Chronic Aripiprazole and Trazodone Polypharmacy Effects on Systemic and Brain Cholesterol Biosynthesis.

The concurrent use of several medications is a common practice in the treatment of complex psychiatric conditions. One such commonly used combination is aripiprazole (ARI), an antipsychotic, and trazodone (TRZ), an antidepressant. In addition to their effects on dopamine and serotonin systems, both of these compounds are inhibitors of the 7-dehydrocholesterol reductase (DHCR7) enzyme. To evaluate the systemic and nervous system distribution of ARI and TRZ and their effects on cholesterol biosynthesis, adult mice were treated with both ARI and TRZ for 21 days. The parent drugs, their metabolites, and sterols were analyzed in the brain and various organs of mice using LC-MS/MS. The analyses revealed that ARI, TRZ, and their metabolites were readily detectable in the brain and organs, leading to changes in the sterol profile. The levels of medications, their metabolites, and sterols differed across tissues with notable sex differences. Female mice showed higher turnover of ARI and more cholesterol clearance in the brain, with several post-lanosterol intermediates significantly altered. In addition to interfering with sterol biosynthesis, ARI and TRZ exposure led to decreased ionized calcium-binding adaptor molecule 1 (IBA1) and increased DHCR7 protein expression in the cortex. Changes in sterol profile have been also identified in the spleen, liver, and serum, underscoring the systemic effect of ARI and TRZ on sterol biosynthesis. Long-term use of concurrent ARI and TRZ warrants further studies to fully evaluate the lasting consequences of altered sterol biosynthesis on the whole body.

Additive Sensory Noise Effects on Operator Performance in a Lunar Landing Simulation.

INTRODUCTION: Adding noise to a system to improve a weak signal's detectability is known as stochastic resonance (SR). SR has been shown to improve sensory perception and cognitive performance in certain individuals, but it is unknown whether this performance improvement can translate to meaningful macrocognitive enhancements in performance for complex, operational tasks.OBJECTIVE: We investigated human operator performance in a lunar landing simulation while applying auditory white noise and/or noisy galvanic vestibular stimulation.METHODS: We measured performance (N = 16 subjects) while completing simulation trials in our Aerospace Research Simulator. Trials were completed with and without the influence of auditory white noise, noisy galvanic vestibular stimulation, and both simultaneously in a multimodal fashion. Performance was observed holistically and across subdimensions of the task, which included flight skill and perception. Subjective mental workload was collected after completing four trials in each treatment.RESULTS: We did not find broad operator improvement under the influence of noise, but a significant interaction was identified between subject and noise treatment, indicating that some subjects were impacted by additive noise. We also found significant interactions between subject and noise treatment in performance subdimensions of flight skill and perception. We found no significant main effects on mental workload.CONCLUSIONS: This study investigated the utility of using additive sensory noise to induce SR for complex tasks. While SR has been shown to improve aspects of performance, our results suggest additive noise does not yield operational performance changes for a broad population, but specific individuals may be affected.Sherman SO, Shen Y-Y, Gutierrez-Mendoza D, Schlittenhart M, Watson C, Clark TK, Anderson AP. Additive sensory noise effects on operator performance in a lunar landing simulation. Aerosp Med Hum Perform. 2023; 94(10):770-779.

Training augmentation using additive sensory noise in a lunar rover navigation task.

Background: The uncertain environments of future space missions means that astronauts will need to acquire new skills rapidly; thus, a non-invasive method to enhance learning of complex tasks is desirable. Stochastic resonance (SR) is a phenomenon where adding noise improves the throughput of a weak signal. SR has been shown to improve perception and cognitive performance in certain individuals. However, the learning of operational tasks and behavioral health effects of repeated noise exposure aimed to elicit SR are unknown. Objective: We evaluated the long-term impacts and acceptability of repeated auditory white noise (AWN) and/or noisy galvanic vestibular stimulation (nGVS) on operational learning and behavioral health. Methods: Subjects (n = 24) participated in a time longitudinal experiment to access learning and behavioral health. Subjects were assigned to one of our four treatments: sham, AWN (55 dB SPL), nGVS (0.5 mA), and their combination to create a multi-modal SR (MMSR) condition. To assess the effects of additive noise on learning, these treatments were administered continuously during a lunar rover simulation in virtual reality. To assess behavioral health, subjects completed daily, subjective questionnaires related to their mood, sleep, stress, and their perceived acceptance of noise stimulation. Results: We found that subjects learned the lunar rover task over time, as shown by significantly lower power required for the rover to complete traverses (p < 0.005) and increased object identification accuracy in the environment (p = 0.05), but this was not influenced by additive SR noise (p = 0.58). We found no influence of noise on mood or stress following stimulation (p > 0.09). We found marginally significant longitudinal effects of noise on behavioral health (p = 0.06) as measured by strain and sleep. We found slight differences in stimulation acceptability between treatment groups, and notably nGVS was found to be more distracting than sham (p = 0.006). Conclusion: Our results suggest that repeatedly administering sensory noise does not improve long-term operational learning performance or affect behavioral health. We also find that repetitive noise administration is acceptable in this context. While additive noise does not improve performance in this paradigm, if it were used for other contexts, it appears acceptable without negative longitudinal effects.

Effects of additive sensory noise on cognition.

Background: Adding noise to a system to improve a weak signal's throughput is known as stochastic resonance (SR). SR has been shown to improve sensory perception. Some limited research shows noise can also improve higher order processing, such as working memory, but it is unknown whether SR can broadly improve cognition. Objective: We investigated cognitive performance while applying auditory white noise (AWN) and/or noisy galvanic vestibular stimulation (nGVS). Methods: We measured cognitive performance (n = 13 subjects) while completing seven tasks in the cognition test battery (CTB). Cognition was assessed with and without the influence of AWN, nGVS, and both simultaneously. Performance in speed, accuracy, and efficiency was observed. A subjective questionnaire regarding preference for working in noisy environments was collected. Results: We did not find broad cognitive performance improvement under the influence of noise (p > 0.1). However, a significant interaction was found between subject and noise condition for accuracy (p = 0.023), indicating that some subjects exhibited cognitive changes with the addition of noise. Across all metrics, noisy environment preference may trend to be a potential indicator of whether subjects will exhibit SR cognitive benefits with a significant predictor in efficiency (p = 0.048). Conclusion: This study investigated using additive sensory noise to induce SR in overall cognition. Our results suggest that using noise to improve cognition is not applicable for a broad population; however, the effect of noise differs across individuals. Further, subjective questionnaires may be a means to identify which individuals are sensitive to SR cognitive benefits, but further investigation is needed.

Performance Risks During Surface Extravehicular Activity and Potential Mitigation Using Multimodal Displays.

BACKGROUND: Surface extravehicular activity (sEVA) will be a critical component of future human missions to the Moon. sEVA presents novel risks to astronaut crews not associated with microgravity operations due to fundamental differences in task demands, physiology, environment, and operations of working on the lunar surface. Multimodal spacesuit informatics displays have been proposed as a method of mitigating sEVA risk by increasing operator autonomy.METHODS: A formalized literature review was conducted. In total, 95 journal articles, conference papers, and technical reports were included. Characteristics of U.S. spacesuits were reviewed, ranging from the Apollo A7L to the xEMU Z-2.5. Multimodal display applications were then reviewed and assessed for their potential in aiding sEVA operations.RESULTS: Through literature review 25 performance impairments were identified. Performance impairments caused by the spacesuit represented the greatest number of sEVA challenges. Multimodal displays were mapped to impairments and approximately 36% of performance impairments could be aided by using display interfaces.DISCUSSION: Multimodal displays may provide additional benefits for alleviating performance impairments during sEVA. Utility of multimodal displays may be greater in certain performance impairment domains, such as spacesuit-related impairments.Zhang JY, Anderson AP. Performance risks during surface extravehicular activity and potential mitigation using multimodal displays. Aerosp Med Hum Perform. 2023; 94(1):34-41.

Modeling the Design Characteristics of Woven Textile Electrodes for long-Term ECG Monitoring.

An electrocardiograph records the periodic voltage generated by the heart over time. There is growing demand to continuously monitor the ECG for proactive health care and human performance optimization. To meet this demand, new conductive textile electrodes are being developed which offer an attractive alternative to adhesive gel electrodes but they come with their own challenges. The key challenge with textile electrodes is that the relationship between the manufacturing parameters and the ECG measurement is not well understood, making design an iterative process without the ability to prospectively develop woven electrodes with optimized performance. Here we address this challenge by applying the traditional skin-electrode interface circuit model to woven electrodes by constructing a parameterized model of the ECG system. Then the unknown parameters of the system are solved for with an iterative MATLAB optimizer using measured data captured with the woven electrodes. The results of this novel analysis confirm that yarn conductivity and total conductive area reduce skin electrode impedance. The results also indicate that electrode skin pressure and moisture require further investigation. By closing this gap in development, textile electrodes can be better designed and manufactured to meet the demands of long-term ECG capture.

Estimation of Subjectively Reported Trust, Mental Workload, and Situation Awareness Using Unobtrusive Measures.

OBJECTIVE: We use a set of unobtrusive measures to estimate subjectively reported trust, mental workload, and situation awareness (henceforth "TWSA"). BACKGROUND: Subjective questionnaires are commonly used to assess human cognitive states. However, they are obtrusive and usually impractical to administer during operations. Measures derived from actions operators take while working (which we call "embedded measures") have been proposed as an unobtrusive way to obtain TWSA estimates. Embedded measures have not been systematically investigated for each of TWSA, which prevents their operational utility. METHODS: Fifteen participants completed twelve trials of spaceflight-relevant tasks while using a simulated autonomous system. Embedded measures of TWSA were obtained during each trial and participants completed TWSA questionnaires after each trial. Statistical models incorporating our embedded measures were fit with various formulations, interaction effects, and levels of personalization to understand their benefits and improve model accuracy. RESULTS: The stepwise algorithm for building statistical models usually included embedded measures, which frequently corresponded to an intuitive increase or decrease in reported TWSA. Embedded measures alone could not accurately capture an operator's cognitive state, but combining the measures with readily observable task information or information about participants' backgrounds enabled the models to achieve good descriptive fit and accurate prediction of TWSA. CONCLUSION: Statistical models leveraging embedded measures of TWSA can be used to accurately estimate responses on subjective questionnaires that measure TWSA. APPLICATION: Our systematic approach to investigating embedded measures and fitting models allows for cognitive state estimation without disrupting tasks when administering questionnaires would be impractical.

Natural Scene Virtual Reality as a Behavioral Health Countermeasure in Isolated, Confined, and Extreme Environments: Three Isolated, Confined, Extreme Analog Case Studies.

INTRODUCTION: Isolated, confined, extreme (ICE) environments are accompanied by a host of stress-inducing circumstances: operational pressure, interpersonal dynamics, limited communication with friends and family, and environmental hazards. We evaluated the effectiveness of attention-restoration-therapy-based immersive Virtual Reality (VR) in three ICE environments: the Canadian Forces Station-Alert (CFS Alert), the 12-month HI-SEAS IV expedition, and the 8-month HI-SEAS V expedition. METHODS: Thirty-one individuals (29 male, 2 female) at CFS Alert, and 12 total crewmembers (7 male, 5 female, six crewmembers per sessions) at HI-SEAS participated. All participants viewed immersive VR scenes, but scene content varied by deployment. Data collection included pre- and post-intervention surveys and semi-structured post-mission interviews. Survey data were analyzed by scene content within each analog using nonparametric approaches. RESULTS: Acceptability and desirability of the VR content varied significantly by ICE analog, as well as by participants within a given analog. The two initial exploratory protocols enabled a more directed study in HI-SEAS V to identify the importance of differences in scene content. DISCUSSION: Use and perceived utility of the VR varied considerably across participants, indicating that psychological support needs to be individualized. Overall, natural scene VR was broadly considered restorative, but after long periods of isolation, dynamic and familiar scenes including those with people were also appealing. Immersive, nature-based VR was highly valued by some, but not all participants, suggesting that this intervention tool holds promise for use in ICE settings but needs to be tailored to the setting and individual.

A Qualitative Investigation of Space Exploration Medical Evacuation Risks.

INTRODUCTION: Exploration beyond low Earth orbit requires innovative solutions to support the crew medically, especially as the opportunity for timely evacuation to Earth diminishes. This includes assessing the risks and benefits that a complicated medical evacuation (MEDEVAC) poses to the injured crewmember, the crew, and the mission. This qualitative study identifies common MEDEVAC risk assessment principles used in spaceflight and other extreme environments to better inform future risk assessment tools and exploration mission concepts.METHODS: Semistructured interviews were conducted with subject matter experts in spaceflight and analog domains, including polar operations, undersea operations, combat medicine, and mountaineering. Transcripts were analyzed using the qualitative method of Thematic Analysis with the technique of consensus, co-occurrence, and comparison.RESULTS: Subject matter experts described 18 themes divided into two main categories: Primary Risk Considerations (e.g., crew, mission, resources, time) and Contributing Factors (e.g., psychological considerations, medical preparation, politics).DISCUSSION: Primary Risk Considerations can assess MEDEVAC risk across mission phases, with Contributing Factors acting as premission tools to adjust those risks. Inter- and intracategory connections identified medical support considerations, MEDEVAC support considerations, and philosophy as the most impactful Contributing Factors. Medical support considerations, psychological considerations, and political considerations were found to have unique aspects given the distances and societal impact of exploration vs. low Earth orbit spaceflight. The Contributing Factor theme of decision making was determined to be unique due to its impacts across both categories. These findings expand current considerations and are important inputs for exploration mission MEDEVAC Concepts of Operations.Almand A, Ko SY, Anderson A, Keller RJ, Zero M, Anderson AP, Laws JM, Lehnhardt K, Easter BD. A qualitative investigation of space exploration medical evacuation risks. Aerosp Med Hum Perform. 2023; 94(12):875-886.

Effects of Psychotropic Medication on Somatic Sterol Biosynthesis of Adult Mice.

Polypharmacy is commonly used to treat psychiatric disorders. These combinations often include drugs with sterol biosynthesis inhibiting side effects, including the antipsychotic aripiprazole (ARI), and antidepressant trazodone (TRZ). As the effects of psychotropic medications are poorly understood across the various tissue types to date, we investigated the effects of ARI, TRZ, and ARI + TRZ polypharmacy on the post-lanosterol biosynthesis in three cell lines (Neuro2a, HepG2, and human dermal fibroblasts) and seven peripheral tissues of an adult mouse model. We found that both ARI and TRZ strongly interfere with the function of 7-dehydrocholesterol reductase enzyme (DHCR7) and lead to robust elevation in 7-dehydrocholesterol levels (7-DHC) and reduction in desmosterol (DES) across all cell lines and somatic tissues. ARI + TRZ co-administration resulted in summative or synergistic effects across the utilized in vitro and in vivo models. These findings suggest that at least some of the side effects of ARI and TRZ are not receptor mediated but arise from inhibiting DHCR7 enzyme activity. We propose that interference with sterol biosynthesis, particularly in the case of simultaneous utilization of medications with such side effects, can potentially interfere with functioning or development of multiple organ systems, warranting further investigation.

Challenges in Quantifying Heel-Lift During Spacesuit Gait.

INTRODUCTION: Heel-lift is a subjectively reported fit issue in planetary spacesuit boot prototypes that has not yet been quantified. Inertial measurement units (IMUs) could quantify heel-lift but are susceptible to integration drift. This work evaluates the use of IMUs and drift-correction algorithms, such as zero-velocity (ZVUs) and zero-position updates (ZPUs), to quantify heel-lift during spacesuited gait.METHODS: Data was originally collected by Fineman et al. in 2018 to assess lower body relative coordination in the spacesuit. IMUs were mounted on the spacesuit lower legs (SLLs) and spacesuit operator's shank as three operators walked on a level walkway in three spacesuit padding conditions. Discrete wavelet transforms were used to identify foot-flat phase and heel-off for each step. Differences in heel-off timepoints were calculated in each step as a potential indicator of heel-lift, with spacesuit-delayed heel-off suggesting heel-lift. Average drift rates were estimated prior to and after applying ZVUs and ZPUs.RESULTS: Heel-off timepoint differences showed instances of spacesuit-delayed heel-off and instances of operator-delayed heel-off. Drift rates after applying ZVUs and ZPUs suggested an upper time bound of 0.03 s past heel-off to measure heel-lift magnitude with an accuracy of 1 cm.DISCUSSION: Results suggest that IMUs may not be appropriate for quantifying the presence and magnitude of heel lift. Operator-delayed heel-off suggests that the SLL may be expanding prior to heel-off, creating a false vertical acceleration signal interpreted by this study to be spacesuit heel-off. Quantifying heel-off will therefore require improvements in IMU mounting to mitigate the effects of SLL, or alternative sensor technologies.Boppana A, Priddy ST, Stirling L, Anderson AP. Challenges in quantifying heel-lift during spacesuit gait. Aerosp Med Hum Perform. 2022; 93(8):643-648.

Knock-in mouse models for studying somatostatin and cholecystokinin expressing cells.

BACKGROUND: Somatostatin (SST) and cholecystokinin (CCK) are peptide hormones that regulate the endocrine system, cell proliferation and neurotransmission. NEW METHOD: We utilized the novel Easi-CRISPR system to generate two knock-in mouse strains with Cre recombinase in SST- and CCK-expressing cells and validated their utility in the developing and adult brain tissues. RESULTS: The full nomenclature for the newly generated strains are C57BL/6-Sstem1(P2A-iCre-T2A-mCherry)Mirn and C57BL/6-Cckem1(iCre-T2A-mCherry-P2A)Mirn. For the Sst locus, a P2A-iCre-T2A-mCherry cassette was inserted immediately upstream of the stop codon (C terminus fusion). For the Cck locus, iCre-P2A-mCherry-T2A cassette was inserted at the start codon (N terminus fusion). Knock-in mice were generated using the Easi-CRISPR method. Developmental and adult SST and CCK expressions were preserved and showed an appropriate expression pattern in both models, with an active fluorescent tag in both animal lines. COMPARISON WITH EXISTING METHODS: Knock-in mouse models to study cell types that produce these critically important molecules are limited to date. The knock-in mice we generated can be used as reporters to study development, physiology, or pathophysiology of SST and CCK expressing cells - without interference with native expression of SST and CCK. In addition, they can be used as Cre driver models to conditionally delete floxed genes in SST and CCK expressing cells across various tissues. CONCLUSIONS: These two mouse models serve as valuable tools for in vitro and in vivo research studies related to SST and CCK biology across the lifespan and across different tissue types.

Utility of the Full ECG Waveform for Stress Classification.

The detection of psychological stress using the electrocardiogram (ECG) signal is most commonly based on the detection of the R peak-the most prominent part of the ECG waveform-and the heart rate variability (HRV) measurements derived from it. For stress detection algorithms focused on short-duration time windows, there is potential benefit in including HRV features derived from the detection of smaller peaks within the ECG waveform: the P, Q, S, and T waves. However, the potential drawback of using these small peaks is their smaller magnitude and subsequent susceptibility to noise, making them more difficult to reliably detect. In this work, we demonstrate the potential benefits of including smaller waves within binary stress classification using a pre-existing data set of ECG recordings from 57 participants (aged 18-40) with a self-reported fear of spiders during exposure to videos of spiders. We also present an analysis of the performance of an automated peak detection algorithm and the reliability of detection for each of the smaller parts of the ECG waveform. We compared two models, one with only R peak features and one with small peak features. They were similar in precision, recall, F1, area under ROC curve (AUC), and accuracy, with the greatest differences less than the standard deviations of each metric. There was a significant difference in the Akaike Information Criterion (AIC), which represented the information loss of the model. The inclusion of novel small peak features made the model 4.29×1028 times more probable to minimize the information loss, and the small peak features showed higher regression coefficients than the R peak features, indicating a stronger relationship with acute psychological stress. This difference and further analysis of the novel features suggest that small peak intervals could be indicative of independent processes within the heart, reflecting a psychophysiological response to stress that has not yet been leveraged in stress detection algorithms.

Individual and simultaneous treatment with antipsychotic aripiprazole and antidepressant trazodone inhibit sterol biosynthesis in the adult brain.

Polypharmacy, or the simultaneous use of multiple drugs to treat a single patient, is a common practice in psychiatry. Unfortunately, data on the health effects of commonly used combinations of medications are very limited. In this study, we therefore investigated the effects and interactions between two commonly prescribed psychotropic medications with sterol inhibiting side effects, trazodone (TRZ), an antidepressant, and aripiprazole (ARI), an antipsychotic. In vitro cell culture experiments revealed that both medications alone disrupted neuronal and astroglial sterol biosynthesis in dose-dependent manners. Furthermore, when ARI and TRZ were combined, exposure resulted in an additive 7-dehydrocholesterol (7-DHC) increase, as well as desmosterol (DES) and cholesterol decreases in both cell types. In adult mice, at baseline, we found that the three investigated sterols showed significant differences in distribution across the eight assessed brain regions. Furthermore, experimental mice treated with ARI or TRZ, or a combination of both medications for 8 days, showed strong sterol disruption across all brain regions. We show ARI or TRZ alone elevated 7-DHC and decreased DES levels in all brain regions, but with regional differences. However, the combined utilization of these two medications for 8 days did not lead to additive changes in sterol disturbances. Based on the complex roles of 7-DHC derived oxysterols, we conclude that individual and potentially simultaneous use of medications with sterol biosynthesis-inhibiting properties might have undesired side effects on the adult brain, with as yet unknown long-term consequences on mental or physical health.

The influence of perceived stress on the human microbiome.

OBJECTIVE: Microbial dysbiosis, a shift from commensal to pathogenic microbiota, is often associated with mental health and the gut-brain axis, where dysbiosis in the gut may be linked to dysfunction in the brain. Many studies focus on dysbiosis induced by clinical events or traumatic incidents; however, many professions in austere or demanding environments may encounter continuously compounded stressors. This study seeks to explore the relationship between microbial populations and stress, both perceived and biochemical. RESULTS: Eight individuals enrolled in the study to provide a longitudinal assessment of the impact of stress on gut health, with four individuals providing enough samples for analysis. Eleven core microbial genera were identified, although the relative abundance of these genera and other members of the microbial population shifted over time. Although our results indicate a potential relationship between perceived stress and microbial composition of the gut, no association with biochemical stress was observed. Increases in perceived stress seem to elucidate a change in potentially beneficial Bacteroides, with a loss in Firmicutes phyla. This shift occurred in multiple individuals, whereas using cortisol as a stress biomarker showed contradictory responses. These preliminary data provide a potential mechanism for gut monitoring, while identifying targets for downstream modulation.

Isolation and confinement due to the COVID-19 pandemic: Lessons for human spaceflight.

Background: Astronauts live and work in isolated, confined, extreme (ICE) environments that create both high stress and the need for high performance. The COVID-19 pandemic created ICE-like conditions across the globe by confining people to their homes under the ever-present threat of disease. Our goal is to understand the impact of prior experience in ICE on coping, using the pandemic as a pseudo space analog environment. Methods: We administered a survey three times with 7 days between administrations. A total of 82 participants completed all three survey sessions, and these participants were divided into three groups for analysis. The first group is those with prior experience in an ICE environment (n = 17; 7F/10 M), the second is those aged 30-55 with a master's or doctoral degree and without prior experience (n = 22; 10F/12 M), and the third is the general population (n = 43; 27F/16 M). Linear mixed models were used for statistical analysis of the results, given the unequal sample sizes. Results: The experienced group did not show healthier mental health scores than the astronaut-like group, but both groups displayed higher scores than the general population. However, work productivity scores for the experienced group were higher on average than the other two groups. Discussion: Results suggest that prior experience in ICE may improve the capability to maintain productivity-corresponding to the idea of resilience. However, experience may not improve mental health maintenance, suggesting that other approaches are needed to prepare astronauts for the mental health stressors of long-duration exploration missions.

A machine learning approach to identify stochastic resonance in human perceptual thresholds.

BACKGROUND: Stochastic resonance (SR) is achieved when a faint signal is improved with the addition of the appropriate amount of white noise. Perceptual thresholds are expected to follow a characteristic performance improvement curve as a function of the white noise level added (i.e., thresholds are reduced with an optimal amount of added white noise, beyond which excessive white noise is no longer beneficial). Since SR exhibition in perceptual thresholds is defined by a shape rather than a statistical difference, the presence of SR is typically identified qualitatively. The current state-of-the-art is for blinded human judges to categorize the presence of SR by visually examining data. While categorizations are made with subject data intermixed within a balanced, simulated dataset, which accounts for false positives, this method is still subjective and prone to human error. NEW METHOD: We use a logistic regression (LR) trained on engineered features in order to quantitatively classify exhibition of SR. The LR was trained on datasets simulated from a model for SR performance enhancement. RESULTS: We implemented the algorithmic classification process in 6 perceptual threshold test cases, informed by the literature and parameters were defined by experimental subject data. Comparison to Existing Method(s): We report algorithmic classifications of SR exhibition, considering the 6 test cases, that outperform existing subjective methods in accuracy (p < 0.05). CONCLUSIONS: We demonstrate that algorithmic classification can effectively identify SR in perceptual thresholds, providing a rigorous, objective, and quantitative approach to identifying the presence of SR.

Side-by-Side Comparison of Human Perception and Performance Using Augmented, Hybrid, and Virtual Reality.

Alternative reality (XR) technologies, including physical, augmented, hybrid, and virtual reality, offer ways for engineered spaces to be evaluated. Traditionally, practitioners (such as those designing spacecraft habitats) have relied on physical mockups to perform such design evaluations, but digital XR technologies present several streamlining advantages over their physical counterparts. These digital environments vary in their level of virtuality, and consequently have different effects on human perception and performance, with respect to a completely physical mockup environment. To date, very little has been done to characterize and quantify such differences in human perception and performance across XR environments of equal fidelity for the same end application. Here, we show that perception and performance in the virtual reality environment most closely mirror those in the physical reality environment, as measured through volumetric assessment and functional task experiments. These experiments required subjects to judge the dimensions of 3D objects and perform operational tasks presented via checklists. Our results highlight the potential for virtual reality systems to accelerate the iterative design of engineered spaces relative to the use of physical mockups, while preserving the human perception and performance characteristics of a completely physical environment. These findings also elucidate specific advantages and disadvantages to specific digital XR technologies with respect to one another and the physical reality baseline. Practitioners may inform their selection of an XR modality for their specific end application based on this comparative analysis, as it contextualizes the niche for each technology in the realm of iterative design for engineered spaces.

When a Pharmacist Health Assessment Simulation Becomes a Real Patient-Provider Experience.

This commentary presents two simulated pharmacist training events during which concerning medical issues were discovered. The simulation exercises, the pharmacist's responsibility in those exercises, and the need to plan for unexpected findings when conducting simulation events are discussed.

Characterization of VU0468554, a New Selective Inhibitor of Cardiac G Protein-Gated Inwardly Rectifying K+ Channels.

G protein-gated inwardly rectifying K+ (GIRK) channels are critical mediators of excitability in the heart and brain. Enhanced GIRK-channel activity has been implicated in the pathogenesis of supraventricular arrhythmias, including atrial fibrillation. The lack of selective pharmacological tools has impeded efforts to investigate the therapeutic potential of cardiac GIRK-channel interventions in arrhythmias. Here, we characterize a recently identified GIRK-channel inhibitor, VU0468554. Using whole-cell electrophysiological approaches and primary cultures of sinoatrial nodal cells and hippocampal neurons, we show that VU0468554 more effectively inhibits the cardiac GIRK channel than the neuronal GIRK channel. Concentration-response experiments suggest that VU0468554 inhibits Gßγ-activated GIRK channels in noncompetitive and potentially uncompetitive fashion. In contrast, VU0468554 competitively inhibits GIRK-channel activation by ML297, a GIRK-channel activator containing the same chemical scaffold as VU0468554. In the isolated heart model, VU0468554 partially reversed carbachol-induced bradycardia in hearts from wild-type mice but not Girk4-/- mice. Collectively, these data suggest that VU0468554 represents a promising new pharmacological tool for targeting cardiac GIRK channels with therapeutic implications for relevant cardiac arrhythmias. SIGNIFICANCE STATEMENT: Although cardiac GIRK-channel inhibition shows promise for the treatment of supraventricular arrhythmias, the absence of subtype-selective channel inhibitors has hindered exploration into this therapeutic strategy. This study utilizes whole-cell patch-clamp electrophysiology to characterize the new GIRK-channel inhibitor VU0468554 in human embryonic kidney 293T cells and primary cultures. We report that VU0468554 exhibits a favorable pharmacodynamic profile for cardiac over neuronal GIRK channels and partially reverses GIRK-mediated bradycardia in the isolated mouse heart model.