A potent and broad neutralization of SARS-CoV-2 variants of concern by DARPins.

We report the engineering and selection of two synthetic proteins-FSR16m and FSR22-for the possible treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. FSR16m and FSR22 are trimeric proteins composed of DARPin SR16m or SR22 fused with a T4 foldon. Despite selection by a spike protein from a now historical SARS-CoV-2 strain, FSR16m and FSR22 exhibit broad-spectrum neutralization of SARS-CoV-2 strains, inhibiting authentic B.1.351, B.1.617.2 and BA.1.1 viruses, with respective IC50 values of 3.4, 2.2 and 7.4 ng ml-1 for FSR16m. Cryo-EM structures revealed that these DARPins recognize a region of the receptor-binding domain (residues 456, 475, 486, 487 and 489) overlapping a critical portion of the angiotensin-converting enzyme 2 (ACE2)-binding surface. K18-hACE2 transgenic mice inoculated with B.1.617.2 and receiving intranasally administered FSR16m showed less weight loss and 10-100-fold lower viral burden in upper and lower respiratory tracts. The strong and broad neutralization potency makes FSR16m and FSR22 promising candidates for the prevention and treatment of infection by SARS-CoV-2.

The incidence of propofol infusion syndrome in critically-ill patients.

PURPOSE: PRIS is a potentially fatal syndrome characterized by various clinical symptoms and abnormalities. Experts suggest that propofol treatment duration ≥48 h or dose ≥83 µg/kg/min is associated with developing PRIS. We hypothesized PRIS might be underdiagnosed due to the overlap of PRIS clinical manifestations with critical illnesses. MATERIALS AND METHODS: Multihospital, retrospective study of adult patients who received continuous propofol infusion ≥48 h or dose ≥60µg/kg/min for >24 h since admission were assessed for the development of PRIS. RESULTS: The incidence of PRIS was 2.9% with a PRIS-associated mortality rate of 36.8%. In PRIS patients, propofol was administered at a median dose of 36.4 µg/kg/min and over a median duration of 147.0 h. The development of PRIS was observed at a median of 125.0 h post-propofol initiation and a cumulative dose of 276.5 mg/kg. The development of metabolic acidosis (78.9%), cardiac dysfunction (52.6%), hypertriglyceridemia (100%), and rhabdomyolysis (26.3%) were observed in our PRIS patients. CONCLUSION: PRIS can often be overlooked and underdiagnosed. It is important to monitor for early signs of PRIS in patients who are on prolonged propofol infusion. Prompt recognition and interventions can minimize the dangers resulting from PRIS.

Inhaled pulmonary vasodilators are not associated with improved gas exchange in mechanically ventilated patients with COVID-19: A retrospective cohort study.

PURPOSE: Measure the effect of inhaled pulmonary vasodilators on gas exchange in mechanically ventilated patients with COVID-19. METHODS: A retrospective observational cohort study at three New York University Hospitals was performed including eighty-four mechanically ventilated SARS Cov-2 nasopharyngeal PCR positive patients, sixty nine treated with inhaled nitric oxide (iNO) and fifteen with inhaled epoprostenol (iEPO). The primary outcomes were change in PAO2:FIO2 ratio, oxygenation Index (OI), and ventilatory ratio (VR) after initiation of inhaled pulmonary vasodilators. RESULTS: There was no significant change in PAO2:FIO2ratio after initiation of iNO (mean - 4.1, 95% CI -17.3-9.0, P = 0.54) or iEPO (mean - 3.4, 95% CI -19.7-12.9, P = 0.66), in OI after initiation of iNO (mean 2.1, 95% CI-0.04-4.2, P = 0.054) or iEPO (mean - 3.4, 95% CI -19.7-12.9, P = 0.75), or in VR after initiation of iNO (mean 0.17, 95% CI -0.03-0.36, P = 0.25) or iEPO (mean 0.33, 95% CI -0.0847-0.74, P = 0.11). PAO2:FIO2, OI and VR did not significantly change over a five day period starting the day prior to drug initiation in patients who received either iNO or iEPO assessed with a fixed effects model. CONCLUSION: Inhaled pulmonary vasodilators were not associated with significant improvement in gas exchange in mechanically ventilated patients with COVID-19.