Impact of distance of the catheter tip from cavo-atrial junction on bubble test (delay) time: A prospective study.

INTRODUCTION: Correct tip positioning is a critical aspect in central vascular access devices insertion. The verification of positioning at the cavo-atrial junction is usually performed by intracavitary electrocardiography. Recently, echocardiographic techniques were proposed, including the direct visualization of the catheter or the visualization of a saline/air bolus (i.e. "bubble test"). As for the latter, a push-to-bubbles delay time below 2 s was proposed to indicate a correct positioning of the catheter tip. The aim of this study was to measure the variations of the push-to-bubbles time at increasing distance from the cavo-atrial junction, to verify if a cut-off of 1-2 s correspond to a well-positioned catheter. METHODS: We performed a prospective study including patients with clinical indication of positioning a peripherally inserted central catheter. The catheter tip was positioned at the cavo-atrial junction (P0) via intracavitary electrocardiography, and the push-to-bubbles delay time was measured. The catheter was then retracted 5 cm (P1) and 10 cm (P2), and the test was repeated at this positioning. Push-to-bubbles time measurements were performed off-line by analyzing an audio/video recording which included the echography screen and the voice signal of the operator. RESULTS: Forty-nine patients were included. The average push-to-bubble time when the catheter tip was in the reference position was 0.41 ± 0.21 s. Retraction of the PICC catheter of 5 and 10 cm determined a significant increase of the push-to-bubbles time: mean time difference was +0.34 (95% IC 0.25-0.43, p < 0.001) s between P0 and P1 (5 cm distance), and +0.77 (95% IC 0.62-0.92, p < 0.001) s between P0 and P2 (10 cm distance). When the catheter was at the reference position (i.e. cavo-atrial junction) only 2.1% of bubbles delay times were above 1 s. CONCLUSION: The push-to-bubbles time is very low when the catheter tip is at the cavo-atrial junction. This delay increases progressively with increasing distance from the target. Push-to-bubbles delay time above 1 s might indicate a catheter not close to the cavo-atrial junction.

Femorally inserted central catheter, migration and catheter damage during contrast media injection: A case report.

Femorally inserted Central Catheters are increasingly used also for medium and long-term catheterization as an alternative to Centrally and Peripherally inserted Central Catheters. If certified as "power injectable," they may be used for contrast media injection during radiological examinations. It is important to consider the risk that, as with other types of catheters, the injection of contrast media could cause migration or damage to the device. The case of a Femoral catheter migration in hepatic vein, during CT scan, is described.

Pentosan polysulfate inhibits attachment and infection by SARS-CoV-2 in vitro: insights into structural requirements for binding.

Two years since the outbreak of the novel coronavirus SARS-CoV-2 pandemic, there remain few clinically effective drugs to complement vaccines. One is the anticoagulant, heparin, which in 2004 was found able to inhibit invasion of SARS CoV (CoV-1) and which has been employed during the current pandemic to prevent thromboembolic complications and moderate potentially damaging inflammation. Heparin has also been shown experimentally to inhibit SARS-CoV-2 attachment and infection in susceptible cells. At high therapeutic doses however, heparin increases the risk of bleeding and prolonged use can cause heparin-induced thrombocytopenia, a serious side-effect. One alternative, with structural similarities to heparin is the plant-derived, semi-synthetic polysaccharide, pentosan polysulfate (PPS). PPS is an established drug for the oral treatment of interstitial cystitis, is well-tolerated and exhibits weaker anticoagulant effects than heparin. In an established Vero cell model, PPS and its fractions of varying molecular weights, inhibited invasion by SARS-CoV-2. Intact PPS and its size-defined fractions were characterized by molecular weight distribution and chemical structure using NMR spectroscopy and LC-MS, then employed to explore the structural basis of interactions with SARS-CoV-2 spike protein receptor-binding domain (S1 RBD) and the inhibition of Vero cell invasion. PPS was as effective as unfractionated heparin, but more effective at inhibiting cell infection than low molecular weight heparin (on a weight/volume basis). Isothermal titration calorimetry and viral plaque-forming assays demonstrated size-dependent binding to S1 RBD and inhibition of Vero cell invasion, suggesting the potential application of PPS as a novel inhibitor of SARS-CoV-2 infection.

Enisamium is an inhibitor of the SARS-CoV-2 RNA polymerase and shows improvement of recovery in COVID-19 patients in an interim analysis of a clinical trial

Pandemic SARS-CoV-2 causes a mild to severe respiratory disease called Coronavirus Disease 2019 (COVID-19). Control of SARS-CoV-2 spread will depend on vaccine-induced or naturally acquired protective herd immunity. Until then, antiviral strategies are needed to manage COVID-19, but approved antiviral treatments, such as remdesivir, can only be delivered intravenously. Enisamium (laboratory code FAV00A, trade name Amizon(R)) is an orally active inhibitor of influenza A and B viruses in cell culture and clinically approved in countries of the Commonwealth of Independent States. Here we show that enisamium can inhibit SARS-CoV-2 infections in NHBE and Caco-2 cells. In vitro, the previously identified enisamium metabolite VR17-04 directly inhibits the activity of the SARS-CoV-2 RNA polymerase. Docking and molecular dynamics simulations suggest that VR17-04 prevents GTP and UTP incorporation. To confirm enisamiums antiviral properties, we conducted a double-blind, randomized, placebo-controlled trial in adult, hospitalized COVID-19 patients, which needed medical care either with or without supplementary oxygen. Patients received either enisamium (500 mg per dose) or placebo for 7 days. A pre-planned interim analysis showed in the subgroup of patients needing supplementary oxygen (n = 77) in the enisamium group a mean recovery time of 11.1 days, compared to 13.9 days for the placebo group (log-rank test; p=0.0259). No significant difference was found for all patients (n = 373) or those only needing medical care (n = 296). These results thus suggest that enisamium is an inhibitor of SARS-CoV-2 RNA synthesis and that enisamium treatment shortens the time to recovery for COVID-19 patients needing oxygen. Significance statementSARS-CoV-2 is the causative agent of COVID-19. Although vaccines are now becoming available to prevent SARS-CoV-2 spread, the development of antivirals remains necessary for treating current COVID-19 patients and combating future coronavirus outbreaks. Here, we report that enisamium, which can be administered orally, can prevent SARS-CoV-2 replication and that its metabolite VR17-04 can inhibit the SARS-CoV-2 RNA polymerase in vitro. Moreover, we find that COVID-19 patients requiring supplementary oxygen, recover more quickly than patients treated with a placebo. Enisamium may therefore be an accessible treatment for COVID-19 patients.

Retrospective survey from Vascular Access Team Lombardy Net in COVID-19 era

BackgroundVenous Access Devices (VADs) are the most used device in COVID-19 patients. ObjectiveIdentify VADs implanted, catheter related thrombosis (CRT), catheter-related bloodstream infection (CRBSI), and accidental remove of VADs in both COVID-19 positive and COVID-19 free patients. Successive analysis was conducted comparing COVID-19 positive patients with COVID-19 free with inverse probability propensity score weights using simple regression to account for these two confounders (peripheral tip as central/peripheral and hospitalization as no/yes). MethodsThis multicenter, retrospective cohort study was conducted using data from 7 hospitals in Lombardy during the pandemic period from February 21st to May 31st 2020. Results2206 VADs were evaluated, of which 1107 (50.2%) were inserted in COVID-19 patients. In COVID-19 cohort the first choice was Long Peripheral Cannula in 388 patients (35.1%) followed by Midline Catheter in 385 (34.8%). The number of "central tip" VADs inserted in COVID-free inpatients and COVID-19 positive were similar (307vs334). We recorded 42 (1.9%) CRT; 32 (79.2%) were observed in COVID-19 patients. 19 CRBSI were diagnosed; 15 (78.95%) were observed in COVID-19. Accidental removals were the more represented complication with 123 cases, 85 (69.1%) of them were in COVID-19. COVID-19 significantly predicted occurrence of CRT (OR = 2.00(1.85-5.03); P<0.001), CRSB (OR = 3.82(1.82-8.97); P<0.001), and Accidental Removal (OR = 2.39(1.80-3.20); P<0.001) in our propensity score weighted models. ConclusionsCRT, CRBSI, and accidental removal are significantly more frequent in COVID-19 patients. Accidental removals are the principal complication, for this reason use of subcutaneously anchored securement is recommended for shorter period than usual.

Glycosaminoglycans induce conformational change in the SARS-CoV-2 Spike S1 Receptor Binding Domain.

The glycosaminoglycan (GAG) class of polysaccharides are utilised by a plethora of microbial pathogens as receptors for adherence and invasion. The GAG heparin prevents infection by a range of viruses when added exogenously, including the S-associated coronavirus strain HSR1 and more recently we have demonstrated that heparin can block cellular invasion by SARS-CoV-2. Heparin has found widespread clinical use as anticoagulant drug and this molecule is routinely used as a proxy for the GAG, heparan sulphate (HS), a structural analogue located on the cell surface, which is a known receptor for viral invasion. Previous work has demonstrated that unfractionated heparin and low molecular weight heparins binds to the Spike (S1) protein receptor binding domain, inducing distinct conformational change and we have further explored the structural features of heparin with regard to these interactions. In this article, previous research is expanded to now include a broader range of GAG family members, including heparan sulphate. This research demonstrates that GAGs, other than those of heparin (or its derivatives), can also interact with the SARS-CoV-2 Spike S1 receptor binding domain and induce distinct conformational changes within this region. These findings pave the way for future research into next-generation, tailor-made, GAG-based antiviral agents, against SARS-CoV-2 and other members of the Coronaviridae.

SARS-CoV-2 Spike S1 Receptor Binding Domain undergoes Conformational Change upon Interaction with Low Molecular Weight Heparins.

The dependence of the host on the interaction of hundreds of extracellular proteins with the cell surface glycosaminoglycan heparan sulphate (HS) for the regulation of homeostasis is exploited by many microbial pathogens as a means of adherence and invasion. The closely related polysaccharide heparin, the widely used anticoagulant drug, which is structurally similar to HS and is a common experimental proxy, can be expected to mimic the properties of HS. Heparin prevents infection by a range of viruses when added exogenously, including S-associated coronavirus strain HSR1 and inhibits cellular invasion by SARS-CoV-2. We have previously demonstrated that unfractionated heparin binds to the Spike (S1) protein receptor binding domain, induces a conformational change and have reported the structural features of heparin on which this interaction depends. Furthermore, we have demonstrated that enoxaparin, a low molecular weight clinical anticoagulant, also binds the S1 RBD protein and induces conformational change. Here we expand upon these studies, to a wide range of low molecular weight heparins and demonstrate that they induce a variety of conformational changes in the SARS-CoV-2 RBD. These findings may have further implications for the rapid development of a first-line therapeutic by repurposing low molecular weight heparins, as well as for next-generation, tailor-made, GAG-based antiviral agents, against SARS-CoV-2 and other members of the Coronaviridae.

Heparin inhibits cellular invasion by SARS-CoV-2: structural dependence of the interaction of the surface protein (spike) S1 receptor binding domain with heparin.

The dependence of the host on the interaction of hundreds of extracellular proteins with the cell surface glycosaminoglycan heparan sulphate (HS) for the regulation of homeostasis is exploited by many microbial pathogens as a means of adherence and invasion. The closely related polysaccharide heparin, the widely used anticoagulant drug, which is structurally similar to HS and is a common experimental proxy, can be expected to mimic the properties of HS. Heparin prevents infection by a range of viruses if added exogenously, including S-associated coronavirus strain HSR1. Heparin prevents infection by a range of viruses if added exogenously, including S-associated coronavirus strain HSR1. Here, we show that the addition of heparin to Vero cells between 6.25 - 200 g.ml-1, which spans the concentration of heparin in therapeutic use, and inhibits invasion by SARS-CoV-2 at between 44 and 80%. We also demonstrate that heparin binds to the Spike (S1) protein receptor binding domain and induces a conformational change, illustrated by surface plasmon resonance and circular dichroism spectroscopy studies. The structural features of heparin on which this interaction depends were investigated using a library of heparin derivatives and size-defined fragments. Binding is more strongly dependent on the presence of 2-O or 6-O sulphation, and the consequent conformational consequences in the heparin structure, than on N-sulphation. A hexasaccharide is required for conformational changes to be induced in the secondary structure that are comparable to those that arise from heparin binding. Enoxaparin, a low molecular weight clinical anticoagulant, also binds the S1 RBD protein and induces conformational change. These findings have implications for the rapid development of a first-line therapeutic by repurposing heparin as well as for next-generation, tailor-made, GAG-based antiviral agents against SARS-CoV-2 and other members of the Coronaviridae.

The 2019 coronavirus (SARS-CoV-2) surface protein (Spike) S1 Receptor Binding Domain undergoes conformational change upon heparin binding.

Many pathogens take advantage of the dependence of the host on the interaction of hundreds of extracellular proteins with the glycosaminoglycans heparan sulphate to regulate homeostasis and use heparan sulphate as a means to adhere and gain access to cells. Moreover, mucosal epithelia such as that of the respiratory tract are protected by a layer of mucin polysaccharides, which are usually sulphated. Consequently, the polydisperse, natural products of heparan sulphate and the allied polysaccharide, heparin have been found to be involved and prevent infection by a range of viruses including S-associated coronavirus strain HSR1. Here we use surface plasmon resonance and circular dichroism to measure the interaction between the SARS-CoV-2 Spike S1 protein receptor binding domain (SARS-CoV-2 S1 RBD) and heparin. The data demonstrate an interaction between the recombinant surface receptor binding domain and the polysaccharide. This has implications for the rapid development of a first-line therapeutic by repurposing heparin and for next-generation, tailor-made, GAG-based antivirals.