Implications of early respiratory support strategies on disease progression in critical COVID-19: a matched subanalysis of the prospective RISC-19-ICU cohort.

Uncertainty about the optimal respiratory support strategies in critically ill COVID-19 patients is widespread. While the risks and benefits of noninvasive techniques versus early invasive mechanical ventilation (IMV) are intensely debated, actual evidence is lacking. We sought to assess the risks and benefits of different respiratory support strategies, employed in intensive care units during the first months of the COVID-19 pandemic on intubation and intensive care unit (ICU) mortality rates. Subanalysis of a prospective, multinational registry of critically ill COVID-19 patients. Patients were subclassified into standard oxygen therapy ≥10 L/min (SOT), high-flow oxygen therapy (HFNC), noninvasive positive-pressure ventilation (NIV), and early IMV, according to the respiratory support strategy employed at the day of admission to ICU. Propensity score matching was performed to ensure comparability between groups. Initially, 1421 patients were assessed for possible study inclusion. Of these, 351 patients (85 SOT, 87 HFNC, 87 NIV, and 92 IMV) remained eligible for full analysis after propensity score matching. 55% of patients initially receiving noninvasive respiratory support required IMV. The intubation rate was lower in patients initially ventilated with HFNC and NIV compared to those who received SOT (SOT: 64%, HFNC: 52%, NIV: 49%, p = 0.025). Compared to the other respiratory support strategies, NIV was associated with a higher overall ICU mortality (SOT: 18%, HFNC: 20%, NIV: 37%, IMV: 25%, p = 0.016). In this cohort of critically ill patients with COVID-19, a trial of HFNC appeared to be the most balanced initial respiratory support strategy, given the reduced intubation rate and comparable ICU mortality rate. Nonetheless, considering the uncertainty and stress associated with the COVID-19 pandemic, SOT and early IMV represented safe initial respiratory support strategies. The presented findings, in agreement with classic ARDS literature, suggest that NIV should be avoided whenever possible due to the elevated ICU mortality risk

Trophoblast invasion: tuning through LIF, signalling via Stat3

Aberrant activity of the signal transducer and activator of transcription 3 (Stat3) is believed to be essential for neoplastic cell behaviour and thus for the malignancy of tumor cells [Bowman T, Garcia R, Turkson J, Jove R. STATs in oncogenesis. Oncogene 2000;19:2474-88]. Extravillous trophoblast cells resemble malignancies in their invasive and destructive features, excluding the fact of sequential restriction to the first trimester of pregnancy. Trophoblast cells from term placentas have reduced invasive capacity [Hohn HP, Denker HW. Experimental modulation of cell-cell adhesion, invasiveness and differentiation in trophoblast cells. Cells Tissues Organs 2002;172:218-36]. Constitutively activated Stat3 DNA-binding activity in choriocarcinoma cells, carcinomatous derivates of trophoblast cells, have been reported to correlate with its invasiveness [Corvinus FM, Fitzgerald JS, Friedrich K, Markert UR. Evidence for a correlation between trophoblast invasiveness and STAT3 activity. Am J Reprod Immunol 2003;50:316-21]. Here we demonstrate using RNAi that Stat3 activation is necessary in the invasive phenotype of trophoblast cells and can be controlled via Leukemia Inhibitory Factor (LIF). LIF provides a soluble extracellular signal that stimulates invasion in trophoblast and Jeg-3 choriocarcinoma cells. Loss of LIF-mediated invasion in these cells subsequent to STAT3 knock-down strongly suggests that STAT3 plays a crucial role in mediating this invasion