ALBERT

Description: Implementation of pharmacogenetic‐guided warfarin dosing has been hindered by inconsistent results from reported clinical trials and a lack of available algorithms that include alleles prevalent in non‐white populations. However, current evidence indicates that algorithm‐guided dosing is more accurate than empirical dosing. To facilitate multiethnic algorithm‐guided warfarin dosing using preemptive genetic testing, we developed a strategy that accounts for the complexity of race and leverages electronic health records for algorithm variables and deploying point‐of‐care dose recommendations.

Description: Large uncertainty remains on how subtropical clouds will respond to anthropogenic climate change and therefore whether they will act as a positive feedback that amplifies global warming or negative feedback that dampens global warming by altering Earth's energy budget. Here, we reduce this uncertainty using an observationally constrained formulation of the response of subtropical clouds to greenhouse forcing. The observed interannual sensitivity of cloud solar reflection to varying meteorological conditions suggests that increasing sea-surface temperature and atmospheric stability in the future climate will have largely cancelling effects on subtropical cloudiness, overall leading to a weak positive shortwave cloud feedback (0.4±0.9 W m -2 K -1 ). The uncertainty of this observationally based approximation of the cloud feedback is narrower than the inter-model spread of the feedback produced by climate models. Subtropical cloud changes will therefore complement positive cloud feedbacks identified by previous work, suggesting that future global cloud changes will amplify global warming.

Description: The Integrated Medical Model (IMM) simulates the medical occurrences and mission outcomes for various mission profiles using probabilistic risk assessment techniques. As part of the work with the Integrated Medical Model (IMM), this project focuses on radiation risks from acute events during extended human missions outside low Earth orbit (LEO). Of primary importance in acute risk assessment are solar particle events (SPEs), which are low probability, high consequence events that could adversely affect mission outcomes through acute radiation damage to astronauts. SPEs can be further classified into coronal mass ejections (CMEs) and solar flares/impulsive events (Fig. 1). CMEs are an eruption of solar material and have shock enhancements that contribute to make these types of events higher in total fluence than impulsive events.

Description: Sensitivity analysis estimates the relative contribution of the uncertainty in input values to the uncertainty of model outputs. Partial Rank Correlation Coefficient (PRCC) and Standardized Rank Regression Coefficient (SRRC) are methods of conducting sensitivity analysis on nonlinear simulation models like the Integrated Medical Model (IMM). The PRCC method estimates the sensitivity using partial correlation of the ranks of the generated input values to each generated output value. The partial part is so named because adjustments are made for the linear effects of all the other input values in the calculation of correlation between a particular input and each output. In SRRC, standardized regression-based coefficients measure the sensitivity of each input, adjusted for all the other inputs, on each output. Because the relative ranking of each of the inputs and outputs is used, as opposed to the values themselves, both methods accommodate the nonlinear relationship of the underlying model. As part of the IMM v4.0 validation study, simulations are available that predict 33 person-missions on ISS and 111 person-missions on STS. These simulated data predictions feed the sensitivity analysis procedures. The inputs to the sensitivity procedures include the number occurrences of each of the one hundred IMM medical conditions generated over the simulations and the associated IMM outputs: total quality time lost (QTL), number of evacuations (EVAC), and number of loss of crew lives (LOCL). The IMM team will report the results of using PRCC and SRRC on IMM v4.0 predictions of the ISS and STS missions created as part of the external validation study. Tornado plots will assist in the visualization of the condition-related input sensitivities to each of the main outcomes. The outcomes of this sensitivity analysis will drive review focus by identifying conditions where changes in uncertainty could drive changes in overall model output uncertainty. These efforts are an integral part of the overall verification, validation, and credibility review of IMM v4.0.

Description: No abstract available

Description: Renal stone disease is not only a concern on earth but can conceivably pose a serious risk to the astronauts health and safety in Space. In this work, two different deterministic models based on a Population Balance Equation (PBE) analysis of renal stone formation are developed to assess the risks of critical renal stone incidence for astronauts during space travel. In the first model, the nephron is treated as a continuous mixed suspension mixed product removal crystallizer and the PBE for the nucleating, growing and agglomerating renal calculi is coupled to speciation calculations performed by JESS. Predictions of stone size distributions in the kidney using this model indicate that the astronaut in microgravity is at noticeably greater but still subcritical risk and recommend administration of citrate and augmented hydration as effective means of minimizing and containing this risk. In the second model, the PBE analysis is coupled to a Computational Fluid Dynamics (CFD) model for flow of urine and transport of Calcium and Oxalate in the nephron to predict the impact of gravity on the stone size distributions. Results presented for realistic 3D tubule and collecting duct geometries, clearly indicate that agglomeration is the primary mode of size enhancement in both 1g and microgravity. 3D numerical simulations seem to further indicate that there will be an increased number of smaller stones developed in microgravity that will likely pass through the nephron in the absence of wall adhesion. However, upon reentry to a 1g (Earth) or 38g (Mars) partial gravitational fields, the renal calculi can lag behind the urinary flow in tubules that are adversely oriented with respect to the gravitational field and grow agglomerate to large sizes that are sedimented near the wall with increased propensity for wall adhesion, plaque formation, and risk to the astronauts.

Description: Visual Impairment and Intracranial Pressure (VIIP) syndrome is a concern for long-duration space flight. Current thinking suggests that the ocular changes observed in VIIP syndrome are related to cephalad fluid shifts resulting in altered fluid pressures [1]. In particular, we hypothesize that increased intracranial pressure (ICP) drives connective tissue remodeling of the posterior eye and optic nerve sheath (ONS). We describe here finite element (FE) modeling designed to understand how altered pressures, particularly altered ICP, affect the tissues of the posterior eye and optic nerve sheath (ONS) in VIIP. METHODS: Additional description of the modeling methodology is provided in the companion IWS abstract by Feola et al. In brief, a geometric model of the posterior eye and optic nerve, including the ONS, was created and the effects of fluid pressures on tissue deformations were simulated. We considered three ICP scenarios: an elevated ICP assumed to occur in chronic microgravity, and ICP in the upright and supine positions on earth. Within each scenario we used Latin hypercube sampling (LHS) to consider a range of ICPs, ONH tissue mechanical properties, intraocular pressures (IOPs) and mean arterial pressures (MAPs). The outcome measures were biomechanical strains in the lamina cribrosa, optic nerve and retina; here we focus on peak values of these strains, since elevated strain alters cell phenotype and induce tissue remodeling. In 3D, the strain field can be decomposed into three orthogonal components, denoted as first, second and third principal strains. RESULTS AND CONCLUSIONS: For baseline material properties, increasing ICP from 0 to 20 mmHg significantly changed strains within the posterior eye and ONS (Fig. 1), indicating that elevated ICP affects ocular tissue biomechanics. Notably, strains in the lamina cribrosa and retina became less extreme as ICP increased; however, within the optic nerve, the occurrence of such extreme strains greatly increased as ICP was elevated (Fig. 2). In particular, c. 48 of simulations in the elevated ICP condition showed peak strains in the optic nerve that exceeded the strains expected on earth. Such extreme strains are likely important, since they represent a larger signal for mechano-responsive resident cells [2]. The models predicted little to no anterior motion of the prelaminar neural tissue (optic nerve swelling, or papilledema, secondary to axoplasmic stasis), typically seen with elevated ICP. Specialized FE models to capture axoplasmic stasis would be required to study papilledema. These results suggest that the most notable effect of elevated ICP may occur via direct optic nerve loading, rather than through connective tissue deformation. These FE models can inform the design of future studies designed to bridge the gap between biomechanics and pathophysiological function in VIIP.

Description: The IMMs ability to assess mission outcome risk levels relative to available resources provides a unique capability to provide guidance on optimal operational medical kit and vehicle resources. Post-processing optimization allows IMM to optimize essential resources to improve a specific model outcome such as maximization of the Crew Health Index (CHI), or minimization of the probability of evacuation (EVAC) or the loss of crew life (LOCL). Mass and or volume constrain the optimized resource set. The IMMs probabilistic simulation uses input data on one hundred medical conditions to simulate medical events that may occur in spaceflight, the resources required to treat those events, and the resulting impact to the mission based on specific crew and mission characteristics. Because IMM version 4.0 provides for partial treatment for medical events, IMM Optimization 4.0 scores resources at the individual resource unit increment level as opposed to the full condition-specific treatment set level, as done in version 3.0. This allows the inclusion of as many resources as possible in the event that an entire set of resources called out for treatment cannot satisfy the constraints. IMM Optimization version 4.0 adds capabilities that increase efficiency by creating multiple resource sets based on differing constraints and priorities, CHI, EVAC, or LOCL. It also provides sets of resources that improve mission-related IMM v4.0 outputs with improved performance compared to the prior optimization. The new optimization represents much improved fidelity that will improve the utility of the IMM 4.0 for decision support.

Description: No abstract available