Resolvin E1 (RvE1) is an omega-3 eicosapentaenoic acid (EPA)-derived lipid mediator generated during resolution of inflammation and in human vasculature via leukocyte-endothelial cell interactions. RvE1 possesses anti-inflammatory and proresolving actions. Here, we report that RvE1 in human whole blood rapidly regulates leukocyte expression of adhesion molecules. RvE1 in the 10-to 100-nM range stimulated L-selectin shedding, while reducing CD18 expression in both neutrophils and monocytes. When added to whole blood, RvE1 did not stimulate reactive oxygen species by either neutrophils or monocytes, nor did it directly stimulate cytokine/chemokine production in heparinized blood. Intravital microscopy (IVM) demonstrated that RvE1 rapidly reduced leukocyte rolling (ϳ ϳ 40%) in venules of mice. In human platelet-rich plasma (PRP), RvE1 selectively blocked both ADP-stimulated and thromboxane receptor agonist U46619-stimulated platelet aggregation in a concentrationdependent manner. In contrast, ⌬6,14- IntroductionInflammation is now widely recognized as a central component in several of the most prevalent human diseases in the developed world, including rheumatic diseases, asthma, diabetes, Alzheimer disease, and various cardiovascular conditions such as thrombosis, stroke, and atherosclerosis. 1,2 Earlier results from humans and animals suggest that omega-3 polyunsaturated fatty acids (PUFAs) such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have diverse beneficial actions in many inflammatory disorders. [3][4][5] The underlying cellular and molecular mechanisms responsible for their beneficial actions had remained for the most part elusive. Recently, we identified novel families of lipid mediators generated from EPA and DHA named resolvins and protectins, because they possess potent anti-inflammatory and proresolving actions. Collectively, these results emphasize the importance of -3 PUFAs as precursors for novel potent bioactive mediators. [6][7][8] The name resolvin (resolution phase interaction products) was introduced for these endogenous bioactive compounds because they were originally identified in spontaneous self-limited murine inflammatory exudates in vivo. 6,7 Resolvin E1 (RvE1) is also generated by human cell types during, for example, cell-cell interactions from EPA typified by endothelial cell and leukocyte interactions. 6 In vascular endothelial cells, aspirin-acetylated COX-2 converts EPA to 18R-hydro(peroxy)-EPE, which is quickly reduced to 18R-HEPE. 18R-HEPE is then released from endothelium and rapidly transformed by activated human polymorphonuclear leukocyte (PMN) in the proximity to a bioactive trihydroxy-containing product, termed resolvin E1 (RvE1). 6 In addition, RvE1 is also produced in vivo in humans via aspirin-independent routes via mechanisms involving P450 6 and was recently found to be generated from EPA by Candida albicans. 9 RvE1 biosynthesis in C albicans, for example, occurs in the absence of other cellular partners when EPA is present in the milieu and its biosy...

During the course of homing to lymph nodes (LNs), T cells undergo a multistep adhesion cascade that culminates in a lymphocyte function-associated antigen 1 (LFA-1)-dependent firm adhesion to the luminal surface of high endothelial venules (HEVs). The importance of LFA-1 affinity regulation in supporting T-cell arrest on HEVs has been well established, however, its importance in the postadhesion phase, which involves intraluminal crawling and diapedesis to the extravascular space, remains elusive. Here we have shown that LFA-1 affinity needs to be appropriately regulated to support these essential steps in the homing cascade. Genetically engineered T cells that were unable to properly down-regulate LFA-1 affinity underwent enhanced, chemokine-independent arrest in HEVs but showed perturbed intravascular crawling to transmigration sites and compromised diapedesis across HEVs. By contrast, the extravascular migration of T cells was insensitive to the affinity-enhancing LFA-1 mutation. These results highlight the requirement for balanced LFA-1 affinity regulation in intravascular and transvascular, but not extravascular, T-cell migration in LNs. (Blood. 2010;115:1572-1581) IntroductionThe constant recirculation of naive T cells through secondary lymphoid organs is critical for immune surveillance. 1 A central event in this process is homing of T cells to lymph nodes (LNs) via high endothelial venules (HEVs). A current model of the homing cascade includes a sequence of at least 4 distinct steps 2-5 : (1) recruitment of circulating T cells to the luminal HEV surface, involving a rolling interaction and its subsequent conversion to firm adhesion upon chemokine activation; (2) intravascular migration of luminally adherent T cells that allows the translocation from the initial attachment site to a suitable exit site; (3) transendothelial diapedesis across HEVs; and (4) random migration of T cells within the extravascular compartment in LN parenchyma. Considerable information is available on the molecular and cellular mechanisms involved in the first and last step in this homing cascade; however, little is known about the rules that control the access of luminally adherent cells to the LN parenchyma.Integrin lymphocyte function-associated antigen 1 (LFA-1; ␣ L ␤ 2 ) is the predominant cell adhesion molecule present on T cells. 6-8 LFA-1 is an ␣/␤ heterodimeric transmembrane membrane protein that contains the ligand binding inserted (I) domain at the most distal part of the extracellular portion. 9 LFA-1 undergoes dynamic and regulated conformational changes in response to internal cues (eg, the intracellular signaling elicited by chemokine and T-cell receptors) as well as in response to external cues (eg, ligand densities and shear stress). [10][11][12] A series of in vitro investigations propose a model that explains how these sequential engagements of internal and external cues regulate LFA-1 conformations in T-cell interactions with intercellular adhesion molecule-1 (ICAM-1), the major LFA-1 ligand on endothelial cell...

Despite being at high risk for extrapulmonary complications, patients undergoing bilateral lung transplantation for scleroderma have similar 1-year and 5-year survival as those with restrictive lung disease. Transplantation is a reasonable treatment option for a carefully selected population of candidates.

IMPORTANCEThe monoclonal antibody combination of casirivimab and imdevimab reduced viral load, hospitalization, or death when administered as a 1200-mg or greater intravenous (IV) dose in a phase 3 COVID-19 outpatient study. Subcutaneous (SC) and/or lower IV doses should increase accessibility and/or drug supplies for patients. OBJECTIVE To assess the virologic efficacy of casirivimab and imdevimab across different IV and SC doses compared with placebo. DESIGN, SETTING, AND PARTICIPANTS This phase 2, randomized, double-blind, placebocontrolled, parallel-group, dose-ranging study included outpatients with SARS-CoV-2 infection at 47 sites across the United States. Participants could be symptomatic or asymptomatic; symptomatic patients with risk factors for severe COVID-19 were excluded. Data were collected from December 15, 2020, to March 4, 2021. INTERVENTIONS Patients were randomized to a single IV dose (523 patients) of casirivimab and imdevimab at 300, 600, 1200, or 2400 mg or placebo; or a single SC dose (292 patients) of casirivimab and imdevimab at 600 or 1200 mg or placebo. MAIN OUTCOMES AND MEASURES The primary end point was the time-weighted average daily change from baseline (TWACB) in viral load from day 1 (baseline) through day 7 in patients seronegative for SARS-CoV-2 at baseline. RESULTS Among 815 randomized participants, 507 (282 randomized to IV treatment, 148 randomized to SC treatment, and 77 randomized to placebo) were seronegative at baseline and included in the primary efficacy analysis. Participants randomized to IV had a mean (SD) age of 34.6 (9.6) years (160 [44.6%] men; 14 [3.9%] Black; 121 [33.7%] Hispanic or Latino; 309 [86.1%] White); those randomized to SC had a mean age of 34.1 (10.0) years (102 [45.3%] men; 75 [34.7%] Hispanicor Latino; 6 [2.7%] Black; 190 [84.4%] White). All casirivimab and imdevimab treatments showed significant virologic reduction through day 7. Least-squares mean differences in TWACB viral load for casirivimab and imdevimab vs placebo ranged from -0.56 (95% CI; -0.89 to -0.24) log 10 copies/mL for the 1200-mg IV dose to -0.71 (95% CI, -1.05 to -0.38) log 10 copies/mL for the 2400-mg IV dose. There were no adverse safety signals or dose-related safety findings, grade 2 or greater infusionrelated or hypersensitivity reactions, grade 3 or greater injection-site reactions, or fatalities. Two serious adverse events not related to COVID-19 or the study drug were reported.

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While several studies have addressed the interconnections between self-assessment and academic stress, much uncertainty still exists about the mediating role of coping styles in this interplay. Therefore, this research aimed to determine the mediating role of coping styles in the relationship between the core of self-assessment and academic stress. To this aim, a total of 384 English as a foreign language (EFL) learners in the training institutes in Woldia, Ethiopia, filled out three questionnaires, including self-evaluations, the coping styles, and the academic stress. The analysis of the data using structural equation modeling revealed that the core of self-assessment had significant negative effects on academic stress, emotion-based coping, and avoidance. Furthermore, self-assessment with the mediating role of other factors, namely problem-oriented coping, emotion-based coping, and avoidance coping showed to have a negative and significant effect on academic stress. Based on the findings, it is possible to receive personality traits as an individual factor, predict differences in individuals coping styles of academic stress, and, as a result, teach appropriate coping styles to EFL learners to reduce their academic stress.

Recent advances in technology have led to significantly greater use of extracorporeal membrane oxygenation (ECMO) as a bridge to lung transplantation with better outcomes. The novel ProtekDuo veno‐venous ECMO (CardiacAssist, Inc.) has gained significance as it facilitates effective decompression of the right heart in patients with acute decompensation, while also providing consistent and effective gas exchange by eliminating recirculation. Here, we report two cases of effectively using ProtekDuo veno‐venous ECMO: one case as a bridge to lung transplantation and another case as a bridge to heart‐lung transplantation.

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