AiiO-AIO6 is a quorum-sensing quenching enzyme that could decrease the virulence of pathogenic bacteria, and improve animal immunity. However, the precise regulatory mechanism of AiiO-AIO6 on intestinal immunity remains unknown. Thus, this study aimed to reduce this knowledge gap. After feeding with graded levels of AIO-AIO6 (0.0 (un-supplemented group), 2.5, 5.0, 7.5, 10.0, and 12.5 U/g) for 70 days, juvenile grass carp was selected from each group for a 6-day Aeromonas hydrophila challenge test. Meanwhile, some other fish selected from un-supplemented control group were injected with saline as un-challenged control. Results showed that A. hydrophila infection increased enteritis morbidity, and caused intestinal inflammation in grass carp compared with saline group, while AiiO-AIO6 supplementation decreased enteritis morbidity, mitigated inflammatory cell infiltration, pyroptosis, and apoptosis in the intestine after A. hydrophila infection. Furthermore, both 5.0 and 7.5 U/g AiiO-AIO6 decreased gene expressions of tumor necrosis factor-α and interleukin-1β, and elevated gene expressions of transforming growth factor-β1 and IL-10, potentially associating with decreased NF-κB p65 and increased PPARγ signaling in the intestine. Supplementing 5.0 or 7.5 U/g AiiO-AIO6 also mitigated intestinal pyroptosis, as indicated by reduced mRNA levels of NLRP3, PYCARD, caspase-1, GSDME a, and GSDME b, and decreased protein levels of N-GSDME and IL-1β. Additionally, AiiO-AIO6 alleviated intestinal apoptosis, demonstrated by reduced gene expressions of pro-apoptotic genes apoptotic protease activating factor-1, Bcl-2 associated X protein, Fas ligand, and caspase-3, as well as c-Jun N-terminal kinase and mitogen-activated protein kinase p38, and elevated gene expressions of anti-apoptotic factors, B-cell lymphoma-2, myeloid cell leukemia 1, and inhibitor of apoptosis protein. Altogether, optimal levels of AiiO-AIO6 attenuated intestinal inflammation probably relating to down-regulated NF-κB signaling, and reduced NLRP3 and GSDME-mediated pyroptosis, and finally reduced apoptosis in the intestine of grass carp.

Macrophage apoptosis is a key contributor to the elimination of immune cells and increased susceptibility during sepsis. CKLF like MARVEL transmembrane domain containing 4 (CMTM4) is a membrane protein with four transmembrane domains. It has recently been implicated in the regulation of immune cell biological functions. However, its role in regulating macrophage apoptosis during sepsis has not been extensively studied.

Clinical samples were analyzed to determine CMTM4 expression levels and their correlation with clinical examination results. An in vitro model was developed using C57BL/6 mice and the THP-1 cell line. An immunofluorescence analysis was used to assess protein expression levels, apoptosis, and protein co-localization. Western blotting (WB) was used to measure protein expression levels, while flow cytometry was used to detect cell apoptosis. Transcriptomic sequencing was conducted to identify differentially expressed genes and to perform a functional enrichment analysis. Transcription factors were screened using databases. Chromatin immunoprecipitation, followed by quantitative PCR (ChIP-qPCR), was conducted to analyze protein-DNA interactions, and co-immunoprecipitation (Co-IP) was used to examine protein-protein interactions.

CMTM4 expression in macrophages was upregulated in sepsis. The inhibition of CMTM4 expression reduced macrophage apoptosis. PD-L1 was identified as a key molecule regulated by CMTM4 in macrophage apoptosis. CMTM4 regulates PD-L1 by promoting the phosphorylation of its transcription factor, STAT2, rather than directly binding to PD-L1.

In sepsis, CMTM4 facilitates PD-L1-dependent macrophage apoptosis by enhancing STAT2 phosphorylation. This discovery offers new insights for the diagnosis and treatment of sepsis.

Sepsis, a life-threatening inflammatory condition due to an imbalanced response to infections, has been a major concern. Necroptosis, a newly discovered programmed cell death form, plays a crucial role in various inflammatory diseases. Our study aims to identify necroptosis - related genes (NRGs) and explore their potential for sepsis diagnosis.

We used weighted gene co-expression network analysis to identify gene modules associated with sepsis. Cox regression and Kaplan-Meier methods were employed to assess the diagnostic and prognostic value of these genes. Single-cell and immune infiltration analyses were carried out to explore the immune environment in sepsis. Plasma CD74 protein levels were quantified in our samples, and relevant clinical data from electronic patient records were analyzed for correlation.

CD74 was identified through the intersection of the hub genes of sepsis and NRGs related modules. Septic patients had lower CD74 expression compared to healthy controls. The CD74-based diagnostic model showed better performance in the training dataset (AUC, 0.79 [95% CI, 0.75-0.84]), was cross-validated in external datasets, and demonstrated better performances than other published diagnostic models. Pathway analysis and single-cell profiling supported further exploration of CD74-related inflammation and immune response in sepsis.

This study presents the first quantitative assessment of human plasma CD74 in sepsis patients. CD74 levels were significantly lower in the sepsis cohort. CD74 warrants further exploration as a potential prognostic and therapeutic target for sepsis.

Sepsis is a critical condition associated with high morbidity and mortality, emphasizing the need for reliable biomarkers for its diagnosis and prognosis. This study uses advanced immunological techniques to evaluate monocytic CD39 (mCD39) expression as a potential marker in sepsis.

This prospective observational cohort study included 206 participants from the First Affiliated Hospital, Zhejiang University School of Medicine between April 2022 and September 2023. Participants were categorized into four groups: healthy donors, patients with mild infections, post-cardiac surgery patients (non-infectious inflammation), and sepsis patients. Peripheral Blood Mononuclear Cells were analyzed using mass cytometry time-of-flight (CyTOF) with a 42-marker immune panel and flow cytometry targeting monocytes. Statistical analyses included ROC curves for diagnostic and prognostic performance and Kaplan-Meier survival analysis for prognostic evaluation.

Sepsis patients exhibited significantly lower monocytic CD39 expression than mild infection and post-surgery groups (p < 0.05). The diagnostic performance analysis revealed that mCD39 effectively distinguished sepsis from mild infection (AUC = 0.877) and non-infectious inflammation (AUC = 0.935). Prognostic analysis identified low mCD39 expression as a strong predictor of short-term survival, with a 7-day survival AUC of 0.85 (p = 0.037). Kaplan-Meier analysis showed that sepsis patients with low mCD39 expression had significantly lower 28-day survival rates (56.7% vs. 80.6%, p = 0.016).

Low CD39 expression on monocytes might serve as a potential diagnostic biomarker and a strong predictor of poor prognosis in sepsis patients.

Understanding the dynamic changes in immune indicators during sepsis and their predictive value for Acute respiratory distress syndrome (ARDS) is crucial for improving patient outcomes.

This single-center, observational retrospective study was conducted at Lishui Central Hospital, Zhejiang Province. Patients diagnosed with Sepsis-3 were categorized into non-ARDS and ARDS groups based on ARDS development. Data collection included demographics, clinical data, and immune parameters. Immune parameters were collected on days 1, 3, and 7 post-admission. Multivariate logistic regression analysis identified independent risk factors for ARDS, and a nomogram model was constructed. The predictive ability of the model was evaluated using ROC curves.

Multivariate analysis identified key factors for the nomogram, including CD4, CD8, Treg, lymphocyte, IgG, and IgA levels on Days 3 and 7. On Day 3, CD8 (P < 0.001), Tregs (P = 0.021), IgG (P < 0.001), and IgA (P < 0.001) showed significant negative correlations with ARDS development. On Day 7, CD4 (P < 0.001), CD8 (P < 0.001), lymphocyte count (P < 0.001), and IgA (P < 0.001) similarly demonstrated significant negative correlations with ARDS risk. The nomogram model had an AUC of 0.998 (95% CI: 0.997-0.999), indicating high predictive ability.

Early dynamic changes in immune indicators, including CD8, CD4, Treg, IgA, IgG, and Lymphocyte, predict ARDS development in ICU sepsis patients.

Noncoding RNAs (ncRNAs) have emerged as pivotal regulators of gene expression, and have attracted significant attention because of their various roles in biological processes. These molecules have transcriptional activity despite their inability to encode proteins. Moreover, research has revealed that ncRNAs, especially microRNAs (miRNAs), long noncoding RNAs (lncRNAs), and circular RNAs (circRNAs), are linked to pervasive regulators of kidney disease, including anti-inflammatory, antiapoptotic, antifibrotic, and proangiogenic actions in acute and chronic kidney disease. Although the exact therapeutic mechanism of ncRNAs remains uncertain, their value in treatment has been studied in clinical trials. The numerous renal diseases and the beneficial or harmful effects of NcRNAs on the kidney will be discussed in this article. Afterward, exploring the biological characteristics of ncRNAs, as well as their purpose and potential contributions to acute and chronic renal disease, were explored. This may offer guidance for treating both acute and long-term kidney illnesses, as well as insights into the potential use of these indicators as kidney disease biomarkers.

Sepsis is a life-threatening disease causing millions of deaths every year. It has been reported that programmed cell death (PCD) plays a critical role in the development and progression of sepsis, which has the potential to be a diagnosis and prognosis indicator for patient with sepsis.

Fourteen PCD patterns were analyzed for model construction. Seven transcriptome datasets and a single cell sequencing dataset were collected from the Gene Expression Omnibus database.

A total of 289 PCD-related differentially expressed genes were identified between sepsis patients and healthy individuals. The machine learning algorithm screened three PCD-related genes, NLRC4, TXN and S100A9, as potential biomarkers for sepsis. The area under curve of the diagnostic model reached 100.0% in the training set and 100.0%, 99.9%, 98.9%, 99.5% and 98.6% in five validation sets. Furthermore, we verified the diagnostic genes in sepsis patients from our center via qPCR experiment. Single cell sequencing analysis revealed that NLRC4, TXN and S100A9 were mainly expressed on myeloid/monocytes and dendritic cells. Immune infiltration analysis revealed that multiple immune cells involved in the development of sepsis. Correlation and gene set enrichment analysis (GSEA) analysis revealed that the three biomarkers were significantly associated with immune cells infiltration.

We developed and validated a diagnostic model for sepsis based on three PCD-related genes. Our study might provide potential peripheral blood diagnostic candidate biomarkers for patients with sepsis.

The application of biomimetic and stimuli-responsive nanocarriers displays considerable promise in improving the management of bacterial sepsis and overcoming antimicrobial resistance. Therefore, the study aimed to synthesize a novel hyaluronic acid-lysine conjugate (HA-Lys) and to utilize the attributes of the synthesized HA-Lys with Tocopherol succinate (TS) and Oleylamine (OLA) in the formulation of multifunctional biomimetic pH-responsive HNLCs loaded with vancomycin (VCM-HNLCs), to combat bacterial sepsis.

A novel hyaluronic acid-lysine conjugate (HA-Lys) was synthesized and characterized using FTIR and 1H NMR spectroscopy. Vancomycin-loaded hybrid nanosystems (VCM-HNLCs) were prepared through hot homogenization ultrasonication and evaluated for particle size, polydispersity index (PDI), zeta potential (ZP), and encapsulation efficiency (EE%). In vitro biocompatibility was assessed via MTT assay and red blood cell hemolysis test. The binding affinity to TLR2 and TLR4 was measured using microscale thermophoresis (MST). Drug release was evaluated using the dialysis bag method. Antimicrobial activity against MRSA and efflux pump inhibition were also determined. Efficacy was demonstrated in an MRSA-induced sepsis mice model.

The VCM-HNLCs, produced via hot homogenization ultrasonication, exhibited particle size (PS), polydispersity index (PDI), zeta potential (ZP), and encapsulation efficiency (EE%) of 110.77 ± 1.692 nm, 0.113 ± 0.022, - 2.92 ± 0.210 mV, and 76.27 ± 1.200%, respectively. In vitro, biocompatibility was proven by hemolysis and cytotoxicity studies. The VCM-HNLCs demonstrated targetability to human Toll-like receptors (TLR 2 and 4) as validated by microscale thermophoresis (MST). VCM-HNLCs showed a twofold reduction in MIC values at physiological pH compared to the bare VCM against S. aureus and MRSA for 48 h. While at pH 6.0, MIC values were reduced by fourfold in the first 24 h and by eightfold in the subsequent 48 and 72 h against tested strains. Furthermore, VCM-HNLCs showed inhibitory effects against MRSA efflux pumps, reactive oxygen species (ROS), and lipopolysaccharide (LPS)-induced hyperinflammation. In an MRSA-induced sepsis mice model, VCM-HNLCs demonstrated superior efficacy compared to free VCM, significantly eliminated bacteria and improved survival rates.

Overall, these results highlight the potential of VCM-HNLCs as novel multifunctional nanocarriers to combat antimicrobial resistance (AMR) and enhance sepsis outcomes.

Sepsis is a life-threatening form of organ dysfunction resulting from a dysregulated response to infection. The complex pathogenesis of sepsis poses challenges because of the lack of reliable biomarkers for early identification and effective treatments. As sepsis progresses to severe forms, cardiac dysfunction becomes a major concern, often manifesting as ventricular dilation, a reduced ejection fraction, and a diminished contractile capacity, known as sepsis-induced cardiomyopathy (SIC). The absence of standardized diagnostic and treatment protocols for SIC leads to varied criteria being used across medical institutions and studies, resulting in significant outcome disparities. Despite the high prevalence of SIC, accurate statistical data are lacking. To understand how SIC affects sepsis prognosis, a thorough exploration of its pathophysiological mechanisms, including systemic factors and complex signalling within myocardial and immune cells, is required. Identifying the factors influencing SIC occurrence and progression is crucial and must be conducted within specific clinical contexts. In this review, the clinical manifestations, pathophysiological mechanisms, and treatment strategies for SIC are discussed, along with the clinical background. We aim to connect current practices with future research challenges, providing clear guidance for clinicians and researchers.

Osteoporosis is a major public health concern characterized by decreased bone density. Among various therapeutic strategies, apoptotic extracellular vesicles (ApoEVs) have emerged as promising agents in tissue regeneration. Specifically, T cell-derived ApoEVs have shown substantial potential in facilitating bone regeneration. However, it remains unclear whether ApoEVs can promote bone mass recovery through enzymatic activity mediated by membrane surface molecules. Therefore, this study aimed to investigate whether T cell-derived ApoEVs could promote bone mass recovery in osteoporosis mice and reveal the underlying mechanisms.

ApoEVs were isolated through sequential centrifugation, and their proteomic profiles were identified via mass spectrometry. Western blot and immunogold staining confirmed the enrichment of CD39 and CD73 on ApoEVs. The role of CD39 and CD73 in hydrolyzing adenosine triphosphate (ATP) to adenosine was evaluated by quantifying the levels of ATP and adenosine. Inhibitors of CD39 and CD73, and an A2BR antagonist were used to explore the molecular mechanism of ApoEVs in promoting bone regeneration.

ApoEVs significantly reduced bone loss and promote the osteogenic differentiation of BMMSCs in ovariectomy (OVX) mice. We observed increased levels of extracellular ATP and a decrease in CD39 and CD73, key enzymes in ATP-to-adenosine conversion in bone marrow of OVX mice. We found that ApoEVs are enriched with CD39 and CD73 on their membranes, which enable the hydrolysis of extracellular ATP to adenosine both in vitro and in vivo. The adenosine generated by ApoEVs inhibits the inflammatory response and promotes osteogenesis through A2BR and downstream PKA signaling.

T cell-derived ApoEVs are enriched with CD39 and CD73, enabling them to hydrolyze extracellular ATP to adenosine, thereby promoting bone regeneration via A2BR and PKA signaling pathway. Our data underscore the substantive role of T cell-derived ApoEVs to treat osteoporosis, thus providing new ideas for the development of ApoEVs-based therapies in tissue regeneration.

Sepsis leads to dysfunctional immune responses with multi-organ damage, and acute kidney injury (AKI) is a common complication of sepsis. To gain a deeper understanding of the specific underlying mechanisms of sepsis, we investigated the effects of specific macrophages on sepsis. To gain a deeper understanding of the specific underlying mechanisms of sepsis, we investigated the effects of specific macrophages on sepsis. Single-cell sequencing of a mouse model of endotoxemia revealed that sepsis is a common complication of sepsis. Single-cell sequencing of a mouse model of endotoxemia revealed that the emerging macrophage subpopulation Ccl5+ Mac was significantly pro-inflammatory, activating a large number of pathways activating a large number of pathways associated with immune response and inflammatory response, including IL6-JAK-STAT3 signaling, TGF-β signaling, and inflammatory response. Interestingly, we found that Ccl5+ Mac recruits neutrophil through CCL5-CCR1 ligand receptor pairs by cellular communication analysis thereby further affecting sepsis. We therefore hypothesize that this macrophage subpopulation is actively involved in the underlying molecular mechanisms of AKI. We therefore hypothesize that this macrophage subpopulation is actively involved in the underlying molecular mechanisms of AKI in sepsis and provide valuable insights.

Sepsis is characterized by a concomitant early pro-inflammatory response by immune cells to an infection, and an opposing anti-inflammatory response that results in protracted immunosuppression. The primary pathological event in sepsis is widespread programmed cell death, or cellular self-sacrifice, of innate and adaptive immune cells, leading to profound immunological suppression. This severe immune dysfunction hampers effective primary pathogen clearance, thereby increasing the risk of secondary opportunistic infections, latent viral reactivation, multiple organ dysfunction, and elevated mortality. The types of cell death include apoptosis (type I programmed cell death), autophagy (type II programmed cell death), NETosis (a program for formation of neutrophil extracellular traps (NETs)) and other programmed cell deaths like pyroptosis, ferroptosis, necroptosis, each contributing to immunosuppression in distinct ways during the later phases of sepsis. Extensive apoptosis of lymphocytes, such as CD4+, CD8+ T cells, and B cells, is strongly associated with immunosuppression. Apoptosis of dendritic cells further compromises T and B cell survival and can induce T cell anergy or promote regulatory Treg cell proliferation. Moreover, delayed apoptosis and impaired neutrophil function contribute to nosocomial infections and immune dysfunction in sepsis. Interestingly, aberrant NETosis and the subsequent depletion of mature neutrophils also trigger immunosuppression, and neutrophil pyroptosis can positively regulate NETosis. The interaction between programmed cell death 1 (PD-1) or programmed cell death 1 ligand (PD-L1) plays a key role in T cell modulation and neutrophil apoptosis in sepsis. The dendritic cell growth factor, Fms-like tyrosine kinase (FLTEL), increases DC numbers, enhances CD 28 expression, attenuates PD-L1, and improves survival in sepsis. Recently, immunoadjuvant therapies have attracted attention for their potential to restore host physiological immunity and homeostasis in patients with sepsis. This review focuses on several potential immunotherapeutic agents designed to bolster suppressed innate and adaptive immune responses in the management of sepsis.

Sepsis (defined as sepsis 3.0) is a life-threatening organ dysfunction caused by a dysregulated host response to a variety of pathogenic microorganisms. Characterized by high morbidity and mortality, sepsis has become a global public health problem. However, there is a lack of appropriate diagnostic and therapeutic strategies for sepsis and current management rely on the limited treatment strategies. Recently, nanomedicines targeting and controlling the release of bio-active agents have shown excellent potency in sepsis management, with improved therapeutic efficacy and reduced adverse effects. In this review, we have summarized the advantages of nanomaterials. Also, the preparation and efficacy of the main categories of anti-sepsis nanomedicines applied in sepsis management are described in detail, including antibiotic-coated nanomaterials, antimicrobial peptides-coated nanomaterials, biomimetic nanomaterials, nanomaterials targeting macrophages and natural products loaded nanomaterials. These advances in nanomedicines establish the huge potential for nanomaterials-based sepsis management, especially in the improved pharmaceutical and pharmacological properties, enhanced therapeutic efficacy, controllable drug-targeting and reduced side effects. To further facilitate clinical translation of anti-sepsis nanomedicines, we propose that the issues involving safety, regulatory laws and cost-effectiveness should receive much more attention in the future.

Persistent lymphopenia can be regarded as an important index of acquired immune dysfunction in sepsis. Whether the specific immune factor changes in septic patients with lymphopenia and the correlation to gut microbiota and metabolites remain unclear.

This single-center prospective observation conducted lymphocyte subgroup analysis of blood samples and 16S rRNA gene amplicons sequencing and untargeted metabolomics analysis of fecal samples from 36 subjects with the persistent (≥3d) (n = 21) and non-persistent lymphopenia (<3d) (n = 15).

The persistent lymphopenia showed higher the 28d mortality and 90d mortality, while significantly lower CD3+T/LY, CD3+T cells, CD3+CD4+T cells, CD3+CD8+T cells, Th1 cells, Th2 cells, CD45RA + Treg cells. The 16S rRNA results showed that Staphylococcus, Peptostreptococcus, Bulleidia, Leuconostoc were significant enriched in the persistent lymphopenia. The metabolomics analysis showed that α-Ketoisovaleric acid was increased and 7-DHCA, α-MCA, β-MCA, HCA, LCA-3S, CA, UCA and Citramalic acid were decreased in the persistent lymphopenia.

In the process of interaction between host receptors and gut microbiota in patients with persistent lymphopenia sepsis, with a significant reduction in gut microbiota diversity and bile acid metabolites. That can affect various inflammatory pathways of gut immune cells, causing immune dysfunction in the body, which may be one of the main causes of death.

Melioidosis is a tropical infection caused by the intracellular pathogen Burkholderia pseudomallei, an underreported and emerging global threat. As melioidosis-associated mortality is frequently high despite antibiotics, novel management strategies are critically needed. Therefore, we sought to determine whether functional changes in the host innate and adaptive immune responses are induced during acute melioidosis and are associated with outcome. Using a unique whole blood stimulation assay developed for use in resource-limited settings, we examined induced cellular functional and phenotypic changes in a cohort of patients with bacteremic melioidosis prospectively enrolled within 24 h of positive blood culture and followed for 28 days. Compared to healthy controls, melioidosis survivors generated an IL-17 response mediated by Th17 cells and terminally-differentiated effector memory CD8+ T cells (P < .05, both), persisting to 28 days after enrolment. Furthermore, melioidosis survivors developed polyfunctional cytokine production in CD8+ T cells (P < .01). Conversely, a reduction in CCR6+ CD4+ T cells was associated with higher mortality, even after adjustments for severity of illness (P = 0.004). Acute melioidosis was also associated with a profound acute impairment in monocyte function as stimulated cytokine responses were reduced in classical, intermediate and non-classical monocytes. Impaired monocyte cytokine function improved by 28-days after enrolment. These data suggest that IL-17 mediated cellular responses may be contributors to host defense during acute melioidosis, and that innate immune function may be impaired. These insights could provide novel targets for the development of therapies and vaccine targets in this frequently lethal disease.

Sepsis often causes severe liver injury and leads to poor patient outcomes. Early detection of sepsis-induced liver injury (SILI) and early treatment are key to improving outcomes.

To investigate the clinical characteristics of SILI patients and analyze the associated risk factors, to identify potential sensitive biomarkers.

Retrospective analysis of clinical data from 546 patients with sepsis treated in the intensive care unit of the 908th Hospital of Chinese People's Liberation Army Joint Logistic Support Force between May 2018 and December 2022. The patients were divided into the sepsis group (n = 373) and SILI group (n = 173) based on the presence of acute liver injury within 2 hours of admission. We used the random forest algorithm to analyze risk factors and assessed potential diagnostic markers of SILI using the area under the receiver operating characteristic curve, Kaplan-Meier survival curves, subgroup analysis and correlation analysis.

Compared with the sepsis group, tissue plasminogen activator-inhibitor complex (t-PAIC) levels in serum were significantly higher in the SILI group (P < 0.05). Random forest results showed that t-PAIC was an independent risk factor for SILI, with an area under the receiver operating characteristic curve of 0.862 (95% confidence interval: 0.832-0.892). Based on the optimal cut-off value of 11.9 ng/mL, patients at or above this threshold had significantly higher levels of lactate and Acute Physiology and Chronic Health Evaluation II score. The survival rate of these patients was also significantly worse (hazard ratio = 2.2, 95% confidence interval: 1.584-3.119, P < 0.001). Spearman's correlation coefficients were 0.42 between t-PAIC and lactate, and 0.41 between t-PAIC and aspartate transaminase. Subgroup analysis showed significant differences in t-PAIC levels between patients with different severity of liver dysfunction.

T-PAIC can serve as a diagnostic indicator for SILI, with its elevation correlated with the severity of SILI.

The neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) have been recognized as predictors of various critical illnesses. Our study aimed to investigate whether the NLR and PLR measured at different timepoints could predict poor neurological outcomes at 6 months. This observational retrospective cohort study included adults who had experienced out-of-hospital cardiac arrest (OHCA) and received targeted temperature management between November 2015 and December 2020. Patients with an active infection, as confirmed by an initial blood culture, were excluded. Multivariate logistic regression models were used to determine the association between the NLR and PLR at 0, 24, and 48 h after return of spontaneous circulation and poor neurological outcomes, defined as a Cerebral Performance Category score of ≥3 at 6 months. The NLR at 24 h, but not the NLR or PLR at other timepoints, was significantly associated with poor neurological outcomes (odds ratio: 1.05; 95% CI: 1.01-1.09; p = 0.018). The NLR at 24 h showed moderate accuracy in predicting poor neurological outcomes, with an AUC of 0.619. A cutoff value of 9.0 achieved 72.5% sensitivity and 47.7% specificity. The NLR measured at 24 h after ROCS could be used for early neuroprognostication given its low cost and widespread availability.

Fungal lung disease encompasses a wide spectrum of organisms and associated clinical conditions, presenting a significant global health challenge. The type and severity of disease are determined by underlying host immunity and infecting fungal strain. The most common group of diseases are associated with the filamentous fungus Aspergillus species and include allergic bronchopulmonary aspergillosis, sensitisation, aspergilloma and chronic and invasive pulmonary aspergillosis. Fungal lung disease remains epidemiologically heterogenous and is influenced by geography, environment and host comorbidities. Diagnostic modalities continue to evolve and now include novel molecular assays and biomarkers; however, persisting challenges include achieving rapid and accurate diagnosis, particularly in resource-limited settings, and in differentiating fungal infection from other pulmonary conditions. Treatment strategies for fungal lung diseases rely mainly on antifungal agents but the emergence of drug-resistant strains poses a substantial global threat and adds complexity to existing therapeutic challenges. Emerging antifungal agents and increasing insight into the lung mycobiome may offer fresh and personalised approaches to diagnosis and treatment. Innovative methodologies are required to mitigate drug resistance and the adverse effects of treatment. This state-of-the-art review describes the current landscape of fungal lung disease, highlighting key clinical insights, current challenges and emerging approaches for its diagnosis and treatment.

The mononuclear phagocytic system clears the circulating inorganic nanomaterials from the bloodstream, which raises concerns about the chronic toxicity of the accumulated metal species. A better understanding of the behavior of each metal after systemic injection is thus required for clinical translations. This study investigates the significance of the metal-ligand interaction on the accumulation of cerium and demonstrates that only the form in which cerium is coordinated to a multidentate chelator with a strong binding affinity does not accumulate in major organs. Specifically, cerium complexed with diethylenetriamine pentaacetic acid (DTPA) forms renally excretable nanoparticles in vivo to circumvent the leaching of cerium ions, whereas weakly coordinated cerium-based nanomaterials produce insoluble precipitates upon encountering physiological phosphate anions. Ceria-based renally clearable nanoparticles (CRNs) derived from cerium-DTPA are utilized as the antioxidant pair with iron-DTPA, in which their combination leverages the Fenton reaction to synergistically scavenge hydrogen peroxide. This reduces the gene expression of pro-inflammatory factors in the macrophages activated with lipopolysaccharide as well as improves the survival rate of septic mice by alleviating the systemic inflammatory response and its downstream tissue injury in the liver, spleen, and kidneys. This study demonstrates that CRNs combined with iron-DTPA can be utilized as nonaccumulative nanomedicines for treating systemic inflammation, thereby overcoming the limitations of conventional ceria nanoparticle-based treatments.

In recent years, researchers have focused on studying the mechanism of sepsis-induced immunosuppression, but there is still a lack of suitable animal models that accurately reflect the process of sepsis-induced immunosuppression. The aim of this study was to evaluate the immune status at various stages in a model of sepsis-induced secondary pneumonia and to demonstrate whether pyroptosis is one of the modes of immune cell death in sepsis. Firstly, we established a sepsis model in C57BL/6J mice using cecal ligation and puncture (CLP). The surviving mice were treated with a 40 μL suspension of P.aeruginosa (Pa) under anesthesia on day 4 post-CLP to establish a sepsis-induced secondary pneumonia model. Secondly, routine blood tests, serum ALT and PCT levels, gross lung specimens, and H&E staining of the lung and liver tissues were used to assess the successful establishment of this model. Serum levels of TNF-α and IL-6, the CD4+/CD8+ratio in blood, H&E staining of the spleen, and immunohistochemistry of CD4 and CD8 in the spleen were detected to evaluate the immune status of the model mice. Finally, the expression levels of pyroptosis-related proteins in the spleen were detected by Western blot. The expression of GSDMD was assessed using immunohistochemistry, and pyroptosis was directly observed through transmission electron microscopy. The experimental results above confirmed the successful construction of the model for sepsis-induced secondary pneumonia, demonstrating its ability to reflect sepsis-induced immunosuppression. Moreover, the expression of pyroptosis-related proteins, immunohistochemical GSDMD, and transmission electron microscopy of the spleen showed that pyroptosis was one of the modes of immune cell death in sepsis.

Septic patients with T2DM were prone to prolonged recovery and unfavorable prognoses. Thus, this study aimed to pinpoint potential genes related to sepsis with T2DM and develop a predictive model for the disease. The candidate genes were screened using protein-protein interaction networks (PPI) and machine learning algorithms. The nomogram and receiver operating characteristic curve were developed to assess the diagnostic efficiency of the biomarkers. The relationship between sepsis and immune cells was analyzed using the CIBERSORT algorithm. The biomarkers were validated by qPCR and western blotting in basic experiments, and differences in organ damage in mice were studied. Three genes (MMP8, CD177, and S100A12) were identified using PPI and machine learning algorithms, demonstrating strong predictive capabilities. These biomarkers presented significant differences in gene expression patterns between diseased and healthy conditions. Additionally, the expression levels of biomarkers in mouse models and blood samples were consistent with the findings of the bioinformatics analysis. The study elucidated the common molecular mechanisms associated with the pathogenesis of T2DM and sepsis and developed a gene signature-based prediction model for sepsis. These findings provide new targets for the diagnosis and intervention of sepsis complicated with T2DM.

Sepsis represents a critical condition characterized by multiple-organ dysfunction resulting from inflammatory response to infection. Disulfidptosis is a newly identified type of programmed cell death that is intimately associated with the actin cytoskeleton collapse caused by glucose starvation and disulfide stress, but its role in sepsis is largely unknown. The study was to adopt a diagnostic and prognostic signature for sepsis with disulfidptosis based on the differentially expressed genes (DEGs) between sepsis and healthy people from GEO database. The disulfidptosis hub genes associated with sepsis were identified, and then developed consensus clustering and immune infiltration characteristics. Next, we evaluated disulfidptosis-related risk genes by using LASSO and Random Forest algorithms, and constructed the diagnostic sepsis model by nomogram. Finally, immune infiltration, GSVA analysis and mRNA-miRNA networks based on disulfidptosis-related DEGs were screened. There are five upregulated disulfidptosis-related genes and seven downregulated genes were filtered out. The six intersection disulfidptosis-related genes including LRPPRC, SLC7A11, GLUT, MYH9, NUBPL and GYS1 exhibited higher predictive ability for sepsis with an accuracy of 99.7%. In addition, the expression patterns of the critical genes were validated. The study provided a comprehensive view of disulfidptosis-based signatures to predict the prognosis, biological features and potential treatment directions for sepsis.

Sepsis is a life-threatening syndrome resulting from a dysregulated host response to infection. It is the primary cause of death in the intensive care unit, posing a substantial challenge to human health and medical resource allocation. The pathogenesis and pathophysiology of sepsis are complex. During its onset, pro-inflammatory and anti-inflammatory mechanisms engage in intricate interactions, possibly leading to hyperinflammation, immunosuppression, and long-term immune disease. Of all critical outcomes, hyperinflammation is the main cause of early death among patients with sepsis. Therefore, early suppression of hyperinflammation may improve the prognosis of these patients. Nafamostat mesilate is a serine protease inhibitor, which can inhibit the activation of the complement system, coagulation system, and contact system. In this review, we discuss the pathophysiological changes occurring in these systems during sepsis, and describe the possible targets of the serine protease inhibitor nafamostat mesilate in the treatment of this condition.

Sepsis frequently causes systemic inflammatory response syndrome and multiple organ failure in patients. Neoastilbin (NAS) is a flavonoid that plays vital functions in inflammation. This work aims to investigate the protective effects of NAS against sepsis-induced liver and kidney injury and elucidate its underlying mechanisms. The mouse model was established using cecal ligation puncture (CLP) induction. NAS was given to mice by gavage for 7 consecutive days before surgery. Liver and kidney function, oxidative stress, and inflammatory factors in serum or tissues were examined by ELISA or related kits. The expression of relevant proteins was assessed by Western blot. Hematoxylin and eosin and/or periodic acid-Schiff staining revealed that NAS ameliorated the pathological damage in liver and kidney tissues of CLP-induced mice. NAS improved liver and kidney functions, as evidenced by elevated levels of blood urea nitrogen, Creatinine, ALT, and AST in the serum of septic mice. TUNEL assay and the expression of Bcl-2 and Bax showed that NAS dramatically reduced apoptosis in liver and renal tissues. NAS treatment lowered the levels of myeloperoxidase and malondialdehyde, while elevated the superoxide dismutase content in liver and kidney tissues of CLP-induced mice. The levels of inflammatory cytokines (IL-6, TNF-α, and IL-1β) in the serum and both tissues of CLP-injured mice were markedly decreased by NAS. Mechanically, NAS downregulated TLR4 expression and inhibited NF-κB activation, and overexpression of TLR4 reversed the protective effects of NAS against liver and kidney injury. Collectively, NAS attenuated CLP-induced apoptosis, oxidative stress, inflammation, and dysfunction in the liver and kidney by restraining the TLR4/NF-κB pathway.

Given the critical role of immune cells and their responses in sepsis pathogenesis, this study aimed to evaluate the prognostic significance of various immune cell ratios in septic children through the collection and analysis of clinical data.

Clinical data were collected from septic children admitted to the pediatric intensive care unit (PICU) of Shenzhen Children's Hospital between January 2019 and September 2021. The peripheral blood immune cell ratios included the neutrophil to lymphocyte ratio (NLR), the derived neutrophil to lymphocyte ratio (dNLR), the neutrophil to lymphocyte and platelet ratio (NLPR), the monocyte to lymphocyte ratio (MLR), and the platelet to lymphocyte ratio (PLR). To investigate the associations between these immune cell ratios and mortality, we utilized the locally weighted scatterplot smoothing (LOWESS) method, receiver operating characteristic (ROC) analysis, and Kaplan‒Meier (K‒M) analysis.

A total of 230 septic children were enrolled in the study. When comparing the immune cell ratios between the deceased and surviving groups, all ratios except for the PLR were elevated in the deceased group. Using the LOWESS method, we observed that the MLR, NLR, dNLR, and NLPR exhibited an approximately linear association with in-hospital mortality. Among the various immune cell ratios, the NLPR exhibited the highest AUC of 0.748, which was statistically comparable to that of the Pediatric Critical Illness Score (PCIS) (0.748 vs. 0.738, P = 0.852). The NLR (0.652), MLR (0.638), and dNLR (0.615) followed in terms of AUC values. K‒M analysis revealed that children with elevated MLR, NLR, dNLR, and NLPR exhibited increased 30-day mortality.

The predictive capacity of the NLPR is comparable to that of the PCIS, suggesting that the NLPR has potential as a robust prognostic indicator for septic children.

This narrative review provides an overview of the evolving significance of lymphopenia in sepsis, emphasizing its critical function in this complex and heterogeneous disease. We describe the causal relationship of lymphopenia with clinical outcomes, sustained immunosuppression, and its correlation with sepsis prediction markers and therapeutic targets. The primary mechanisms of septic lymphopenia are highlighted. In addition, the paper summarizes various attempts to treat lymphopenia and highlights the practical significance of promoting lymphocyte proliferation as the next research direction.

Sepsis is a dysregulated immune response to an infection that leads to organ dysfunction. Sepsis-associated organ dysfunction involves multiple inflammatory mechanisms and complex metabolic reprogramming of cellular function. These mechanisms cooperate through multiple organs and systems according to a complex set of long-distance communications mediated by cellular pathways, solutes, and neurohormonal actions. In sepsis, the concept of organ crosstalk involves the dysregulation of one system, which triggers compensatory mechanisms in other systems that can induce further damage. Despite the abundance of studies published on ​​organ crosstalk in the last decade, there is a need to formulate a more comprehensive framework involving all organs to create a more detailed picture of sepsis. In this paper, we review the literature published on organ crosstalk in the last 10 years and explore how these relationships affect the progression of organ failure in patients with septic shock. We explored these relationships in terms of the heart-kidney-lung, gut-microbiome-liver-brain, and adipose tissue-muscle-bone crosstalk in sepsis patients. A deep connection exists among these organs based on crosstalk. We also review how multiple therapeutic interventions administered in intensive care units, such as mechanical ventilation, antibiotics, anesthesia, nutrition, and proton pump inhibitors, affect these systems and must be carefully considered when managing septic patients. The progression to multiple organ dysfunction syndrome in sepsis patients is still one of the most frequent causes of death in critically ill patients. A better understanding and monitoring of the mechanics of organ crosstalk will enable the anticipation of organ damage and the development of individualized therapeutic strategies.

Sepsis is considered a high risk factor for new-onset atrial fibrillation (NOAF), with neutrophil extracellular traps (NETs) being implicated in the pathogenesis of numerous diseases. However, the precise role of NETs and NETs-related genes (NRGs) in the occurrence of NOAF in sepsis remains inadequately elucidated. The objective of this study was to identify hub NRGs connecting sepsis and AF, and to investigate the potential association between NETs and NOAF in sepsis.

The AF and sepsis microarray datasets were retrieved from the Gene Expression Omnibus (GEO) database for analysis of shared pathophysiological mechanisms and NRGs implicated in both sepsis and AF using bioinformatics techniques. The CIBERSORT algorithm was employed to assess immune cell infiltration and identify common immune characteristics in these diseases. Additionally, a rat model of lipopolysaccharide (LPS)-induced sepsis was utilized to investigate the association between NETs, NRGs, and sepsis-induced AF. Western blotting, enzyme-linked immunosorbent assay, hematoxylin-eosin staining, immunohistochemistry, and immunofluorescence were employed to assess the expression of NRGs, the formation of NETs, and the infiltration of neutrophils. Electrophysiological analysis and multi-electrode array techniques were utilized to examine the vulnerability and conduction heterogeneity of AF in septic rats. Furthermore, intervention was conducted in LPS-induced sepsis rats using DNase I, a pharmacological agent that specifically targets NETs, in order to assess its impact on neutrophil infiltration, NETs formation, hub NRGs protein expression, and AF vulnerability.

A total of 61 commonly differentially expressed genes (DEGs) and four hub DE-NRGs were identified in the context of sepsis and AF. Functional enrichment analysis revealed that these DEGs were predominantly associated with processes related to inflammation and immunity. Immune infiltration analysis further demonstrated the presence of immune infiltrating cells, specifically neutrophil infiltration, in both sepsis and AF. Additionally, a positive correlation was observed between the relative expression of the four hub DE-NRGs and neutrophil infiltration. In rats with LPS-induced sepsis, we observed a notable upregulation in the expression of four DE-NRGs, the formation of NETs, and infiltration of neutrophils in atrial tissue. Through electrophysiological assessments, we identified heightened vulnerability to AF, reduced atrial surface conduction velocity, and increased conduction heterogeneity in LPS-induced sepsis rats. Notably, these detrimental effects can be partially ameliorated by treatment with DNase I.

Through bioinformatics analysis and experimental validation, we identified four hub NRGs in sepsis and AF. Subsequent experiments indicated that the formation of NETs in the atria may contribute to the pathogenesis of NOAF in sepsis. These discoveries offer potential novel targets and insights for the prevention and treatment of NOAF in sepsis.

With the emergence of COVID-19, there is an increased focus in human literature on cytokine production, the implications of cytokine overproduction, and the development of novel cytokine-targeting therapies for use during sepsis. In addition to viral infections such as COVID-19, bacterial infections resulting in exposure to endotoxins and exotoxins in humans can also lead to sepsis, resulting in organ failure and death. Like humans, horses are exquisitely sensitive to endotoxin and are among the veterinary species that develop clinical sepsis similar to humans. These similarities suggest that horses may serve as a naturally occurring model of human sepsis. Indeed, evidence shows that both species experience cytokine dysregulation, severe neutropenia, the formation of neutrophil extracellular traps, and decreased perfusion parameters during sepsis. Sepsis treatments that target cytokines in both species include hemoperfusion therapy, steroids, antioxidants, and immunomodulation therapy. This review will present the shared cytokine physiology across humans and horses as well as historical and updated perspectives on cytokine-targeting therapy. Finally, this review will discuss the potential benefits of increased knowledge of equine cytokine mechanisms and their potential positive impact on human medicine.

Sepsis is a heterogeneous syndrome. This study aimed to identify new sepsis sub-phenotypes using plasma cortisol trajectory.

This retrospective study included patients with sepsis admitted to the intensive care unit of Zhongshan Hospital Fudan University between March 2020 and July 2022. A group-based cortisol trajectory model was used to classify septic patients into different sub-phenotypes. The clinical characteristics, biomarkers, and outcomes were compared between sub-phenotypes.

A total of 258 patients with sepsis were included, of whom 186 were male. Patients were divided into two trajectory groups: the lower-cortisol group (n = 217) exhibited consistently low and slowly declining cortisol levels, while the higher-cortisol group (n = 41) showed relatively higher levels in comparison. The 28-day mortality (65.9% vs.16.1%, P < 0.001) and 90-day mortality (65.9% vs. 19.8%, P < 0.001) of the higher-cortisol group were significantly higher than the lower-cortisol group. Multivariable Cox regression analysis showed that the trajectory sub-phenotype (HR = 5.292; 95% CI 2.218-12.626; P < 0.001), APACHE II (HR = 1.109; 95% CI 1.030-1.193; P = 0.006), SOFA (HR = 1.161; 95% CI 1.045-1.291; P = 0.006), and IL-1β (HR = 1.001; 95% CI 1.000-1.002; P = 0.007) were independent risk factors for 28-day mortality. Besides, the trajectory sub-phenotype (HR = 4.571; 95% CI 1.980-10.551; P < 0.001), APACHE II (HR = 1.108; 95% CI 1.043-1.177; P = 0.001), SOFA (HR = 1.270; 95% CI 1.130-1.428; P < 0.001), and IL-1β (HR = 1.001; 95% CI 1.000-1.001; P = 0.015) were also independent risk factors for 90-day mortality.

This study identified two novel cortisol trajectory sub-phenotypes in patients with sepsis. The trajectories were associated with mortality, providing new insights into sepsis classification.

An 8-year-old American Quarter Horse gelding was treated with extracorporeal hemoperfusion (HP) therapy for treatment of Clostridioides difficile (C. difficile) colitis-induced systemic inflammatory response syndrome (SIRS). The gelding developed C. difficile associated peracute colitis and severe SIRS as evidenced by a positive fecal C. difficile PCR and tachypnea, tachycardia, fever, neutropenia, altered mucous membrane color, and hyperlactatemia. Concurrent acute kidney injury in the horse limited the use of routine anti-inflammatory and anti-lipopolysaccharide treatments, including flunixin meglumine and polymyxin B, because of potential for nephrosis. Extracorporeal HP therapy was performed twice within 48 hours of the onset of severe SIRS during which the horse's physical examination variables stabilized. The horse was euthanized after 4 days because of laminitis. These findings support further investigation of extracorporeal HP therapy as an adjunctive treatment for severe SIRS/sepsis in horses.

This research aims to investigate the prognosis value using the time-weighted average neutrophil-to-lymphocyte ratio (TWA-NLR) for predicting all-cause hospital mortality among sepsis patients. Data were analyzed through the use of the eICU Collaborative Research Database (eICU-CRD 2.0) as well as Medical Information Mart for Intensive Care IV 2.2 (MIMIC-IV 2.2).

Septic patients from both eICU-CRD 2.0 as well as MIMIC-IV 2.2 databases were included. The neutrophil-to-lymphocyte ratios (NLR) were available for analysis, utilizing complete blood counts obtained on days one, four, and seven following ICU admission. The TWA-NLR was computed at the end of the seven days, and patients were then stratified based on TWA-NLR thresholds. 90-day all-cause mortality during hospitalization was the primary objective, with 60-day all-cause hospital mortality as a secondary objective. The correlation between TWA-NLR and sepsis patients' primary outcome was analyzed using univariable and multivariable Cox proportional hazard regressions. A restricted cubic spline (RCS) analysis was conducted in an attempt to confirm this association further, and subgroup analyses were employed to evaluate the correlation across various comorbidity groups.

3921 patients were included from the eICU-CRD 2.0, and the hospital mortality rate was 20.8 %. Both multivariable as well as univariable Cox proportional hazard regression analyses revealed that TWA-NLR was independently correlated with 90-day all-cause hospital mortality, yielding a hazard ratio (HR) of 1.02 (95 % CI 1.01-1.02, P-value<0.01) as well as 1.12 (95 % CI 1.01-1.15, P-value<0.01), respectively. The RCS analysis demonstrated a significant nonlinear relationship between TWA-NLR and 90-day all-cause hospital mortality risk. The study subjects were divided into higher (>10.5) and lower (≤10.5) TWA-NLR cohorts. A significantly decreased incidence of 90-day all-cause hospital mortality (HR = 0.56, 95 % CI 0.48-0.64, P-value<0.01) and longer median survival time (40 days vs 24 days, P-value<0.05) were observed in the lower TWA-NLR cohort. However, septic patients with chronic pulmonary (interaction of P-value = 0.009) or renal disease (interaction of P-value = 0.008) exhibited significant interactive associations between TWA-NLR and 90-day all-cause hospital mortality, suggesting the predictive power of TWA-NLR may be limited in these subgroups. The MIMIC-IV 2.2 was utilized as a validation cohort and exhibited a similar pattern.

Our findings suggest that TWA-NLR is a powerful and independent prognostic indicator for 90-day all-cause hospital mortality among septic patients, and the TWA-NLR cutoff value may prove a useful method for identifying high-risk septic patients.

To explore the value of metagenomic next-generation sequencing (mNGS) and culture in microbial diagnosis of patients with acute infection.

We retrospectively analyzed 206 specimens from 163 patients who were admitted to the emergency department of The First Affiliated Hospital of Sun Yat-sen University between July 2020, and July 2021. We evaluated the diagnostic efficacy of mNGS and in-hospital traditional culture.

The total positive rate of mNGS was significantly higher than that culture methods (71.4 % vs 40.8 %, p < 0.001), while the sensitivity and accuracy of mNGS were found to be 92.9 % and 88.2 % respectively. However, culture exhibited superior specificity with a value of 92.6 % compared to 75.9 % for mNGS. The detection efficiency of mNGS and culture for fungi was comparable, but mNGS showed superior performance for bacterial detection. In the analysis of sepsis samples, mNGS outperformed traditional culture methods in diagnosing various types of samples, especially for sputum and bronchoalveolar lavage fluid. Among the identified infections, bacterial infections were the most common single infection (37.5 %). Additionally, bacterial-fungal infections represented the most prevalent form of mixed infection (77.3 %). Candida albicans and Staphylococcus aureus were identified as the predominant pathogens in the survival and death groups, respectively. No significant differences in microbial diversity were observed.

Compared to culture methods, mNGS demonstrates superior positive rates, sensitivity, and accuracy in the rapid detection of acute infections, particularly in critically ill patients such as those with sepsis. This capability establishes a foundation for the swift and precise identification of pathogens, allowing for the analysis of clinical indicators and patient prognosis based on the extensive data generated from mNGS.

In sepsis, the relationship between lymphocyte counts and patient outcomes is complex. Lymphocytopenia and lymphocytosis significantly influence survival, illustrating the dual functionality of lymphocytes in responding to infections. This study investigates this complex interaction, focusing on how variations in lymphocyte counts correlate with all-cause hospital mortality among sepsis patients.

This retrospective cohort study analyzed data from two extensive critical care databases: the Medical Information Mart for Intensive Care IV 2.0 (MIMIC-IV 2.0) from Beth Israel Deaconess Medical Center, Boston, Massachusetts, and the eICU Collaborative Research Database (eICU-CRD), which was Multi-center database from over 200 hospitals across the United States conducted by Philips eICU Research Institute. We included adult patients aged 18 years and older who met the Sepsis-3 criteria, characterized by documented or suspected infection and a Sequential Organ Failure Assessment (SOFA) score of 2 or higher. Sepsis patients were categorized into quartiles based on lymphocyte counts. The primary outcome was all-cause mortality in the hospital, with 90 and 60-day all-cause mortality as the secondary outcomes. Univariable and multivariable Cox proportional hazard regressions were utilized to assess lymphocyte counts' impact on hospital mortality. An adjusted restricted cubic spline (RCS) analysis was performed to elucidate this relationship further. Subgroup analyses were also conducted to explore the association across various comorbidity groups among sepsis and septic shock patients.

Our study included 37,054 patients, with an observed in-hospital mortality rate of 16.6%. Univariable and multivariable Cox proportional hazard regression models showed that lymphocyte counts were independently associated with in-hospital mortality (HR = 1.04, P < 0.01; HR = 1.06, P < 0.01). RCS regression analysis revealed a U-shaped relationship between lymphocyte levels and hospital mortality risk in sepsis and septic shock patients (P for overall < 0.001, P for nonliner < 0.01; P for overall = 0.002, P for nonliner = 0.014). Subgroup analyses revealed that elevated lymphocyte counts correlated with increased hospital mortality among sepsis patients with liver disease and requiring renal replacement therapy (P for overall = 0.021, P for nonliner = 0.158; P for overall = 0.025, P for nonliner = 0.759). These findings suggest that lymphocytes may have enhanced prognostic value in specific subsets of critically ill sepsis patients.

Our findings demonstrate that lymphocyte counts are a significant independent predictor of hospital mortality in sepsis and septic shock patients. We observed a U-shaped association between lymphocyte levels and mortality risk, indicating that high and low counts are linked to increased mortality. This result highlights the complex role of lymphocytes in sepsis outcomes and suggests the need for further investigation into the underlying mechanisms and potential therapeutic approaches. Integrating lymphocyte count assessment into risk stratification algorithms and clinical decision support tools could enhance the early identification of high-risk sepsis patients.

Background: Septic patients with persistent lymphopenia may be in an immunosuppressed state. Therefore, we evaluated and compared the clinical characteristics and outcomes of septic patients with persistent lymphopenia (≥2d) and those with nonpersistent lymphopenia. Methods: A retrospective cohort study was designed. A total of 1306 patients with sepsis who were attended to the First Affiliated Hospital of Dalian Medical University from March 2016 to August 2022 were included. The primary clinical outcome was 90d mortality. The secondary clinical outcomes were the length of stay, hospital mortality, 28d mortality, the incidence of secondary infection, and differences in clinical characteristics. Results: Among 1306 patients with sepsis, 913 (69.9%) patients developed persistent lymphopenia. Compared with patients with nonpersistent lymphopenia, patients with persistent lymphocytopenia were admitted to intensive care unit (75.7% vs 52.7%, P < .05), treated with mechanical ventilation (67.6% vs 39.2%, P < .05), positive rate of microbial culture pathogens (86.7% vs 71.2%, P < .05), SOFA [8.0 (6.0-10.0) vs 6.0 (4.0-8.0), P < .05], length of stay [17.0d (12.0-27.0) vs 13.0d (10.0-21.0), P < .05], hospital mortality (37.7% vs 24.2%, P < .05), 28d mortality (38.0% vs 22.9%, P < .05), and 90d mortality (51.2% vs 31.3%, P < .05) were higher. As the duration of lymphocytopenia increased, so did the mortality rate in hospital. In addition, the onset time of persistent lymphopenia was not associated with SOFA. But we found that the frequency of persistent lymphopenia during hospitalization was positively associated with SOFA. Conclusion: Septic patients with persistent lymphopenia have higher mortality, worse conditions, increased risk of secondary infection, and poor prognosis regardless of shock.

Radiation enteritis is the most common complication of pelvic radiotherapy, but there is no effective prevention or treatment drug. Apoptotic T cells and their products play an important role in regulating inflammation and maintaining physiological immune homeostasis. Here it is shown that systemically infused T cell-derived apoptotic extracellular vesicles (ApoEVs) can target mice irradiated intestines and alleviate radiation enteritis. Mechanistically, radiation elevates the synthesis of intestinal 2'3' cyclic GMP-AMP (cGAMP) and activates cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) proinflammatory pathway. After systemic infusion of ApoEVs, the ectonucleotide pyrophosphatase phosphodiesterase 1 (ENPP1) enriches on the surface of ApoEVs hydrolyze extracellular cGAMP, resulting in inhibition of the cGAS-STING pathway activated by irradiation. Furthermore, after ApoEVs are phagocytosed by phagocytes, ENPP1 on ApoEVs hydrolyzed intracellular cGAMP, which serves as an intracellular cGAMP hydrolyzation mode, thereby alleviating radiation enteritis. The findings shed light on the intracellular and extracellular hydrolysis capacity of ApoEVs and their role in inflammation regulation.