Heterogeneity in association of myocardial injury and mortality in sepsis or acute respiratory distress syndrome by subphenotype: a retrospective study.

Rationale: Myocardial injury is common in acute respiratory distress syndrome (ARDS) and sepsis and associated with increased mortality. Two latent class analysis derived subphenotypes are associated with differential risk of mortality in these populations, though the association of troponin-I with mortality within each subphenotype is unknown.

Methods: The derivation (n = 597 in EARLI) and validation (n = 452 in VALID) cohorts consisted of patients with sepsis or ARDS admitted to the ICU and enrolled in two separate prospective observational studies.

Research Priorities for Noninvasive Sampling of the Lower Respiratory Tract during Acute Respiratory Failure: An Official American Thoracic Society Workshop Report.

Research using lower respiratory tract (LRT) sampling may lead to improved understanding and management of patients with acute respiratory failure (ARF). Research bronchoscopy is a valuable tool for sampling the LRT during ARF. However, bronchoscopy may be limited by challenges with repeated sampling, the inability to sample the most severely ill patients, and increased resource utilization.

Advanced Age in Mice Exacerbates Sepsis-Induced Inflammation, Vascular Permeability, and Multi-Organ Dysfunction.

Sepsis is a life-threatening syndrome marked by a dysregulated immune response to an infection and significant endothelial vascular permeability, often leading to multi-organ failure. Elderly patients are particularly vulnerable to sepsis, with higher morbidity and mortality rates. We hypothesized that advanced age exacerbates sepsis-induced inflammation and endothelial vascular permeability, resulting in a delayed recovery, persistent inflammation, and sustained organ injury.

Advanced Age in Mice Exacerbates Sepsis-Induced Inflammation, Vascular Permeability, and Multi-Organ Dysfunction.

Sepsis is a life-threatening syndrome marked by a dysregulated immune response to an infection and significant endothelial vascular permeability, often leading to multi-organ failure. Elderly patients are particularly vulnerable to sepsis, with higher morbidity and mortality rates. We hypothesized that advanced age exacerbates sepsis-induced inflammation and endothelial vascular permeability, resulting in a delayed recovery, persistent inflammation, and sustained organ injury.

Oxidized Cell-Free Hemoglobin Induces Mitochondrial Dysfunction by Activation of the Mitochondrial Permeability Transition Pore in the Pulmonary Microvasculature.

Objective: Cell-free hemoglobin (CFH) is released into the circulation during sepsis where it can redox cycle from the ferrous 2+ to ferric 3+ and disrupt endothelial function, but the mechanisms of CF-mediated endothelial dysfunction are unknown. We hypothesized that oxidized CFH induces mitochondrial dysfunction via the mitochondrial permeability transition pore (mPTP) in pulmonary endothelial cells, leading to the release of mitochondrial DNA (mtDNA).

Methods: Human lung microvascular endothelial cells were treated with CFH2+/CFH3+.

Matrix metalloproteinase-7 is dispensable in a mouse model of sepsis-induced acute lung injury.

Acute respiratory distress syndrome (ARDS) is a life-threatening form of acute lung injury whose pathogenesis is characterized by excessive lung inflammation and alveolar-capillary barrier permeability. Matrix metalloproteinase 7 (MMP7) can regulate leukocyte recruitment and the production of pro-inflammatory cytokines, but whether it plays a role in acute lung injury (ALI) is an unanswered question. We hypothesized that global loss of MMP7 would attenuate sepsis-induced ALI and systemic inflammation.

Oxidation of low-density lipoprotein by hemoglobin causes pulmonary microvascular endothelial barrier dysfunction through lectin-like oxidized LDL receptor 1.

Elevated circulating cell-free hemoglobin (Hb) is a pathological driver of endothelial injury and contributes to disease severity and organ dysfunction during several pathologies, including sickle cell disease, pulmonary hypertension, primary graft dysfunction after lung transplantation, and sepsis. However, the signaling mechanisms involved in Hb-mediated pulmonary microvascular endothelial barrier dysfunction are not well understood. One mechanism by which Hb may contribute to microvascular endothelial barrier dysfunction is through its ability to oxidize circulating lipids and lipoproteins, including low-density lipoproteins (LDLs).

Metabolic Adaptations Rewire CD4 T Cells in a Subset-Specific Manner in Human Critical Illness with and without Sepsis.

Host immunity in sepsis has features of hyperinflammation together with progressive immunosuppression, particularly among CD4 T cells, that can predispose to secondary infections and ineffectual organ recovery. Metabolic and immunologic dysfunction are archetypal findings in critically ill patients with sepsis, but whether these factors are mechanistically linked remains incompletely defined. We characterized functional metabolic properties of human CD4 T cells from critically ill patients with and without sepsis and healthy adults.

Cellular Mechanisms of Lung Injury: Current Perspectives.

The alveolar-capillary barrier includes microvascular endothelial and alveolar epithelial cells and their matrices, and its disruption is a critical driver of lung injury during development of acute respiratory distress syndrome. In this review, we provide an overview of the structure and function of the alveolar-capillary barrier during health and highlight several important signaling mechanisms that underlie endothelial and epithelial injury during critical illness, emphasizing areas with potential for development of therapeutic strategies targeting alveolar-capillary leak. We also emphasize the importance of biomarker and preclinical studies in developing novel therapies and highlight important areas warranting future investigation.

Electronic health record biobank cohort recapitulates an association between the promoter polymorphism and ARDS in critically ill adults.

Background: Large population-based DNA biobanks linked to electronic health records (EHRs) may provide novel opportunities to identify genetic drivers of ARDS.

Research Question: Can we develop an EHR-based algorithm to identify ARDS in a biobank database, and can this validate a previously reported ARDS genetic risk factor?

Study Design And Methods: We analyzed two parallel genotyped cohorts: a prospective biomarker cohort of critically ill adults (VALID), and a retrospective cohort of hospitalized participants enrolled in a de-identified EHR biobank (BioVU). ARDS was identified by clinician-investigator review in VALID and an EHR algorithm in BioVU (EHR-ARDS).

Studying the Pulmonary Endothelium in Health and Disease: An Official American Thoracic Society Workshop Report.

Lung endothelium resides at the interface between the circulation and the underlying tissue, where it senses biochemical and mechanical properties of both the blood as it flows through the vascular circuit and the vessel wall. The endothelium performs the bidirectional signaling between the blood and tissue compartments that is necessary to maintain homeostasis while physically separating both, facilitating a tightly regulated exchange of water, solutes, cells, and signals. Disruption in endothelial function contributes to vascular disease, which can manifest in discrete vascular locations along the artery-to-capillary-to-vein axis.

LNK/SH2B3 loss of function increases susceptibility to murine and human atrial fibrillation.

Aims: The lymphocyte adaptor protein (LNK) is a negative regulator of cytokine and growth factor signalling. The rs3184504 variant in SH2B3 reduces LNK function and is linked to cardiovascular, inflammatory, and haematologic disorders, including stroke. In mice, deletion of Lnk causes inflammation and oxidative stress.

A preclinical systematic review and meta-analysis assessing the effect of biological sex in lipopolysaccharide-induced acute lung injury.

It is unclear what effect biological sex has on outcomes of acute lung injury (ALI). Clinical studies are confounded by their observational design. We addressed this knowledge gap with a preclinical systematic review of ALI animal studies.

Bacterial pneumonia-induced shedding of epithelial heparan sulfate inhibits the bactericidal activity of cathelicidin in a murine model.

Bacterial pneumonia is a common clinical syndrome leading to significant morbidity and mortality worldwide. In the current study, we investigate a novel, multidirectional relationship between the pulmonary epithelial glycocalyx and antimicrobial peptides in the setting of methicillin-resistant (MRSA) pneumonia. Using an in vivo pneumonia model, we demonstrate that highly sulfated heparan sulfate (HS) oligosaccharides are shed into the airspaces in response to MRSA pneumonia.

Ascorbate protects human kidney organoids from damage induced by cell-free hemoglobin.

Sepsis-associated acute kidney injury is associated with high morbidity and mortality in critically ill patients. Cell-free hemoglobin (CFH) is released into the circulation of patients with severe sepsis and the levels of CFH are independently associated with mortality. CFH treatment increased cytotoxicity in the human tubular epithelial cell line HK-2.

Next-generation phenotyping: introducing phecodeX for enhanced discovery research in medical phenomics.

Motivation: Phecodes are widely used and easily adapted phenotypes based on International Classification of Diseases codes. The current version of phecodes (v1.2) was designed primarily to study common/complex diseases diagnosed in adults; however, there are numerous limitations in the codes and their structure.

Accuracy and Reliability of Chatbot Responses to Physician Questions.

Importance: Natural language processing tools, such as ChatGPT (generative pretrained transformer, hereafter referred to as chatbot), have the potential to radically enhance the accessibility of medical information for health professionals and patients. Assessing the safety and efficacy of these tools in answering physician-generated questions is critical to determining their suitability in clinical settings, facilitating complex decision-making, and optimizing health care efficiency.

Objective: To assess the accuracy and comprehensiveness of chatbot-generated responses to physician-developed medical queries, highlighting the reliability and limitations of artificial intelligence-generated medical information.

Liraglutide pretreatment attenuates sepsis-induced acute lung injury.

There are no effective targeted therapies to treat acute respiratory distress syndrome (ARDS). Recently, the commonly used diabetes and obesity medications, glucagon-like peptide-1 (GLP-1) receptor agonists, have been found to have anti-inflammatory properties. We, therefore, hypothesized that liraglutide pretreatment would attenuate murine sepsis-induced acute lung injury (ALI).