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Contains fulltext : 286889.pdf (Publisher’s version ) (Open Access) BACKGROUND: Thrombosis is a frequent and severe complication in patients with coronavirus disease 2019 (COVID-19) admitted to the intensive care unit (ICU). Lupus anticoagulant (LA) is a strong acquired risk factor for thrombosis in various diseases and is frequently observed in patients with COVID-19. Whether LA is associated with thrombosis in patients with severe COVID-19 is currently unclear. OBJECTIVE: To investigate if LA is associated with thrombosis in critically ill patients with COVID-19. PATIENTS/METHODS: The presence of LA and other antiphospholipid antibodies was assessed in patients with COVID-19 admitted to the ICU. LA was determined with dilute Russell's viper venom time (dRVVT) and LA-sensitive activated partial thromboplastin time (aPTT) reagents. RESULTS: Of 169 patients with COVID-19, 116 (69%) tested positive for at least one antiphospholipid antibody upon admission to the ICU. Forty (24%) patients tested positive for LA; of whom 29 (17%) tested positive with a dRVVT, 19 (11%) tested positive with an LA-sensitive aPTT, and 8 (5%) tested positive on both tests. Fifty-eight (34%) patients developed thrombosis after ICU admission. The odds ratio (OR) for thrombosis in patients with LA based on a dRVVT was 2.5 (95% confidence interval [CI], 1.1-5.7), which increased to 4.5 (95% CI, 1.4-14.3) in patients at or below the median age in this study (64 years). LA positivity based on a dRVVT or LA-sensitive aPTT was only associated with thrombosis in patients aged less than 65 years (OR, 3.8; 95% CI, 1.3-11.4) and disappeared after adjustment for C-reactive protein. CONCLUSION: Lupus anticoagulant on admission is strongly associated with thrombosis in critically ill patients with COVID-19, especially in patients aged less than 65 years.

Pressurised metered dose inhalers (pMDI) are one of the most common devices to deliver therapeutic treatment to patients with asthma or COPD. The atomisation mechanism responsible for droplet production is poorly understood because of the short length and timescales involved, making experimental investigations to characterise fluid flow structures and spray formation processes difficult. This article reports the findings of new high-speed and high-resolution imaging and temperature measurements seeking to improve the fundamental understanding of the atomisation mechanism of the pMDI. An annular flow regime of gaseous core in liquid annulus was observed in the orifice. Shock diamonds within the flow, viewed via Schlieren imaging, confirmed experimentally for the first time the choked nature of the orifice exit flow. Propellant formulation flow in the orifice was found to be superheated to a degree that significant flashing and evaporation at the orifice exit is likely to take place. This information points to a hybrid mechanism of predominantly aerodynamic atomisation with significant liquid flashing upon exit from the orifice producing a near instantaneous formation of respirable droplets. Large irrespirable droplets are produced by two mechanisms; breakup of liquid slugs ejected from the orifice, due to unsteady transient fluid structures in the actuator sump and stripping of ligaments from a liquid pool around the orifice exit, which subsequently break up into large droplets in the periphery of the plume. This new understanding will aid development of next generation, high efficiency pMDIs, particularly those employing low global warming potential propellants such as HFA152a or HFO1234ze(E).

Metastasis results from a complex set of traits acquired by tumor cells, distinct from those necessary for tumorigenesis. Here, we investigate the contribution of enhancer elements to the metastatic phenotype of osteosarcoma. Through epigenomic profiling, we identify substantial differences in enhancer activity between primary and metastatic tumors in human patients as well as nearisogenic pairs of high and low lung-metastatic osteosarcoma cells. We term these regions Metastatic Variant Enhancer Loci (Met-VELs). We demonstrate that these Met-VELs drive coordinated waves of gene expression during metastatic colonization of the lung. Met-VELs cluster non-randomly, indicating that activity of these enhancers and their associated gene targets are positively selected. As evidence of this causal association, osteosarcoma lung metastasis is inhibited by global interruptions of Met-VEL-associated gene expression via pharmacologic BET inhibition, by knockdown of AP-1 transcription factors that occupy Met-VELs, and by knockdown or functional inhibition of individual genes activated by Met-VELs, such as F3. We further show that genetic deletion of a single Met-VEL at the F3 locus blocks metastatic cell outgrowth in the lung. These findings indicate that Met-VELs and the genes they regulate play a functional role in metastasis and may be suitable targets for anti-metastatic therapies.