Background: Sepsis is a life-threatening condition driven by a dysregulated immune response to infection. Identifying the genetic factors underlying sepsis pathogenesis remains a major challenge in developing effective treatments. Methods: The Summary data-based Mendelian Randomization method was used to integrate Genome-Wide Association Studies and expression quantitative trait loci data to identify sepsis-related genes. These genes were intersected with prognostic gene sets from Gene Expression Omnibus transcriptomic datasets and validated using an independent dataset. Comprehensive single-cell RNA sequencing analysis, including cell clustering, differential expression analysis, cell-cell communication mapping, and pseudotime trajectory analysis, was performed to explore the roles of the identified genes within the sepsis microenvironment. Results: Intersection of Summary data-based Mendelian Randomization and Gene Expression Omnibus gene sets, followed by validation, identified two risk genes and five protective genes as significantly differentially expressed. The risk gene BEND7, predominantly expressed in platelets, was further analyzed using single-cell RNA sequencing, revealing strong interactions with immune cells, particularly monocytes and neutrophils, via the intercellular adhesion molecule signaling pathway. Functional enrichment analysis suggested that BEND7-positive platelets play a role in immune modulation and platelet activation. Conclusion: BEND7 was identified as a platelet-specific gene involved in immune regulation during sepsis. Targeting BEND7-positive platelets may present new therapeutic opportunities in sepsis management.

Xuebijing (XBJ) injection is a Traditional Chinese medicine (TCM) injection extracted and prepared using modern TCM formulation techniques. As a widely used treatment for critically ill patients, XBJ injection has shown significant therapeutic effects in clinical applications in China. It plays an indispensable role in sepsis-induced myocardial dysfunction (SIMD). However, its underlying mechanisms require further investigation.

This study aims to investigate the cardioprotective effects of XBJ in sepsis and to elucidate its underlying mechanisms.

Network pharmacology was used to predict the potential active components and core targets of XBJ against SIMD. Furthermore, animal models were used to verify its pharmacodynamics. Metabolomics was integrated to track the myocardial tissue metabolites from septic rats. Molecular docking, qRT-PCR, Western blot, and immunofluorescence were performed to investigate the mechanisms of action.

Network pharmacology predicted that the efficacy of XBJ is attributed to 104 active components and 178 targets. Metabolomics of myocardial tissue from CLP rats revealed that the key metabolic pathways included the tricarboxylic acid (TCA) cycle, pyrimidine metabolism, and purine metabolism. Five core active components of XBJ (quercetin, luteolin, rutin, β-sitosterol, and cryptotanshinone) can modulate interleukin-6 (IL-6), epidermal growth factor receptor (EGFR), B-cell lymphoma 2 (BCL2), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), and hypoxia-inducible factor 1-alpha (HIF-1α). Molecular docking analysis confirmed that the core components of XBJ have a strong affinity for these key targets. Additionally, qRT-PCR, Western blotting, and immunofluorescence results indicated that XBJ can reverse the expression of these targets, ameliorated energy metabolism dysregulation, and alleviated SIMD.

XBJ exerts protective effects in a rat model of sepsis-induced myocardial injury, by modulating energy metabolism pathways that regulate key SIMD-related targets (IL-6, EGFR, BCL2, PGC-1α, and HIF-1α), thereby improving myocardial energy metabolism and alleviating inflammatory responses.

Objective : Recent studies have proposed that Krebs cycle metabolites may serve as potential biomarkers for prognosis in sepsis. However, whether these metabolites are associated with disease severity and can be applied to improve the effectiveness of current prognosis assessment in sepsis remains unclear and is explored in this study. Methods : This prospective multicenter cohort study was conducted in medical intensive care units (ICUs). From December 2019 to September 2022, consecutive patients admitted to medical ICUs for sepsis were screened and recruited. Plasma samples were obtained for measurements of cytokines and Krebs cycle metabolites, including citrate/isocitrate, cis-aconitate, alpha-ketoglutarate, succinate, fumarate, and malate. Results : In total, 97 patients admitted for sepsis were enrolled in the study. The 28-day mortality rate was 17.5%, and nonsurvivors exhibited significantly increased plasma lactate levels and Sequential Organ Failure Assessment (SOFA) scores. Plasma levels of Krebs cycle metabolites were significantly correlated with both plasma lactate and interleukin-6 levels. Except for citrate/isocitrate, all Krebs cycle metabolites were significantly elevated in patients with acute kidney injury. Multivariate Cox proportional hazard models, adjusted for plasma lactate levels and SOFA scores, revealed that plasma levels of alpha-ketoglutarate (adjusted hazard ratio [HR]: 2.404, P = 0.002), fumarate (adjusted HR: 1.904, P = 0.001) and malate (adjusted HR: 1.327, P = 0.019) were associated with increased risk of 28-day mortality. Conclusions : Study findings indicate that Krebs cycle metabolites, particularly alpha-ketoglutarate, fumarate, and malate, when applied with SOFA score, might enhance prognostic assessment in patients with sepsis.

This observational study focused on the impact of Interleukin-6 (IL-6)-related factors (notably the IL-6 receptor (IL-6R) gene's rs2228145 polymorphism) on long-COVID risk in individuals who had previously experienced COVID-19 infection(s). The purpose of the study was to better understand such factors' contribution to long-COVID risk, and thus possibly initiate future strategies for using IL-6-related factors as biomarkers predictive of risk (while also obtaining data that may influence long-COVID management and treatment more generally). DNA and blood samples, plus questionnaire responses regarding long-COVID symptoms (including chronic fatigue and cognitive impairment), were collected from 175 participants who had previously experienced COVID-19 infection(s). Potential associations between self-reported long-COVID symptoms and participants' rs2228145 genotypes (determined using TaqMan-based genotyping assays) and/or their circulating IL-6, sIL-6R and sgp130 levels (determined using ELISA) were evaluated. Univariate-regression analyses demonstrated that odds of exhibiting long-COVID symptoms increased with severity/number of previous COVID-19 infection(s) and with hypertension as a co-morbidity, while vaccination decreased the likelihood of developing long-COVID. While long-COVID sufferers exhibited higher IL-6 signalling activity than healthy control individuals, rs2228145 genotype was not associated with long-COVID odds-ratios in- the entire-study cohort. Following identification of significant seasonal variations within our dataset, the entire-study cohort was stratified depending on when samples/questionnaire responses were obtained. In the resulting 'summer' sub-cohort (but not the 'winter' sub-cohort), the rs2228145 AA genotype was significantly over-represented amongst those exhibiting long-COVID symptoms, and long-COVID odds-ratios were significantly reduced for the CC and AC genotypes. While interpretation is complicated by seasonal variations, these findings may be of medical/biomedical value. Importantly, as IL-6 was higher in long-COVID sufferers than healthy controls, and rs2228145 AA genotype-bearing individuals within our 'summer' sub-cohort were at elevated risk of developing long-COVID, these findings point towards possible future use of IL-6 and/or rs2228145 genotype as biomarkers predictive of long-COVID risk, which may bring advantages regarding management and treatment of long-COVID.

This study aims to examine the dose-response relationship between visceral adipose tissue (VAT), abdominal subcutaneous adipose tissue (ASAT), and sepsis and sepsis-related mortality. Additionally, we seek to determine whether VAT or ASAT offers better prognostic value for above outcomes compared to traditional measures such as waist circumference (WC) and body mass index (BMI), using data from the UK Biobank.

In this secondary analysis of the UK Biobank, 25,083 participants with available abdominal MRI data were included. Cox proportional hazards regression was used to examine the association between VAT and ASAT, both as tertiles and continuous variables, and the incidence of sepsis as well as sepsis-related mortality.

Over a median follow-up of 14.1 years (interquartile range: 13.4-14.9 years), 305 cases of incident sepsis (0.86 per 1000 person-years) and 90 sepsis-related deaths (0.25 per 1000 person-years) were identified. Both VAT and ASAT showed a linear relationship with sepsis risk, with hazard ratios (HR) of 1.29 (95% CI: 1.12-1.47) for VAT and 1.22 (95% CI: 1.07-1.40) for ASAT per standard deviation increase. After further adjusting for BMI or WC, the association with ASAT was eliminated, while VAT remained significant. Only VAT was positively associated with sepsis-related mortality, although this association was nullified after adjusting for BMI or WC. VAT was a more important predictor of sepsis risk than BMI or WC, and its inclusion improved the predictive model already adjusted for BMI or WC. In contrast, ASAT did not provide any additional predictive value for either sepsis risk or sepsis-related mortality compared to BMI and WC.

VAT is independently associated with sepsis risk and improves its prediction beyond traditional measures like BMI and WC. However, VAT does not enhance the prediction of sepsis-related mortality, with BMI and WC performing better in this context.

Objective: The causality between cardiometabolic disease (CMD) and sepsis has remained largely unknown. To elucidate this, we conducted a Mendelian randomization (MR) and population study. Methods: First, we used univariable and multivariable MR analyses to investigate causal associations between CMD and sepsis-related outcomes. We obtained genome-wide association study summary from both the MRC Integrative Epidemiology Unit and the FinnGen consortium. Subsequently, a two-step mediation MR analysis was performed to explore mediators. Afterward, we conducted an observational study using the Medical Information Mart for Intensive Care IV database, in which multivariable logistic regression models were utilized to examine the relationship between CMD and sepsis-related outcomes. Results: In the MR study, type 2 diabetes mellitus (OR = 1.058, 95% CI = 1.017-1.100, P = 0.005), obesity (OR = 1.113, 95% CI = 1.057-1.172, P < 0.001), and heart failure (HF) (OR = 1.178, 95% CI = 1.063-1.305, P = 0.002) were independently causally related to sepsis. Obesity (OR = 1.215, 95% CI = 1.027-1.437, P = 0.023) and HF (OR = 1.494, 95% CI = 1.080-2.065, P = 0.015) also showed independent causal associations with sepsis critical care admission. Mediation MR analysis identified 23 blood metabolites potentially causally linked to sepsis ( P < 0.05), yet none mediated the relationship between CMD and sepsis. In the observational study, we found associations between sepsis and several conditions including type 2 diabetes mellitus, obesity, hypertension, stroke, HF, and hyperlipidemia after adjusting for confounding factors. Moreover, hypertension, stroke, HF, coronary artery disease, and hyperlipidemia were linked to sepsis critical care admission. Conclusion: This study has, for the first time, revealed indicative evidence of a causal relationship between CMD and sepsis through observational and genetic evidence. Taken together, clinical attention to sepsis may be warranted among patients with CMD.

Sepsis is a syndrome of life-threatening acute organ dysfunction caused by a dysregulated host response to infection. Sepsis-associated encephalopathy (SAE) refers to the diffuse brain dysfunction observed in sepsis cases, clinically characterized by a spectrum of neuropsychiatric manifestations ranging from delirium to coma. SAE is independently associated with increased short-term mortality and long-term neurological abnormalities, with currently no effective preventive or treatment strategies. The pathogenesis is intricate, involving disruptions in neurotransmitters, blood-brain barrier (BBB) breakdown, abnormal brain signal transmission, and oxidative stress, among others. These mechanisms interact or act in conjunction, contributing to the complexity of SAE. Scholars worldwide have made significant strides in understanding the pathogenesis of SAE, offering new perspectives for diagnosis and treatment. This review synthesizes recent mechanistic breakthroughs and clinical evidence to guide future research directions, particularly in targeting BBB restoration and oxidative stress.

Sepsis is a life-threatening inflammatory condition, and its underlying genetic mechanisms are not yet fully elucidated. We applied methods such as Mendelian randomization (MR), genetic correlation analysis, and colocalization analysis to integrate multi-omics data and explore the relationship between genetically associated genes and sepsis, as well as sepsis-related mortality, with the goal of identifying key genetic factors and their potential mechanistic pathways.

To identify therapeutic targets for sepsis and sepsis-related mortality, we conducted an MR analysis on 11,643 sepsis cases and 1,896 cases of 28-day sepsis mortality from the UK Biobank cohort. The exposure data consisted of 15,944 potential druggable genes (expression quantitative trait loci, eQTL) and 4,907 plasma proteins (protein quantitative trait loci, pQTL). We then performed sensitivity analysis, SMR analysis, reverse MR analysis, genetic correlation analysis, colocalization analysis, enrichment analysis, and protein-protein interaction network analysis on the overlapping genes. Validation was conducted using 17,133 sepsis cases from FinnGen R12. Drug prediction and molecular docking were subsequently used to further assess the therapeutic potential of the identified drug targets, while PheWAS was used to evaluate potential side effects. Finally, mediation analysis was conducted to identify the mediating role of related metabolites.

The MR analysis results identified a significant causal relationship between 24 genes and sepsis. The robustness of these causal associations was further strengthened by SMR analysis, sensitivity analysis, and reverse MR analysis. Genetic correlation analysis revealed that only two of these genes were genetically correlated with sepsis. Colocalization analysis showed that only one gene was closely associated with sepsis, while validation using the FinnGen dataset identified three genes. In the MR analysis of 28-day sepsis mortality, seven genes were found to have significant associations, with reverse MR analysis excluding one gene. The remaining genes passed sensitivity analysis, with no significant genes identified in genetic correlation and colocalization analyses. Molecular docking demonstrated excellent binding affinity between drugs and proteins with available structural data. PheWAS at the gene level did not reveal any potential side effects of the related drugs.

The identified drug targets, associated pathways, and metabolites have enhanced our understanding of the complex relationships between genes and sepsis. These genes and metabolites can serve as effective targets for sepsis treatment, paving new pathways in this field and laying a foundation for future research.

BTB and CNC homology 1 (BACH1) plays a crucial role in the pathogenesis of acute lung injury (ALI) caused by gram-negative bacteria. However, its exact mechanisms in Staphylococcus aureus (SA)-induced ALI, a gram-positive bacterial infection, remain incompletely understood. In this study, we generated a BACH1-knockout mouse model (BACH1-/-) to investigate the role of BACH1 and its underlying mechanisms in regulating the development of sepsis-induced acute lung injury (ALI). Elevated levels of BACH1 were observed in both serum samples from septic patients and mouse models. Deletion of BACH1 alleviated ALI symptoms induced by sepsis. In bone marrow-derived macrophages, BACH1 deletion or knockdown suppressed NF-κB p65 phosphorylation and the induction of pro-inflammatory cytokines. Mechanistic studies demonstrated that BACH1 downregulated tumor necrosis factor-alpha-induced protein 3 (TNFAIP3) mRNA expression by binding to its promoter region. These findings uncover inhibiting BACH1 may be a promising therapeutic strategy for treating gram-positive bacteria-induced ALI.

Sepsis is a life-threatening organ dysfunction resulting from a dysregulated host response to infection. Due to the high mortality rates and treatment costs associated with sepsis, research is focusing on innovative treatment strategies to replace one dimensional approaches. Recent studies are being conducted on the use of immunotherapeutics in sepsis and the impact of treatment timing. This study aimed to elucidate the significance of treatment timing in sepsis immunotherapy with Tocilizumab (TCZ) and the implications of differences in treatment timing.

LPS-induced sepsis model was established in rats to assess the changes in interleukin-6 (IL-6) over a 24-h sepsis period and its correlation with lung and kidney injury. The impact of TCZ treatments at various time points was evaluated by molecular and histopathological methods. The effect of TCZ treatment timing on survival was analyzed using Kaplan-Meier survival analysis.

IL-6 reached peak concentrations in the early stages of sepsis, whereas lung damage peaked subsequent to the IL-6 peak, and kidney damage manifested considerably later. The early treatment group, receiving intervention one hour post-sepsis induction, exhibited the most favorable molecular and histopathological outcomes. Conversely, the group receiving the latest treatment, at sixteen hours post-sepsis induction, demonstrated the poorest results. Survival analysis indicated that the group treated at the tenth hour exhibited the highest survival rate.

Variations in the timing of sepsis treatment with TCZ yield significantly different molecular outcomes, histopathological results, and survival rates. A thorough investigation of the timing of immunotherapeutic applications in sepsis treatment will enhance the efficiency of sepsis treatments.

Gastroesophageal reflux disease (GERD), akin to sepsis, is mediated by inflammatory reactions and exhibits a strong correlation with intestinal dysbiosis. We sought to examine whether these associations reflect causality using the Mendelian randomization (MR) mediation analysis. Genetic data were obtained from genome-wide association studies. Two-sample MR were performed to evaluate the causal association, accompanied by sensitivity analyses. Reverse direction MR was undertaken to assess the potential for reverse causation. Then, mediation analysis was performed to evaluate the mediating effect of gut bacterial pathway abundance in this relationship. Genetic predisposition to GERD was significantly associated with sepsis [inverse variance weighting: odds ratio = 1.366, P = 2.13E-09, 95% confidence interval [CI] 1.233-1.513] and sepsis-related 28-day mortality (inverse variance weighting: odds ratio = 1.412, P = 6.64E-03, 95% CI 1.101-1.812). There is no convincing evidence for reverse causation. Gut bacterial pathway abundance (ARO.PWY..chorismate.biosynthesis.I) mediates the effect of GERD on sepsis (β = 0.036, 95% CI 0.004-0.067, P = .025), accounting for 11.406% of the total effect; Gut bacterial pathway abundance (PWY.7219..adenosine.ribonucleotides.de.novo.biosynthesis) mediates the effect of GERD on sepsis (β = 0.026, 95% CI -0.003 to 0.056, P = .083), accounting for 8.486% of the total effect; gut bacterial pathway abundance (ARO.PWY..chorismate.biosynthesis.I) mediates the effect of GERD on sepsis (28-day death) (β = 0.079, 95% CI 0.005-0.153, P = .036), accounting for 22.890% of the total effect; gut bacterial pathway abundance (TRNA.CHARGING.PWY..tRNA.charging) mediates the effect of GERD on sepsis (28-day death) (β = -0.066, 95% CI -0.140 to 0.007, P = .078), accounting for -19.171% of the total effect. The present MR study supported GERD as a causal risk factor of sepsis and sepsis-related 28-day mortality. Three specific gut bacterial pathway abundances were identified that played a partial mediating role in the aforementioned causal relationship between GERD and sepsis.

The role that sleep patterns play in sepsis risk remains poorly understood.

The objective was to evaluate the association between various sleep behaviours and the incidence of sepsis.

In this prospective cohort study, we analysed data from the UK Biobank (UKB). A total of 409,570 participants who were free of sepsis at baseline were included. We used a composite sleep score that considered the following five sleep behaviours: sleep chronotype, sleep duration, insomnia, snoring, and daytime sleepiness. Cox proportional hazards regression analysis was used to estimate the associations between healthy sleep scores and incident sepsis.

During a mean follow-up of 13.54 years, 13,357 (3.26%) incident sepsis cases were recorded. Among the 409,570 participants with a mean age of 56.47 years, 184,124 (44.96%) were male; 9942 (2.43%) reported 0 to 1 of the five healthy sleep behaviours; 46,270 (11.30%) reported 2 behaviours; 115,272 (28.14%) reported 3 behaviours; 150,522 (36.75%) reported 4 behaviours; and 87,564 (21.38%) reported 5 behaviours at baseline. Each one-point increase in the sleep score was associated with a 5% lower risk of developing sepsis (hazard ratio (HR), 0.95; 95% confidence interval (CI), 0.93-0.97). Compared with a healthy sleep score of 0-1, for a sleep score of 5, the multivariate-adjusted HR (95% CI) for sepsis was 0.76 (0.69-0.83). In addition, we found that the negative correlation was stronger in participants who were aged < 60 years than in their older counterparts (p for interaction < 0.001). However, healthy sleep pattern was not associated with sepsis-related death and critical care admission.

Findings from this cohort study suggest that a healthy sleep pattern may reduce the risk of developing sepsis, particularly among younger individuals.

Background : The interrelation between the plasma proteome and plasma metabolome with sepsis presents a multifaceted dynamic that necessitates further research to elucidate the underlying causal mechanisms. Methods : Our investigation used public genome-wide association study data to explore the relationships among the plasma proteome, metabolome, and sepsis, considering different sepsis subgroup. Initially, two-sample Mendelian randomization established causal connections between the plasma proteome and metabolome with sepsis. Subsequently, multivariate and iterative Mendelian randomization analyses were performed to understand the complex interactions in plasma during sepsis. The validity of these findings was supported by thorough sensitivity analyses. Result : The study identified 25 plasma proteins that enhance risk and 34 that act as protective agents in sepsis. After P value adjustment (0.05/1306), ICAM5 emerged with a positive correlation to sepsis susceptibility ( P value = 2.14E-05, OR = 1.10, 95% CI = 1.05-1.15), with this significance preserved across three sepsis subgroup examined. Additionally, 29 plasma metabolites were recognized as risk factors, and 15 as protective factors for sepsis outcomes. After P value adjustment (0.05/997), elevated levels of 1,2,3-benzenetriol sulfate (2) was significantly associated with increased sepsis risk ( P value = 3.37E-05, OR = 1.18, 95% CI = 1.09-1.28). Further scrutiny revealed that this plasma metabolite notably augments the abundance of ICAM5 protein ( P value = 3.52E-04, OR = 1.11, 95% CI = 1.04-1.17), devoid of any detected heterogeneity, pleiotropy, or reverse causality. Mediated Mendelian randomization revealed ICAM5 mediated 11.9% of 1,2,3-benzenetriol sulfate (2)'s total effect on sepsis progression. Conclusion : This study details the causal link between the plasma proteome and metabolome with sepsis, highlighting the roles of ICAM5 and 1,2,3-benzenetriol sulfate (2) in sepsis progression, both independently and through crosstalk.

We hypothesised that the biological heterogeneity of sepsis may highlight sepsis subtypes with differences in response to intravenous vitamin C treatment in the Lessening Organ Dysfunction with VITamin C (LOVIT) trial. Our aims were to identify sepsis subtypes and to test whether sepsis subtypes have differences in treatment effect to vitamin C and describe putative biological effects of vitamin C treatment.

We measured biomarkers of inflammation, at baseline and at 7 days post-randomisation, in 457/863 (53.0%) of participants with plasma samples in the LOVIT trial. We used agglomerative hierarchical clustering on log10-transformed baseline data of 26 biomarkers to identify sepsis subtypes. We analysed differences in vitamin C treatment effect with regression models incorporating robust standard errors to report odds ratio and 95% confidence intervals (OR(95% CI)). All analyses were completed blinded to treatment allocation.

Our cohort included 233/429 (54.3%) allocated to vitamin C and 224/434 (51.6%) allocated to placebo. A three-subtype model best explained the variance in our data. Subtype-2 had the highest, and subtype-3 had the lowest levels of inflammatory response. In paired longitudinal samples, vitamin C did not have discernible anti-inflammatory effects, with anti-inflammatory effects related to time since randomisation and concomitant hydrocortisone treatment. The treatment effect estimates (OR (95% CI)) for subtype-1, subtype-2 and subtype-3 were 1.04 (0.63-1.73), 1.33 (0.53-3.36) and 1.95 (0.85-4.49), respectively (test of heterogeneity p = 0.002).

We report three sepsis subtypes based on inflammatory response profile. No subtype benefitted from vitamin C treatment in the LOVIT trial, with heterogeneity of treatment effect in the magnitude of harm.

Funded by the Lotte and John Hecht Memorial Foundation; LOVIT ClinicalTrials.gov number, NCT03680274.

The role of IL-6 responses in human tuberculosis risk is unknown. IL-6 signalling inhibitors, such as tocilizumab, are thought to increase the risk of progression to tuberculosis, and screening for latent Mycobacterium tuberculosis infection before using these drugs is widely recommended. We used single nucleotide polymorphisms (SNPs) in and near the IL-6 receptor gene (IL6R), including the non-synonymous variant, rs2228145, for which the C allele contributes to reduced classic (cis) IL-6 signalling activity, to test the hypothesis that altered IL-6 signalling is causally associated with the risk of developing tuberculosis.

We performed a meta-analysis of genome-wide association studies (GWAS) published in English from database inception to Jan 1, 2024. GWAS were identified from the European Bioinformatics Institute, MRC Integrative Epidemiology Unit catalogues, and MEDLINE, selecting publicly available studies for which tuberculosis was an outcome and that included the IL6R rs2228145 SNP. Using each study's population-level summary statistics, effect estimates were extracted for each additional copy of the C allele of rs2228145. We used these estimates to perform multi-ancestry, two-sample mendelian randomisation analyses to estimate the causal effect of reduced IL-6 signalling on tuberculosis. Our primary analyses used rs2228145-C as a genetic instrument, weighted on C-reactive protein (CRP) reduction as a measure of the effect on IL-6 signalling. We also took an alternative, ancestry-specific, multiple SNP approach using IL-6 receptor plasma protein as an exposure. Additionally, we compared the effects of rs2228145 in tuberculosis with those in critical COVID-19, rheumatoid arthritis, Crohn's disease, and coronary artery disease using the summary statistics extracted from GWAS.

17 GWAS were included, collating data for 19 302 individuals with tuberculosis (cases) and 1 019 821 population controls across multiple ancestries. For each additional rs2228145-C allele, the odds of tuberculosis reduced (odds ratio [OR] 0·94 [95% CI 0·92-0·97]; p=6·8 × 10-6). Multi-ancestry mendelian randomisation analyses supported these findings, with decreased odds of tuberculosis associated with readouts of reduced IL-6 signalling (0·52 [0·39-0·69] for each natural log CRP decrease; p=6·8 × 10-6), with weak evidence of heterogeneity (I2=0·315; p=0·11). Ancestry-specific, multiple SNP mendelian randomisation using increase in IL-6 receptor plasma protein as an exposure revealed a similar reduced risk of tuberculosis (OR 0·94 [95% CI 0·93-0·96]; p=2·4 × 10-10). The protective effects on tuberculosis seen with rs2228145-C were similar in size and direction to those observed in critical COVID-19 (0·66 [0·50-0·86]), Crohn's disease (0·57 [0·44-0·74]), and rheumatoid arthritis (0·45 [0·36-0·58]), all of which benefit from the therapeutic effects of IL-6 antagonism.

Our findings propose a causal relationship between reduced IL-6 signalling and lower risk of tuberculosis, akin to the effect seen in other IL-6 mediated diseases. This study suggests that IL-6 antagonists do not increase the risk of tuberculosis but rather should be investigated as therapeutic adjuncts in its treatment.

UK National Institute for Health and Care Research, Wellcome Trust, EU European Regional Development Fund, the Welsh Government, and UK Research and Innovation.

Aims/Background Sepsis is a life-threatening condition resulting from dysregulated immune responses to infection, leading to organ dysfunction. High-density lipoprotein (HDL) and red cell distribution width (RDW) have shown significant correlations with sepsis severity, yet the combined prognostic value of HDL and RDW in evaluating sepsis severity and outcomes remains unclear. This study examines the relationship between HDL and RDW levels and sepsis severity, as well as evaluates the combined utility of these markers in predicting disease severity and patient outcomes. Methods This retrospective study included 103 patients diagnosed with sepsis. Clinical data, including HDL and RDW levels, were collected for analysis. Patients were divided into shock and non-shock groups based on the presence of septic shock and into survival and death groups based on 30-day in-hospital mortality. Multivariate logistic regression was used to identify factors influencing sepsis severity and prognosis, while the predictive value of HDL in combination with RDW was evaluated using receiver operating characteristic (ROC) curve analysis. Results Multivariate analysis identified sequential organ failure assessment (SOFA) score (OR = 6.566), interleukin-6 (IL-6) (OR = 2.568), HDL (OR = 0.864), and RDW (OR = 4.052) as independent predictors of sepsis severity (p < 0.05 for all). ROC analysis demonstrated that HDL combined with RDW yielded the highest diagnostic accuracy for sepsis severity, with an area under curve (AUC) of 0.962, sensitivity of 97.56%, and specificity of 91.94%. Additionally, SOFA score (OR = 2.354), interleukin-6 (IL-6) (OR = 1.446), HDL (OR = 0.870), and RDW (OR = 3.502) were independent prognostic indicators (p < 0.05 for all). ROC analysis for prognosis showed that HDL combined with RDW had the highest predictive efficacy for the prognosis of sepsis, with an AUC of 0.922, sensitivity of 79.31%, and specificity of 93.24%. Conclusion The combination of HDL and RDW is a robust indicator for the evaluation of sepsis severity and is a valuable prognostic tool for assessing 30-day mortality risk in sepsis patients.

Acute respiratory distress syndrome (ARDS) is caused by a complex interplay among hyperinflammation, endothelial dysfunction, and alveolar epithelial injury. Targeted treatments toward the underlying pathways have been unsuccessful in unselected patient populations. The first reliable biological subphenotypes reflective of these biological disease states have been identified in the past decade. Subphenotype targeted intervention studies are needed to advance the pharmacologic treatment of ARDS.

Sepsis remains a major global health challenge, yet specific diagnostic biomarkers are still lacking. This study aims to investigate the causal relationship between B7 homologue 3 (B7-H3) and sepsis susceptibility, severity, and clinical outcomes using Mendelian randomization (MR) analysis, in order to evaluate its potential as a biomarker.

Genetic data related to sepsis (including overall sepsis, sepsis-related mortality with 28 days, severe sepsis, and severe sepsis with 28-day mortality) were extracted from genome-wide association study (GWAS) datasets. Single nucleotide polymorphisms (SNPs) associated with B7-H3 were selected as instrumental variables. The inverse-variance weighted (IVW) was used as the primary approach for causal effect estimation, while weighted median (WME) and MR-Egger regression served as supplementary methods. Additionally, a constrained maximum likelihood-model average (cML-MA) approach was employed to enhance the reliability of causal effect estimation. Cochran's Q test was conducted to assess heterogeneity, and MR-PRESSO along with the MR-Egger intercept method were used to detect horizontal pleiotropy. Sensitivity analyses were performed using the leave-one-out method. A reverse MR analysis was performed with sepsis as the exposure and B7-H3 as the outcome to exclude potential reverse causation.

IVW analysis indicated a significant positive causal association between B7-H3 and sepsis susceptibility, severity, and clinical outcomes. A genetically predicted 1-standard deviation (SD) increase in B7-H3 levels was associated with a 10.4% increased risk of sepsis (OR=1.104, 95% CI 1.021 to 1.194, P=0.013), a 26.2% increased risk of sepsis-related 28-day mortality (OR=1.262, 95% CI 1.078 to 1.476, P=0.004), a 22.3% increased risk of severe sepsis (OR=1.223, 95% CI 1.023 to 1.463, P=0.027), and a 60.2% increased risk of severe sepsis with 28-day mortality (OR=1.602, 95% CI 1.119 to 2.294, P=0.010). The causal effect direction remained consistent across IVW, WME, MR-Egger, and cML-MA analyses, reinforcing the robustness and reliability of the results. Cochran's Q test showed no heterogeneity (P>0.05), while MR-PRESSO and MR-Egger intercept tests indicated no evidence of horizontal pleiotropy (both P>0.05). The leave-one-out analysis showed that removing individual SNPs did not significantly alter the causal estimates. Reverse MR analysis showed no causal association between sepsis and B7-H3.

B7-H3 may serve as an important biomarker for sepsis, as it is closely associated with sepsis susceptibility, severity, and clinical outcomes.

This study investigated the causal effect of gut microbiota on critical pneumonia. Data came from a large-scale gut microbiota data set (n = 18,340) and the critical pneumonia genome-wide genotyping array (cases n = 2758 and controls n = 42,8607). Inverse variance weighting was used as the primary Mendelian randomization (MR) analysis method. Weighted median, MR-Egger, simple model, weighted model, and MR-Egger, were used to evaluate robustness. Sensitivity analysis used Cochran Q test, MR-Egger intercept test, and MR-PRESSO. For critical pneumonia, inverse variance weighting estimates suggested that Class Verrucomicrobiae (OR = 0.415; 95% CI: 0.207, 0.833; P = .013), Family Verrucomicrobiaceae (OR = 0.415; 95% CI: 0.207, 0.833; P = .013), Genus Akkermansia (OR = 0.415; 95% CI: 0.207, 0.833; P = .013), Genus LachnospiraceaeFCS020group (OR = 0.449; 95% CI: 0.230, 0.890; P = .021), Genus Parasutterella (OR = 0.466; 95% CI: 0.233, 0.929; P = .030), Genus Prevotella7 (OR = 0.645; 95% CI: 0.432, 0.960; P = .031), Order Verrucomicrobiales (OR = 0.415; 95% CI: 0.207, 0.833; P = .013), and Phylum Cyanobacteria (OR = 0.510; 95% CI: 0.272, 0.956; P = .036) had a reduced risk, while Family Enterobacteriaceae (OR = 2.746; 95% CI: 1.008, 7.474; P = .048), Genus RuminococcaceaeUCG003 (OR = 2.811; 95% CI: 1.349, 5.851; P = .006) and Order Enterobacteriales (OR = 2.746; 95% CI: 1.008, 7.474; P = .048) were associated with an increased risk. Sensitivity analyses confirmed that the aforementioned correlations were robust.

Despite the exploration of the connections between serum low-density lipoprotein cholesterol (LDL-C) levels and aneurisms in epidemiological studies, causality remains unclear. Therefore, this study aimed to assess the causal impact of LDL-C-lowering targets (HMGCR, PCSK9, NPC1L1, CETP, APOB, and LDLR) on various forms of aneurisms using Mendelian Randomization (MR) analysis.

Two genetic instruments acted as proxies for exposure to LDL-C-lowering drugs: expression quantitative trait loci of drug target genes and genetic variants linked to LDL-C near drug target genes. Summary-data-based MR (SMR), inverse-variance-weighted MR (IVW-MR), and multivariable MR (MVMR) methods were employed to compute the effect estimates.

The SMR analysis revealed substantial associations between increased HMGCR expression and a heightened risk of aortic aneurism (odds ratio [OR] = 1.603, 95% confidence interval [CI] = 1.209-2.124), thoracic aortic aneurism (OR = 1.666, 95% CI = 1.122-2.475), and abdominal aortic aneurism (OR = 1.910, 95% CI = 1.278-2.856). Likewise, IVW-MR analysis demonstrated positive correlations between HMGCR-mediated LDL-C and aortic aneurism (OR = 2.228, 95% CI = 1.702-2.918), thoracic aortic aneurism (OR = 1.751, 95% CI = 1.191-2.575), abdominal aortic aneurism (OR = 4.784, 95% CI = 3.257-7.028), and cerebral aneurism (OR = 1.993, 95% CI = 1.277-3.110). Furthermore, in the MVMR analysis, accounting for body mass index, smoking, and hypertension, a significant positive relationship was established between HMGCR-mediated LDL-C levels and the development of aortic aneurisms, encompassing both thoracic and abdominal subtypes. Similarly, consistent positive associations were observed for PCSK9 and CETP genes, as well as PCSK9-mediated and CETP-mediated LDL-C levels, with the occurrence of aortic aneurism and abdominal aortic aneurism. Nonetheless, the evidence for potential associations between APOB, NPC1L1 and LDLR with specific subtypes of aortic aneurisms lacked consistent support from both SMR and IVW-MR analyses.

Our MR analysis offered compelling evidence of a plausible causal link between HMGCR and an increased risk of aortic aneurism, encompassing both thoracic and abdominal types. These groundbreaking findings further bolster the case for the deployment of HMGCR inhibitors in the treatment of aortic aneurisms, including both thoracic and abdominal variants.

Inflammation and immune dysregulation are hypothesized contributors to endometrial carcinogenesis; however, the precise underlying mechanisms remain unclear.

We measured pre-diagnostically 152 plasma protein biomarkers in 624 endometrial cancer case-control pairs nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Odds ratios (ORs) were estimated using conditional logistic regression, accounting for confounding and multiple comparisons. Proteins considered as associated with endometrial cancer risk were further tested in a two-sample Mendelian randomization (MR) analysis using summary data from the UK Biobank (n = 52,363) and the Endometrial Cancer Association Consortium (12,270 cases and 46,126 controls).

In the EPIC nested case-control study, IL-6 [OR per NPX (doubling of concentration) = 1.28 (95% confidence interval (CI) 1.03-1.57)], HGF [1.48 (1.06-2.07)], PIK3AP1 [1.22 (1.00-1.50)] and CLEC4G [1.52 (1.00-2.32)] were positively associated; HSD11B1 [0.67 (0.49-0.91)], SCF [0.68 (0.49-0.94)], and CCL25 [0.80 (0.65-0.99)] were inversely associated with endometrial cancer risk; all estimates had multiple comparisons adjusted P-value > 0.05. In complementary MR analysis, IL-6 [OR per inverse-rank normalized NPX = 1.19 (95% CI 1.04-1.36)] and HSD11B1 [0.91 (0.84-0.99)] were associated with endometrial cancer risk.

Altered IL-6 signalling and reduced glucocorticoid activity via HSD11B1 might play important roles in endometrial carcinogenesis.

Funding for IIG_FULL_2021_008 was obtained from Wereld Kanker Onderzoek Fonds (WKOF), as part of the World Cancer Research Fund International grant programme; Funding for INCA_15849 was obtained from Institut National du Cancer (INCa).

Background/Objectives: Sepsis and septic shock remain significant contributors to high early mortality rates among patients admitted to the emergency department (ED). The objective of this study was to identify among newer biomarkers those with the highest sensitivity in early mortality prediction. Methods: This prospective, unicentric, observational study enrolled 47 adult patients admitted to the ED between November 2020 and December 2022. This study monitored the kinetics of the older and newer biomarkers, including azurocidin (AZU1), soluble triggering receptor expressed on myeloid cells (sTREM), soluble urokinase-type plasminogen activator receptor (suPAR), high-sensitivity C-reactive protein (hsCRP), procalcitonin (PCT), and interleukin-6 (IL-6), and their capacity in predicting mortality. Results: SuPAR showed the most significant predictive utility for early prognosis of mortality in the ED, with an area under the curve (AUC) of 0.813 (95% CI: 0.672 to 0.912), a cutoff value > 8168 ng/mL, sensitivity of 75%, and specificity of 81.48% (p < 0.001). IL-6 and PCT showed comparable prognostic accuracy, whereas hsCRP and AZU1 demonstrated lower predictive performance. Conclusions: In our study, suPAR, IL-6, and PCT showed good predictive value for short-term mortality in sepsis and septic shock patients.

Sepsis is an inflammatory disease that leads to severe mortality, highlighting the urgent need to identify new therapeutic strategies for sepsis. Proteomic research serves as a primary source for drug target identification. We employed proteome-wide Mendelian randomization (MR), genetic correlation analysis, and colocalization analysis to identify potential targets for sepsis and sepsis-related death.

Genetic data for plasma proteomics were obtained from 35,559 Icelandic individuals and an initial MR analysis was conducted using 13,531 sepsis cases from the FinnGen R10 cohort to identify associations between plasma proteins and sepsis. Subsequently, significant proteins underwent genetic correlation analysis, followed by replication in 54,306 participants from the UK Biobank Pharma Proteomics Project and validation in 11,643 sepsis cases from the UK Biobank. The identified proteins were then subjected to colocalization analysis, enrichment analysis, and protein-protein interaction network analysis. Additionally, we also investigated a MR analysis using plasma proteins on 1,896 sepsis cases with 28-day mortality from the UK Biobank.

After FDR correction, MR analysis results showed a significant causal relationship between 113 plasma proteins and sepsis. Genetic correlation analysis revealed that only 8 proteins had genetic correlations with sepsis. In the UKB-PPP replication analysis, only 4 proteins were found to be closely associated with sepsis, while validation in the UK Biobank sepsis cases found overlaps for 21 proteins. In total, 30 proteins were identified in the aforementioned analyses, and colocalization analysis revealed that only 2 of these proteins were closely associated with sepsis. Additionally, in the 28-day mortality MR analysis of sepsis, we also found that only 2 proteins were significant.

The identified plasma proteins and their associated metabolic pathways have enhanced our understanding of the complex relationship between proteins and sepsis. This provides new avenues for the development of drug targets and paves the way for further research in this field.

Previous research has shown a strong correlation between sepsis and brain structure. However, whether this relationship represents a causality remains elusive. In this study, we employed Mendelian randomization (MR) to probe the associations of genetically predicted sepsis and sepsis-related death with structural changes in specific brain regions. Genome-wide association study (GWAS) data for sepsis phenotypes (sepsis and sepsis-related death) were obtained from the IEU OpenGWAS. Correspondingly, GWAS data for brain structural traits (volume of the subcortical structure, cortical thickness, and surface area) were derived from the ENIGMA consortium. Inverse variance weighted was mainly utilized to assess the causal effects, while weighted median and MR-Egger regression served as complementary methods. Sensitivity analyses were implemented with Cochran Q test, MR-Egger regression, and MR-PRESSO. In addition, a reverse MR analysis was carried out to assess the possibility of reverse causation. We identified that genetic liability to sepsis was normally significantly associated with a reduced surface area of the postcentral gyrus (β = -35.5280, SE = 13.7465, P = .0096). The genetic liability to sepsis-related death showed a suggestive positive correlation with the surface area of fusiform gyrus (β = 11.0920, SE = 3.6412, P = .0023) and posterior cingulate gyrus (β = 3.6530, SE = 1.6684, P = .0286), While it presented a suggestive negative correlation with surface area of the caudal middle frontal gyrus (β = -11.4586, SE = 5.1501, P = .0261) and frontal pole (β = -1.0024, SE = 0.4329, P = .0206). We also indicated a possible bidirectional causal association between genetic liability to sepsis-related death and the thickness of the transverse temporal gyrus. Sensitivity analyses verified the robustness of the above associations. These findings suggested that genetically determined liability to sepsis might influence the specific brain structure in a causal way, offering new perspectives to investigate the mechanism of sepsis-related neuropsychiatric disorders.

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 disproportionally affects children across all health-care settings and is one of the leading causes of morbidity and mortality in neonatal and paediatric age groups. As shown in the first paper in this Series, the age-specific incidence of sepsis is highest during the first years of life, before approaching adult incidence rates during adolescence. In the second paper in this Series, we focus on the unique susceptibility of paediatric patients to sepsis and how the underlying dysregulated host response relates to developmental aspects of children's immune system, genetic, perinatal, and environmental factors, and comorbidities and socioeconomic determinants of health, which often differ between children and adults. State-of-the-art clinical management of paediatric sepsis is organised around three treatment pillars-diagnosis, early resuscitation, and titration of advanced care-and we examine available treatment guidelines and the limitations of their supporting evidence. Serious evidence gaps remain in key areas of paediatric sepsis care, especially surrounding recognition, common interventions, and survivor support, and to this end we offer a research roadmap for the next decade that could accelerate targeted diagnostics and personalised use of immunomodulation. However, improving outcomes for children with sepsis relies fundamentally on systematic quality improvement in both recognition and treatment, which is the theme of the third paper in this Series. Digital health, as shown in the fourth and final paper of this Series, holds promising potential in breaking down the barriers that hinder progress in paediatric sepsis care and, ultimately, global child health.

The interplay between inflammation, immune dysregulation, and the onset of neurological disorders, including epilepsy, has become increasingly recognized. Interleukin (IL)-6, a pro-inflammatory cytokine, is suspected to not only mediate traditional inflammatory pathways but also contribute to neuroinflammatory responses that could underpin neuropsychiatric symptoms and broader psychiatric disorders in epilepsy patients. The role of IL-6 receptor (IL6R) blockade presents an intriguing target for therapeutic intervention due to its potential to attenuate these processes.

To explore the potential of IL6R blockade in reducing the risk of epilepsy and investigate whether this pathway might also influence associated psychiatric and neuropsychiatric conditions due to neuroinflammation.

Mendelian randomization (MR) analysis employing single nucleotide polymorphisms (SNPs) in the vicinity of the IL6R gene (total individuals = 408225) was used to evaluate the putative causal relationship between IL6R blockade and epilepsy (total cases/controls = 12891/312803), focal epilepsy (cases/controls = 7526/399290), and generalized epilepsy (cases/controls = 1413/399287). SNP weights were determined by their effect on C-reactive protein (CRP) levels and integrated using inverse variance-weighted meta-analysis as surrogates for IL6R effects. To address potential outlier and pleiotropic influences, sensitivity analyses were conducted employing a variety of MR methods under different modeling assumptions.

The genetic simulation targeting IL6R blockade revealed a modest but significant reduction in overall epilepsy risk [inverse variance weighting: Odds ratio (OR): 0.827; 95% confidence interval (CI): 0.685-1.000; P = 0.05]. Subtype analysis showed variability, with no significant effect observed in generalized, focal, or specific childhood and juvenile epilepsy forms. Beyond the primary inflammatory marker CRP, the findings also suggested potential non-inflammatory pathways mediated by IL-6 signaling contributing to the neurobiological landscape of epilepsy, hinting at possible links to neuroinflammation, psychiatric symptoms, and associated mental disorders.

The investigation underscored a tentative causal relationship between IL6R blockade and decreased epilepsy incidence, likely mediated via complex neuroinflammatory pathways. These results encouraged further in-depth studies involving larger cohorts and multifaceted psychiatric assessments to corroborate these findings and more thoroughly delineate the neuro-psychiatric implications of IL-6 signaling in epilepsy. The exploration of IL6R blockade could herald a novel therapeutic avenue not just for seizure management but also for addressing the broader psychiatric and cognitive disturbances often associated with epilepsy.

Observational epidemiological studies have indicated a potential association between asthma and sepsis, although the causal relationship between these 2 conditions remains uncertain. To further investigate this relationship, the present study utilized Mendelian randomization (MR) analysis approach to explore the potential links between asthma and various types of sepsis.

In a large-scale genome-wide association study, single nucleotide polymorphisms (SNPs) associated with asthma were selected as instrumental variables. Three methods, including inverse-variance weighted (IVW), MR-Egger regression, and weighted median were used to assess the causal relationship between asthma and sepsis. The odds ratio (OR) and 95% confidence interval (CI) were used as the evaluation metrics for causal relationships, and sensitivity analysis was conducted to assess pleiotropy and instrument validity. Finally, a reverse MR analysis was conducted to investigate whether there is a causal relationship between sepsis and asthma.

We found a positive association between asthma and an increased risk of sepsis (OR=1.18, P＜0.05), streptococcal sepsis (OR=1.23, P=0.04), pneumonia-related sepsis (OR=1.57, P＜0.05), pneumococcal sepsis (OR=1.58, P=0.01), other sepsis (OR=1.15, P＜0.05), and sepsis in intensive care unit (ICU) settings (OR=1.23, P=0.02). Sensitivity analysis showed consistent results without heterogeneity or pleiotropy. The reverse MR analysis reveals no causal relationship between various types of sepsis and asthma.

Our study demonstrates a causal relationship between asthma and different types of sepsis. These findings suggest the importance of healthcare providers paying attention to the potential risk of sepsis in asthma patients and implementing appropriate preventive and intervention measures in a timely manner.

Damage of the endothelial glycocalyx (eGC) plays a central role in the development of vascular hyperpermeability and organ damage during systemic inflammation. However, the specific signalling pathways for eGC damage remain poorly defined. Aim of this study was to combine sublingual video-microscopy, plasma proteomics and live cell imaging to uncover further pathways of eGC damage in patients with coronavirus disease 2019 (COVID-19) or bacterial sepsis. This secondary analysis of the prospective multicenter MICROCODE study included 22 patients with COVID-19 and 43 patients with bacterial sepsis admitted to intermediate or intensive care units and 10 healthy controls. Interleukin-6 (IL-6) was strongly associated with damaged eGC and correlated both with eGC dimensions (rs=0.36, p = 0.0015) and circulating eGC biomarkers. In vitro, IL-6 reduced eGC height and coverage, which was inhibited by blocking IL-6 signalling with the anti-IL-6 receptor antibody tocilizumab or the Janus kinase inhibitor tofacitinib. Exposure of endothelial cells to 5% serum from COVID-19 or sepsis patients resulted in a significant decrease in eGC height, which was attenuated by co-incubation with tocilizumab. In an external COVID-19 cohort of 219 patients from Massachusetts General Hospital, a previously identified proteomic eGC signature correlated with IL-6 (rs=-0.58, p < 0.0001) and predicted the combined endpoint of 28-day mortality and/or intubation (ROC-AUC: 0.86 [95% CI: 0.81-0.91], p < 0.001). The data suggest that IL-6 may significantly drive eGC damage in COVID-19 and bacterial sepsis. Our findings provide valuable insights into pathomechanisms of vascular dysfunction during systemic inflammation and highlight the need for further in vivo studies.

Many cancers metastasize to the pleura, resulting in effusions that cause dyspnea and discomfort. Regardless of the tissue of origin, pleural malignancies are aggressive and uniformly fatal, with no treatment shown to prolong life. The pleural mesothelial monolayer is joined by tight junctions forming a contained bioreactor-like space, concentrating cytokines and chemokines secreted by the mesothelium, tumor, and infiltrating immune cells. This space represents a unique environment that profoundly influences tumor and immune cell behavior. Defining the pleural secretome is an important step in the rational development localized intrapleural immunotherapy.

We measured cytokine/chemokine content of 252 malignant pleural effusion (MPE) samples across multiple cancers using a 40-analyte panel and Luminex multiplexing technology.

Eleven analytes were consistently present in concentrations ≥ 10.0 pM: CXCL10/IP10 (geometric mean = 672.3 pM), CCL2/MCP1 (562.9 pM), sIL-6Rα (403.1 pM), IL-6 (137.6 pM), CXCL1/GRO (80.3 pM), TGFβ1 (76.8 pM), CCL22/MDC (54.8 pM), CXCL8/IL-8 (29.2 pM), CCL11/Eotaxin (12.6 pM), IL-10 (11.3 pM), and G-CSF (11.0 pM). All are capable of mediating chemotaxis, promotion of epithelial to mesenchymal transition, or immunosuppression, and many of are reportedly downstream of a pro-inflammatory cytokine cascade mediated by cytokine IL-6 and its soluble receptor.

The data indicate high concentrations of several cytokines and chemokines across epithelial cancers metastatic to the pleura and support the contention that the pleural environment is the major factor responsible for the clinical course of MPE across cancer types. A sIL-6Rα to IL-6 molar ratio of 2.7 ensures that virtually all epithelial, immune and vascular endothelial cells in the pleural environment are affected by IL-6 signaling. The central role likely played by IL-6 in the pathogenesis of MPE argues in favor of a therapeutic approach targeting the IL-6/IL-6R axis.

Sepsis, a condition characterized by life-threatening organ dysfunction due to a dysregulated host response to infection, significantly impacts global health, with mortality rates varying widely across regions. Traditional therapeutic strategies that target hyperinflammation and immunosuppression have largely failed to improve outcomes, underscoring the need for innovative approaches. This review examines the development of therapeutic agents for sepsis, with a focus on clinical trials addressing hyperinflammation and immunosuppression. It highlights the frequent failures of these trials, explores the underlying reasons, and outlines current research efforts aimed at bridging the gap between theoretical advancements and clinical applications. Although personalized medicine and phenotypic categorization present promising directions, this review emphasizes the importance of understanding the complex pathogenesis of sepsis and developing targeted, effective therapies to enhance patient outcomes. By addressing the multifaceted nature of sepsis, future research can pave the way for more precise and individualized treatment strategies, ultimately improving the management and prognosis of sepsis patients.

Sepsis poses a significant threat to human health due to its high morbidity and mortality rates worldwide. Traditional diagnostic methods for identifying sepsis or its causative organisms are time-consuming and contribute to a high mortality rate. Biomarkers have been developed to overcome these limitations and are currently used for sepsis diagnosis, prognosis prediction, and treatment response assessment. Over the past few decades, more than 250 biomarkers have been identified, a few of which have been used in clinical decision-making. Consistent with the limitations of diagnosing sepsis, there is currently no specific treatment for sepsis. Currently, the general treatment for sepsis is conservative and includes timely antibiotic use and hemodynamic support. When planning sepsis-specific treatment, it is important to select the most suitable patient, considering the heterogeneous nature of sepsis. This comprehensive review summarizes current and evolving biomarkers and therapeutic approaches for sepsis.

Objective: Several epidemiological studies have identified a potential link between serum uric acid (UA), gout, and sepsis. The primary objective of this study is to delve deeper into this connection, investigating the causal effect of UA and gout on sepsis by applying Mendelian randomization (MR). Methods: The causal relationship was analyzed using data from Genome-Wide Association Study (GWAS). Inverse variance weighting (IVW) was used as the main analysis method. Three complementary methods were used for our MR analysis, which included the MR-Egger regression method, the weighted median method, the simple median method. Horizontal pleiotropy was identified by MR-Egger intercept test. Cochran's Q statistics were employed to assess the existence of instrument heterogeneity. The leave-one-out method was used as a sensitivity analysis. Results: The IVW results indicated that there was a positive causal relationship between UA and sepsis (critical care) (odds ratio [OR] = 0.24, 95% confidence interval [CI]: 0.04 to 0.43, P = 0.018, F = 4,291.20). There was no significant association between UA and sepsis (28-day death in critical care) (OR = 0.10, 95% CI = -0.29 to 0.50, P = 0.604). There was no significant association between gout and sepsis (critical care) (OR = 0.85, 95% CI = -4.87 to 6.57, P = 0.771), and sepsis (28-day death in critical care) (OR = -6.30, 95% CI = -17.41 to 4.81, P = 0.267). Horizontal pleiotropy was absent in this study. The results were robust under all sensitivity analyses. Conclusion: The study revealed that elevated UA levels were causally linked with sepsis (critical care). No causal relationship had been found between UA and sepsis (28-day death in critical care), as well as between gout and sepsis.

To analyze the relationship between IL and 6 572C/G polymorphism with sepsis.

Searching 8 databases the Cochrane Library, China National Knowledge Infrastructure (CNKI), China Biology Medicine (CBM), Chongqing VIP, Embase, PubMed, WanFang Data, and Web of Science from inception to October 1, 2023. Meta-analysis was performed by using Review Manager 5.4 and STATA 15.0.

9 studies were included, 1 study was excluded from the previous meta-analysis, and 6 studies were added. Sensitivity analysis suggested that the results were relatively robust. The P values of Egger test indicated that no conspicuous publication bias was found.

According to the meta-analysis results of existing studies, the IL-6 572C/G GG genotype and G allele are risk factors for sepsis, this result changes the previous conclusion that the IL-6 572 polymorphism is not related to sepsis. However, the results still need to be conservatively treated due to the sample size was not large enough.

Dysregulation of inflammation can lead to multiple chronic respiratory diseases, such as chronic obstructive pulmonary disease (COPD) and asthma. Interleukin-6 (IL6) is crucial in regulating the inflammatory cascade, but the causal link between IL6 signaling downregulation and respiratory diseases risk is unclear. This study uses Mendelian randomization to examine the effects of IL6R blockade on respiratory diseases. Analyzing data from 522,681 Europeans, 26 genetic variants were obtained to mimic IL6R inhibition. Our findings show that IL6R blockade significantly reduces the risk of COPD (OR = 0.71, 95% CI = 0.60-9.84) and asthma (OR = 0.82, 95% CI = 0.74-0.90), with protective trends for bronchitis, pulmonary embolism, and lung cancer. Results were consistent across methods, with no significant heterogeneity or pleiotropy. These insights suggest IL6R downregulation as a potential therapeutic target for respiratory diseases, meriting further clinical investigation.

Pneumonia and lung cancer are both major respiratory diseases, and observational studies have explored the association between their susceptibility. However, due to the presence of potential confounders and reverse causality, the comprehensive causal relationships between pneumonia and lung cancer require further exploration.

Genome-wide association study (GWAS) summary-level data were obtained from the hitherto latest FinnGen database, COVID-19 Host Genetics Initiative resource, and International Lung Cancer Consortium. We implemented a bidirectional Mendelian randomization (MR) framework to evaluate the causal relationships between several specific types of pneumonia and lung cancer. The causal estimates were mainly calculated by inverse-variance weighted (IVW) approach. Additionally, sensitivity analyses were also conducted to validate the robustness of the causalty.

In the MR analyses, overall pneumonia demonstrated a suggestive but modest association with overall lung cancer risk (Odds ratio [OR]: 1.21, 95% confidence interval [CI]: 1.01 - 1.44, P = 0.037). The correlations between specific pneumonia types and overall lung cancer were not as significant, including bacterial pneumonia (OR: 1.07, 95% CI: 0.91 - 1.26, P = 0.386), viral pneumonia (OR: 1.00, 95% CI: 0.95 - 1.06, P = 0.891), asthma-related pneumonia (OR: 1.18, 95% CI: 0.92 - 1.52, P = 0.181), and COVID-19 (OR: 1.01, 95% CI: 0.78 - 1.30, P = 0.952). Reversely, with lung cancer as the exposure, we observed that overall lung cancer had statistically crucial associations with bacterial pneumonia (OR: 1.08, 95% CI: 1.03 - 1.13, P = 0.001) and viral pneumonia (OR: 1.09, 95% CI: 1.01 - 1.19, P = 0.037). Sensitivity analysis also confirmed the robustness of these findings.

This study has presented a systematic investigation into the causal relationships between pneumonia and lung cancer subtypes. Further prospective study is warranted to verify these findings.

The current investigation deployed Mendelian randomization (MR) to elucidate the causal relationship between circulating proteins and sepsis. A rigorous two-sample MR analysis evaluated the effect of plasma proteins on the sepsis susceptibility. To affirm the integrity of MR findings, a suite of supplementary analyses, including Bayesian colocalization, Steiger filtering, the assessment of protein-altering polymorphisms, and the correlation between expression quantitative trait loci and protein quantitative trait loci (pQTLs), was employed. The study further integrated the examination of protein-protein interactions and pathway enrichment, along with the identification of pharmacologically actionable targets, to advance our comprehension and outline potential sepsis therapies. Subsequent analyses leveraging cis-pQTLs within MR studies unveiled noteworthy relationships: 94 specific proteins exhibited significant links with sepsis-related 28 day mortality, while 96 distinct proteins correlated with survival outcomes in sepsis. Furthermore, incorporating both cis- and trans-pQTLs in MR investigations revealed more comprehensive findings, associating 201 unique proteins with sepsis-related 28 day mortality and 199 distinct proteins with survival outcomes in sepsis. Markedly, colocalization analyses confirmed that eight of these proteins exhibited prominent evidence for colocalization, emphasizing their potential criticality in sepsis pathophysiology. Further in silico analyses were conducted to delineate putative regulatory networks and to highlight prospective drug targets among these proteins. Employing the MR methodology has shed light on plasma proteins implicated in the etiopathogenesis of sepsis. This novel approach unveiled numerous biomarkers and targets, providing a scientific rationale for the development of new therapeutic strategies and prophylactic measures against sepsis.