Proton pump inhibitors (PPIs) are an effective first-line treatment for eosinophilic esophagitis (EoE). However, half of the patients are refractory to PPI therapy, and predictive markers for therapy decision are lacking. Thus, this study aimed to investigate the differences in esophageal immunologic transcriptome between PPI-non-responders and PPI-responders and identify molecular biomarkers to guide therapy decisions. Forty-eight pediatric EoE patients were enrolled and classified due to PPI-therapy response. Pre-treatment esophagus biopsy was collected for gene expression analysis, differentially expressed genes (DEGs) between PPI-responders and non-responders were identified, followed by gene enrichment and protein-protein interaction network analyses. Expression of identified hub genes was confirmed by immunohistochemistry in an extended cohort comprising 62 patients. PPI-non-responders and responders exhibit a partially different transcriptomic profile, as 12 DEGs were up-regulated and one down-regulated. These DEGs are closely related to antigen processing and presentation function. PSMB8 was identified as a hub gene differing between these two groups, and immunohistochemistry confirmed significantly increased expression in PPI-non-responders (P < 0.0001). Notably, receiver operating characteristic curves curve analysis of PSMB8 reveals it as highly predictive for PPI response (sensitivity/specificity: 0.61/1.00). PPI-non-responding EoE patients exhibited a more profound dysregulation of gene expression. PSMB8 represents a promising esophageal biomarker for predicting therapy response in pediatric EoE.
BACKGROUND:Extremely preterm infants require respiratory support with supplemental oxygen and have frequent hypoxaemic episodes. These episodes, and exposure to inadequately high concentrations of oxygen, are associated with major complications and death. Closed-loop automated control of the fractional concentration of oxygen in inspired air (FiO2-C) reduces the time below and above the target range for the pulse oximeter oxygen saturation (SpO2) and caregivers' workload. We aimed to study whether FiO2-C during respiratory support versus routine manual control might also improve clinical outcomes. METHODS:This multicentre, parallel-group, randomised, controlled, superiority trial was done in 32 neonatal intensive care units in China, Germany, the Netherlands, and the UK. Infants born at 23+0 weeks to 27+6 weeks postmenstrual age were included and randomly assigned to FiO2-C or routine manual care stratified within centres by postmenstrual age at birth and sex. FiO2-C was provided in addition to routine manual control of FiO2 using infant ventilators. The composite primary endpoint was death, necrotising enterocolitis, or bronchopulmonary dysplasia up to 36 weeks postmenstrual age, or severe retinopathy of prematurity by 44 weeks postmenstrual age. Secondary endpoints were the components of the primary endpoint and the maximum retinopathy of prematurity severity score in either eye on the International Neonatal Consortium Retinopathy of Prematurity Activity Scale. The trial was stopped early because of poor recruitment. The primary analysis included the intention-to-treat population with non-missing primary outcome data. This trial was registered with ClinicalTrials.gov (NCT03168516) and is closed. FINDINGS:Between July 1, 2018, and Oct 31, 2023, 1082 infants were enrolled and randomly assigned to the FiO2-C group (n=539) or routine manual control group (n=543). Median postmenstrual age was 26+1 weeks (IQR 24+6-27+1). 557 (51%) of 1082 infants were male and 525 (49%) were female. The primary endpoint occurred in 206 (39%) of 534 infants in the FiO2-C group versus 222 (41%) of 538 infants in the routine manual control group (adjusted odds ratio 0·90, 97·5% CI 0·65-1·24; p=0·47). Rates of death (48 [9%] of 536 infants vs 50 [9%] of 541 infants), necrotising enterocolitis (27 [5%] of 538 vs 36 [7%] of 542), bronchopulmonary dysplasia (104 [21%] of 486 vs 110 [23%] of 485), and severe retinopathy of prematurity (86 [18%] of 491 vs 95 [19%] of 496) were also similar between groups. The maximum retinopathy of prematurity severity score was similar between groups (median 7 [IQR 0-9]; p=0·24). Overall, 197 serious adverse events were reported in the FiO2-C group and 192 in the routine manual control group, with no evidence of harm related to the intervention. Postnatal age at death and primary causes of death were similar in both groups. Four serious incidents related to software function without apparent harm to affected infants were reported. INTERPRETATION:FiO2-C did not improve neonatal clinical outcomes. The long-term application of FiO2-C to reduce caregivers' workload might be considered safe. FiO2-C algorithms should be tested before routine application. FUNDING:German Federal Ministry of Education and Research.
Abstract Background and aims Balloon guide catheters (BGC) provide proximal flow arrest during mechanical thrombectomy (MT), potentially improving thrombus retrieval efficiency and reducing distal embolization. However, prospective randomized data comparing BGC versus non-BGC approaches remain limited. We analyzed the impact of BGC use on clinical and angiographic outcomes in the PROST trial. Methods PROST was a multicenter, prospective, randomized trial comparing pRESET versus Solitaire stent retrievers in patients with large vessel occlusion stroke (NCT04102046). In this post-hoc analysis, we compared patients treated with BGC (n=152) versus non-BGC (n=170). The primary outcome was 90-day functional independence (modified Rankin Scale [mRS] 0-2). Secondary outcomes included first-pass effect (FPE; expanded TICI [eTICI] ≥2c), complete reperfusion (eTICI ≥2c), and 90-day mortality. Multivariable logistic regression adjusted for age, sex, baseline NIHSS, comorbidities, IV tPA, and anesthesia type. Results Of 322 patients with BGC data, baseline characteristics were balanced between groups (median age 71vs74 years,p=0.11). BGC use was associated with significantly higher rates of 90-day functional independence (63.2% vs 45.3%; OR2.07, 95% CI1.32-3.24;p=0.002). BGC patients demonstrated superior FPE (51.7%vs36.3%;OR1.87,95%CI1.20-2.93;p=0.007). Mortality at 90 days was significantly lower with BGC (9.2% vs 18.2%;OR 0.45,95%CI0.23-0.89;p=0.024). No difference was observed in symptomatic intracranial hemorrhage or embolization to new territory. After multivariable adjustment, BGC remained independently associated with functional independence (adjusted OR1.74,95%CI1.02-3.06). Conclusions In this post-hoc analysis of the PROST trial, BGC use was associated with significantly improved functional outcomes, higher first-pass and complete reperfusion rates, and reduced mortality compared to non-BGC approaches. Conflict of interest None
The microbiota shapes postnatal gut development and physiology. In the small intestine, epithelial-to-endothelial crosstalk governs the microbiota-induced remodeling of villus capillary networks essential for nutrient transport. The intestinal epithelial enzyme dual oxidase-2 (DUOX2), an established regulator of the microbiome-host interaction, exerts microbicidal functions through the generation of reactive oxygen species. However, its role in intestinal vascular development remains poorly understood. Here, we demonstrate a Toll-like receptor-2 (TLR2)-dependent regulatory pathway controlling DUOX2 expression that influences villus vascularization in the small intestine. Mice globally lacking DUOX2 activity exhibited a notable reduction in vascularization in the small intestine, accompanied by alterations in gut microbial community structure. Conversely, mice with an intestinal epithelial-specific deficiency of TLR2 displayed an increase in villus vascularization along with elevated expression levels of DUOX2. Notably, DUOX2 expression was strongly upregulated in intestinal epithelial biopsies from patients with Crohn’s disease. Similarly, inflammatory conditions induced by dextran sulfate sodium (DSS) treatment in mice resulted in increased epithelial Duox2 expression accompanied by enhanced villus vascularization. Together, our findings suggest a microbiota–TLR2–DUOX2 signaling axis in intestinal epithelial cells that promotes villus vascularization. This mechanism links microbial sensing in the intestinal epithelium to structural remodeling of the villus microvasculature during homeostasis and inflammation.
