Manifestations Of Sepsis Research Articles

Utility of doppler ultrasound in early-onset neonatal sepsis: A case-control study.

Early-onset sepsis is one of the leading causes of neonatal morbidity and mortality worldwide and timely diagnosis is, therefore, of paramount importance. As there is a lack of literature regarding early alteration of the cerebral blood flow (CBF) in neonatal sepsis, our study aimed to appraise changes in the CBF velocities and Doppler indices in neonates with early-onset neonatal sepsis (EONS) and to assess its diagnostic accuracy. A total of 99 neonates were recruited in the study; 56 neonates with EONS, and the age-matched 43 neonates without any manifestations of sepsis. A Transcranial Doppler examination and cerebral hemodynamics were assessed in neonates during the first seventy-two hours of life. Doppler indices and CBFV were measured in the anterior cerebral artery (ACA), and middle cerebral artery (MCA), of either side. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and diagnostic accuracy were calculated. A significantly lower resistance in Resistivity (RI) and Pulsatility (PI) indices, a significant high end-diastolic velocity (EDV), and relatively higher peak systolic velocity (PSV) in both ACA and MCA have been documented within 72 hours of birth in neonates with EONS compared to the control group of neonates without sepsis. Our Study revealed that assessment of CBF at early hours of birth by Transcranial Doppler examination showed alteration in cerebral hemodynamics in neonates with EONS with an increase in the CBF and a decrease in the resistance. It can be adopted as a bedside, noninvasive tool with immediate diagnostic value.

Improving prevention and early detection of sepsis among patient groups at risk: Introducing a model for a multimodal information campaign-The SepWiss study protocol.

Sepsis is a life-threatening organ dysfunction due to a dysregulated host response to infection. Annually, sepsis leads to approx. 90.000 deaths in Germany. Risk factors include amongst others older age (>60), innate or acquired dysfunction of the immune system, and underlying chronic diseases of the lung, heart, liver, or kidneys. The manifestation of sepsis is a medical emergency, and patient outcomes depend on timely diagnosis and immediate treatment. In addition, vaccinations e.g., against pneumococci or influenza virus, are a highly effective public health tool to prevent the most common underlying infections that may lead to sepsis. However, a lack of public awareness for the relevance of vaccination and detecting sepsis as an emergency underlines the need for public health interventions that address these issues. SepWiss aims to evaluate the effects of a multimodal information campaign designed to address this lack of awareness among the risk population in Germany. SepWiss is an intervention at state level, consisting of a multimodal information campaign targeting risk groups in the German federal states of Berlin and Brandenburg (intervention region). Based on available evidence, various information formats were developed and implemented by outdoor advertising, social media, educational formats and through stakeholders' platforms, starting in August 2021. The control region comprises of the remaining 14 German federal states. We will analyze vaccination coverage (primary outcome), and sepsis knowledge, the ability to detect sepsis as an emergency, and attitude towards vaccination (secondary outcomes) amongst the risk population in a controlled before-after comparison. The implementation is accompanied by a mixed-method process evaluation. SepWiss is the first project of its kind to evaluate a complex multi-faceted evidence-based information campaign with regards to the topics of vaccination coverage, and the importance of sepsis detection and prevention for the most vulnerable populations in Germany. Results will be valuable for informing further nationwide campaigns. German Registry for Clinical Trials: DRKS00024475. Registered February 24th, 2021.

Procalcitonin-A Marker of Sepsis

Background: Sepsis remains a significant health concern, particularly in resource-limited regions like Bangladesh. Despite available diagnostic methods, identifying bacterial infections in septic patients proves challenging, prompting the exploration of biomarkers. Procalcitonin (PCT) has emerged as a promising biomarker for bloodstream infections like sepsis. Objective: This study aims to evaluate the utility of measuring serum PCT levels in diagnosing and assessing the severity of sepsis, with a focus on enhancing early treatment in intensive care units (ICUs). Method: A prospective study was conducted on 50 patients admitted to the Combined Military Hospital, Dhaka ICU, exhibiting clinical manifestations of sepsis between April and September 2015. Patients of all ages and genders were included, while those with recent major surgery, trauma, or burn history were excluded. Detailed clinical assessments and laboratory investigations were performed, with data recorded on a standardized proforma. Result: Of the 50 patients evaluated, 64% were male, and 36% were female, with a mean age of 56.11±10.89 years. Sepsis was more prevalent in patients aged >50 years (60%) and in males (64%). Respiratory tract infection (RTI) was the most common source of sepsis (40% of cases), with Klebsiella pneumonia being the predominant organism. Higher Sequential Organ Failure Assessment (SOFA) scores correlated significantly with elevated serum PCT concentrations. Serum PCT demonstrated a significant difference between non-septic and septic groups (p-value <0.001), exhibiting sensitivity and specificity of 91% and 83.3%, respectively. Conclusion: Serum PCT emerges as a promising marker for sepsis in critically ill patients, enhancing diagnostic certainty and informing patient management. Its addition to routine work-ups could improve outcomes and patient care in ICUs.

P2X7 receptor: A receptor closely linked with sepsis-associated encephalopathy.

Sepsis is defined as a dysregulated host response to infection resulting in life-threatening organ dysfunction. Sepsis-associated encephalopathy (SAE) is the main manifestation of sepsis. Inflammation, peroxidation stress injury, and apoptosis are the main factors involved in the pathogenesis of SAE. A growing body of evidence has proved that P2X7 receptor (P2X7R), a cationic channel receptor that is widely distributed in the body, plays a major role in the occurrence and development of inflammatory injury. Therefore, this review mainly describes the activation of P2X7R in sepsis, which leads to the recruitment of inflammatory cells to the cerebral vasculature, the destruction of the blood-brain barrier, the activation of microglial cells in the brain, the apoptosis of brain cells, and other damage processes. This review also illustrates the potential therapeutic value of P2X7R inhibition in SAE.

Complementary and alternative medicine on cognitive defects and neuroinflammation after sepsis.

Sepsis-associated encephalopathy (SAE) is a common manifestation of sepsis, ranging from mild confusion and delirium to severe cognitive impairment and deep coma. SAE is associated with higher mortality and long-term outcomes, particularly substantial declines in cognitive function. The mechanisms of SAE probably include neuroinflammation that is mediated by systemic inflammation and ischemic lesions in the brain, a disrupted blood-brain barrier, oxidative stress, neurotransmitter dysfunction, and severe microglial activation. Increasing evidence suggests that complementary and alternative medicine, especially Traditional Chinese Medicine (TCM), is favorable in alleviating cognitive decline after sepsis. Here, we summarized the studies of traditional herbal remedies, TCM formulas and acupuncture therapy in animal models of neurological dysfunctions after sepsis in recent decades and reviewed their potential mechanisms.

Suppressing the Substance P-NK1R Signalling Protects Mice against Sepsis-Associated Acute Inflammatory Injury and Ferroptosis in the Liver and Lungs.

Substance P (SP), encoded by the TAC1/Tac1 gene, acts as a significant mediator in dysregulated systemic inflammatory response and associated organ injury in sepsis by activating the neurokinin-1 receptor (NK1R). This study investigated the impact of SP-NK1R signaling on ferroptosis in the liver and lungs of mice with sepsis. Sepsis was induced by caecal ligation puncture (CLP) surgery in mice. The SP-NK1R signaling was suppressed by Tac1 gene deletion, NK1R blockade, and a combination of these two approaches. The physiological conditions of mice were recorded. The profile of the SP-NK1R cascade, inflammatory response, ferroptosis, and tissue histology were investigated in the liver and lungs. Several manifestations of sepsis occurred in Tac1+/+ mice during the development of sepsis. Notably, hypothermia became significant four hours after the induction of sepsis. In the liver and lungs of mice subjected to CLP surgery, the concentrations of SP and NK1R were upregulated. Additionally, the concentrations of pro-inflammatory mediators, including cytokines (IL-1β, IL-6, and TNF-α) and chemokines (MCP-1 and MIP-2), were increased. Moreover, ferroptosis was elevated, as evidenced by increased concentrations of iron and MDA and reduced concentrations of GSH, Nrf2, and Gpx4. Suppressing the SP-NK1R cascade significantly mitigated CLP-surgery-induced alterations in mice. Importantly, these three approaches used to suppress SP-NK1R signaling showed similar effects on protecting mice against sepsis. In conclusion, increased SP-mediated acute inflammatory response and injury in the liver and lungs in mice with CLP-surgery-induced sepsis was associated with elevated ferroptosis. The detrimental effect of SP on sepsis was predominantly mediated by NK1R. Therefore, the suppression of increased SP-NK1R signaling and ferroptosis may be a promising adjuvant therapeutic candidate for sepsis and associated acute liver and lung injury.

Positive Blood Culture Results Predominantly Unrevealed among Adults Patients with Sepsis

Sepsis is increasing every year and can be life-threatening. In the diagnosis of sepsis, it is challenging to identify the causative agent of infection. This research aims to determine the proportion of positive blood culture in sepsis patients at Hasanuddin University Hospital, Makassar. Blood cultures were collected from 98 adult patients with sepsis manifestations. This research design is cross-sectional with a descriptive observation approach. The data analysed in descriptive statistics were utilised to summarise patient demographics, treatments, and outcomes. Thirteen of 98 samples were positive for microbial pathogens (13.26%). The elderly group had the highest percentage (76.5%); eighty-seven patients (88.77%) were treated with antibiotic therapy prior to blood culture collection. Cephalosporins are the most administered antibiotics (72.4%). Administration of empirical therapy prior to blood culture collection may decrease the sensitivity of culture results. The culture of the infectious focus should be done to assist in the consideration of antimicrobial treatment.

Activation of sigma-1 receptor ameliorates sepsis-induced myocardial injury by mediating the Nrf2/HO1 signaling pathway to attenuate mitochondrial oxidative stress

BackgroundSepsis is a condition that triggers the release of large amounts of reactive oxygen species and inflammatory factors in the body, leading to myocardial injury and cardiovascular dysfunction — an important contributor to the high mortality rate associated with sepsis. Although it has been demonstrated that the sigma-1 receptor (S1R) is essential for preventing oxidative stress, its effectiveness in treating sepsis is yet unknown. AimThis study aimed to investigate the role and mechanisms of S1R activation in sepsis-induced myocardial injury. MethodsA model of sepsis-induced myocardial injury was constructed by performing cecum ligation and puncture(CLP) surgery on rats. Flv or BD1047 were intraperitoneally injected into rats for one consecutive week before performing CLP, and then intraperitoneally injected into the rats again 1 h after the surgery.The effects of Flv and BD1047 were detected by HE staining, immunofluorescence staining, IHC staining, echocardiography measurements,TUNEL, oxidative stress detection, TEM, flow cytometry and western blot. We further validated the mechanism in vitro using neonatal rat cardiomyocites and H9C2 cells. ResultsS1R protein level was reduced in the hearts of septic rats, whereas administration of Flv, an S1R activator, ameliorated myocardial injury, mitochondrial oxidative stress, and pathological manifestations of sepsis. On the other hand, administration of the S1R inhibitor BD1047 exacerbated the mitochondrial oxidative stress, and apoptosis, as well as symptoms and pathological manifestations of sepsis. In addition, we found that up-regulation of S1R activated the Nrf2/HO1 signaling pathway and promoted nuclear translocation of Nrf2, which activated downstream proteins to generate antioxidant factors, such as HO1, in turn alleviating oxidative stress and countering myocardial damage. ConclusionBy scavenging ROS accumulation and reducing mitochondrial oxidative stress via the Nrf2/HO1 signaling pathway, activation of S1R improves cardiac function, mitigates death of cardiomyocytes, and attenuates sepsis-induced myocardial injury.

Morphine aggravates inflammatory, behavioral, and hippocampal structural deficits in septic rats

Although pain and sepsis are comorbidities of intensive care units, reported data on whether pain control by opioid analgesics could alter inflammatory and end-organ damage caused by sepsis remain inconclusive. Here, we tested the hypothesis that morphine, the gold standard narcotic analgesic, modifies behavioral and hippocampal structural defects induced by sepsis in male rats. Sepsis was induced with cecal ligation and puncture (CLP) and behavioral studies were undertaken 24 h later in septic and/or morphine-treated animals. The induction of sepsis or exposure to morphine (7 mg/kg) elicited similar: (i) falls in systolic blood pressure, (ii) alterations in spatial memory and learning tested by the Morris water maze, and (iii) depression of exploratory behavior measured by the new object recognition test. These hemodynamic and cognitive defects were significantly exaggerated in septic rats treated with morphine compared with individual interventions. Similar patterns of amplified inflammatory (IL-1β) and histopathological signs of hippocampal damage were noted in morphine-treated septic rats. Additionally, the presence of intact opioid receptors is mandatory for the induction of behavioral and hemodynamic effects of morphine because no such effects were observed when the receptors were blocked by naloxone. That said, our findings suggest that morphine provokes sepsis manifestations of inflammation and interrelated hemodynamic, behavioral, and hippocampal deficits.

Catalpol rescues LPS-induced cognitive impairment via inhibition of NF-Κb-regulated neuroinflammation and up-regulation of TrkB-mediated BDNF secretion in mice

Ethnopharmacological relevanceSeptic-associated encephalopathy (SAE) is a key manifestation of sepsis. Nevertheless, specific treatment for SAE is still lacking. Catalpol is an active component derived from Rehmanniae Radix, and has been demonstrated to be a potential neuroprotective agent. However, its effect on SAE still needs to be fully explored. AimTo address the benefits of catalpol on post-sepsis cognitive deterioration and related mechanisms. Materials and methodsNovel object recognition test, temporal order task, histopathology, and immunochemistry were applied to address the benefits of catalpol on LPS-triggered post-sepsis cognitive decline in mice. Xuebijing injection (10 ml/kg) has been utilized as a positive control in the above animal studies. After treatment, the catalpol content in the hippocampus was determined using LC-MS/MS. Finally, the mechanisms of catalpol were further assessed in BV2 and PC12 cells in vitro using Western blot, RT-PCR, flow cytometry, molecular docking tests, thermal shift assay, transmission electron microscopy, and immunofluorescence analysis. ResultsBehavior tests showed that catalpol therapy could lessen the cognitive impairment induced by LPS damage. HE, Nissl, immunofluorescence, transmission electron microscopy, and Golgi staining further reflected that catalpol treatment could restore lymphocyte infiltration, blood-brain barrier (BBB) degradation, and the decreasing complexity of dendritic trees. According to LC-MS/MS analysis, catalpol had a 136 ng/mg concentration in the hippocampus. In vitro investigation showed that catalpol could inhibit microglia M1 polarization via blocking NF-κB phosphorylation, translocation and then reducing inflammatory cytokine release in BV2 microglia cells. Brain-derived neurotrophic factor (BDNF) release up-regulation and TrkB pathway activation were observed in the catalpol treatment group in vivo and in vitro. The effect of catalpol on enhancing BDNF expression was inhibited by the specific inhibitor of TrkB (GNF-5837) in PC12 cells. Further molecular docking tests showed that catalpol formed weak hydrophobic bonds with TrkB. Besides, thermal shift assay also reflected that catalpol incubation caused a considerable change in the melting temperature of the TrkB. ConclusionCatalpol alleviates LPS-triggered post-sepsis cognitive impairment by reversing neuroinflammation via blocking the NF-κB pathway, up-regulating neurotrophic factors via the activation of TrkB pathway, and preserving BBB integrity.

Immune Diagnostics and Immunotherapy of Burn Sepsis

The paper analyzes the literature data and authors proper experience in the study of immunopathogenesis and immunodiagnosis of burn sepsis. It argues the issues of effective use of immunocorrection in the complex treatment of severely burned patients.Diagnosis of sepsis after severe burn injury is challenging due to the overlap of signs and clinical manifestations of the hypermetabolic reaction of thermal injury and sepsis. The systemic inflammatory response caused by burns can mimic manifestations of sepsis and complicate its early diagnosis. Considering this, modern immunodiagnostics can serve as an effective tool in identifying damaged key immune markers in burns, determining the severity of immune status disorders in burn disease and the risk of developing septic complications for timely immunocorrection and providing appropriate complex therapy for patients with extensive burns.However, the problem of immunocorrective therapy in severely burned patients remains extremely relevant, debatable and not fully resolved. It is a personalized approach based on immune analysis and clinical recommendations for the complex treatment of burn injury that should be applied in the immunotherapy of burn sepsis to improve the clinical outcomes and, possibly, prevent the development of sepsis in patients with severe burn injury.

A-155 Unlocking the Complete Blood Count: Derivation of a Single-Panel Laboratory Test That Includes Monocyte Distribution Width to Create a Universal Sepsis Screening Tool

Abstract Background Sepsis is the leading cause of in-hospital death. Outcome improvement requires rapid detection and early antimicrobial therapy. The complete blood count (CBC) is ordered for more than two-thirds of all patients in the emergency department (ED). Individual CBC components have limited utility for sepsis screening due to low specificity and sensitivity. We sought to create a reliable sepsis screening tool by combining components of the CBC differential. Methods In this single-center retrospective cohort study, all adult patients who had a CBC with differential performed within 6 h of ED arrival during a 20-month period were eligible for inclusion. Repeat ED visits by the same patient were excluded. Our primary outcome was manifestation of sepsis within 72 h of ED arrival, detected from timestamped electronic health records using a previously validated electronic phenotype based on Sepsis-3 consensus criteria. Multivariable logistic regression was performed to identify individual components of the CBC differential that were independently associated with our outcome and to identify optimal cutoffs for discretization. Odds ratios were used to assign weights to each component and to derive a 10-point system for scoring likelihood of sepsis. Results 34 864 patients were included; 1306 (3.7%) met sepsis outcome criteria within 72 h of ED arrival and 181 (0.5%) had septic shock. White blood cell (WBC) count, monocyte distribution width (MDW), and the neutrophil to lymphocyte count ratio were found to predict sepsis. As shown in the figure, there was a linear relationship between our CBC infection severity index and likelihood of developing sepsis and septic shock. Patients with a high risk score (8 or above) had a greater than one in four chance of developing sepsis within 72 h. Conclusion A simple ten-point index derived from the most commonly used laboratory panel in medicine reliably estimated likelihood of developing sepsis.

Plasminogen System in the Pathophysiology of Sepsis: Upcoming Biomarkers.

Severe hemostatic disturbances and impaired fibrinolysis occur in sepsis. In the most serious cases, the dysregulation of fibrinolysis contributes to septic shock, disseminated intravascular coagulation (DIC), and death. Therefore, an analysis of circulating concentrations of pro- and anti-fibrinolytic mediators could be a winning strategy in both the diagnosis and the treatment of sepsis. However, the optimal cutoff value, the timing of the measurements, and their combination with coagulation indicators should be further investigated. The purpose of this review is to summarize all relevant publications regarding the role of the main components of the plasminogen activation system (PAS) in the pathophysiology of sepsis. In addition, the clinical value of PAS-associated biomarkers in the diagnosis and the outcomes of patients with septic syndrome will be explored. In particular, experimental and clinical trials performed in emergency departments highlight the validity of soluble urokinase plasminogen activator receptor (suPAR) as a predictive and prognostic biomarker in patients with sepsis. The measurements of PAI-I may also be useful, as its increase is an early manifestation of sepsis and may precede the development of thrombocytopenia. The upcoming years will undoubtedly see progress in the use of PAS-associated laboratory parameters.

Emodin protects lipopolysaccharide-induced myocardial injury and mitochondrial dysfunction via PI3K/AKT signaling pathway based on Network Pharmacology

Sepsis combined with myocardial injury is an important cause of septic shock and multiple organ failure. Cardiac dysfunction is a significant manifestation of sepsis and it is associated with the prognosis of the disease. It is assumed that damage to myocardial mitochondrial function is one of the main causes of cardiac dysfunction in septic patients, and the repair of myocardial mitochondrial function may alleviate cardiac dysfunction in septic patients. Emodin has been discovered to serve a variety of pharmacological effects, including anti-tumor, anti-inflammatory, antioxidant, and anti-apoptotic properties. In this study, we investigated the potential protective effect of Emodin on sepsis and revealed the underlying mechanisms using a network pharmacology approach coupled with experimental validation. The model of myocardial injury induced by LPS was established and divided into three groups: the control group, the lipopolysaccharide (LPS) group, and the LPS+Emodin group. The apoptosis rate, reactive oxygen species (ROS), mitochondrial permeability transition pore(MPTP), and mitochondrial membrane potential (MMP) were determined in LPS-induced sepsis Cardiacmyocytes treated with different concentrations of Emodin. In addition, the degree of myocardial mitochondrial damage was evaluated by electron microscopy. Signal pathway-related proteins were determined by Western blotting in vitro. And then, network pharmacology screening revealed TP53, CASP3, ILB, MYC, TNF, PTGS2, and PPARG as the critical overlapping targets in a PPI network, and GO and KEGG analyses revealed the top 10 enriched biological processes and signaling pathways associated with the therapeutic effects of emodin on sepsis. The results show the PI3K-AKT pathway is mainly involved in the emodin-sepsis myocardial injury network. Meanwhile, Emodin has been demonstrated to protect the myocardium from LPS-induced myocardial injury in vitro, and moderate doses of Emodin showed the most prominent effect. Emodin alleviates mitochondrial damage by reducing apoptosis and inhibiting oxidative stress and ameliorates protecting LPS-induced myocardial injury and mitochondrial dysfunction through the PI3K-AKT pathway. This provides a feasible strategy for preventing and treating myocardial injury and mitochondrial dysfunction in sepsis. This study was supported by the Science and Technology Bureau of Zhengjiang (Grant No.SH2022068 and SH2022042). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

What are the conclusions of the recent studies about administrating vitamin C in sepsis? The review

Introduction and purpose: Sepsis is defined by the Sepsis-3 definition as life-threatening organ dysfunction caused by a dysregulated host response to infection1. Common manifestations of sepsis are fever, tachycardia, tachypnoea, confusion, hemodynamic dysfunction, and worsening of tissue perfusion. Sepsis may cause septic shock. The immune system produces reactive oxygen species which can also have an adverse influence on vasoconstruction5. There is a decrease in vitamin C levels in the plasma of patients with multiple organ failure6. Vitamin C plays a role in the synthesis of catecholamines and has antioxidant properties. The usage of vitamin C in sepsis patients has been arousing expectations for many years.
 Brief description of the state of knowledge: The current state of knowledge indicates that there is no beneficent effect of ascorbic acid on the population which suffered from sepsis. What is more, there is some proof that administrating that vitamin can be noxious and factor into brain functions19. There are also suggestions that it could increase mortality8.
 Conclusions: Recent studies do not recommend ascorbic acid as a treatment for sepsis. There is not out of the question that in some subpopulations due to pathogens or failed organs administrating vitamin C would benefit. Further research on this topic needs to be followed up.

Activation of NR1H3 attenuates the severity of septic myocardial injury by inhibiting NLRP3 inflammasome.

Most sepsis deaths are due to the development of multiple organ failure, in which heart failure is a recognized manifestation of sepsis. To date, the role of liver X receptors α (NR1H3) in sepsis is still uncertain. Here, we hypothesized that NR1H3 mediates multiple essential sepsis-related signalings to attenuate septic heart failure. Adult male C57BL/6 or Balbc mice and HL-1 myocardial cell line were performed for in vivo and in vitro experiments, respectively. NR1H3 knockout mice or NR1H3 agonist T0901317 was applied to evaluate the impact of NR1H3 on septic heart failure. We found decreased myocardial expression levels of NR1H3-related molecules while increased NLRP3 level in septic mice. NR1H3 knockout worsensed cardiac dysfunction and injury in mice subjected to cecal ligation and puncture (CLP), in association with exacerbated NLRP3-mediated inflammation, oxidative stress, mitochondrial dysfunction, endoplasmic reticulum stress, and apoptosis-related markers. The administration of T0901317 reduced systemic infection and improve cardiac dysfunction in septic mice. Moreover, Co-IP assays, luciferase reporter assays, and chromatin immunoprecipitation analysis, confirmed that NR1H3 directly repressed NLRP3 activity. Finally, RNA-seq detection further clarified an overview of the roles of NR1H3 in sepsis. In general, our findings indicate that NR1H3 had a significant protective effect against sepsis and sepsis-induced heart failure.

Use of machine learning algorithms to predict life-threatening ventricular arrhythmia in sepsis.

Life-threatening ventricular arrhythmias (LTVAs) are common manifestations of sepsis. The majority of sepsis patients with LTVA are unresponsive to initial standard treatment and thus have a poor prognosis. There are very limited studies focusing on the early identification of patients at high risk of LTVA in sepsis to perform optimal preventive treatment interventions. We aimed to develop a prediction model to predict LTVA in sepsis using machine learning (ML) approaches. Six ML algorithms including CatBoost, LightGBM, and XGBoost were employed to perform the model fitting. The least absolute shrinkage and selection operator (LASSO) regression was used to identify key features. Methods of model evaluation involved in this study included area under the receiver operating characteristic curve (AUROC), for model discrimination, calibration curve, and Brier score, for model calibration. Finally, we validated the prediction model both internally and externally. A total of 27 139 patients with sepsis were identified in this study, 1136 (4.2%) suffered from LTVA during hospitalization. We screened out 10 key features from the initial 54 variables via LASSO regression to improve the practicability of the model. CatBoost showed the best prediction performance among the six ML algorithms, with excellent discrimination (AUROC = 0.874) and calibration (Brier score = 0.157). The remarkable performance of the model was presented in the external validation cohort (n = 9492), with an AUROC of 0.836, suggesting certain generalizability of the model. Finally, a nomogram with risk classification of LTVA was shown in this study. We established and validated a machine leaning-based prediction model, which was conducive to early identification of high-risk LTVA patients in sepsis, thus appropriate methods could be conducted to improve outcomes.

The Regulatory Roles of Ezh2 in Response to Lipopolysaccharide (LPS) in Macrophages and Mice with Conditional Ezh2 Deletion with LysM-Cre System.

The responses of macrophages to lipopolysaccharide (LPS) might determine the direction of clinical manifestations of sepsis, which is the immune response against severe infection. Meanwhile, the enhancer of zeste homologue 2 (Ezh2), a histone lysine methyltransferase of epigenetic regulation, might interfere with LPS response. Transcriptomic analysis on LPS-activated wild-type macrophages demonstrated an alteration of several epigenetic enzymes. Although the Ezh2-silencing macrophages (RAW264.7), using small interfering RNA (siRNA), indicated a non-different response to the control cells after a single LPS stimulation, the Ezh2-reducing cells demonstrated a less severe LPS tolerance, after two LPS stimulations, as determined by the higher supernatant TNF-α. With a single LPS stimulation, Ezh2 null (Ezh2flox/flox; LysM-Crecre/-) macrophages demonstrated lower supernatant TNF-α than Ezh2 control (Ezh2fl/fl; LysM-Cre-/-), perhaps due to an upregulation of Socs3, which is a suppressor of cytokine signaling 3, due to the loss of the Ezh2 gene. In LPS tolerance, Ezh2 null macrophages indicated higher supernatant TNF-α and IL-6 than the control, supporting an impact of the loss of the Ezh2 inhibitory gene. In parallel, Ezh2 null mice demonstrated lower serum TNF-α and IL-6 than the control mice after an LPS injection, indicating a less severe LPS-induced hyper-inflammation in Ezh2 null mice. On the other hand, there were similar serum cytokines after LPS tolerance and the non-reduction of serum cytokines after the second dose of LPS, indicating less severe LPS tolerance in Ezh2 null mice compared with control mice. In conclusion, an absence of Ezh2 in macrophages resulted in less severe LPS-induced inflammation, as indicated by low serum cytokines, with less severe LPS tolerance, as demonstrated by higher cytokine production, partly through the upregulated Socs3.

Exploring the molecular mechanism of notoginsenoside R1 in sepsis-induced cardiomyopathy based on network pharmacology and experiments validation.

Sepsis-induced cardiomyopathy (SIC) is an important manifestation of sepsis, and abnormal cardiac function affects the development of sepsis. Notoginsenoside R1 (NG-R1) is a unique bioactive component of Panax notoginseng with anti-inflammatory and antioxidant effects. However, the effects and possible mechanisms of NG-R1 on SIC are not clear. The purpose of this study was to identify the potential targets and regulatory mechanisms of the action of NG-R1 on SIC. To investigate the potential mechanism, we used network pharmacology, molecular docking, qRT-PCR, and immunofluorescence. The results showed that NG-R1 ameliorated myocardial fibrosis in septic mice. Validation of network pharmacology and molecular docking results revealed that NG-R1 reduced tumor necrosis factor-Alpha (TNF-α) expression in myocardial tissues and AC16 cardiomyocytes in mice, as well as inflammatory factor release in AC16 cells, so TNF-α may be a potential target of NG-R1 against SIC. The present study demonstrated that NG-R1 could protect against SIC and by regulating the expression of TNF-α inflammatory factors, providing a new idea for sepsis drug development.

Secukinumab alleviates cognitive impairment by attenuating oxidative stress and neuronal apoptosis via the IL-17RA/AKT/ERK1/2 pathway in a rat model of sepsis

BackgroundSeptic-associated encephalopathy (SAE) is a critical manifestation of sepsis that leads to long-term cognitive impairment. Interleukin (IL)-17A has been shown to mediate neuronal apoptosis in central nervous system diseases, while oxidative stress has been found to have a detrimental effect in SAE. However, the relationship between IL-17A and oxidative stress in SAE remains unclear. This study aimed to investigate the effects of secukinumab on alleviating cognitive impairment in a rat model of sepsis, as well as examine its underlying molecular mechanism of action. MethodsA total of 282 male 8-week-old Sprague-Dawley rats were randomly subjected to cecal ligation and puncture (CLP) or sham treatment followed by volume resuscitation immediately after surgery. Secukinumab was administered intranasally 1 h post-CLP. Rats were given the p-ERK activator ceramide C6 intracerebroventricularly (i.c.v) 24 h before CLP surgery. Recombinant rIL-17A was administered i.c.v. at 0 h in naive rats, followed by intraperitoneal injection of the AKT inhibitor GDC0068 1 h post-rIL-17A injection. Clinical scores, body weight, and survival rate were assessed. In addition, immunofluorescence staining, neurobehavioral tests, Nissl staining, and western blotting were performed. Cognitive function was assessed 15–20 days post-CLP using the Morris water maze test. ResultsIL-17A and IL-17RA protein expression levels in the rat hippocampus increased and peaked 24 h post-CLP. Furthermore, IL-17RA was found to be expressed in neurons. The survival rate after CLP was 50%. Following CLP, an increased clinical score and significant decrease in body weight were observed. However, treatment with secukinumab led to a decrease in the clinical score of rats 24 h post-CLP. CLP resulted in spatial and memory impairment and anxiety-like behaviors in rats, while secukinumab treatment significantly alleviated cognitive impairment compared to the CLP group (p < 0.05). In addition, oxidative stress and neuronal apoptosis were found to be increased in the CLP group, while secukinumab significantly reduced oxidative stress and neuronal apoptosis in the hippocampus following CLP. Furthermore, secukinumab treatment led to a significant decrease in the protein expression levels of p-AKT, p-ERK1/2, Romo1, and Bax, together with increased Bcl-2 protein expression. Finally, treatment with ceramide C6 and GDC0068 abolished the neuroprotective effects of secukinumab post-CLP. ConclusionOur results demonstrated that secukinumab attenuated oxidative stress and neuronal apoptosis and partially ameliorated cognitive impairment via the IL-17RA/AKT/ERK1/2 pathway in a rat model of sepsis. Thus, secukinumab may be a potential therapeutic strategy for septic patients.