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.
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.
BACKGROUND:The prenatal detection rate (PDR) of congenital heart disease (CHD) has been scarcely reported in Japan. This study aimed to investigate PDR of critical CHD in a region of Japan and to evaluate the impact of prenatal diagnosis on postnatal mortality and severe morbidity. MATERIALS AND METHODS:We included patients diagnosed with CHD either prenatally and postnatally between January 1st 2018 and December 31st 2020, based on the institutional database. The Kyu-Yama region comprises the seven prefectures of Kyushu island, Yamaguchi prefecture, and Okinawa prefecture. Clinical outcome was compared with prenatal versus postnatal diagnosis. RESULTS:The overall PDR of critical CHD in the region was 64% (400 of 626 cases). Fifty-four (14%) fetuses were diagnosed within 22 weeks of gestational age. Among these cases, termination of pregnancy was selected in 5 (1%) cases. In subgroup analyses by CHD type, heterotaxy had the highest detection rate (91%), followed by hypoplastic left heart syndrome (86%). In contrast, lower detection rates were observed in transposition of the great arteries (43%) and total anomalous pulmonary venous connection (15%). Detection rates varied by prefectures, ranging from 41% to 75%. Among actively managed cases, overall, there was a significant difference in mortality and severe morbidity between prenatal and postnatal groups [66 (18%) vs. 20 (9%), p = 0.0031]. CONCLUSION:The overall PDR in this regional cohort was favorable; however, substantial differences remained across prefectures and CHD types. Reducing these disparities may require guideline-based education. Further research is warranted to clarify the prognostic impact of prenatal diagnosis.
Background Endoscopic retrograde cholangiopancreatography (ERCP), a procedure to treat pancreaticobiliary disorders, is generally safe. However, adverse events (AEs) of post-ERCP pancreatitis (PEP) can occur, which can be fatal. Physicians performing ERCP can take measures to prevent PEP, including endoscopic pancreatic duct stents and pharmacological prophylaxis. Periprocedural aggressive hydration has been investigated for its potential for reducing PEP risk. This study aims to evaluate the efficacy and safety of periprocedural aggressive hydration plus intrarectal diclofenac versus standard hydration therapy plus intrarectal diclofenac in preventing PEP onset in Japanese patients. Methods This phase 3, multicenter, open-label, randomized controlled study is being conducted at an anticipated 27 sites in Japan. The study plans to enroll 780 adults (aged ≥ 18 years) who are scheduled to receive an ERCP procedure. Patients will be randomized 1:1 to the aggressive hydration or standard hydration group. Approximately 8 h prior to the ERCP procedure, patients in both groups will be administered the main infusion (≤ 1.5 mL/kg/h). The aggressive hydration group will receive a bolus of 500 mL Ringer’s solution at the start of the ERCP procedure (500 mL/h) followed by Ringer’s solution administered at 3mL/kg/h for 8 h. The standard hydration group will be administered Ringer’s solution at 1.5 mL/kg/h initiated at the start of the ERCP procedure and continuing for 9 h. Within 30 min of completing the ERCP procedure, patients in both groups will receive intrarectal diclofenac sodium (standard, 50 mg; patients weighing < 50 kg or aged ≥ 80 years, 25 mg). The primary endpoint is the incidence of PEP (serum amylase ≥ 400 U/I after ERCP completion and persistent abdominal pain for ≥ 24 h). Secondary endpoints include the incidence of PEP by severity, the incidence of hyperamylasemia (increase in amylase ≥ 400 U/I), and the incidence of infusion-related AEs. AEs will be monitored throughout the study. Discussion This study aims to clarify whether aggressive hydration reduces PEP incidence versus standard hydration, and to compare PEP incidence by severity, and the incidence of hyperamylasemia and infusion-related AEs. Safety will be determined in both groups. Trial registration: Japan Registry of Clinical Trials (jRCT: s041230145; registered February 6, 2024; https://jrct.mhlw.go.jp/latest-detail/jRCTs041230145)
