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Abstract Rationale Mucosal-associated invariant T (MAIT) cells have been proven to play an important role in host defense against mycobacterial infection in animal infection models; however, the functional role of MAIT cells in patients with active tuberculosis (TB) is still largely unknown. Objectives To understand the clinical features and functions of MAIT cells in patients with active TB. Methods MAIT cells were analyzed in patients with pulmonary TB, tuberculous pleurisy, and tuberculous peritonitis by flow cytometry. The functions of MAIT cells were compared between patients with active TB and healthy control subjects. Measurements and Main Results The frequency of MAIT cells was significantly reduced both in peripheral blood from patients with active pulmonary TB (P < 0.0001) and in tuberculous pleural effusions compared with healthy control subjects but not in ascitic fluids from patients with tuberculous peritonitis. A comparison of bacillus Calmette-Guérin (BCG)–stimulated cytokine production showed that patients with active TB had significantly higher production of IFN-γ (P = 0.0034) and tumor necrosis factor (TNF)-α (P = 0.0399) compared with healthy control subjects. In contrast, when MAIT cells were stimulated with Escherichia coli, patients with active TB had significantly lower production of IFN-γ (P = 0.0007) and TNF-α (P = 0.0032). MAIT cells in patients with active TB exhibited elevated expression of programmed death-1 (PD-1) (P = 0.0015), and blockade of PD-1 signaling resulted in a significantly higher frequency of BCG-stimulated IFN-γ production in MAIT cells (P = 0.0178). Conclusions MAIT-cell immune response to antigen stimulation in patients with active TB is regulated by PD-1, which could be a potential target for TB immunotherapy.

Idiopathic inflammatory myopathies (IIMs) are systemic autoimmune disorders with unknown etiology. Despite the established link between gut microbes and immunity, the roles of gut bacteriome, mycobiome, and virome in IIM are unexplored. We performed shotgun metagenomic sequencing on fecal samples from 34 IIM patients and 37 healthy controls to profile gut microbiota. Taxonomic, functional, network, and machine-learning analyses revealed microbial dysbiosis and its potential for discriminating IIM. All three microbial kingdoms were significantly altered in IIM. Several inflammation-associated bacterial taxa (e.g., Rothia mucilaginosa , Streptococcus parasanguinis , Trueperella pyogenes ) and opportunistic fungi (e.g., Aspergillus spp.) were enriched in IIM, while SCFA-producing bacteria and fungi were depleted. Virome analysis revealed substantial shifts, with higher abundance of Siphoviridae in IIM. Altered viral functional gene profiles suggesting enhanced phage-mediated genome integration, recombination, and bacterial stress adaptation. Multi-kingdom network analysis showed extensive rewiring in IIM, characterized by increased network connectivity and a shift toward fungi-centered ecological hubs, contrasting with bacteria/virus-dominated networks in controls. In machine-learning models, the virome demonstrated the strongest discriminatory power, and viral signatures dominated the combined multi-kingdom classifier (AUC = 0.997). This first comprehensive multi-kingdom gut microbiota analysis in IIM provides a foundation for developing diagnostic and therapeutic strategies.

Background The treatment regimen for tuberculous meningitis (TBM) remains unclear and requires optimization. There are some reports on successful adjunct intrathecal dexamethasone and isoniazid (IDI) treatment strategies for TBM, however, there is equivocal evidence on their efficacy and safety. Methods A comprehensive search of English and Chinese databases was conducted from inception to February 2024. A meta-analysis was performed on randomized controlled trials (RCTs) estimating the effects of adjunct IDI on conventional anti-TB (C anti-TB) treatments or C anti-TB alone. Efficacy, adverse reaction rate, cerebrospinal fluid (CSF) leukocytes, and CSF protein were used as primary outcome indicators. CSF glucose, CSF chlorides, CSF pressure, recovery time for laboratory indicators and recovery time for clinical symptoms were used as secondary outcome indicators. Results A total of 17 studies involving 1360 (IDI group vs. C anti-TB group: 392 vs. 372; higher-dose IDI group vs. lower-dose IDI group: 319 vs. 277) patients were included in our analysis. Efficacy was significantly higher (RR 1.3, 95% CI 1.2-1.4, P  < 0.001) and adverse reaction rate was significantly lower in the IDI groups (RR 0.59, 95% CI 0.37-0.92, P  = 0.021). Furthermore, CSF leukocytes (WMD - 29.33, 95% CI [- 40.64 to-18.02], P  < 0.001) and CSF protein (WMD - 0.79, 95%CI [-0.96 to-0.61], P  < 0.001) were significantly lower in the IDI groups. Recovery time indicators were all shorter in the IDI groups, fever (SMD - 2.45, 95% CI [-3.55 to-1.35], P  < 0.001), coma (SMD-3.75, 95% CI [-4.33 to-3.17], P  < 0.001), and headache (SMD  - 3.06, 95% CI [- 4.05 to-2.07], P  < 0.001), respectively. Higher-dose IDI was more effective than lower-dose IDI (RR 1.23, 95% CI 1.14-1.33, P  < 0.001), with no significant difference in adverse reaction rate between the two (RR 0.82, 95%CI 0.43–1.56, P  = 0.544). Conclusion Adjunct IDI with C anti-TB can enhance therapeutic outcomes and reduce adverse reaction rate in adult TBM patients, with higher-dose IDI showing superior efficacy. These findings highlight the potential of IDI as an adjunctive therapy in TBM management. However, more high-quality RCTs from more regions should be conducted to support our results. Trial registration Retrospectively registered in PROSPERO  https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023388860 .

Chronic functional constipation (CFC) is a common gastrointestinal disorder increasingly linked to gut microbiome dysbiosis. However, multi-kingdom metagenomic characterization of bacterial, fungal, and viral communities in CFC remains limited. Fecal samples from 53 CFC patients and 48 healthy controls were analyzed using whole-metagenome shotgun sequencing. Microbial composition, function, cross-kingdom interactions, and diagnostic potential were evaluated using diversity analyses, KEGG annotation, network analysis, and random forest modeling. Compared with healthy controls, CFC patients exhibited marked alterations across multiple microbial kingdoms. The gut bacteriome showed significant community-structure shifts despite comparable α-diversity, characterized by depletion of health-associated Firmicutes (e.g., and ) and enrichment of Proteobacteria (e.g., ). The mycobiome displayed selective changes in diversity and composition, with several potentially pathogenic fungal taxa enriched in CFC (e.g., sp. ). In the virome, community composition differed significantly between groups, with higher viral richness in CFC and widespread depletion of diverse bacteriophages in CFC patients. Functional profiling suggested feature-level functional differences without a clear global shift, including reduced carbohydrate transport and utilization pathways and relatively higher abundance of stress-response and metabolic adaptation modules in CFC. Cross-kingdom network analysis demonstrated substantially denser microbial interactions in CFC, dominated by viral associations, with and _SGB15346 acting as central hubs. Machine-learning models showed strong discriminatory power for CFC classification based on bacterial and viral features, whereas fungal features contributed less. CFC is associated with coordinated multi-kingdom gut microbiome dysbiosis involving bacteria, fungi, and viruses, accompanied by functional shifts and intensified cross-kingdom interactions. Bacterial and viral signatures show strong potential as microbiome-based biomarkers for CFC, highlighting the importance of integrating multi-kingdom analyses to better understand disease-associated gut ecosystem alterations.

Background and Aims Observational studies frequently report co‐occurrence between endocrine, nutritional, and metabolic disease (ENMD) and pulmonary tuberculosis (PTB). However, the causal properties between them remain poorly defined. Our aim in this study was to investigate the causal effect of ENMD on PTB using Mendelian randomization analysis. Methods We obtained single nucleotide polymorphisms linked to ENMD, ENMD‐related diseases, and clinical features, as well as PTB, from the IEU OpenGWAS project. Inverse variance weighting was used as the primary analytical method, complemented by Weighted median and MR‐Egger regression to assess their causal relationship. Heterogeneity and horizontal pleiotropy were assessed using Cochran's Q test and MR regression intercepts. The robustness of the results is evaluated by sensitivity analysis leave‐one‐out and MR‐PRESSO. Results The inverse variance weighting analyses indicated that ENMD significantly increased the risk of PTB (OR = 1.41, 95% CI: 1.18–1.68, p < 0.001) after removing outliers. Interestingly, at the genetic level of European ancestry, there is no evidence of increased risk of PTB with T2DM (OR = 1.05, 95% CI: 0.99–1.12, p = 0.10), whereas high cholesterol (OR = 0.41, 95% CI: 0.22–0.79, p < 0.05), BMI (OR = 0.78, 95% CI: 0.69–0.88, p < 0.001) was negatively correlated with the risk of PTB, and LDL‐c showed a weak inverse correlation with PTB (OR = 0.90, 95% CI: 0.81–0.99, p = 0.03). Sensitivity analyses confirmed the robustness of these findings. Conclusion This MR study provides novel genetic evidence that ENMD significantly elevates PTB risk. Notably, high cholesterol, BMI, and LDL‐c exhibit protective effects against PTB at the genetic level in European ancestry, while T2DM shows no causal association. These findings highlight the complex role of metabolic factors in tuberculosis susceptibility and suggest potential biological mechanisms linking metabolic dysregulation to PTB pathogenesis.

The traditional radiation air conditioning system has some problems, such as easy condensation, insufficient refrigeration capacity, complex structure, and control system. Therefore, this study proposes a new type of finned metal radiant plate with large heat flow per unit area, sufficient cooling capacity, and simplified heat exchange system, in order to realize large temperature difference between cooling and heating. The temperature field uniformity and thermal comfort test of a novel type of finned ceiling radiant panel and independent fresh air linked air conditioning system under summer cooling and winter heating circumstances are accomplished through artificially generated climate environments. The study’s findings demonstrate that in the radiation and fresh air modes, the maximum interior temperature differential under cooling conditions does not rise over 2.1°C. The maximum temperature differential in the space at any one moment in the radiation and fresh air modes cannot be greater than 3°C when heating conditions are present. The fresh air’s cooling and dehumidifying effects are clear. The dehumidification efficiency may reach 50%, and the moisture content ranges from 5.48 to 9.63 g/kg. With PMV ranging from −0.34 to 0.54, the enhanced air conditioning system in this research provides exceptionally good thermal comfort. Additionally, the finned radiant panel’s installation area occupies just 14% of the ceiling, which is sufficient to fulfill the room’s cooling and heating load needs as well as provide high thermal comfort and consistent indoor temperature. The theoretical investigation and practical implementation of the direct expansion radiant air conditioning system are both strongly supported by this research.

Acute myeloid leukemia (AML) is a notably lethal disease, characterized by malignant clonal proliferation of hematopoietic stem cells in the bone marrow. This study seeks to unveil potential therapeutic targets for AML, using a combined approach of microarray analysis and Mendelian randomization (MR). We collected data samples from the Gene Expression Omnibus (GEO) database and extracted pQTL data from genome-wide association studies (GWAS) to identify overlapping genes between the DEGs and GWAS data. Gene enrichment and pathway annotation analyses were performed on these genes. Furthermore, we validated gene expression levels and assessed their clinical relevance. By taking the intersection of these gene sets, we obtained a list of co-expressed genes, including four upregulated genes (REC8, TPM2, ZMIZ1, CD82) and two downregulated genes (IFNAR1, TMCO3). MR analysis demonstrated that genetically predicted protein levels of CD82, REC8, ZMIZ1, and TPM2 were significantly associated with increased odds of AML, while IFNAR1 and TMCO3 showed a protective effect. Gene ontology and KEGG pathway analyses revealed significant enrichment in functions related to female gamete generation, meiosis, p53 signaling pathway, and cardiac muscle contraction. Differences in immune cell profiles were observed between AML survivors and those with poor prognosis, including lower levels of neutrophils and higher levels of follicular helper T cells in the latter group. This study identifies a causal relationship between gene expression and AML and highlights the potential role of REC8 in leukemogenesis, possibly through its impact on gametocyte meiotic abnormalities. The findings provide new insights into the prevention and treatment of leukemia.

Myocardial infarction (MI), the leading cause of death among patients with cardiovascular diseases, is characterized by acute cardiac muscle injury due to severe impairment of the coronary blood supply, which may lead to cardiogenic shock and cardiac arrest. Particularly interesting new cysteine histidine rich 1 (PINCH1) protein, a key component of the integrin signaling pathway, interacts with several proteins and serves a vital role in numerous cellular processes, including cytoskeleton remodeling, cell proliferation and cell migration. To investigate the role of PINCH1 in heart injury in the present study, PINCH1 was knocked out in the myocardial tissue of mice (age, 18 weeks) to induce MI. In addition, cell viability, migration and apoptosis, as well as the expression levels of NF-κB-associated proteins were determined in murine HL1 cardiomyocytes with a conditional PINCH1 shRNA using Cell Counting Kit-8, Transwell, flow cytometry and western blot assays, respectively. Furthermore, the cardiac expansion and myocardial fibrosis in PINCH1 knockout mice was investigated in vivo by performing morphological and histological examinations. Additionally, the murine ventricular myocardial ultrastructure was evaluated using an electron microscope, and the cardiomyocyte apoptotic rate and expression levels of NF-κB-related proteins were determined using TUNEL and western blot assays, respectively. The results showed that the apoptotic rate in the in vivo PINCH1 knockdown group was significantly increased. In addition, the protein expression levels of NF-κB signaling pathway-related proteins, including NF-κB, myeloid differentiation factor 88, TNF-α and caspase-3, were significantly increased in the in vivo PINCH1 knockdown group compared with the wild-type group, but the protein expression of MMP2 and MMP9 were the opposite. Overall, the in vitro and in vivo results revealed that PINCH1 knockout in mice significantly aggravated MI via the NF-κB signaling pathway.

Myocardial infarction (MI), the leading cause of death among patients with cardiovascular diseases, is characterized by acute cardiac muscle injury due to severe impairment of the coronary blood supply, which may lead to cardiogenic shock and cardiac arrest. Particularly interesting new cysteine histidine rich 1 (PINCH1) protein, a key component of the integrin signaling pathway, interacts with several proteins and serves a vital role in numerous cellular processes, including cytoskeleton remodeling, cell proliferation and cell migration. To investigate the role of PINCH1 in heart injury in the present study, PINCH1 was knocked out in the myocardial tissue of mice (age, 18 weeks) to induce MI. In addition, cell viability, migration and apoptosis, as well as the expression levels of NF-[kappa]B-associated proteins were determined in murine HL1 cardiomyocytes with a conditional PINCH1 shRNA using Cell Counting Kit-8, Transwell, flow cytometry and western blot assays, respectively. Furthermore, the cardiac expansion and myocardial fibrosis in PINCH1 knockout mice was investigated in vivo by performing morphological and histological examinations. Additionally, the murine ventricular myocardial ultrastructure was evaluated using an electron microscope, and the cardiomyocyte apoptotic rate and expression levels of NF-[kappa]B-related proteins were determined using TUNEL and western blot assays, respectively. The results showed that the apoptotic rate in the in vivo PINCH1 knockdown group was significantly increased. In addition, the protein expression levels of NF-[kappa]B signaling pathway-related proteins, including NF-[kappa]B, myeloid differentiation factor 88, TNF-[alpha] and caspase-3, were significantly increased in the in vivo PINCH1 knockdown group compared with the wild-type group, but the protein expression of MMP2 and MMP9 were the opposite. Overall, the in vitro and in vivo results revealed that PINCH1 knockout in mice significantly aggravated MI via the NF-[kappa]B signaling pathway. Key words: particularly interesting new cysteine histidine rich 1, myocardial infarction, NF-[kappa]B signaling pathway, cardiomyopathy, HL1 cell line

The purpose of this study was to investigate sedation practices and the perception of discomfort during mechanical ventilation in Chinese intensive care units (ICUs). A prospective, observational, cohort study was conducted in 31 Chinese ICUs in academic hospitals from June 15 to August 15, 2006. Conscious patients who were discharged from the ICU after mechanical ventilation were consecutively included. Using a standardized questionnaire, a personal interview was conducted with each patient within 2 days after discharge from the ICU. Patients were asked about recollections of emotional and physical discomfort. Sedation and analgesia administration data were collected from patient records. As prospectively defined, 83 (50.9%) of 163 patients met criteria for complex-mixed discomfort (ie, at least 1 emotional and 2 physical disturbances). Similarly, 79.1% of patients remembered seriously uncomfortable experiences associated with 1 of the 3 predefined sources. Both protocolized sedation and continuous sedation without a defined protocol, but not intermittent sedation, significantly reduced the relative risk of complex-mixed discomfort occurrences ( P < .001). Notably, only 14.7% of patients received protocolized sedation, and 61 (37.4%) of 163 were not given any sedatives. Mechanically ventilated ICU patients in Chinese academic hospitals were inadequately treated for discomfort. Protocolized sedation can effectively improve patient comfort.