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Abstract: Background: Critical illness stemming from severe traumatic injury is a leading cause of morbidity and mortality worldwide and involves the dysfunction of multiple organ systems, driven, at least in part, by dysregulated inflammation. We and others have shown a key role for genetic predisposition to dysregulated inflammation and downstream adverse critical illness outcomes. Recently, we demonstrated an association among genotypes at the single-nucleotide polymorphism (SNP) rs10404939 in LYPD4 , dysregulated systemic inflammation, and adverse clinical outcomes in a broad sample of ~1,000 critically ill patients. Methods: We sought to gain mechanistic insights into the role of LYPD4 in critical illness by bioinformatically analyzing potential interactions among rs10404939 and other SNPs. We analyzed a dataset of common (i.e., not rare) SNPs previously defined to be associated with genotype-specific, significantly dysregulated systemic inflammation trajectories in trauma patients, in comparison to a control dataset of common SNPs determined to exhibit an absence of genotype-specific inflammatory responses. Results: In the control dataset, this analysis implicated SNPs associated with phosphatidylinositol and various membrane transport proteins, but not LYPD4. In the patient subset with genotypically dysregulated inflammation, our analysis suggested the co-localization to lipid rafts of LYPD4 and the complement receptor CD55, as well as the neurally related CNTNAP2 and RIMS4. Segregation of trauma patients based on genotype of the CD55 SNP rs11117564 showed distinct trajectories of organ dysfunction and systemic inflammation despite similar demographics and injury characteristics. Conclusion: These analyses define novel interactions among SNPs that could enhance our understanding of the response to traumatic injury and critical illness.

Background: Sepsis, a life-threatening response to infection leading to systemic inflammation and organ dysfunction, has been hypothesized to be influenced by metabolic alterations in cerebrospinal fluid (CSF). Despite extensive research, the specific metabolic pathways contributing to sepsis remain unclear. This study aims to elucidate the causal relationships between CSF metabolites and sepsis risk using Mendelian Randomization (MR), offering insights that could lead to novel therapeutic strategies.

Methods: We conducted a two-sample MR analysis using genetic variants as instrumental variables (IVs) to investigate 338 CSF metabolites identified through a genome-wide association study. Data on sepsis-related outcomes were extracted from the genome-wide association study (GWAS) catalog encompassing 486,484 individuals of European descent. IVs were rigorously selected based on stringent genetic association and linkage disequilibrium criteria. Statistical analyses, including inverse variance weighting (IVW) and weighted median methods, were performed using the 'TwoSampleMR' package in R software, supplemented by comprehensive sensitivity analyses to ensure the robustness of our findings.

Results: Our analysis identified 19 CSF metabolites causally associated with sepsis risk. Notably, metabolites such as 1-palmitoyl-2-stearoyl-gpc (16:0/18:0) and 2-hydroxyglutarate showed significant negative correlations with sepsis risk. The reverse MR analysis further revealed that sepsis could negatively impact certain CSF metabolite levels, particularly Ribonate, suggesting a bidirectional relationship. These relationships were substantiated by rigorous statistical testing and sensitivity analyses confirming the absence of horizontal pleiotropy and the stability of our results across various MR methods.

Conclusions: This study demonstrates significant causal associations between specific CSF metabolites and the risk of developing sepsis, highlighting the potential for these metabolites to serve as biomarkers or therapeutic targets. The bidirectional nature of these findings also suggests that sepsis itself may alter metabolic profiles, offering further avenues for intervention.

Background: Early, accurate determination of disease severity in an emergency setting is paramount for improving patient outcomes and healthcare costs. Monocyte anisocytosis, quantified as monocyte distribution width (MDW), has been shown to correspond with immune dysregulation. We hypothesize that MDW is broadly associated with illness severity related to sepsis and serious infection in children.

Methods: We designed a retrospective study to analyze MDW, as measured by UniCel DxH 900 analyzer, on whole blood samples that were collected from children presenting for medical care between 4/2020-9/2022. SIRS criteria and Pediatric Sequential Organ Failure Assessment (pSOFA) scores were calculated, and source of infection was documented. Outcomes were compared by t-test or ANOVA, and receiver operating characteristic (ROC) curves assessed accuracy of MDW in identifying sepsis in children.

Results: We analyzed samples from 394 children presenting with illness to two pediatric medical centers. MDW was significantly higher in children with sepsis (28.2 ± 7.8) than children with suspected or confirmed infection who did not display signs of sepsis (21.5 ± 5.2). A ROC curve comparing MDW of children with sepsis against infected children without sepsis displayed an area under the curve of 0.78, suggesting MDW may serve as a useful tool in identifying children with sepsis.

Discussion: When children present to the urgent care/emergency setting with signs of infection, MDW may serve as a prompt tool to aid clinicians in identifying those who are at high risk for severe illness and require closer monitoring/intervention compared to those who may be safely discharged home.

Objective: Patients with sepsis often experience reductions or increases in platelet counts, but the implications of these temporal patterns on prognosis remain unclear. The aim of this study was to investigate the impact of changes in platelet trajectories on the clinical prognosis of sepsis.

Methods: This study was a retrospective analysis using data from the Medical Information Mart for Intensive Care (MIMIC)-IV database. Patients with sepsis were identified from the database, and their platelet trajectories were categorized into four distinct models based on the changes in platelet counts over a period of 14 days post-diagnosis of sepsis. The effect of these trajectories on patient prognosis was subsequently evaluated.

Results: A total of 15,250 patients with sepsis were included to construct a model, and the following four distinct platelet count trajectories were identified: normal platelet levels (phenotype 1); persistently low platelet levels (phenotype 2); gradually increasing platelet levels exceeding the normal range (phenotype 3); and consistently significantly elevated platelet levels (phenotype 4). Statistically significant differences were found in the 28-day mortality, in-hospital mortality, and 90-day mortality among the four phenotypes. Multivariate regression analysis showed that compared to the group with normal platelet levels (phenotype 1), the group with persistently low platelet levels (phenotype 2) had higher in-hospital mortality (odds ratio [OR] = 1.34, 95% confidence interval [CI]: 1.16-1.54), 28-day mortality (OR = 1.69, 95% CI: 1.47-1.94), and 90-day mortality (OR = 1.50, 95% CI: 1.32-1.69). There was no difference in in-hospital mortality between phenotypes 3 and 4 compared to phenotype 1, although phenotype 4 showed an increase in 28-day mortality (p < 0.05), and phenotype 3 showed a decreasing trend in 90-day mortality (p < 0.05). The results of inverse probability weighting adjusted by regression were basically consistent with the above findings, except that there was no statistical difference in 28-day mortality between phenotype 4 and phenotype 1. In the subgroups based on age, weight, and antiplatelet drugs or therapies, there was an interaction between platelet levels and these factors.

Conclusion: In patients with sepsis, a decrease in platelet count is associated with increased mortality, while a moderate increase in platelet count can reduce 90-day mortality. However, for patients with persistently elevated platelet counts, caution is advised when using antiplatelet drugs or therapies, as it may increase mortality.

Objective: Cardiac arrest (CA) is one of the most severe complications in patients with intracerebral hemorrhage (ICH), increasing the risk of death. This study explored the factors influencing CA occurrence and its resuscitation characteristics in ICH patients.

Methods: Data were retrieved from the Chinese Stroke Center Alliance database. The primary outcome was CA, and the secondary outcomes were in-hospital death and survival post-CA. Absolute standardized and rate differences were utilized for intergroup comparisons, while logistic regression was employed for correlation analysis.

Results: A total of 85,105 patients were enrolled in this study. Among them, 1651 (1.9%) patients experienced CA, of whom 1032 (62.5%) died in hospital. At baseline, prehospital notification from the emergency medical service system (PRE-EMS) was a co-factor influencing CA occurrence and the presence of a death outcome (OR: 1.71, 95% CI: 1.47-1.98, p < 0.001; OR: 0.50, 95% CI: 0.41-0.62, p < 0.001). In terms of complications, post-hospital hematoma expansion and swallowing dysfunction were co-factors influencing CA occurrence and the presence of a death outcome (OR: 3.78, 95% CI: 3.20-4.47, p < 0.001, OR: 1.39, 95% CI: 1.11-1.76; p < 0.001; OR: 7.66, 95% CI:5.48-10.70, p < 0.001, OR: 1.66, 95% CI: 1.08-2.57, p < 0.001). The incidence of CA in ICH patients decreased annually from 2015 to 2019, while survival after CA increased annually (p < 0.001).

Conclusions: PRE-EMS, posthospital hematoma expansion, and swallowing dysfunction were identified as co-factors contributing to CA occurrence and post-CA mortality following ICH. The proportion of CA patients following ICH decreased, while survival rates improved annually from 2015 to 2019.

Aims: Sepsis progression is marked by a complex immune response, where the involvement of hypoxia-inducible factors (HIF) plays an uncertain role. The study aims to elucidate the involvement of HIF-1α in monocyte function during sepsis and its potential as a prognostic indicator.

Methods and results: Transcriptomic data from healthy individuals and septic patients in datasets GSE54514, GSE167363, and GSE46955 were analyzed. Additionally, human monocytes were employed to elucidate how HIF regulates immune responses in the context of sepsis. Septic non-survivors exhibited sustained upregulation of HIF-1α expression alongside compromised inflammatory response and antigen presentation, with downregulation of NF-κB and HLADRB1 genes associated with poor sepsis prognosis. Conversely, septic survivors displayed an increased proportion of classical monocytes and enhanced inflammation and expression of antigen presentation-related genes. During the recovery phase of sepsis, monocytes continued to demonstrate elevated HIF-1α expression. In cultured THP1 cells and septic CD14+ monocytes, HIF hindered inflammatory responses and antigen presentation, while also suppressing the proportion of classical monocytes after LPS stimulation. Mechanistically, HIF significantly attenuated LPS-induced immune responses in monocytes by inhibiting the phosphorylation of IKK.

Conclusions: HIF in monocytes acts as a suppressor of immune-inflammatory responses and antigen presentation, and may serve as a negative molecular marker for sepsis development.

Abstract: Background: Acute liver failure (ALF) is a severe clinical syndrome characterized by massive hepatocyte death in a short time due to viruses, drugs, alcohol, or other factors. Oxidative stress is an important pathogenic mechanism of ALF. LPS-induced internalization of toll-like receptor 4 (TLR4) and the subsequent activation of the toll/IL-1R domain-containing adaptor-inducing IFN-beta (TRIF) signaling pathway widely mediate inflammatory responses in a series of diseases. However, whether the TLR4-TRIF signaling pathway contributes to ALF by mediating oxidative stress processes remains unclear. Methods: An ALF mouse model was induced by lipopolysaccharide (LPS)/D-galactosamine (D-GalN). TLR4-TRIF systemic knockout mice and TLR4 conditional knockout mice were used to determine the role of the TLR4-TRIF signaling pathway in ALF. The effects of TLR4 or TRIF deficiency on oxidative stress were investigated. In addition, we examined the protective role of the clodronate liposomes (macrophage scavengers) and the antioxidant N-acetylcysteine (NAC) in ALF. Results: TLR4 or TRIF deficiency significantly alleviated LPS/D-GalN-induced lethality, hepatic dysfunction, and hepatic pathologic injury, which was dependent on myeloid-derived TLR4. Hence, macrophage clearance exhibits a similar protective effect. Mechanically, TLR4 or TRIF deficiency was observed to inhibit oxidative stress by increasing glutathione, while decreasing malondialdehyde, 8-hydroxy-2-deoxyguanosine, and γ-H2AX. Therefore, the pharmacologic antioxidant NAC exhibited significant hepato-protective effects. Conclusions: Targeting myeloid-derived TLR4-TRIF signaling pathway or antioxidant therapy may be a potential therapeutic direction to treat ALF.

Abstract: Although there have been numerous advancements in burn wound management, burn injuries are still a major cause of morbidity and mortality in the United States, and novel therapeutics are still needed to improve outcomes. Poloxamer 188 (P188) is a synthetic copolymer with Food and Drug Administration (FDA) approval that has many biological applications. This study aimed to review the literature on P188 in burn injuries and its effects based on burn mechanisms. We employed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to complete this systematic literature review. We searched the databases of Google Scholar, PubMed, and SCOPUS using the keywords burn, p188, poloxamer 188, and pluronic F68 in combination. Two reviewers independently screened the articles for inclusion. Articles that were not in English, were book chapters or conference proceedings, or did not evaluate P188 in the setting of burn injuries were excluded. We included a total of 33 full-text articles with both in vivo and in vitro preclinical studies. P188 was found to be beneficial in animal and cell studies evaluating electrical and thermal burn injuries. P188 was also found to be useful in burn wound management. Although its utility may be limited in radiation injuries, P188 may be helpful in delaying the initial damage caused by radiation burns. P188 therefore has the potential to be used as a therapy in both burn wound management and in the treatment of systemic injuries sustained through burns. Future studies should aim to assess the efficacy of P188 in clinical models of burn injury.

Abstract: Objective: To investigate factors influencing the late prognosis of patients with acute ST-segment elevation myocardial infarction treated by direct percutaneous coronary intervention. Methods: We retrospectively analyzed 349 ST-segment elevation myocardial infarction patients treated with direct percutaneous coronary intervention. Patients were categorized based on catheter laboratory activation time (CLAT) (≤15 or >15 min), time of arrival (working hours or out-of-hours), and mode of arrival (emergency medical services transportation or self-presentation). The primary endpoint was the 2-year major adverse cardiovascular events (MACEs), defined as all-cause death, nonfatal myocardial infarction, and target vessel revascularization. Results: Patients with CLAT ≤15 min showed significant differences in oxygen saturation, FMC-to-device time, symptom-to-device time, symptom-to-FMC time, presentation mode, presentation duration, and MACEs (all P < 0.005). Self-presentation (odds ratio = 0.593, 95% confidence interval = 0.413-0.759) and out-of-hours presentation (odds ratio = 0.612, 95% confidence interval = 0.433-0.813) were risk factors for CLAT >15 min. The working-hours group showed significant differences in FMC-to-device time, activation-to-arrival time at the catheter laboratory, and the number of cases with activation time ≤15 min (all P < 0.005). The emergency medical services and self-presentation groups differed significantly in age, blood pressure, FMC-to-device time, and electrocardiography-to-CLAT (all P < 0.005). Conclusion: Reducing CLAT to 15 min significantly lowers the 2-year MACE rate. Self-presentation and out-of-hours presentation are risk factors for delayed catheter laboratory activation.

Abstract: Background: Pediatric sepsis is a common and complex syndrome characterized by a dysregulated immune response to infection. Aberrations in the renin-angiotensin system (RAS) are factors in several infections of adults. However, the precise impact of RAS dysregulation in pediatric sepsis remains unclear. Methods: Serum samples were collected from a derivation cohort (58 patients with sepsis, 14 critically ill control subjects, and 37 healthy controls) and validation cohort (50 patients with sepsis, 37 critically ill control subjects, and 46 healthy controls). Serum RAS levels on day of pediatric intensive care unit admission were determined and compared with survival status and organ dysfunction. Results: In the derivation cohort, the serum renin concentration was significantly higher in patients with sepsis (3,678 ± 4,746) than that in healthy controls (635.6 ± 199.8) ( P < 0.0001). Meanwhile, the serum angiotensin (1-7) was significantly lower in patients with sepsis (89.7 ± 59.7) compared to that in healthy controls (131.4 ± 66.4) ( P < 0.01). These trends were confirmed in a validation cohort. Nonsurvivors had higher levels of renin (8,207 ± 7,903) compared to survivors (2,433 ± 3,193) ( P = 0.0001) and lower levels of angiotensin (1-7) (60.9 ± 51.1) compared to survivors (104.0 ± 85.1) ( P < 0.05). A combination of renin, angiotensin (1-7) and procalcitonin achieved a model for diagnosis with an area under the receiver operating curve of 0.87 (95% CI: 0.81-0.92). Conclusion: Circulating renin and angiotensin (1-7) have predictive value in pediatric sepsis.