Metal-Bound Methisazone; Novel Drugs Targeting Prophylaxis and Treatment of SARS-CoV-2, a Molecular Docking Study.

SARS-CoV-2 currently lacks effective first-line drug treatment. We present promising data from in silico docking studies of new Methisazone compounds (modified with calcium, Ca; iron, Fe; magnesium, Mg; manganese, Mn; or zinc, Zn) designed to bind more strongly to key proteins involved in replication of SARS-CoV-2. In this in silico molecular docking study, we investigated the inhibiting role of Methisazone and the modified drugs against SARS-CoV-2 proteins: ribonucleic acid (RNA)-dependent RNA polymerase (RdRp), spike protein, papain-like protease (PlPr), and main protease (MPro). We found that the highest binding interactions were found with the spike protein (6VYB), with the highest overall binding being observed with Mn-bound Methisazone at -8.3 kcal/mol, followed by Zn and Ca at -8.0 kcal/mol, and Fe and Mg at -7.9 kcal/mol. We also found that the metal-modified Methisazone had higher affinity for PlPr and MPro. In addition, we identified multiple binding pockets that could be singly or multiply occupied on all proteins tested. The best binding energy was with Mn-Methisazone versus spike protein, and the largest cumulative increases in binding energies were found with PlPr. We suggest that further studies are warranted to identify whether these compounds may be effective for treatment and/or prophylaxis.

Timing of Tracheostomy in Pediatric Patients: A Systematic Review and Meta-Analysis.

OBJECTIVES: Tracheostomy is a very common clinical intervention in critically ill adult patients. The indications for tracheostomy procedures in pediatric patients with complex conditions have increased dramatically in recent years, but there are currently no guidelines on the optimal timing of tracheostomy in pediatric patients undergoing prolonged ventilation. DATA SOURCES: We performed a systematic search of the existing literature in MEDLINE via PubMed and Embase databases and the Cochrane Library to identify clinical trials, observational studies, and cohort studies that compare early and late tracheostomy in children. The date of the last search was August 27, 2018. Included articles were subjected to manual searching. STUDY SELECTION: Studies in mechanically ventilated children that compared early with late tracheostomy were included. DATA EXTRACTION: Data were extracted into a spreadsheet and copied into Review Manager 5.3 (The Cochrane Collaboration, Copenhagen, Denmark). DATA SYNTHESIS: Data were meta-analyzed using an inverse variance, random effects model. Continuous outcomes were calculated as mean differences with 95% CIs, and dichotomous outcomes were calculated as Mantel-Haenszel risk ratios with 95% CIs. We included eight studies (10 study arms). These studies were all retrospective cohort studies. Early tracheostomy was associated with significant reductions in mortality, days on mechanical ventilation, and length of intensive care and total hospital stay, although the lack of randomized, controlled trials limits the validity of these findings. Although variance was imputed for some studies, these conclusions did not change after removing these studies from the analysis. CONCLUSIONS: In children on mechanical ventilation, early tracheostomy may improve important medical outcomes. However, our data demonstrate the urgent need for high-quality, randomized controlled trials in the pediatric population.

Antistasis Retrograde Flow Vascular Catheter: A Novel Solution to Thrombogenicity: A Computational Fluid Dynamics Study.

BACKGROUND: Catheter-related thrombosis (CRT) is a serious complication of vascular catheters. Retrograde catheter insertion has been shown to decrease pericatheter hemostasis and thrombosis, but it is technically challenging. The current in silico trial is an analytical approach to evaluating different approaches to designing retrograde flow into a vascular catheter. METHODS: The novel catheter design aims to provide antistasis retrograde flow (ASRF) of fluid through multiple backward-directed side openings, with a self-closing terminal opening to facilitate standard insertion. Four different models of the catheter were evaluated by computational fluid dynamic studies, with retrograde-angled openings of 15°, 30°, 45°, and 60° to the long axis of the catheter. RESULTS: ASRF successfully reduced the areas of fluid stagnation in models with 15° and 30° openings. Models with 45° and 60° did not significantly reduce stagnation. ASRF is reversed by the main bloodstream after a few millimeters. The novel catheter design achieved a slightly higher saline flow rate compared with the standard catheter (89.75, 91.72, 94.13, and 94.26 mL/min for 15°, 30°, 45°, and 60° designs, respectively, versus 86.93 mL/min for the standard catheter). CONCLUSIONS: The novel ASRF vascular catheter reduces pericatheter fluid stasis and has the potential to reduce CRT. Further in vitro and in vivo trials are warranted to validate these findings and evaluate clinical efficacy.