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INTRODUCTION: The phase 2 MANTA and MANTA-RAy studies were developed in consultation with global regulatory authorities to investigate potential impacts of filgotinib, a Janus kinase 1 preferential inhibitor, on semen parameters in men with active inflammatory diseases. Here we describe the methods and rationale for these studies. METHODS AND RATIONALE: The MANTA and MANTA-RAy studies included men (aged 21-65 years) with active inflammatory bowel disease (IBD) and rheumatic diseases, respectively. Participants had no history of reproductive health issues, and the following semen parameter values (≥ 5th percentile of World Health Organization reference values) at baseline: semen volume ≥ 1.5 mL, total sperm/ejaculate ≥ 39 million, sperm concentration ≥ 15 million/mL, sperm total motility ≥ 40% and normal sperm morphology ≥ 30%. Each trial included a 13-week, randomized, double-blind, placebo-controlled period (filgotinib 200 mg vs placebo, up to N = 125 per arm), for pooled analysis of the week-13 primary endpoint (proportion of participants with ≥ 50% decrease from baseline in sperm concentration). All semen assessments were based on two samples (≤ 14 days apart) to minimize effects of physiological variation; stringent standardization processes were applied across assessment sites. From week 13, MANTA and MANTA-RAy study designs deviated owing to disease-specific considerations. All subjects with a ≥ 50% decrease in sperm parameters continued the study in the monitoring phase until reversibility, or up to a maximum of 52 weeks, with standard of care as treatment. Overall conclusions from MANTA and MANTA-RAy will be based on the totality of the data, including secondary/exploratory measures (e.g. sperm motility/morphology, sex hormones, reversibility of any effects on semen parameters). CONCLUSIONS: Despite the complexities, the MANTA and MANTA-RAy studies form a robust trial programme that is the first large-scale, placebo-controlled evaluation of potential impacts of an advanced IBD and rheumatic disease therapy on semen parameters. TRIAL REGISTRATION: EudraCT numbers 2017-000402-38 and 2018-003933-14; ClinicalTrials.gov identifiers NCT03201445 and NCT03926195. ispartof: ADVANCES IN THERAPY vol:39 issue:7 pages:3403-3422 ispartof: location:United States status: published

Clinical trials in nonalcoholic steatohepatitis (NASH) require histologic scoring for assessment of inclusion criteria and endpoints. However, guidelines for scoring key features have led to variability in interpretation, impacting clinical trial outcomes. We developed an artificial intelligence (AI)-based measurement (AIM) tool for scoring NASH histology (AIM-NASH). AIM-NASH predictions for NASH Clinical Research Network (CRN) grades of necroinflammation and stages of fibrosis aligned with expert consensus scores and were reproducible. Continuous scores produced by AIM-NASH for key histological features of NASH correlated with mean pathologist scores and with noninvasive biomarkers and strongly predicted patient outcomes. In a retrospective analysis of the ATLAS trial, previously unmet pathological endpoints were met when scored by the AIM-NASH algorithm alone. Overall, these results suggest that AIM-NASH may assist pathologists in histologic review of NASH clinical trials, reducing inter-rater variability on trial outcomes and offering a more sensitive and reproducible measure of patient therapeutic response.

ObjectivesThe phase 2 MANTA and MANTA-RAy studies aimed to determine if the oral Janus kinase 1 preferential inhibitor filgotinib affects semen parameters and sex hormones in men with inflammatory diseases.MethodsMANTA (NCT03201445) and MANTA-RAy (NCT03926195) included men (21–65 years) with active inflammatory bowel disease (IBD) and rheumatic diseases (rheumatoid arthritis, spondyloarthritis or psoriatic arthritis), respectively. Eligible participants had semen parameters in the normal range per the WHO definition. In each study, participants were randomised 1:1 to receive once-daily, double-blind filgotinib 200 mg or placebo for 13 weeks for pooled analysis of the primary endpoint (proportion of participants with a ≥50% decrease from baseline in sperm concentration at week 13). Participants who met the primary endpoint were monitored over an additional 52 weeks for ‘reversibility’. Secondary endpoints included change from baseline to week 13 in: sperm concentration, total motility, normal morphology, total count and ejaculate volume. Sex hormones (luteinising hormone, follicle stimulating hormone, inhibin B and total testosterone) and reversibility were exploratory endpoints.ResultsAcross both studies, 631 patients were screened, and 248 were randomised to filgotinib 200 mg or placebo. Baseline demographics and characteristics were similar within indications between treatment groups. Numerically similar proportions of filgotinib-treated versus placebo-treated patients met the primary endpoint (8/120 (6.7%) vs 10/120 (8.3%)), Δ−1.7% (95% CI −9.3% to 5.8%)). There were no clinically relevant changes from baseline to week 13 in semen parameters or sex hormones, or patterns of reversibility between treatment groups. Filgotinib was well tolerated, with no new safety events.ConclusionsResults suggest that once daily filgotinib 200 mg for 13 weeks has no measurable impact on semen parameters or sex hormones in men with active IBD or inflammatory rheumatic diseases.

This study summarizes drug resistance analyses in 4 recent phase 2b trials of the respiratory syncytial virus (RSV) fusion inhibitor presatovir in naturally infected adults. Adult hematopoietic cell transplant (HCT) recipients, lung transplant recipients, or hospitalized patients with naturally acquired, laboratory-confirmed RSV infection were enrolled in 4 randomized, double-blind, placebo-controlled studies with study-specific presatovir dosing. Full-length RSV F sequences amplified from nasal swabs obtained at baseline and postbaseline were analyzed by population sequencing. Substitutions at RSV fusion inhibitor resistance-associated positions are reported. Genotypic analyses were performed on 233 presatovir-treated and 149 placebo-treated subjects. RSV F variant V127A was present in 8 subjects at baseline. Population sequencing detected treatment-emergent substitutions in 10/89 (11.2%) HCT recipients with upper and 6/29 (20.7%) with lower respiratory tract infection, 1/35 (2.9%) lung transplant recipients, and 1/80 (1.3%) hospitalized patients treated with presatovir; placebo-treated subjects had no emergent resistance-associated substitutions. Subjects with substitutions at resistance-associated positions had smaller decreases in viral load during treatment relative to those without, but they had similar clinical outcomes. Subject population type and dosing regimen may have influenced RSV resistance development during presatovir treatment. Subjects with genotypic resistance development had decreased virologic responses compared to those without genotypic resistance but had comparable clinical outcomes.

Filgotinib (FIL) is a potent and selective JAK1 inhibitor in clinical development for treatment of severe inflammatory diseases. A drug-drug interaction study to evaluate the potential effect of FIL on the pharmacokinetics (PK) of the oral contraceptive levonorgestrel (LEVO)/ethinyl estradiol (EE) was conducted. This was a phase 1, open-label, randomized, crossover study in healthy female subjects (N = 24). Subjects received a single dose of LEVO (150 μg)/EE (30 μg) alone (reference), or in combination with multiple-dose FIL (200 mg once daily for 15 days; test). Intensive PK sampling was conducted, and safety was assessed throughout the study. PK interactions were evaluated using 90% confidence intervals of the geometric least squares mean ratios of the test versus reference treatments. All 24 subjects enrolled completed study treatments. Coadministration of FIL with the oral contraceptive did not alter the PK of LEVO and EE; the 90% confidence intervals of the geometric least squares mean ratios were contained within bioequivalence bounds (80%-125%). Exposures of FIL were consistent with observed clinical exposure data. Study treatments were generally well tolerated. All adverse events were mild. Coadministration with FIL did not alter the PK of LEVO/EE, and hormonal contraceptives can serve as an effective contraception method for subjects on FIL treatment.

Background Presatovir significantly reduced nasal viral load, signs, and symptoms of respiratory syncytial virus (RSV) infection in a human challenge study. We evaluated presatovir in hematopoietic-cell transplant (HCT) recipients with RSV lower respiratory tract infection (LRTI). Methods Patients with confirmed RSV in upper and lower respiratory tract and new chest X-ray abnormalities were randomized (1:1), stratified by supplemental oxygen and ribavirin use, to receive oral presatovir 200 mg or placebo every 4 days for 5 doses. The primary endpoint was time-weighted average change in nasal RSV viral load through day 9. Secondary endpoints included supplemental oxygen-free days, incident respiratory failure requiring mechanical ventilation, and all-cause mortality. Results From January 31, 2015, to March 20, 2017, 60 patients from 17 centers were randomized (31 presatovir, 29 placebo); 59 received study treatment (50 allogeneic, 9 autologous HCT). In the efficacy population (29 presatovir, 28 placebo), presatovir treatment did not significantly reduce time-weighted average change in viral load (−1.12 vs −1.09 log10 copies/mL; treatment difference −0.02 log10 copies/mL, 95% confidence interval: −.62, .57; P = .94), median supplemental oxygen-free days (26 vs 28 days, P = .84), incident respiratory failure (10.3 vs 10.7%, P = .98), or all-cause mortality (0 vs 7.1%, P = .19) versus placebo. Adverse events were similar between arms (presatovir 80%, placebo 79%). Resistance-associated substitutions in RSV fusion protein emerged in 6/29 presatovir-treated patients. Conclusions Presatovir treatment was well tolerated in HCT patients with RSV LRTI but did not improve virologic or clinical outcomes versus placebo. Clinical Trials Registration www.clinicaltrials.gov, NCT02254421; EudraCT, #2014-002475-29, Presatovir treatment was safe but did not improve viral or clinical outcomes in hematopoietic-cell transplant recipients with respiratory syncytial virus lower respiratory tract infection. Future studies in this population should incorporate novel methods to evaluate virus-related injury and treatment effects.

Background Clinically meaningful endpoints for respiratory syncytial virus (RSV) treatment trials are lacking for hematopoietic cell transplant (HCT) recipients. We evaluated supplemental oxygen use among HCT recipients with RSV infection. Methods Subjects were grouped according to the presence of upper respiratory tract infection (URTI) without lower respiratory tract infection (LRTI), URTI progressing to LRTI, and LRTI at presentation. LRTI was defined as a positive lower respiratory tract sample with or without radiographic abnormality (defined as proven or probable LRTI, respectively) or a positive upper respiratory tract sample with radiographic abnormality (possible LRTI). Supplemental oxygen-free days were defined as any day while alive after diagnosis of RSV infection during which ≤2 L of supplemental oxygen per minute was received. Results Among 230 patients, supplemental oxygen use by day 28 after the first diagnosis of RSV infection was lowest in patients presenting with URTI (31 of 197 [16%]). Supplemental oxygen use was lower in patients with possible LRTI (12 of 45 [27%]) than in those with proven/probable LRTI (29 of 42 [69%]). Patients presenting with proven/probable LRTI had a median of 16 fewer supplemental oxygen-free days than those presenting with URTI (P < .0001). Death only occurred among patients with proven/probable LRTI (11 of 42 [26%]). Conclusions Confirmation of RSV infection in the lower respiratory tract provides prognostic information that may help prioritize therapies. Supplemental oxygen-free days as a clinical endpoint may allow smaller sample sizes for trials evaluating RSV antivirals.

Background Hematopoietic-cell transplant (HCT) recipients are at risk for severe respiratory syncytial virus (RSV) infection. We evaluated the RSV fusion inhibitor presatovir in a randomized, double-blind, Phase II trial in HCT recipients with RSV upper respiratory tract infections. Methods Patients were stratified by lymphopenia (, Presatovir treatment was safe but did not improve viral or clinical outcomes in hematopoietic-cell transplant recipients with respiratory syncytial virus upper respiratory tract infections. Exploratory analyses suggest clinical benefit in hematopoietic-cell transplant patients with lymphopenia at presentation.

Background Presatovir is an oral respiratory syncytial virus (RSV) fusion inhibitor in development for the treatment of RSV infection. Results from a healthy volunteer challenge study show that presatovir significantly reduced RSV viral load and clinical signs and symptoms. Here we present combined resistance analyses from 4 phase 2b studies in naturally RSV-infected adults. Methods RSV RNA was isolated from nasal swabs collected at baseline and postbaseline in studies GS-US-218-0108, GS-US-218–1502, GS-US-218–1227, and GS-US-218–1797. Full-length RSV fusion (F) gene was PCR amplified and population sequencing was performed. Results Of 233 presatovir-treated adults in the efficacy analyses, post-baseline resistance-associated substitutions were detected in 18 (7.7%) subjects. Frequencies of resistance development varied by study (Table 1). Resistance substitutions known to confer high-level (>200 fold) reduced susceptibility to presatovir detected in >1 subject were: T400I (n = 6), S398L (n = 3), L141F (n = 2), and F140I (n = 2) in F. Subjects with resistant virus had less viral load reduction than presatovir-treated subjects without resistant virus. Resistance development did not impact clinical outcomes. In study GS-US-218-0108, subjects with lymphopenia ( Conclusion Presatovir treatment resulted in varying rates of resistance development across 4 phase 2b studies. Resistance development impacted virologic response without affecting clinical outcomes. Differences among study populations and dosing regimens may have influenced rates of resistance development. Disclosures D. Porter, Gilead Sciences, Inc.: Employee and Shareholder, Salary and stocks. Y. Guo, Gilead Sciences, Inc.: Employee and Shareholder, Salary and stocks. J. Perry, Gilead Sciences, Inc.: Employee and Shareholder, Salary and stocks. D. Gossage, Gilead Sciences, Inc.: Employee and Shareholder, Salary and stocks. T. Watkins, Gilead Sciences, Inc.: Employee and Shareholder, Salary and stocks. J. Chien, Gilead Sciences, Inc.: Employee and Shareholder, Salary and stocks. R. Jordan, Gilead Sciences, Inc.: Employee and Shareholder, Salary and stocks.

BACKGROUND Methods used to produce platelet (PLT) components, pooling of PLT-rich plasma (PRP-PLT) and apheresis (AP-PLT), may variably contribute to the pathogenesis and severity of idiopathic pneumonia syndrome (IPS). STUDY DESIGN AND METHODS We performed a retrospective cohort study of 906 allogeneic hematopoietic cell transplant recipients to examine associations between PLT product type and risks of developing IPS and dying after IPS onset. Proportional hazards models included separate terms for the sum of all PLT transfusions and the sum of PRP-PLT units received in the 3 or 7 days before IPS onset. Similarly constructed models analyzed the outcome of time to death after IPS onset. All analyses were adjusted for known IPS risk factors. RESULTS Patients received a median of three PRP-PLT transfusions (interquartile range [IQR], 0-6) and five AP-PLT transfusions (IQR, 1-13) while at risk for IPS. Seventy-five patients (8%) developed IPS by Posttransplant Day 120. The proportion of PRP-PLT transfusions was not associated with risk of developing IPS (3-day hazard ratio [HR] 0.98, 95% CI 0.74-1.29, p = 0.86; 7-day HR 1.00, 95% CI 0.86-1.15, p = 0.95) or dying after IPS onset (3-day HR 0.99, 95% CI 0.75-1.31, p = 0.97; 7-day HR 0.98, 95% CI 0.78-1.12, p = 0.47). CONCLUSION The association between PLT transfusions and risk of developing IPS or dying after IPS onset does not differ according to PLT product type. Further research is required to identify potentially modifiable steps in PLT component production that contribute to IPS.

Objective Acute traumatic coagulopathy (ATC) is associated with adverse outcomes including death. Previous studies examining ATC's relationship with mortality are limited by inconsistent criteria for syndrome diagnosis, inadequate control of confounding and single-center designs. In this study, we validated the admission international normalized ratio (INR) as an independent risk factor for death and other adverse outcomes after trauma and compared two common INR-based definitions for ATC.

In the Fluid and Catheter Treatment Trial (FACTT) of the National Institutes of Health Acute Respiratory Distress Syndrome Network, a conservative fluid protocol (FACTT Conservative) resulted in a lower cumulative fluid balance and better outcomes than a liberal fluid protocol (FACTT Liberal). Subsequent Acute Respiratory Distress Syndrome Network studies used a simplified conservative fluid protocol (FACTT Lite). The objective of this study was to compare the performance of FACTT Lite, FACTT Conservative, and FACTT Liberal protocols.Retrospective comparison of FACTT Lite, FACTT Conservative, and FACTT Liberal. Primary outcome was cumulative fluid balance over 7 days. Secondary outcomes were 60-day adjusted mortality and ventilator-free days through day 28. Safety outcomes were prevalence of acute kidney injury and new shock.ICUs of Acute Respiratory Distress Syndrome Network participating hospitals.Five hundred three subjects managed with FACTT Conservative, 497 subjects managed with FACTT Liberal, and 1,124 subjects managed with FACTT Lite.Fluid management by protocol.Cumulative fluid balance was 1,918 ± 323 mL in FACTT Lite, -136 ± 491 mL in FACTT Conservative, and 6,992 ± 502 mL in FACTT Liberal (p0.001). Mortality was not different between groups (24% in FACTT Lite, 25% in FACTT Conservative and Liberal, p = 0.84). Ventilator-free days in FACTT Lite (14.9 ± 0.3) were equivalent to FACTT Conservative (14.6 ± 0.5) (p = 0.61) and greater than in FACTT Liberal (12.1 ± 0.5, p0.001 vs Lite). Acute kidney injury prevalence was 58% in FACTT Lite and 57% in FACTT Conservative (p = 0.72). Prevalence of new shock in FACTT Lite (9%) was lower than in FACTT Conservative (13%) (p = 0.007 vs Lite) and similar to FACTT Liberal (11%) (p = 0.18 vs Lite).FACTT Lite had a greater cumulative fluid balance than FACTT Conservative but had equivalent clinical and safety outcomes. FACTT Lite is an alternative to FACTT Conservative for fluid management in Acute Respiratory Distress Syndrome.

BACKGROUND Blood transfusions are common during hematopoietic stem cell transplantation (HSCT) and may contribute to lung injury.

EDITORIALS Association of sleep apnea and snoring with incident atrial fibrillation in the multi-ethnic study of atherosclerosis. Am J Epidemiol 2015; 14. Somers VK, White DP, Amin R, Abraham WT, Costa F, Culebras A, Daniels S, Floras JS, Hunt CE, Olson LJ, et al. Sleep apnea and cardiovascular disease: an American Heart Association/American College of Cardiology Foundation Scientific Statement from the American Heart Association Council for High Blood Pressure Research Professional Education Committee, Council on Clinical Cardiology, Stroke Council, and Council on Cardiovascular Nursing. J Am Coll Cardiol 2008;52:686–717. 15. Monahan K, Storfer-Isser A, Mehra R, Shahar E, Mittleman M, Rottman J, Punjabi N, Sanders M, Quan SF, Resnick H, et al. Triggering of nocturnal arrhythmias by sleep-disordered breathing events. J Am Coll Cardiol 2009;54:1797–1804. 16. Leung RS, Huber MA, Rogge T, Maimon N, Chiu KL, Bradley TD. Association between atrial fibrillation and central sleep apnea. Sleep 17. Mehra R, Stone KL, Varosy PD, Hoffman AR, Marcus GM, Blackwell T, Ibrahim OA, Salem R, Redline S. Nocturnal Arrhythmias across a spectrum of obstructive and central sleep-disordered breathing in older men: outcomes of sleep disorders in older men (MrOS sleep) study. Arch Intern Med 2009;169:1147–1155. 18. Javaheri S. Sleep disorders in systolic heart failure: a prospective study of 100 male patients. The final report. Int J Cardiol 2006;106: 19. McMillan A, Bratton DJ, Faria R, Laskawiec-Szkonter M, Griffin S, Davies RJ, Nunn AJ, Stradling JR, Riha RL, Morrell MJ; PREDICT Investigators. Continuous positive airway pressure in older people with obstructive sleep apnoea syndrome (PREDICT): a 12-month, multicentre, randomised trial. Lancet Respir Med 2014; 20. McMillan A, Bratton DJ, Faria R, Laskawiec-Szkonter M, Griffin S, Davies RJ, Nunn AJ, Stradling JR, Riha RL, Morrell MJ. A multicentre randomised controlled trial and economic evaluation of continuous positive airway pressure for the treatment of obstructive sleep apnoea syndrome in older people: PREDICT. Health Technol Assess Copyright © 2016 by the American Thoracic Society BEAR Cage: Mentoring through Engagement The Way is in training. Become acquainted with every art. Know the way of all Professions. —Miyamoto Musashi, A Book of Five Rings As health sciences is broadening its focus to include transforming new knowledge into various health care system improvements, establishing a career as a scientific investigator is increasingly a challenging process. To achieve success in this environment, young investigators need to integrate knowledge from many different disciplines. They also require understanding of both the art and science of research translation, as it enhances scientific creativity and efficient strategic thinking, leading to real-world innovations (1–3). Furthermore, this knowledge will better position young investigators for careers and leadership positions across university, industry, nonprofit, and government settings, including regulatory agencies such as the U.S. Food and Drug Administration and the European Medicines Agency. And it will improve their ability to compete for ever-tightening resources in these environments. Going forward, we must make every effort to find new venues to enhance and further develop this art and wisdom as a complementary discipline to the more traditional research skills (4–7). The Solution The American Thoracic Society (ATS) needs to further enhance its leadership position in educating early-stage researchers by preparing them for these challenging translational careers. In new ways, we, as active ATS members, need to show junior faculty Supported by the Intramural Research Program, National Institutes of Health, NHLBI (J.M.). Originally Published in Press as DOI: 10.1164/rccm.201602-0297ED on February 24, 2016 that they have the support of their professional organization and that continuing guidance will be available as their careers develop. Although already enhancing the careers of its junior investigators on many levels, the ATS should continue to evolve by being recognized as an exemplary professional organization for facilitating translational research training and career development. Our goal, however, is not only to train investigators but also to convey the excitement of translational science: learning how to adapt ideas to the real world of improving health, be it in health policy or clinical care. The ATS, with its diverse membership and expertise, is uniquely positioned to achieve this vision through coordinated activities, including learning opportunities and mentoring of early-career investigators. To these ends, the ATS Drug, Device, Discovery, and Development (Quad D) Committee was given the assignment to promote translational science by training and inspiring young investigators in respiratory medicine, critical care, and sleep disorders through providing an infrastructure for teaching and mentorship. It began as an ATS “Academy of Translational Sciences” (ATS 2 ), dedicated to filling in learning gaps and providing mentoring for early career investigators, who will be the future of translational science. The Quad D Committee considered ways to maximize impact and leverage resources for ATS members. A survey of committee members indicated that components of a Translational Core Curriculum, some developed, in part, to facilitate the Clinical and Translational Science Award program, are already available. Duplication of these training modules, many available online, was deemed unnecessary and would not contribute meaningfully to career advancement of ATS members, especially junior faculty. We chose to follow complementary routes to achieve these goals, in part through activities at or around the ATS International American Journal of Respiratory and Critical Care Medicine Volume 193 Number 7 | April 1 2016

To determine early clinical predictors of acute respiratory distress syndrome after major traumatic injury and characterize the performance of this acute respiratory distress syndrome prediction model, and two previously published acute respiratory distress syndrome prediction models, in an independent cohort of severely injured patients.Prospective cohort study.University-affiliated level I trauma center in Seattle, WA, and nine hospitals participating in the Inflammation and Host Response to Injury Consortium.Model derivation utilized data from 224 patients participating in a randomized controlled trial. All models were validated in an independent cohort of 1,762 trauma patients.Variables strongly associated with acute respiratory distress syndrome in bivariate analysis (p.01) were entered into a multiple logistic regression equation to generate an acute respiratory distress syndrome predictive model. We evaluated the performance of all models using the area under the receiver operator characteristic curve. Acute respiratory distress syndrome occurred in 79 subjects (35%) belonging to the development cohort and in 423 subjects (24%) from the validation cohort. Multivariable predictors of acute respiratory distress syndrome after trauma included subject age, Acute Physiology and Chronic Health Evaluation II Score, injury severity score, and the presence of blunt traumatic injury, pulmonary contusion, massive transfusion, and flail chest injury (area under the receiver operator characteristic curve 0.79 [95% confidence interval 0.73, 0.85]). Validation of the prediction model resulted in an area under the receiver operator characteristic curve of 0.71 (95% confidence interval 0.68, 0.74). Our model's performance in the validation cohort was superior to that of two other published acute respiratory distress syndrome prediction models (0.65 [95% confidence interval 0.63, 0.68] and 0.66 [95% confidence interval 0.64, 0.69], p.01 for all comparisons).Using routinely available clinical data, our prediction model identifies patients at high risk for acute respiratory distress syndrome early after severe traumatic injury. This predictive model could facilitate enrollment of subjects into future clinical trials designed to prevent this serious complication.

Anemia is common in the intensive care unit, and may be associated with adverse consequences. However, current options for correcting anemia are not without problems and presently lack convincing efficacy for improving survival in critically ill patients. In this article we review normal red blood cell physiology; etiologies of anemia in the intensive care unit; its association with adverse outcomes; and the risks, benefits, and efficacy of various management strategies, including blood transfusion, erythropoietin, blood substitutes, iron therapy, and minimization of diagnostic phlebotomy.

Administration of eicosapentaenoic acid and docosahexanoic acid, omega-3 fatty acids in fish oil, has been associated with improved patient outcomes in acute lung injury when studied in a commercial enteral formula. However, fish oil has not been tested independently in acute lung injury. We therefore sought to determine whether enteral fish oil alone would reduce pulmonary and systemic inflammation in patients with acute lung injury.Phase II randomized controlled trial.Five North American medical centers.Mechanically ventilated patients with acute lung injury ≥18 yrs of age.Subjects were randomized to receive enteral fish oil (9.75 g eicosapentaenoic acid and 6.75 g docosahexanoic acid daily) or saline placebo for up to 14 days.Bronchoalveolar lavage fluid and blood were collected at baseline (day 0), day 4 ± 1, and day 8 ± 1. The primary end point was bronchoalveolar lavage fluid interleukin-8 levels. Forty-one participants received fish oil and 49 received placebo. Enteral fish oil administration was associated with increased serum eicosapentaenoic acid concentration (p.0001). However, there was no significant difference in the change in bronchoalveolar lavage fluid interleukin-8 from baseline to day 4 (p = .37) or day 8 (p = .55) between treatment arms. There were no appreciable improvements in other bronchoalveolar lavage fluid or plasma biomarkers in the fish oil group compared with the control group. Similarly, organ failure score, ventilator-free days, intensive care unit-free days, and 60-day mortality did not differ between the groups.Fish oil did not reduce biomarkers of pulmonary or systemic inflammation in patients with acute lung injury, and the results do not support the conduct of a larger clinical trial in this population with this agent. This experimental approach is feasible for proof-of-concept studies evaluating new treatments for acute lung injury.

Research that applies an unreliable definition for transfusion-related acute lung injury (TRALI) may draw false conclusions about its risk factors and biology. The effectiveness of preventive strategies may decrease as a consequence. However, the reliability of the consensus TRALI definition is unknown.To prospectively study the effect of applying two plausible definitions of acute respiratory distress syndrome onset time on TRALI epidemiology.We studied 316 adults admitted to the intensive care unit and transfused red blood cells within 24 hours of blunt trauma. We identified patients with acute respiratory distress syndrome, and defined acute respiratory distress syndrome onset time two ways: (1) the time at which the first radiographic or oxygenation criterion was met, and (2) the time both criteria were met. We categorized two corresponding groups of TRALI cases transfused in the 6 hours before acute respiratory distress syndrome onset. We used Cohen's kappa to measure agreement between the TRALI cases and implicated blood components identified by the two acute respiratory distress syndrome onset time definitions. In a nested case-control study, we examined potential risk factors for each group of TRALI cases, including demographics, injury severity, and characteristics of blood components transfused in the 6 hours before acute respiratory distress syndrome onset.Forty-two of 113 patients with acute respiratory distress syndrome were TRALI cases per the first acute respiratory distress syndrome onset time definition and 63 per the second definition. There was slight agreement between the two groups of TRALI cases (κ = 0.16; 95% confidence interval, -0.01 to 0.33) and between the implicated blood components (κ = 0.15, 95% confidence interval, 0.11-0.20). Age, Injury Severity Score, high plasma-volume components, and transfused plasma volume were risk factors for TRALI when applying the second acute respiratory distress syndrome onset time definition but not when applying the first definition.The epidemiology of TRALI varies when applying two plausible definitions of acute respiratory distress syndrome onset time to severely injured trauma patients. A TRALI definition that standardizes acute respiratory distress syndrome onset time might improve reliability and align efforts to understand epidemiology, biology, and prevention.

Acute traumatic coagulopathy is associated with adverse outcomes including death. Previous studies examining acute traumatic coagulopathy's relation with mortality are limited by inconsistent criteria for syndrome diagnosis, inadequate control of confounding, and single-center designs. In this study, we validated the admission international normalized ratio as an independent risk factor for death and other adverse outcomes after trauma and compared two common international normalized ratio-based definitions for acute traumatic coagulopathy.Multicenter prospective observational study.Nine level I trauma centers in the United States.A total of 1,031 blunt trauma patients with hemorrhagic shock.None.International normalized ratio exhibited a positive adjusted association with all-cause in-hospital mortality, hemorrhagic shock-associated in-hospital mortality, venous thromboembolism, and multiple organ failure. Acute traumatic coagulopathy affected 50% of subjects if defined as an international normalized ratio greater than 1.2 and 21% of subjects if defined by international normalized ratio greater than 1.5. After adjustment for potential confounders, acute traumatic coagulopathy defined as an international normalized ratio greater than 1.5 was significantly associated with all-cause death (odds ratio [OR], 1.88; p0.001), hemorrhagic shock-associated death (OR, 2.44; p = 0.001), venous thromboembolism (OR, 1.73; p0.001), and multiple organ failure (OR, 1.38; p = 0.02). Acute traumatic coagulopathy defined as an international normalized ratio greater than 1.2 was not associated with an increased risk for the studied outcomes.Elevated international normalized ratio on hospital admission is a risk factor for mortality and morbidity after severe trauma. Our results confirm this association in a prospectively assembled multicenter cohort of severely injured patients. Defining acute traumatic coagulopathy by using an international normalized ratio greater than 1.5 but not an international normalized ratio greater than 1.2 identified a clinically meaningful subset of trauma patients who, adjusting for confounding factors, experienced more adverse outcomes. Targeting future therapies for acute traumatic coagulopathy to patients with an international normalized ratio greater than 1.5 may yield greater returns than using a lower international normalized ratio threshold.

Although the prognostic information and treatment approach for increases in low-density lipoprotein (LDL) cholesterol have been advanced significantly over the last 10 years (with continuing controversy over baseline trigger points for treatment and degree of required LDL-cholesterol lowering), the management of abnormal triglyceride (TG) or high-density lipoprotein (HDL) cholesterol values to achieve cardiovascular benefits remains poorly defined. The recently published Adult Treatment Panel (ATP) III guidelines, expertly crafted based on current evidence and economic considerations, provide second-tier strategies for increased TGs (200 mg/dl used as the trigger point and non-HDL cholesterol as a complex target) and suggest the use of therapeutic lifestyle changes and pharmaceutical agents when HDL cholesterol is 40 mg/dl. For today’s practice, we believe the current data support a more explicit and perhaps more aggressive set of guidelines for HDL cholesterol and TG therapy, as well as the common coexistence of both. Furthermore, studies that will augment our understanding of hypertriglyceridemic treatment must be initiated to allow for the presentation of improved strategic plans related to HDL cholesterol and TGs within ATP IV.

Red blood cell (RBC) transfusion is linked to poor functional recovery after surgery and trauma. To investigate one potential mechanism, we examined the association between RBC transfusion and muscle strength in a cohort of critically ill patients.We performed a secondary analysis of 124 critically ill, mechanically ventilated patients enrolled in 2 prospective cohort studies where muscle strength testing was performed at a median of 12 days after mechanical ventilation onset. We examined the association between RBC transfusion and dynamometry handgrip strength using multivariable linear regression, adjusting for study site, age, sex, Acute Physiology and Chronic Health Evaluation, Sequential Organ Failure Assessment score, days from hospital admission to examination, and steroid use. Secondary outcomes included systematic manual muscle strength and intensive care unit-acquired paresis.Among 124 subjects, 73 (59%) received RBC transfusion in the 30 days before examination. In adjusted analyses, RBC transfusion was significantly associated with weaker handgrip (adjusted mean difference, -9.9 kg; 95% confidence interval, -16.6 to -3.2; P.01) and proximal manual muscle strength (adjusted mean difference in Medical Research Council score, -0.5; 95% confidence interval, -0.7 to -0.2; P.01) but not intensive care unit-acquired paresis.Red blood cell transfusion was associated with decreased muscle strength in this cohort of critically ill patients after adjusting for illness severity and organ dysfunction. Further studies are needed to validate these results and probe mechanisms.

Amiodarone has been implicated as a risk factor for acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) when used in the hospital. This study aims to estimate whether prehospital amiodarone also increases the risk of ALI/ARDS.Adult patients admitted to 22 centers with at least 1 risk factor for developing ALI were recruited. In a secondary analysis of this cohort, the prehospital use of amiodarone was documented on admission, and the patients followed for the primary outcome of ALI and secondary outcomes of ARDS, the need for invasive ventilation, and mortality. Dose/duration of amiodarone therapy was not available. Propensity matching was performed to account for imbalances in being assigned to amiodarone. The adjusted risk for ALI/ARDS was then estimated from a conditional logistic regression model of this propensity-matched set.Forty of 5584 patients were on amiodarone at the time of hospitalization; of those, 6 developed ALI, with 5 progressing to ARDS. In comparison, 371 patients not on amiodarone developed ALI, with 224 having ARDS. After propensity score matching, the prehospital use of amiodarone was not statistically associated with an increased risk for all ALI (odds ratio [OR], 1.8; 95% confidence interval [CI], 0.7-5.0; P = .25), invasive ventilation (OR, 1.9; 95% CI, 1.0-3.6; P = .059), or in-hospital mortality (OR, 1.2; 95% CI, 0.5-2.9; P = .75); but its use appeared to significantly increase the risk for ARDS (OR 3.8; 95% CI, 1.1-13.1; P = .036).Prehospital use of amiodarone may independently increase the risk for ARDS in patients who have at least 1 predisposing condition for ALI.

Introduction: In this study, we sought to determine the association between red blood cell (RBC) transfusion and outcomes in patients with acute lung injury (ALI), sepsis and shock. Methods: We performed a secondary analysis of new-onset ALI patients enrolled in the Acute Respiratory Distress Syndrome Network Fluid and Catheter Treatment Trial (2000 to 2005) who had a documented ALI risk factor of sepsis or pneumonia and met shock criteria (mean arterial pressure (MAP) < 60 mmHg or vasopressor use) within 24 hours of randomization. Using multivariable logistic regression, we examined the association between RBC transfusion and 28-day mortality after adjustment for age, sex, race, randomization arm and Acute Physiology and Chronic Health Evaluation III score. Secondary end points included 90-day mortality and ventilator-free days (VFDs). Finally, we examined these end points among the subset of subjects meeting prespecified transfusion criteria defined by five simultaneous indicators: hemoglobin < 10.2 g/dL, central or mixed venous oxygen saturation < 70%, central venous pressure ≥ 8 mmHg, MAP ≥ 65 mmHg, and vasopressor use. Results: We identified 285 subjects with ALI, sepsis, shock and transfusion data. Of these, 85 also met the above prespecified transfusion criteria. Fifty-three (19%) of the two hundred eighty-five subjects with shock and twenty (24%) of the subset meeting the transfusion criteria received RBC transfusion within twenty-four hours of randomization. We found no independent association between RBC transfusion and 28-day mortality (odds ratio = 1.49, 95% CI (95% confidence interval) = 0.77 to 2.90; P = 0.23) or VFDs (mean difference = -0.35, 95% CI = -4.03 to 3.32; P = 0.85). Likewise, 90-day mortality and VFDs did not differ by transfusion status. Among the subset of patients meeting the transfusion criteria, we found no independent association between transfusion and mortality or VFDs. Conclusions: In patients with new-onset ALI, sepsis and shock, we found no independent association between RBC transfusion and mortality or VFDs. The physiological criteria did not identify patients more likely to be transfused or to benefit from transfusion.

Rationale: Accurate, early identification of patients at risk for developing acute lung injury (ALI) provides the opportunity to test and implement secondary prevention strategies. Objectives: To determine the frequency and outcome of ALI development in patients at risk and validate a lung injury prediction score (LIPS). Methods: In this prospective multicenter observational cohort study, predisposing conditions and risk modifiers predictive of ALI development were identified from routine clinical data available during initial evaluation. The discrimination of the model was assessed with area under receiver operating curve (AUC). The risk of death from ALI was determined after adjustment for severity of illness and predisposing conditions. Measurements and Main Results: Twenty-two hospitals enrolled 5,584 patients at risk All developed a median of 2 (interquartile range 1-4) days after initial evaluation in 377 (6.8%; 148 ALI-only, 229 adult respiratory distress syndrome) patients. The frequency of ALI varied according to predisposing conditions (from 3% in pancreatitis to 26% after smoke inhalation). LIPS discriminated patients who developed ALI from those who did not with an AUC of 0.80(95% confidence interval, 0.78-0.82). When adjusted for severity of illness and predisposing conditions, development of ALI increased the risk of in-hospital death (odds ratio, 4.1; 95% confidence interval, 2.9-5.7). Conclusions: ALI occurrence varies according to predisposing conditions and carries an independently poor prognosis. Using routinely available clinical data, LIPS identifies patients at high risk for ALI early in the course of their illness. This model will alert clinicians about the risk of ALI and facilitate testing and implementation of ALI prevention strategies. United States Department of Health & Human Services National Institutes of Health (NIH) - USA HL78743-01A1, 1 KL2 RR024151 Mayo Clinic Critical Care Research Committee Sanofi-Aventis Pfizer University of Missouri Vital Therapies Maquet Inc. Eli Lilly Artisan Pharma Allen Grice Ammons American Lung Association American College of Surgeons Vapotherm in industry United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Center for Advancing Translational Sciences (NCATS) United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Center for Research Resources (NCRR) - KL2RR024151 United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Heart Lung & Blood Institute (NHLBI) - K23HL087934 Walker

Early identification of nontrauma patients in need of critical care services in the emergency setting may improve triage decisions and facilitate regionalization of critical care.To determine the out-of-hospital clinical predictors of critical illness and to characterize the performance of a simple score for out-of-hospital prediction of development of critical illness during hospitalization.Population-based cohort study of an emergency medical services (EMS) system in greater King County, Washington (excluding metropolitan Seattle), that transports to 16 receiving facilities.Nontrauma, non-cardiac arrest adult patients transported to a hospital by King County EMS from 2002 through 2006. Eligible records with complete data (N = 144,913) were linked to hospital discharge data and randomly split into development (n = 87,266 [60%]) and validation (n = 57,647 [40%]) cohorts.Development of critical illness, defined as severe sepsis, delivery of mechanical ventilation, or death during hospitalization.Critical illness occurred during hospitalization in 5% of the development (n = 4835) and validation (n = 3121) cohorts. Multivariable predictors of critical illness included older age, lower systolic blood pressure, abnormal respiratory rate, lower Glasgow Coma Scale score, lower pulse oximetry, and nursing home residence during out-of-hospital care (P.01 for all). When applying a summary critical illness prediction score to the validation cohort (range, 0-8), the area under the receiver operating characteristic curve was 0.77 (95% confidence interval [CI], 0.76-0.78), with satisfactory calibration slope (1.0). Using a score threshold of 4 or higher, sensitivity was 0.22 (95% CI, 0.20-0.23), specificity was 0.98 (95% CI, 0.98-0.98), positive likelihood ratio was 9.8 (95% CI, 8.9-10.6), and negative likelihood ratio was 0.80 (95% CI, 0.79- 0.82). A threshold of 1 or greater for critical illness improved sensitivity (0.98; 95% CI, 0.97-0.98) but reduced specificity (0.17; 95% CI, 0.17-0.17).In a population-based cohort, the score on a prediction rule using out-of-hospital factors was significantly associated with the development of critical illness during hospitalization. This score requires external validation in an independent population.

Little is known about the participation of racial/ethnic minorities, women, and the elderly into critical care clinical trials. We sought to characterize the representation of racial and ethnic minorities, women, and older patients in clinical trials of patients with acute lung injury and to determine the reasons for nonenrollment.We performed a cross-sectional analysis of pooled screening logs from 44 academic hospitals participating in three multicentered, randomized, controlled trials conducted by the Acute Respiratory Distress Syndrome Network from 1996 to 2005.None.We calculated odds ratios of enrollment for age, sex, racial groups, and the odds ratio for the presence of each exclusion criterion by age, sex, and race adjusted for demographics, acute lung injury risk factor, study, and study center. A total of 10.4% of 17,459 screened patients with acute lung injury were enrolled. The median (range) enrollment by center was 15% (2% to 88%). Older patients of both sexes were less likely to be enrolled, but older women were more likely to be enrolled than older men. The adjusted odds ratio (95% confidence interval) for enrollment among menor =75 yrs of age was 0.59 (0.45 to 0.77) and for womenor =75 yrs of age was 0.45 (0.32 to 0.62) compared with men35 yrs of age. There were no differences in the likelihood of enrollment among all racial/ethnic groups. Older patients and men were less likely to be enrolled because of medical comorbidity. Among all patients who were not enrolled, black patients and their families refused participation more often than white patients.Older patients are less likely to be enrolled in acute lung injury clinical trials. There is no evidence that women or racial/ethnic minorities are underrepresented in acute lung injury clinical trials.

Background Despite widespread guidelines recommending the use of lung-protective ventilation (LPV) in patients with acute lung injury (ALI), many patients do not receive this lifesaving therapy. We sought to estimate the incremental clinical and economic outcomes associated with LPV and determined the maximum cost of a hypothetical intervention to improve adherence with LPV that remained cost-effective. Methods Adopting a societal perspective, we developed a theoretical decision model to determine the cost-effectiveness of LPV compared to non-LPV care. Model inputs were derived from the literature and a large population-based cohort of patients with ALI. Cost-effectiveness was determined as the cost per life saved and the cost per quality-adjusted life-years (QALYs) gained. Results Application of LPV resulted in an increase in QALYs gained by 15% (4.21 years for non-LPV vs 4.83 years for LPV), and an increase in lifetime costs of $7,233 per patient with ALI ($99,588 for non-LPV vs $106,821 for LPV). The incremental cost-effectiveness ratios for LPV were $22,566 per life saved at hospital discharge and $11,690 per QALY gained. The maximum, cost-effective, per patient investment in a hypothetical program to improve LPV adherence from 50 to 90% was $9,482. Results were robust to a wide range of economic and patient parameter assumptions. Conclusions Even a costly intervention to improve adherence with low-tidal volume ventilation in patients with ALI reduces death and is cost-effective by current societal standards.

Objective: The requirement for a blood transfusion after trauma is associated with an increased risk of acute lung injury. Residual leukocytes contaminating red cells are potential mediators of this syndrome. The goal of this trial was to test our hypothesis that prestorage leukoreduction of blood would reduce rates of posttraumatic lung injury. Design: Double blind, randomized, controlled clinical trial. Setting: University-affiliated level I trauma center in King County, Seattle, WA. Patients: Two hundred sixty-eight injured patients requiring red blood cell transfusion within 24 hrs of injury. Interventions: Prestorage leukoreduced vs. standard allogeneic blood transfusions. Measurements and Main Results: We compared the incidence of acute lung injury and acute respiratory distress syndrome at early (≤72 hrs) and late (>72 hrs) time points after injury. In a subset, we compared plasma levels of surfactant protein-D and von Willebrand factor antigen between intervention arms. Rates of acute lung injury (relative risk [RR] 1.06, 95% confidence interval [Cl].69-1.640) and acute respiratory distress syndrome (RR.96, 95% Cl 0.48-1.91) were not statistically different between intervention arms early after injury. Similarly, no statistically significant effect of leukoreduced transfusion on rates of acute lung injury (RR.88, 95% Cl.54-1.44) or acute respiratory distress syndrome (RR.95, 95% Cl.58-1.57) was observed to occur late after injury. There was no significant difference in the number of ventilator-free days or in other ventilator parameters between intervention arms. No statistically significant effect of leukoreduced blood on plasma levels of surfactant protein-D or von Willebrand factor antigen was identified. Conclusions: Prestorage leukoreduction had no effect on the incidence or timing of lung injury or on plasma measures of systemic alveolar and endothelial inflammation in a population of trauma patients requiring transfusion. The relationship between transfusion and lung injury is not obviously explained by mechanistic pathways involving the presence of transfused leukocytes.

Noninfectious conditions are now the major pulmonary causes of morbidity and mortality after hematopoietic stem cell transplantation (HSCT). The idiopathic pneumonia syndrome (IPS) remains one of the more common and serious pulmonary complications within months after transplantation. Epidemiological data suggest that, although graft versus host disease (GVHD) reactions may play an etiological role, the major contributing factor is conditioning-related toxicity. Among lung conditions that are more closely associated with GVHD are both obliterative bronchiolitis (usually occurring months to years after HSCT) and bronchiolitis obliterans organizing pneumonia (BOOP). The former is an inexorably progressive condition, whereas BOOP behaves similarly to idiopathic BOOP seen in other populations. Also addressed in this article are engraftment syndrome, diffuse alveolar hemorrhage, and pulmonary veno-occlusive disease. Knowledge of these complications is now a part of the contemporary practice of pulmonary medicine, no longer isolated to the transplant pulmonologist.

Over the past decade, the scientific community has gained a deeper understanding of the epidemiology of acute lung injury (ALI) and ARDS. Several high-quality studies have provided estimates of the incidence of ALI/ARDS, and have shown how incidence varies by age and what predicts mortality in this disease.1,2 Our understanding of how race/ethnicity influences an individual’s risk of developing ALI, however, is much less clear. Past population-based studies that characterized the incidence of ALI were conducted in geographic regions that did not reflect the typical racial/ethnic diversity of the United States, which prevented the presentation of race-specific estimates.1,2 At least one study of all-cause respiratory failure that included patients with ALI suggested that black patients experience a higher incidence of ALI.3 However, the International Classification of Diseases, Ninth Revision-based definition of respiratory failure used in this study left open the possibility that the observed racial differences in respiratory failure were due to causes other than true ALI. Most experts speculate that black patients are at an increased risk of developing ALI largely because black patients are at greater risk of sepsis and pneumonia,4,5 the two most common causes of ALI. In addition, several studies demonstrated that black patients die of ALI in greater numbers but appear to experience only slightly greater mortality once acquiring ALI, compared with white patients.6,7 Perhaps the most plausible explanation for the results of these studies is that the greater number of deaths due to ALI among black patients is most attributable to a higher incidence. In this issue of CHEST (see page 901), Lemos-Filho and colleagues8 provide data that challenge this assumption. The authors examined >5,000 participants enrolled in a multicenter cohort study designed to characterize the predictors of ALI among those hospitalized with established ALI risk factors. This unique at-risk population allowed the authors to compare the percentage of patients who eventually developed ALI across race, sex, and age groups. The strengths of the study included the prospective (most centers) collection of data, the use of the consensus definition for ALI, the diversity in the sites participating in the study, and a rich collection of information on each individual allowing adjustment for differences across race groups. Consistent with past studies, the risk factors of sepsis and pneumonia were more common among black compared with white patients. Somewhat surprisingly, even contradictory to most racial disparities work, black patients were less likely to develop ALI compared with white patients. Of those at risk, 6.5% of white patients and only 4.5% of black patients developed ALI, a finding that persisted after adjustment for other patient differences across race groups. Given the greater rates of sepsis and pneumonia among black Americans, both in this study and in the population, why then are black patients less likely to develop ALI? Through their careful analysis, the authors were able to exclude several potential explanations. First, the authors appropriately adjusted for race-based differences in the prevalence of diabetes across race groups, a comorbidity that may reduce the risk of ALI.9 Second, the authors adjusted for tidal volume delivered to patients before ALI was present. It is becoming increasingly recognized that lower tidal volumes may protect individuals who are mechanically ventilated from developing ALI.10 Third, the authors also appropriately accounted for center effects in their analysis. An extensive body of literature now demonstrates that a minority of hospitals care for the majority of black patients.11 If the hospitals where black patients seek care provide higher-quality care, black patients on average would develop ALI less often. Yet the race-based differences in the current study were observed despite conditioning on hospital (ie, the relationship between race and the development of ALI was the same for each hospital included in the analysis). There is at least one important explanation for the lower risk of ALI among black patients that Lemos-Filho and colleagues8 were unable to address. Specifically, 35% of patients with ALI (n =166) were given a diagnosis of ALI at hospital admission and, per the study protocol, these individuals were excluded from data extraction, preventing the authors from characterizing the racial makeup in this group. If the percentage of black patients in this excluded group was greater than that in the study sample, it is possible that the lower risk of developing ALI among black patients may not result from a true difference in the incidence of ALI, but rather from a difference in the timing of incident ALI. In other words, many of the incident cases of ALI in black patients may have already occurred by the time of hospital admission but were excluded by design. Indeed, past studies suggest that black patients often present to health-care providers later in the course of their critical illness, resulting in greater severity of illness at the time of admission.5,7 Had the authors been able to include the group of patients with early ALI in their analysis, one can only speculate as to how the relationship between race and ALI would change. Nevertheless, the possibility that differences in the occurrence of ALI across race groups may be a function of timing suggests that further studies are needed and leaves open the possibility that the population-based incidence of ALI in black patients may be equivalent to or even greater than that of white patients,3 even if the hospital-based incidence is lower. Racial disparities in medicine are pervasive and continue to exist despite decades of effort to eradicate them.12 As we seek to further address such disparities through research, many health disparities experts argue for a moratorium on studies that aim to document the existence of racial disparities. Instead, they suggest that investigators focus on determining the mechanisms underlying disparities or on interventions to remediate them. The study by Lemos-Filho et al8 provides a nice countervailing point to this argument, demonstrating why descriptive work is still important: On occasion, the results of such studies may surprise us.

Abstract 2282 The transfusion of red blood cells (RBC) is associated with adverse outcomes in critically ill patients. One hypothesis explaining this observation involves the accumulation of potentially inflammatory/prothrombotic microparticles (MPs), released from cellular membranes during unit processing and storage. Despite their implication, the exact nature of MPs within RBC units remains incompletely defined. Here, we characterized the MP phenotypes present within stored RBC units and quantified the various populations. We directly sampled 11 O-positive non-leukoreduced RBC unit bags and isolated MPs by sequential centrifugation. We used a two-step process to detect MPs by flow cytometry. First, we used commercially available Megamix beads to define MPs according to their size during flow cytometric analysis and Trucount beads to quantify MP counts/mL (reported as median [IQR]). MPs ≤1 μm in size were subsequently classified into the following populations: total annexin V-positive, tissue factor-positive (CD142), and those staining for RBC- (intra/extracellular domain-specific glycophorin A, and band-3), leukocyte- (CD45), platelet- (CD42b), and endothelial-specific (CD144) markers. The total concentration of MPs was 1.52×109 MPs/mL [1.39×109]; however, only 4.3% were Annexin V-positive (5.16×107 MPs/mL [7.27×107]), and 11.7% were tissue factor-positive (4.24×107 MPs/mL [1.11×108]). Likewise, MPs with leukocyte-, platelet-, and endothelial-specific markers accounted for only 0.05% (4.44×105 MPs/mL [7.83×105]), 0.17% (1.99×106 MPs/mL [3.11×106]), and 0.06% (7.58×105 MPs/mL [8.04×105]), respectively (Figure 1). The amount of RBC-derived MPs varied depending on the antibody used. While only 4.2% of MPs (3.40×107 MPs/mL [2.91×107]) stained positive for the extracellular domain of glycophorin A, 41.3% (8.20×108 MPs/mL [4.06×108]) and 20.6% MPs (3.03×108 MPs/mL [3.53×108]) stained positive for the cytoplasmic domain of glycophorin A and band-3 respectively (Figure 1). The concentration of MPs positive for the cytoplasmic domain of glycophorin A was significantly greater their extracellular domain-specific counterparts (p Disclosures: No relevant conflicts of interest to declare.