Clinical subtypes in critically ill patients with sepsis: validation and parsimonious classifier model development.

Background: The application of sepsis subtypes to enhance personalized medicine in critically ill patients is hindered by the lack of validation across diverse cohorts and the absence of a simple classification model. We aimed to validate the previously identified SENECA clinical sepsis subtypes in multiple large ICU cohorts, and to develop parsimonious classifier models for δ-type adjudication in clinical practice.

Methods: Data from four cohorts between 2008 and 2023 were used to assign α, β, γ and δ-type in patients fulfilling the Sepsis-3 criteria using clinical variables: (I) The Molecular diAgnosis and Risk stratification of Sepsis (MARS, n = 2449), (II) a contemporary continuation of the MARS study (MARS2, n = 2445) (III) the Dutch National Intensive Care Evaluation registry (NICE, n = 28,621) and (IV) the Medical Information Mart for Intensive Care including (MIMIC-IV, n = 18,661).

The blood transcriptional response in patients developing intensive care unit-acquired pneumonia.

Introduction: Immune response dysregulation has been implicated in the development of intensive care unit (ICU)-acquired pneumonia. We aimed to determine differences in the longitudinal blood transcriptional response between patients who develop ICU-acquired pneumonia (cases) and those who do not (controls).

Methods: We performed a case-cohort study in mechanically ventilated trauma and surgery patients with ICU stays >2 days, enrolled in 30 hospitals across Europe.

Proteomic profiling of peripheral blood mononuclear cells reveals immune dysregulation and metabolic alterations in kidney transplant recipients with COVID-19.

The COVID-19 pandemic has significantly impacted global health, especially in vulnerable populations like kidney transplant recipients (KTRs). Recently, mass spectrometry-based proteomics has emerged as a powerful tool to shed light on a broad spectrum of dysregulated biological processes in KTRs with COVID-19. In this study, we prospectively collected blood samples from 17 COVID-19-positive KTRs and 10 non-infected KTRs between May and September 2020.

Next generation brain health: transforming global research and public health to promote prevention of dementia and reduce its risk in young adult populations.

Efforts to prevent dementia can benefit from precision interventions delivered to the right population at the right time; that is, when the potential to reduce risk is the highest. Young adults (aged 18-39 years) are a neglected population in dementia research and policy making despite being highly exposed to several known modifiable risk factors. The risk and protective factors that have the biggest effect on dementia outcomes in young adulthood, and how these associations differ across regions and groups, still remain unclear.

Effect of mesenchymal stem cells on the host response in severe community-acquired pneumonia.

Mesenchymal stem cells (MSC) have immune regulatory properties that may ameliorate pathophysiological processes in sepsis. We determined the effect of allogeneic adipose-derived MSCs (Cx611) on the host response during sepsis due to community-acquired bacterial pneumonia (CABP) by measuring 29 plasma biomarkers and blood transcriptomes at six time points in 82 patients randomised to two intravenous infusions of Cx611 or placebo. Cx611 treatment enhanced several endothelial cell and procoagulant response plasma biomarkers, and led to increased expression of pathways related to innate immunity, haemostasis and apoptosis.

Monocyte state 1 (MS1) cells in critically ill patients with sepsis or non-infectious conditions: association with disease course and host response.

Background: Sepsis is a life-threatening condition arising from an aberrant host response to infection. Recent single-cell RNA sequencing investigations identified an immature bone-marrow-derived CD14 monocyte phenotype with immune suppressive properties termed "monocyte state 1" (MS1) in patients with sepsis. Our objective was to determine the association of MS1 cell profiles with disease presentation, outcomes, and host response characteristics.

The shifting lipidomic landscape of blood monocytes and neutrophils during pneumonia.

The lipidome of immune cells during infection has remained unexplored, although evidence of the importance of lipids in the context of immunity is mounting. In this study, we performed untargeted lipidomic analysis of blood monocytes and neutrophils from patients hospitalized for pneumonia and age- and sex-matched noninfectious control volunteers. We annotated 521 and 706 lipids in monocytes and neutrophils, respectively, which were normalized to an extensive set of internal standards per lipid class.

The development and validation of a digital biomarker for remote assessment of Alzheimer's diseases risk.

Background: Digital cognitive assessment is becoming increasingly widespread in ageing research and care, especially since the COVID-19 pandemic. Remote online collection provides opportunities for ageing and dementia professionals to collect larger datasets, increase the diversity of research participants and patients and offer cost-effective screening and monitoring methods for clinical practice and trials. However, the reliability of self-administered at-home tests compared to their lab-based counterparts often goes unexamined, compromising the validity of adopting such measures.

The Plasma Lipidomic Landscape in Patients with Sepsis due to Community-acquired Pneumonia.

The plasma lipidome has the potential to reflect many facets of the host status during severe infection. Previous work is limited to specific lipid groups or was focused on lipids as prognosticators. To map the plasma lipidome during sepsis due to community-acquired pneumonia (CAP) and determine the disease specificity and associations with clinical features.

Platelets of COVID-19 patients display mitochondrial dysfunction, oxidative stress, and energy metabolism failure compatible with cell death.

Background: Alterations in platelet function have been implicated in the pathophysiology of COVID-19 since the beginning of the pandemic. While early reports linked hyperactivated platelets to thromboembolic events in COVID-19, subsequent investigations demonstrated hyporeactive platelets with a procoagulant phenotype. Mitochondria are important for energy metabolism and the function of platelets.

Inflammatory and glycolytic programs underpin a primed blood neutrophil state in patients with pneumonia.

Neutrophils are potent immune cells with key antimicrobial functions. Previous work has shown that neutrophil effector functions are mainly fueled by intracellular glycolysis. Little is known about the state of neutrophils still in the circulation in patients during infection.

A Rare Cause of Headache and an Unorthodox Transfer: A Case Report.

Introduction: Emergency department (ED) crowding and hospital diversion times are increasing nationwide, with negative effects on patient safety and an association with increased mortality. Crowding in referral centers makes transfer of complex or critical patients by rural emergency physicians (EP) more complicated and difficult. We present a case requiring an unorthodox transfer method to navigate extensive hospital diversion and obtain life-saving neurosurgical care.

Association between age and the host response in critically ill patients with sepsis.

Background: The association of ageing with increased sepsis mortality is well established. Nonetheless, current investigations on the influence of age on host response aberrations are largely limited to plasma cytokine levels while neglecting other pathophysiological sepsis domains like endothelial cell activation and function, and coagulation activation. The primary objective of this study was to gain insight into the association of ageing with aberrations in key host response pathways and blood transcriptomes in sepsis.

C/EBPδ Suppresses Motility-Associated Gene Signatures and Reduces PDAC Cell Migration.

Pancreatic Ductal Adenocarcinoma (PDAC) is among the most aggressive human cancers and occurs globally at an increasing incidence. Metastases are the primary cause of cancer-related death and, in the majority of cases, PDAC is accompanied by metastatic disease at the time of diagnosis, making it a particularly lethal cancer. Regrettably, to date, no curative treatment has been developed for patients with metastatic disease, resulting in a 5-year survival rate of only 11%.

Intracellular pyruvate levels positively correlate with cytokine production capacity in tolerant monocytes from patients with pneumonia.

Background: Community-acquired pneumonia (CAP) is responsible for a high morbidity and mortality worldwide. Monocytes are essential for pathogen recognition and the initiation of an innate immune response. Immune cells induce intracellular glycolysis upon activation to support several functions.

Rectal microbiota are coupled with altered cytokine production capacity following community-acquired pneumonia hospitalization.

Human studies describing the immunomodulatory role of the intestinal microbiota in systemic infections are lacking. Here, we sought to relate microbiota profiles from 115 patients with community-acquired pneumonia (CAP), both on hospital admission and following discharge, to concurrent circulating monocyte and neutrophil function. Rectal microbiota composition did not explain variation in cytokine responses in acute CAP (median 0%, IQR 0.

HIF-1α Stabilization in Flagellin-Stimulated Human Bronchial Cells Impairs Barrier Function.

The respiratory epithelium provides a first line of defense against pathogens. Hypoxia-inducible factor (HIF)1α is a transcription factor which is stabilized in hypoxic conditions through the inhibition of prolyl-hydroxylase (PHD)2, the enzyme that marks HIF1α for degradation. Here, we studied the impact of HIF1α stabilization on the response of primary human bronchial epithelial (HBE) cells to the bacterial component, flagellin.

Role of Myeloid Tet Methylcytosine Dioxygenase 2 in Pulmonary and Peritoneal Inflammation Induced by Lipopolysaccharide and Peritonitis Induced by .

Tet methylcytosine dioxygenase 2 (Tet2) mediates demethylation of DNA. We here sought to determine the expression and function of Tet2 in macrophages upon exposure to lipopolysaccharide (LPS), and in the host response to LPS induced lung and peritoneal inflammation, and during induced peritonitis. LPS induced expression in mouse macrophages and human monocytes in vitro, as well as in human alveolar macrophages after bronchial instillation in vivo.

Source-specific host response and outcomes in critically ill patients with sepsis: a prospective cohort study.

Purpose: There is limited knowledge on how the source of infection impacts the host response to sepsis. We aimed to compare the host response in sepsis patients with a single, known source at admission (< 24 h) to the intensive care unit.

Methods: From the molecular diagnosis and risk stratification of sepsis (MARS) prospective cohort, we measured 16 plasma host response biomarkers reflective of key host response pathways in 621 sepsis patients.

HIVEP1 Is a Negative Regulator of NF-κB That Inhibits Systemic Inflammation in Sepsis.

Our previous work identified human immunodeficiency virus type I enhancer binding protein 1 (HIVEP1) as a putative driver of LPS-induced NF-κB signaling in humans . While HIVEP1 is known to interact with NF-ĸB binding DNA motifs, its function in mammalian cells is unknown. We report increased HIVEP1 mRNA expression in monocytes from patients with sepsis and monocytes stimulated by Toll-like receptor agonists and bacteria.