Early Intravascular Events Are Associated with Development of Acute Respiratory Distress Syndrome. A Substudy of the LIPS-A Clinical Trial.

RATIONALE: Acute respiratory distress syndrome (ARDS) is a devastating illness with limited therapeutic options. A better understanding of early biochemical and immunological events in ARDS could inform the development of new preventive and treatment strategies. OBJECTIVES: To determine select peripheral blood lipid mediator and leukocyte responses in patients at risk for ARDS. METHODS: Patients at risk for ARDS were randomized as part of a multicenter, double-blind clinical trial of aspirin versus placebo (the LIPS-A [Lung Injury Prevention Study with Aspirin] trial; NCT01504867). Plasma thromboxane B2 (TXB2), aspirin-triggered lipoxin A4 (15-epi-LXA4, ATL), and peripheral blood leukocyte number and activation were determined on enrollment and after treatment with either aspirin or placebo. MEASUREMENTS AND MAIN RESULTS: Thirty-three of 367 subjects (9.0%) developed ARDS after randomization. Baseline ATL levels, total monocyte counts, intermediate monocyte counts, and monocyte-platelet aggregates were associated with the development of ARDS. Peripheral blood neutrophil count and monocyte-platelet aggregates significantly decreased over time. Of note, nine subjects developed ARDS after randomization yet before study drug initiation, including seven subjects assigned to aspirin treatment. Subjects without ARDS at the time of first dose demonstrated a lower incidence of ARDS with aspirin treatment. Compared with placebo, aspirin significantly decreased TXB2 and increased the ATL/TXB2 ratio. CONCLUSIONS: Biomarkers of intravascular monocyte activation in at-risk patients were associated with development of ARDS. The potential clinical benefit of early aspirin for prevention of ARDS remains uncertain. Together, results of the biochemical and immunological analyses provide a window into the early pathogenesis of human ARDS and represent potential vascular biomarkers of ARDS risk. Clinical trial registered with www.clinicaltrials.gov (NCT01504867).

Maresin 1 biosynthesis during platelet-neutrophil interactions is organ-protective.

Unregulated acute inflammation can lead to collateral tissue injury in vital organs, such as the lung during the acute respiratory distress syndrome. In response to tissue injury, circulating platelet-neutrophil aggregates form to augment neutrophil tissue entry. These early cellular events in acute inflammation are pivotal to timely resolution by mechanisms that remain to be elucidated. Here, we identified a previously undescribed biosynthetic route during human platelet-neutrophil interactions for the proresolving mediator maresin 1 (MaR1; 7R,14S-dihydroxy-docosa-4Z,8E,10E,12Z,16Z,19Z-hexaenoic acid). Docosahexaenoic acid was converted by platelet 12-lipoxygenase to 13S,14S-epoxy-maresin, which was further transformed by neutrophils to MaR1. In a murine model of acute respiratory distress syndrome, lipid mediator metabololipidomics uncovered MaR1 generation in vivo in a temporally regulated manner. Early MaR1 production was dependent on platelet-neutrophil interactions, and intravascular MaR1 was organ-protective, leading to decreased lung neutrophils, edema, tissue hypoxia, and prophlogistic mediators. Together, these findings identify a transcellular route for intravascular maresin 1 biosynthesis via platelet-neutrophil interactions that regulates the extent of lung inflammation.

Total healthcare cost savings through improved bipolar I disorder identification using the Rapid Mood Screener in patients diagnosed with major depressive disorder.

INTRODUCTION: Misdiagnosis of bipolar I disorder (BP-I) as major depressive disorder (MDD) leads to increased healthcare resource utilization and costs. The cost-effectiveness of the Rapid Mood Screener (RMS), a tool to identify BP-I in patients with depressive symptoms, was assessed in patients diagnosed with MDD presenting with depressive episodes. METHODS: A decision-tree model of a hypothetical cohort of 1000 patients in a US health plan was used to estimate the number of correct diagnoses and overall total, direct healthcare costs over a 3-year timeframe for RMS-screened versus unscreened patients. Model inputs included the prevalence of BP-I in patients diagnosed with MDD, RMS sensitivity/specificity, and the cost of misdiagnosing BP-I as MDD. RESULTS: Screening with the RMS resulted in 171, 159, and 143 additional correct BP-I or MDD diagnoses at Years 1, 2, and 3, respectively. Total healthcare plan cost savings were $1279 per patient in Year 1. Cumulative cost savings per patient for RMS screening versus no RMS screening were $2307 over 2 years and $3011 over 3 years. Scenario analyses showed that the RMS would remain cost-saving assuming a lower prevalence of BP-I (20% or 10%) versus the base case (24.3%). CONCLUSION: The RMS is a cost-effective tool to identify BP-I in patients who would otherwise be misdiagnosed with MDD. Screening with the RMS resulted in cost-savings over 3 years, with model results remaining robust even with lower prevalence of BP-I and reduced RMS sensitivity assumptions.