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Background Endocrine complications such as impaired growth, delayed puberty, and low bone mineral density (BMD) can be associated with inflammatory bowel disease (IBD) in children and adolescents. This study was performed to investigate the frequency, characteristics, and outcomes of endocrine complications of IBD in children and adolescents. Methods This study included 127 patients with IBD diagnosed before 18 years of age [117 with Crohn disease (CD) and 10 with ulcerative colitis (UC)]. Growth profiles, pubertal status, 25-hydroxyvitamin D 3 [25(OH)D 3 ] levels, and BMD were reviewed retrospectively. Results Short stature was observed in 14 of 127 (11.0 %) with a mean height-SDS of -2.31 ± 0.72. During a 2-year follow-up period, height-SDS did not significantly improve, while weight-SDS significantly improved. Among 109 patients who were older than 13 (girls) or 14 (boys) years of age during the study period, 11 patients (10.1 %) showed delayed puberty, which was associated with low weight-SDS. Vitamin D deficiency was documented in 81.7 % (94/115) with the average 25(OH)D 3 level of 14.5 ± 7.0 ng/mL. Lumbar BMD Z-score was below − 2 SDS in 25 of 119 patients (21.0 %). Height-SDS, weight-SDS, and body mass index (BMI)-SDS were lower in patients with osteoporosis than those without osteoporosis. When pediatric CD activity index scores were high (≥ 30), weight-SDS, BMI-SDS, insulin-like growth factor 1 (IGF-1)-SDS, and testosterone levels were significantly decreased. Conclusions Vitamin D deficiency and osteoporosis are common in pediatric IBD patients. As disease severity deteriorates, weight-SDS, IGF-1-SDS, and testosterone levels were decreased. Optimal pubertal development is necessary for bone health.

Mutations in SLC25A13 cause citrin deficiency, which has three phenotypes: neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD), failure to thrive and dyslipidemia caused by citrin deficiency (FTTDCD) and adult-onset type 2 citrullinemia (CTLN2). The purpose of this study was to determine the mutation spectrum and the clinical and biochemical characteristics of citrin deficiency in Korean patients. Thirty-four patients were diagnosed with citrin deficiency based on mutations in SLC25A13, as verified by direct sequencing and long PCR screening of a large transposon insertion. A total of 66 alleles from 33 unrelated families of 34 patients with citrin deficiency (27 NICCD, 2 FTTDCD and 5 CTLN2) were retrospectively identified. The common pathogenic alleles were IVS16ins3kb (33%), c.851_854del (30%) and c.1177+1G>A (12%), and three novel variants were identified. Levels of citrulline, threonine, methionine, tyrosine and arginine and the threonine-to-serine ratio were higher in children with neonatal intrahepatic cholestasis caused by NICCD compared with that in patients with idiopathic neonatal hepatitis (INH). We concluded that Korean patients with citrin deficiency showed the highest frequency of the IVS16ins3kb mutation and that plasma amino-acid profiles can be used to differentiate between NICCD and INH.

Purpose: This study evaluated the accuracy of attenuation imaging (ATI) for the assessment of hepatic steatosis in pediatric patients, in comparison with the FibroScan vibration-controlled transient elastography controlled attenuation parameter (CAP).Methods: Consecutive pediatric patients referred for evaluation of obesity who underwent both ATI and FibroScan between February 2020 and September 2021 were included. The correlation between attenuation coefficient (AC) and CAP values was assessed using the Spearman test. The AC cutoff value for discriminating hepatic steatosis corresponding to a CAP value of 241 dB/m was calculated. Multivariable linear regression analysis was performed to estimate the strength of the association between AC and CAP. The diagnostic accuracy of AC cutoffs was estimated using the imperfect gold-standard methodology based on a two-level Bayesian latent class model.Results: Seventy patients (median age, 12.5 years; interquartile range, 11.0 to 14.0 years; male:female, 58:12) were included. AC and CAP showed a moderate-to-good correlation (ρ =0.646, P<0.001). Multivariable regression analysis affirmed the significant association between AC and CAP (P<0.001). The correlation was not evident in patients with a body mass index ≥30 kg/m2 (ρ=-0.202, P=0.551). Linear regression revealed that an AC cutoff of 0.66 dB/cm/MHz corresponded to a CAP of 241 dB/m (sensitivity, 0.93; 95% confidence interval [CI], 0.85 to 0.98 and specificity, 0.87; 95% CI, 0.56 to 1.00).Conclusion: ATI showed an acceptable correlation with CAP values in a pediatric population, especially in patients with a body mass index <30 kg/m2. An AC cutoff of 0.66 dB/cm/MHz, corresponding to a CAP of 241 dB/m, can accurately diagnose hepatic steatosis.

Proper placental development in early pregnancy ensures a positive outcome later on. The developmental relationship between the placenta and embryonic organs, such as the heart, is crucial for a normal pregnancy. However, the mechanism through which the placenta influences the development of embryonic organs remains unclear. Trophoblasts fuse to form multinucleated syncytiotrophoblasts (SynT), which primarily make up the placental materno-fetal interface. We discovered that endogenous progesterone immunomodulatory binding factor 1 (PIBF1) is vital for trophoblast differentiation and fusion into SynT in humans and mice. PIBF1 facilitates communication between SynT and adjacent vascular cells, promoting vascular network development in the primary placenta. This process affected the early development of the embryonic cardiovascular system in mice. Moreover, in vitro experiments showed that PIBF1 promotes the development of cardiovascular characteristics in heart organoids. Our findings show how SynTs organize the barrier and imply their possible roles in supporting embryogenesis, including cardiovascular development. SynT-derived factors and SynT within the placenta may play critical roles in ensuring proper organogenesis of other organs in the embryo. The genetic link between placenta function and congenital heart defects has been established, though the cellular mechanisms underlying this connection is less clear. Here they show that PIBF1 regulates syncytiotrophoblast fusion and that loss of PIBF1 also negatively impacts heart development, providing a potential link between the development of these two organs.

X-linked inhibitor of apoptosis protein (XIAP) deficiency causes refractory inflammatory bowel disease. The XIAP protein plays a pivotal role in the pro-inflammatory response through the nucleotide-binding oligomerization domain-containing signaling pathway that is important in mucosal homeostasis. We analyzed the molecular mechanism of non-synonymous pathogenic variants (PVs) of XIAP BIR2 domain. We generated N-terminally green fluorescent protein-tagged XIAP constructs of representative non-synonymous PVs. Co-immunoprecipitation and fluorescence cross-correlation spectroscopy showed that wild-type XIAP and RIP2 preferentially interacted in live cells, whereas all non-synonymous PV XIAPs failed to interact properly with RIP2. Structural analysis showed that various structural changes by mutations, such as hydrophobic core collapse, Zn-finger loss, and spatial rearrangement, destabilized the two loop structures (174–182 and 205–215) that critically interact with RIP2. Subsequently, it caused a failure of RIP2 ubiquitination and loss of protein deficiency by the auto-ubiquitination of all XIAP mutants. These findings could enhance our understanding of the role of XIAP mutations in XIAP-deficient inflammatory bowel disease and may benefit future therapeutic strategies.

Background Resistance to tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) is a main limitation in breast cancer therapy. Identifying effective sensitizers is crucial to overcome this hurdle. Cyclin-dependent kinase-9 (CDK-9) inhibition has recently emerged as a potential strategy to enhance apoptotic responses in cancer cells. Materials and methods We investigated the effect of A09-003, a novel CDK9 inhibitor, on TRAIL-induced apoptosis and cell signaling in TNBC breast cancer cells. Cell viability was assessed by CellTiter-Glo assays, while apoptotic induction was evaluated using Flow cytometry analysis with Annexin V/PI staining, DNA fragmentation, and caspase activity assay. Protein expression levels of Mcl-1 and death receptors were analyzed via Western blotting and real time PCR. Mechanistic studies explored Mcl-1 protein degradation and transcriptional regulation through CDK-9 inhibition. Results A09-003 significantly enhanced TRAIL-induced apoptosis in tested breast cancer cells by increasing death receptor 5 expression, promoting caspase activation, and DNA fragmentation. Mechanistically, A09-003 downregulated Mcl-1 expression through dual pathways: promoting its proteasomal degradation and suppressing transcription via inhibition of CDK9-dependent RNA polymerase II phosphorylation. Conclusion A09-003 restores TRAIL sensitivity through Mcl-1 downregulation, identifying CDK-9 as a therapeutic target in resistant breast cancers.

Due to the genotype–phenotype heterogeneity in retinitis pigmentosa (RP), molecular diagnoses and prediction of disease progression is difficult. This study aimed to report ocular and genetic data from Korean patients with PDE6B -associated RP ( PDE6B -RP), and establish genotype–phenotype correlations to predict the clinical course. We retrospectively reviewed targeted next-generation sequencing or whole exome sequencing data for 305 patients with RP, and identified PDE6B -RP in 15 patients (median age, 40.0 years). Amongst these patients, ten previously reported PDE6B variants (c.1280G > A, c.1488del, c.1547T > C, c.1604T > A, c.1669C > T, c.1712C > T, c.2395C > T, c.2492C > T, c.592G > A, and c.815G > A) and one novel variant (c.712del) were identified. Thirteen patients (86.7%) experienced night blindness as the first symptom at a median age of 10.0 years. Median age at diagnosis was 21.0 years and median visual acuity (VA) was 0.20 LogMAR at the time of genetic analysis. Nonlinear mixed models were developed and analysis revealed that VA exponentially decreased over time, while optical coherence tomography parameters linearly decreased, and this was related with visual field constriction. A high proportion of patients with the c.1669C > T variant (7/9, 77.8%) had cystoid macular edema; despite this, patients with this variant did not show a higher rate of functional or structural progression. This study will help clinicians predict functional and structural progression in patients with PDE6B -RP.

This study evaluated the diagnostic performance of two-dimensional shear-wave elastography (2D SWE) for assessing allograft pathology in pediatric liver transplantation (LT) recipients, with subgroup analyses according to sonographic approach and age group. Additionally, the present study aimed to identify factors associated with SWE-derived parameters. This study retrospectively analyzed pediatric LT recipients who had received a left lobe or left lateral segment graft during childhood and underwent paired 2D SWE and liver biopsy. Associations between elasticity and dispersion slope measurements and clinicopathologic parameters were evaluated using univariable and multivariable regression analyses. Subgroup analyses were performed according to sonographic approach and age group. Diagnostic performance was assessed using receiver operating characteristic analysis. A total of 108 patients (median age, 13.4 years; 47 males) were included. Elasticity measured using the intercostal approach in patients aged ≥13 years showed significant associations with METAVIR (Meta-analysis of Histological Data in Viral Hepatitis) fibrosis grade, necroinflammatory activity grade, liver allograft fibrosis score, and rejection activity index score. In multivariable analysis incorporating clinical parameters, METAVIR fibrosis grade remained the only independent predictor of intercostal elasticity in this age group (coefficient, 2.17; P<0.001). Intercostal elasticity demonstrated excellent diagnostic performance for distinguishing F0-F2 from F3-F4 fibrosis (area under the curve [AUC], 0.95; P<0.001; cut-off, 11.0 kPa) and good performance for distinguishing F0-F1 from F2-F4 fibrosis (AUC, 0.83; P<0.001; cut-off, 7.2 kPa). In contrast, subcostal measurements and dispersion slope showed no significant association with any pathologic parameter. Intercostal elasticity demonstrated diagnostic value for predicting graft fibrosis in pediatric LT recipients aged ≥13 years who received left lobe or left lateral segment grafts. Among the evaluated clinicopathologic parameters, METAVIR fibrosis grade was the only independent predictor of elasticity in this subgroup.

Lay Summary Capsule endoscopy is a modality increasingly applied to small bowel evaluation in very early-onset inflammatory bowel disease. By directly visualizing mucosal lesions, it complements magnetic resonance enterography and enables clinicians to actively interpret disease status. Its safety and clinical usefulness in very early-onset inflammatory bowel disease should be further assessed through prospective studies.

Purpose: The aim of this study was to evaluate diagnostic accuracy and to establish computed tomography (CT) and Doppler ultrasonography (US) criteria for hepatic outflow obstruction after pediatric liver transplantation (LT) using left lobe (LL) or left lateral section (LLS) grafts.Methods: Pediatric patients who underwent LT using LL or LLS grafts between January 1999 and December 2021 were retrospectively included. The diagnostic performance of Doppler US and CT parameters for hepatic outflow obstruction was calculated using receiver operating characteristic (ROC) curve analysis. A diagnostic decision tree model combining the imaging parameters was developed.Results: In total, 288 patients (150 girls; median age at LT, 1.8 years [interquartile range, 0.9 to 3.6 years]) were included. Among the Doppler US parameters, venous pulsatility index (VPI) showed excellent diagnostic performance (area under the ROC curve [AUROC], 0.90; 95% confidence interval [CI], 0.86 to 0.93; Youden cut-off value, 0.40). Among the CT parameters, anastomotic site diameter (AUROC, 0.92; 95% CI, 0.88 to 0.95; Youden cut-off, 4.2 mm) and percentage of anastomotic site stenosis (AUROC, 0.88; 95% CI, 0.84 to 0.92; Youden cut-off, 35%) showed excellent and good diagnostic performance, respectively. A decision tree model combining the VPI, peak systolic velocity, and percentage of anastomotic site stenosis stratified patients according to the risk of hepatic outflow obstruction.Conclusion: VPI, anastomotic site diameter, and percentage of anastomotic site stenosis were reliable imaging parameters for diagnosing hepatic outflow obstruction after pediatric LT using LL or LLS grafts.