Background COVID-19’s pulmonary manifestations are broad, ranging from pneumonia with no supplemental oxygen requirements to acute respiratory distress syndrome (ARDS) with acute respiratory failure (ARF). In response, new oxygenation strategies and therapeutics have been developed, but their large-scale effects on outcomes in severe COVID-19 patients remain unknown. Therefore, we aimed to examine the trends in mortality, mechanical ventilation, and cost over the first six months of the pandemic for adult COVID-19 patients in the US who developed ARDS or ARF. Methods and findings The Vizient Clinical Data Base, a national database comprised of administrative, clinical, and financial data from academic medical centers, was queried for patients ≥ 18-years-old with COVID-19 and either ARDS or ARF admitted between 3/2020-8/2020. Demographics, mechanical ventilation, length of stay, total cost, mortality, and discharge status were collected. Mann-Kendall tests were used to assess for significant monotonic trends in total cost, mechanical ventilation, and mortality over time. Chi-square tests were used to compare mortality rates between March-May and June-August. 110,223 adult patients with COVID-19 ARDS or ARF were identified. Mean length of stay was 12.1±13.3 days and mean total cost was $35,991±32,496. Mechanical ventilation rates were 34.1% and in-hospital mortality was 22.5%. Mean cost trended downward over time (p = 0.02) from $55,275 (March) to $18,211 (August). Mechanical ventilation rates trended down (p<0.01) from 53.8% (March) to 20.3% (August). Overall mortality rates also decreased (p<0.01) from 28.4% (March) to 13.7% (August). Mortality rates in mechanically ventilated patients were similar over time (p = 0.45), but mortality in patients not requiring mechanical ventilation decreased from March-May compared to June-July (13.5% vs 4.6%, p<0.01). Conclusions This study describes the outcomes of a large cohort with COVID-19 ARDS or ARF and the subsequent decrease in cost, mechanical ventilation, and mortality over the first 6 months of the pandemic in the US.

No abstract

Sorafenib has an antitumor activity in patients with radioactive iodine-refractory differentiated thyroid carcinoma (RAIR-DTC). Prior research has implicated signaling through the MAPK and AKT/PI3K pathways in the progression of DTC. To assess whether the activity of these pathways is predictive of response to sorafenib, we retrospectively studied molecular tumor markers from these two pathways from a phase 2 study of sorafenib in RAIR-DTC. Tumor samples from 40 of 53 DTC subjects obtained prior to initiation of sorafenib were immunostained with DAB-labeled antibodies to phospho-AKT (pAKT), phospho-ERK (pERK), and phospho-S6 (pS6). BRAFV600E genetic mutation analysis was performed on all samples. Expression levels and mutational status were compared to response and progression-free survival (PFS) for each patient. Low tumor expression of nuclear pAKT was associated with partial response to sorafenib (p < 0.01). Patients with nuclear pAKT expression that was below the median for our sample were more than three times as likely to have a partial response as patients with equal to or above median expression. There was no correlation between tumor expression of nuclear pERK or pS6 and response. Endothelial cell and pericyte expression of pERK, pAKT, and pS6 were not predictive of response. There was no correlation between BRAFV600E mutation status and partial response. No correlation was observed between either the expression of pAKT, pERK, or pS6, or the presence of the BRAFV600E mutation, and PFS. In conclusion, lower tumor expression of nuclear pAKT was associated with higher rate of response to sorafenib. This observation justifies evaluation of combination therapy with sorafenib and an inhibitor of the PI3K/AKT signaling pathway in RAIR-DTC.

Women who undergo chemotherapy during a pregnancy are more likely to report breastfeeding difficulties.

The functional significance of decreased RAP1GAP protein expression in human tumors is unclear. To identify targets of RAP1GAP downregulation in the thyroid gland, RAP1 and RAP2 protein expression in human thyroid cells and in primary thyroid tumors were analyzed. RAP1GAP and RAP2 were co-expressed in normal thyroid follicular cells. Intriguingly, RAP1 was not detected in normal thyroid cells, although it was detected in papillary thyroid carcinomas, which also expressed RAP2. Both RAP proteins were detected at the membrane in papillary thyroid tumors, suggesting that they are activated when RAP1GAP is downregulated. To explore the functional significance of RAP1GAP depletion, RAP1GAP was transiently expressed at the lowest level that is sufficient to block endogenous RAP2 activity in papillary and anaplastic thyroid carcinoma cell lines. RAP1GAP impaired the ability of cells to spread and migrate on collagen. Although RAP1GAP had no effect on protein tyrosine phosphorylation in growing cells, RAP1GAP impaired phosphorylation of focal adhesion kinase and paxillin at sites phosphorylated by SRC in cells acutely plated on collagen. SRC activity was increased in suspended cells, where it was inhibited by RAP1GAP. Inhibition of SRC kinase activity impaired cell spreading and motility. These findings identify SRC as a target of RAP1GAP depletion and suggest that the downregulation of RAP1GAP in thyroid tumors enhances SRC-dependent signals that regulate cellular architecture and motility.