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Background Post-traumatic acute kidney injury has occurred in every major military conflict since its initial description during World War II. To ensure the proper treatment of combat casualties, early detection is critical. This study therefore aimed to investigate combat-related post-traumatic acute kidney injury in recent military conflicts, used machine learning algorithms to identify clinical and biomarker variables associated with the development of post-traumatic acute kidney injury, and evaluated the effects of post-traumatic acute kidney injury on wound healing and nosocomial infection. Methods We conducted a retrospective clinical cohort review of 73 critically injured US military service members who sustained major combat-related extremity wounds and had collected injury characteristics, assayed serum and tissue biopsy samples for the expression of protein and messenger ribonucleic acid biomarkers. Bivariate analyses and random forest recursive feature elimination classification algorithms were used to identify associated injury characteristics and biomarker variables. Results The incidence of post-traumatic acute kidney injury was 20.5%. Of that, 86% recovered baseline renal function and only 2 (15%) of the acute kidney injury group required renal replacement therapy. Random forest recursive feature elimination algorithms were able to estimate post-traumatic acute kidney injury with the area under the curve of 0.93, sensitivity of 0.91, and specificity of 0.91. Post-traumatic acute kidney injury was associated with injury severity score, serum epidermal growth factor, and tissue activin A type receptor 1, matrix metallopeptidase 10, and X-C motif chemokine ligand 1 expression. Patients with post-traumatic acute kidney injury exhibited poor wound healing and increased incidence of nosocomial infections. Conclusion The occurrence of acute kidney injury in combat casualties may be estimated using injury characteristics and serum and tissue biomarkers. External validations of these models are necessary to generalize for all trauma patients.

Intensive care unit (ICU) telemedicine is an established entity that has the ability to not only improve the effectiveness, efficiency, and safety of critical care, but to also serve as a tool to combat staffing shortages and resource-limited environments. Several areas for future innovation exist within the field, including the use of advanced practice providers, robust inclusion in medical education, and concurrent application of advanced machine learning. The globalization of critical care services will also likely be predominantly delivered by ICU telemedicine. Limitations faced by the field include technical issues, financial concerns, and organizational elements.

Purpose Management of sepsis in critically ill patients remains difficult and requires prolonged intensive care. Genetic testing has been proposed as a strategy to identify patients at risk for adverse outcome of critical illnesses. Therefore, we wished to determine the influence of heredity on predisposition to poor outcome and on duration of ventilator support of intensive care unit (ICU) patients. Methods A study was conducted from July 2001 to December 2005 in heterogeneous population of patients from 12 US ICUs represented by the Genetic Predisposition to Severe Sepsis (GenPSS) archive. In 1057 Caucasian critically ill patients with SAPS II probability of survival of >0.2 in the US, six functional single nucleotide polymorphisms in relation to inflammatory cytokines and innate immunity (rs1800629, rs16944, rs1800795, rs1800871, rs2569190, and rs909253) were evaluated in terms of mortality and ventilator free days. Results The AA homozygote of TNF (−308) (rs1800629) was most over-represented in the deceased patient group ( P = 0.015 with recessive model). The carriage of the TNF (−308)*AA genotype showed significantly higher odds ratio of 2.67(1.29–5.55) ( P = 0.008) after adjustment with the covariates. However, the presence of 1, 2, or 3 acute organ dysfunctions was larger prognostic factors for the adverse outcome (OR(95%CI) = 2.98(2.00–4.45), 4.01(2.07–7.77), or 19.95(4.99–79.72), P TNF (−308)*AA patient significantly diverged from that of TNF (−308)*(GG + GA) ((AA v GG + GA), Adjusted HR(95%CI) = 2.53(1.11–5.79) with Cox regression, P = 0.028). Conclusions TNF (−308)*AA is significantly associated with susceptibility to adverse outcome and to longer ventilator duration. Therefore, heredity likely affects both predisposition to ICU prognosis as well as the resource utilization.

Purpose Complex autonomic communication can be assessed by autonomic information flow (AIF) functions. The objective was to evaluate new complexity measures involving physiologically relevant time scales to predict the length of stay (LOS) in the hospital after abdominal aortic surgery (AAS). Our hypothesis was that AAS disrupts AIF, that restoration of AIF is necessary for recovery from major surgery, and that measures of AIF are superior to conventional heart rate variability (HRV) measures and equivalent to APACHE IV score in predicting LOS. Materials and Methods Twenty-four–hour Holter recordings were analyzed in 94 patients after AAS for standard time, frequency domain, and several complexity measures of different time scales derived from AIF functions. The risk of staying in the hospital for longer than 7 days as a function of HRV measures and APACHE IV score was modeled by logistic regression. The area under the curve (AUC) of receiver operating characteristic with 95% confidence interval as measure of predictive accuracy was calculated and internally cross-validated. Results The long-term dacay of AIF over 100s (LD100) with cross-validated AUC = 0.67 (0.56-0.79) nearly reached the predictive accuracy of the APACHE IV score with AUC = 0.69 (0.58-0.79). None of the traditional time and frequency domain HRV measures remained in the multivariate models. The LD100 adjusted for ventilatory support with AUC = 0.70 (0.59-0.81) was equivalent to the APACHE IV score in this patient group. Although the strongest correlation between AIF measures and the APACHE IV score was found for LD100, r was only −0.37. Conclusions Results confirm the hypothesis that AIF measures characterize pathophysiologic autonomic communication better than traditional HRV measures and may have similar predictive value to the APACHE IV score for LOS. The relative independence of the APACHE IV score and AIF measures suggests that AIF measures could add to clinical risk prediction.

When a patient enters the intensive care unit, the admitting surgeon also enters a new environment. In some hospitals, the surgical intensive care unit (SICU) is "closed"--critical care providers manage care; in others the unit is "open," and the admitting surgeon is in charge. A third system is the "mixed" model of ICU administration; a collaborative approach. This article addresses concerns and conflicts that frequently arise between admitting surgeons and intensivists. It is written from the perspective of two surgeon-intensivists who have been in both roles. Recent behavioral and social research on ICU conflicts and their resolution is reviewed, and and new strategies for conflict resolution are also presented.

Background Sepsis, iron loading, and aging cause independent increases in gut epithelial and splenic apoptosis. It is unknown how their combination will affect apoptosis and systemic cytokine levels. Materials and Methods Hfe−/− mice (a murine homologue of hemochromatosis) abnormally accumulate iron in their tissues. Aged (24–26 months) or mature (16–18 months) Hfe−/− mice and wild type (WT) littermates were subjected to cecal ligation and puncture (CLP) or sham laparotomy. Intestine, spleen, and blood were harvested 24 h later and assessed for apoptosis and cytokine levels. Results Gut epithelial and splenic apoptosis were low in both aged septic and sham Hfe−/− mice, regardless of the amount of iron in their diet. Mature septic WT mice had increased apoptosis compared to age-matched sham WT mice. Mature septic Hfe−/− mice had similar levels of intestinal cell death to age-matched septic WT mice but higher levels of splenic apoptosis. Apoptosis was significantly lower in septic aged Hfe−/− mice than septic mature Hfe−/− animals. Interleukin-6 was elevated in septic aged Hfe−/− mice compared to sham mice. Conclusions Although sepsis, chronic iron dysregulation, and aging each increase gut and splenic apoptosis, their combination yields cell death levels similar to sham animals despite the fact that aged Hfe−/− mice are able to mount an inflammatory response following CLP and mature Hfe−/− mice have elevated sepsis-induced apoptosis. Combining sepsis with two risk factors that ordinarily increase cell death and increase mortality in CLP yields an apoptotic response that could not have been predicted based upon each element in isolation.

Diseases attributable to acute thrombosis contribute to the morbidity and mortality of critically ill patients [1]. While common variants present in genes encoding mediators of the coagulation pathway have been implicated in conditions such as myocardial infarction and deep venous thrombosis in population-based studies, their clinical significance has not been thoroughly analyzed in patients hospitalized for acute illness [2–8]. More precise characterization of the role of genetic variation in predisposition to cardiovascular and thromboembolic events in the critical care setting may be useful in aiding diagnostic evaluation and guiding therapy. High throughput genotyping, i.e., the ability to accurately and economically analyze a large number of patient samples at numerous genetic loci, is essential to this task. Current approaches to high throughput genotyping are based on the principles of either allele-specific hybridization (e.g., microarrays, molecular beacon), primer extension (pyrosequencing), flap probe cleavage (InvaderR assay), or oligonucleotide ligation [9]. To date, no single technique has been extensively field-tested [9]. Thus, the adaptability of any given approach to a specific situation is relatively unstudied. Template-directed dye-terminator incorporation with fluorescence polarization detection (TDI-FP) is a single base extension technique in which an oligonucleotide probe anneals to

Background: Warfarin use is complicated by an erratic dose response. Interpatient variability associated with warfarin therapy may be partly attributable to polymorphisms of the cytochrome P450 (CYP) complex. The purpose of this study was to ascertain the frequency and influence of CYP polymorphisms on warfarin dosing in our patient population. Methods: Patients receiving warfarin therapy were recruited from the inpatient divisions of our hospital. Genotyping for known polymorphic alleles of the CYP subfamilies CYP2C9 (CYP2C9*1, CYP2C9*2, and CYP2C9*3) and CYP2A6 (CYP2A6*1, CYP2A6*2) with the use of standard methods of polymerase chain reaction amplification was performed. An unpaired t test was used to statistically compare genotypes. Results: Genotype frequency in 38 patients is as follows: CYP2C9*1/CYP2C9*1, 71%; CYP2C9*1/CYP2C9*2, 21%; CYP2C9*2/CYP2C9*2, 3%; CYP2C9*1/CYP2C9*3, 5%; CYP2A6*1/CYP2A6*1, 95%; CYP2A6*1/CYP2A6*2, 5%. Compared to a wild-type genotype, the presence of the CYP2C9*2, CYP2C9*3, or CYP2A6*2 allele was associated with a significant reduction in weekly warfarin dose (mean weekly warfarin dose [± SE] for wild-type genotype was 0.397 ± 0.024 mg/kg/wk vs 0.307 ± 0.03 mg/kg/wk for carriers of CYP2C9*2, CYP2C9*3, or CYP2A6*2 polymorphism; P =.03). Conclusions: Polymorphisms that impair warfarin metabolism are common, occurring in 34% of patients, and are associated with increased warfarin sensitivity. The use of genotypic information to prescribe more accurate doses of warfarin may increase the safety and efficacy of this medication. (Surgery 2000;128:281-5.)

Background. Nitric oxide (NO) produced by the inducible isoform of NO synthase (iNOS or NOS2) has been implicated in the hypotension, organ failure, and death that complicate sepsis. To avoid the confounding effects and limitations of iNOS inhibitors, we used iNOS gene knockout mice to examine the effect of inducible NO production in a model of polymicrobial abdominal sepsis treated with antibiotics. We hypothesized that iNOS gene deficiency would significantly alter outcome. Methods. C57BL6 wild-type (control) and congenic iNOS knockout mice were studied concurrently. Under halothane anesthesia, the ceca were ligated with 4-0 silk suture and punctured twice with a 26-gauge needle (cecal ligation and puncture, CLP). Survival was followed for 7 days, after which necropsies were performed in surviving animals. In an accompanying study examining the acute effects of sepsis, organ injury at 18 hours after CLP as determined by histology and the degree of cell death by apoptosis were examined with the use of hematoxylin and eosin (H&E) and TUNEL staining and two-channel fluorescence-activated cell sorter (FACS) analysis. Results. Sham laparotomy produced no lethality in either knockout (n = 3) or wild-type (n = 3) animals. Compared with survival in controls (n = 20), survival after CLP in iNOS knockout mice (n = 21) was significantly decreased (P

Background: Apoptosis, a mechanism of cell death prominent in critical illnesses including disseminated inflammation and multiorgan dysfunction syndrome, is characterized by morphologic changes including cell shrinkage, condensation of organelles, blebbing, and chromatin fragmentation. These phenomena suggest substantial changes in cytoskeletal structure. We hypothesized that stress-induced apoptosis in endothelial cells is, in part, a consequence of a critical cytoskeletal rearrangement. Methods: Porcine aortic endothelial cells in culture, surrogates for the microvasculature in vivo, were exposed sequentially to Escherichia coli endotoxin (25 μ g/mL; 18 hours) to induce the inflammatory response and then to sodium arsenite (160 μ mol/L; 120 minutes) to induce the heat-shock response, a well-characterized model of stress-induced apoptosis. Laser confocal micrographs of fluorescein isothiocyanate–labeled phalloidin-stained cells were analyzed to calculate the border fractal dimension of the cytoskeleton. Other cells were exposed to cytochalasin D, a fungal metabolite, which interferes with polymerization of actin from its globular to its filamentous form, and similarly were analyzed with respect to fractal dimension, viability (neutral red assay), and manner of death (annexin V fluorescence–activated cell scanning analysis). Results: Induction of the inflammatory or heat-shock responses caused subtle and distinct rearrangement of the actin cytoskeleton. When these stimuli were applied in sequence, a synergistic interaction led to profound cytoskeletal collapse. Reversal of the sequence did not induce the cytoskeletal disruption. Cytochalasin D alone induced a dose-dependent cytoskeletal collapse indistinguishable from that caused by the acute phase–heat shock sequence that caused cell death by apoptosis. The effect of lower doses of cytochalasin D could be potentiated by subsequent induction of the heat-shock response. Conclusions: Sequential stresses that mimic pathophysiologic “two-hit” stimuli induce a characteristic fractal rearrangement of the actin cytoskeleton. Because cytochalasin D–induced rearrangement of this cytoskeleton produced apoptosis indistinguishable from the stress-induced apoptosis, we conclude that the cytoskeletal rearrangement is likely a critical event in the pathway to apoptosis. This disruption of intracellular interconnections mirrors endotoxin-induced disruption in signals among organs and supports the mechanistic hypothesis that multiorgan dysfunction syndrome generally reflects disruption of signals and connections at several levels of biologic organization. (Surgery 1998;124:362-71.)

Background. Iron participates in diverse pathologic processes by way of the Fenton reaction, which catalyzes the formation of reactive oxygen species (ROS). To test the hypothesis that this reaction accelerates apoptosis, we used human umbilical vein endothelial cells (HUVECs) as surrogates for the microvasculature in vivo. Methods. HUVECs were loaded with Fe [III](ferric chloride and ferric ammonium citrate) with 8-hydroxyquinoline as carrier and were then challenged with two stimuli of the heat shock response, authentic heat or sodium arsenite. Iron dependence was tested with two chelators, membrane-impermeable deferoxamine and membrane-permeable o-phenanthroline. The role of ROS was assessed with superoxide dismutase, catalase, and the reporter compound dichlorofluorescein diacetate. The mechanism of cell death was assessed with three complementary techniques, Annexin V/propidium iodide labeling, the TUNEL stain, and electron microscopy. Results. Iron-loaded HUVECs executed apoptosis after a heat shock stimulus. Iron-catalyzed formation of ROS appeared to be a critical mechanism, because both chelation of iron and enzymatic detoxification of ROS attenuated this apoptosis. Conclusions. Inorganic iron, in concert with chemical and physical inducers of the heat shock response, may trigger apoptosis. The accumulation of iron in injured tissue may thereby predispose to accelerated apoptosis and account, in part, for poor wound healing and organ failure.

Good health, which reflects the harmonious integration of molecules, cells, tissues and organs, is dynamically stable: when displaced by disease, compensation and correction are common, even without medical care. Physiology and computational biology now suggest that healthy dynamic stability arises through the combination of specific feedback mechanisms and spontaneous properties of interconnected networks. Today's physicians are already testing to 'see if the network is right'; tomorrow's physicians may well use therapies to 'make the network right'.

components, and the interactions between those components within an organizational structure that exists in dynamic equilibrium. Furthermore, the organization of biologic systems is identified as necessarily hierarchical and recursive, stressing the importance of addressing both context and concurrency in any description. The resulting category-theoretical description is general enough to abstractly describe any biologic system: the general category of biology can be expressed as an abstracted biologic computational unit (ABCU) [1,2]. Mathematical descriptions of biologic systems can be constructed from instances of ABCUs and the processes that link them. Inversely, incomplete descriptions of aspects of biologic systems (such as biochemical pathways) do not fulfill the associative requirement of a category and are, therefore, not considered as members of the ABCU set. This “completeness” requirement places a constraint on the internal structure of a category-theoretical description of a biologic system and can be seen as analogous to the fact that biologic systems must follow basic physical and chemical laws. Conclusions: Biology is more than an aggregate of chemistry and physics. Although it incorporates and uses the laws of those domains, the richness of biology cannot be effectively characterized using merely the descriptive capacity of physics or chemistry. To develop the mathematics of biology, it is necessary to present a mathematical description of the fundamental properties that set biology apart from these other domains. Given the organizational complexity of biologic systems, this goal requires the use of more abstract and powerful mathematical tools that are used to delineate the laws of physics or chemistry. Category theory is particularly well suited to this goal, and it is further suggested that being able to produce a category-theoretical description may be both necessary and sufficient to define a complete biologic system, as distinguished from either a biophysical or biochemical one. Furthermore, because category theory is also being applied to various aspects of computer science, programming languages, and logic, it may provide a means of formalizing the transition from a biologic description to a computable one.

Background Physiologic data display is essential to decision making in critical care. Current displays echo first-generation hemodynamic monitors dating to the 1970s and have not kept pace with new insights into physiology or the needs of clinicians who must make progressively more complex decisions about their patients. The effectiveness of any redesign must be tested before deployment. Tools that compare current displays with novel presentations of processed physiologic data are required. Regenerating conventional physiologic displays from archived physiologic data is an essential first step. Objectives The purposes of the study were to (1) describe the SSSI (single sensor single indicator) paradigm that is currently used for physiologic signal displays, (2) identify and discuss possible extensions and enhancements of the SSSI paradigm, and (3) develop a general approach and a software prototype to construct such "extended SSSI displays" from raw data. Results We present Multi Wave Animator (MWA) framework—a set of open source MATLAB (MathWorks, Inc., Natick, MA, USA) scripts aimed to create dynamic visualizations (eg, video files in AVI format) of patient vital signs recorded from bedside (intensive care unit or operating room) monitors. Multi Wave Animator creates animations in which vital signs are displayed to mimic their appearance on current bedside monitors. The source code of MWA is freely available online together with a detailed tutorial and sample data sets.

the use of the neutral networks is restricted to assigning IVA strains to reservoirs. All of the populations are treated as well mixed, so there is no network structure within any reservoir. That is, any agent in a given reservoir is equally likely to contact any other agent. The reservoirs are connected by weighted edges, where the weight of an edge determines how strongly the IVA strains can be passed between the different reservoirs. Each population is assigned characteristics such as birth and death rates, transmission rates, and seasonal effects. Within each population, we model every individual as an agent, where on the order of 10 agents are currently being simulated. Each agent retains a history of all previous IVA infections as well as the strains with which it is currently infected. Agents are added and removed from the populations. The trans-reservoir transmissions are done between specific agents. Two main types of evolutionary processes are incorporated in our model. The first is point mutations of the IVA strains' genotypes. Here we conceptualize each of the 8 genes to have a certain number of loci. This allows the strains to evolve over a particular reservoir's neutral network. If a strain evolves onto a network that can infect multiple reservoirs, we can have trans-reservoir infections. The second evolutionary process is the reassortment of 2 IVA strains within an agent. The genome of IVA is composed of 8 individual strands of RNA. If an agent is currently infected by more than a single strain, the RNA strands can be reassorted, allowing for the rise of novel strains. Results: We hope to demonstrate that using a multi-reservoir model can reproduce the effects of using neutral networks. In this way, the model will reproduce the phylodynamics of the IVA. We have also included the important features of multiple different species and strain reassortment for IVA evolution. Conclusions: We have examined an agent-based model of IVA evolution and epidemiology. The model includes multiple interacting reservoirs (eg, avian, swine and human) of agents. Each reservoir is assigned IVA strains by which it can be infected. One of the reservoirs acts as a bridge between other reservoirs. In this, transreservoir transmission is allowed. In addition, IVA can evolve within each reservoir through the processes of mutation and reassortment.

capabilities. The intent is not to suggest that an agent-based framework is “the” format for an executable ontology layer; the experience with classic ontologies suggests that it is impossible to produce a definitive knowledge representation tool. It is fully expected that other researches will develop similar types of tools, using different modeling paradigms. However, we believe that an ABMF demonstrates a robust, evolvable approach and will provide an essential translational step toward the goal of having as many steps as possible of the discovery process be automated. Eventually, this type of architecture would allow the automated generation of models that can be picked through by the researcher, providing a truly evolutionary solution to the synthetic aspect of biomedical research.