The IN-CONTROL II consortium builds upon the success of IN-CONTROL I, which highlighted the pivotal role of the microbiome in low-grade inflammation associated with atherosclerotic cardiovascular diseases (CVD) and related risk factors such as lipid levels and microbiome-derived metabolites. These insights are crucial for addressing the rising rates of CVD-related mortality, particularly in aging and overweight populations.

The Focus
The objectives of IN-CONTROL II are to:

  • Investigate the mechanisms underlying trained immunity in CVD patients, considering factors like senescence, age, sex, and obesity.
  • Elucidate the interactions between microbiome-derived signals (aromatic amino acids, metabolites, bile acids) and immune senescence in obesity-related cardio-metabolic diseases.
  • Identify novel therapeutic targets and develop pharmacological and microbiome-based therapies to counteract inappropriate induction of trained immunity and inflammation in cardiovascular disease.

The Research
The consortium aims to shift from association to causality, from population-based cohorts to patient groups with atherosclerotic cardiovascular disease (CVD) and from observation to intervention. In this transition, it will also take advantage of recent developments in the network of the consortium, delineating cellular senescence as a druggable target for the broad spectrum of age-related chronic diseases, including cardiovascular diseases, and identification of components of the bile acid-signaling system for this purpose. Another recent development of the recognition of innate immune memory (‘trained immunity’) as pathophysiological mechanism in atherosclerotic CVD.

The consortium will conduct proof-of-principle trials in specific patient cohorts, employing advanced experimental techniques such as systems biology, single cell sequencing, innovative animal models, and metabolic flux quantification (fluxomics). A talent program will facilitate knowledge transfer and skill development for young researchers within the consortium, emphasizing rapid translation of research findings into clinical applications.

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The SARS-CoV-2 pandemic has a high burden of morbidity and mortality due to development of the acute respiratory distress syndrome (ARDS). The reninangiotensin-system (RAS) plays an important role in the development of ARDS, with ACE2 (angiotensin-converting enzyme 2) being a key enzyme within this. The virus's spike protein binds to ACE2, facillitating cellular internalization. Downregulation of ACE2 results in the excessive accumulation of angiotensin II, which in turn increases pulmonary vascular permeability through stimulation of the angiotensin II type 1a receptor (AT1R), thereby exacerbating lung pathology associated with decreased ACE2 activity. Currently available AT1R blockers (ARBs) such as valsartan, have shown potential to block this pathological process mediated by angiotensin II. The Focus The primary aim of the PRAETORIAN-COVID trial is to investigate the effect of the ARB valsartan compared to placebo on the composite end point of admission to an intensive care unit, mechanical ventilation, or death of COVID-19 patients. The Research Participants receiving active treatment are administered valsartan at a dosage titrated to blood pressure, with a maximum of 160 mg twice daily. Participants receiving placebo are provided with a matching placebo. The treatment duration was 14 days or until reaching the primary endpoint, or until hospital discharge, if applicable within 14 days.Two complementary mechanisms underpin the potential efficacy of angiotensin II type 1 receptor blockers (ARBs) in preventing acute respiratory distress syndrome (ARDS) and reducing morbidity and mortality: ARBs block excessive angiotensin-mediated activation of the AT1R. ARBs upregulate ACE2 expression, leading to reduced angiotensin II levels and increased production of the protective vasodilator angiotensin 1–7. Given these mechanisms, ARBs show promise in preventing ARDS development, potentially reducing the need for intensive care unit (ICU) admission and mechanical ventilation, and ultimately lowering mortality rates associated with SARS-CoV-2 infection.
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Clinical staff in hospital wards traditionally collect vital signs periodically to assess a patient's cardiorespiratory status, often with intervals of 6 to 10 hours. This method, known as spot-checking, has limitations due to its infrequent nature and dependence on contact sensors, which can be uncomfortable for patients, particularly during sleep. The Focus Recent advancements demonstrate that vital signs like heart rate, respiration rate, blood oxygen saturation, and temperature can be monitored remotely using camera-based methods, which are less invasive compared to contact sensors. This innovation could significantly enhance patient comfort by enabling continuous monitoring without the need for frequent interventions by clinical staff. Continuous monitoring also allows for trend analysis of vital signs, offering a comprehensive assessment of a patient's cardiorespiratory condition. Additionally, camera-based methods enable video context analysis, such as detecting patient movements or identifying pain through facial expression analysis. This project explores the use of continuous video monitoring as an unobtrusive method to predict and monitor patient deterioration or adverse events. The Research Initially, the feasibility and reliability of camera-based continuous monitoring will be evaluated using data from consenting patients in the ICU at Catharina Hospital in Eindhoven and healthy volunteers. Subsequently, robust technologies will be developed to automatically detect signs of patient deterioration by generating automated early warning scores based on measured vital signs. Throughout the project, feedback from clinical staff and patient experiences will inform the design and implementation of camera-based technologies and early warning systems.
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