International University of Health and Welfare

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.

Summary Early walnut powder introduction in high‐risk infants may suppress walnut sensitisation without safety concerns. This randomised non‐inferiority trial compares introduction at 6–8 months versus 12–14 months of age.

Accurate clinical staging of upper tract urothelial carcinoma (UTUC) remains challenging, and discrepancies between clinical and pathological T stages may result in missed opportunities for appropriate treatment. This study aimed to elucidate real-world discrepancies between clinical and pathological T staging in UTUC, emphasizing the diagnostic uncertainty associated with clinical T2 (cT2) disease. A retrospective analysis was conducted involving 739 patients with cTa–4N0M0 UTUC who underwent radical nephroureterectomy (RNU) at multiple institutions. Patients who received neoadjuvant therapy or had missing pathological T stage data were excluded. Discrepancies between clinical and pathological staging, treatment patterns, and survival outcomes were evaluated. Among 739 patients, substantial discrepancies between clinical and pathological T stages were observed, with an overall diagnostic concordance rate of 44.7%. Only 16% of cT2 cases were pathologically confirmed as pathological T2 (pT2), whereas most were either down-staged to ≤pT1 or up-staged to ≥pT3, indicating marked diagnostic uncertainty. Clinical heterogeneity within the cT2 group resulted in marked survival differences based on pathological stage, as pT3 patients had significantly worse outcomes than pT2 patients. Within the pT3 subgroup, lymphovascular invasion independently correlated with poor prognosis, whereas adjuvant therapy improved survival. However, only approximately one-third of patients with pT3 disease received adjuvant therapy, indicating a treatment gap in this high-risk population. This multicenter study identified real-world discrepancies between clinical and pathological staging in UTUC. cT2 disease represents a heterogeneous and diagnostically uncertain category, requiring careful interpretation for appropriate treatment planning.

It is becoming increasingly important to investigate not only micro-/macrovascular complications, but also comorbidities associated with diabetes. In the Asahi Diabetes Complications Study (Asahi Study), in addition to micro-/macrovascular complications, the onset and progression of dementia and sarcopenia were also investigated in patients with diabetes. The Asahi Study is a prospective 8-year observational cohort study of subjects with diabetes receiving outpatient care at the Institute of Medical Science, Asahi Life Foundation. Participants were enrolled between November 2014 and December 2017. The baseline data include the age, HbA1c level, and median duration of diabetes. In addition, medication use, prevalence of micro-/macrovascular complications, and presence/absence of malignant neoplasms were also assessed. A total of 49 patients with type 1 DM (T1DM group) and 791 patients with type 2 DM (T2DM group) were enrolled in the study. The mean age was 58.4 years in the T1DM group and 64.9 years in the T2DM group. Other baseline characteristics (T1DM/T2DM) were: mean HbA1c 7.5%/7.0%; median duration of diabetes 23 years/18 years. In regard to medication history, in the T2DM group, 57.3% were receiving oral hypoglycemic agents, 5.6% were receiving injectable GLP-1 receptor agonists, and 28.4% were receiving insulin therapy. The prevalences of microvascular complications, macrovascular complications, and malignant neoplasms were approximately 30-50%, 10%, and 7%, respectively, in the study participants. This 8-year observation study may offer valuable insights into the relationship between risk factor management and development of diabetic complications/comorbidities in persons with diabetes.