Zinc finger MYND-type containing 11 (ZMYND11)-related neurodevelopmental disorder is an autosomal dominant condition caused by pathogenic variants in ZMYND11. Most previously reported patients harbor loss-of-function (LoF) variants, whereas missense variants are rare and their clinical and mechanistic characteristics remain insufficiently defined. Here we report a patient with a heterozygous ZMYND11 c.1798C>T, p.(Arg600Trp) variant identified through the Initiative on Rare and Undiagnosed Diseases program. Detailed clinical evaluation, developmental assessment and whole-exome sequencing were performed. In addition, a systematic review of previously published ZMYND11 cases was conducted to compare genotype-phenotype correlations between missense and LoF variants. The present patient showed global developmental delay, hypotonia, distinctive craniofacial features, microcephaly, short stature, cryptorchidism and right-sided inguinal hernia. Comparison with two previously reported individuals carrying the same c.1798C>T variant demonstrated consistent shared features, including microcephaly, broad nasal alae, short stature, cryptorchidism and nipple anomalies, findings that are not typically emphasized in LoF-associated cases. Aggregate analysis of reported 13 missense variants suggested higher frequencies of strabismus, hypotonia and severe intellectual disability compared with LoF variants, supporting the hypothesis that missense variants including c.1798C>T may define a partially distinct clinical subgroup. These findings expand the phenotypic spectrum associated with ZMYND11 missense variants and suggest variant-specific clinical patterns, particularly for c.1798C>T, which may reflect a mechanism different from simple haploinsufficiency.
BACKGROUND:The efficacy and safety of early direct oral anticoagulant (DOAC) (re)initiation in patients with non-valvular atrial fibrillation (NVAF) after acute onset of intracranial hemorrhage (ICH) are unknown. This study evaluated ischemic and hemorrhagic risks following early DOAC (re)initiation after ICH in patients with NVAF. METHODS AND RESULTS:SAFE-ICH is a multicenter prospective observational single-arm registry study at 32 Japanese hospitals. Eligible patients had NVAF, were aged ≥20 years, and (re)initiated DOAC ≤14 days following symptomatic ICH. Among 240 patients who (re)initiated DOAC (61.3% male; mean [±SD] age 79.4±9.3 years), intraparenchymal hemorrhage predominated (84.6%), followed by subdural (12.9%), intraventricular (1.7%), and epidural (0.8%) hemorrhage. The median (interquartile range) baseline National Institutes of Health Stroke Scale score was 10 (3-16) and time to DOAC (re)initiation was 7 days (5-10 days). Edoxaban, apixaban, and rivaroxaban were used in 55.0%, 35.8%, and 9.2% of patients, respectively. The primary endpoint (composite of symptomatic ICH, any stroke, or death ≤30 days following DOAC [re]initiation) occurred in 12 (5.0%) patients. There were 4 recurrent ICH events (1.7%; all recurrent subdural hemorrhages). Five (2.1%) patients died of non-vascular causes. CONCLUSIONS:In Japanese patients with NVAF, early DOAC (re)initiation ≤14 days after ICH appears to have an acceptable risk for ischemic and hemorrhagic events, particularly in patients with intraparenchymal hemorrhage. In patients with subdural hematoma, early DOAC (re)initiation requires vigilant monitoring.
As therapeutic options for ulcerative colitis increase, optimizing the sequencing of advanced therapies has become an important challenge. We examined whether baseline clinical characteristics influence the effectiveness of ustekinumab and investigated molecular signatures associated with ustekinumab resistance. This multicenter, retrospective study enrolled 102 patients with ulcerative colitis who initiated ustekinumab at 11 institutions. Clinical response and remission were assessed at 2, 6, and 12 months. Ustekinumab persistence was evaluated by Kaplan–Meier analysis. Predictive factors of nonresponse at 6 months were analyzed by logistic regression. To explore the molecular determinants of ustekinumab nonresponse, colonic tissue analyses were performed to identify candidate genes and their cellular sources. Cytokine stimulation experiments using intestinal fibroblasts were conducted to investigate upstream regulatory pathways. The 6-month clinical response and remission rates were 69.6
Bile-based liquid biopsy presents a promising approach for identifying novel biomarkers for biliary tract cancer (BTC) given its proximity to tumor sites. The aim of this study was to identify bile-derived exosomal microRNAs (miRNAs) with diagnostic potential for BTC. The candidate miRNAs were initially screened by RNA sequencing of exosomal RNA from the bile samples of 10 BTC patients and 10 controls, resulting in the identification of miR-196a, miR-196b, and miR-424. Subsequent validation using TaqMan PCR in an independent cohort (50 BTC, 53 controls) confirmed that miR-196a and miR-196b were specifically elevated in the bile of BTC patients, with miR-196a also elevated in early-stage BTC. MiR-196a achieved an area under the receiver operating characteristic curve (AUROC) of 0.79 for the diagnosis of BTC. The combination of miR-196a and CA19-9 increased the AUROC to 0.86, and further improvement to 0.88 was observed upon the addition of CEA. Furthermore, serum levels of these miRNAs were analyzed in 64 BTC patients and 79 controls; serum miR-196a levels were significantly elevated in patients with metastatic BTC. Analysis of public datasets confirmed that both miR-196a and miR-196b were significantly upregulated in invasive BTC tissues compared to normal biliary epithelium and biliary intraepithelial neoplasia. Functional assays demonstrated that miR-196a and miR-196b promoted the proliferation and invasion of cholangiocarcinoma cells (p < 0.05). In conclusion, bile-derived exosomal miR-196a and miR-196b are novel BTC-specific biomarkers. MiR-196a may contribute to early BTC detection, enhance diagnostic accuracy in combination with serum markers, and assist in detecting metastasis.
