Determining prognostic indicator for anticoagulant therapy in sepsis-induced disseminated intravascular coagulation.
Journal of intensive care
BACKGROUND:There is no reliable indicator that can assess the treatment effect of anticoagulant therapy for sepsis-associated disseminated intravascular coagulation (DIC) in the short term. The aim of this study is to develop and validate a prognostic index identifying 28-day mortality in septic DIC patients treated with antithrombin concentrate after a 3-day treatment. METHODS:The cohort for derivation was established utilizing the dataset from post-marketing surveys, while the cohort for validation was acquired from Japan's nationwide sepsis registry data. Through univariate and multivariate analyses, variables that were independently associated with 28-day mortality were identified within the derivation cohort. Risk variables were then assigned a weighted score based on the risk prediction function, leading to the development of a composite index. Subsequently, the area under the receiver operating characteristic curve (AUROC). 28-day survival was compared by Kaplan-Meier analysis. RESULTS:In the derivation cohort, 252 (16.9%) of the 1492 patients deceased within 28 days. Multivariable analysis identified DIC resolution (hazard ratio [HR]: 0.31, 95% confidence interval [CI]: 0.22-0.45, P < 0.0001) and rate of Sequential Organ Failure Assessment (SOFA) score change (HR: 0.42, 95% CI: 0.36-0.50, P < 0.0001) were identified as independent predictors of death. The composite prognostic index (CPI) was constructed as DIC resolution (yes: 1, no: 0) + rate of SOFA score change (Day 0 SOFA score-Day 3 SOFA score/Day 0 SOFA score). When the CPI is higher than 0.19, the patients are judged to survive. Concerning the derivation cohort, AUROC for survival was 0.76. As for the validation cohort, AUROC was 0.71. CONCLUSION:CPI can predict the 28-day survival of septic patients with DIC who have undergone antithrombin treatment. It is simple and easy to calculate and will be useful in practice.
10.1186/s40560-024-00739-x
Isaridin E Protects against Sepsis by Inhibiting Von Willebrand Factor-Induced Endothelial Hyperpermeability and Platelet-Endothelium Interaction.
Marine drugs
Endothelial hyperpermeability is pivotal in sepsis-associated multi-organ dysfunction. Increased von Willebrand factor (vWF) plasma levels, stemming from activated platelets and endothelium injury during sepsis, can bind to integrin αvβ3, exacerbating endothelial permeability. Hence, targeting this pathway presents a potential therapeutic avenue for sepsis. Recently, we identified isaridin E (ISE), a marine-derived fungal cyclohexadepsipeptide, as a promising antiplatelet and antithrombotic agent with a low bleeding risk. ISE's influence on septic mortality and sepsis-induced lung injury in a mouse model of sepsis, induced by caecal ligation and puncture, is investigated in this study. ISE dose-dependently improved survival rates, mitigating lung injury, thrombocytopenia, pulmonary endothelial permeability, and vascular inflammation in the mouse model. ISE markedly curtailed vWF release from activated platelets in septic mice by suppressing vesicle-associated membrane protein 8 and soluble N-ethylmaleide-sensitive factor attachment protein 23 overexpression. Moreover, ISE inhibited healthy human platelet adhesion to cultured lipopolysaccharide (LPS)-stimulated human umbilical vein endothelial cells (HUVECs), thereby significantly decreasing vWF secretion and endothelial hyperpermeability. Using cilengitide, a selective integrin αvβ3 inhibitor, it was found that ISE can improve endothelial hyperpermeability by inhibiting vWF binding to αvβ3. Activation of the integrin αvβ3-FAK/Src pathway likely underlies vWF-induced endothelial dysfunction in sepsis. In conclusion, ISE protects against sepsis by inhibiting endothelial hyperpermeability and platelet-endothelium interactions.
10.3390/md22060283
Tofacitinib Treatment Suppresses CD4+ T-Cell Activation and Th1 Response, Contributing to Protection against Staphylococcal Toxic Shock.
International journal of molecular sciences
Staphylococcal toxic shock syndrome (STSS) is a rare, yet potentially fatal disease caused by () enterotoxins, known as superantigens, which trigger an intense immune response. Our previous study demonstrated the protective effect of tofacitinib against murine toxin-induced shock and a beneficial effect against sepsis. In the current study, we examined the effects of tofacitinib on T-cell response in peripheral blood using a mouse model of enterotoxin-induced shock. Our data revealed that tofacitinib suppresses the activation of both CD4+ and CD8+ T cells in peripheral blood. Furthermore, both gene and protein levels of Th1 cytokines were downregulated by tofacitinib treatment in mice with enterotoxin-induced shock. Importantly, we demonstrated that CD4+ cells, but not CD8+ cells, are pathogenic in mice with enterotoxin-induced shock. In conclusion, our findings suggest that tofacitinib treatment suppresses CD4+ T-cell activation and Th1 response, thereby aiding in protection against staphylococcal toxic shock in mice. This insight may guide the future development of novel therapies for STSS.
10.3390/ijms25137456
Association of inflammatory score with all-cause and cardiovascular mortality in patients with metabolic syndrome: NHANES longitudinal cohort study.
Frontiers in immunology
Background:Inflammatory scores are known to reflect the systemic inflammatory burden. Despite this, the association between the inflammatory score and the risk of all-cause and cardiovascular mortality in patients with metabolic syndrome (MetS) remains poorly understood. To address this gap in the literature, this study investigated this potential association between these two factors. Methods:A total of 3401 patients with MetS from the National Health and Nutrition Examination Survey (1999-2010) were enrolled. Survival status and cause of death were obtained by linking data from the National Death Index (NDI). The inflammatory score was calculated based on the sum of the Z-scores for white blood cell (WBC) count and C-reactive protein (CRP) at baseline. The patients were divided into inflammatory score quartiles. Cox proportional hazards regression was used to determine the association between inflammatory score and mortality. Restricted cubic splines (RCS) were used to explore the dose-response relationship between inflammatory score and mortality. Stratified analyses and interaction tests were conducted according to sex, age, body mass index (BMI), alcohol consumption, smoking status, hypertension, diabetes, and stroke status. Results:After a mean follow-up of 145.9 months, 1039 all-cause deaths and 295 cardiovascular deaths were recorded. The results of multivariate Cox regression analysis showed that compared to the lowest quartile (Q1), patients in the highest quartile (Q4) had a 1.74-fold increased risk of all-cause mortality (Model 3: HR = 1.74, 95%CI 1.30-2.32, < 0.001) and a 1.87-fold increased risk of cardiovascular mortality (Model 3: HR = 1.87, 95%CI 1.12-3.13, = 0.020). There was a 'J'-shaped nonlinear relationship between the inflammatory score and all-cause mortality ( for nonlinearity = 0.001), and a marginally significant 'J'-shaped relationship with cardiovascular mortality ( for nonlinearity = 0.057). The threshold points of the inflammatory score for adverse outcomes were - 0.643 and - 0.621, respectively. Conclusion:The inflammatory score is independently associated with increased all-cause and cardiovascular mortality in patients with MetS, and risk stratification of these patients using inflammatory scores may provide specific therapeutic strategies to improve their prognosis.
10.3389/fimmu.2024.1410871
Shifting paradigm in electrochemical biosensing matrices comprising metal organic frameworks and their composites in disease diagnosis.
Wiley interdisciplinary reviews. Nanomedicine and nanobiotechnology
Metal Organic Frameworks (MOFs) are an evolving category of crystalline microporous materials that have grabbed the research interest for quite some time due to their admirable physio-chemical properties and easy fabrication methods. Their enormous surface area can be a working ground for innumerable molecular adhesions and site for potential sensor matrices. They have been explored in the last decade for incorporation in electrochemical sensor matrices as diagnostic solutions for a plethora of diseases. This review emphasizes on some of the recent advancements in the area of MOF-based electrochemical biosensors with focus on various important diseases and their significance in upgrading the sensor performance. It summarizes MOF-based biosensors for monitoring biomarkers relevant to diabetes, viral and bacterial sepsis infections, neurological disorders, cardiovascular diseases, and cancer in a wide range of real matrices. The discussion has been supplemented with extensive tables elaborating recent trends in the field of MOF-composite probe fabrication strategies with their respective sensing parameters. The article sums up the future scope of these materials in the field of biosensors and enlightens the reader with recent trends for future research scope. This article is categorized under: Diagnostic Tools > Biosensing Diagnostic Tools > Diagnostic Nanodevices.
10.1002/wnan.1980
Brain hemodynamics in septic patients.
Minerva anestesiologica
Brain dysfunction is a frequent complication of sepsis. Most likely, sepsis-associated brain dysfunction (SABD) results from the interaction between multiple factors: neurodegeneration due to microglial activation, altered neurotransmission, neuroinflammation and impairment of cerebral macro- and microcirculation. Altered brain perfusion might results from several mechanism: global or regional alterations in cerebral blood flow (CBF); reduced cerebral perfusion pressure - which is the driving force propelling blood through cerebral blood vessels - due to systemic hypotension; global or regional vasoconstriction; dysfunction of the intrinsic regulatory mechanisms of CBF, such as cerebral autoregulation and cerebrovascular reactivity; endothelial and blood-brain barrier dysfunction; autonomic nervous system dysfunction and metabolic uncoupling. Disorders of brain perfusion and CBF regulation are frequently observed in humans with sepsis, and intracranial hemodynamics monitoring can potentially be useful in clinical management of septic patients. The aim of this review is to provide an update of the current knowledge on alterations in brain hemodynamics associated with sepsis, along with physiological and methodological considerations intended to help the reader navigate the diverse results from published literature and a practical guide to apply non-invasive intracranial hemodynamics monitoring to septic patients in clinical practice.
10.23736/S0375-9393.24.17978-3
A roadmap for implementing a successful clinical experience with intradialytic parenteral nutrition.
Clinical nutrition ESPEN
BACKGROUND AND AIMS:Intradialytic parenteral nutrition (IDPN) is a safe and effective patient-tailored nutritional strategy for providing nutrient supplementation to malnourished or at risk of malnutrition patients on hemodialysis (HD), who did not adequately respond to intensive dietary counselling and oral nutritional supplementation. Although IDPN is recommended by current ESPEN and KDOQI guidelines for nutrition in HD patients, none of these documents informs how to successfully implement this therapy, being the lack of knowledge on practical aspects of IDPN one of the main limitations to its use. The aim of this narrative review was to provide a practical roadmap for guiding the nephrologists, dietitians, and renal nurses in their everyday clinical practice about the use of IDPN. METHODS:A multidisciplinary group formed by specialists from the areas of Nephrology and Nutrition agreed to address different practical aspects related to IDPN in HD patients. Based on the available evidence in the literature and on the authors' clinical experience, different topics were selected to develop a detailed plan for implementing a successful experience with IDPN, proposing a practical IDPN roadmap. RESULTS:This IDPN roadmap provides practical information on when an IDPN should be started; what type of nutrients should be part of an IDPN; how the IDPN should be administered; how the effectiveness and safety of the IDPN should be monitored; how to determine the effectiveness of IDPN; and the conditions that advise discontinuing the IDPN. CONCLUSIONS:IDPN is a safe and effective nutritional therapy for HD patients, although the lack of staff training may limit its use. This review addresses different practical aspects of IDPN, helping interdisciplinary teams in their daily clinical practice to improve the nutritional care of HD patients, either malnourished or at risk of malnutrition.
10.1016/j.clnesp.2024.06.044
Engineered exosomes: a potential therapeutic strategy for septic cardiomyopathy.
Frontiers in cardiovascular medicine
Septic cardiomyopathy, a life-threatening complication of sepsis, can cause acute heart failure and carry a high mortality risk. Current treatments have limitations. Fortunately, engineered exosomes, created through bioengineering technology, may represent a potential new treatment method. These exosomes can both diagnose and treat septic cardiomyopathy, playing a crucial role in its development and progression. This article examines the strategies for using engineered exosomes to protect cardiac function and treat septic cardiomyopathy. It covers three innovative aspects: exosome surface modification technology, the use of exosomes as a multifunctional drug delivery platform, and plant exosome-like nanoparticle carriers. The article highlights the ability of exosomes to deliver small molecules, proteins, and drugs, summarizing several RNA molecules, proteins, and drugs beneficial for treating septic cardiomyopathy. Although engineered exosomes are a promising biotherapeutic carrier, they face challenges in clinical application, such as understanding the interaction mechanism with host cells, distribution within the body, metabolism, and long-term safety. Further research is essential, but engineered exosomes hold promise as an effective treatment for septic cardiomyopathy.
10.3389/fcvm.2024.1399738
Models of sepsis-induced acute kidney injury.
Life sciences
Sepsis-induced acute kidney injury (S-AKI) is one of the most serious life-threatening complications of sepsis. The pathogenesis of S-AKI is complex and there is no effective specific treatment. Therefore, it is crucial to choose suitable preclinical models that are highly similar to human S-AKI to study the pathogenesis and drug treatment. In this review, we summarized recent advances in the development models of S-AKI, providing reference for the reasonable selection of experimental models as basic research and drug development of S-AKI.
10.1016/j.lfs.2024.122873
Calcitriol in Sepsis-A Single-Centre Randomised Control Trial.
Journal of clinical medicine
: Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. Sepsis is a significant cause of hospital admission and the leading reason for admission to the ICU and is associated with high mortality. Vitamin D has shown promising immunomodulatory effects by upregulating the antimicrobial peptide, cathelicidin. However, previous studies analysing the use of calcitriol in sepsis have shown variable results and did not utilise APACHE II (Acute Physiology and Chronic Health Evaluation II) scores as endpoints. This study evaluates the efficacy of intramuscular calcitriol in patients admitted to the ICU with sepsis, focusing on its impact on APACHE II scores. The primary aim was to determine if intramuscular calcitriol improved APACHE II scores from day 1 to day 7 or discharge from the ICU, whichever was earlier. Secondary outcomes included 28-day mortality, ventilator days, vasopressor days, ICU stay length, adverse events, and hospital-acquired infections in ICU patients. : This was a triple-blinded phase III randomised control trial. A total of 152 patients with suspected sepsis were block-randomised to receive either intramuscular calcitriol (300,000 IU) ( = 76) or a placebo ( = 76). The trial was registered with the Clinical Trials Registry-India (CTRI No: CTRI 2019/01/17066) following ethics committee approval and was not funded. : There was no significant difference in APACHE II scores between the calcitriol and placebo groups from day 1 to day 7 ( = 0.382). There were no significant changes in 28-day mortality (14.4% vs. 17%, = 0.65), number of days on a ventilator (5 vs. 5, = 0.84), number of days on vasopressors (3 vs. 3, = 0.98), length of ICU stay (10 days vs. 11 days, = 0.78), adverse events (27.6% vs. 19.7%, = 0.25), and hospital-acquired infections (17.1% vs. 15.8%, = 0.82). : There was no effect of intramuscular calcitriol in patients admitted to the ICU with sepsis.
10.3390/jcm13133823
Analyzing the molecular mechanism of Scutellaria Radix in the treatment of sepsis using RNA sequencing.
BMC infectious diseases
BACKGROUND:Sepsis is a life-threatening organ dysfunction, which seriously threatens human health. The clinical and experimental results have confirmed that Traditional Chinese medicine (TCM), such as Scutellariae Radix, has anti-inflammatory effects. This provides a new idea for the treatment of sepsis. This study systematically analyzed the mechanism of Scutellariae Radix treatment in sepsis based on network pharmacology, RNA sequencing and molecular docking. METHODS:Gene expression analysis was performed using Bulk RNA sequencing on sepsis patients and healthy volunteers. After quality control of the results, the differentially expressed genes (DEGs) were analyzed. The active ingredients and targets of Scutellariae Radix were identified using The Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP). Gene Ontology (GO) and Protein-Protein Interaction (PPI) analysis were performed for disease-drug intersection targets. With the help of GEO database, Survival analysis and Meta-analysis was performed on the cross-targets to evaluate the prognostic value and screen the core targets. Subsequently, single-cell RNA sequencing was used to determine where the core targets are located within the cell. Finally, in this study, molecular docking experiments were performed to further clarify the interrelationship between the active components of Scutellariae Radix and the corresponding targets. RESULTS:There were 72 active ingredients of Scutellariae Radix, and 50 common targets of drug and disease. GO and PPI analysis showed that the intersection targets were mainly involved in response to chemical stress, response to oxygen levels, response to drug, regulation of immune system process. Survival analysis showed that PRKCD, EGLN1 and CFLAR were positively correlated with sepsis prognosis. Meta-analysis found that the three genes were highly expressed in sepsis survivor, while lowly in non-survivor. PRKCD was mostly found in Macrophages, while EGLN1 and CFLAR were widely expressed in immune cells. The active ingredient Apigenin regulates CFLAR expression, Baicalein regulates EGLN1 expression, and Wogonin regulates PRKCD expression. Molecular docking studies confrmed that the three active components of astragalus have good binding activities with their corresponding targets. CONCLUSIONS:Apigenin, Baicalein and Wogonin, important active components of Scutellaria Radix, produce anti-sepsis effects by regulating the expression of their targets CFLAR, EGLN1 and PRKCD.
10.1186/s12879-024-09589-2
Association between the triglyceride glucose index and short-term mortality in septic patients with or without obesity: a retrospective cohort study.
Adipocyte
BACKGROUND:Sepsis is a significant contributor to both intensive care unit (ICU) admissions and mortality among patients in ICU, with a rising prevalence of obesity. There is a lack of extensive research on the correlation between TyGI and findings in patients with sepsis, especially in obese patients. METHODS:This study used a retrospective cohort design and included patients with sepsis (≥18 years) from the Medical Information Mart for Intensive Care IV database. The association between TyGI and outcome was examined using multivariable logistic regression analysis. RESULTS:8,840 patients with sepsis were included in the analysis. The in-ICU mortality rate was 9.7%. Non-survivors exhibited significantly greater TyGI levels than survivors [9.19(8.76-9.71) vs. 9.10(8.67-9.54), < 0.001]. The adjusted multivariate regression model showed that elevated TyGI values were linked to a greater likelihood of death in ICU (odds ratio [OR] range 1.072-1.793, < 0.001) and hospital (OR range 1.068-1.445, = 0.005). Restricted Cubic Spline analysis revealed a nonlinear association between TyGI and in-ICU and in-hospital mortality risks within specified ranges. Subgroup analysis revealed interaction effects in the general obesity, abdominal obesity, and impaired fasting glucose subgroups ( = 0.014, 0.016, and < 0.001, respectively). CONCLUSION:TyGI was associated with an increased sepsis-related short-term mortality risk and adverse outcomes after ICU admission.
10.1080/21623945.2024.2379867