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Introduction: High-dose catecholamines can impair hypoxic pulmonary vasoconstriction and increase shunt fraction. We aimed to determine if Angiotensin II (Ang-2) is associated with improved PaO2/FiO2 and SpO2/FiO2 in patients in shock. Methods: Adult patients at four tertiary care centers and one community hospital in the United States who received Ang-2 from July 2018-September 2020 were included in this retrospective, observational cohort study. PaO2, SpO2, and FiO2 were measured at 13 timepoints during the 48-h before and after Ang-2 initiation. Piecewise linear mixed models of PaO2/FiO2 and SpO2/FiO2 were created to evaluate hourly changes in oxygenation after Ang-2 initiation. The difference in the proportion of patients with PaO2/FiO2 ≤ 300 mm Hg at the time of Ang-2 initiation and 48 h after was also examined. Results: The study included 254 patients. In the 48 h prior to Ang-2 initiation, oxygenation was significantly declining (hourly PaO2/FiO2 change −4.7 mm Hg/hr, 95% CI − 6.0 to −3.5, p <.001; hourly SpO2/FiO2 change −3.1/hr, 95% CI−3.7 to −2.4, p <.001). Ang-2 treatment was associated with significant improvements in PaO2/FiO2 and SpO2/FiO2 in the 48-h after initiation (hourly PaO2/FiO2 change +1.5 mm Hg/hr, 95% CI 0.5-2.5, p =.003; hourly SpO2/FiO2 change +0.9/hr, 95% CI 0.5-1.2, p <.001). The difference in the hourly change in oxygenation before and after Ang-2 initiation was also significant (p interaction < 0.001 for both PaO2/FiO2 and SpO2/FiO2). This improvement was associated with significantly fewer patients having a PaO2/FiO2 ≤ 300 mm Hg at 48 h compared to baseline (mean difference −14.9%, 95% CI −25.3% to −4.6%, p =.011). Subgroup analysis found that patients with either a baseline PaO2/FiO2 ≤ 300 mm Hg or a norepinephrine-equivalent dose requirement >0.2 µg/kg/min had the greatest associations with oxygenation improvement. Conclusions: Ang-2 is associated with improved PaO2/FiO2 and SpO2/FiO2. The mechanisms for this improvement are not entirely clear but may be due to catecholamine-sparing effect or may also be related to improved ventilation-perfusion matching, intrapulmonary shunt, or oxygen delivery. [ABSTRACT FROM AUTHOR]

In this work, the heterodimeric phospholipase A2, HDP-2, from viper venom was investigated for its hydrolytic activity in model myelin membranes as well as for its effects on intermembrane exchange of phospholipids (studied by phosphorescence quenching) and on phospholipid polymorphism (studied by 1H-NMR spectroscopy) to understand the role of sphingomyelin (SM) in the demyelination of nerve fibers. By using well-validated in vitro approaches, we show that the presence of SM in model myelin membranes leads to a significant inhibition of the hydrolytic activity of HDP-2, decreased intermembrane phospholipid exchange, and reduced phospholipid polymorphism. Using AutoDock software, we show that the NHδ+ group of the sphingosine backbone of SM binds to Tyr22(C=Opbδ–) of HDP-2 via a hydrogen bond which keeps only the polar head of SM inside the HDP-2’s active center and positions the sn-2 acyl ester bond away from the active center, thus making it unlikely to hydrolyze the alkyl chains at the sn-2 position. This observation strongly suggests that SM inhibits the catalytic activity of HDP-2 by blocking access to other phospholipids to the active center of the enzyme. Should this observation be verified in further studies, it would offer a tantalizing opportunity for developing effective pharmaceuticals to stop the demyelination of nerve fibers by aberrant PLA2s with overt activity – as observed in brain degenerative diseases – by inhibiting SM hydrolysis and/or facilitating SM synthesis in the myelin sheath membrane.Binding of sphingomyelin (SM) to catalytic subunits of HDP-2 predicted by Autodock. SM is given in sticks representation and HDP-2P is displayed in molecular surface (A) and line stick representation (B). For the stick diagrams, emerald represents carbon, blue–nitrogen, orange–phosphorus, red–oxygen, white–hydrogen. For molecular surface and lines, green represents carbon, blue–nitrogen, red–oxygen, white–hydrogen, yellow–sulfur. Yellow broken lines identify intermolecular bonds. Arrows point to sn-2 bonds. Hydrogen bond between NHδ+ group and Tyr22(C=Opbδ–) and ionic bond between PO4– group and His48 drive the positioning of the sn-2 acyl ester bond away from the active center that suggests that SM binds non-productively in the active center of HDP-2 enzyme.Graphical Abstract: In this work, the heterodimeric phospholipase A2, HDP-2, from viper venom was investigated for its hydrolytic activity in model myelin membranes as well as for its effects on intermembrane exchange of phospholipids (studied by phosphorescence quenching) and on phospholipid polymorphism (studied by 1H-NMR spectroscopy) to understand the role of sphingomyelin (SM) in the demyelination of nerve fibers. By using well-validated in vitro approaches, we show that the presence of SM in model myelin membranes leads to a significant inhibition of the hydrolytic activity of HDP-2, decreased intermembrane phospholipid exchange, and reduced phospholipid polymorphism. Using AutoDock software, we show that the NHδ+ group of the sphingosine backbone of SM binds to Tyr22(C=Opbδ–) of HDP-2 via a hydrogen bond which keeps only the polar head of SM inside the HDP-2’s active center and positions the sn-2 acyl ester bond away from the active center, thus making it unlikely to hydrolyze the alkyl chains at the sn-2 position. This observation strongly suggests that SM inhibits the catalytic activity of HDP-2 by blocking access to other phospholipids to the active center of the enzyme. Should this observation be verified in further studies, it would offer a tantalizing opportunity for developing effective pharmaceuticals to stop the demyelination of nerve fibers by aberrant PLA2s with overt activity – as observed in brain degenerative diseases – by inhibiting SM hydrolysis and/or facilitating SM synthesis in the myelin sheath membrane.Binding of sphingomyelin (SM) to catalytic subunits of HDP-2 predicted by Autodock. SM is given in sticks representation and HDP-2P is displayed in molecular surface (A) and line stick representation (B). For the stick diagrams, emerald represents carbon, blue–nitrogen, orange–phosphorus, red–oxygen, white–hydrogen. For molecular surface and lines, green represents carbon, blue–nitrogen, red–oxygen, white–hydrogen, yellow–sulfur. Yellow broken lines identify intermolecular bonds. Arrows point to sn-2 bonds. Hydrogen bond between NHδ+ group and Tyr22(C=Opbδ–) and ionic bond between PO4– group and His48 drive the positioning of the sn-2 acyl ester bond away from the active center that suggests that SM binds non-productively in the active center of HDP-2 enzyme. [ABSTRACT FROM AUTHOR]

Aspect-dependent landslide initiation is an interesting finding and previous studies merely address the role of plant roots on this observed connection between landslide probability and slope aspect. In this work, the aspect-dependent landslide initiation in catchment with same plant species and high vegetation coverage was examined by pore water pressure and hillslope hydrology behavior. Remote sensing interpretation using the high-resolution GeoEye-1 image and digitalized topography found that the landslides on south-facing slope have higher probability, larger basal area and shallower depth than those on north-facing slope. The lower limit of upslope contributing area and slope gradient condition for south-facing landslides is no less than north-facing landslides. The higher basal area of south-facing landslides over north-facing landslides may attribute to the high peak values and slow dissipation of pore water pressure. The absorbed and drained water flow in given time interval, together with the calculated water storage and leakage during the measured rainy season, sufficiently prove that the soil mass above the failure zone for the south-facing slopes are more prone to form pore-water pressure and result in slope failures. In comparison, the two stability fluctuation results from finite and infinite models imply that landslides on south-facing slopes may fail on condition of prolonged antecedent precipitation and intensive rainfall, while those on north-facing slopes may fail merely in response to intensive rainfall. The results of this work provide an insightful view on the aspect-dependent landslide initiation from both classical mechanics and the state of stress. [ABSTRACT FROM AUTHOR]

Introduction: Angiotensin II (Ang-2) is a non-catecholamine vasopressor that targets the renin-angiotensin-aldosterone system by agonism of the angiotensin type 1 receptor. Its utility as a vasopressor and a catecholamine-sparing agent was demonstrated in the pivotal ATHOS-3 trial, and numerous post-hoc analyses have shown reduced mortality in certain subsets of the population. Methods: Consecutive adult patients at 5 centers who received Ang-2 from 2017-2020 were included in this multicenter, retrospective observational cohort study. Patient demographics, hemodynamics, and adverse events were collected. The primary outcomes of the study were the mean difference in MAP and norepinephrine (NEpi)-equivalent dose at hours 0 and 3 following initiation of Ang-2 therapy. Results: One hundred and sixty-two patients were included in this study. The primary outcomes of an increase in MAP (mean difference 9.3 mmHg, 95% CI 6.4-12.1, p < 0.001) and a reduction in NEpi equivalent dose (mean difference 0.16 µg/kg/min, 95% CI 0.10-0.22, p < 0.001) between hours 0 and 3 were statistically significant. The median time to reach a MAP ≥65 was 16 minutes (IQR 5-60 min). After stratifying patients by the NED dose and number of vasopressors administered prior to the initiation of Ang-2, those with a NED dose < 0.2 µg/kg/min, NED dose < 0.3 µg/kg/min, or those on ≤ 3 vasopressors had a significantly greater reduction in NED by hour 3 than those patients above these thresholds. Conclusion: Ang-2 is an effective vasopressor and reduces catecholamine dose significantly. Its effect is rapid, with target MAP obtained within 30 minutes in most patients. Given the critical importance of adequate blood pressure to organ perfusion, Ang-2 should be considered when target MAP cannot be achieved with conventional vasopressors. Ang-2 should be utilized early in the course of shock, before the NED dose exceeds 0.2-0.3 µg/kg/min and before the initiation of the fourth-line vasopressor. [ABSTRACT FROM AUTHOR]

Introduction: High-dose catecholamines can impair hypoxic pulmonary vasoconstriction and increase shunt fraction. We aimed to determine if Angiotensin II (Ang-2) is associated with improved PaO 2 /FiO 2 and SpO 2 /FiO 2 in patients in shock., Methods: Adult patients at four tertiary care centers and one community hospital in the United States who received Ang-2 from July 2018-September 2020 were included in this retrospective, observational cohort study. PaO 2 , SpO 2 , and FiO 2 were measured at 13 timepoints during the 48-h before and after Ang-2 initiation. Piecewise linear mixed models of PaO 2 /FiO 2 and SpO 2 /FiO 2 were created to evaluate hourly changes in oxygenation after Ang-2 initiation. The difference in the proportion of patients with PaO 2 /FiO 2  ≤ 300 mm Hg at the time of Ang-2 initiation and 48 h after was also examined., Results: The study included 254 patients. In the 48 h prior to Ang-2 initiation, oxygenation was significantly declining (hourly PaO 2 /FiO 2 change -4.7 mm Hg/hr, 95% CI - 6.0 to -3.5, p  < .001; hourly SpO 2 /FiO 2 change -3.1/hr, 95% CI-3.7 to -2.4, p  < .001). Ang-2 treatment was associated with significant improvements in PaO 2 /FiO 2 and SpO 2 /FiO 2 in the 48-h after initiation (hourly PaO 2 /FiO 2 change +1.5 mm Hg/hr, 95% CI 0.5-2.5, p   =  .003; hourly SpO 2 /FiO 2 change +0.9/hr, 95% CI 0.5-1.2, p  < .001). The difference in the hourly change in oxygenation before and after Ang-2 initiation was also significant ( p interaction  < 0.001 for both PaO 2 /FiO 2 and SpO 2 /FiO 2 ). This improvement was associated with significantly fewer patients having a PaO 2 /FiO 2  ≤ 300 mm Hg at 48 h compared to baseline (mean difference -14.9%, 95% CI -25.3% to -4.6%, p   =  .011). Subgroup analysis found that patients with either a baseline PaO 2 /FiO 2  ≤ 300 mm Hg or a norepinephrine-equivalent dose requirement >0.2 µg/kg/min had the greatest associations with oxygenation improvement., Conclusions: Ang-2 is associated with improved PaO 2 /FiO 2 and SpO 2 /FiO 2 . The mechanisms for this improvement are not entirely clear but may be due to catecholamine-sparing effect or may also be related to improved ventilation-perfusion matching, intrapulmonary shunt, or oxygen delivery.