CYP1A2 Polymorphism and Drug Co-administration Affect the Blood Levels and Adverse Effects of Pirfenidone.

BACKGROUND: Mutations in metabolic enzymes and co-administration of drugs may affect the blood concentration of pirfenidone effective in pulmonary fibrosis. To provide a basis for the precise clinical use of pirfenidone, the authors analyzed the correlation between steady-state pirfenidone trough concentration and adverse drug reactions (ADRs) and examined the impact of CYP1A2*1C (rs2069514) and *1F (rs762551) variants and co-administration on pirfenidone blood concentrations and ADRs. METHODS: Forty-four patients were enrolled. The blood concentration of pirfenidone was determined using high-performance liquid chromatography. CYP1A2*1C and *1F genotypes were determined using direct SNP sequencing. Additional information related to drug associations was collected to screen factors affecting drug metabolism. RESULTS: The highest predictive value of ADRs was observed when the steady-state trough concentration of pirfenidone was 3.18 mcg·mL-1 and the area under the receiver operating characteristic curve was 0.701 (P = 0.024). The pirfenidone concentration-to-dose ratio (C/D) in CYP1A2*1F homozygous AA mutants was lower than that in C carriers (CC+AC) (1.28 ± 0.85 vs. 2.03 ± 1.28 mcg·mL-1; P = 0.036). Adverse drug reaction (ADR) incidence in the homozygous AA mutant group (28.0%) was significantly lower than that in the C carriers (CC+AC) (63.2%; P = 0.020), and ADR incidence in the A carriers (AC+AA) was considerably lower than that in the CC group (85.7%; P = 0.039). The C/D value of the combined lansoprazole/rabeprazole group was lower than that of the noncombination group (P < 0.05). CONCLUSIONS: The ADR incidence was positively correlated with pirfenidone blood concentration. The CYP1A2 (rs762551) AA genotype is associated with lower pirfenidone concentrations and fewer ADRs. Lansoprazole/rabeprazole co-administration reduced pirfenidone concentrations. Randomized controlled trials should further explore personalized dosing of pirfenidone and combination therapies.

Prognostic factors in lung transplantation after extracorporeal membrane oxygenation bridging therapy: a systematic review and meta-analysis.

Background: Extracorporeal membrane oxygenation (ECMO) has recently emerged as a critical support system for lung function in patients awaiting lung transplantation. This meta-analysis investigates the prognostic factors of lung transplantation following ECMO bridging therapy. Methods: A comprehensive search was conducted in PubMed, Cochrane Library, Embase, CINAHL, Web of Science, Scopus, and ProQuest databases from inception to August 11, 2023. Included were cohort or case-control studies focusing on prognostic factors of lung transplantation with ECMO bridging therapy. Data extraction was performed independently, and study quality was assessed. A meta-analysis was carried out using RevMan 5.4 and Stata17.0 software to aggregate mortality rates and pertinent prognostic factors of ECMO as a bridge to lung transplantation. Results: The search identified eight trials encompassing 1,086 participants. The prognosis of patients undergoing lung transplantation with ECMO bridging was significantly associated with several factors: prolonged ECMO support [odds ratio 1.07, 95% confidence interval (CI): 1.02-1.12, I2=77%], deterioration in liver and kidney function (odds ratio 3.62, 95% CI: 2.37-5.54, I2=0%), and complications during ECMO (odds ratio 2.24, 95% CI: 1.45-3.44, I2=5%). Conclusions: Prolonged ECMO support, declining liver and kidney functions, and complications during ECMO are vital prognostic factors in lung transplantation following ECMO bridging therapy.

Trends in colorectal cancer screening compliance and incidence among 60- to 74-year-olds in China.

BACKGROUND: Compliance with colonoscopy among elderly individuals participating in colorectal cancer (CRC) screening programs is unsatisfactory, despite a high detection rate of bowel-related diseases. In this study, our aim was to analyze the impact of risk factors on the trends of compliance and detection rates in colonoscopy among high-risk individuals aged 60-74. METHODS: A retrospective study was conducted on the high-risk individuals aged 60-74 participating in the 2021 CRC screening program in Tianjin, China. Logistic regression analyses, including both univariate and multivariate analyses, were performed to explore the impact of different risk factors on colonoscopy compliance among the high-risk individuals. Besides, the study investigated the influence of various risk factors on the detection rates of bowel-related diseases among the high-risk individuals who underwent colonoscopy. RESULTS: A total of 24,064 high-risk individuals were included, and 5478 individuals received a free colonoscopy, with an overall compliance of 22.76%. Among them, the adenoma detection rate was 55.46%. Males and individuals with a positive FIT had high compliance and detection rates for CRC, advanced adenomas (AA), advanced colorectal neoplasia (ACN), and colorectal neoplasm (CN). Individuals aged 70-74 were associated with low compliance but high CRC, ACN, and CN detection rates. Individuals who reported a history of chronic constipation, bloody mucous, and CRC in first-degree relative showed high compliance but no significantwere associated with the detection rates of CRC, AA, and CN. CONCLUSION: This study reported several risk factors associated with the screening behaviors for CRC. Patterns and trends in CRC, AA, ACN, and CN compliance and detection rates correlate with risk factors.

Hydralazine loaded nanodroplets combined with ultrasound-targeted microbubble destruction to induce pyroptosis for tumor treatment.

Pyroptosis, a novel type of programmed cell death (PCD), which provides a feasible therapeutic option for the treatment of tumors. However, due to the hypermethylation of the promoter, the critical protein Gasdermin E (GSDME) is lacking in the majority of cancer cells, which cannot start the pyroptosis process and leads to dissatisfactory therapeutic effects. Additionally, the quick clearance, systemic side effects, and low concentration at the tumor site of conventional pyroptosis reagents restrict their use in clinical cancer therapy. Here, we described a combination therapy that induces tumor cell pyroptosis via the use of ultrasound-targeted microbubble destruction (UTMD) in combination with DNA demethylation. The combined application of UTMD and hydralazine-loaded nanodroplets (HYD-NDs) can lead to the rapid release of HYD (a demethylation drug), which can cause the up-regulation of GSDME expression, and produce reactive oxygen species (ROS) by UTMD to cleave up-regulated GSDME, thereby inducing pyroptosis. HYD-NDs combined with ultrasound (US) group had the strongest tumor inhibition effect, and the tumor inhibition rate was 87.15% (HYD-NDs group: 51.41 ± 3.61%, NDs + US group: 32.73%±7.72%), indicating that the strategy had a more significant synergistic anti-tumor effect. In addition, as a new drug delivery carrier, HYD-NDs have great biosafety, tumor targeting, and ultrasound imaging performance. According to the results, the combined therapy reasonably regulated the process of tumor cell pyroptosis, which offered a new strategy for optimizing the therapy of GSDME-silenced solid tumors.

Wernicke encephalopathy induced by glucose infusion: A case report and literature review.

Introduction: Wernicke encephalopathy (WE) is a potentially fatal condition caused by thiamine (vitamin B1) deficiency. Chronic alcoholism is the most common cause of WE; however, other conditions responsible for thiamine deficiency should also be considered. Case Report: We report the case of a 64-year-old woman with a history of diabetes who presented with confusion and apathy. Magnetic resonance imaging of the brain showed T2 hyperintensities involving dorsolateral medulla oblongata, tegmentum of the pons, vermis of the cerebellum, periaqueductal region, and the bilateral mammillary bodies. She had a history of intravenous glucose administration before her mental symptoms developed. On suspicion of WE, she was treated with a high dose of thiamine empirically. Her clinical condition improved rapidly in 2 weeks. Conclusion: Endogenous thiamine stores can be rapidly depleted in the case of enhanced glucose oxidation. Patients who receive glucose should also be prescribed thiamine to avoid inducing or exacerbating WE.

Clinical evaluation of droplet digital pcr for suspected ascites infection in patients with liver cirrhosis.

BACKGROUND: Droplet digital PCR (ddPCR) is increasingly used in diagnosing clinical pathogens, but its effectiveness in cirrhosis patients with suspected ascites infection remains uncertain. METHODS: The diagnostic performance of ddPCR was assessed in 305 ascites samples, utilizing culture and clinical composite standards. The quantitative value and potential clinical impact of ddPCR were further analyzed in patients with spontaneous bacterial peritonitis. RESULTS: With culture standards, ddPCR demonstrated a sensitivity of 86.5% and specificity of 83.2% for bacterial or fungal detection. After adjustment of clinical composite criteria, specificity increased to 96.4%. Better diagnostic performance for all types of targeted pathogens, particularly fungi, was observed with ddPCR compared to culture, and more polymicrobial infections were detected (30.4% versus 5.7%, p < 0.001). Pathogen loads detected by ddPCR correlated with white blood cell count in ascites and blood, as well as polymorphonuclear cell (PMN) count in ascites, reflecting infection status rapidly. A positive clinical impact of 55.8% (43/77) was observed for ddPCR, which was more significant among patients with PMN count ≤ 250/mm3 in terms of medication adjustment and new diagnosis. ddPCR results for fungal detection were confirmed by clinical symptoms and other microbiological tests, which could guide antifungal therapy and reduce the risk of short-term mortality. CONCLUSIONS: ddPCR, with appropriate panel design, has advantages in pathogen detection and clinical management of ascites infection, especially for patients with fungal and polymicrobial infections. Patients with atypical spontaneous bacterial peritonitis benefited more from ddPCR.

Anxiety and depression status in patients with idiopathic pulmonary fibrosis and outcomes of nintedanib treatment: an observational study.

BACKGROUND: Anxiety and depression are common comorbidities in idiopathic pulmonary fibrosis (IPF) that impair health-related quality of life. However, there is a lack of studies focusing on the mental disorder of IPF after antifibrotic treatment and their related predictive factors. METHODS: Patients with an initial diagnosis of IPF were enrolled. Data on demographics, lung function, Generalized Anxiety Disorder-7 (GAD-7) Scale, Patient Health Questionnaire 9 (PHQ-9), Patient Health Questionnaire-15 (PHQ-15), and St. George's Respiratory Questionnaire total score(SGRQ-T) were collected. Changes in anxiety, depression, somatic symptoms, and quality of life scores before and after nintedanib treatment were compared, and the related predictive factors were analyzed. RESULTS: A total of 56 patients with a first diagnosis of IPF were enrolled, with 42 and 35 patients suffering from anxiety and depression, respectively. The GAD-7, PHQ-9, PHQ-15, and SGRQ scores were higher in the anxiety and depression groups. SGRQ total score (SGRQ-T) [OR = 1.075, 95%CI= (1.011, 1.142)] was an independent predictor of IPF combined with anxiety (p < 0.05); SGRQ-T [OR = 1.080, 95%CI= (1.001, 1.167)] was also an independent predictor of IPF combined with depression (p < 0.05). After treatment, GAD-7, PHQ-9, PHQ-15, and SGRQ scores decreased (p < 0.05). ΔSGRQ-T significantly affected ΔGAD-7 (ß = 0.376, p = 0.009) and ΔPHQ-9 (ß = 0.329, p = 0.022). CONCLUSION: Anxiety and depression in IPF patients are closely related to somatic symptoms, pulmonary function, and quality of life. The SGRQ-T score is of great value for assessing anxiety and depression in patients with IPF. Short-term treatment with nintedanib antifibrotic therapy can alleviate anxiety and depression in IPF patients.

Biolinguistic graph fusion model for circRNA-miRNA association prediction.

Emerging clinical evidence suggests that sophisticated associations with circular ribonucleic acids (RNAs) (circRNAs) and microRNAs (miRNAs) are a critical regulatory factor of various pathological processes and play a critical role in most intricate human diseases. Nonetheless, the above correlations via wet experiments are error-prone and labor-intensive, and the underlying novel circRNA-miRNA association (CMA) has been validated by numerous existing computational methods that rely only on single correlation data. Considering the inadequacy of existing machine learning models, we propose a new model named BGF-CMAP, which combines the gradient boosting decision tree with natural language processing and graph embedding methods to infer associations between circRNAs and miRNAs. Specifically, BGF-CMAP extracts sequence attribute features and interaction behavior features by Word2vec and two homogeneous graph embedding algorithms, large-scale information network embedding and graph factorization, respectively. Multitudinous comprehensive experimental analysis revealed that BGF-CMAP successfully predicted the complex relationship between circRNAs and miRNAs with an accuracy of 82.90% and an area under receiver operating characteristic of 0.9075. Furthermore, 23 of the top 30 miRNA-associated circRNAs of the studies on data were confirmed in relevant experiences, showing that the BGF-CMAP model is superior to others. BGF-CMAP can serve as a helpful model to provide a scientific theoretical basis for the study of CMA prediction.

The individuals' awareness and adoption of electronic health records in China: a questionnaire survey of 1,337 individuals.

BACKGROUND: Electronic health records (EHRs) are digital records of individual health information. However, their adoption and utilization remain low. This study explores the factors influencing the implementation of EHRs through a questionnaire survey to enhance individual awareness and adoption of EHRs. METHODS: A questionnaire and an expert rating scale were developed sequentially, and the consistency of the scores from five experts was calculated using Kendall's W to generate a final questionnaire. A non-parametric test was utilized to analyze differences in continuous data that did not follow a normal distribution. Categorical variables were expressed as percentages (%), the chi-square test was employed for group comparisons, and multiple logistic regression was implemented to assess individuals' awareness and adoption of EHRs. RESULTS: In total, 1,341 survey questionnaires were distributed between January and December 2022, with 1,337 valid responses (99.7%). The results indicated that the proportion of participants who were aware of EHRs and had a bachelor's degree or higher education, an income of ≥$700 per month, residence in urban areas, possessed self-care abilities, and underwent annual physical examinations was significantly higher than that without awareness of EHRs (P < 0.05), while in hearing problems and walking abilities was markedly lower than that of participants without awareness of EHRs (P < 0.05). Additionally, the proportion of individuals willing to self-manage EHRs was significantly higher than those reluctant to do so (P < 0.05) among participants with a bachelor's degree or higher education, an income of ≥$700 per month, residence in urban areas, possession of self-care abilities, annual physical examinations, hearing problems, and poor walking abilities. Age (Odds Ratio [OR] = 1.104, 95% Confidence Interval [CI] 1.001-1.028, P = 0.033), hearing problems (OR = 0.604, 95% CI 0.377-0.967, P = 0.036), self-care ability (OR = 5.881, 95% CI 1.867-18.529, P = 0.002), and annual physical examinations (OR = 3.167, 95% CI 2.31-4.34, P < 0.001) were independently associated with willingness to self-manage EHRs. Annual physical examination (OR = 2.507, 95%CI 1.585-2.669, P < 0.001) also independently made a difference to the awareness of EHRs. CONCLUSIONS: Our findings suggest that annual physical examinations, age, hearing problems, and self-care abilities are significant factors in assessing individuals' awareness and adoption of EHRs. Understanding the characteristics of individuals who are aware of or are willing to take advantage of EHRs plays a positive role in promoting their popularization and application.

Photoredox-catalyzed unsymmetrical diamination of alkenes for access to vicinal diamines.

A photoredox-catalyzed unsymmetrical diamination of alkenes by using N-aminopyridinium salts and nitriles as the amination reagents has been developed. Various vicinal diamines were obtained in moderate to excellent yields under mild reaction conditions. Furthermore, this protocol could be applied in the late-stage modification of pharmaceuticals and natural products. Preliminary mechanistic studies suggested that this methodology may undergo a radical pathway followed by a Ritter-type reaction.

Prognostic value of circulating tumor cells combined with neutrophil-lymphocyte ratio in patients with hepatocellular carcinoma.

BACKGROUND: Circulating tumor cell (CTC) count and neutrophil-to-lymphocyte ratio (NLR) are both closely associated with the prognosis of hepatocellular carcinoma (HCC). AIM: To investigate the prognostic value of combining these two indicators in HCC. METHODS: Clinical data were collected from patients with advanced HCC who received immune therapy combined with targeted therapy at the Department of Oncology, the Affiliated Hospital of Southwest Medical University, Sichuan, China, from 2021 to 2023. The optimal cutoff values for CTC programmed death-ligand 1 (PD-L1) (+) > 1 or CTC PD-L1 (+) ≤ 1 and NLR > 3.89 or NLR ≤ 3.89 were evaluated using X-Tile software. Patients were categorized into three groups based on CTC PD-L1 (+) counts and NLR: CTC-NLR (0), CTC-NLR (1), and CTC-NLR (2). The relationship between CTC-NLR and clinical variables as well as survival rates was assessed. RESULTS: Patients with high CTC PD-L1 (+) expression or NLR at baseline had shorter median progression-free survival (mPFS) and median overall survival (mOS) than those with low levels of CTC PD-L1 (+) or NLR (P < 0.001). Meanwhile, patients in the CTC-NLR (2) group showed a significant decrease in mPFS and mOS. Cox regression analysis revealed that alpha-fetoprotein (AFP), CTC PD-L1 (+), and CTC-NLR were independent predictors of OS. The time-dependent receiver operating characteristic curve showed that the area under the curve of CTC-NLR at 12 months (0.821) and 18 months (0.821) was superior to that of AFP and CTC PD-L1 (+). CONCLUSION: HCC patients with high CTC PD-L1 (+) or NLR expression tend to exhibit poor prognosis, and a high baseline CTC-NLR score may indicate low survival. CTC-NLR may serve as an effective prognostic indicator for patients with advanced HCC receiving immunotherapy combined with targeted therapy.

The ligand binding domain of a type IV pilus chemoreceptor PilJ has a different fold from that of another PilJ-type receptor McpN.

Bacterial chemoreceptors sense the extracellular signals and regulate bacterial motilities, biofilm formation, etc. The periplasmic ligand binding domains of chemoreceptors occur as different structural folds and recognize a diversity of chemical molecules. In Pseudomonas aeruginosa (PAO1), two bacterial chemoreceptors, McpN (PA2788) and PilJ (PA0411), are proposed to both contain a PilJ-like ligand-binding domain (LBD) (Pfam motif PF13675) and involved in nitrate chemotaxis and type IV pilus-mediated motility, respectively. The LBDs of McpN and PilJ consist of 135 and 263 residues, respectively, and share very low sequence identity, suggesting they might occur as different structures. Here, we found that PilJ-LBD folded into an HBM module, the same as the sensor domains of McpS-LBD and TorS-LBD, but it differed from that of McpN-LBD. We also observed a trimer in SEC and AUC and proposed a trimeric model based on the crystal structure. Based on the sequence, we classified the Pfam containing McpN-LBD and PilJ-LBD into three classes: sPilJ (single PilJ) represented by McpN-LBD with only one PilJ domain, dPilJ (dual PilJ) that contained dual PilJ domains, and hPilJ (hybrid PilJ) that comprises of a PilJ domain and another non-PilJ domain. Our work indicates a significant structural difference between the ligand binding domains of PilJ and McpN and will help our further study on both kinds of chemoreceptors.

Likelihood-based feature representation learning combined with neighborhood information for predicting circRNA-miRNA associations.

Connections between circular RNAs (circRNAs) and microRNAs (miRNAs) assume a pivotal position in the onset, evolution, diagnosis and treatment of diseases and tumors. Selecting the most potential circRNA-related miRNAs and taking advantage of them as the biological markers or drug targets could be conducive to dealing with complex human diseases through preventive strategies, diagnostic procedures and therapeutic approaches. Compared to traditional biological experiments, leveraging computational models to integrate diverse biological data in order to infer potential associations proves to be a more efficient and cost-effective approach. This paper developed a model of Convolutional Autoencoder for CircRNA-MiRNA Associations (CA-CMA) prediction. Initially, this model merged the natural language characteristics of the circRNA and miRNA sequence with the features of circRNA-miRNA interactions. Subsequently, it utilized all circRNA-miRNA pairs to construct a molecular association network, which was then fine-tuned by labeled samples to optimize the network parameters. Finally, the prediction outcome is obtained by utilizing the deep neural networks classifier. This model innovatively combines the likelihood objective that preserves the neighborhood through optimization, to learn the continuous feature representation of words and preserve the spatial information of two-dimensional signals. During the process of 5-fold cross-validation, CA-CMA exhibited exceptional performance compared to numerous prior computational approaches, as evidenced by its mean area under the receiver operating characteristic curve of 0.9138 and a minimal SD of 0.0024. Furthermore, recent literature has confirmed the accuracy of 25 out of the top 30 circRNA-miRNA pairs identified with the highest CA-CMA scores during case studies. The results of these experiments highlight the robustness and versatility of our model.

Gastroesophageal Reflux Revealed by 18 F-MFBG PET/CT.

ABSTRACT: A 56-year-old woman who had a lung transplant 4 months ago presented frequent vomiting for 1 month. Barium meal and 99m Tc gastroesophageal scintigraphy showed no gastroesophageal reflux. The patient was enrolled in a clinical trial and underwent 18 F-MFBG PET/CT dynamic imaging. At the seventh minute of dynamic imaging, the images revealed reflux from the cardia into the esophagus and reached the oral cavity.

Comprehensive analysis of anoikis-related genes in diagnosis osteoarthritis: based on machine learning and single-cell RNA sequencing data.

Osteoarthritis (OA) is a degenerative disease closely associated with Anoikis. The objective of this work was to discover novel transcriptome-based anoikis-related biomarkers and pathways for OA progression.The microarray datasets GSE114007 and GSE89408 were downloaded using the Gene Expression Omnibus (GEO) database. A collection of genes linked to anoikis has been collected from the GeneCards database. The intersection genes of the differential anoikis-related genes (DEARGs) were identified using a Venn diagram. Infiltration analyses were used to identify and study the differentially expressed genes (DEGs). Anoikis clustering was used to identify the DEGs. By using gene clustering, two OA subgroups were formed using the DEGs. GSE152805 was used to analyse OA cartilage on a single cell level. 10 DEARGs were identified by lasso analysis, and two Anoikis subtypes were constructed. MEgreen module was found in disease WGCNA analysis, and MEturquoise module was most significant in gene clusters WGCNA. The XGB, SVM, RF, and GLM models identified five hub genes (CDH2, SHCBP1, SCG2, C10orf10, P FKFB3), and the diagnostic model built using these five genes performed well in the training and validation cohorts. analysing single-cell RNA sequencing data from GSE152805, including 25,852 cells of 6 OA cartilage.

KLF4 interacts with TXNIP to modulate the pyroptosis in ulcerative colitis via regulating NLRP3 signaling.

INTRODUCTION: Ulcerative colitis (UC) is one of the most common diseases in the gastrointestinal tract related to abnormal inflammation. Pyroptosis, which is characterized by the formation of inflammasome, activation of caspase-1, and separation of N- and C-terminus of gasdermin D (GSDMD), and may be involved in the pathogenesis of IBD. Krüppel-like factor 4 (KLF4) is a zinc finger transcription factor expressed in differentiated epithelial cells. KLF4 mediates proinflammatory signaling in macrophages. Here, we tested whether KLF4 is functional in pyroptosis of UC. METHODS: In human UC tissues and/or lipopolysaccharide (LPS)/adenosine 5-triphosphate (ATP) stimulation human colon epithelial cells, KLF4, TXNIP, Cleave-Caspase-1, and GSDMD expression were detected through quantitative reverse transcription polymerase chain reaction (PCR), immunohistochemical and western blot assay. Interleukin (IL)-1ß and IL-18 levels were quantified by enzyme-linked immunosorbent assay. We successfully constructed a KLF4-silenced colon epithelial cell line using an adenovirus vector. We apply the UCSC and JASPAR to predict the KLF4 binding sites in the promoter region of TXNIP. RESULTS: In human UC tissues and/or LPS/ATP stimulation human colon epithelial cells, KLF4, TXNIP, Caspase-1, and GSDMD expression level were significantly elevated via quantitative reverse transcription PCR, immunohistochemical and western blot assay. Moreover, We identified that there is an interaction between KLF4 and TXNIP through Yeast double hybrid assay and CO-IP assay. We successfully constructed a KLF4-silenced human intestinal epithelial cell line. In LPS/ATP stimulation KLF4-silenced human intestinal epithelial cells, KLF4, TXNIP, Cleave Caspase-1, ASC, and GSDMD expression level were significantly decreased via quantitative reverse transcription PCR. CONCLUSION: Our results confirm that KLF4 can positively regulate the expression of TXNIP and regulate the pyroptosis process of UC through the TXNIP/NLRP3 pathway.

Effect of 10-year cumulative blood pressure exposure on atherosclerotic cardiovascular disease of different age groups: kailuan cohort study.

Background: The level at which cumulative blood pressure (BP) can increase the risk of ASCVD in different age groups remains unclear. This study aimed to investigate the association of 10-year cumulative BP levels with the long-term risk of ASCVD of different age groups. Methods: Cumulative BP exposure was assessed using the time-weighted average (TWA) BP divided into four BP groups. The participants were also divided into four groups according to their baseline age (<50, 50-59, 60-69, or ≥70 years). The association between TWA BP and the risk of ASCVD was assessed by age group using multivariate Cox models. The China-PAR prediction model was used to assess the ability of TWA BP to predict ASCVD. Results: In the group aged <50 years, the hazard ratios and 95% confidence intervals for the risk of ASCVD were 2.66 (1.04-6.80), 3.38 (1.54-7.43), and 3.13 (1.36-7.24) for the elevated BP, stage 1 hypertension, and stage 2 hypertension groups, respectively, when compared with the normal BP group. There was a significant difference in the risk of ASCVD between the age groups, with participants aged <50 years having the highest risk, followed by those aged 50-59, 60-69, and ≥70 years. Conclusions: The risk of ASCVD with high cumulative BP exposure was age-dependent, with a gradual decrease in risk with increasing age.

EPO regulates the differentiation and homing of bone marrow mesenchymal stem cells through Notch1/Jagged pathway to treat pulmonary hypertension.

Purpose: To investigate whether erythropoietin (EPO) can treat pulmonary arterial hypertension (PAH) in rats by regulating the differentiation and homing of bone marrow mesenchymal stem cells (BMSCs) through Notch1/Jagged signaling pathway. Materials & methods: BMSCs were isolated from the bone marrow of 6-week-old male SD rats by whole bone marrow method and identified. BMSCs were treated with 500 IU/mL EPO, and the proliferation, migration, invasion and differentiation ability, and the expression of MMP-2 and MMP-9 protein of BMSCs were detected in vitro. After the establishment of the pulmonary hypertension model in rats, BMSCs were intervened with different concentrations of EPO and injected into the rats through intravenous injection. The levels of TNF-α, IL-1ß and IL-6 in lung tissue, the expression of SRY CXCR4, CCR2, Notch1 and Jagged protein in lung tissue, and the levels of TGF-α, vascular endothelial factor (VEGF), IGF-1 and HGF in serum were detected. Immunofluorescence (IF) staining was used to detect the co-localization of CD34. Results: EPO promoted the proliferation, migration, and invasion of BMSCs by inhibiting Notch1/Jagged pathway in vitro, and induced BMSCs to differentiate into vascular smooth muscle cells and vascular endothelial cells. EPO inhibited Notch1/Jagged pathway in PAH rats, induced BMSCs homing and differentiation, increased the levels of TGF-α, VEGF, IGF-1 and HGF, and decreased the levels of TNF-α, IL-1ß and IL-6. Discussion & conclusion: EPO can inhibit the Notch1/Jagged pathway and promote the proliferation, migration, invasion, homing and differentiation of BMSCs to treat pulmonary hypertension in rats in vitro and in vivo.

Body mass index and weight loss as risk factors for poor outcomes in patients with idiopathic pulmonary fibrosis: a systematic review and meta-analysis.

OBJECTIVE: The association between nutritional status and prognosis of idiopathic pulmonary fibrosis (IPF) remains unclear. This systematic review and meta-analysis aimed to explore the effect of body mass index (BMI) and weight loss on the prognosis of IPF patients. METHODS: We accumulated studies on IPF, BMI, and weight loss from databases including PubMed, Embase, Web of science, Scopus, Ovid and Cochrane Library up to 4 August 2023. Using Cox proportional hazard regression model for subgroup analysis, hazard ratio (HR) and 95% confidence intervals (CI) for BMI in relation to mortality, acute exacerbation (AE), and hospitalization in IPF patients were calculated, and HR, odds ratio (OR), and 95% CI for weight loss corresponding to IPF patient mortality were assessed. Sensitivity analysis was peformed by eliminating every study one by one, and publication bias was judged by Egger's test and trim-and-fill method. RESULTS: A total of 34 eligible studies involving 18,343 IPF patients were included in the meta-analysis. The pooled results by univariate Cox regression analysis showed that baseline BMI was a predictive factor for IPF mortality (HR = 0.93, 95%CI = [0.91, 0.94]). Furthermore, the results by the multivariable regression model indicated that baseline BMI was an independent risk factor for predicting IPF mortality (HR = 0.94, 95%CI = [0.91, 0.98]). Weight loss was identified as a risk factor for IPF mortality (HR = 2.74, 95% CI = [2.12, 3.54]; OR = 4.51, 95% CI = [1.72, 11.82]) and there was no predictive value of BMI for acute exacerbation (HR = 1.00, 95% CI= [0.93, 1.07]) or hospitalization (HR = 0.95, 95% CI = [0.89, 1.02]). CONCLUSION: Low baseline BMI and weight loss in the course of IPF may indicate a high risk of mortality in patients with IPF, so it is meaningful to monitor and manage the nutritional status of IPF patients, and early intervention should be conducted for low BMI and weight loss.

A combination of PD-L1-targeted IL-15 mRNA nanotherapy and ultrasound-targeted microbubble destruction for tumor immunotherapy.

PD-1/PD-L1-based immune checkpoint blockade therapy has shown limited benefits in tumor patients, partially attributed to the inadequate infiltration of immune effector cells within tumors. Here, we established a nanoplatform named DPPA/IL-15 NPs to target PD-L1 for the tumor delivery of IL-15 messenger RNA (mRNA). DPPA/IL-15 NPs were endowed with ultrasound responsiveness and contrast-enhanced ultrasound (CEUS) imaging performance. They effectively protected IL-15 mRNA from degradation and specifically transfected it into tumor cells through the utilization of ultrasound-targeted microbubble destruction (UTMD). This resulted in the activation of IL-15-related immune effector cells while blocking the PD-1/PD-L1 pathway. In addition, UTMD could generate reactive oxygen species (ROS) that induce endoplasmic reticulum (ER) stress-driven immunogenic cell death (ICD), initiating anti-tumor immunity. In vitro and in vivo studies revealed that this combination therapy could induce a robust systemic immune response and enhance anti-tumor efficacy. Thus, this combination therapy has the potential for clinical translation through enhanced immunotherapy and provides real-time ultrasound imaging guidance.