Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

ABCG2-Dependent Dye Exclusion Activity and Clonal Potential in Epithelial Cells Continuously Growing for 1 Month from Limbal Explants

In limbal explant cultures, side population cells can account for >30% of the cells. These highly clonogenic cells are continuously generated from the core explants, suggesting that the original stem cells are preserved in the tissue biopsy. The results have multiple implications for the behavior of the limbal stem cell ex vivo in niche and the practice of limbal epithelial culture for ocular surface stem cell therapies

Lipid Exchange and Transfer on Nanoparticle Supported Lipid Bilayers: Effect of Defects, Ionic Strength, and Size

Lipid exchange/transfer has been compared for zwitterionic 1,2-dimyristoyl-<i>sn</i>-glycero-3-phosphocholine (DMPC) and 1,2-dimyristoyl-d₅₄-<i>sn</i>-glycero-3-phosphocholine (DMPC) small unilamellar vesicles (SUVs) and for the same lipids on silica (SiO₂) nanoparticle supported lipid bilayers (NP-SLBs) as a function of ionic strength, temperature, temperature cycling, and NP size, above the main gel-to-liquid crystal phase transition temperature, <i>T</i>_m, using d- and h-DMPC and DPPC. Increasing ionic strength decreases the exchange kinetics for the SUVs, but more so for the NP-SLBs, due to better packing of the lipids and increased attraction between the lipid and support. When the NP-SLBs (or SUVs) are cycled above and below <i>T</i>_m, the exchange rate increases compared with exchange at the same temperature without cycling, for similar total times, suggesting that defects provide sites for more facile removal and thus exchange of lipids. Defects can occur: (i) at the phase boundaries between coexisting gel and fluid phases at <i>T</i>_m; (ii) in bare regions of exposed SiO₂ that form during NP-SLB formation due to mismatched surface areas of lipid and NPs; and (iii) during cycling as the result of changes in area of the lipids at <i>T</i>_m and mismatched thermal expansion coefficient between the lipids and SiO₂ support. Exchange rates are faster for NP-SLBs prepared with the nominal amount of lipid required to form a NP-SLB compared with NP-SLBs that have been prepared with excess lipids to minimize SiO₂ patches. Nanosystems prepared with equimolar mixtures of NP-SLBs composed of d-DMPC (d^DMPC-NP-SLB) and SUVs composed of h-DMPC (h^DMPC-SUV) show that the calorimetric transition of the “donor” h^DMPC-SUV decreases in intensity without an initial shift in <i>T</i>_m, indicating that the “acceptor” d^DMPC-NP-SLB can accommodate more lipids, through either further fusion or insertion of lipids into the distal monolayer. Exchange for d/h^DMPC-NP-SLB is in the order 100 nm SiO₂ > 45 nm SiO₂ > 5 nm SiO₂

Effect of lamellarity and size on calorimetric phase transitions in single component phosphatidylcholine vesicles

Nano-differential scanning calorimetry (nano-DSC) is a powerful tool in the investigation of unilamellar (small unilamellar, SUVs, or large unilamellar, LUVs) vesicles, as well as lipids on supported bilayers, since it measures the main gel-to-liquid phase transition temperature (Tm), enthalpies and entropies. In order to assign these transitions in single component systems, where Tm often occurred as a doublet, nano-DSC, dynamic light scattering and cryo-transmission electron microscopy (cryo-TEM) data were compared. The two Tms were not attributable to decoupled phase transitions between the two leaflets of the bilayer, i.e. nano-DSC measurements were not able to distinguish between the outer and inner leaflets of the vesicle bilayers. Instead, the two Tms were attributed to mixtures of oligolamellar and unilamellar vesicles, as confirmed by cryo-TEM images. Tm for the oligolamellar vesicles was assigned to the peak closest to that of the parent multilamellar vesicle (MLV) peak. The other transition was higher than that of the parent MLVs for 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), and increased in temperature as the vesicle size decreased, while it was lower in temperature than that of the parent MLVs for 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), and decreased as the vesicle size decreased. These subtle shifts arose due to small differences in the values of ΔH and ΔS, since Tm is determined by their ratio (ΔH/ΔS). It was not possible to completely eliminate oligolamellar structures for MLVs extruded with the 200 nm pore size filter, even after 120 passes, while these structures were eliminated for MLVs extruded through the 50 nm pore size filter

Effect of Antiplatelet Therapy on Survival and Organ Support–Free Days in Critically Ill Patients With COVID-19

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