YKK (Japan)

Moyamoya disease (MMD) has a strong genetic basis, with the rare RNF213 p.Arg4810Lys variant (rs112735431) representing a major risk factor, while the broader genetic architecture and disease-relevant vascular cell types remain incompletely understood. We conducted a genome-wide association study in Japanese individuals (n=47 656; 401 MMD cases and 47 255 controls). Population-level features at MMD risk loci were examined by regional allele frequency and haplotype analyses. We performed single-nucleus RNA-seq of superficial temporal arteries from patients with MMD (n=3). Cell type-specific enrichment of genome-wide association study signals was assessed using the Single-Cell Disease Relevance Score. Endothelial signatures were validated by integration with publicly available single-cell data sets from controls (n=5) and immunohistochemistry for candidate markers (n=1). Beyond rs112735431, we identified a genome-wide significant signal in the HDAC9-TWIST1 region (rs12530920; P=3.3×10-14; odds ratio, 1.77). Conditional analysis on rs112735431 revealed a protective RNF213 missense variant, p.Asp1331Gly (rs8074015; P=3.7×10-9; odds ratio, 0.53), whose minor allele was mutually exclusive with rs112735431-A on haplotypes. Population analysis revealed geographic variation and extended haplotype structure of the rs112735431-A allele in Japan. Single-nucleus RNA-seq identified a mesenchymal-like endothelial cell (MEC) population with selective FN1 expression. Genome-wide association study-prioritized disease genes were strongly enriched in MECs. MECs showed mesenchymal pathway activation with a regulatory program distinct from canonical endothelial states. The proportion of MECs was markedly increased in MMD (72% versus 28% in controls), and fibronectin 1 (FN1) expression in endothelial regions was confirmed by immunohistochemistry. Our findings identify a protective RNF213 p.Asp1331Gly variant (rs8074015) that is mutually exclusive with the known rs112735431-A allele. Genetic risk converges on an MEC state markedly expanded in MMD.

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

Abstract In this study, we developed a new process for grain refinement in the A6063 aluminum alloy using extrusion with aluminum billets fabricated by additive manufacturing. The resultant extruded profile exhibited fine grains with an average diameter of 3 μm and displayed a fibrous structure elongated in the extrusion direction. The internal microstructure exhibited the typical texture of a plate-shaped extruded profile, characterized by < 001 > + β-fiber{110} < 112 > . The results obtained using this method were superior to those obtained using the conventional approach, in which cast billets were used for A6063 extruded profiles. Specifically, the tensile strength and elongation values improved by 10% and 40%, respectively. Additionally, we detected the development of a yield point (which is generally not observed in aluminum alloys). This outcome confirmed that uniform fine grains were successfully obtained using this process. In addition, this method facilitated the production of extruded profiles, with complex cross-sectional shapes and fine grains, in an alloy with a low transition-metal concentration, such as the A6063 alloy (whose manufacturing has hitherto remained challenging).

Digital therapeutics (DTx) for hypertension are among the most promising treatment options, demonstrating proven antihypertensive effects. This study investigates the determinants of the home blood pressure (BP) lowering effect of DTx, using prospectively collected daily data. The B-INDEX study (Behavioral Modification Index) is a multicenter intervention study in patients with hypertension, involving a 6-month DTx period, followed by an additional 6 months without it. Home BP, body weight and composition, physical activity, and sleep patterns were monitored daily using digital devices. This first report on B-INDEX analyzed data collected during a 6-month DTx treatment period. A total of 198 patients with hypertension (mean age, 54.9±10.6 years; 57.1% male; mean body mass index, 26.7±5.3 kg/m2; 57.6% taking antihypertensives) were included in the analysis. A marked reduction in BP was observed in the first 4 weeks (morning home BP, -6.2/-2.6 mm Hg). Mixed model analysis demonstrated that baseline home BP, older age, self-efficacy score, reduction in self-reported salt intake, and mild initial weight loss (-0.5 kg at week 4) were significant determinants of home BP reduction at 6 months. Older age, salt reduction, and initial weight loss were predictive factors for effective BP reduction through DTx, independent of baseline BP values. We propose that the first 4 weeks are the key period for hypertension treatment with DTx. URL: https://www.umin.ac.jp/ctr/; Unique identifier: UMIN000050479.

Historically, the lower River Skjern (Denmark) was a biodiversity hotspot of national and European importance, but in the 1960s this part of the river was channelized and the wetlands drained to improve conditions for agriculture. However, to regain former biodiversity, a major restoration project was conducted in 2000–2002, which transformed a 19 km straight channel into a 26 km meandering river. In this study, we use historical data to evaluate how the channelization of the river and its restoration 40 years later affected the aquatic biodiversity. Generally, and as expected, we observed a significant reduction in the taxon richness of aquatic plants and EPT taxa (Ephemeroptera, Plecoptera, and Trichoptera) in response to the channelization, especially taxa associated with backwaters. As hoped, the restoration mediated an increase in taxon richness for both aquatic plants and EPT taxa. This positive response took place immediately after the restoration (1 year) and persisted throughout the study period (10 years). However, taxon richness did not reach the pre-channelization levels. Especially, we observed that the recovery of backwater-associated taxa was limited. The main reason for this is likely that only 5.8 % of the original backwater area was recreated and, additionally, that natural regeneration of these areas relies on natural hydromorphological processes that might take several decades. Furthermore, the possibility of several taxa to recolonize from other and distant areas is poor, reflecting today's rarity of backwater habitats in Danish rivers. Full recovery of the river's former biodiversity might therefore take decades or more without implementing active measures. • The study of a former near-pristine lowland river is unique in size and details. • Largest N-European physical restoration project. • Taxon richness of aquatic plants and EPT taxa is assessed on species level. • Evaluate effects of both channelization (30 year period) and restoration (1–10 years). • Link recolonization of taxa to river area, physical habitats, and dispersal range.

Remdesivir (RDV) was approved in Japan for the treatment of coronavirus disease 2019 (COVID-19) in May 2020. However, large-scale research describing the characterized use of RDV in the inpatient setting in Japan is limited. This study aimed to describe the treatment patterns and clinical outcomes of immunocompromised patients with COVID-19 treated with RDV. We used a secondary nationwide administrative claims database of acute care hospitals in Japan. The study period was from October 19, 2020, to September 30, 2022. Patients with COVID-19 treated with RDV during hospitalization were included, and the proportion of patients with death and disease progression were calculated. The analysis included a total of 2171 immunocompromised patients treated with RDV. The mean (standard deviation) age at index date was 75.1 (13.6) years. The median time to RDV initiation from hospitalization was 1.0 days (Q1-Q3: 1.0-2.0), and the median duration of RDV treatment was 5.0 days (Q1-Q3: 3.0-5.0). At RDV initiation, 53.02% (n=1151) of patients required non-invasive positive pressure ventilation, nasal high-flow or low-flow oxygen, and 2.26% (n=49) required mechanical ventilation, extracorporeal membrane oxygenation, or intensive care unit admission. Inpatient mortality rate by day 28 was 8.98% (95% confidence interval, 7.81-10.26). By day 28, the rate of disease progression was 9.86% (n=214), and 76.83% (n=1668) were discharged. This study presents practical information on outcomes and treatment patterns of RDV in immunocompromised inpatients diagnosed with COVID-19.

The aim of the study is to evaluate changes in dizziness, postural stability, and sensory integration after mild traumatic brain injury over a 12-wk period. One hundred adults with mild traumatic brain injury were analyzed. The Dizziness Handicap Inventory questionnaire was used for subjective evaluations. Postural stability and modified Clinical Test of Sensory Interaction in Balance were used as objective measures at 0, 6, and 12 wks after mild traumatic brain injury. Observational follow-up study. Dizziness Handicap Inventory scores decreased significantly over time, indicating improved functional, emotional, physical, and overall aspects. Most indices of postural stability and modified Clinical Test of Sensory Interaction in Balance decreased significantly over time. The postural stability indices (overall and anteroposterior) and the modified Clinical Test of Sensory Interaction in Balance indices (eyes open on firm and foam surfaces) differed significantly between weeks 0 and 6, according to post hoc analysis. Furthermore, the modified Clinical Test of Sensory Interaction in Balance indices of eyes open on firm and foam surfaces and eyes closed on foam surface demonstrated significant differences between weeks 0 and 12. Subjective and objective measurements indicated improvements in included adults from 0 wks to 6 and 12 wks after mild traumatic brain injury. However, balance dysfunction and sensory integration issues may persist beyond 12 wks after mild traumatic brain injury. The findings highlight the need for longer follow-up and tailored rehabilitation programs.

Abstract One of the promising mechanisms to explain the stable jet speed of SS 433 is the magic speed, which is established by the balance between radiation pressure and radiation drag (and gravity). We examine the magic speed in the optically thick sub-relativistic flows for several typical situations, such as plane-parallel and spherical cases, and show that it is difficult to establish the magic speed in the simple optically thick flows in contrast to the optically thin ones. Instead, we propose the funnel jets as an improved model. That is, we consider the optically thick flows in the funnel, which is formed by the supercritical accretion disk, and mass and radiation energy are injected from the funnel wall. In this model the mass-accretion rate determines the configuration of the funnel, the increasing mass-loss rate of jets, the radiative environments, and then the sub-relativistic magic speed is naturally established.