Background. The present study aimed to investigate the prognostic value of serum ferritin in critically ill patients with sepsis by using the MIMIC-IV database. Methods. Data were extracted from the MIMIC-IV database. Adult patients who met the sepsis-3 criteria and had the test of ferritin were included. Patients were divided into subgroups according to the initial serum ferritin. The association between initial serum ferritin and in-hospital mortality was performed by using Lowessregression, logistic regression, and ROC analysis. Subgroup analysis was used to search for the interacting factors and verify the robustness of the results. Results. Analysis of the 2,451 patients revealed a positive linear relationship between serum ferritin and in-hospital mortality. Patients with high-ferritin had a higher risk of in-hospital mortality, but no significant association was found in the low-ferritin subgroup compared with those whose ferritin was in the normal reference range. Serum ferritin had moderate predictive power for in-hospital mortality (AUC=0.651), with an optimal cut-off value of 591.5ng/ml. Ferritin 591.5ng/ml acted as an independent prognostic predictor of in-hospital mortality, which increased the risk of in-hospital mortality by 119. Our findings were still robust in subgroup analysis, and acute kidney injury and anemia were considered interactive factors. Conclusion. High-level serum ferritin was an independent prognostic marker for the prediction of mortality in patients with sepsis. Further high-quality research is needed to confirm the relationship between ferritin and the prognosis of septic patients.

As an indispensable, even lifesaving practice, red blood cell (RBC) transfusion is challenging due to several issues, including supply shortage, immune incompatibility, and blood‐borne infections since donated blood is the only source of RBCs. Although large‐scale in vitro production of functional RBCs from human stem cells is a promising alternative, so far, no such system has been reported to produce clinically transfusable RBCs due to the poor understanding of mechanisms of human erythropoiesis, which is essential for the optimization of in vitro erythrocyte generation system. We previously reported that inhibition of mammalian target of rapamycin (mTOR) signaling significantly decreased the percentage of erythroid progenitor cells in the bone marrow of wild‐type mice. In contrast, rapamycin treatment remarkably improved terminal maturation of erythroblasts and anemia in a mouse model of β‐thalassemia. In the present study, we investigated the effect of mTOR inhibition with rapamycin from different time points on human umbilical cord blood‐derived CD34⁺ cell erythropoiesis in vitro and the underlying mechanisms. Our data showed that rapamycin treatment significantly suppressed erythroid colony formation in the commitment/proliferation phase of erythropoiesis through inhibition of cell‐cycle progression and proliferation. In contrast, during the maturation phase of erythropoiesis, mTOR inhibition dramatically promoted enucleation and mitochondrial clearance by enhancing autophagy. Collectively, our results suggest contrasting roles for mTOR in regulating different phases of human erythropoiesis.

The objective of this phase 1 study was to evaluate the pharmacokinetics, safety, and tolerability of baricitinib after single and multiple doses in healthy Chinese adults. Eligible subjects received a once‐daily dose of baricitinib 2, 4, or 10 mg or placebo on day 1 (single dose) and days 4 through 10 for 7 consecutive days (multiple doses). Plasma pharmacokinetic samples were collected up to 48 hours after dosing on days 1 and 10, with predose samples collected before dosing on day 1 and days 4 through 10. Safety and tolerability were also assessed. Baricitinib was rapidly absorbed, reaching peak plasma concentrations within 0.5 to 1 hour (median). Plasma concentrations declined rapidly following the attainment of peak concentrations, with a mean terminal half‐life of 5.7 to 7.3 hours. Steady‐state plasma concentrations of baricitinib were achieved after the second day of once‐daily dosing, with minimal accumulation of baricitinib in plasma (up to 10% increase in area under the plasma concentration–time curve). Single‐ and multiple‐dose mean values for area under the plasma concentration–time curve from time zero to infinity and maximum plasma concentration appeared to increase in an approximately dose‐proportional manner across the dose range. Single and multiple oral doses of once‐daily baricitinib up to 10 mg were well tolerated by healthy Chinese subjects.

Background: There is no evidence to determine the association between the lactate dehydrogenase to albumin ratio (LAR) and the development of sepsis-associated acute kidney injury (SAKI). We aimed to investigate the predictive impact of LAR for SAKI in patients with sepsis. Methods: A total of 4,087 patients with sepsis from the Medical Information Mart for Intensive Care IV (MIMIC IV) database were included. Logistic regression analysis was used to identify the association between LAR and the risk of developing SAKI, and the relationship was visualized using restricted cubic spline (RCS). The clinical predictive value of LAR was evaluated by ROC curve analysis. Subgroup analysis was used to search for interactive factors. Results: The LAR level was markedly increased in the SAKI group (p < 0.001). There was a positive linear association between LAR and the risk of developing SAKI (p for nonlinearity = 0.867). Logistic regression analysis showed an independent predictive value of LAR for developing SAKI. The LAR had moderate clinical value, with an AUC of 0.644. Chronic kidney disease (CKD) was identified as an independent interactive factor. The predictive value of LAR for the development of SAKI disappeared in those with a history of CKD but remained in those without CKD. Conclusions: Elevated LAR 12 h before and after the diagnosis of sepsis is an independent risk factor for the development of SAKI in patients with sepsis. Chronic comorbidities, especially the history of CKD, should be taken into account when using LAR to predict the development of AKI in patients with sepsis.

Background: The molecular mechanisms underlying obstructive sleep apnea (OSA) and its comorbidities may involve mitochondrial dysfunction. However, very little is known about the relationships between mitochondrial dysfunction-related genes and OSA.Methods: Mitochondrial dysfunction-related differentially expressed genes (DEGs) between OSA and control adipose tissue samples were identified using data from the Gene Expression Omnibus database and information on mitochondrial dysfunction-related genes from the GeneCards database. A mitochondrial dysfunction-related signature of diagnostic model was established using least absolute shrinkage and selection operator Cox regression and then verified. Additionally, consensus clustering algorithms were used to conduct an unsupervised cluster analysis. A protein–protein interaction network of the DEGs between the mitochondrial dysfunction-related clusters was constructed using STRING database and the hub genes were identified. Functional analyses, including Gene Ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, gene set enrichment analysis (GSEA), and gene set variation analysis (GSVA), were conducted to explore the mechanisms involved in mitochondrial dysfunction in OSA. Immune cell infiltration analyses were conducted using CIBERSORT and single-sample GSEA (ssGSEA).Results: we established mitochondrial dysfunction related four-gene signature of diagnostic model consisted of NPR3, PDIA3, SLPI, ERAP2, and which could easily distinguish between OSA patients and controls. In addition, based on mitochondrial dysfunction-related gene expression, we identified two clusters among all the samples and three clusters among the OSA samples. A total of 10 hub genes were selected from the PPI network of DEGs between the two mitochondrial dysfunction-related clusters. There were correlations between the 10 hub genes and the 4 diagnostic genes. Enrichment analyses suggested that autophagy, inflammation pathways, and immune pathways are crucial in mitochondrial dysfunction in OSA. Plasma cells and M0 and M1 macrophages were significantly different between the OSA and control samples, while several immune cell types, especially T cells (γ/δ T cells, natural killer T cells, regulatory T cells, and type 17 T helper cells), were significantly different among mitochondrial dysfunction-related clusters of OSA samples.Conclusion: A novel mitochondrial dysfunction-related four-gen signature of diagnostic model was built. The genes are potential biomarkers for OSA and may play important roles in the development of OSA complications.

Purpose: The aim of present study was to explore the pharmacological mechanisms of Niaoduqing granules on the treatment of podocyte injury in diabetic nephropathy (DN) via network pharmacology and experimental validation.Methods: Active ingredients and related targets of Niaoduqing, as well as related genes of podocyte injury, proteinuria and DN, were obtained from public databases. Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and protein-protein interaction (PPI) network analysis were performed to investigate the potential mechanisms. High glucose (HG) -induced MPC5 cell injury model was treated with the major core active ingredients of Niaoduqing and used to validate the predicted targets and signaling pathways.Results: Totally, 16 potential therapeutic targets were identified by intersecting the targets of Niaoduqing and disease, in which 7 of them were considered as the core targets via PPI network analysis. KEGG enrichment analysis showed that AGE-RAGE signaling pathway was identified as the most crucial signaling pathway. The results of in vitro experiments revealed that the treatment of Niaoduqing active ingredients significantly protected MPC5 cells from HG-induced apoptosis. Moreover, Niaoduqing could significantly attenuate the HG-induced activation of AGE-RAGE signaling pathway, whereas inhibited the over-expression of VEGF-A, ICAM-1, PTGS-2 and ACE in HG-induced MPC5 cells.Conclusion: Niaoduqing might protect against podocyte injury in DN through regulating the activity of AGE/RAGE pathway and expression of multiple genes. Further clinical and animal experimental studies are necessary to confirm present findings.