ganciclovir and foscarnet are two representative anti-cytomegalovirus (CMV) agents. A previous regional study revealed a lower risk of chronic graft-versus-host disease (GVHD) in patients who received pre-emptive foscarnet. We conducted a retrospective nationwide study to confirm the results. A total of 8890 patients aged 16 or older with hematological malignancies who received foscarnet (n = 1555) or ganciclovir (n = 7335) during their first hematopoietic stem cell transplantation (HSCT) were included. The risks of chronic GVHD (hazard ratio [HR], 1.26; 95% confidence interval [CI], 1.13-1.40; P < 0.001) and extensive chronic GVHD (HR, 1.16; 95% CI, 1.01-1.33; P = 0.033) were higher with ganciclovir. Among male patients with a female donor, the incidence of extensive chronic GVHD 3 years after HSCT was clearly lower with foscarnet (13%; 95% CI, 9-16%) than with ganciclovir (27%; 95% CI, 25-29%; P < 0.001). In male patients who received HSCT from female donors, foscarnet recipients showed significantly lower incidence of extensive chronic GVHD than ganciclovir recipients, regardless of donor source or previous acute GVHD. While caution is necessary, these results indicate that foscarnet affects alloimmunization and might reduce the incidence of chronic GVHD., Competing Interests: Declarations. Conflict of interest: The authors declare that there are no competing financial interest to report. S. Terakura and Y.K are editors of International Journal of Hematology., (© 2024. Japanese Society of Hematology.)

The gut-kidney axis represents the complex interactions between the gut microbiota and kidney, which significantly impact the progression of chronic kidney disease (CKD) and overall patient health. In CKD patients, imbalances in the gut microbiota promote the production of uremic toxins, such as indoxyl sulfate and p-cresyl sulfate, which impair renal function and contribute to systemic inflammation. Mechanisms like endotoxemia, immune activation and oxidative stress worsen renal damage by activating pro-inflammatory and oxidative pathways. Insights into these mechanisms highlight the impact of gut-derived metabolites, bacterial translocation, and immune response changes on kidney health, suggesting new potential approaches for CKD treatment. Clinical applications, such as dietary interventions, prebiotics, probiotics and fecal microbiota transplantation, are promising in adjusting the gut microbiota to alleviate CKD symptoms and slow disease progression. Current research highlights the clinical relevance of the gut-kidney axis, but further study is essential to clarify these mechanisms' diagnostic biomarkers and optimize therapeutic interventions. This review emphasizes the importance of an integrated approach to CKD management, focusing on the gut microbiota as a therapeutic target to limit kidney injury.

Background: In freeze-thawed embryo transfer (FET) cycles, hormone replacement treatment (HRT) is crucial for implantation and pregnancy maintenance. HRT typically continues until the 10th week of pregnancy owing to a luteoplacental shift, although a definitive HRT regimen remains undetermined. We present the case of a woman who underwent FET during an HRT cycle and ceased HRT after a negative pregnancy test at 3 weeks and 5 days, who went on to deliver a healthy baby., Case Presentation: A 30-year-old Japanese woman with primary infertility was scheduled for FET. Estrogen supplementation was initiated as part of the HRT cycle for endometrial preparation. After achieving an endometrial thickness of 8 mm, progesterone supplementation was commenced, and the transfer of a 4BB blastocyst occurred 5 days after initiating progesterone treatment. At a gestational age of 3 weeks and 5 days, her serum human chorionic gonadotropin (hCG) level was only 8.3 mIU/mL, leading to discontinuation of HRT due to the absence of pregnancy. However, at 6 weeks and 1 day, her serum hCG levels significantly rose to 9359 mIU/mL, prompting the resumption of HRT. Ultrasonography confirmed the presence of a gestational sac and cardiac activity in the uterus, and HRT was continued until the 10th week. Ultimately, she delivered a healthy female neonate vaginally, weighing 2601 g at 40 weeks and 6 days., Conclusions: Progesterone supplementation is customary in FET with HRT cycles, although it has raised the possibility that there is demonstrating the potential for an ongoing pregnancy and resulting in a healthy baby under no progesterone replacement prior to the luteoplacental shift in this case. The duration and dosage of progesterone in luteal support for FET with HRT warrant further investigation., Competing Interests: Declarations. Ethics approval and consent to participate: The study was conducted according to the guidelines of the Declaration of Helsinki. Ethical review and approval were for this study waived due to a case report by the Institutional Review Board of Kameda IVF Clinic, Makuhari. Consent for publication: Written informed consent was obtained from the patient for publication of this case report and all accompanying images. We are prepared to provide a copy of the consent form upon request. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Competing Interests: Ethics approval and consent to participate: This study was approved by the Japanese Data Center for Hematopoietic Cell Transplantation and the Institutional Review Board of Kobe City Medical Center General Hospital and conducted in accordance with the Declaration of Helsinki (approval number: zn240506). Written informed consent was obtained from each patient at each institution before Transplant Registry Unified Management Program 2 registration. Competing interests: Shohei Mizuno received research funding from Hayashikane Sangyo and lecture fees from Janssen Pharmaceutical. The other authors declare no conflicts of interest associated with this manuscript.

Editing the +58 region of the BCL11A erythroid enhancer has shown promise in treating β-globin disorders. To address variations in fetal hemoglobin (HbF) response, we investigated editing both +58 and +55 enhancers. Rhesus macaques transplanted with edited hematopoietic stem/progenitor cells (HSPCs) following busulfan conditioning exhibited durable, high-level (∼90%) editing frequencies post transplantation with sustained HbF reactivation over 4 years, without hematological perturbations. HbF levels were further boosted by stress erythropoiesis or hydroxyurea. Bone marrow analysis revealed that gene edits were predominantly programmed deletions, programmed inversions, and short indels, each disrupting the enhancer core TGN 7-9 WGATAR half E-box/GATA binding motifs. Nonprogrammed long deletions were disfavored in engrafting cells. CD45 antibody-drug conjugate (ADC) conditioning achieved comparable engraftment and HbF reactivation, whereas lentiviral vector tracking showed polyclonal reconstitution with dynamics similar to animals conditioned with total body irradiation (TBI) or busulfan. Joining CD45-ADC conditioning with combined enhancer editing presents an effective strategy for β-hemoglobinopathies, enabling durable HbF reactivation without chemotherapy., Competing Interests: Declaration of interests R.P., L.L., A.B., K.H., T.T., and L.M.O. were employees of Magenta Therapeutics at the time of the initiation of the project., (Published by Elsevier Inc.)

The widespread adoption of deep learning to build models that capture the dynamics of neural populations is typically based on "black-box" approaches that lack an interpretable link between neural activity and network parameters. Here, we propose to apply algorithm unrolling, a method for interpretable deep learning, to design the architecture of sparse deconvolutional neural networks and obtain a direct interpretation of network weights in relation to stimulus-driven single-neuron activity through a generative model. We characterize our method, referred to as deconvolutional unrolled neural learning (DUNL), and show its versatility by applying it to deconvolve single-trial local signals across multiple brain areas and recording modalities. To exemplify use cases of our decomposition method, we uncover multiplexed salience and reward prediction error signals from midbrain dopamine neurons in an unbiased manner, perform simultaneous event detection and characterization in somatosensory thalamus recordings, and characterize the heterogeneity of neural responses in the piriform cortex and in the striatum during unstructured, naturalistic experiments. Our work leverages the advances in interpretable deep learning to gain a mechanistic understanding of neural activity., Competing Interests: Competing interests: The authors declare no competing interests.

Systemic corticosteroid therapy is a well-established first-line treatment for grades II-IV acute graft-versus-host disease (aGVHD). Recently, several developments have occurred, including the introduction of transplantation from human leukocyte antigen (HLA) haploidentical donors using post-transplant cyclophosphamide (PTCY-Haplo), and improvements in prognosis after cord blood transplantation (CBT) in Japan. This study aimed to analyze the association between donor sources and outcomes in patients with aGVHD. Our study included 2732 patients who developed grades II-IV aGVHD, and were treated with systemic corticosteroids. We compared HLA-matched related donors (MRD), HLA-matched unrelated donors (MUD), PTCY-Haplo, and CBT. We set endpoint as response rate, 1-year cumulative incidence of non-relapse mortality (NRM), and overall survival (OS). The adjusted odds ratios for a complete response (CR) were 0.99 (95% confidence interval [CI]: 0.74-1.31, P = 0.925) for MUD, 2.08 (95% CI: 1.35-3.25, P = 0.001) for PTCY-Haplo, and 1.08 (95% CI: 0.83-1.41, P = 0.550) for CBT compared with MRD. A significant increase in response rates for PTCY were only found in a single-organ involvement. No significant association was observed between the donor source and NRM or OS. In conclusion, PTCY-Haplo is associated with a high response rate in patients with a single-organ aGVHD; however, MUD and CBT were not associated with treatment response., Competing Interests: Competing interests: The authors declare no competing interests. Ethics approval and consent to participate statement: This study was approved by the Data Management Committee of the Japanese Data Center for Hematopoietic Cell Transplantation and the Ethics Committee of the Kobe City Hospital Organization, Kobe City Medical Center General Hospital. All methods were performed in accordance with the relevant guidelines and regulations. Patient consent was obtained prior to registration in the Transplant Registry Unified Management Program 2., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative treatment for relapsed or refractory non-Hodgkin lymphoma (R/R NHL). Allo-HSCT using post-transplant cyclophosphamide (PTCY-haplo) and umbilical cord blood transplantation (uCBT) are important donor options in the absence of matched related siblings. However, the data comparing these two donor sources in R/R NHL are limited. Using the Japanese nationwide transplantation registry data, we identified 857 patients with R/R NHL, including 169 patients who received PTCY-haplo and 688 who received uCBT for their first allo-HSCT between January 2013 and December 2021; 514 patients (60%) had B-cell lymphoma. More PTCY-haplo recipients received allo-HSCT using a reduced-intensity conditioning regimen in recent years. The 3-year overall survival (OS), progression-free survival (PFS), and graft-versus-host disease (GVHD)-free/relapse-free survival (GRFS) rates in the PTCY-haplo and uCBT groups were 44% versus 39% (P = 0.326), 34% versus 33% (P = 0.660), and 19% versus 23% (P = 0.910), respectively; the adjusted hazard ratios for OS, PFS, and GRFS were 0.89 (95% confidence interval: 0.69-1.15, P = 0.373), 0.98 (0.78-1.22, P = 0.852), and 0.92 (0.83-1.21, P = 0.920), respectively. The PTCY-haplo group showed faster neutrophil and platelet engraftment and a lower incidence of grade III-IV acute GVHD. Thus, PTCY-haplo and uCBT could serve as alternative donor sources in patients with R/R NHL., Competing Interests: Competing interests: The authors declare no competing interests. Ethics approval statement: This study was approved by the Japanese Data Center for Hematopoietic Cell Transplantation (JDCHCT) and Institutional Review Board of Kobe City Medical Center General Hospital and was conducted in accordance with the Declaration of Helsinki (approval number: zn230805). Informed consent: Written informed consent was obtained from all patients prior to TRUMP2 registration., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

This study aimed to investigate the prognostic relevance of cytogenetic risk in 9826 adults with acute myeloid leukemia (AML) who underwent allogeneic hematopoietic cell transplantation (HCT) during the first or second complete remission. The 5-year probabilities of overall survival (OS) were 66%, 61%, and 47% (P < 0.001), the cumulative incidences of relapse were 14%, 19%, and 32% (P < 0.001), and the cumulative incidences of non-relapse mortality (NRM) were 23%, 23%, and 25% (P = 0.208) in patients with favorable (n = 1418), intermediate (n = 6747), and poor cytogenetic risk (n = 1661), respectively. The significant effect of cytogenetic risk on OS was strong in all subgroups stratified by age, sex, performance status, disease status, donor type, conditioning intensity, graft-versus-host disease prophylaxis, and transplantation period (P < 0.001 for all). The evaluation of trends in posttransplant outcomes for patients in each cytogenetic risk category indicated that the risk of relapse declined in patients with favorable and intermediate cytogenetics and that the risk of NRM decreased in those with intermediate and poor cytogenetics. Therefore, patients with intermediate cytogenetics experienced the best OS improvement. These results confirm cytogenetic risk as a universal prognostic factor in patients with AML undergoing allogeneic HCT while highlighting the requirement for further improvements in posttransplant OS by reducing NRM in patients with favorable cytogenetics and by reducing relapse in patients with poor cytogenetics., Competing Interests: Declarations. Ethical approval: This study was approved by the institutional review board of the Aichi Medical University and was conducted in accordance with the Declaration of Helsinki. All patients provided informed consent for the use of their clinical information for research. Competing interests: SM received research funding from Hayashikane Sangyo, and AT received research funding from Air Water, lecture fees from Novartis Pharmaceutical, and donated funds from Chugai Pharmaceutical, Kyowa Kirin, and Zenyaku Kogyo., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Ruxolitinib, a Janus kinase (JAK1-JAK2) inhibitor, has demonstrated safety and efficacy in patients with graft-versus-host disease (GvHD). This phase 3 randomized trial (REACH3) evaluated the efficacy and the safety of ruxolitinib 10 mg twice daily compared with investigator-selected best available therapy (BAT) in a subgroup of Japanese patients (n = 37) with steroid-refractory or dependent (SR/D) chronic GvHD. At data cut-off, treatment was ongoing in 17 patients and discontinued in 20. The overall response rate (complete or partial) at week 24 was greater with ruxolitinib than BAT (50% vs. 20%; odds ratio, 4.13 [95% CI, 0.90-18.9]). The best overall response rate (complete or partial response at any time point up to week 24) was higher with ruxolitinib than BAT (68.2% vs. 46.7%; odds ratio, 2.69 [95% CI, 0.66-10.9]). Ruxolitinib led to longer median failure-free survival than BAT (18.6 months vs. 3.7 months; hazard ratio, 0.34; [95% CI, 0.14-0.85]). The most common grade ≥ 3 adverse events up to week 24 were anemia (ruxolitinib: 22.7%; BAT: 6.7%) and pneumonia (22.7% and 20.0%, respectively). Ruxolitinib showed a higher response rate and improvement in failure-free survival in Japanese patients with SR/D chronic GvHD, with a safety profile consistent with the overall study population., Competing Interests: Declarations. Conflict of interest: SS, ND, MO, TK, TIshikawa and TIkeda have nothing to disclose. KF and MT received honoraria from Janssen. YO received honoraria from Novartis, Pfizer, Janssen, AsahiKasei, Abbvie, Astellas, Amgen, Chugai, Bristol-Myers Squibb, Symbio, MSD, Meiji Seika, Sumitomo Dainippon, Daiichi Sankyo, Nippon Shinyaku, IQVIA, KISSEI and Kyowa Kirin; research funding from Novartis, Pfizer, Janssen, Meiji Seika, Incyte, and Takara Bio. TG received honoraria from Novartis and Mallinckrodt. HN received honoraria from Novartis, Janssen, Chugai, Astellas, Bristol-Myers Squibb and Takeda; research funding from Novartis, Astellas, Bristol-Myers Squibb and Takeda. YM received research funding from from Asahi Kasei, Eisai, Otsuka, Kyowa Kirin, Taiho, Takeda, Chugai, Japan blood products, Nippon Kayaku, Nippon Shinyaku, Mallinckrodt, and Regimmune; and honoraria from Asahi Kasei, AstraZeneca, Astellas, Amgen, AbbVie, Viatris, Eisai, MSD, Otsuka, ONO, Gilead, Kyorin, Kyowa, Kissei, Konica, Sanofi, Celgene, Bristol-Myers Squibb, Bayer, CSL Behring, Daiichi Sankyo, Sumitomo Dainippon, Takeda, Terumo, Chugai, Nippon Shinyaku, Novartis, Pfizer, Mundipharma, Human Life CORD, Meiji Seika, Janssen and Yakult Honsha. KK received consulting fees from AbbVie, AstraZeneca, Chugai, Daiichi Sankyo, Eisai, Janssen, and Novartis; honoraria from Bristol-Myers Squibb, Chugai, Sumitomo Pharma Co., Ltd., Janssen, Kyowa Kirin, MSD, Novartis and ONO; and research funding from AbbVie, MSD, Bristol-Myers Squibb, Janssen, Novartis, Chugai, Daiichi Sankyo, Eisai, Kyowa Kirin, and ONO. NU received honoraria from Novartis and Otsuka. AM, FS and TT are employees of Novartis Pharma K.K., Tokyo, Japan. TS is an employee of Novartis Pharma AG, Basel, Switzerland. TTeshima received honoraria from Novartis, Abbvie, Astellas, NIPPON SHINYAKU, Kyowa Kirin, Bristol-Myers Squibb, Sumitomo Pharma, Merck Sharp & Dohme, Celgene, Chugai, and Janssen; research funding from Astellas, Chugai, Fuji Pharma, Kyowa Kirin, Nippon Shinyaku, Asahi Kasei Pharma, Eisai, Sumitomo Pharma, ONO, Shionogi, Priothera SA, LUCA science and Otsuka; advisory board fees from Meiji Seika Pharma, Daiichi Sankyo, Asahi Kasei Pharma, Astellas, AstraZeneca, Takeda, Janssen, Toche Diagnostics, Sumitomo Pharma, Celgene, and Sanofi., (© 2024. The Author(s).)

Unrelated cord blood transplantation (UCBT) and haploidentical transplantation using posttransplant cyclophosphamide (PTCy-haplo) are alternatives for patients lacking a human leukocyte antigen-matched donor. CD34 + cell counts in cord blood affect transplantation outcomes, particularly nonrelapse mortality (NRM). The primary objective of this study was to compare the transplantation outcomes after UCBT and PTCy-haplo focusing on CD34 + cell counts in cord blood. This retrospective study used data from 2014 to 2020 from a Japanese nationwide database. UCBT cases were divided into those with UCBT with higher (UCB-H; ≥.84 × 10 5 /kg) and lower (UCB-L; <.84 × 10 5 /kg) CD34 + cell counts, depending on the median CD34 + cell count. The study cohort comprised cases of PTCy-haplo (n = 1142), UCB-H (n = 3185), and UCB-L (n = 3172). In the multivariate analysis, neutrophil engraftment was significantly better in the PTCy-haplo than in the UCB-H (hazard ratio [HR], .64; 95% confidence interval [CI], .57 to .70; P < .001) and UCB-L groups (HR, .45; 95% CI, .41 to .50; P < .001). The UCB-H group showed similar NRM (HR, 1.19, 95% CI, 1.00 to 1.43, P = .051) and OS (HR, 1.05, 95% CI, .94 to 1.18, P = .38) compared with PTCy-haplo, whereas UCB-L was significantly associated with poor NRM (HR, 1.35, 95% CI, 1.13 to 1.61, P = .001) and OS (HR, 1.13, 95% CI, 1.01 to 1.26, P = .038). In contrast, the UCB-H (HR, .86; 95% CI, .75 to .98; P = .027) and UCB-L groups (HR, .80; 95% CI, .70 to .92; P = .001) were associated with lower relapse rate. Regarding the graft-versus-host disease (GVHD), the UCB-H and UCB-L groups were identified as significant risk factors for the development of grade II-IV acute GVHD (UCB-H: HR, 1.73; 95% CI, 1.51 to 1.99; P < .001; UCB-L: HR, 1.55; 95% CI, 1.35 to 1.78; P < .001) and grade III-IV acute GVHD (UCB-H: HR, 2.28; 95% CI, 1.78 to 2.91; P < .001; UCB-L: HR, 1.85; 95% CI, 1.44 to 2.37; P < .001), but neither were associated with the incidence of all-grade GVHD (UCB-H: HR, 1.12; 95% CI, .95 to 1.32; P = .16; UCB-L: HR, 1.08; 95% CI, .91 to 1.27; P = .37) or extensive chronic GVHD (UCB-H: HR, .86; 95% CI, .68 to 1.09; P = .21; UCB-L: HR, .88; 95% CI, .69 to 1.12; P = .31). Furthermore, higher NRM in UCB-L was attributed to higher infection-related mortality (HR, 1.50; 95% CI, 1.15 to 1.95; P = .003) but not GVHD-related mortality (HR, 1.15; 95% CI, .82 to 1.62; P = .43), whereas UCB-H was not a significant risk factor for both infection-related mortality (HR, 1.29; 95% CI, .99 to 1.69; P = .06) and GVHD-related mortality (HR, 1.28; 95% CI, .90 to 1.80; P = .16). UCB-H offered similar NRM and OS to PTCy-haplo, whereas UCB-L had worse outcomes. Our results can provide useful information for optimal donor selection., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Background: The advantage of intensified myeloablative conditioning (MAC) over standard MAC has not been determined in haematopoietic stem cell transplantation (HSCT) for adult acute lymphoblastic leukemia (ALL) patients., Methods: To evaluate heterogeneous effects of intensified MAC among individuals, we analyzed the registry database of adult ALL patients between 2000 and 2021. After propensity score matching, we applied a machine-learning Bayesian causal forest algorithm to develop a prediction model of individualized treatment effect (ITE) of intensified MAC on reduction in overall mortality at 1 year after HSCT., Results: Among 2440 propensity score-matched patients, our model shows heterogeneity in the association between intensified MAC and 1-year overall mortality. Individuals in the high-benefit group (n = 1220), defined as those with ITEs greater than the median, are more likely to be younger, male, and to have higher refined Disease Risk Index (rDRI), T-cell phenotype, and grafts from related donors than those in the low-benefit group (n = 1220). The high-benefit approach (applying intensified MAC to individuals in the high-benefit group) shows the largest reduction in overall mortality at 1 year (risk difference [95% confidence interval], +5.94 percentage points [0.88 to 10.51], p = 0.011). In contrast, the high-risk approach (targeting patients with high or very high rDRI) does not achieve statistical significance (risk difference [95% confidence interval], +3.85 percentage points [-1.11 to 7.90], p = 0.063)., Conclusions: These findings suggest that the high-benefit approach, targeting patients expected to benefit from intensified MAC, has the capacity to maximize HSCT effectiveness using intensified MAC., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Most synthetic self-assemblies grow indefinitely into size-unlimited structures, whereas some biological self-assemblies autonomously regulate their size and shape. One mechanism of such self-regulation arises from the chirality of building blocks, inducing their mutual twisting that is incompatible with their long-range ordered packing and thus halts the assembly's growth at a certain stage. This self-regulation occurs robustly in thermodynamic equilibrium rather than kinetic trapping, and therefore is attractive yet elusive. Until now, studies of self-regulating assemblies have focused on non-responsive systems, whose equilibrium point and corresponding size and shape are hardly changeable. Here, we demonstrate a stimuli-responsive, self-regulating assembly. This assembly consists of chiral and magnetically orientable nanorods, where the effective chirality can be changed by balancing chirality-induced twisting and magnet-induced flattening between nanorods. Consequently, the strength of self-regulation in the assembly is modulable by magnetic field intensity, allowing robust, tunable, and reversible control of its size and shape. Our strategy would provide more biomimetic materials with precision and responsiveness., Competing Interests: Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Caloric depletion leads to behavioral changes that help an animal find food and restore its homeostatic balance. Hunger increases exploration and risk-taking behavior, allowing an animal to forage for food despite risks; however, the neural circuitry underlying this change is unknown. Here, we characterize how hunger restructures an animal's spontaneous behavior as well as its directed exploration of a novel object. We show that hunger-induced changes in exploration are accompanied by and result from modulation of dopamine signaling in the tail of the striatum (TOS). Dopamine signaling in the TOS is modulated by internal hunger state through the activity of agouti-related peptide (AgRP) neurons, putative "hunger neurons" in the arcuate nucleus of the hypothalamus. These AgRP neurons are poly-synaptically connected to TOS-projecting dopaminergic neurons through the lateral hypothalamus, the central amygdala, and the periaqueductal grey. We thus delineate a hypothalamic-midbrain circuit that coordinates changes in exploration behavior in the hungry state.

Dopamine signalling modes differ in kinetics and spatial patterns of receptor activation 1,2 . How these modes contribute to motor function, motivation and learning has long been debated 3-21 . Here we show that action-potential-induced dopamine release is dispensable for movement initiation but supports reward-oriented behaviour. We generated mice with dopamine-neuron-specific knockout of the release site organizer protein RIM to disrupt action-potential-induced dopamine release. In these mice, rapid in vivo dopamine dynamics were strongly impaired, but baseline dopamine persisted and fully supported spontaneous movement. Conversely, reserpine-mediated dopamine depletion or blockade of dopamine receptors disrupted movement initiation. The dopamine precursor L-DOPA reversed reserpine-induced bradykinesia without restoring fast dopamine dynamics, a result that substantiated the conclusion that these dynamics are dispensable for movement initiation. In contrast to spontaneous movement, reward-oriented behaviour was impaired in dopamine-neuron-specific RIM knockout mice. In conditioned place preference and two-odour discrimination tasks, the mice effectively learned to distinguish the cues, which indicates that reward-based learning persists after RIM ablation. However, the performance vigour was reduced. During probabilistic cue-reward association, dopamine dynamics and conditioned responses assessed through anticipatory licking were disrupted. These results demonstrate that action-potential-induced dopamine release is dispensable for motor function and subsecond precision of movement initiation but promotes motivation and performance during reward-guided behaviours., Competing Interests: Competing interests Y.L. is listed as an inventor on a patent application (PCT/CN2018/107533) describing GRAB probes. T.P. is listed as an inventor on a patent application (PCT/US2017/062993) describing the RdLight1 probe. The other authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

BK virus (BKV) encephalitis is a rare complication after hematopoietic stem cell transplantation (HSCT). A 43-year-old woman with recurrent follicular lymphoma after autologous HSCT received allogeneic bone marrow transplantation from a human leukocyte antigen-matched related donor. Neutrophil engraftment was achieved on post-transplant day 13. Memory loss and noncooperative attitude toward the medical staff were observed on day 16, and her mental status worsened progressively. Magnetic resonance imaging (MRI) showed nonspecific findings on day 19; however, cerebrospinal fluid (CSF) analysis including real-time polymerase chain reaction on day 20 revealed elevated levels of BKV 4.67 × 10 4 copy/mL. BKV encephalitis was diagnosed based on CSF findings, intravenous administration of immunoglobulin and cidofovir was started, and the immunosuppressive agent dose was reduced. Diffusion-weighted MRI on day 28 showed signal abnormalities in the bilateral periventricular white matter. Although the follow-up CSF analysis on day 35 was negative for BKV, her mental status and MRI findings did not improve, and she died on day 55 because of respiratory failure. This case emphasizes the importance of considering BKV encephalitis as a differential diagnosis of post-transplant encephalitis, considering the central nervous system-associated immune reconstitution inflammatory syndrome in patients with worsening central nervous system findings after eradication of BKV in the CSF., (Copyright © 2024 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) provides durable remission for patients with adult T-cell leukemia/lymphoma (ATL); however, few studies have focused on post-transplant outcomes in ATL patients ≤49 years. To clarify prognostic factors in ATL among patients <40 years (adolescents and young adult [AYA]; n = 73) and 40-49 years (Young; n = 330), we conducted a nationwide retrospective study. Estimated 3-year overall survival (OS) rates were 61.8% and 43.1% in AYA and Young patients, respectively (p = 0.005). In the multivariate analysis, Young patients showed worse OS (Hazard ratio (HR) [95% confidential interval] 1.62 [1.10-2.39], p = 0.015), chronic graft-versus-host disease (GVHD)-free and relapse-free survival (CRFS) (HR 1.54 [1.10-2.14], p = 0.011), and GVHD-free and relapse-free survival (GRFS) (HR 1.40 [1.04-1.88], p = 0.026) than AYA patients. No significant differences were observed in OS, CRFS, or GRFS between the myeloablative conditioning (MAC) and reduced-intensity conditioning (RIC) regimens; however, non-relapse mortality was significantly lower in patients with the RIC regimen than those with the MAC regimen (HR 0.46 [0.24-0.86], p = 0.015). In summary, OS was worse in Young patients than in AYA patients in the allo-HSCT setting for ATL. Furthermore, the RIC regimen has potential as an alternative treatment option for ATL patients ≤49 years., (© 2024 John Wiley & Sons Ltd.)

Objective: Single-center studies or randomized controlled trials have evaluated the impact of radiotherapy for bone metastases on quality of life (QOL). We investigated the real-world impact of radiotherapy for bone metastases on QOL using nationwide multicenter cohort data., Methods: We conducted a prospective observational study at 26 centers in Japan. Of 333 patients who received radiotherapy for bone metastases between December 2020 and March 2021, 232 (70%) were enrolled in the study. Patient-reported QOL was evaluated at enrollment and at two- and six-month follow-up using the European Organization for Research and Treatment of Cancer (EORTC) QOL Questionnaire Core 15-Palliative and the EORTC QOL Questionnaire Bone Metastases module (QLQ-BM22). Possible predictors (patient-, tumor -, and treatment-related factors) of QOL improvement were screened using logistic regression models., Results: QOL scores showed significant improvement at two-month follow-up in seven (global health status/QOL, emotional functioning, pain, insomnia, painful sites, pain characteristics and functional interference) of the 14 scales. Of these seven scales, mean improvement ≥ the minimal clinically important difference (defined by a change of 10 or more on the 0 to 100 scale) was seen in four scales (pain, insomnia, pain characteristics and functional interference). We did not find any predictors of QOL improvement in the functional interference scale of QLQ-BM22., Conclusion: Radiotherapy for bone metastases performed in daily practice is effective in improving some scales of QOL., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Influential models hold that neurons in the cerebral cortex signal the difference between actual and expected inputs. A new study instead finds that cortical prediction errors reflect not subtraction but rather stimulus-specific amplification of unexpected inputs., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

BIVV003 is a gene-edited autologous cell therapy in clinical development for the potential treatment of sickle cell disease (SCD). Hematopoietic stem cells (HSC) are genetically modified with mRNA encoding zinc finger nucleases (ZFN) that target and disrupt a specific regulatory GATAA motif in the BCL11A erythroid enhancer to reactivate fetal hemoglobin (HbF). We characterized ZFN-edited HSC from healthy donors and donors with SCD. Results of preclinical studies show that ZFN-mediated editing is highly efficient, with enriched biallelic editing and high frequency of on-target indels, producing HSC capable of long-term multilineage engraftment in vivo, and express HbF in erythroid progeny. Interim results from the Phase 1/2 PRECIZN-1 study demonstrated that BIVV003 was well-tolerated in seven participants with SCD, of whom five of the six with more than 3 months of follow-up displayed increased total hemoglobin and HbF, and no severe vaso-occlusive crises. Our data suggest BIVV003 represents a compelling and novel cell therapy for the potential treatment of SCD., (© 2024. The Author(s).)

Background/Objective: It is not uncommon for elderly patients to experience difficulties with feeding and swallowing. In the simple suspension method, tablets are dissolved and suspended in warm water without prior crushing or decapsulation, and then administered via a tube. Despite the prevalence of this method, the pharmacokinetics of suspended tablet dosage forms remain poorly understood. Methods: Verapamil was employed in dissolution tests following both the simple suspension and crushing methods. A pharmacokinetics study was conducted on healthy adult males. Results : The resultant dissolution profiles from the two methods exhibited notable dissimilarities. Drug release from the crushed product commenced earlier than that from the simple suspension and intact tablet. Furthermore, the area under the curve for verapamil during the initial 24 h period was 1.7 and 1.3 times greater in the crushed and simple suspension groups, respectively, than in the tablet group. Conclusions : The crushing and simple suspension methods are safe techniques for administering medications to patients with dysphagia, thereby preventing aspiration. Nevertheless, the processing of medications may result in an increased frequency of adverse effects. It is recommended that the processing of medicines prior to administration be avoided.

Wnt/β-catenin signaling is essential for adrenocortical development. Zinc and ring finger 3 (ZNRF3), an E3 ubiquitin ligase that attenuates Wnt/β-catenin signaling, is negatively regulated by R-spondin via an extracellular domain that is partially encoded by exon 2 of ZNRF3. We recently identified ZNRF3 exon 2 deletions in three individuals with congenital adrenal hypoplasia. ZNRF3 exon 2 deletion impairs R-spondin binding, thereby attenuating β-catenin expression and eventually leading to the development of congenital adrenal hypoplasia. To elucidate the influence of ZNRF3/Znrf3 exon 2 deletion on adrenocortical development, we generated homozygous Znrf3 exon 2 deletion (Znrf3Δ2/Δ2) mice. Whereas the adrenal glands of Znrf3Δ2/Δ2 mice did not show gross morphological changes at birth, moderate hyperplasia of the zona fasciculata (ZF), dispersed medulla arrangement, and a radially spreading zone with macrophage infiltration between the ZF and medulla were observed at 6 weeks of age. 20α-hydroxysteroid dehydrogenase, a marker of the adrenal X-zone, was hardly detected by immunostaining, and gene expression was significantly downregulated. The number of activated β-catenin-positive cells decreased in the zona glomerulosa, consistent with the results of in situ hybridization for Axin2, a Wnt/β-catenin target gene. Plasma ACTH and serum corticosterone levels in Znrf3Δ2/Δ2 mice did not differ significantly from those in wild-type mice. These results show a species-specific difference in the effects of ZNRF3/Znrf3 exon 2 deletions in humans and mice; Znrf3Δ2/Δ2 mice do not develop congenital adrenal hypoplasia but instead exhibit moderate ZF hyperplasia, dispersed medulla arrangement, X-zone dysplasia, and macrophage infiltration occurred in the inner cortex.

Objectives: Patients with advanced cancer present various symptoms as their disease progresses. Among these, fatigue is a frequent symptom in patients with advanced cancer and is associated with decreased quality of life (QOL). However, there are few reports regarding its association with thiamine deficiency (TD)., Methods: We report a case in which we found TD in a patient with advanced lung cancer who presented with weight loss, significant fatigue, and appeared to have a worsening general condition, for whom symptoms were dramatically improved within a short period of time by intravenous administration of thiamine., Results: The patient was a 76-year-old woman who had been diagnosed with lung cancer and liver metastases 6 months earlier. Due to interstitial pneumonia, she was not a candidate for chemotherapy and so palliative care was started. At 8 months after initial diagnosis, the patient complained of fatigue during a medical examination, so a blood sample was taken. A week later, she visited the hospital with a cane. She felt extremely fatigued and was unable to stand, but results from the previous blood test revealed that a TD. The fatigue disappeared 15 minutes after intravenous administration of thiamine and she was able to return home without the cane., Significance of Results: Fatigue is a frequent symptom in advanced cancer patients, and TD may be the underlying cause. Inclusion of TD in the differential diagnosis may contribute to improving patient QOL.

Sickle cell disease (SCD) is a common, severe genetic blood disorder. Current pharmacotherapies are partially effective and allogeneic hematopoietic stem cell transplantation is associated with immune toxicities. Genome editing of patient hematopoietic stem cells (HSCs) to reactivate fetal hemoglobin (HbF) in erythroid progeny offers an alternative potentially curative approach to treat SCD. Although the FDA released guidelines for evaluating genome editing risks, it remains unclear how best to approach pre-clinical assessment of genome-edited cell products. Here, we describe rigorous pre-clinical development of a therapeutic γ-globin gene promoter editing strategy that supported an investigational new drug application cleared by the FDA. We compared γ-globin promoter and BCL11A enhancer targets, identified a potent HbF-inducing lead candidate, and tested our approach in mobilized CD34 + hematopoietic stem progenitor cells (HSPCs) from SCD patients. We observed efficient editing, HbF induction to predicted therapeutic levels, and reduced sickling. With single-cell analyses, we defined the heterogeneity of HbF induction and HBG1/HBG2 transcription. With CHANGE-seq for sensitive and unbiased off-target discovery followed by targeted sequencing, we did not detect off-target activity in edited HSPCs. Our study provides a blueprint for translating new ex vivo HSC genome editing strategies toward clinical trials for treating SCD and other blood disorders., Competing Interests: Declaration of interests A.S. has received consultant fees from Spotlight Therapeutics, Medexus Inc., Vertex Pharmaceuticals, Sangamo Therapeutics, and Editas Medicine. He is a medical monitor for RCI BMT CSIDE clinical trials, for which he receives financial compensation. He has also received research funding from CRISPR Therapeutics and honoraria from Vindico Medical Education. A.S. is the St. Jude Children’s Research Hospital site principal investigator of clinical trials for genome editing of sickle cell disease sponsored by Vertex Pharmaceuticals/CRISPR Therapeutics (NCT03745287), Novartis Pharmaceuticals (NCT04443907), and Beam Therapeutics (NCT05456880). The industry sponsors provide funding for the clinical trial, which includes salary support paid to A.S.’s institution. A.S. has no direct financial interest in these therapies. J.S.Y. is an equity owner of Beam Therapeutics. M.J.W. is on advisory boards for Cellarity Inc., Novartis, and Forma Therapeutics. S.Q.T. is a co-inventor on licensed patents for CHANGE-seq and other genome engineering technologies. S.Q.T. is a member of the scientific advisory boards of Prime Medicine and Ensoma., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Thelazia callipaeda , the oriental eyeworm, is a zoonotic parasite that primarily infects the eyes, causing symptoms such as foreign body sensation, tearing, and itching. It is transmitted by fruit flies like Phortica okadai and commonly affects dogs and cats. This case report describes an 18-year-old woman who presented with complaints of "a worm in her left eye." Despite two visits to an ophthalmology clinic, she was initially diagnosed with conjunctivitis. The patient's history of dog ownership raised the possibility of zoonotic transmission; however, the worm was not detected during clinical examinations. Eventually, the patient removed the worm herself, and it was identified as the larval stage of T. callipaeda . This case emphasizes the importance of considering T. callipaeda in patients with nonspecific conjunctivitis symptoms, especially those with a history of contact with animals. It highlights the challenges in diagnosing this rare infection due to its nonspecific presentation and the small size of the larvae. Clinicians should be aware of this possibility and conduct thorough examinations, including double eversion of the eyelids, to avoid misdiagnosis and ensure appropriate treatment., 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, Uchida et al.)

Objective: Heyndrickxia coagulans SANK70258, a representative probiotic, is known for alleviating inflammation caused by cedar pollen, improving the intestinal environment and bowel movements. A previous study on consuming H. coagulans SANK70258 together with galactooligosaccharides showed a trend toward improvement in skin scaliness scores and subjective assessments of skin roughness. However, the effect of H. coagulans SANK70258 alone on the skin remains unclear. Thus, we aimed to re-evaluate the effects of the intake of H. coagulans SANK70258 alone on skin conditions and the intestinal environment through a clinical trial., Methods: This placebo-controlled, double-blind clinical trial involved 80 Japanese women aged 30 to 65 with perceived skin roughness. Participants were divided into placebo and test groups. Over eight weeks, the test group consumed H. coagulans SANK70258, and its effects on skin condition and intestinal health were examined., Results: The probiotic group showed significant intestinal improvements, with reduced fecal phenol levels (p = 0.044) and pH (p = 0.022), as well as enhanced skin lightness (L* value) (p = 0.040) and liver function tests. Metabolic analyses revealed decreases in fecal Nε-(carboxymethyl)lysine and plasma hydroxyproline, suggesting skin health benefits. There were also significant improvements in skin scaliness (p = 0.015) and bowel movement frequency (p = 0.032) in subgroup analysis., Conclusions: H. coagulans SANK70258 can improve skin health by improving the intestinal lining. This probiotic reduces the levels of intestinal putrefactive products and advanced glycation end-product levels in feces, suggesting that it may affect not only skin health but also systemic tissues such as the liver., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Naoyuki Togawa reports financial support was provided by Mitsubishi Chemical Corporation. Ryouichi Yamada, Yoshinori Aoki, Shouhei Suehiro, Noriyoshi Uchida reports financial support was provided by Mitsubishi Chemical Corporation. Akane Haseda, Hiroyo Kagami-Katsuyama, Naoyuki Honma, Jun Nishihira reports financial support was provided by Hokkaido Information University. Naoyuki Togawa reports a relationship with Mitsubishi Chemical Corporation that includes: employment. Ryouichi Yamada, Yoshinori Aoki, Shouhei Suehiro, Noriyoshi Uchida reports a relationship with Mitsubishi Chemical Corporation that includes: employment. Akane Haseda, Hiroyo Kagami-Katsuyama, Naoyuki Honma, Jun Nishihira reports a relationship with Hokkaido Information University that includes: employment. Naoyuki Togawa has patent Compositions for skin tone improvement pending to Mitsubishi chemical corporation. Ryouichi Yamada, Yoshinori Aoki, Shouhei Suehiro, Noriyoshi Uchida has patent Compositions for skin tone improvement pending to Mitsubishi chemical corporation. 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 The Author(s). Published by Elsevier Inc. All rights reserved.)

We report the case of a 46-year-old female patient who developed a subacute progression of axial and proximal muscle weakness. Laboratory findings revealed mildly elevated serum creatine kinase levels. No monoclonal gammopathy was detected. A muscle biopsy revealed that she had nemaline myopathy. Serological tests and a lip biopsy revealed Sjögren's syndrome (SjS). We diagnosed her as having sporadic late-onset nemaline myopathy without monoclonal gammopathy of undetermined significance associated with SjS. Her symptoms improved after methylprednisolone pulse therapy followed by intravenous immunoglobulin therapy. A good response to immunotherapy demonstrates the necessity of making a correct diagnosis, for which a muscle biopsy is required.