PurposeSepsis-associated acute kidney injury (SA-AKI) is associated with high mortality rates, yet prognostic biomarkers that jointly reflect nutritional, inflammatory and immune status remain limited. This study aimed to assess the prognostic value of the C-reactive protein-albumin-lymphocyte (CALLY) index in this patient population.Patients and methodsIn this retrospective two-center cohort study, 1,019 adult patients with SA-AKI were included. Kaplan–Meier and log-rank analyses identified the Day 3 CALLY index as the primary prognostic variable. Restricted cubic spline (RCS) analysis was used to characterize nonlinear associations with mortality, multivariable Cox proportional hazards models were applied to adjust for potential confounders, exploratory causal mediation analysis were performed to assess the contribution of the CALLY index to age-related mortality risk, and Bayesian joint models were used to evaluate the prognostic value of longitudinal CALLY trajectories.ResultsA higher Day 3 CALLY index was independently correlated with lower 30-day mortality (HR: 0.997, 95% CI: 0.995–0.999) and showed similar associations with 60-day, 365-day, and in-hospital outcomes (all p < 0.05). RCS analysis revealed a significant L-shaped nonlinear association with the Day 3 CALLY index and 30-day mortality, with an inflection point of 11.52. Mediation analysis indicated that the CALLY index explained 23.8–28.7% of the association between age and mortality. In Bayesian joint models, the inverse association between the CALLY index and mortality became progressively stronger over time.ConclusionThe CALLY index, an integrated marker of nutritional, inflammatory, and immune status, was independently associated with mortality in patients with SA-AKI. The Day 3 CALLY index provided clinically relevant prognostic stratification, and its longitudinal changes further improved risk assessment.

Intervertebral disc degeneration (IVDD) is characterized by excessive inflammation and extracellular matrix (ECM) degradation in the nucleus pulposus (NP), with limited current therapeutic options. Specialized pro-resolving mediators (SPMs) such as Maresin 1 (MaR1) have emerged as key regulators of inflammation resolution and tissue repair. Here, we report that MaR1 and its receptor LGR6 are significantly downregulated in degenerated human NP tissues, suggesting a loss of endogenous resolution capacity. Exogenous MaR1 administration effectively attenuated IL-1β-induced inflammation and ECM degradation in human NP cells and alleviated IVDD progression in rat models. Mechanistically, MaR1 simultaneously suppressed the catabolic AP-1/MMP pathway and activated the pro-anabolic OSR1/GDF7 axis, rebalancing ECM homeostasis. Notably, the therapeutic efficacy of MaR1 was completely abrogated in Lgr6-knockout mice, demonstrating that LGR6 is the indispensable mediator of MaR1's protective effects in vivo. Our findings identify the MaR1-LGR6 axis as a critical regulator of disc homeostasis and highlight MaR1 supplementation as a novel and promising strategy for IVDD treatment.

Background:To assess the global burden and trends of childhood sepsis, and to evaluate whether clarifying these aspects can provide a basis for formulating targeted prevention and treatment strategies for the condition. Methods:Using the Global Burden of Disease (GBD) 2021 database, we analyzed sepsis in 0-14-year-olds, covering 62 pathogens (21 drug-resistant), 84 "pathogen-drug" combinations, 12 infection syndromes, and indicators (deaths, disability-adjusted life years [DALYs], age-standardized rates). Antimicrobial resistance (AMR) was defined by two counterfactual scenarios; an autoregressive integrated moving average (ARIMA) model forecast AMR-related sepsis to 2050. Results:From 1990 to 2021, global sepsis-related deaths among children declined from 6.43 million to 2.24 million, and DALYs dropped from 578 million to 203 million. The estimated annual percentage change (EAPC) in age-standardized mortality rate (ASMR) and DALY rate (ASDR) was -3.35 and -3.33, respectively. AMR-related sepsis burden also decreased, with notable declines in both AMR-associated and AMR-attributable deaths and DALYs. In 2021, the highest burden remained in Sub-Saharan Africa, while the lowest was in High-income regions. Leading pathogens causing child sepsis deaths included Streptococcus pneumoniae, Klebsiella pneumoniae, Escherichia coli, Staphylococcus aureus, and Pseudomonas aeruginosa. Bloodstream infections, lower respiratory infections, and diarrhea were the most common infection syndromes leading to sepsis-related deaths. Conclusion:Global childhood sepsis burden dropped, but high-burden regions (e.g., Sub-Saharan Africa, South Asia) need focus. Future efforts should optimize healthcare, strengthen AMR control, promote vaccination, and improve sanitation.

Sepsis-induced acute lung injury (ALI) is a life-threatening condition associated with high mortality rates. While emerging evidence suggests that KIAA1199 (also known as cell migration-inducing protein, CEMIP) contributes to the pathogenesis of bacterial infections, its specific role in sepsis-induced ALI remains largely unexplored. In this study, we find that serum levels of KIAA1199 are significantly elevated in sepsis patients compared to healthy individuals, demonstrating a positive correlation with the SOFA scores. Additionally, we observe the expression of KIAA1199 increased in the lung tissue of septic mice, particularly in alveolar epithelial Type II (AT2) cells. We further generate AT2-specific KIAA1199 knockout mice on a male C57BL/6 J background and establish LPS-induced ALI model. The results indicate that KIAA1199-deficient mice exhibit improved survival rates, reduced lung injury, and decreased levels of proinflammatory cytokines. Transcriptomic analysis and functional validation reveal that KIAA1199 promotes pulmonary complement activation by downregulating complement factor H (CFH), a critical regulator of the alternative complement pathway. Mechanistically, KIAA1199 downregulates CFH expression by enhancing the ubiquitinated degradation of its transcription factor of p53. In conclusion, our data demonstrate that KIAA1199 exacerbates sepsis-induced ALI via promoting local complement activation through CFH suppression, which may serve as a potential therapeutic target for sepsis-induced ALI.

Repeated morphine administration leads to analgesic tolerance, reducing its pain-relief effectiveness and increasing overdose risks. However, the changes in endogenous levels of specialized pro-resolving mediators and their relationship with the mu-opioid receptor, as well as their role in analgesic tolerance during extended morphine use, have yet to be fully understood. Our study demonstrates that chronic morphine exposure reduces maresin1 levels in mice, correlating with morphine dosage in tolerant patients. Systemic or intrathecal administration of maresin1 alleviates morphine tolerance, but intracerebroventricular administration does not. Additionally, Lgr6 expression decreases in the dorsal root ganglia of morphine-tolerant mice, and reducing Lgr6 expression in dorsal root ganglia via AAV injection negates the protective effects of maresin1. Maresin1 works by preventing β-arrestin2 recruitment and mu-opioid receptor internalization, preserving morphine's pain-relief effects. In conclusion, this study elucidates the functions of maresin1 in the modulation of morphine tolerance, suggesting it as a potential target to improve opioid effectiveness.

Background and Purpose Heatstroke is a life-threatening condition characterised by severe inflammation and often linked to necroptosis, a form of programmed cell death mediated by receptor-interacting protein kinase 3 (RIPK3) and mixed lineage kinase domain-like pseudokinase (MLKL). Annexin A1 (AnxA1) is known to play a role in resolving inflammation, but its effects on heatstroke remain unclear. This study investigates the role of AnxA1 in heatstroke and its potential mechanisms.Experimental Approach The levels of AnxA1 were measured in patients with heatstroke and in a mouse model of heatstroke. The severity of heatstroke symptoms was compared between wild-type (WT) male C57BL/6 mice and those lacking AnxA1 or its receptor FPR2 on a C57BL/6 background. Additionally, recombinant AnxA1 was administered in vivo and in vitro to assess its therapeutic potential and to investigate underlying mechanisms.Key Results The expression of AnxA1 increased significantly in response to heat stress in both heatstroke patients and mice. The absence of AnxA1 or FPR2 exacerbated heatstroke severity, while administering AnxA1 alleviated the symptoms in heat-stressed mice and cell models. These protective effects were mediated through the FPR2 receptor. Further analysis of the mechanism revealed that AnxA1 treatment inhibited the phosphorylation of key necroptosis proteins, RIPK3 and MLKL.Conclusion and Implications This study highlights the activation of the endogenous AnxA1-FPR2 signalling pathway following heat exposure and demonstrates that AnxA1 can mitigate heatstroke by inhibiting RIPK3/MLKL-mediated necroptosis. These findings suggest that enhancing endogenous AnxA1 levels or administering recombinant AnxA1 may be promising therapeutic strategies for managing heatstroke.

The lymphatic system plays a central role in fluid transport and immune regulation, yet its contribution to sepsis remains incompletely understood. Analysis of more than 500,000 individuals from the UK Biobank reveals that lymphatic system disorders and genetic variants in FLT4 (VEGFR3) are strongly associated with increased sepsis risk. Single-cell RNA sequencing further shows a marked reduction of VEGFR3^high lymphatic endothelial cells during sepsis. LEC-specific deletion of VEGFR3 impairs lymphatic reflux without disrupting vessel architecture, leading to barrier failure, systemic inflammation, bacterial dissemination, and sepsis. Mechanistically, VEGFR3 sustains lymphatic glycocalyx integrity by promoting SOX18-dependent HSPG2 transcription and heparan sulfate biosynthesis. Consistently, LEC-specific HSPG2 knockdown or pharmacological inhibition of SOX18 phenocopies VEGFR3 deficiency, whereas heparan sulfate supplementation alleviates sepsis-like pathology. Moreover, HSPG2 genetic variants are significantly associated with both lymphatic disorders and sepsis. Collectively, these findings identify lymphatic reflux dysfunction as a pathogenic determinant of sepsis and establish disruption of the VEGFR3-SOX18-HSPG2-heparan sulfate axis as an active driver of disease. ### Competing Interest Statement The authors have declared no competing interest.

Acute respiratory distress syndrome (ARDS) is a life-threatening clinical condition associated with high morbidity and mortality, mainly resulting from excessive inflammation and failure of inflammation-resolving mechanisms. Fibroblast growth factor 21 (FGF21) is a metabolic regulator possessing anti-inflammatory properties; however, its role and mechanism in the resolution of inflammation remain unclear. This study showed that FGF21 facilitated the resolution of inflammation by promoting the production of specialized pro-resolving mediators (SPMs) in a mouse model of LPS-induced lung injury. SPMs, generated from arachidonic acid, docosahexaenoic acid, and eicosapentaenoic acid through enzymatic conversion by ALOX15 and related enzymes, exerted anti-inflammatory and pro-resolving effects by binding to their specific receptors. Furthermore, FGF21 was secreted by alveolar macrophages and acted in an autocrine manner to induce their polarization toward the M2 phenotype. Liquid chromatography-mass spectrometry revealed that FGF21 upregulated SPM production during the resolution phase by enhancing the expression of ALOX15 and SPM receptors on M2-polarized resident alveolar macrophages, thereby promoting the resolution of inflammation and attenuating lung injury. These findings provide new mechanistic insights into the resolution of ARDS.

Doxorubicin (DOX) cardiotoxicity (DiCM) is mediated by macrophages. c-Kit inhibition drives M2 macrophage polarization, and emerging evidence suggests that cardiomyocyte-derived extracellular vesicles (CM-EVs) participate in immune modulation during cardiac injury. Building on these observations, we hypothesized that cardiomyocyte-specific c-Kit mutation (Tg-Wv) protects against DiCM by altering EV-mediated cardiomyocyte-macrophage crosstalk. In DiCM models, Tg-Wv mice exhibited improved survival, reduced cardiac atrophy, and enhanced function, with a shift toward CD163+ M2 anti-inflammatory macrophages, a higher M2/M1 ratio, and diminished tissue damage, oxidative stress, and apoptosis. CM-EVs reporter mice showed real-time uptake by cardiac macrophages. Micro RNA (miRNA) sequencing identified upregulated miR-142-3p and miR-135a-5p in Tg-Wv cardiomyocytes and EVs. Cardiac macrophages displayed reduced HIF-1α and elevated Arg-1. Transfection of these miRNAs induced CD163+ M2-like polarization in vitro. Our findings demonstrate that cardiomyocyte c-Kit mutation enriches miR-142-3p and miR-135a-5p in EVs, which suppress HIF-1α and promote protective M2-like macrophage polarization, unveiling a novel EV-mediated cardioprotective pathway.

BackgroundClimate change significantly impacts health, particularly for individuals aged 65 and older, increasing heat-related illnesses and mortality. Understanding this burden is vital for public health planning.MethodsThis study analyzes data from the Global Burden of Disease (GBD) Study 2021, focusing on deaths, disability-adjusted life years (DALYs), and age-standardized ratios related to high-temperature exposure in individuals aged 65+ across 204 nations and territories. It examines trends from 1990 to 2021, assesses health inequities using measures like the Inequality Slope Index and Concentration Index, and projects future trends using a Bayesian Age-Period-Cohort (BAPC) model.ResultsIn 2021, there were 247,098 heat-related deaths globally among those aged 65+, with an age-standardized mortality rate (ASMR) increase from 26.3 to 27.1 per 100,000 (annual average percentage change (AAPC): 0.22). Aggregate DALYs reached 3,986,215, with the age-standardized DALYs rate (ASDR) rising from 419.6 to 526.7 per 100,000. South Asia and East Asia experienced higher burdens, while Oceania and Western Australia had lower rates. Lower-middle Socio-demographic Index (SDI) regions faced greater burdens, with absolute inequality increasing and relative inequality slightly declining. Non-communicable diseases (NCDs), such as ischemic heart disease and stroke, accounted for a significant proportion of heat-related deaths and DALYs, with upward trends. Projections indicate continued increases in deaths and DALYs by 2050.ConclusionsThis study highlights the growing global burden of high-temperature exposure on older adults, emphasizing regional disparities and the dominance of NCDs. These findings underscore the need for targeted public health strategies to address climate-related health risks in vulnerable populations.

Acute respiratory distress syndrome (ARDS) involves impaired macrophage function in clearing apoptotic cells. The link between clinical hyperlactatemia in ARDS patients and poor outcomes prompted this study on the immunometabolic role of lactate in disease progression. In an LPS-induced ARDS mouse model, mice received either exogenous lactate or a lactate dehydrogenase inhibitor. Inflammatory cell infiltration was evaluated through flow cytometry and histological analysis with hematoxylin and eosin staining. Lactate signaling was confirmed in GPR81-deficient mice. In vitro, lactate metabolism during efferocytosis was studied using primary Alveolar Macrophages (AMs). Lactate accumulation, neutrophil infiltration, and elevated inflammatory factors were observed in this ARDS model. External lactate delayed inflammation resolution and worsened lung injury. GPR81-/- mice exhibited reduced neutrophil infiltration and better outcomes. Macrophages produced substantial amounts of lactate during efferocytosis in vitro, concurrent with upregulated expression of the glucose transporter Glut1, the lactate transporter MCT1, and the lactate receptor GPR81. Pharmacological inhibition using an LDH inhibitor, an MCT1 antagonist, or extra lactate significantly impaired efferocytic capacity. Efferocytosis triggered Myc upregulation in vitro, which was suppressed by exogenous lactate. Genetic ablation of GPR81 elevated both MCT1 and Myc expression. Silencing Myc via siRNA significantly impaired efferocytosis in vitro. These findings indicate that the activation of GPR81 by lactate delays the resolution of inflammation in acute lung injury. This effect may be attributed to the suppression of alveolar macrophage efferocytosis, which subsequently impairs the clearance of apoptotic cells and exacerbates lung injury.

Pulmonary arterial hypertension (PAH) is a devastating disease complicated by pathological features such as proliferation of pulmonary artery smooth muscle cells (PASMCs), vasoconstriction, increased pulmonary artery pressure, and hypertrophic right heart failure. Among these features, excessive proliferation of PASMCs is the most significant pathological change in this disease. Lipid droplets (LDs) are ubiquitous cellular organelles that serve as energy storage sites. Previous studies have shown that large accumulations of intracellular LDs are observed in proliferating cells (such as stem cells and cancer cells) and that the modulation of LD accumulation can affect cell proliferation. These findings suggest that LDs play important roles in cell proliferation. This review aimed to investigate the role of LDs in PAH by focusing on the proliferation of PASMCs.

ObjectiveIt is well recognized that high heterogeneity represents a key driver of the elevated mortality in severe community-acquired pneumonia (sCAP). Precise subtype classification is therefore critical for both treatment strategy formulation and prognostic evaluation in this patient population. This study aimed to develop a predictive model for novel clinical subtypes of sCAP, leveraging microbiome profiles identified via metagenomic next-generation sequencing (mNGS).MethodsThis retrospective multicenter cohort study enrolled adult patients with sCAP who underwent clinical mNGS testing of bronchoalveolar lavage fluid in intensive care units (ICUs) across 17 medical centers in China. Based on mNGS-identified microbiome characteristics, unsupervised machine learning (UML) was employed for clustering analysis of sCAP patients. LASSO regression and random forest (RF) algorithms were applied to screen and identify predictors of novel sCAP subtypes. A predictive model for the new clinical subtypes was constructed according to the screening results, with a nomogram generated. The discriminative ability, calibration, and clinical utility of the model were evaluated using ROC curves, calibration curves, and decision curve analysis, respectively.ResultsA total of 1,051 sCAP patients were included in the final analysis. The 28-day all-cause mortality rate was 45% (473/1,051). UML clustering identified two distinct sCAP subtypes: the 28-day mortality rate was 42.19% (343/813) in subtype 1 and 54.62% (130/238) in subtype 2. Incorporating clinical and microbial features, a predictive model for the novel sCAP subtypes was developed using the following predictors: immunosuppression (OR = 37,411.46, P < 0.001), connective tissue disease (CTD) (OR = 12,144.60, P = 0.004), hematological malignancy (HM) (OR = 107,768.13, P < 0.001), chronic kidney disease (CKD) (OR = 49.71, P < 0.001), cytomegalovirus (CMV) (OR = 0.00, P < 0.001), Epstein-Barr virus (EBV) (OR = 131.97, P < 0.001), Pneumocystis (OR = 47,949.56, P < 0.001), and Klebsiella (OR = 0.02, P = 0.003). The model demonstrated excellent discriminative ability with an area under the ROC curve (AUC) of 0.992. Calibration curves showed good agreement between predicted and observed outcomes. Decision curve analysis confirmed high clinical utility for predicting novel sCAP subtypes.ConclusionThis study identified novel clinical subtypes of sCAP based on mNGS-derived microbiome characteristics. This approach exhibits superior performance in identifying high-risk sCAP patients, facilitating precise subtyping.

Summary Introduction Data regarding the incidence of 12‐month postoperative cognitive decline following regional or general anaesthesia in older patients undergoing hip fracture surgery remain observational. Compared with general anaesthesia, we hypothesised that regional anaesthesia would decrease the incidence of 12‐month postoperative cognitive decline. Methods This is substudy of a multicentre randomised trial of regional anaesthesia with no sedation vs. general anaesthesia with 12‐month follow‐up, conducted in nine university hospitals in south‐eastern China. Patients aged ≥ 65 y with hip fractures requiring surgery were eligible for inclusion. The prespecified 1‐year primary outcome was the incidence of postoperative cognitive decline at 12 months post‐randomisation. Secondary outcomes included major or mild postoperative cognitive decline; changes in Mini‐Mental State Examination; newly developed dementia; affective status; and health‐related quality of life. Results We recruited 950 patients between October 2014 and September 2018 (n = 474 general and n = 476 regional), with the last participant interviewed in November 2019. A total of 293 patients (139 general vs. 154 regional) were included in the primary analysis of the 12‐month outcome. Median (IQR [range]) age of patients was 78 (71–82 [65–96]) y and 217 (74.1%) were female. The incidence of cognitive decline at 12 months was 29.7% vs. 25.4% of patients allocated to general vs. regional anaesthesia, respectively (unadjusted OR 1.2 (95%CI 0.7–2.1), p = 0.43, Bayes factor = 0.28). Major cognitive decline developed in 8.6% vs. 8.5% of patients allocated to general vs. regional anaesthesia, respectively (unadjusted OR 1.0 (95%CI 0.4–2.4)). Discussion The incidence of 12‐month postoperative cognitive decline was not significantly different in patients having general or regional anaesthesia for hip fracture surgery.

BACKGROUND:Erythropoietin (EPO), a glycoprotein hormone primarily produced in the kidneys, plays pleiotropic roles in hematopoietic and non-hematopoietic system. However, the clinical relevance of circulating EPO in sepsis progression and outcomes remains contentious and requires further elucidation. METHODS:Participants were categorized into three groups on the basis of EPO tertiles. The primary outcome was 28-day mortality. Multivariate Cox proportional regression analysis and restricted cubic spline regression were employed to evaluate the association between EPO levels and 28-day mortality in sepsis patients. Subgroup analyses were also conducted. Causal mediation analysis was conducted to explore the potential mediating role of EPO in the relationship between lactate and 28-day mortality. RESULTS:A total of 267 patients (65.17% male) were included in the study. The 28-day and hospital mortality rates were 23.22 and 31.20%, respectively. Multivariate Cox regression revealed significantly higher 28-day and hospital mortality in the highest EPO tertile compared to the lowest (HR 2.93, 95% CI 1.20-7.22; HR 2.47, 95% CI 1.05-5.81, respectively). Restricted cubic spline analysis demonstrated a progressively increasing mortality risk with elevated EPO levels. Subgroup analyses confirmed the consistency and stability of the effect size and direction across different subgroups. Moreover, causal intermediary analysis revealed that the association between lactate and 28-day mortality was partially mediated by EPO, with a mediation ratio of 12.59%. CONCLUSIONS:Elevated EPO levels in patients with sepsis are correlated with unfavorable prognoses and may function as a prognostic biomarker for adverse outcomes.

Elevated lactate in the joint microenvironment of rheumatoid arthritis patients is crucial for disease progression, though the mechanism remains unclear. This study shows significantly increased global lactylation levels within fibroblast-like synoviocytes from RA patients compared to healthy controls, with lactylated proteins being enriched in histones. Furthermore, we find anti-lactylated histone autoantibodies present in RA patients that positively correlate with Disease Activity Score 28. Using CUT&Tag and RNA-seq, we identify NFATc2 as a key target gene regulated by histone H3 lysine 9 lactylation. Functional studies reveal that NFATc2 promotes migration of RA-FLSs. Additionally, using collagen antibody-induced arthritis and collagen-induced arthritis mouse models, we demonstrate that NFATc2 exacerbates RA disease progression through enhancing the cartilage invasive function of FLS. Here, we show that upregulated target gene NFATc2 by lactate-dependent histone lactylation, can be used as a potential therapeutic target for intervention, anti-lactylated histone autoantibodies is promising as a diagnostic marker for RA.