COVID-19 continues to present ongoing global health challenges driven by diverse immune responses and heterogeneous clinical outcomes. The ACCORD trial evaluated 3 investigational treatments-bemcentinib, tozorakimab, and zilucoplan-in patients hospitalized with COVID-19, each of which has demonstrated clinical efficacy. To better understand their molecular mechanisms, we conducted a mechanistic follow-up study, integrating transcriptomic and clinical data from 65 patients and applying cellular deconvolution, differential expression, coexpression, and pathway enrichment analyses to uncover treatment-specific immune responses. Each therapy induced transcriptional shifts and modulated distinct immune pathways implicated in severe disease. Bemcentinib primarily modulated myeloid cell populations and inflammatory signalling; zilucoplan enhanced B-cell signalling and lymphocyte-associated pathways; and tozorakimab exerted broad immune and cellular responses across immune cell types. Co-expression analysis revealed gene networks associated with clinical improvement, each driven by distinct treatment-specific hub genes, indicating diverse regulatory mechanisms across treatments. Improved outcomes correlated with gene expression shifts in 4 key immunological pathways: B-cell signalling, antiviral defense, innate inflammation, and platelet/coagulation activity. In contrast, nonresponders had persistent dysregulation of 1 or more of these gene signatures. Our findings define molecular signatures of treatment response and failure in COVID-19, providing mechanistic insight into how distinct therapies modulate the immune system. These insights support the need for adaptive precision medicine approaches tailored to individual, evolving immune trajectories. Moreover, the immunological mechanisms targeted by these repurposed immunomodulatory therapies may inform treatment strategies across a broader spectrum of immune-mediated diseases beyond COVID-19.

Mild pulmonary arterial hypertension (PAH) represents an early and potentially reversible complication stage in children with congenital structural heart disease (CHD). Early identification of high-risk children is crucial for improving prognosis. This study aimed to develop and validate a nomogram model for predicting the risk of mild PAH in children with left-to-right shunt CHD. This single-center retrospective study enrolled 340 children diagnosed with CHD who underwent cardiac catheterization at the Department of Pediatrics, The First Affiliated Hospital of Guangxi Medical University, between January 2005 and April 2022. Patients were divided into a training set (n = 237) and an internal validation set (n = 103) at a 7:3 ratio using stratified random sampling. In the training set, predictors were selected from 35 candidate variables using least absolute shrinkage and selection operator regression combined with 10-fold cross-validation, and the final prediction model was constructed using multivariate logistic regression. Model performance was comprehensively evaluated through Bootstrap internal validation (1000 resampling iterations) and on the independent validation set, including discrimination (area under the curve [AUC]), calibration (calibration curve), and clinical utility (decision curve analysis). The model ultimately identified 5 independent predictive factors: loud P2, decreased exercise tolerance, defect size, left ventricular systolic diameter Z SCORE, and age. The nomogram constructed based on these factors achieved a Bootstrap-corrected AUC of 0.871 (95% confidence interval = 0.824-0.919) in the training set and an AUC of 0.861 (95% confidence interval = 0.769-0.938) in the independent validation set. The calibration curve indicated high consistency between predicted probabilities and actual observed values. Decision curve analysis demonstrated that the model provided clinical net benefit across a wide range of threshold probabilities. This study successfully developed and validated a well-performing nomogram model for predicting the risk of mild PAH in children with left-to-right shunt CHD. This model integrates easily accessible clinical, imaging, and demographic indicators, facilitating the early identification of high-risk children and providing a practical tool for personalized intervention and clinical decision-making.

While lead exposure is hypothesized to promote Th2-type allergic responses, large-scale epidemiological data on its link to adult allergic rhinitis (AR) are scarce. This study aimed to explore the association between serum lead levels and AR risk and immunoglobulin E (IgE) levels in the general adult population of the United States. Using data from the 2005-2006 National Health and Nutrition Examination Survey, a cross-sectional study included 2876 participants aged ≥ 20 years, 682 AR patients and 2194 controls. AR was defined as having a positive serum-specific IgE (≥0.35 kU/L) and reporting pollen-related or non-cold-related nasal symptoms in the past 12 months. Serum lead levels was measured using inductively coupled plasma mass spectrometry, and the natural logarithm of serum lead levels (Ln Pb) was adopted. Multivariable logistic regression, linear regression, and Cox regression models were employed to assess the associations after stepwise adjustment for demographic characteristics, lifestyle factors, and laboratory indicators, along with subgroup analyses and restricted cubic spline (RCS) tests for dose-response relationships. Blood lead levels were significantly negatively associated with the risk of AR. Quartile analysis indicated that the highest exposure group (Q4) had a 53% lower risk of AR compared to the lowest group (Q1) (adjusted odds ratio [aOR] = 0.467, 95% confidence interval [CI]: 0.269 to 0.811, P for trend = .014). RCS analysis suggested a linear trend in this association (P-non-linear = .954). Additionally, Ln Pb was positively associated with serum total IgE levels (β = 1.179, 95% CI: 1.005 to 1.383, P = .045), indicating that lead exposure may promote Th2-type immune responses. Higher blood lead levels were also significantly associated with an increased risk of all-cause mortality (HR = 2.535, 95% CI: 1.509 to 4.261, P < .001). Subgroup analyses showed that the negative association between lead and AR was consistent across most populations, but was most pronounced in nondrinkers (HR = 0.53, P = .003), with borderline interaction effects related to smoking status (P for interaction = 0.039). The dissociation between reduced AR risk and elevated IgE levels suggests a complex immunomodulatory effect of lead. Furthermore, lead exposure was confirmed as a significant risk factor for all-cause mortality, underscoring its broader systemic toxicity.

Tracheostomy insertion is common in patients requiring prolonged mechanical ventilation (MV), with cuff deflation and voice restoration a critical step in the weaning process. However, the optimal timing for cuff deflation and its impact on clinical outcomes remain unclear. This study aims to examine local tracheostomy cuff deflation practices and assess associations with outcomes in patients requiring prolonged MV.

A retrospective study was conducted at a large UK ICU between November 2021 and October 2023, which included patients without significant neurological injury requiring tracheostomy insertion for prolonged MV (defined as WIND 3). Data were extracted from electronic health records for patient demographics and outcomes including weaning milestones; physical, cognitive, and psychological outcomes; ICU and hospital length of stay (LOS); ventilator-acquired pneumonia (VAP); and mortality. These were compared across subgroups defined based on the time from tracheostomy to cuff deflation, namely 0-5, 6-10, and >10 days; patients who died prior to achieving this were included in the latter subgroup.

The 157 included patients comprised those with tracheostomy to cuff deflation of 0-5 days (N = 58), 6-10 days (N = 54) and >10 days/death (N = 45). Patient characteristics at ICU admission were not found to differ significantly between these groups. Delayed cuff deflation was associated with prolonged MV (p < 0.001); delayed weaning milestones, including decannulation (p < 0.001); higher rates of VAP (p = 0.010); increased ICU LOS (p < 0.001) and mortality (p < 0.001); and greater levels of anxiety (p = 0.040) and psychological distress (p = 0.046) at ICU discharge.

Delayed tracheostomy cuff deflation maybe associated with inferior clinical and patient outcomes. Further research examining the relationship between cuff deflation timing and clinical outcomes is warranted.

Tuberculous pleurisy is the most common form of extrapulmonary tuberculosis. Diagnosis remains challenging due to the paucibacillary nature of pleural effusions, leading to low sensitivity of conventional microbiological methods and frequent reliance on invasive biopsy. Cell-free DNA (cfDNA), comprising fragmented genetic material released from host cells and pathogens into biofluids, presents a promising minimally-invasive biomarker. This protocol outlines a systematic review and meta-analysis designed to evaluate the overall diagnostic accuracy of cfDNA for tuberculous pleurisy and to identify factors influencing its performance.

This protocol is prospectively registered with PROSPERO. We will systematically search PubMed, Embase, Web of Science, Scopus, The Cochrane Library from inception to June 2027. Diagnostic accuracy studies directly comparing cfDNA detection (in pleural fluid, plasma/serum) against a composite reference standard for tuberculous pleurisy (including microbiological, histological, or clinical diagnosis) will be included. Two reviewers will independently screen studies, extract data, and assess risk of bias using the QUADAS-2 tool. A bivariate random-effects meta-analysis will be performed to calculate pooled sensitivity, specificity, positive/negative likelihood ratios, and diagnostic odds ratios. A hierarchical summary receiver operating characteristic curve will be plotted. Subgroup analyses and meta-regression will explore sources of heterogeneity. The GRADE approach will be used to evaluate the certainty of evidence.

This review will provide pooled estimates of the diagnostic sensitivity and specificity of cfDNA for tuberculous pleurisy, evaluate its clinical utility, and identify key factors-such as sample type, detection technology, and pre-analytical procedures-associated with optimal performance. The findings will offer high-level evidence to guide clinical application and future research. Systematic review registration: PROSPERO Registration number: CRD420261424501.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease characterized by persistent alveolar epithelial injury and aberrant tissue remodeling. Increasing evidence suggests that senescence of alveolar epithelial cells (AECs) contributes to impaired epithelial regeneration and maladaptive tissue repair by limiting reparative capacity and promoting profibrotic signaling. However, the molecular drivers of AEC senescence and their impact on the immune microenvironment in IPF remain incompletely understood. Here, we investigated senescence-associated genes involved in IPF pathogenesis and evaluated their diagnostic and therapeutic potential. IPF transcriptomic datasets were retrieved from the Gene Expression Omnibus (GEO). Senescence-related differentially expressed genes (SRDEGs) were identified by intersecting IPF-derived differentially expressed genes with a curated human senescence gene list. Functional enrichment analyses were performed to delineate SRDEG-associated biological processes. Hub genes were prioritized using machine-learning approaches, and a diagnostic model was constructed and assessed by receiver operating characteristic (ROC) analysis. Candidate genes were further validated through in vivo and in vitro experiments. Given the upstream regulatory role of CHEK2 in DNA damage response-associated cellular senescence, Fostamatinib was screened as a potential therapeutic agent, and its interaction with CHEK2 and functional effects were examined using molecular docking, molecular dynamics simulations, and experimental assays. Two senescence-associated hub genes, CHEK2 and TP53 BP1, were identified as key contributors to IPF pathology (FDR-adjusted P < 0.05), and a model incorporating both genes achieved high diagnostic performance. Experimental validation, however, indicated that only CHEK2 showed IPF-specific differential expression and was closely associated with AEC senescence and fibrotic progression. In silico analyses supported stable binding between Fostamatinib and CHEK2, and subsequent molecular and cellular experiments suggested that Fostamatinib may attenuate CHEK2-associated senescence and profibrotic responses. Collectively, these findings identify CHEK2 as a critical regulator of AEC senescence and IPF development, supporting its potential use as a diagnostic biomarker and therapeutic target. Fostamatinib may represent a candidate therapeutic strategy for IPF by modulating CHEK2-related senescence pathways.

The interaction between nasopharyngeal pneumococcal carriage (NPC) and respiratory viral infections (RVI) is poorly understood. This study aimed to investigate the prevalence and epidemiology of NPC, and its correlation with RVI.

This retrospective study included patients aged < 18 years who presented with RVI symptoms between 1 February and 30 June 2023. Naso-oropharyngeal swabs were tested using quantitative polymerase chain reaction (PCR) for Streptococcus pneumoniae and respiratory viruses. Patients were grouped by NPC status and compared for viral detection, and clinical and demographic characteristics.

NPC was detected in 15.7% (n = 1,185) of the 7,522 samples analyzed. The mean age was 56.5 ± 49.3 months, being significantly lower in NPC-positive patients (p < 0.001). Most (82%) were fully vaccinated against pneumococcus; 16% had underlying conditions. The most frequent viruses were adenovirus (17.2%), influenza B (9.0%), severe acute respiratory syndrome coronavirus 2 (5.3%), respiratory syncytial virus (4.9%), and influenza A (2.8%). Adenovirus (19.7%) and influenza B (11.0%) were significantly more frequent in NPC-positive patients than in NPC-negative patients (p < 0.001 for both). Overall, 20.5% were hospitalized, and 2.4% required intensive care. Intensive care admission was higher among NPC-positive patients, whereas mortality did not differ.

NPC was epidemiologically associated with the detection of certain respiratory viruses, particularly adenovirus and influenza B. Given the retrospective design and lack of pneumococcal serotype data, these findings should be interpreted as associations rather than evidence of causality. Further prospective studies are warranted to clarify the bacterial-viral interactions and their clinical relevance.

Uncertainty and rapid changes in treatment guidelines are influencing factors for medication use during the COVID-19 pandemic. Therefore, this study aimed to evaluate antibiotic utilization in Community Health Centers (CHCs) between 2020 and 2021.

Prescription data from adult outpatient visits (≥ 18 years) receiving prescription services at 35 CHCs in South Jakarta, Malang regency, and Bengkulu city, comprising 796,598 prescriptions, were examined using the ATC/DDD methodology and DU90% analysis. These regions were purposively selected to represent three distinct healthcare archetypes, namely metropolitan (South Jakarta), rural-urban continuum (Malang Regency), and regional cities outside Java (Bengkulu City). Wilcoxon signed-rank and Chi-square tests were used to determine statistical differences between years.

The proportion of adult patient visits receiving a minimum of one antibiotic prescription decreased by 1.56% in 2021 (p < 0.001). Malang Regency recorded the highest rates, decreasing by 2.24% in 2021. Furthermore, the highest DDD values for all antibiotics each year were recorded in South Jakarta, except for Cefadroxil, which peaked in Malang regency. Six antibiotics were constituted in the DU90% segment, with Amoxicillin accounting for over 50% of prescriptions and reaching 425 DDD/1000 patient visits/year in South Jakarta in 2020. In 2021, Azithromycin prescriptions increased significantly by 7.51%, as shown by a p of 0.0161. The average prescribing rate (14.57%) remained below the WHO optimal indicator (< 30%).

Antibiotic use in CHCs declined during the pandemic, but there was a significant increase in Azithromycin prescriptions.

DNA methylation might influence the expression of genes that regulate coronavirus disease 2019 (COVID-19) progression. This work explored the significance of DNA methylation of 7 genes (TAC1, CDO1, HOXA9, ZFP42, SOX17, RASSF1A, and SHOX2) in blood circulating free DNA (cfDNA) in differentiating COVID-19 infections and recoveries. The correlation with changes in the proportion of immune cell populations in the recovery period was analyzed.

18 COVID-19-infected, 65 COVID-19-recovered, and 11 uninfected individuals were included. DNA methylation expression was determined by quantitative multiplex methylation-specific PCR (qMSP). The immune function of the recovered group versus uninfected group was evaluated by full-spectrum flow cytometry.

The infected population showed a higher methylation positivity rate for 7 genes compared to the uninfected/recovered population. A model was constructed to distinguish the infected patients from uninfected/recovered individuals using the methylation status of 7 genes, with a sensitivity, specificity and area under curve (AUC) of 0.889, 0.842 and 0.931, respectively. The results of flow cytometry revealed that CD8+ T cells and CD38+ CD8+ T cells were significantly upregulated in recovered individuals compared to those in uninfected individuals. DNA methylation was correlated with immune cell changes, with a significant increase in the percentage of T cells, PD-1+ function CD4+ T cells, TCRγδ+ cells, and CD38+ NKT cells upon an increase in 7 gene methylation positivity.

This work revealed the significance of 7 gene methylation in the diagnosis of COVID-19 recovery, and demonstrated that these genes were significant in evaluating the immune function during the recovery period.

Respiratory infections and tuberculosis are leading causes of global morbidity and mortality; yet comprehensive research on their associated risk factors remains limited, hindering the development of effective preventive strategies.

The 2021 Global Burden of Disease data from 204 countries (1990-2021) was used to measure deaths, disability-adjusted life years (DALYs), and their age-standardized rates (ASMR and ASDR) tied to 9 risk factors. The trends were analyzed by age, gender, and socio-demographic index (SDI) regions, with annual and average annual percentage changes (APC, AAPC) used to track changes over time.

Globally, mortality rates (ASMR) for respiratory infections and tuberculosis linked to traditional risks-malnutrition, air pollution, and alcohol use-declined significantly; annual decreases of 4.46%, 3.18%, and 3.35%, respectively. Deaths attributed to metabolic risks like high BMI and blood sugar increased, despite falling ASMR. Geographic disparities were notable: Lesotho saw the sharpest rise in BMI-related mortality (3.92%), while Hungary had the steepest decline (-7.4%). Men faced a higher burden from behavioral risks, with tobacco-related mortality 3.6 times higher than in women. Children under 5 years were especially vulnerable to environmental risks, with unsafe water and sanitation contributing to a 4.55% annual decline in mortality rates.

This study highlights the need for targeted actions, such as tobacco control in high-middle SDI regions, air quality improvements in South Asia, and nutrition programs in Sub-Saharan Africa. It offers a precise public health framework to reduce respiratory infections and tuberculosis, and promote global health equity by analyzing sociodemographic and time trends.