Enteral administration of the protease inhibitor gabexate mesilate preserves vascular function in experimental trauma/hemorrhagic shock.

Preserving vascular function is crucial for preventing multiorgan failure and death in ischemic and low-pressure states such as trauma/hemorrhagic shock (T/HS). It has recently been reported that inhibiting circulating proteases released from the bowel to the circulation during T/HS may preserve vascular function and improve outcomes following T/HS. This study aimed to evaluate the role of the serine protease inhibitor gabexate mesilate (GM) in preserving vascular function during T/HS when given enterally.

NEW INSIGHTS INTO THE PATHOPHYSIOLOGY OF TRAUMA AND HEMORRHAGE.

Circulatory shock from trauma and hemorrhage remains a clinical challenge with mortality still high within the first hours after impact. It represents a complex disease involving the impairment of a number of physiological systems and organs and the interaction of different pathological mechanisms. Multiple external and patient-specific factors may further modulate and complicate the clinical course.

Plasma enzymatic activity, proteomics and peptidomics in COVID-19-induced sepsis: A novel approach for the analysis of hemostasis.

Infection by SARS-CoV-2 and subsequent COVID-19 can cause viral sepsis. We investigated plasma protease activity patterns in COVID-19-induced sepsis with bacterial superinfection, as well as plasma proteomics and peptidomics in order to assess the possible implications of enhanced proteolysis on major protein systems (e.g.

Enteral gabexate mesilate improves volume requirements and autonomic cardiovascular function after experimental trauma/hemorrhagic shock in the absence of blood reperfusion.

The standard of care for fluid resuscitation of trauma/hemorrhagic shock (T/HS) is the infusion of blood. However, in many instances, blood product transfusion may not be feasible. Consequently, crystalloid solutions may be utilized as temporizing cost-effective resuscitation fluids.

Case Report: Invasive Fungal Infection and Daratumumab: A Case Series and Review of Literature.

Life expectancy of multiple myeloma (MM) patients has improved in last years due to the advent of anti-CD38 monoclonal antibodies in combination with immunomodulators and proteasome inhibitors. However, morbidity and mortality related to infections remain high and represent a major concern. This paper describes the "real life" risk of invasive fungal infections (IFI) in patients treated with daratumumab-based therapy and reviews the relevant literature.

Efficacy of Tranexamic Acid in Blood Versus Crystalloid-Resuscitated Trauma/Hemorrhagic Shock.

Introduction: Whole blood (WB) or blood products are not always immediately available for repletion of lost intravascular volume in trauma/hemorrhagic shock (T/HS), and thus, resuscitation with crystalloid solutions is often necessary. Recently, we have shown enteral tranexamic acid (TXA) to be effective as a mild protease inhibitor in blood-resuscitated T/HS by counteracting proteolytic activity in and leaking from the gut with resultant preservation of systemic vascular integrity. We hypothesized that enteral TXA would improve hemodynamic stability after T/HS in the absence of blood reperfusion.

Application of an Exploratory Knowledge-Discovery Pipeline Based on Machine Learning to Multi-Scale OMICS Data to Characterise Myocardial Injury in a Cohort of Patients with Septic Shock: An Observational Study.

Currently, there is no therapy targeting septic cardiomyopathy (SC), a key contributor to organ dysfunction in sepsis. In this study, we used a machine learning (ML) pipeline to explore transcriptomic, proteomic, and metabolomic data from patients with septic shock, and prospectively collected measurements of high-sensitive cardiac troponin and echocardiography. The purposes of the study were to suggest an exploratory methodology to identify and characterise the multiOMICs profile of (i) myocardial injury in patients with septic shock, and of (ii) cardiac dysfunction in patients with myocardial injury.

Involvement of Toll-Like Receptor 4 in Decreased Vasopressor Response Following Trauma/Hemorrhagic Shock.

Unlabelled: Refractory vascular failure due to the inability of vascular smooth muscle to respond to vasoconstrictors such as phenylephrine is a final common pathway for severe circulatory shock of any cause, including trauma/hemorrhagic shock. Increased inflammation, Toll-like receptor 4 activation, and decreased response of the alpha-1 adrenergic receptors which control vascular tone have been reported in trauma/hemorrhagic shock.

Hypothesis: In trauma/hemorrhagic shock, Toll-like receptor 4 activation contributes to vascular failure via decreased bioavailability of adrenergic receptors.

Acute ingestion of a high-fructose drink impairs vascular autonomic modulation and reflex control of blood pressure in first-degree relatives of diabetic patients.

First-degree relatives of diabetes patients, despite being euglycemic, presented impaired BRS and exacerbation of sympathetic modulation after ingestion of a high fructose drink when challenged to orthostatic stress. This finding alerts the importance of early autonomic dysfunction even in clinically healthy people, especially in face of a stressful situation.

Continuous enteral protease inhibition as a novel treatment for experimental trauma/hemorrhagic shock.

Purpose: Trauma and hemorrhagic shock (T/HS) is a major cause of morbidity and mortality. Existing treatment options are largely limited to source control and fluid and blood repletion. Previously, we have shown that enteral protease inhibition improves outcomes in experimental models of T/HS by protecting the gut from malperfusion and ischemia.

Resuscitation After Hemorrhagic Shock in the Microcirculation: Targeting Optimal Oxygen Delivery in the Design of Artificial Blood Substitutes.

Microcirculatory preservation is essential for patient recovery from hemorrhagic shock. In hemorrhagic shock, microcirculatory flow and pressure are greatly reduced, creating an oxygen debt that may eventually become irreversible. During shock, tissues become hypoxic, cellular respiration turns to anaerobic metabolism, and the microcirculation rapidly begins to fail.

Evaluation of autonomic modulation of lung function and heart rate in children with cystic fibrosis.

The autonomic nervous system (ANS) plays an important role in modulating bronchial smooth muscle contractility, which is altered in cystic fibrosis (CF). A convenient approach to probe ANS regulation is the quantitative analysis of heart rate variability (HRV). The purpose of this study was to evaluate ANS regulation in children with CF and to investigate the influence of colonization by Pseudonomas aeruginosa via assessment of HRV in colonized CF (CCF) children and noncolonized CF (NCCF) children.

High-Resolution Mass Spectrometry-Based Approaches for the Detection and Quantification of Peptidase Activity in Plasma.

Proteomic technologies have identified 234 peptidases in plasma but little quantitative information about the proteolytic activity has been uncovered. In this study, the substrate profile of plasma proteases was evaluated using two nano-LC-ESI-MS/MS methods. Multiplex substrate profiling by mass spectrometry (MSP-MS) quantifies plasma protease activity in vitro using a global and unbiased library of synthetic peptide reporter substrates, and shotgun peptidomics quantifies protein degradation products that have been generated in vivo by proteases.

SARS-CoV-2/COVID-19: Evolving Reality, Global Response, Knowledge Gaps, and Opportunities.

Approximately 3 billion people around the world have gone into some form of social separation to mitigate the current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. The uncontrolled influx of patients in need of emergency care has rapidly brought several national health systems to near-collapse with deadly consequences to those afflicted by Coronavirus Disease 2019 (COVID-19) and other critical diseases associated with COVID-19. Solid scientific evidence regarding SARS-CoV-2/COVID-19 remains scarce; there is an urgent need to expand our understanding of the SARS-CoV-2 pathophysiology to facilitate precise and targeted treatments.

A longitudinal study highlights shared aspects of the transcriptomic response to cardiogenic and septic shock.

Background: Septic shock (SS) and cardiogenic shock (CS) are two types of circulatory shock with a different etiology. Several studies have described the molecular alterations in SS patients, whereas the molecular factors involved in CS have been poorly investigated. We aimed to assess in the whole blood of CS and SS patients, using septic patients without shock (SC) as controls, transcriptomic modifications that occur over 1 week after ICU admission and are common to the two types of shock.

Enteral Tranexamic Acid Decreases Proteolytic Activity in the Heart in Acute Experimental Hemorrhagic Shock.

The mechanisms for cardiac injury after hemorrhagic shock (HS) are unresolved. We hypothesize that remote organ damage can be caused by uncontrolled pancreatic proteolytic activity, as enteral protease inhibition improves outcomes in experimental HS. Uncontrolled proteolysis in the heart may disrupt cardiac metabolism and adrenergic control with subsequent deleterious outcomes.

Feature selection for the accurate prediction of septic and cardiogenic shock ICU mortality in the acute phase.

Circulatory shock is a life-threatening disease that accounts for around one-third of all admissions to intensive care units (ICU). It requires immediate treatment, which is why the development of tools for planning therapeutic interventions is required to deal with shock in the critical care environment. In this study, the ShockOmics European project original database is used to extract attributes capable of predicting mortality due to shock in the ICU.

Proteolysis in septic shock patients: plasma peptidomic patterns are associated with mortality.

Background: Uncontrolled proteolysis contributes to cell injury and organ dysfunction in animal models of circulatory shock. We investigated in humans the relationship between septic shock, proteolysis, and outcome.

Methods: Intensive care patients with septic shock (n=29) or sepsis (n=6) and non-hospitalised subjects (n=9) were recruited as part of the prospective observational trial 'ShockOmics' (ClinicalTrials.

Characterization of a metabolomic profile associated with responsiveness to therapy in the acute phase of septic shock.

The early metabolic signatures associated with the progression of septic shock and with responsiveness to therapy can be useful for developing target therapy. The Sequential Organ Failure Assessment (SOFA) score is used for stratifying risk and predicting mortality. This study aimed to verify whether different responses to therapy, assessed as changes in SOFA score at admission (T1, acute phase) and 48 h later (T2, post-resuscitation), are associated with different metabolite patterns.

Preliminary profiling of blood transcriptome in a rat model of hemorrhagic shock.

Hemorrhagic shock is a leading cause of morbidity and mortality worldwide. Significant blood loss may lead to decreased blood pressure and inadequate tissue perfusion with resultant organ failure and death, even after replacement of lost blood volume. One reason for this high acuity is that the fundamental mechanisms of shock are poorly understood.

Enteral tranexamic acid attenuates vasopressor resistance and changes in α1-adrenergic receptor expression in hemorrhagic shock.

Background: Irreversible hemorrhagic shock is characterized by hyporesponsiveness to vasopressor and fluid therapy. Little is known, however, about the mechanisms that contribute to this phenomenon. Previous studies have shown that decreased intestinal perfusion in hemorrhagic shock leads to proteolytically mediated increases in gut permeability, with subsequent egress of vasoactive substances systemically.

Set up of a protocol for rat plasma peptidomics in hemorrhagic shock model in presence of heparin.

A preliminary mass spectrometry based shotgun protocol was set up to compare the peptidome of plasma samples from healthy and hemorrhagic shock rats with the aim of verifying the possible role of uncontrolled proteolytic activity in circulatory shock. Since the hemorrhagic shock model requires heparin as anticoagulant, a preliminary experiment using plasma sample obtained in the presence/absence of heparin from healthy rats was performed to determine whether its presence is fully compatible with the peptidomic protocol proposed. The entire protocol was tested in a pilot experiment to compare the peptidome of healthy or heparin-anticoagulated rats subjected to hemorrhagic shock.

A review of methods for the signal quality assessment to improve reliability of heart rate and blood pressures derived parameters.

The assessment of signal quality has been a research topic since the late 1970s, as it is mainly related to the problem of false alarms in bedside monitors in the intensive care unit (ICU), the incidence of which can be as high as 90 %, leading to alarm fatigue and a drop in the overall level of nurses and clinicians attention. The development of efficient algorithms for the quality control of long diagnostic electrocardiographic (ECG) recordings, both single- and multi-lead, and of the arterial blood pressure (ABP) signal is therefore essential for the enhancement of care quality. The ECG signal is often corrupted by noise, which can be within the frequency band of interest and can manifest similar morphologies as the ECG itself.