Interferon regulatory factor 4 (IRF4) is a critical transcription factor that governs the differentiation of cluster of differentiation 4⁺ (CD4⁺) T cells. The pathogenesis and progression of psoriasis are primarily attributed to an immune imbalance stemming from the overproduction of interleukin-17A (IL-17A) by T lymphocytes. However, the role of IRF4 in psoriasis remains unexplored. In this study, we found that IRF4 activity is increased in the cutaneous lesions of patients with psoriasis in response to stimulation by IL-23A and IL-1β. This IRF4 elevation heightens its binding to the E1A binding protein p300 (EP300) promoter, triggering the transcription of downstream retinoic acid receptor-related orphan receptor-γt (RORγt) and increasing the secretion of IL-17A, thereby establishing the IL-1β/IL-23A-IRF4-EP300-RORC-IL-17A inflammatory cascade in psoriasis. The alleviation of imiquimod (IMQ)-induced psoriatic-like symptoms was achieved through the creation of a Irf4 ^-/- gene deletion mouse model and pharmacological inhibition using antisense oligonucleotides targeted for Irf4. This amelioration was accompanied by a decreased number of IL-17A-producing CD4⁺ T cells in the skin. The findings of this study suggest that IRF4 plays a crucial role in the promotion of inflammation and exacerbation of IMQ-induced psoriasiform dermatitis. Consequently, IRF4 targeting could be a promising therapeutic strategy.

In order to solve the problem of resistance of Pseudomonas aeruginosa to multiple antibiotics, it is an effective way to find inhibitors of P. aeruginosa efflux pump. In this study, 15 new ornithine peptidomimetic derivatives were designed and synthesized by changing the side chain structure of natural amino acids with PAβN, a dipeptide efflux pump inhibitor, and their synergic activity with aztreonam, a monocyclic β-lactam antibiotic, against P. aeruginosa was evaluated. Among them, the representative compound 12b not only enhanced the antibacterial activity of β-lactam antibiotics aztreonam, ceftazidime and meropenem, but also significantly enhanced the antibacterial action of macrolide antibiotics clarithromycin, showing a broad-spectrum synergic sensitization effect. In addition, compound 12b also has a good safety. Preliminary mechanisms suggest that 12b works by directly targeting the efflux transporter MexB. These results provide a new lead compound for the development of a new class of efflux pump inhibitors against P. aeruginosa.

Objectives The combined use of bedaquiline and delamanid(BDQ-DLM)is limited by an increased risk of prolonging the QTc interval.We retrospectively evaluated patients who received DLM/BDQ-containing regimens at a TB-specialized hospital.We aimed to present clinical efficacy and safety data for Chinese patients. Methods This case-control study included patients with multidrug-resistant tuberculosis(MDR-TB)treated with BDQ alone or BDQ plus DLM. Results A total of 96 patients were included in this analysis:64 in the BDQ group and 32 in the BDQ+DLM group.Among the 96 patients with positive sputum culture at the initiation of BDQ alone or BDQ combined with DLM,46 patients(71.9%)in the BDQ group and 29(90.6%)in the BDQ-DLM group achieved sputum culture conversion during treatment.The rate of sputum culture conversion did not differ between the two groups.The time to sputum culture conversion was significantly shorter in the BDQ-DLM group than in the BDQ group.The most frequent adverse event was QTc interval prolongation;however,the frequency of adverse events did not differ between the groups. Conclusion In conclusion,our results demonstrate that the combined use of BDQ and DLM is efficacious and tolerable in Chinese patients infected with MDR-TB.Patients in the BDQ-DLM group achieved sputum culture conversion sooner than those in the BDQ group.

Objective To evaluate the perioperative safety and feasibility of day-case transurethral holmium laser enucleation of prostate(HoLEP)under over-night mode.Method From January 2021 to March 2023,83 patients of benign prostatic hyperplasia(BPH)were elected and treated with HoLEP by the one surgeon.According to different management methods,these patients were divided into the over-night day-case HoLEP group and the ordinary HoLEP group.Again,these patients were divided into large volume(≥50 mL)group and small volume(<50 mL)group according to the prostate volume.Record the age and perioperative data of all patients[total prostate volume,prostate resection weight,proportion of prostate resection,operating time,changes in peripheral venous blood hemoglobin(Hb),bladder flushing duration,catheter insertion duration,and success rate of first tube removal],the parameters of each group were compared.Result All of the 83 patients undergoing HoLEP surgery in this study,and there were no cases of HoLEP related reoperation or readmission.Among them,there were 43 cases in the over-night HoLEP group,aged 57～90 with an average of(70.1±7.3)years old,and the prostate volume was 29～161 mL with an average of(63.0±28.8)mL,All of them were discharged within 24 h,and there were no cases transferred to the ordinary HoLEP group,the success rate of first tube removal was 88.4%(38/43),and with average catheterization duration was(17.8±3.6)h;The other 40 cases were included into the ordinary HoLEP group,aged 55～87 with an average of(70.4±8.2)years old,the volume of the prostate was 22～118 mL with an average of(59.4±29.0)mL,the success rate of first tube removal was 90.0%(36/40),and with average catheterization duration was(77.5±25.1)h;There was no statistically significant difference in the perioperative parameters(total prostate volume,prostate resection weight,proportion of prostate resection,operating time,changes in peripheral venous blood Hb,and bladder flushing time)between the two groups(P>0.05),while the difference in catheter duration was statistically significant(P<0.01).Conclusion Regardless of the size of the prostate volume,day-case HoLEP is safe and feasible.Day-case HoLEP under the over-night mode is suitable for widespread and routine implementation in China,especially in medical centers with rich experience of HoLEP.

To explore the predictive efficacy of fragmented red blood cells (FRC) and fragmented red blood cells percentage(FRC%) with regarding for the prognosis of septic patients, along with comparing with routine coagulation parameters. A prospective study was conducted. A total of 101 patients with sepsis who met the requirements admitted to the Intensive Care Department of the Third Xiangya Hospital of Central South University from June 1, 2022 to January 10, 2023 were selected as the research objects, they were divided into survival group and death group according to the 30-day prognosis. The clinical data and laboratory indexes such as FRCs, FRC% and Platelet (PLT) were compared between the survival group and the death group. Univariate logistic regression analysis was used first, then multivariate logistic regression analysis was used to analyze the factors affecting the prognosis. Receiver operator characteristic curve (ROC curve) was drawn to evaluate the predictive value of each parameter in the regression model for the prognosis of sepsis. The results showed that the levels of FRCs, FRC%, prothrombin time (PT), activated partial thromboplastin time (APTT) and D-dimer in death group were significantly higher than those in survival group, and PLT in death group were significantly lower than those in survival group (Z or t values were -3.712,-3.793,-2.119,-2.007,-2.209,all P<0.05). FRCs or FRC% and PLT could be independent predictors of 30-day mortality. The area under the ROC curve (AUC) of PLT for predicting 30-day death in sepsis patients was 0.727 (95%CI 0.629-0.811, P<0.01), when the optimal threshold was 137 ×10⁹/L, the sensitivity was 83.87% and the specificity was 57.14%. The AUC of FRCs for predicting 30-day death in sepsis patients was was 0.732 (95%CI 0.635-0.815, P<0.01), when the optimal threshold was 10.1×10⁹/L, the sensitivity was 77.42%, and the specificity was 67.14%. The AUC of FRC% for predicting 30-day death in sepsis patients was 0.737 (95%CI 0.640-0.820, P<0.01), When the optimal threshold was 0.34%, the sensitivity was 77.42%, and the specificity was 65.71%. In conclusion,PLT, FRCs and FRC% have great application value in the prognosis of sepsis. When the PLT, FRCs and FRC% of sepsis patients are more than 137 ×10⁹/L, 10.1×10⁹/L and 0.34% respectively, it is necessary to take necessary and reasonable clinical intervention measures as soon as possible.

To explore the predictive efficacy of fragmented red blood cells (FRC) and fragmented red blood cells percentage(FRC%) with regarding for the prognosis of septic patients, along with comparing with routine coagulation parameters. A prospective study was conducted. A total of 101 patients with sepsis who met the requirements admitted to the Intensive Care Department of the Third Xiangya Hospital of Central South University from June 1, 2022 to January 10, 2023 were selected as the research objects, they were divided into survival group and death group according to the 30-day prognosis. The clinical data and laboratory indexes such as FRCs, FRC% and Platelet (PLT) were compared between the survival group and the death group. Univariate logistic regression analysis was used first, then multivariate logistic regression analysis was used to analyze the factors affecting the prognosis. Receiver operator characteristic curve (ROC curve) was drawn to evaluate the predictive value of each parameter in the regression model for the prognosis of sepsis. The results showed that the levels of FRCs, FRC%, prothrombin time (PT), activated partial thromboplastin time (APTT) and D-dimer in death group were significantly higher than those in survival group, and PLT in death group were significantly lower than those in survival group (Z or t values were -3.712,-3.793,-2.119,-2.007,-2.209,all P<0.05). FRCs or FRC% and PLT could be independent predictors of 30-day mortality. The area under the ROC curve (AUC) of PLT for predicting 30-day death in sepsis patients was 0.727 (95%CI 0.629-0.811, P<0.01), when the optimal threshold was 137 ×10⁹/L, the sensitivity was 83.87% and the specificity was 57.14%. The AUC of FRCs for predicting 30-day death in sepsis patients was was 0.732 (95%CI 0.635-0.815, P<0.01), when the optimal threshold was 10.1×10⁹/L, the sensitivity was 77.42%, and the specificity was 67.14%. The AUC of FRC% for predicting 30-day death in sepsis patients was 0.737 (95%CI 0.640-0.820, P<0.01), When the optimal threshold was 0.34%, the sensitivity was 77.42%, and the specificity was 65.71%. In conclusion,PLT, FRCs and FRC% have great application value in the prognosis of sepsis. When the PLT, FRCs and FRC% of sepsis patients are more than 137 ×10⁹/L, 10.1×10⁹/L and 0.34% respectively, it is necessary to take necessary and reasonable clinical intervention measures as soon as possible.

Zona Incerta ; Prefrontal Cortex ; Fear ; Neural Pathways

BACKGROUND: Type 2 diabetes mellitus (T2DM) is an independent risk factor for colorectal cancer (CRC), and the patients with CRC and T2DM have worse survival. The human gut microbiota (GM) is linked to the development of CRC and T2DM, respectively. However, the GM characteristics in patients with CRC and T2DM remain unclear. METHODS: We performed fecal metagenomic and targeted metabolomics studies on 36 samples from CRC patients with T2DM (DCRC group, n = 12), CRC patients without diabetes (CRC group, n = 12), and healthy controls (Health group, n = 12). We analyzed the fecal microbiomes, characterized the composition and function based on the metagenomics of DCRC patients, and detected the short-chain fatty acids (SCFAs) and bile acids (BAs) levels in all fecal samples. Finally, we performed a correlation analysis of the differential bacteria and metabolites between different groups. RESULTS: Compared with the CRC group, LefSe analysis showed that there is a specific GM community in DCRC group, including an increased abundance of Eggerthella , Hungatella , Peptostreptococcus , and Parvimonas , and decreased Butyricicoccus , Lactobacillus , and Paraprevotella . The metabolomics analysis results revealed that the butyric acid level was lower but the deoxycholic acid and 12-keto-lithocholic acid levels were higher in the DCRC group than other groups ( P < 0.05). The correlation analysis showed that the dominant bacterial abundance in the DCRC group ( Parvimonas , Desulfurispora , Sebaldella , and Veillonellales , among others) was negatively correlated with butyric acid, hyodeoxycholic acid, ursodeoxycholic acid, glycochenodeoxycholic acid, chenodeoxycholic acid, cholic acid and glycocholate. However, the abundance of mostly inferior bacteria was positively correlated with these metabolic acid levels, including Faecalibacterium , Thermococci , and Cellulophaga . CONCLUSIONS Unique fecal microbiome signatures exist in CRC patients with T2DM compared to those with non-diabetic CRC. Alterations in GM composition and SCFAs and secondary BAs levels may promote CRC development.
Humans ; Gastrointestinal Microbiome/genetics* ; Diabetes Mellitus, Type 2 ; Microbiota ; Bacteria/genetics* ; Fatty Acids, Volatile ; Colorectal Neoplasms/metabolism* ; Butyrates ; Feces/microbiology*

Objective:To explore the characteristics of intestinal microbiota in patients with systemic lupus erythematosus (SLE), and further explore the relationship between microbiota and CD4 +T lymphocyte subsets and disease activity. Methods:Fecal samples were collected from 96 patients with SLE, and 96 sex- and age-matched healthy controls (HCs). The gut microbiota were investigated via 16s rRNA sequencing. Flow cytometry was used to detect peripheral CD4 +T lymphocyte subsets of Th1, Th2, Th17 and Treg cells. Indicators of disease activity such as erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), complement C3 and C4, Systemic lupus erythematosus disease activity index(SLEDAI) for each patient were recorded. Differential abundance analysis was carried out using the edgeR algorithm. The Wilcoxon rank-sum test was used to compare alpha diversity indices, bacterial abundances, and the F/B ratio between groups. R (version 4.0.1) was used for comparative statistics, and Pearson′s correlation analysis was used to assess the correlations between the relative abundances of bacterial genera and serum levels of ESR, CRP, C3 and C4 in the samples. Results:The alpha estimators of richness (ACE and Chao 1) were significantly reduced in SLE feces samples compared with those of HCs ( P<0.01). Bacterial diversity estimators, including the Shannon ( P<0.01) and Simpson′s ( P<0.01) indices, were also significantly lower in SLE. Significant differences in gut microbiota composition between SLE and HCs were found using the edgeR algorithm. Compared with HC, 24 species of bacteria were significantly different in SLE patients at the genus level ( P<0.05). Moreover, there was a significant positive correlation between CRP and Coprococcus ( r=0.30, P=0.014), C4 and Corynebacterium ( r=0.31, P=0.013) and Faecalibacterium( r=0.25, P=0.048), Hemoglobin and Morganella( r=0.41, P=0.001), as well as SLIDA and Corynebacterium( r=0.25, P=0.047). In terms of lymphocyte subsets, there was significant positive correlation between B cells, Treg cells and Eubacterium eligens group, as well as CD8 +T, CD4 +T, NK cells and Corynebacterium. In additional, Th1 was positively correlated with Shigella Escherichia coli ( r=0.52, P=0.008), and Th2 was positively correlated with Dielma ( r=0.51, P<0.001). Conclusion:The abundance and diversity of intestinal flora in SLE patients were significantly reduced, and the differentially expressed bacteria were closely related to the CD4 +T lymphocyte subsets and disease activity indicators of patients.

Chronic kidney disease (CKD) is an important global public health problem that greatly threatens population health. Application of risk prediction model is a crucial way for the primary prevention of CKD, which can stratify the risk for developing CKD and identify high-risk individuals for more intensive interventions. By now, more than twenty risk prediction models for CKD have been developed worldwide. There are also four domestic risk prediction models developed for Chinese population. However, none of these models have been recommended in clinical guidelines yet. The existing risk prediction models have some limitations in terms of outcome definition, predictors, strategies for handling missing data, and model derivation. In the future, the applications of emerging biomarkers and polygenic risk scores as well as advances in machine learning methods will provide more possibilities for the further improvement of the model.
Humans ; Renal Insufficiency, Chronic ; Risk Factors ; Biomarkers