Explore the vast range of titles available.

Sepsis is the primary cause of burn-related mortality and morbidity. Traditional indicators of sepsis exhibit poor performance when used in this unique population due to their underlying hypermetabolic and inflammatory response following burn injury. To address this challenge, we developed the Machine Intelligence Learning Optimizer (MILO), an automated machine learning (ML) platform, to automatically produce ML models for predicting burn sepsis. We conducted a retrospective analysis of 211 adult patients (age ≥ 18 years) with severe burn injury (≥ 20% total body surface area) to generate training and test datasets for ML applications. The MILO approach was compared against an exhaustive “non-automated” ML approach as well as standard statistical methods. For this study, traditional multivariate logistic regression (LR) identified seven predictors of burn sepsis when controlled for age and burn size (OR 2.8, 95% CI 1.99–4.04, P = 0.032). The area under the ROC (ROC-AUC) when using these seven predictors was 0.88. Next, the non-automated ML approach produced an optimal model based on LR using 16 out of the 23 features from the study dataset. Model accuracy was 86% with ROC-AUC of 0.96. In contrast, MILO identified a k -nearest neighbor-based model using only five features to be the best performer with an accuracy of 90% and a ROC-AUC of 0.96. Machine learning augments burn sepsis prediction. MILO identified models more quickly, with less required features, and found to be analytically superior to traditional ML approaches. Future studies are needed to clinically validate the performance of MILO-derived ML models for sepsis prediction.

Kawasaki disease (KD) is a form of systemic vasculitis that occurs in children under the age of 5 years old. Due to prolonged fever and elevated inflammatory markers that are found in both KD and sepsis, the treatment approach differs for each. We enrolled a total of 420 children (227 KD and 193 sepsis) in this study. Logistic regression and a nomogram model were used to analyze the laboratory markers. We randomly selected 247 children as the training modeling group and 173 as the validation group. After completing a logistic regression analysis, white blood cell (WBC), anemia, procalcitonin (PCT), C-reactive protein (CRP), albumin, and alanine transaminase (ALT) demonstrated a significant difference in differentiating KD from sepsis. The patients were scored according to the nomogram, and patients with scores greater than 175 were placed in the high-risk KD group. The area under the curve of the receiver operating characteristic curve (ROC curve) of the modeling group was 0.873, sensitivity was 0.893, and specificity was 0.746, and the ROC curve in the validation group was 0.831, sensitivity was 0.709, and specificity was 0.795. A novel nomogram prediction model may help clinicians differentiate KD from sepsis with high accuracy.

Abstract Rationale In patients on prior statin therapy who are hospitalized for acute infections, current literature is unclear on whether statins should be continued during their hospitalization. Objectives To test the hypothesis that continuation of therapy with statins influences the inflammatory response to infection and that cessation may cause an inflammatory rebound. Methods Prospective randomized double-blind placebo-controlled trial of atorvastatin (20 mg) or matched placebo in 150 patients on preexisting statin therapy requiring hospitalization for infection. Measurements and Main Results The primary end point was progression of sepsis during hospitalization. At baseline, the rate of severe sepsis was 32% in both groups. Compared with baseline, the odds ratio for severe sepsis declined in both groups: 0.43 placebo and 0.5 statins (Day 3) versus 0.14 placebo and 0.12 statins (Day 14). The rate of decline of severe sepsis was similar between the groups (odds ratio 1.17 [0.56–2.47], P = 0.7 Day 3; 0.85 [0.21–3.34], P = 0.8 Day 14). IL-6 and C-reactive protein declined in both groups with no statistically significant difference (P = 0.7 and P = 0.2, respectively). An increase in cholesterol occurred in the placebo group (P < 0.0001). Most patients were not critically ill. Hospital mortality was 6.6%, with no difference between the groups (6 [8%] of 75 statin group; 4 [5.3%] of 75 placebo group; P = 0.75). Conclusions This study does not support a beneficial role of continuing preexisting statin therapy on sepsis and inflammatory parameters. Cessation of established statin therapy was not associated with an inflammatory rebound. Clinical trial registered at the Australian New Zealand Clinical Trials Registry (ACTRN 12605000756628).

Objective. We sought to compare daptomycin with ceftriaxone for the treatment of patients with community-acquired pneumonia (CAP). Methods. Two phase-3 randomized, double-blind trials that enrolled adult patients hospitalized with CAP were conducted. Patients received intravenous daptomycin (4 mg/kg) or ceftriaxone (2 g) once daily for 5–14 days. Aztreonam could be added for patients with gram-negative infections. Clinical responses at the test-of-cure visit among patients in the intent-to-treat and clinically evaluable populations were the primary efficacy end points. Results. After combining data from the trials, the intent-to-treat population included 413 daptomycin-treated patients and 421 ceftriaxone-treated patients, and the clinically evaluable population included 369 daptomycin-treated patients and 371 ceftriaxone-treated patients. In the intent-to-treat population, the clinical cure rate among daptomycin-treated patients with CAP was 70.9%, compared with 77.4% among ceftriaxone-treated patients (95% confidence interval for the difference between cure rates, −12.4% to −0.6%). In the clinically evaluable population, the clinical cure rate was lower among daptomycin-treated patients (79.4%) than among ceftriaxone-treated patients (87.9%; 95% confidence interval for the difference between cure rates, −13.8% to −3.2%). A posthoc analysis revealed that, among those who had received up to 24 h of prior effective therapy, cure rates were similar among daptomycin-treated (90.7%) and ceftriaxone-treated patients (88.0%; 95% confidence interval for the difference between cure rates, −6.1% to 11.5%). Conclusions. Daptomycin is not effective for the treatment of CAP, including infections caused by Streptococcus pneumoniae and Staphylococcus aureus. The observation that as little as 24 h of prior effective therapy may impact clinical outcome suggests that trials to evaluate CAP treatment may need to exclude patients who have received any potentially effective therapy before enrollment.

Sepsis-associated encephalopathy (SAE) is a neurological dysfunction induced by sepsis, with symptoms ranging from mild delirium to deep coma. About 70% of patients with severe systemic infection develop SAE and with more than half of surviving patients suffering from long-term cognitive deficits, which seriously damaged the quality of their daily life and brought a heavy burden to society. The pathogenesis of SAE is multifactorial, including activated inflammation, blood- brain barrier (BBB) disruption, cerebral blood flow impairment, and neurotransmitter disturbances. Microglia mediate multiple SAE pathologies. In this review, we summarized the most recent findings in the roles of microglia in every stage of SAE pathogenesis, focusing on the molecular pathways in microglia activation and downstream effects. We also demonstrated the novel therapeutic studies targeting microglia in SAE. Deep insight into the role of microglia in SAE is of great importance in exploring pathogenesis and developing effective remedies of SAE.

Neuroinflammation and oxidative stress contribute to the progression of sepsis-associated encephalopathy (SAE). Angiotensin-converting enzyme 2 (ACE2) is considered to be a neuroprotective factor due to its anti-inflammatory and antioxidant properties. However, the role of ACE2 on myeloid cells in regulating SAE and the underlying mechanism warrants further exploration. SAE was induced in ACE2 transgenic (TG), knockout (KO), and bone marrow (BM) chimeric mice by cecal ligation and puncture (CLP). The expression levels of apoptosis-, oxidation- and neuroinflammation-associated mediators and morphological changes were monitored by quantitative real-time PCR analyses and histological examinations in the cortex of septic mice. The contents of angiotensin (Ang) II and Ang-(1–7) along with the activity of ACE2 were examined with commercial kits. The expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and Sestrin2 was detected by immunoblotting analysis. Our results indicated that the expression of cortical ACE2 was significantly reduced in the early phase of CLP-induced sepsis. Moreover, ACE2 overexpression in TG mice conferred neuroprotection against sepsis, as evidenced by alleviated neuronal apoptosis, oxidative stress, and proinflammatory M1-like microglial polarization, accompanied by upregulation of the Ang-(1–7), Nrf2, and Sestrin2 protein levels. Conversely, ACE2 deficiency in KO mice exacerbated SAE. The neuroprotective effects of ACE2 were further confirmed in wild-type mice transplanted with ACE2-TG and KO BM cells. Therefore, our data suggest that myeloid ACE2 exerts a protective role in the pathogenesis of SAE, potentially by activating Ang-(1–7)-Nrf2/sestrin2 signaling pathway, and highlight that upregulating ACE2 expression and activity may represent a promising approach for the treatment of SAE in patients with sepsis.

Sepsis-associated encephalopathy (SAE) is a severe neurological syndrome marked by widespread brain dysfunctions due to sepsis. Despite increasing data supporting the hypothesis of neuronal damage, the exact mechanism of sepsis-related cognitive disorders and therapeutic strategies remain unclear and need further investigation. In this study, a sepsis model was established in C57 mice using lipopolysaccharide (LPS). The findings demonstrated that LPS exposure induced neuronal loss, synaptic and cognitive deficits accompanied by mitochondrial damage. Bioinformatics and western blot analyses demonstrated a significant increase in Lipocalin-2 (LCN2) during sepsis as a key hub gene involved in immune and neurological inflammation. Interestingly, the recombinant LCN2 protein exhibited similar effects on synaptic dysfunction and cognitive deficits in C57 mice. Conversely, downregulating LCN2 effectively nullified the impact of LPS, leading to the amelioration of synaptic and cognitive deficits, neuronal loss, and reactive oxygen species (ROS)-associated mitochondrial damage. These findings suggest a novel etiopathogenic mechanism of SAE, which is initiated by the increased LCN2, leading to neuronal loss and cognitive deficit. Inhibition of LCN2 could be therapeutically beneficial in treating sepsis-induced synaptic and cognitive impairments.

Key Points Sepsis is a life-threatening organ dysfunction that is caused by a dysregulated host response to infection. The sepsis-associated host response is characterized by concurrent excessive inflammatory, catabolic, metabolic and immune-suppressive features, and a failure to return to homeostasis, which often results in a condition referred to as chronic critical illness and is not fundamentally different from the sustained host response aberrations that are induced by severe non-infectious injuries. Sepsis is a very heterogeneous syndrome, and current knowledge does not enable the stratification of patients into more homogeneous subgroups in which specific and potentially targetable host response derailments drive pathology. Key pro-inflammatory responses during sepsis include the activation of the complement system, the coagulation system, the vascular endothelium, neutrophils and platelets, whereas immune suppression is primarily caused by the reprogramming of antigen-presenting cells, and the apoptosis and exhaustion of lymphocytes. Individuals who survive sepsis frequently suffer from long-term cognitive and physical impairments, the aetiology of which is uncertain. Strategies to modulate the aberrant host response have been unsuccessful in a large number of clinical trials, which may at least in part be related to the inadequate selection of therapeutic targets and an inability to select the patients who might benefit from a certain intervention. Future research should focus the discovery and validation of biomarkers that reflect the predominant pathophysiological mechanisms at different body sites, and that can guide the selection of patients for targeted therapies and the monitoring thereof. Sepsis — which is caused by a dysregulated host response to infection — is a life-threatening organ dysfunction. This Review describes the recent advances in our understanding of sepsis pathogenesis and discusses strategies for the development of successful therapies. Sepsis is defined as a life-threatening organ dysfunction that is caused by a dysregulated host response to infection. In sepsis, the immune response that is initiated by an invading pathogen fails to return to homeostasis, thus culminating in a pathological syndrome that is characterized by sustained excessive inflammation and immune suppression. Our understanding of the key mechanisms involved in the pathogenesis of sepsis has increased tremendously, yet this still needs to be translated into novel targeted therapeutic strategies. Pivotal for the clinical development of new sepsis therapies is the selection of patients on the basis of biomarkers and/or functional defects that provide specific insights into the expression or activity of the therapeutic target.

The lung is a primary organ for gas exchange in mammals that represents the largest epithelial surface in direct contact with the external environment. It also serves as a crucial immune organ, which harbors both innate and adaptive immune cells to induce a potent immune response. Due to its direct contact with the outer environment, the lung serves as a primary target organ for many airborne pathogens, toxicants (aerosols), and allergens causing pneumonia, acute respiratory distress syndrome (ARDS), and acute lung injury or inflammation (ALI). The current review describes the immunological mechanisms responsible for bacterial pneumonia and sepsis-induced ALI. It highlights the immunological differences for the severity of bacterial sepsis-induced ALI as compared to the pneumonia-associated ALI. The immune-based differences between the Gram-positive and Gram-negative bacteria-induced pneumonia show different mechanisms to induce ALI. The role of pulmonary epithelial cells (PECs), alveolar macrophages (AMs), innate lymphoid cells (ILCs), and different pattern-recognition receptors (PRRs, including Toll-like receptors (TLRs) and inflammasome proteins) in neutrophil infiltration and ALI induction have been described during pneumonia and sepsis-induced ALI. Also, the resolution of inflammation is frequently observed during ALI associated with pneumonia, whereas sepsis-associated ALI lacks it. Hence, the review mainly describes the different immune mechanisms responsible for pneumonia and sepsis-induced ALI. The differences in immune response depending on the causal pathogen (Gram-positive or Gram-negative bacteria) associated pneumonia or sepsis-induced ALI should be taken in mind specific immune-based therapeutics.

The blood–brain barrier (BBB) protects the central nervous system from infections or harmful substances 1 ; its impairment can lead to or exacerbate various diseases of the central nervous system 2 – 4 . However, the mechanisms of BBB disruption during infection and inflammatory conditions 5 , 6 remain poorly defined. Here we find that activation of the pore-forming protein GSDMD by the cytosolic lipopolysaccharide (LPS) sensor caspase-11 (refs. 7 – 9 ), but not by TLR4-induced cytokines, mediates BBB breakdown in response to circulating LPS or during LPS-induced sepsis. Mice deficient in the LBP–CD14 LPS transfer and internalization pathway 10 – 12 resist BBB disruption. Single-cell RNA-sequencing analysis reveals that brain endothelial cells (bECs), which express high levels of GSDMD, have a prominent response to circulating LPS. LPS acting on bECs primes Casp11 and Cd14 expression and induces GSDMD-mediated plasma membrane permeabilization and pyroptosis in vitro and in mice. Electron microscopy shows that this features ultrastructural changes in the disrupted BBB, including pyroptotic endothelia, abnormal appearance of tight junctions and vasculature detachment from the basement membrane. Comprehensive mouse genetic analyses, combined with a bEC-targeting adeno-associated virus system, establish that GSDMD activation in bECs underlies BBB disruption by LPS. Delivery of active GSDMD into bECs bypasses LPS stimulation and opens the BBB. In CASP4 -humanized mice, Gram-negative Klebsiella pneumoniae infection disrupts the BBB; this is blocked by expression of a GSDMD-neutralizing nanobody in bECs. Our findings outline a mechanism for inflammatory BBB breakdown, and suggest potential therapies for diseases of the central nervous system associated with BBB impairment. Lipopolysaccharide-induced breakdown of the blood–brain barrier requires activation of GSDMD-mediated plasma membrane permeabilization and pyroptosis in brain endothelial cells.