Current opinion in critical care
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Decisions made in critical care are often complicated, requiring an in-depth understanding of the relations between complex diseases, available interventions, and patients with a wide range of characteristics. Standard modeling techniques such as decision trees and statistical modeling have difficulty in capturing these interactions as the complexity of the problem increases. ⋯ Simulation models provide useful tools for organizing and analyzing the interactions between therapies, tradeoffs, and outcomes.
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Despite substantial advances in our understanding of the biology of sepsis and inflammation, improvements in clinical outcomes have been more sporadic and, with few notable exceptions, are related to improvements in supportive care rather than to specific therapies. As a result, morbidity, mortality, and cost remain high. Investigation into the genetic determinants of this response span a broad spectrum and include those aimed at deciphering the mechanisms and involved pathways on a molecular level, to those aiming to identify how genetic variation may be clinically important. While it is clear that gene sequencing and manipulation of experimental models have provided insight into the biology of the inflammatory response to infection, these technologies and their application to the study of naturally occurring human genetic variation have yet to provide the same insight or clinical benefit. The purpose of this review is to summarize what is known about the genetic determinants of the inflammatory response. We make particular reference to this broad scope of investigation introduced above but with a focus on the present status of studies examining the role of human genetic variation in the risk for and outcome from severe bacterial infection, or sepsis. ⋯ Naturally occurring genetic variants in important inflammatory mediators such as TNF-alpha and TLR4 appear to alter inflammatory responses in numerous experimental and a few clinical models of inflammation. However, inconsistencies exist in the literature regarding the association between these genetic variants and disease (eg, sepsis) susceptibility and prognosis. The main limitations relate to the translation of experimental observations into reproducible genotype-phenotype associations. The reasons for these are multifactorial and include deficiencies in study design (insufficient sample size), and the complexities introduced by background genetic heterogeneity.
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Trauma and infection elicit an acute inflammatory response. In certain circumstances the degree of the acute inflammatory response may result in pathologic manifestations, namely, sepsis and multiple organ failure. Despite an extensive series of clinical trials designed to modulate inflammation in sepsis, only one compound, activated protein C, has emerged from more than 250 failed trials. There is a growing recognition that the complexity of the acute inflammatory response precludes the efficient development of therapies for sepsis and multiple organ failure until systems approaches are brought to bear on this problem. ⋯ Simulations using various methods can shed insight into the pathophysiology of the acute inflammatory response and may lead to better design of clinical trials in sepsis and trauma.
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Curr Opin Crit Care · Oct 2004
ReviewAdvances in statistical methodology and their application in critical care.
To review some of the major advances in statistical methodology of the past two decades and their application to investigations in critical care. ⋯ By becoming familiar with advances in statistical methodology, researchers and clinicians can enhance collaboration with their statistical colleagues, toward the goal of better study design and analysis.