A randomized, open-label, adaptive, proof-of-concept clinical trial of modulation of host thromboinflammatory response in patients with COVID-19: the DAWn-Antico study.

BACKGROUND: The peak of the global COVID-19 pandemic has not yet been reached, and many countries face the prospect of a second wave of infections before effective vaccinations will be available. After an initial phase of viral replication, some patients develop a second illness phase in which the host thrombotic and inflammatory responses seem to drive complications. Severe COVID-19 disease is linked to high mortality, hyperinflammation, and a remarkably high incidence of thrombotic events. We hypothesize a crucial pathophysiological role for the contact pathway of coagulation and the kallikrein-bradykinin pathway. Therefore, drugs that modulate this excessive thromboinflammatory response should be investigated in severe COVID-19. METHODS: In this adaptive, open-label multicenter randomized clinical trial, we compare low molecular weight heparins at 50 IU anti-Xa/kg twice daily-or 75 IU anti-Xa twice daily for intensive care (ICU) patients-in combination with aprotinin to standard thromboprophylaxis in hospitalized COVID-19 patients. In the case of hyperinflammation, the interleukin-1 receptor antagonist anakinra will be added on top of the drugs in the interventional arm. In a pilot phase, the effect of the intervention on thrombotic markers (D-dimer) will be assessed. In the full trial, the primary outcome is defined as the effect of the interventional drugs on clinical status as defined by the WHO ordinal scale for clinical improvement. DISCUSSION: In this trial, we target the thromboinflammatory response at multiple levels. We intensify the dose of low molecular weight heparins to reduce thrombotic complications. Aprotinin is a potent kallikrein pathway inhibitor that reduces fibrinolysis, activation of the contact pathway of coagulation, and local inflammatory response. Additionally, aprotinin has shown in vitro inhibitory effects on SARS-CoV-2 cellular entry. Because the excessive thromboinflammatory response is one of the most adverse prognostic factors in COVID-19, we will add anakinra, a recombinant interleukin-1 receptor antagonist, to the regimen in case of severely increased inflammatory parameters. This way, we hope to modulate the systemic response to SARS-CoV-2 and avoid disease progressions with a potentially fatal outcome. TRIAL REGISTRATION: The EU Clinical Trials Register 2020-001739-28 . Registered on April 10, 2020.

Staphylococcus aureus, master manipulator of the human hemostatic system.

The coagulation system does not only offer protection against bleeding, but also aids in our defense against invading microorganisms. The hemostatic system and innate immunity are strongly entangled, which explains why so many infections are complicated by either bleeding or thrombosis. Staphylococcus aureus (S. aureus), currently the most deadly infectious agent in the developed world, causes devastating intravascular infections such as sepsis and infective endocarditis. During these infections S. aureus comes in close contact with the host hemostatic system and proves to be a master in manipulating coagulation. The coagulases of S. aureus directly induce coagulation by activating prothrombin. S. aureus also manipulates fibrinolysis by triggering plasminogen activation via staphylokinase. Furthermore, S. aureus binds and activates platelets and interacts with key coagulation proteins such as fibrin(ogen), fibronectin and von Willebrand factor. By manipulating the coagulation system S. aureus gains a significant advantage over the host defense mechanisms. Studying the interplay between S. aureus and the hemostatic system can therefore lead to new innovative therapies for battling S. aureus infections.

Clumping factor A, von Willebrand factor-binding protein and von Willebrand factor anchor Staphylococcus aureus to the vessel wall.

Essentials Staphylococcus aureus (S. aureus) binds to endothelium via von Willebrand factor (VWF). Secreted VWF-binding protein (vWbp) mediates S. aureus adhesion to VWF under shear stress. vWbp interacts with VWF and the Sortase A-dependent surface protein Clumping factor A (ClfA). VWF-vWbp-ClfA anchor S. aureus to vascular endothelium under shear stress. SUMMARY: Objective When establishing endovascular infections, Staphylococcus aureus (S. aureus) overcomes shear forces of flowing blood by binding to von Willebrand factor (VWF). Staphylococcal VWF-binding protein (vWbp) interacts with VWF, but it is unknown how this secreted protein binds to the bacterial cell wall. We hypothesized that vWbp interacts with a staphylococcal surface protein, mediating the adhesion of S. aureus to VWF and vascular endothelium under shear stress. Methods We studied the binding of S. aureus to vWbp, VWF and endothelial cells in a micro-parallel flow chamber using various mutants deficient in Sortase A (SrtA) and SrtA-dependent surface proteins, and Lactococcus lactis expressing single staphylococcal surface proteins. In vivo adhesion of bacteria was evaluated in the murine mesenteric circulation using real-time intravital vascular microscopy. Results vWbp bridges the bacterial cell wall and VWF, allowing shear-resistant binding of S. aureus to inflamed or damaged endothelium. Absence of SrtA and Clumping factor A (ClfA) reduced adhesion of S. aureus to vWbp, VWF and activated endothelial cells. ADAMTS-13 and an anti-VWF A1 domain antibody, when combined, reduced S. aureus adhesion to activated endothelial cells by 90%. Selective overexpression of ClfA in the membrane of Lactococcus lactis enabled these bacteria to bind to VWF and activated endothelial cells but only in the presence of vWbp. Absence of ClfA abolished bacterial adhesion to the activated murine vessel wall. Conclusions vWbp interacts with VWF and with the SrtA-dependent staphylococcal surface protein ClfA. The complex formed by VWF, secreted vWbp and bacterial ClfA anchors S. aureus to vascular endothelium under shear stress.

Presbyfagie: de invloed van het primair verouderingsproces op de slikfunctie.

PRESBYPHAGIA: THE INFLUENCE OF PRIMARY AGING ON SWALLOWING FUNCTION: Elderly often get confronted with swallowing difficulties. It is important to differentiate between presbyphagia, which describes the influence of primary aging on swallow function and dysphagia, which is a pathological swallowing disorder caused by age related diseases and their treatment. In this literature overview the focus is on presbyphagia. The influence of primary aging on the oropharyngeal swallowing function and on other body functions that are indirectly related to swallowing will be discussed. From the literature we learn that in primary aging a number of functions stay preserved, a number of functions deteriorate, and some compensatory mechanisms are evident. The swallow safety as such however, stays preserved. To conclude with we discuss some clinical implications concerning both the detection of swallowing disorders in the elderly and the establishment of preventive action for the healthy elderly.

Diffusion coefficient through the blood-aqueous barrier using a standard protocol.

AIMS/BACKGROUND: Comparison of the diffusion coefficient through the blood-aqueous barrier of healthy volunteers measured in different cities with identical fluorophotometers using a standardised protocol. METHODS: Healthy volunteers aged between 20 and 70 years were studied in seven European cities. The fluorescein concentration in the anterior segment of each eye was measured with a commercial scanning fluorophotometer 30 and 40 minutes after intravenous fluorescein. The decay of non-protein bound fluorescein concentration in blood plasma was determined with the use of three blood samples taken at 7, 15, and 55 minutes after injection. The diffusion coefficient through the blood-aqueous barrier was calculated from the ratio between the fluorescein concentration in the anterior chamber and the time integral of non-protein bound fluorescein concentration in plasma using specially developed software. RESULTS: The mean values of the diffusion coefficient (SD) (X10(-4) min-1) were 4.76 (1.51) (n = 20, Brussels), 5.48 (2.33) (n = 17, Coimbra), 3.47 (2.09) (n = 12, Cologne), 6.09 (2.77) (n = 21, Frankfurt), 3.85 (1.59) (n = 11, Ghent), 4.99 (1.69) (n = 23, Leiden), and 4.87 (1.05) (n = 20, Madrid). The values between centres were similar (Kruskal-Wallis test p > 0.05) except for Cologne and Frankfurt (p = 0.013). No differences were found when repeating measurements (four centres, interval time 1-8 months, Wilcoxon paired test p > 0.39). CONCLUSION: The diffusion coefficients had similar values and standard deviations. The concerted action demonstrated the usefulness of a standardised protocol.

Phacoemulsification and IOL implantation in eyes with cornea guttata.

During the period from April 1990 until August 1991 in 217 eyes with cornea guttata (and clear cornea) a cataract extraction with implantation of a posterior chamber lens was performed. Of these, 189 eyes (146 patients) underwent a phacoemulsification procedure. According to semiquantitative endothelial cell microscopy in the central area of the cornea, the eyes were classified into three groups: Group I (n = 126): solitary defects (< 5) in the central endothelial layer. Group II (n = 49): several defects (> 5) in the central endothelial layer. Group III (n = 14): considerable defects (> 50% of the central endothelial layer). Postoperative follow-up (2 to 7 months) was without any complication in Group I: i.e. all corneas were immediately clear and remained clear until today. In Group II we observed a mild transient corneal edema in 4 of 49 eyes on the first postoperative day which disappeared spontaneously after one to three days. In Group III a mild transient corneal edema was seen in 11 of 14 eyes on the first postoperative day which disappeared in 1 to 4 weeks. All 14 corneas are still clear today.

Iohexol: a new nonionic contrast medium for myelography and cisternography with markedly reduced neurotoxicity.

Nonionic contrast media have been proven safe for intrathecal opacification, but adverse effects, including psycho-organic syndrome and asterixis, have been reported and appear more frequently when contrast medium enters intracranial spaces. Using compressed spectral array (CSA), transient, EEG changes can be monitored more efficiently, and bioelectrical neurotoxicities of various contrast media can be better observed. The nonionic contrast medium, iohexol, was evaluated for safety, patient tolerance, and image quality in studies of the higher regions of the spinal canal and intracranial spaces. Fifty-nine patients received iohexol injections while undergoing myelography, cisternography, or ventriculography. Measurements included detailed neurologic examination, blood pressure and pulse rate, EEG, and CSA EEG analysis. Iohexol provided excellent opacification of the craniocervical region and of brain cisterns. It is safe for use in pericerebral spaces and is exceptionally well tolerated by patients. Due to its safety and convenience for use in myelography, iohexol is expected to facilitate the development and use of new neuroradiologic techniques.

Ioglunide: a new nonionic contrast medium for myelography and cisternography with reduced neurotoxicity.

Ioglunide, a new nonionic contrast medium, has attracted attention by its virtual absence of immediate or delayed effect on brain electrical activity in animal studies. After 126 myelographies or cisternographies with ioglunide, routine electroencephalograms (EEG) and brain potential frequency analyses were performed in 109 and 73 patients, respectively. EEG changes were noted in 3.7% of subjects. Moderate meningeal signs were present in 16% of subjects. No severe adverse reactions (psychoorganic syndrome, asterixis, or hallucination) were observed. Ioglunide appears to represent a marked advance in neuroradiology in providing for the comfort of patients and the safety of the radiological procedures.