CRYSTALLOIDS OR COLLOIDS… WHAT’S IN YOUR IV? Determining Fluid Type for Septic Shock Resuscitation

Objective: To compare the efficacy of crystalloid versus colloid solutions, specifically normal saline versus albumin, in decreasing mortality among patients with septic shock requiring resuscitation fluids in the intensive care unit (ICU) setting. Design: Systematic literature review. Methods: Research was conducted in PubMed and UpToDate, utilizing the search terms sepsis, septic shock, fluid resuscitation, colloids and crystalloids. Specifically, in PubMed, the following limits and terms were used: randomized control trial, human subjects, English, and within the last 7 years. Results: The Annane et al study found no significant difference in colloid fluid resuscitation versus crystalloid fluid resuscitation in the decreasing 28-day mortality in hypovolemic shock patients specifically in the ICU setting. The Finfer et al study found no significant difference between albumin and normal saline when assessing 28-day mortality and morbidity for patients in the ICU with severe sepsis. The Caironi et al study found no significant difference in albumin and crystalloids co-administration compared to crystalloids alone in 28-day mortality and morbidity outcomes for those with septic shock admitted to the ICU. Conclusion: The choice of fluid in aggressive resuscitation has no significant effect on patient mortality in those with septic shock in the intensive care unit (ICU)

Change in Acoustic Startle as an Indicator of Continuous Tonal Tinnitus

Currently, there is no accepted objective measure of tinnitus in humans. The gap prepulse inhibition of acoustic startle (GPIAS) paradigm is an objective measure that has been used in the animal model to identify tinnitus based on the theory of tinnitus filling in the silent gap that would normally promote startle inhibition. The current study applied the GPIAS paradigm in human subjects with normal hearing thresholds without hyperacusis. Individuals with continuous tonal tinnitus (N=31) characterized their tinnitus by adjusting a signal to match the frequency, bandwidth, and intensity. These individual parameters were used to create maximally matched background sounds in the GPIAS paradigm for each subject. A group without tinnitus (N=8) also participated using the averaged parameter values of the background sound from the group with tinnitus. Startle inhibition percentage was calculated by comparing ocular EMG blinking amplitudes between gap embedded conditions and the condition without a gap. As expected, the group with no tinnitus revealed startle inhibition as evidenced by reduced EMG blink amplitudes when the background sound was interrupted by a silent gap prior to the startle impulse (100 dB SPL white noise). The group with tinnitus did not have a significant startle inhibition in this same condition supporting the theory that the background sound carefully matched to their tinnitus eliminated the perception of a silent gap, thereby removing the cue that would produce startle inhibition. Gradually increasing the contrast between the individual’s continuous tonal tinnitus and ongoing background sound leads to a nonlinear change in startle inhibition percentage, providing guidelines for how closely the background sound needs to match the tinnitus of an individual in order to get the expected result of no startle inhibition when tinnitus is filling in the gap. Collectively, these findings support the use of the GPIAS paradigm for objectively identifying continuous tonal tinnitus in humans. Further, certain deviations in frequency, intensity, or bandwidth in the ongoing background sound from the tinnitus match result in startle inhibition, which may help explain the inconsistent findings across human GPIAS studies and allow more confidence for animal researchers to use GPIAS for animal tinnitus studies

Change blindness: eradication of gestalt strategies

Arrays of eight, texture-defined rectangles were used as stimuli in a one-shot change blindness (CB) task where there was a 50% chance that one rectangle would change orientation between two successive presentations separated by an interval. CB was eliminated by cueing the target rectangle in the first stimulus, reduced by cueing in the interval and unaffected by cueing in the second presentation. This supports the idea that a representation was formed that persisted through the interval before being 'overwritten' by the second presentation (Landman et al, 2003 Vision Research 43149–164]. Another possibility is that participants used some kind of grouping or Gestalt strategy. To test this we changed the spatial position of the rectangles in the second presentation by shifting them along imaginary spokes (by ±1 degree) emanating from the central fixation point. There was no significant difference seen in performance between this and the standard task [F(1,4)=2.565, p=0.185]. This may suggest two things: (i) Gestalt grouping is not used as a strategy in these tasks, and (ii) it gives further weight to the argument that objects may be stored and retrieved from a pre-attentional store during this task

On the Modeling of Dynamic-Systems using Sequence-based Deep Neural-Networks

The objective of this thesis is the adaptation and development of sequence-based Neural-Networks (NNs) applied to the modeling of dynamic systems. More specifically, we will focus our study on 2 sub-problems: the modeling of time-series, the modeling and control of multiple-input multiple-output (MIMO) systems. These 2 sub-problems will be explored through the modeling of crops, and the modeling and control of robots. To solve these problems, we build on NNs and training schemes allowing our models to out-perform the state-of-the-art results in their respective fields. In the irrigation field, we show that NNs are powerful tools capable of modeling the water consumption of crops while observing only a portion of what is currently required by reference methods. We further demonstrate the potential of NNs by inferring irrigation recommendations in real-time. In robotics, we show that prioritization techniques can be used to learn better robot dynamic models. We apply the models learned using these methods inside an Model Predictive Control (MPC) controller, further demonstrating their benefits. Additionally, we leverage Dreamer, an Model Based Reinforcement Learning (MBRL) agent, to solve visuomotor tasks. We demonstrate that MBRL controllers can be used for sensor-based control on real robots without being trained on real systems. Adding to this result, we developed a physics-guided variant of DREAMER. This variation of the original algorithm is more flexible and designed for mobile robots. This novel framework enables reusing previously learned dynamics and transferring environment knowledge to other robots. Furthermore, using this new model, we train agents to reach various goals without interacting with the system. This increases the reusability of the learned models and makes for a highly data-efficient learning scheme. Moreover, this allows for efficient dynamics randomization, creating robust agents that transfer well to unseen dynamics.Ph.D

Invasive versus medical management in patients with prior coronary artery bypass surgery with a non-ST segment elevation acute coronary syndrome: a pilot randomized controlled trial

Background: The benefits of routine invasive management in patients with prior coronary artery bypass grafts presenting with non-ST elevation acute coronary syndromes are uncertain because these patients were excluded from pivotal trials. Methods: In a multicenter trial, non-ST elevation acute coronary syndromes patients with prior coronary artery bypass graft were prospectively screened in 4 acute hospitals. Medically stabilized patients were randomized to invasive management (invasive group) or noninvasive management (medical group). The primary outcome was adherence with the randomized strategy by 30 days. A blinded, independent Clinical Event Committee adjudicated predefined composite outcomes for efficacy (all-cause mortality, rehospitalization for refractory ischemia/angina, myocardial infarction, hospitalization because of heart failure) and safety (major bleeding, stroke, procedure-related myocardial infarction, and worsening renal function). Results: Two hundred seventeen patients were screened and 60 (mean±SD age, 71±9 years, 72% male) were randomized (invasive group, n=31; medical group, n=29). One-third (n=10) of the participants in the invasive group initially received percutaneous coronary intervention. In the medical group, 1 participant crossed over to invasive management on day 30 but percutaneous coronary intervention was not performed. During 2-years’ follow-up (median [interquartile range], 744 [570–853] days), the composite outcome for efficacy occurred in 13 (42%) subjects in the invasive group and 13 (45%) subjects in the medical group. The composite safety outcome occurred in 8 (26%) subjects in the invasive group and 9 (31%) subjects in the medical group. An efficacy or safety outcome occurred in 17 (55%) subjects in the invasive group and 16 (55%) subjects in the medical group. Health status (EuroQol 5 Dimensions) and angina class in each group were similar at 12 months. Conclusions: More than half of the population experienced a serious adverse event. An initial noninvasive management strategy is feasible. A substantive health outcomes trial of invasive versus noninvasive management in non-ST elevation acute coronary syndromes patients with prior coronary artery bypass grafts appears warranted. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01895751

Reconstruction, Reconciliation, and Validation of Metabolic Networks

University of Minnesota Ph.D. dissertation. May 2018. Major: Plant Biological Sciences. Advisor: Igor Libourel. 1 computer file (PDF); ix, 120 pages.Metabolic networks are rigorous and computable representations of metabolism that describe the connections between genes, enzymes, reactions, and metabolites. The comprehensive nature of metabolic networks has allowed them to become the first truly “genome-scale” models, and they have served as a foundational framework for the broader effort of systems biology, which aims to model all aspects of cellular function. A more thorough and accurate understanding of metabolism has the potential to improve the synthesis of important biological compounds, better model metabolic diseases, and progress towards simulations of entire cells. The thesis research presented here focuses on the reconstruction of organism-specific metabolic networks from genome annotations and methods for improving metabolic networks by reconciling them with observed phenotypes, specifically the synthesis of essential cellular metabolites such as DNA, amino acids, and other small molecules. Gene sequence similarity and estimations of thermodynamic reaction parameters are used to guide network reconciliation through the use of numerical optimization algorithms. Particular attention is devoted to the validation of metabolic networks using experimental data, such as gene essentiality, and the development of computational controls using parameter randomization

Development and Bioavailability/Bioequivalence of a Fixed-Dose Combination Antiretroviral Reconstitutable Suspension Intended for Pediatrics

This dissertation was designed to develop and assess bioavailability/ bioequivalence of age-appropriate fixed-dose combination granules of lamivudine/zidovudine/nevirapine as reconstitutable suspension for pediatrics for use in pediatric patients. The granules were developed via roller compaction process to improve granule flow characteristics, minimize segregation of the multi-component active pharmaceutical ingredients, and avoid introducing moisture into the formulation and thereby improve the stability of the product. Optimization of the roller compaction process for the roll pressure and the ratio of the horizontal feed screw speed to the roll speed showed that these parameters had minimal effect on granule quality. Subsequently, a replicated 32 factorial design was utilized to optimize the levels of the suspending agent (Avicel RC 591) and the anticaking agent (Aerosil 200). Modeling of the formulation viscosity through multiple regression analysis showed that the viscosity was a quadratic function of the concentration of Avicel RC 591. An assessment of the stability of the granules for reconstitution under International Conference on Harmonization stability conditions at 40 oC/75 %RH and 30 oC/65 %RH indicated the granule formulation to be stable with an estimated shelf-life of not less than 6 months. Similarly, the evaluation of the chemical stability of the reconstituted suspension at 30 oC/65 %RH showed the suspension to be stable for several weeks. A clinical batch of the granules for reconstitution manufactured under Good Manufacturing Practices was tested for bioavailability and bioequivalence in a clinical study. A randomized single dose two-way complete crossover design in 24 healthy adult cohorts was performed, and the plasma samples from the subjects were analyzed by HPLC with UV detection. Non-compartmental pharmacokinetic analysis was performed to obtain the Cmax, AUCo-t, and AUCo-inf utilizing WinNonlin software. Analysis of variance of the formulation, period, sequence, and subject effects established the absence of any significant effects due to these parameters. Application of the two one-sided statistical tests using the Anderson-Hauck method showed that the 90 % confidence interval for the ratio of test/reference for various pharmacokinetic parameters was within 82.6 - 124.5 % bioequivalence limits for all the three drugs. This confirms that the fixed-dose combination granule for reconstitution was bioequivalent to the simultaneously administered single-entity reference products