BACKGROUND:Optimizing efavirenz (EFV) dosing to minimize adverse events (AEs) remains a critical issue. Studies indicate that reducing the EFV dose from 600 to 400 mg daily lowers side effect intensity while maintaining virological suppression. We previously showed that 600 mg daily EFV may lead to unnecessarily high exposure in Chinese patients, but the long-term efficacy and safety of dose reduction beyond 48 weeks in this population remain unknown. METHODS:We conducted a multicenter, randomized controlled trial comparing EFV 400 vs 600 mg, each combined with lamivudine (3TC) and tenofovir (TDF), in antiretroviral therapy-naïve Chinese adults with human immunodeficiency virus (HIV)-1. The primary endpoint was virological suppression (HIV-ribonucleic acid [RNA] <50 copies/ml) at week 72. A total of 422 participants were randomized (215 in the 400 mg group, 207 in the 600 mg group); 334 (169 and 165, respectively) completed the week 72 primary endpoint assessment, while an optional extension to week 96 was conducted for exploratory analyses. RESULTS:At baseline, demographic and clinical characteristics were comparable between groups. At week 72, virological suppression (HIV-RNA <50 copies/ml) was achieved in 86.5% (186/215) of the EFV 400 mg group and 84.1% (174/207) of the EFV 600 mg group (difference +2.5 percentage points, 95% confidence interval -4.3 to 9.2, P = 0.57), meeting the noninferiority criteria. While overall AE profiles were comparable, the EFV 600 mg group exhibited a significantly higher incidence of serious nonrash AEs (P = 0.042), and a numerically higher but nonsignificant rate of drug discontinuation due to AEs (4.8% vs 1.9%, P = 0.094). CONCLUSION:EFV 400 mg is noninferior to EFV 600 mg in treatment-naïve Chinese patients over 72 weeks, offering improved safety and tolerability. TRIAL REGISTRATION:#NCT04463784 on ClinicalTrials.gov, Registered by Peking Union Medical College Hospital on April 1, 2018 (URL: https://clinicaltrials.gov/study/NCT04463784).
BACKGROUND:The prompt and precise diagnosis of active pulmonary tuberculosis (TB) is crucial for controlling this disease and yet it remains a global challenge. The objective of this study was to identify a set of microRNAs (miRNAs) whose expression in plasma could be used as a triage test for diagnosing TB. METHODS:A total of 879 plasma samples were collected in seven clinical centres from healthy individuals and patients displaying TB-like symptoms and/or radiological features consistent with TB. The samples were classified as TB, pneumonia, lung cancer and HC subgroups based on subsequent diagnostic assessments.We performed quantitative profiling of 264 plasma miRNAs in a training cohort (n=410) and an independent external test cohort (n=469). After dimensionality reduction and feature selection analysis, we identified nine discriminative miRNAs and used them to train an ensemble model in a training cohort using the scikit-learn library, which was subsequently evaluated in the external test cohort. RESULTS:The ensemble model showed notable accuracy in discriminating TB from non-TB patients, yielding areas under the curve (AUC) of 0.84 (95% CI 0.80 to 0.88) for the training cohort and 0.86 (95% CI 0.82 to 0.90) for the external test cohort. When tested against subgroups of laboratory confirmed and clinically diagnosed but unconfirmed TB, the AUC values were 0.89 (95% CI 0.85 to 0.93) and 0.83 (95% CI 0.79 to 0.88), respectively. In smear-negative confirmed TB patients, the AUC exceeded 0.83, with a sensitivity and specificity of 0.75. CONCLUSIONS:Our miRNA ensemble model, based on detecting a nine-miRNA expression biosignature in plasma, demonstrated promising ability to diagnose TB and distinguish it from other common lung diseases but further studies are needed to assess its clinical applicability. TRIAL REGISTRATION NUMBER:ChiCTR2000039734.
Background Lactic acid accumulates in periodontal tissues during periodontitis, suggesting disrupted metabolism may contribute to disease progression. However, the role of lactic acid and its modifications, such as lactylation, remains unclear. Methods Gingival tissues were collected from healthy controls and periodontitis patients. Protein lactylation levels were evaluated through immunohistochemistry and molecular detection. A mouse periodontitis model was established with local lactate intervention, and bone resorption was quantified using micro-computed tomography (micro-CT). Periodontitis transcriptomic and single-cell sequencing data from the Gene Expression Omnibus (GEO) database were integrated to screen differentially expressed lactylation-related genes (DE-LRGs). The Least Absolute Shrinkage and Selection Operator (LASSO), random forest, and support vector machine (SVM) algorithms were applied to identify core genes. Cell-type Identification By Estimating Relative Subsets Of RNA Transcripts (CIBERSORT) was employed to analyze their association with immune infiltration. A CALR knockdown mouse model was constructed to validate gene function. Results Protein lactylation levels were significantly elevated in gingival tissues of periodontitis patients and positively correlated with inflammation severity. In mouse models, lactate intervention alleviated gingival inflammation and bone resorption. Through multi-omics analysis, CALR was identified as a core regulatory factor among key lactylation-related genes. CALR knockdown mice exhibited decreased lactate levels, aggravated inflammation, and significantly increased bone resorption, confirming its role in regulating the periodontal immune microenvironment through lactate metabolism. Conclusions Lactylation modification participates in immune regulation during periodontitis. The screened core LRGs, especially CALR , represent potential therapeutic targets.
BACKGROUND:Given high symptom recurrence rates after discontinuation of antifungal therapy (AF), a comparison was made between AF alone and in combination with bronchoscopic aspergilloma removal (BRA) for treating post-tuberculosis chronic cavitary pulmonary aspergillosis (PTB-CCPA) patients, focusing on fungal ball clearance rate, relapse rate, and relapse risk factors. METHODS:This retrospective cohort study was conducted at Guangzhou Chest Hospital, China, from January 2014 to December 2021, with follow-up through October 2023. Patients with PTB-CCPA who met diagnostic criteria (cavitary tuberculosis history, CT-confirmed fungal balls, and microbiological/serological Aspergillus evidence) were included. RESULTS:The enrolled patients were divided into two groups: the control group (32 patients, 36.4%) received only AF, and the treatment group (56 patients, 63.6%) received a combination of AF and BRA (AF+BRA). The aspergilloma clearance rate in the cavity was 14.8% in the AF group and 100% in the AF+BRA group (p < 0.001). For patients who received AF less than 8 months, Kaplan-Meier survival curve analysis showed that the AF+BRA group had a significantly higher cumulative recurrence-free survival rate (p < 0.05). Notably, AF+BRA shortened the duration of oral AF compared with the AF treatment. Further analysis identified age ≥60 years (HR = 0.12, 95% CI 0.03-0.57, p = 0.007) and the disappearance or reduction in size of the aspergillomas (HR = 0.07, 95% CI 0.01-0.58, p = 0.014) as protective factors against recurrence, while more than one pulmonary cavity increased recurrence risk (HR = 7.4, 95% CI 1.67-32.69, p = 0.008). CONCLUSIONS:AF+BRA can eliminate Aspergillus fungal balls, may cure PTB-CCPA, shorten antifungal treatment duration, and reduce recurrence and mortality, suggesting that it is a superior treatment approach.
