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  • 1
    Article
    Article
    Language: English
    In: JAMA, 05 June 2013, Vol.309(21), pp.2270-1
    Description: 〈p〉The Prospective, Observational, Multicenter, Major Trauma Transfusion (PROMMTT) Study: Comparative Effectiveness of a Time-Varying Treatment With Competing RisksJohn B. Holcomb, MD; Deborah J. del Junco, PhD; Erin E. Fox, PhD; Charles E. Wade, PhD; Mitchell J. Cohen, MD; Martin A. Schreiber, MD; Louis H. Alarcon, MD; Yu Bai, MD, PhD; Karen J. Brasel, MD, MPH; Eileen M. Bulger, MD; Bryan A. Cotton, MD, MPH; Nena Matijevic, PhD; Peter Muskat, MD; John G. Myers, MD; Herb A. Phelan, MD, MSCS; Christopher E. White, MD; Jiajie Zhang, PhD; Mohammad H. Rahbar, PhD; for the PROMMTT Study GroupObjective: To relate in-hospital mortality to early transfusion of plasma and/or platelets and to time-varying plasma:red blood cell (RBC) and platelet:RBC ratios.Design: Prospective cohort study documenting the timing of transfusions during active resuscitation and patient outcomes. Data were analyzed using time-dependent proportional hazards models.Setting: Ten US level I trauma centers.Patients: Adult trauma patients surviving for 30 minutes after admission who received a transfusion of at least 1 unit of RBCs within 6 hours of admission (n = 1245, the original study group) and at least 3 total units (of RBCs, plasma, or platelets) within 24 hours (n = 905, the analysis group).Main Outcome Measure: In-hospital mortality.Results: Plasma:RBC and platelet:RBC ratios were not constant during the first 24 hours (P 〈 .001 for both). In a multivariable time-dependent Cox model, increased ratios of plasma:RBCs (adjusted hazard ratio = 0.31; 95% CI, 0.16-0.58) and platelets:RBCs (adjusted hazard ratio = 0.55; 95% CI, 0.31-0.98) were independently associated with decreased 6-hour mortality, when hemorrhagic death predominated. In the first 6 hours, patients with ratios less than 1:2 were 3 to 4 times more likely to die than patients with ratios of 1:1 or higher. After 24 hours, plasma and platelet ratios were unassociated with mortality, when competing risks from nonhemorrhagic causes prevailed.Conclusions: Higher plasma and platelet ratios early in resuscitation were associated with decreased mortality in patients who received transfusions of at least 3 units of blood products during the first 24 hours after admission. Among survivors at 24 hours, the subsequent risk of death by day 30 was not associated with plasma or platelet ratios.JAMA Surg. 2013; 148(2):127-136.doi:10.1001/2013.jamasurg.387〈/p〉
    Keywords: Medicine;
    ISSN: 00987484
    E-ISSN: 1538-3598
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  • 2
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 27 January 2015, Vol.112(4), pp.E345
    Description: 〈p〉Vertebrates vary in resistance and resilience to infectious diseases, and the mechanisms that regulate the trade-off between these often opposing protective processes are not well understood. Variability in the sensitivity of species to the induction of damaging inflammation in response to equivalent pathogen loads (resilience) complicates the use of animal models that reflect human disease. We found that induction of proinflammatory cytokines from macrophages in response to inflammatory stimuli in vitro is regulated by proteins in the sera of species in inverse proportion to their in vivo resilience to lethal doses of bacterial lipopolysaccharide over a range of 10,000-fold. This finding suggests that proteins in serum rather than intrinsic cellular differences may play a role in regulating variations in resilience to microbe-associated molecular patterns between species. The involvement of circulating proteins as key molecules raises hope that the process might be manipulated to create better animal models and potentially new drug targets.〈/p〉
    Keywords: Databases, Genetic ; Disease Models, Animal ; Gene Expression Profiling ; Gene Expression Regulation ; Inflammation
    ISSN: 00221899
    E-ISSN: 1091-6490
    E-ISSN: 15376613
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  • 3
    Language: English
    In: The Lancet, 22 September 2012, Vol.380(9847), pp.1099-1108
    Description: Most surgeons have adopted damage control surgery for severely injured patients, in which the initial operation is abbreviated after control of bleeding and contamination to allow ongoing resuscitation in the intensive-care unit. Developments in early resuscitation that emphasise rapid control of bleeding, restrictive volume replacement, and prevention or early management of coagulopathy are making definitive surgery during the first operation possible for many patients. Improved topical haemostatic agents and interventional radiology are becoming increasingly useful adjuncts to surgical control of bleeding. Better understanding of trauma-induced coagulopathy is paving the way for the replacement of blind, unguided protocols for blood component therapy with systemic treatments targeting specific deficiencies in coagulation. Similarly, treatments targeting dysregulated inflammatory responses to severe injury are under investigation. As point-of-care diagnostics become more suited to emergency environments, timely targeted intervention for haemorrhage control will result in better patient outcomes and reduced demand for blood products. Our Series paper describes how our understanding of the roles of the microcirculation, inflammation, and coagulation has shaped new and emerging treatment strategies.
    Keywords: Medicine
    ISSN: 0140-6736
    E-ISSN: 1474-547X
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  • 4
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 01 March 2011, Vol.108(9), pp.3707-12
    Description: A 6.9 million-feature oligonucleotide array of the human transcriptome [Glue Grant human transcriptome (GG-H array)] has been developed for high-throughput and cost-effective analyses in clinical studies. This array allows comprehensive examination of gene expression and genome-wide identification of alternative splicing as well as detection of coding SNPs and noncoding transcripts. The performance of the array was examined and compared with mRNA sequencing (RNA-Seq) results over multiple independent replicates of liver and muscle samples. Compared with RNA-Seq of 46 million uniquely mappable reads per replicate, the GG-H array is highly reproducible in estimating gene and exon abundance. Although both platforms detect similar expression changes at the gene level, the GG-H array is more sensitive at the exon level. Deeper sequencing is required to adequately cover low-abundance transcripts. The array has been implemented in a multicenter clinical program and has generated high-quality, reproducible data. Considering the clinical trial requirements of cost, sample availability, and throughput, the GG-H array has a wide range of applications. An emerging approach for large-scale clinical genomic studies is to first use RNA-Seq to the sufficient depth for the discovery of transcriptome elements relevant to the disease process followed by high-throughput and reliable screening of these elements on thousands of patient samples using custom-designed arrays.
    Keywords: Gene Expression Profiling -- Methods ; High-Throughput Screening Assays -- Methods ; Oligonucleotide Array Sequence Analysis -- Methods
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 5
    In: Shock, 2014, Vol.41(5), pp.373-377
    Keywords: Hemostasis -- Physiology ; Resuscitation -- Methods;
    ISSN: 1073-2322
    E-ISSN: 15400514
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  • 6
    Article
    Article
    In: Annals of Surgery, 2018, Vol.268(3), pp.391-402
    Keywords: Career Choice ; General Surgery ; Mentors;
    ISSN: 0003-4932
    E-ISSN: 15281140
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  • 7
    Language: English
    In: Journal of the American College of Surgeons, September 2014, Vol.219(3), pp.335-345
    Description: To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.jamcollsurg.2014.04.011 Byline: Ronald V. Maier Author Affiliation: Division of Trauma, Burn, General and Critical Care Surgery, Department of Surgery, Harborview Medical Center, University of Washington, Seattle, WA Article History: Received 24 April 2014; Accepted 28 April 2014 Article Note: (footnote) Disclosure Information: Nothing to disclose.
    Keywords: History, 20th Century–History ; History, 21st Century–Methods ; Humans–Physiopathology ; Resuscitation–Therapy ; United States–Therapy ; Wounds and Injuries–Therapy ; Abridged;
    ISSN: 1072-7515
    E-ISSN: 1879-1190
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  • 8
    In: Critical Care Medicine, 2015, Vol.43(7), pp.1429-1438
    Description: OBJECTIVES:: 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. DESIGN:: Multicenter prospective observational study. SETTING:: Nine level I trauma centers in the United States. PATIENTS:: A total of 1,031 blunt trauma patients with hemorrhagic shock. INTERVENTIONS:: None. MEASUREMENTS AND MAIN RESULTS:: 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; p 〈 0.001), hemorrhagic shock–associated death (OR, 2.44; p = 0.001), venous thromboembolism (OR, 1.73; p 〈 0.001), 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. CONCLUSIONS:: 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.
    Keywords: Medicine;
    ISSN: 0090-3493
    E-ISSN: 15300293
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  • 9
    In: Critical Care Medicine, 2014, Vol.42(6), pp.1397-1405
    Description: OBJECTIVES:: Bacteremic trauma victims have a higher risk of death than their nonbacteremic counterparts. The role that altered immunity plays in the development of bacteremia is unknown. Using an existing dataset, we sought to determine if differences in early postinjury immune-related gene expression are associated with subsequent Gram-negative bacteremia. DESIGN:: Retrospective cohort study, a secondary analysis of the Glue Grant database. SETTING:: Seven level I trauma centers across the United State. SUBJECTS:: Severely injured blunt trauma patients. INTERVENTIONS:: None. MEASUREMENTS AND MAIN RESULTS:: Total leukocyte gene expression was compared between the subjects in whom Gram-negative bacteremia developed and those in whom it did not develop. We observed that Gram-negative bacteremia was an independent risk factor for death (odds ratio, 1.86; p = 0.015). We then compared gene expression at 12 and 96 hours after injury in 10 subjects in whom subsequently Gram-negative bacteremia developed matched to 26 subjects in whom it did not develop. At 12 hours, expression of 64 probes differed more than or equal to 1.5-fold; none represented genes related to innate or adaptive immunity. By 96 hours, 102 probes were differentially expressed with 20 representing 15 innate or adaptive immunity genes, including down-regulation of IL1B and up-regulation of IL1R2, reflecting suppression of innate immunity in Gram-negative bacteremia subjects. We also observed down-regulation of adaptive immune genes in the Gram-negative bacteremia subjects. CONCLUSIONS:: By 96 hours after injury, there are differences in leukocyte gene expression associated with the development of Gram-negative bacteremia, reflecting suppression of both innate and adaptive immunity. Gram-negative bacteremia after trauma is, in part, consequence of host immunity failure and may not be completely preventable by standard infection-control techniques.
    Keywords: Medicine;
    ISSN: 0090-3493
    E-ISSN: 15300293
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  • 10
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States, Feb 26, 2013, Vol.110(9), p.3507(6)
    Description: A cornerstone of modern biomedical research is the use of mouse models to explore basic pathophysiological mechanisms, evaluate new therapeutic approaches, and make go or no-go decisions to carry new drug candidates forward into clinical trials. Systematic studies evaluating how well murine models mimic human inflammatory diseases are nonexistent. Here, we show that, although acute inflammatory stresses from different etiologies result in highly similar genomic responses in humans, the responses in corresponding mouse models correlate poorly with the human conditions and also, one another. Among genes changed significantly in humans, the murine orthologs are close to random in matching their human counterparts (e.g., [R.sup.2] between 0.0 and 0.1). In addition to improvements in the current animal model systems, our study supports higher priority for translational medical research to focus on the more complex human conditions rather than relying on mouse models to study human inflammatory diseases. human disease | translational medicine | inflammation immune response | injury doi/ 10.1073/pnas.1222878110
    Keywords: Genomics -- Research ; Immune Response -- Research ; Inflammation -- Genetic Aspects;
    ISSN: 0027-8424
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