ABSTRACT
BACKGROUND: Optimizing resuscitation to reduce inflammation and organ dysfunction following human trauma-associated hemorrhagic shock is a major clinical hurdle. This is limited by the short duration of pre-clinical studies and the sparsity of early data in the clinical setting. METHODS: We sought to bridge this gap by linking preclinical data in a porcine model with clinical data from patients from the Prospective, Observational, Multicenter, Major Trauma Transfusion (PROMMTT) study via a three-compartment ordinary differential equation model of inflammation and coagulation. RESULTS: The mathematical model accurately predicts physiologic, inflammatory, and laboratory measures in both the porcine model and patients, as well as the outcome and time of death in the PROMMTT cohort. Model simulation suggests that resuscitation with plasma and red blood cells outperformed resuscitation with crystalloid or plasma alone, and that earlier plasma resuscitation reduced injury severity and increased survival time. CONCLUSIONS: This workflow may serve as a translational bridge from pre-clinical to clinical studies in trauma-associated hemorrhagic shock and other complex disease settings.
Research to improve survival in patients with severe bleeding after major trauma presents many challenges. Here, we created a computer model to simulate the effects of severe bleeding. We refined this model using data from existing animal studies to ensure our simulations were accurate. We also used patient data to further refine the simulations to accurately predict which patients would live and which would not. We studied the effects of different treatment protocols on these simulated patients and show that treatment with plasma (the fluid portion of blood that helps form blood clots) and red blood cells jointly, gave better results than treatment with intravenous fluid or plasma alone. Early treatment with plasma reduced injury severity and increased survival time. This modelling approach may improve our ability to evaluate new treatments for trauma-associated bleeding and other acute conditions.
ABSTRACT
Trauma-induced critical illness is driven by acute inflammation, and elevated systemic interleukin-6 (IL-6) after trauma is a biomarker of adverse outcomes. We constructed a multicompartment, ordinary differential equation model that represents a virtual trauma patient. Individual-specific variants of this model reproduced both systemic inflammation and outcomes of 33 blunt trauma survivors, from which a cohort of 10,000 virtual trauma patients was generated. Model-predicted length of stay in the intensive care unit, degree of multiple organ dysfunction, and IL-6 area under the curve as a function of injury severity were in concordance with the results from a validation cohort of 147 blunt trauma patients. In a subcohort of 98 trauma patients, those with high-IL-6 single-nucleotide polymorphisms (SNPs) exhibited higher plasma IL-6 levels than those with low IL-6 SNPs, matching model predictions. Although IL-6 could drive mortality in individual virtual patients, simulated outcomes in the overall cohort were independent of the propensity to produce IL-6, a prediction verified in the 98-patient subcohort. In silico randomized clinical trials suggested a small survival benefit of IL-6 inhibition, little benefit of IL-1ß inhibition, and worse survival after tumor necrosis factor-α inhibition. This study demonstrates the limitations of extrapolating from reductionist mechanisms to outcomes in individuals and populations and demonstrates the use of mechanistic simulation in complex diseases.
Subject(s)
Models, Statistical , Wounds, Nonpenetrating/physiopathology , Animals , Cohort Studies , Computer Simulation , Humans , Interleukin-6/physiologyABSTRACT
BACKGROUND: There has been much debate about the orientation of multi-hair grafts in order to obtain an appearance of fullness after the hair transplantation. OBJECTIVES: To analyze natural orientation of multi-hair follicles and the influence of hair flow from the crown swirl. METHODS: Natural orientation of follicles was analyzed microscopically in 100 nonbald men: a clockwise whorl flow group (50 men) and a counterclockwise group (50 men). RESULTS: The majority of multi-hair follicles were oriented perpendicular to the radial line from the whorl in both the groups. The percentage of perpendicular orientation was large in the peripheral and middle scalp areas (49-79%), and it decreased in the vertex (38-49%, p<.05 or .01). The percentages of parallel, right oblique, and left oblique orientation were small in the peripheral area with a slight increase in the vertex (3-12% vs. 14-24%, p<.05 or .01). CONCLUSION: Original orientation of multi-hair follicles was mainly perpendicular to the radial line from the whorl irrelevant to the crown swirl hair flow. Multi-hair grafts transplanted perpendicularly would look similar to the natural hair follicles in the front half of the scalp.