APPRAISE-HRI: AN ARTIFICIAL INTELLIGENCE ALGORITHM FOR TRIAGE OF HEMORRHAGE CASUALTIES.

ABSTRACT: Background: Hemorrhage remains the leading cause of death on the battlefield. This study aims to assess the ability of an artificial intelligence triage algorithm to automatically analyze vital-sign data and stratify hemorrhage risk in trauma patients. Methods: Here, we developed the APPRAISE-Hemorrhage Risk Index (HRI) algorithm, which uses three routinely measured vital signs (heart rate and diastolic and systolic blood pressures) to identify trauma patients at greatest risk of hemorrhage. The algorithm preprocesses the vital signs to discard unreliable data, analyzes reliable data using an artificial intelligence-based linear regression model, and stratifies hemorrhage risk into low (HRI:I), average (HRI:II), and high (HRI:III). Results: To train and test the algorithm, we used 540 h of continuous vital-sign data collected from 1,659 trauma patients in prehospital and hospital (i.e., emergency department) settings. We defined hemorrhage cases (n = 198) as those patients who received ≥1 unit of packed red blood cells within 24 h of hospital admission and had documented hemorrhagic injuries. The APPRAISE-HRI stratification yielded a hemorrhage likelihood ratio (95% confidence interval) of 0.28 (0.13-0.43) for HRI:I, 1.00 (0.85-1.15) for HRI:II, and 5.75 (3.57-7.93) for HRI:III, suggesting that patients categorized in the low-risk (high-risk) category were at least 3-fold less (more) likely to have hemorrhage than those in the average trauma population. We obtained similar results in a cross-validation analysis. Conclusions: The APPRAISE-HRI algorithm provides a new capability to evaluate routine vital signs and alert medics to specific casualties who have the highest risk of hemorrhage, to optimize decision-making for triage, treatment, and evacuation.

2B-Alert App: A mobile application for real-time individualized prediction of alertness.

Knowing how an individual responds to sleep deprivation is a requirement for developing personalized fatigue management strategies. Here we describe and validate the 2B-Alert App, the first mobile application that progressively learns an individual's trait-like response to sleep deprivation in real time, to generate increasingly more accurate individualized predictions of alertness. We incorporated a Bayesian learning algorithm within the validated Unified Model of Performance to automatically and gradually adapt the model parameters to an individual after each psychomotor vigilance test. We implemented the resulting model and the psychomotor vigilance test as a smartphone application (2B-Alert App), and prospectively validated its performance in a 62-hr total sleep deprivation study in which 21 participants used the app to perform psychomotor vigilance tests every 3 hr and obtain real-time individualized predictions after each test. The temporal profiles of reaction times on the app-conducted psychomotor vigilance tests were well correlated with and as sensitive as those obtained with a previously characterized psychomotor vigilance test device. The app progressively learned each individual's trait-like response to sleep deprivation throughout the study, yielding increasingly more accurate predictions of alertness for the last 24 hr of total sleep deprivation as the number of psychomotor vigilance tests increased. After only 12 psychomotor vigilance tests, the accuracy of the model predictions was comparable to the peak accuracy obtained using all psychomotor vigilance tests. With the ability to make real-time individualized predictions of the effects of sleep deprivation on future alertness, the 2B-Alert App can be used to tailor personalized fatigue management strategies, facilitating self-management of alertness and safety in operational and non-operational settings.

Biophysical properties of microvascular endothelium: Requirements for initiating and conducting electrical signals.

OBJECTIVE: Electrical signaling along the endothelium underlies spreading vasodilation and blood flow control. We use mathematical modeling to determine the electrical properties of the endothelium and gain insight into the biophysical determinants of electrical conduction. METHODS: Electrical conduction data along endothelial tubes (40 µm wide, 2.5 mm long) isolated from mouse skeletal muscle resistance arteries were analyzed using cable equations and a multicellular computational model. RESULTS: Responses to intracellular current injection attenuate with an axial length constant (λ) of 1.2-1.4 mm. Data were fitted to estimate the axial (ra ; 10.7 MΩ/mm) and membrane (rm ; 14.5 MΩ∙mm) resistivities, EC membrane resistance (Rm ; 12 GΩ), and EC-EC coupling resistance (Rgj ; 4.5 MΩ) and predict that stimulation of ≥30 neighboring ECs is required to elicit 1 mV of hyperpolarization at distance = 2.5 mm. Opening Ca2+ -activated K+ channels (KCa ) along the endothelium reduced λ by up to 55%. CONCLUSIONS: High Rm makes the endothelium sensitive to electrical stimuli and able to conduct these signals effectively. Whereas the activation of a group of ECs is required to initiate physiologically relevant hyperpolarization, this requirement is increased by myoendothelial coupling and KCa activation along the endothelium inhibits conduction by dissipating electrical signals.

Can endothelial hemoglobin-α regulate nitric oxide vasodilatory signaling?

We used mathematical modeling to investigate nitric oxide (NO)-dependent vasodilatory signaling in the arteriolar wall. Detailed continuum cellular models of calcium (Ca2+) dynamics and membrane electrophysiology in smooth muscle and endothelial cells (EC) were coupled with models of NO signaling and biotransport in an arteriole. We used this theoretical approach to examine the role of endothelial hemoglobin-α (Hbα) as a modulator of NO-mediated myoendothelial feedback, as previously suggested in Straub et al. (Nature 491: 473-477, 2012). The model considers enriched expression of inositol 1,4,5-triphosphate receptors (IP3Rs), endothelial nitric oxide synthase (eNOS) enzyme, Ca2+-activated potassium (KCa) channels and Hbα in myoendothelial projections (MPs) between the two cell layers. The model suggests that NO-mediated myoendothelial feedback is plausible if a significant percentage of eNOS is localized within or near the myoendothelial projection. Model results show that the ability of Hbα to regulate the myoendothelial feedback is conditional to its colocalization with eNOS near MPs at concentrations in the high nanomolar range (>0.2 µM or 24,000 molecules). Simulations also show that the effect of Hbα observed in in vitro experimental studies may overestimate its contribution in vivo, in the presence of blood perfusion. Thus, additional experimentation is required to quantify the presence and spatial distribution of Hbα in the EC, as well as to test that the strong effect of Hbα on NO signaling seen in vitro, translates also into a physiologically relevant response in vivo.NEW & NOTEWORTHY Mathematical modeling shows that although regulation of nitric oxide signaling by hemoglobin-α (Hbα) is plausible, it is conditional to its presence in significant concentrations colocalized with endothelial nitric oxide synthase in myoendothelial projections. Additional experimentation is required to test that the strong effect of Hbα seen in vitro translates into a physiologically relevant response in vivo.

Stochastic model of endothelial TRPV4 calcium sparklets: effect of bursting and cooperativity on EDH.

We examined the endothelial transient receptor vanilloid 4 (TRPV4) channel's vasodilatory signaling using mathematical modeling. The model analyzes experimental data by Sonkusare and coworkers on TRPV4-induced endothelial Ca(2+) events (sparklets). A previously developed continuum model of an endothelial and a smooth muscle cell coupled through microprojections was extended to account for the activity of a TRPV4 channel cluster. Different stochastic descriptions for the TRPV4 channel flux were examined using finite-state Markov chains. The model also took into consideration recent evidence for the colocalization of intermediate-conductance calcium-activated potassium channels (IKCa) and TRPV4 channels near the microprojections. A single TRPV4 channel opening resulted in a stochastic localized Ca(2+) increase in a small region (i.e., few µm(2) area) close to the channel. We predict micromolar Ca(2+) increases lasting for the open duration of the channel sufficient for the activation of low-affinity endothelial KCa channels. Simulations of a cluster of four TRPV4 channels incorporating burst and cooperative gating kinetics provided quantal Ca(2+) increases (i.e., steps of fixed amplitude), similar to the experimentally observed Ca(2+) sparklets. These localized Ca(2+) events result in endothelium-derived hyperpolarization (and SMC relaxation), with magnitude that depends on event frequency. The gating characteristics (bursting, cooperativity) of the TRPV4 cluster enhance Ca(2+) spread and the distance of KCa channel activation. This may amplify the EDH response by the additional recruitment of distant KCa channels.

Role of microprojections in myoendothelial feedback--a theoretical study.

We investigated the role of myoendothelial projections (MPs) in endothelial cell (EC) feedback response to smooth muscle cell (SMC) stimulation using mathematical modelling. A previously developed compartmental EC-SMC model is modified to include MPs as subcellular compartments in the EC. The model is further extended into a 2D continuum model using a finite element method (FEM) approach and electron microscopy images to account for MP geometry. The EC and SMC are coupled via non-selective myoendothelial gap junctions (MEGJs) which are located on MPs and allow exchange of Ca(2+), K(+), Na(+) and Cl(-) ions and inositol 1,4,5-triphosphate (IP3). Models take into consideration recent evidence for co-localization of intermediate-conductance calcium-activated potassium channels (IKCa) and IP3 receptors (IP3Rs) in the MPs. SMC stimulation causes an IP3-mediated Ca(2+) transient in the MPs with limited global spread in the bulk EC. A hyperpolarizing feedback generated by the localized IKCa channels is transmitted to the SMC via MEGJs. MEGJ resistance (Rgj) and the density of IKCa and IP3R in the projection influence the extent of EC response to SMC stimulation. The predicted Ca(2+) transients depend also on the volume and geometry of the MP. We conclude that in the myoendothelial feedback response to SMC stimulation, MPs are required to amplify the SMC initiated signal. Simulations suggest that the signal is mediated by IP3 rather than Ca(2+) diffusion and that a localized rather than a global EC Ca(2+) mobilization is more likely following SMC stimulation.

Multiple factors influence calcium synchronization in arterial vasomotion.

The intercellular synchronization of spontaneous calcium (Ca(2+)) oscillations in individual smooth muscle cells is a prerequisite for vasomotion. A detailed mathematical model of Ca(2+) dynamics in rat mesenteric arteries shows that a number of synchronizing and desynchronizing pathways may be involved. In particular, Ca(2+)-dependent phospholipase C, the intercellular diffusion of inositol trisphosphate (IP(3), and to a lesser extent Ca(2+)), IP(3) receptors, diacylglycerol-activated nonselective cation channels, and Ca(2+)-activated chloride channels can contribute to synchronization, whereas large-conductance Ca(2+)-activated potassium channels have a desynchronizing effect. Depending on the contractile state and agonist concentrations, different pathways become predominant, and can be revealed by carefully inhibiting the oscillatory component of their total activity. The phase shift between the Ca(2+) and membrane potential oscillations can change, and thus electrical coupling through gap junctions can mediate either synchronization or desynchronization. The effect of the endothelium is highly variable because it can simultaneously enhance the intercellular coupling and affect multiple smooth muscle cell components. Here, we outline a system of increased complexity and propose potential synchronization mechanisms that need to be experimentally tested.

Intercellular communication in the vascular wall: a modeling perspective.

Movement of ions (Ca(2+) , K(+) , Na(+) , and Cl(-) ) and second messenger molecules like inositol 1, 4, 5-trisphosphate inside and in between different cells is the basis of many signaling mechanisms in the microcirculation. In spite of the vast experimental efforts directed toward evaluation of these fluxes, it has been a challenge to establish their roles in many essential microcirculatory phenomena. Recently, detailed theoretical models of calcium dynamics and plasma membrane electrophysiology have emerged to assist in the quantification of these intra and intercellular fluxes and enhance understanding of their physiological importance. This perspective reviews selected models relevant to estimation of such intra and intercellular ionic and second messenger fluxes and prediction of their relative significance to a variety of vascular phenomena, such as myoendothelial feedback, conducted responses, and vasomotion.

Modeling Ca2+ signaling in the microcirculation: intercellular communication and vasoreactivity.

A network of intracellular signaling pathways and complex intercellular interactions regulate calcium mobilization in vascular cells, arteriolar tone, and blood flow. Different endothelium-derived vasoreactive factors have been identified and the importance of myoendothelial communication in vasoreactivity is now well appreciated. The ability of many vascular networks to conduct signals upstream also is established. This phenomenon is critical for both short-term changes in blood perfusion as well as long-term adaptations of a vascular network. In addition, in a phenomenon termed vasomotion, arterioles often exhibit spontaneous oscillations in diameter. This is thought to improve tissue oxygenation and enhance blood flow. Experimentation has begun to reveal important aspects of the regulatory machinery and the significance of these phenomena for the regulation of local perfusion and oxygenation. Mathematical modeling can assist in elucidating the complex signaling mechanisms that participate in these phenomena. This review highlights some of the important experimental studies and relevant mathematical models that provide the current understanding of these mechanisms in vasoreactivity.

Multiscale FEM modeling of vascular tone: from membrane currents to vessel mechanics.

Regulation of vascular tone is a complex process that remains poorly understood. Here, we present our recent efforts for the development of physiologically realistic models of arterial segments for the analysis of vasoreactivity in health and disease. Multiscale modeling integrates intracellular and cell membrane components into whole-cell models of calcium and membrane potential dynamics. Single-cell models of vascular cells are combined into a multicellular model of the vascular wall, and vessel wall biomechanics are integrated with calcium dynamics in the smooth muscle layer. At each scale, continuum models using finite element method can account for spatial heterogeneity in calcium signaling and for nonuniform deformations of a vessel segment. The outlined approach can be used to investigate cellular mechanisms underlying altered vasoreactivity in hypertension.

A mathematical model of vasoreactivity in rat mesenteric arterioles. II. Conducted vasoreactivity.

This study presents a multicellular computational model of a rat mesenteric arteriole to investigate the signal transduction mechanisms involved in the generation of conducted vasoreactivity. The model comprises detailed descriptions of endothelial (ECs) and smooth muscle (SM) cells (SMCs), coupled by nonselective gap junctions. With strong myoendothelial coupling, local agonist stimulation of the EC or SM layer causes local changes in membrane potential (V(m)) that are conducted electrotonically, primarily through the endothelium. When myoendothelial coupling is weak, signals initiated in the SM conduct poorly, but the sensitivity of the SMCs to current injection and agonist stimulation increases. Thus physiological transmembrane currents can induce different levels of local V(m) change, depending on cell's gap junction connectivity. The physiological relevance of current and voltage clamp stimulations in intact vessels is discussed. Focal agonist stimulation of the endothelium reduces cytosolic calcium (intracellular Ca(2+) concentration) in the prestimulated SM layer. This SMC Ca(2+) reduction is attributed to a spread of EC hyperpolarization via gap junctions. Inositol (1,4,5)-trisphosphate, but not Ca(2+), diffusion through homocellular gap junctions can increase intracellular Ca(2+) concentration in neighboring ECs. The small endothelial Ca(2+) spread can amplify the total current generated at the local site by the ECs and through the nitric oxide pathway, by the SMCs, and thus reduces the number of stimulated cells required to induce distant responses. The distance of the electrotonic and Ca(2+) spread depends on the magnitude of SM prestimulation and the number of SM layers. Model results are consistent with experimental data for vasoreactivity in rat mesenteric resistance arteries.

A mathematical model of vasoreactivity in rat mesenteric arterioles: I. Myoendothelial communication.

To study the effect of myoendothelial communication on vascular reactivity, we integrated detailed mathematical models of Ca(2+) dynamics and membrane electrophysiology in arteriolar smooth muscle (SMC) and endothelial (EC) cells. Cells are coupled through the exchange of Ca(2+), Cl(-), K(+), and Na(+) ions, inositol 1,4,5-triphosphate (IP(3)), and the paracrine diffusion of nitric oxide (NO). EC stimulation reduces intracellular Ca(2+) ([Ca(2+)](i)) in the SMC by transmitting a hyperpolarizing current carried primarily by K(+). The NO-independent endothelium-derived hyperpolarization was abolished in a synergistic-like manner by inhibition of EC SK(Ca) and IK(Ca) channels. During NE stimulation, IP(3) diffusing from the SMC induces EC Ca(2+) release, which, in turn, moderates SMC depolarization and [Ca(2+)](i) elevation. On the contrary, SMC [Ca(2+)](i) was not affected by EC-derived IP(3). Myoendothelial Ca(2+) fluxes had no effect in either cell. The EC exerts a stabilizing effect on calcium-induced calcium release-dependent SMC Ca(2+) oscillations by increasing the norepinephrine concentration window for oscillations. We conclude that a model based on independent data for subcellular components can capture major features of the integrated vessel behavior. This study provides a tissue-specific approach for analyzing complex signaling mechanisms in the vasculature.

A mathematical model of Ca2+ dynamics in rat mesenteric smooth muscle cell: agonist and NO stimulation.

A mathematical model of calcium dynamics in vascular smooth muscle cell (SMC) was developed based on data mostly from rat mesenteric arterioles. The model focuses on (a) the plasma membrane electrophysiology; (b) Ca2+ uptake and release from the sarcoplasmic reticulum (SR); (c) cytosolic balance of Ca2+, Na+, K+, and Cl ions; and (d) IP3 and cGMP formation in response to norepinephrine(NE) and nitric oxide (NO) stimulation. Stimulation with NE induced membrane depolarization and an intracellular Ca2+ ([Ca2+]i) transient followed by a plateau. The plateau concentrations were mostly determined by the activation of voltage-operated Ca2+ channels. NE causes a greater increase in [Ca2+]i than stimulation with KCl to equivalent depolarization. Model simulations suggest that the effect of[Na+]i accumulation on the Na+/Ca2+ exchanger (NCX) can potentially account for this difference.Elevation of [Ca2+]i within a concentration window (150-300 nM) by NE or KCl initiated [Ca2+]i oscillations with a concentration-dependent period. The oscillations were generated by the nonlinear dynamics of Ca2+ release and refilling in the SR. NO repolarized the NE-stimulated SMC and restored low [Ca2+]i mainly through its effect on Ca2+-activated K+ channels. Under certain conditions, Na+-K+-ATPase inhibition can result in the elevation of [Na+]i and the reversal of NCX, increasing resting cytosolic and SR Ca2+ content, as well as reactivity to NE. Blockade of the NCX's reverse mode could eliminate these effects. We conclude that the integration of the selected cellular components yields a mathematical model that reproduces, satisfactorily, some of the established features of SMC physiology. Simulations suggest a potential role of intracellular Na+ in modulating Ca2+ dynamics and provide insights into the mechanisms of SMC constriction, relaxation, and the phenomenon of vasomotion. The model will provide the basis for the development of multi-cellular mathematical models that will investigate microcirculatory function in health and disease.

A mathematical model of plasma membrane electrophysiology and calcium dynamics in vascular endothelial cells.

Vascular endothelial cells (ECs) modulate smooth muscle cell (SMC) contractility, assisting in vascular tone regulation. Cytosolic Ca(2+) concentration ([Ca(2+)](i)) and membrane potential (V(m)) play important roles in this process by controlling EC-dependent vasoactive signals and intercellular communication. The present mathematical model integrates plasmalemma electrophysiology and Ca(2+) dynamics to investigate EC responses to different stimuli and the controversial relationship between [Ca(2+)](i) and V(m). The model contains descriptions for the intracellular balance of major ionic species and the release of Ca(2+) from intracellular stores. It also expands previous formulations by including more detailed transmembrane current descriptions. The model reproduces V(m) responses to volume-regulated anion channel (VRAC) blockers and extracellular K(+) concentration ([K(+)](o)) challenges, predicting 1) that V(m) changes upon VRAC blockade are [K(+)](o) dependent and 2) a biphasic response of V(m) to increasing [K(+)](o). Simulations of agonist-induced Ca(2+) mobilization replicate experiments under control and V(m) hyperpolarization blockade conditions. They show that peak [Ca(2+)](i) is governed by store Ca(2+) release while Ca(2+) influx (and consequently V(m)) impacts more the resting and plateau [Ca(2+)](i). The V(m) sensitivity of rest and plateau [Ca(2+)](i) is dictated by a [Ca(2+)](i) "buffering" system capable of masking the V(m)-dependent transmembrane Ca(2+) influx. The model predicts plasma membrane Ca(2+)-ATPase and Ca(2+) permeability as main players in this process. The heterogeneous V(m) impact on [Ca(2+)](i) may elucidate conflicting reports on how V(m) influences EC Ca(2+). The present study forms the basis for the development of multicellular EC-SMC models that can assist in understanding vascular autoregulation in health and disease.

A theoretical model of the high-frequency arrhythmogenic depolarization signal following myocardial infarction.

Theoretical body-surface potentials were computed from single, branching and tortuous strands of Luo-Rudy dynamic model cells, representing different areas of an infarct scar. When action potential (AP) propagation either in longitudinal or transverse direction was slow (3-12 cm/s), the depolarization signals contained high-frequency (100-300 Hz) oscillations. The frequencies were related to macroscopic propagation velocity and strand architecture by simple formulas. Next, we extended a mathematical model of the QRS-complex presented in our earlier work to simulate unstable activation wavefront. It combines signals from different strands with small timing fluctuations relative to a large repetitive QRS-like waveform and can account for dynamic changes of real arrhythmogenic micropotentials. Variance spectrum of wavelet coefficients calculated from the composite QRS-complex contained the high frequencies of the individual abnormal signals. We conclude that slow AP propagation through fibrotic regions after myocardial infarction is a source of high-frequency arrhythmogenic components that increase beat-to-beat variability of the QRS, and wavelet variance parameters can be used for ventricular tachycardia risk assessment.