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.

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.

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.

Host Response Changes and Their Association with Mortality in COVID-19 Patients with Lymphopenia.

Lymphopenia in coronavirus disease (COVID-19) is associated with increased mortality. To explore the association between lymphopenia, host response aberrations, and mortality in patients with lymphopenic COVID-19. We determined 43 plasma biomarkers reflective of four pathophysiological domains: endothelial cell and coagulation activation, inflammation and organ damage, cytokine release, and chemokine release.

Thrombocytopenia is associated with a dysregulated host response in severe COVID-19.

Background: Thrombocytopenia is associated with increased mortality in COVID-19 patients.

Objective: To determine the association between thrombocytopenia and alterations in host response pathways implicated in disease pathogenesis in patients with severe COVID-19.

Patients/methods: We studied COVID-19 patients admitted to a general hospital ward included in a national (CovidPredict) cohort derived from 13 hospitals in the Netherlands.

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.

Age-related changes in plasma biomarkers and their association with mortality in COVID-19.

Background: Coronavirus disease 2019 (COVID-19)-induced mortality occurs predominantly in older patients. Several immunomodulating therapies seem less beneficial in these patients. The biological substrate behind these observations is unknown.

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.

Association of Hyperferritinemia With Distinct Host Response Aberrations in Patients With Community-Acquired Pneumonia.

Background: Strongly elevated ferritin levels have been proposed to reflect systemic hyperinflammation in patients admitted to the intensive care unit. Knowledge of the incidence and pathophysiological implications of hyperferritinemia in patients with acute infection admitted to a non-intensive care setting is limited.

Methods: We determined the association between hyperferritinemia, defined by 2 cutoff values (500 and 250 ng/mL), and aberrations in key host response mechanisms among patients with community-acquired pneumonia (CAP) on admission to a general hospital ward (clinicaltrials.

Communication practices in conversations about sexual health in medical healthcare settings: A systematic review.

Objective: Many healthcare professionals experience difficulties in discussing sexual health with their patients. The aim of this review was to synthesize results of studies on communication practices in interactions about sexual health in medical settings, to offer healthcare professionals suggestions on how to communicate about this topic.

Methods: We searched for studies using five databases.

Corrigendum: Concurrent Immune Suppression and Hyperinflammation in Patients With Community-Acquired Pneumonia.

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The circular RNA landscape in specific peripheral blood mononuclear cells of critically ill patients with sepsis.

Background: Dysregulation of the host immune response is a pathognomonic feature of sepsis. Abnormal physiological conditions are understood to shift efficient linear splicing of protein-coding RNA towards non-canonical splicing, characterized by the accumulation of non-coding circularized (circ)RNA. CircRNAs remain unexplored in specific peripheral blood mononuclear cells (PBMCs) during sepsis.

Concurrent Immune Suppression and Hyperinflammation in Patients With Community-Acquired Pneumonia.

Background: The nature and timing of the host immune response during infections remain uncertain and most knowledge is derived from critically ill sepsis patients. We aimed to test the hypothesis that community-acquired pneumonia (CAP) is associated with concurrent immune suppression and systemic inflammation.

Methods: Blood was collected from 79 CAP patients within 24 h after hospitalization and 1 month after discharge; 42 age- and sex-matched subjects without acute infection served as controls.

CXCR4-targeting nanobodies differentially inhibit CXCR4 function and HIV entry.

The chemokine receptor CXCR4 and its ligand CXCL12 contribute to a variety of human diseases, such as cancer. CXCR4 is also a major co-receptor facilitating HIV entry. Accordingly, CXCR4 is considered as an attractive therapeutic target.

Nanobody-Fc constructs targeting chemokine receptor CXCR4 potently inhibit signaling and CXCR4-mediated HIV-entry and induce antibody effector functions.

Upregulation of the chemokine receptor CXCR4 contributes to the progression and metastasis of both solid and hematological malignancies, rendering this receptor an attractive therapeutic target. Besides the only FDA-approved CXCR4 antagonist Plerixafor (AMD3100), multiple other classes of CXCR4-targeting molecules are under (pre-)clinical development. Nanobodies (Nb), small single variable domains of heavy-chain only antibodies from Camelids, have appeared to be ideal antibody-fragments for targeting a broad range of epitopes and cavities within GPCRs such as CXCR4.

DNA immunization combined with scFv phage display identifies antagonistic GCGR specific antibodies and reveals new epitopes on the small extracellular loops.

The identification of functional monoclonal antibodies directed against G-protein coupled receptors (GPCRs) is challenging because of the membrane-embedded topology of these molecules. Here, we report the successful combination of llama DNA immunization with scFv-phage display and selections using virus-like particles (VLP) and the recombinant extracellular domain of the GPCR glucagon receptor (GCGR), resulting in glucagon receptor-specific antagonistic antibodies. By immunizing outbred llamas with plasmid DNA containing the human GCGR gene, we sought to provoke their immune system, which generated a high IgG1 response.

Structural Mimicry of Receptor Interaction by Antagonistic Interleukin-6 (IL-6) Antibodies.

Interleukin 6 plays a key role in mediating inflammatory reactions in autoimmune diseases and cancer, where it is also involved in metastasis and tissue invasion. Neutralizing antibodies against IL-6 and its receptor have been approved for therapeutic intervention or are in advanced stages of clinical development. Here we describe the crystal structures of the complexes of IL-6 with two Fabs derived from conventional camelid antibodies that antagonize the interaction between the cytokine and its receptor.

Combining somatic mutations present in different in vivo affinity-matured antibodies isolated from immunized Lama glama yields ultra-potent antibody therapeutics.

Highly potent human antibodies are required to therapeutically neutralize cytokines such as interleukin-6 (IL-6) that is involved in many inflammatory diseases and malignancies. Although a number of mutagenesis approaches exist to perform antibody affinity maturation, these may cause antibody instability and production issues. Thus, a robust and easy antibody affinity maturation strategy to increase antibody potency remains highly desirable.

Camelid Ig V genes reveal significant human homology not seen in therapeutic target genes, providing for a powerful therapeutic antibody platform.

Camelid immunoglobulin variable (IGV) regions were found homologous to their human counterparts; however, the germline V repertoires of camelid heavy and light chains are still incomplete and their therapeutic potential is only beginning to be appreciated. We therefore leveraged the publicly available HTG and WGS databases of Lama pacos and Camelus ferus to retrieve the germline repertoire of V genes using human IGV genes as reference. In addition, we amplified IGKV and IGLV genes to uncover the V germline repertoire of Lama glama and sequenced BAC clones covering part of the Lama pacos IGK and IGL loci.

Transmission of Mycobacterium pinnipedii to humans in a zoo with marine mammals.

Objectives: An outbreak of tuberculosis (TB) in sea lions occurred recently in a zoo in the Netherlands. The disease was detected in a captive colony consisting of 29 animals kept in an open air basin with an indoor night house. Approximately 25 animal keepers were in close contact with the animals.