OBJECTIVE:The primary hyperventilation syndrome (HVS) is characterized by somatic/psychological symptoms, which may be related to abnormalities of ventilatory control, accompanied by sustained hypocapnia and respiratory alkalosis. The purpose of this study is to compare primary HVS with HVS secondary to respiratory infections. METHOD:A total of 167 patients diagnosed with HVS from January 1st, 2024, to May 31st, 2025, were included in this research. Participants were grouped according to positive or negative respiratory infection status. Demographic characteristics, laboratory examinations, and clinical outcomes were retrospectively collected and compared between the two groups. RESULTS:In total, seventy-six HVS patients were secondary to respiratory infections, while the remaining 91 patients were primary. Primary HVS patients were mainly induced by psychological factors, since 85% felt tense or anxious before. There was a significantly higher Nijmegen Questionnaire score in patients with HVS secondary to respiratory infections. Besides, this group presented a significantly lower level of electrolytes, as well as a higher level of inflammatory condition on admission. The six-month recurrence rate also showed significantly higher for those in the secondary group. CONCLUSION:HVS patients secondary to respiratory infections presented more severe hyperventilation syndromes and worse clinical outcomes. Appropriate managements specific to infection prevention, as well as respiratory training methods, could be provided to impede the recurrence of hyperventilation syndrome. CLINICAL TRIAL NUMBER:Not applicable.

Background: N6-methyladenosine (m6A) and copper-induced cell-death (CD) have been implicated in sepsis; however, their combined contribution to this syndrome remains unclear. The joint evaluation of m6A-related genes (m6A-RGs) and CD-related genes (CD-RGs) may help uncover sepsis biomarkers with mechanistic and diagnostic relevance.,Methods: Public sepsis datasets were collected from the GEO database, whereas m6A-RGs and CD-RGs were assembled from published sources. Biomarker selection was performed using a multistep workflow incorporating differential expression analysis, WGCNA, gene-set overlap, four machine-learning models, expression verification, and receiver operating characteristic assessment. The resulting biomarkers were further examined using immune infiltration analysis, GSEA, and drug prediction. The single-cell RNA sequencing (scRNA-seq) data were also processed to define cell populations, evaluate biomarker distribution, determine key cell types, and reconstruct pseudotime trajectories. Finally, experimental validation of the expression levels of biomarkers was conducted through reverse transcription-quantitative polymerase chain reaction (RT-qPCR).,Results: CD4, ADM, and SOCS3 were identified as sepsis-associated biomarkers. Immune infiltration profiling revealed significant changes in 25 immune cell subsets, including activated B cells, activated CD4 T cells, and macrophages. GSEA indicated that the biomarkers converged on several pathways, including cell cycle and retinol metabolism. Drug-gene prediction returned 2 candidate drugs for CD4, 4 for ADM, and 3 for SOCS3. In scRNA-seq analysis, monocytes emerged as the key cell population among the 9 annotated cell types, including NK T cells, CD4+T cells, and B cells. Finally, RT-qPCR results showed that ADM and SOCS3 were upregulated in the sepsis group, whereas CD4 was downregulated.,Conclusion: CD4, ADM, and SOCS3 were identified as biomarkers that link m6A and CD to sepsis. These findings provide additional clues for the diagnosis of sepsis and therapeutic exploration.

Background: Sepsis-induced acute lung injury (ALI) is a life-threatening condition with limited therapeutic options. Neutrophil extracellular traps (NETs) contribute to its pathogenesis. This study investigated whether polydatin (PD) protects against septic ALI by inhibiting NETs via the Nrf2/HO-1 pathway. Methods: A cecal ligation and puncture (CLP)-induced septic ALI mouse model and an LPS-stimulated neutrophil model were established. Lung injury was assessed by histology, lung wet/dry ratio, BALF protein, and inflammatory cytokines. Endothelial junction proteins and NETs markers were examined by Western blot, immunofluorescence, and SYTOX Green staining. Nrf2/HO-1 pathway activation and ML385 inhibitor experiments were performed for mechanistic validation. Results: PD dose-dependently attenuated lung injury, preserved endothelial junction proteins (ZO-1, VE-cadherin, occludin), and suppressed NETs formation in vivo. In vitro, PD activated Nrf2/HO-1, promoted Nrf2 nuclear translocation, reduced ROS, and inhibited LPS-induced NETs. These effects were abrogated by ML385, confirming pathway specificity. Conclusions: PD mitigates septic ALI by inhibiting NETs formation. In vitro mechanistic studies further suggest that this effect is mediated through activation of the Nrf2/HO-1 antioxidant pathway, positioning PD as a potential therapeutic candidate for sepsis-induced ALI.

Objective: This study aimed to determine the relationship between the total cholesterol to high-density lipoprotein cholesterol (TC/HDL-C) ratio and adverse outcomes in patients with first-ever ischemic stroke (IS), and to validate its potential as a prognostic indicator. Methods: A dual-cohort study integrating retrospective and prospective designs was conducted. The retrospective cohort included 45,162 patients with first-ever IS, and the prospective cohort comprised an independent sample of 2151 patients with first-ever IS. The primary outcome was a composite of stroke recurrence or all-cause death within five years. In the retrospective cohort, logistic regression and regression discontinuity design (RDD) were used to assess the relationship between TC/HDL-C ratio and adverse outcomes, adjusting for confounding factors (e.g., age, sex, comorbidities, and medication use). In the prospective cohort, logistic regression was employed to validate the association, with Kaplan-Meier survival analysis used to characterize prognosis across TC/HDL-C subgroups. Odds ratio (OR) and 95% confidence interval (CI) were calculated. Results: In the retrospective cohort, a higher TC/HDL-C ratio was identified as an independent risk factor for Five-year adverse outcomes (univariate analysis: OR 1.35 (95% CI, 1.28-1.42), P < 0.001; multivariate analysis: OR 1.30 (95% CI, 1.22-1.39), P < 0.001), and this association was confirmed by RDD. In the prospective cohort, logistic regression replicated these findings, with each unit increase in TC/HDL-C associated with a 12% higher risk of adverse outcomes [OR 1.12 (95% CI, 1.02-1.23), P < 0.05]. Kaplan-Meier analysis further showed that patients with lower TC/HDL-C ratios had significantly longer event-free survival over the 5-year follow-up (log-rank P < 0.001). Conclusion: Elevated TC/HDL-C ratio is independently associated with an increased risk of stroke recurrence or death within 5 years in patients with first-ever IS. These findings support the utility of the TC/HDL-C ratio as a clinically relevant prognostic marker for long-term outcomes in IS patients. (c) 2026 International Hemorrhagic Stroke Association. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co. Ltd. This is an open access article under the CC BY-NC-ND license (http://creati-vecommons.org/licenses/by-nc-nd/4.0/).

BACKGROUND:Neutrophil extracellular traps (NETs) can mediate sepsis-induced lung injury, but the upstream regulatory mechanisms remain unclear. IL-33 is involved in neutrophil activation and may serve as an upstream regulator of NET formation. Therefore, this study aims to elucidate the molecular mechanism by which the IL-33/ST2 axis regulates NET formation to mediate sepsis-induced lung injury. METHODS:A mouse model of sepsis-induced lung injury was established using the CLP method to assess lung damage and NETs formation. The destructive effect of NETs on the endothelial barrier was examined through DNase I intervention and HUVECs cell experiments. IL-33 or ST2 gene knockout mice were used to investigate the role of the IL-33/ST2 axis in sepsis-induced lung injury and its regulatory effect on NETs formation. Differentially expressed genes were identified via transcriptome sequencing of mouse neutrophils, and the downstream molecular mechanism of IL-33-induced NETs formation was explored by silencing or overexpressing REDD1 in dHL-60 cells. RESULTS:In septic mice, neutrophil infiltration and elevated levels of NETs were observed in lung tissue, accompanied by pulmonary edema and increased vascular permeability. These injuries were reversed by DNase I intervention. The IL-33/ST2 signaling axis was activated in septic mice, and knockout of either the IL-33 or ST2 gene alleviated lung injury, reduced endothelial barrier disruption, and inhibited NETs formation. In vitro experiments and transcriptome sequencing results demonstrated that IL-33 induces NETs formation in neutrophils through the ST2 receptor, and the ATF4/REDD1 signaling pathway is the key downstream mechanism by which IL-33 promotes NETs formation. CONCLUSION:This study demonstrates that IL-33/ST2 signaling leads to activation of the PERK/eIF2α/ATF4 pathway in neutrophils, upregulates REDD1 to induce NETosis triggered by oxidative stress, and thereby disrupts the pulmonary vascular endothelial barrier, exacerbating sepsis-induced lung injury. INTRODUCTION:

Nutritional therapy is an essential supportive intervention for patients with COVID-19 who are at high nutritional risk, although the optimal timing for initiating nutritional support remains unclear. The present study investigated the association between the initiation of enteral nutrition (EN) and the incidence of refeeding syndrome (RS) in severely ill patients with COVID-19 and high nutritional risk. Patients from Tongji Hospital (Wuhan, China), with a Nutrition Risk Screening-2002 score ≥3 and who received EN, were retrospectively analyzed and categorized into an early EN (EEN) group and a late EN (LEN) group based on the time-frame of EN initiation. Serum electrolyte levels were assessed on the third day after EN initiation to evaluate the incidence of RS. A total of 211 patients were included in this analysis (EEN group, n=125; LEN group, n=86). The mean time to EN initiation was 2 days in the EEN group and 5 days in the LEN group. Both the incidence and severity of RS were markedly higher in the LEN group, and serum potassium, sodium, phosphorus and magnesium levels were significantly lower in the LEN group on the third day after EN initiation. These findings suggest that early EN initiation may help reduce the risk of RS in critically ill patients with COVID-19 and high nutritional risk.

ABSTRACT Metabolic syndrome (MetS) poses a significant risk to the cerebrovascular system, impacting the prognosis of stroke patients. This study investigated the link between MetS and stroke‐related outcomes, exploring tissue kallikrein 1 (KLK1) as a potential mediator. In the derivation cohort, a total of 17,106 stroke‐diagnosed patients were assessed, with 6917 individuals (40.4%) presenting comorbid MetS. Multifactorial analysis identified stroke concurrent with MetS (adjusted odds ratio = 1.42; 95% confidence interval: 1.17–1.72; p < 0.001) as a risk factor for unfavorable outcomes among stroke patients. Further bioinformatics analyses indicated that obesity, diabetes, and hypertension were associated with reduced KLK1 levels (all p < 0.05). In the validation cohort, 1268 first‐ever stroke patients were enrolled, confirming a higher incidence of adverse outcomes in those with MetS, compared with those without (223 (28.1%) vs. 167 (35.2%); p < 0.01). Stroke patients with MetS, exhibited lower KLK1 levels (16.8 ± 6.52 vs. 15.6 ± 6.3; p < 0.01). Mediation analyses supported that MetS contributed to adverse outcomes through the mediating effect of decreased KLK1 levels (p < 0.05). This study highlights the risk of MetS in stroke patients and suggests a potential role for KLK1 as a mediating factor.

Background: Ulinastatin, widely used in Asia for sepsis management, lacks a comprehensive evaluation regarding its efficacy in preventing sepsis-associated encephalopathy (SAE). This study investigates ulinastatin's association with SAE incidence and explores combined biomarkers for early SAE prediction.Methods: This study employed a dual-cohort design involving 2,200 sepsis patients from a multicenter retrospective cohort and an independent validation cohort of 534 patients from a single-center prospective study. Using logistic regression and propensity score matching, we assessed the association between ulinastatin treatment and SAE incidence in the retrospective cohort. The findings were subsequently validated in the prospective cohort. We also evaluated clinical outcomes in ulinastatin-treated patients and examined the predictive utility of combining nitric oxide levels with key clinical indicators-including fasting blood glucose/high-density lipoprotein cholesterol ratio, Sequential Organ Failure Assessment score, and lactate levels-for early SAE risk stratification.Results: In the retrospective cohort, both univariate (odds ratio [OR] 0.618, 95% confidence interval [CI] 0.472-0.811; P = 0.001) and multivariate analyses (OR 0.603, 95% CI 0.453-0.802; P < 0.001) demonstrated that ulinastatin administration was significantly associated with reduced SAE risk. Propensity score matching confirmed this protective relationship. The prospective validation cohort similarly showed ulinastatin treatment was independently associated with lower SAE incidence (adjusted OR 0.491; 95% CI 0.302-0.800; P = 0.004). While individual biomarkers (nitric oxide, fasting blood glucose/high-density lipoprotein cholesterol, Sequential Organ Failure Assessment, and lactate) showed limited predictive value (all area under the receiver operating characteristic curves <0.70), their combination significantly improved SAE prediction accuracy, achieving a maximum area under the receiver operating characteristic curve of 0.726.Conclusions: Ulinastatin treatment is significantly associated with reduced SAE incidence in sepsis patients, offering novel insights and potential therapeutic strategies for preventing SAE and improving neurological outcomes.

BACKGROUND:Postoperative delirium (POD) after cardiac surgery correlates with endothelial dysfunction, but the role of dynamic nitric oxide (NO) changes remains unquantified. This study investigates whether perioperative NO fluctuations predict POD and the potential mechanism of ulinastatin in regulating NO. METHODS:This integrated study combined clinical investigation, in vitro experiments, and network toxicology-guided molecular docking. We prospectively enrolled 264 adults undergoing elective cardiac surgery, measuring plasma NO preoperatively, immediately post-surgery, and 24 hours post-surgery. In vitro, we assessed ulinastatin's efficacy in attenuating hypoxia/inflammation-induced NO overproduction and preserving endothelial barrier integrity. Network toxicology and molecular docking identified ulinastatin-NO regulatory targets. RESULTS:Among 264 patients, 60 (22.7%) developed POD. Preoperative NO levels did not differ significantly between POD and non-POD groups, but significantly higher NO levels were observed in POD patients both immediately and 24 hours post-surgery. A greater increase in NO from pre- to immediately post-surgery was independently associated with POD (adjusted OR, 1.03; 95% CI, 1.01-1.05, P = 0.016), and changes from immediate to 24-hour post-surgery were associated with in-hospital mortality (OR, 1.06; 95% CI, 1.00-1.13; P = 0.042). Subgroup analyses revealed significant interactions with ulinastatin administration, operative duration, and cardiopulmonary bypass. In vitro, ulinastatin dose-dependently attenuated NO overproduction and preserved endothelial barrier integrity in both POD plasma and oxygen-glucose deprivation models. Network toxicology prioritized 92 core targets mediating NO-induced neurovascular injury, with molecular docking confirming ulinastatin's high-affinity binding to PTGS2, MMP3, ACE, CTSD, F2, and SIRT1, supporting its mechanistic link to POD regulation. CONCLUSIONS:Dynamic perioperative NO surges independently predict POD and postoperative mortality in cardiac surgery. Ulinastatin mitigates this risk by suppressing pathological NO elevation and preserving endothelial integrity, supporting a biomarker-guided neuroprotection strategy.

ObjectiveThis study aimed to develop and validate a predictive risk nomogram for sepsis-associated severe anemia.MethodsA prediction model was built using data from 252 sepsis patients in a single institution (January 2022 to December 2023). Severe anemia was defined as a hemoglobin level <60 g/L. Least absolute shrinkage and selection operator regression was used to identify key predictors, and multivariable logistic regression was used to construct the nomogram. Model performance was assessed via the receiver operating characteristic curve (C-index), calibration plots, and decision curve analysis. Internal validation was performed using bootstrapping.ResultsPredictors included age, length of intensive care unit stay, nutritional method, and Acute Physiology and Chronic Health Evaluation II score. The model demonstrated good discrimination (C-index: 0.8848) and calibration, with high internal validation performance. Decision curve analysis indicated optimal clinical utility at risk thresholds between 5% and 75%.ConclusionsThe constructed nomogram, incorporating age, length of intensive care unit stay, nutritional method, and Acute Physiology and Chronic Health Evaluation II score, provides a practical tool for early individualized care in sepsis patients.

Ulinastatin (UTI), recognized for its anti-inflammatory properties, holds promise for patients undergoing cardiac surgery. This study aimed to investigate the relationship between intraoperative UTI administration and the incidence of delirium following cardiac surgery. A retrospective analysis was performed on a retrospective cohort of 6,522 adult cardiac surgery patients to evaluate the relationship between UTI treatment and the incident of postoperative delirium (POD) in patients ongoing cardiac surgery. This was followed by a prospective observational cohort study of 241 patients and an in vitro study to explore the findings and the potential role of UTI in preventing cardiac ischemia–reperfusion induced glycocalyx degradation. Both univariate and multivariate logistic regression analyses in retrospective cohort indicated that intraoperative administration of UTI was associated with a significant lower risk of POD among cardiac surgery patients, a finding confirmed through employing propensity score matching. The subsequent prospective observational cohort further supported these findings (adjusted Odds Ratio = 0.392, 95

1 Department of Critical Care Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. 2 Department of Emergency Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. The authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: [email protected]

Sepsis is characterized by organ dysfunction resulting from a dysregulated inflammatory response triggered by infection, involving multifactorial and intricate molecular mechanisms. Hypoxia-inducible factor-1α (HIF-1α), a notable transcription factor, assumes a pivotal role in the onset and progression of sepsis. This review aims to furnish a comprehensive overview of HIF-1α's mechanism of action in sepsis, scrutinizing its involvement in inflammatory regulation, hypoxia adaptation, immune response, and organ dysfunction. The review encompasses an analysis of the structural features, regulatory activation, and downstream signaling pathways of HIF-1α, alongside its mechanism of action in the pathophysiological processes of sepsis. Furthermore, it will delve into the roles of HIF-1α in modulating the inflammatory response, including its association with inflammatory mediators, immune cell activation, and vasodilation. Additionally, attention will be directed toward the regulatory function of HIF-1α in hypoxic environments and its linkage with intracellular signaling, oxidative stress, and mitochondrial damage. Finally, the potential therapeutic value of HIF-1α as a targeted therapy and its significance in the clinical management of sepsis will be discussed, aiming to serve as a significant reference for an in-depth understanding of sepsis pathogenesis and potential therapeutic targets, as well as to establish a theoretical foundation for clinical applications.

Tissue kallikrein (TK) has emerged as a potential neuroprotective agent in ischemic stroke (IS), yet the optimal timing and mechanisms of TK therapy remain unclear. Here, we established a causal link between lower baseline TK levels and an increased risk of stroke through a retrospective, multicenter cohort study involving 2115 initially non-stroke subjects monitored for 5 years. Sequentially, we observed a notable increase in bradykinin receptor 2 (B2R) levels during the ischemic phase of the IS model, while levels of TK and bradykinin receptor 1 (B1R) remained stable. Intriguingly, both B1R and B2R exhibited a significant elevation 24 h after reperfusion. Further investigations in preclinical models demonstrated that TK supplementation activates the PI3K/AKT signaling pathway via enhanced B2R expression during the ischemic phase, leading to nuclear translocation of Hif-1α. This activation enhances the expression of VEGF and eNOS, thereby fortifying the neurovascular unit. Moreover, it suppresses the activation of the kallikrein-kinin system induced by reperfusion injury, effectively reducing inflammation, ROS production, apoptosis, and endothelial barrier dysfunction. Thus, our findings highlight the significance of TK supplementation during the ischemic phase in attenuating reperfusion-induced injury in IS, providing a mechanistic rationale for determining the optimal timing for TK supplementation therapy.

Fulminant myocarditis is an acute diffuse inflammatory disease of myocardium. It is characterized by acute onset, rapid progress and high risk of death. Its pathogenesis involves excessive immune activation of the innate immune system and formation of inflammatory storm. According to China's practical experience, the adoption of the "life support-based comprehensive treatment regimen" (with mechanical circulation support and immunomodulation therapy as the core) can significantly improve the survival rate and long-term prognosis. Special emphasis is placed on very early identification,very early diagnosis,very early prediction and very early treatment.

Background This multicenter observational study aimed to determine whether dyslipidemia or obesity contributes more significantly to unfavorable clinical outcomes in patients experiencing a first-ever ischemic stroke (IS). Methods The study employed a machine learning predictive model to investigate associations among body mass index (BMI), body fat percentage (BFP), high-density lipoprotein (HDL), triglycerides (TG), and total cholesterol (TC) with adverse outcomes in IS patients. Extensive real-world clinical data was utilized, and risk factors significantly linked to adverse outcomes were identified through multivariate analysis, propensity score matching (PSM), and regression discontinuity design (RDD) techniques. Furthermore, these findings were validated via a nationwide multicenter prospective cohort study. Results In the derived cohort, a total of 45,162 patients diagnosed with IS were assessed, with 522 experiencing adverse outcomes. A multifactorial analysis incorporating PSM and RDD methods identified TG (adjusted odds ratio (OR) = 1.110; 95% confidence interval (CI): 1.041–1.183; P < 0.01) and TC (adjusted OR = 1.139; 95%CI: 1.039–1.248; P < 0.01) as risk factors. However, BMI, BFP, and HDL showed no significant effect. In the validation cohort, 1410 controls and 941 patients were enrolled, confirming that lipid levels are more strongly correlated with the prognosis of IS patients compared to obesity (TC, OR = 1.369; 95%CI: 1.069–1.754; P < 0.05; TG, OR = 1.332; 95%CI: 1.097–1.618; P < 0.01). Conclusion This study suggests that dyslipidemia has a more substantial impact on the prognosis of IS patients compared to obesity. This highlights the importance of prioritizing dyslipidemia management in the treatment and prevention of adverse outcomes in IS patients. Graphical abstract

With the development of digital technology and urbanization, media facades (MF) has gradually become an important part of modern architecture design. To explore the research progress and development trends in MF, this study used the bibliometric tools VOSViewer and Pajek to analyse research articles on MF in the Web of Science database from 2003 to 2022. The results indicate that there has been an upward trend in the number of research articles, and the turning points of Literature publication have corresponded to some major events. Its evolution can be categorized into three periods. The research interests are mainly focused on: design methodology, technology realization, interaction model, value utility and policy planning research. In addition, this study identifies potential development challenges in the field. By comprehensively analyzing the current research status, research hotspots and research trends in the field, this study provides valuable theoretical guidance for subsequent research.

BACKGROUND AND PURPOSE:Ulinastatin has beneficial effects in patients undergoing coronary artery bypass grafting (CABG) surgery due to its anti-inflammatory properties, but the underlying mechanism remains unclear. EXPERIMENTAL APPROACH:We used samples from patients undergoing CABG, a model of cardiac ischaemia-reperfusion injury (IRI) in mice and murine cardiac endothelial cell cultures to investigate links between ulinastatin, the kallikrein-kinin system (KKS), endothelial dysfunction and cardiac inflammation in the response to ischaemia/reperfusion injury (IRI). These links were assessed using clinical investigations, in vitro and in vivo experiments and RNA sequencing analysis. KEY RESULTS:Ulinastatin inhibited the activity of tissue kallikrein, a key enzyme of the KKS, at 24 h after CABG surgery, which was verified in our murine cardiac ischaemia-reperfusion model. Under normal conditions, ulinastatin only inhibited kallikrein activity but did not affect bradykinin (B1/B2) receptors. Ulinastatin protected against IRI, in vivo and in vitro, by suppressing activation of the kallikrein-kinin system and down-regulating B1/B2 receptor-related signalling pathways including ERK/ iNOS, which resulted in enhanced endothelial barrier function, mitigation of inflammation and oedema, decreased infarct size, improved cardiac function and decreased mortality. Inhibition of kallikrein and knockdown of B1, but not B2 receptors prevented ERK translocation into the nucleus, reducing reperfusion-induced injury in murine cardiac endothelial cells. CONCLUSIONS AND IMPLICATIONS:Treatment with ulinastatin exerts a protective influence on cardiac reperfusion by suppressing activation of the kallikrein-kinin system. Our findings highlight the potential of targeting kallikrein /bradykinin receptors to alleviate endothelial dysfunction, thus improving cardiac IRI.

Fulminant myocarditis (FM) is characterized by rapid cardiac deterioration often instigated by an inflammatory cytokine storm. The kallikrein-kinin system (KKS) is a metabolic cascade known for releasing vasoactive kinins, such as bradykinin-related peptides, possessing diverse pharmacological activities that include inflammation, regulation of vascular permeability, endothelial barrier dysfunction, and blood pressure modulation. The type 1 and type 2 bradykinin receptors (B1R and B2R), integral components of the KKS system, mediate the primary biological effects of kinin peptides. This review aims to offer a comprehensive overview of the primary mechanisms of the KKS in FM, including an examination of the structural components, regulatory activation, and downstream signaling pathways of the KKS. Furthermore, it explores the involvement of the tissue kallikrein/B1R/inducible nitric oxide synthase (TK/B1R/iNOS) pathway in myocyte dysfunction, modulation of the immune response, and preservation of endothelial barrier integrity. The potential therapeutic advances targeting the inhibition of the KKS in managing FM will be discussed, providing valuable insights for the development of clinical treatment strategies.

Background The present study aimed to investigate the correlation between weight status and mortality in mechanically ventilated patients and explore the potential mediators. Methods Three medical centers encompassing 3301 critically ill patients receiving mechanical ventilation were assembled for retrospective analysis to compare mortality across various weight categories of patients using machine learning algorithms. Bioinformatics analysis identified genes exhibiting differential expression among distinct weight categories. A prospective study was then conducted on a distinct cohort of 50 healthy individuals and 193 other mechanically ventilated patients. The expression levels of the genes identified through bioinformatics analysis were quantified through enzyme-linked immunosorbent assay (ELISA). Results The retrospective analysis revealed that overweight individuals had a lower mortality rate than underweight individuals, and body mass index (BMI) was an independent protective factor. Bioinformatics analysis identified matrix metalloproteinase 8 (MMP-8) as a differentially expressed gene between overweight and underweight populations. The results of further prospective studies showed that overweight patients had significantly lower MMP-8 levels than underweight patients ((3.717 (2.628, 4.191) vs. 2.763 (1.923, 3.753), ng/ml, P = 0.002). High MMP-8 levels were associated with increased mortality risk (OR = 4.249, P = 0.005), indicating that elevated level of MMP-8 predicts the mortality risk of underweight patients receiving mechanical ventilation. Conclusions This study provides evidence for a protective effect of obesity in mechanically ventilated patients and highlights the potential role of MMP-8 level as a biomarker for predicting mortality risk in this population.