Syrian Hamsters Model Does Not Reflect Human-like Disease after Aerosol Exposure to Encephalitic Alphaviruses.

Venezuelan (VEE), eastern (EEE), and western (WEE) equine encephalitis viruses are encephalitic New World alphaviruses that cause periodic epizootic and epidemic outbreaks in horses and humans that may cause severe morbidity and mortality. Currently there are no FDA-licensed vaccines or effective antiviral therapies. Each year, there are a limited number of human cases of encephalitic alphaviruses; thus, licensure of a vaccine or therapeutic would require approval under the FDA animal rule. Approval under the FDA animal rule requires the disease observed in the animal model to recapitulate what is observed in humans. Currently, initial testing of vaccines and therapeutics is performed in the mouse model. Unfortunately, alphavirus disease manifestations in a mouse do not faithfully recapitulate human disease; the VEEV mouse model is lethal whereas in humans VEEV is rarely lethal. In an effort to identify a more appropriate small animal model, we evaluated hamsters in an aerosol exposure model of encephalitic alphavirus infection. The pathology, lethality, and viremia observed in the infected hamsters was inconsistent with what is observed in NHP models and humans. These data suggest that hamsters are not an appropriate model for encephalitic alphaviruses to test vaccines or potential antiviral therapies.

Thymic Lymphomas in a 6-Month rasH2-Tg Mouse Carcinogenicity Study With the RORγt Inverse Agonist, BMS-986251.

BMS-986251 is a retinoid-related orphan receptor γt (RORγt) inverse agonist that was in development for the treatment of autoimmune diseases. RORγt is a nuclear hormone receptor and transcription factor that is involved in the differentiation and function of T helper 17 cells. RORγt-deficient (constitutive or conditional) mice develop thymic lymphomas with >50% mortality at 4 months, whereas heterozygous mice are normal. A 6-month study was conducted in rasH2-Tg hemizygous mice to assess the potential carcinogenicity of BMS-986251. BMS-986251 was administered once daily by oral gavage to groups of 27 mice/sex at doses of 0 (water control), 0 (vehicle control), 5, 25, or 75 mg/kg. The positive control, N-methyl-N-nitrosourea, was administered by a single intraperitoneal injection to 15 mice/sex at a dose of 75 mg/kg. There were no tumors attributed to BMS-986251 except for thymic lymphomas. Thymic lymphoma was observed in 1 male (3.7%) and 3 females (11.1%) at the mid dose, and 6 females (22.2%) at the high dose. No lymphomas were observed in the negative control groups whereas the incidence of lymphomas in the positive control group was 47-60%. The incidence of thymic lymphomas in the BMS-986251-treated groups was higher than published literature and test facility historical control data. Furthermore, increased thymic lymphoid cellularity (lymphoid hyperplasia) was observed at the mid dose in males and at all doses in females. Since lymphoid hyperplasia may represent a preneoplastic change, a no-effect dose for potential tumor induction was not identified in this study. These results led to the discontinuation of BMS-986251 and underscore the challenges in targeting RORγt for drug development.

Data-Driven Estimation of the Impact of Diversions Due to In-Flight Medical Emergencies on Flight Delay and Aircraft Operating Costs.

INTRODUCTION: In-flight medical emergencies (IFMEs) average 1 of every 604 flights and are expected to increase as the population ages and air travel increases. Flight diversions, or the rerouting of a flight to an alternate destination, occur in 2 to 13% of IFME cases, but may or may not be necessary as determined after the fact. Estimating the effect of IFME diversions compared to nonmedical diversions can be expected to improve our understanding of their impact and allow for more appropriate decision making during IFMEs.METHODS: The current study matched multiple disparate datasets, including medical data, flight plan and track data, passenger statistics, and financial data. Chi-squared analysis and independent samples t-tests compared diversion delays and costs metrics between flights diverted for medical vs. nonmedical reasons. Data were restricted to domestic flights between 1/1/2018 and 6/30/2019.RESULTS: Over 70% of diverted flights recover (continue on to their intended destination after diverting); however, flights diverted due to IFMEs recover more often and more quickly than do flights diverted for nonmedical reasons. IFME diversions introduce less delay overall and cost less in terms of direct operating costs and passenger value of time (averaging around 38,000) than do flights diverted for nonmedical reasons.DISCUSSION: Flights diverted due to IFMEs appear to have less impact overall than do flights diverted for nonmedical reasons. However, the lack of information related to costs for nonrecovered flights and the decision factors involved during nonmedical diversions hinders our ability to offer further insights.Lewis BA, Gawron VJ, Esmaeilzadeh E, Mayer RH, Moreno-Hines F, Nerwich N, Alves PM. Data-driven estimation of the impact of diversions due to in-flight medical emergencies on flight delay and aircraft operating costs. Aerosp Med Hum Perform. 2021; 92(2):99105.

Validation of Essential Acoustic Parameters for Highly Urgent In-Vehicle Collision Warnings.

Objective The aim of this study was to validate the importance of key acoustic criteria for use as in-vehicle forward collision warning (FCW) systems. Background Despite recent advances in vehicle safety, automobile crashes remain one of the leading causes of death. As automation allows for more control of noncritical functions by the vehicle, the potential for disengagement and distraction from the driving task also increases. It is, therefore, as important as ever that in-vehicle safety-critical interfaces are intuitive and unambiguous, promoting effective collision avoidance responses upon first exposure even under divided-attention conditions. Method The current study used a driving simulator to assess the effectiveness of two warnings, one that met all essential acoustic parameters, one that met only some essential parameters, and a no-warning control in the context of a lead vehicle-following task in conjunction with a cognitive distractor task and collision event. Results Participants receiving an FCW comprising five essential acoustic components had improved collision avoidance responses relative to a no-warning condition and an FCW missing essential elements on their first exposure. Responses to a consistently good warning (GMU Prime) improved with subsequent exposures, whereas continued exposure to the less optimal FCW (GMU Sub-Prime) resulted in poorer performance even relative to receiving no warning at all. Conclusions This study provides support for previous warning design studies and for the validity of five key acoustic parameters essential for the design of effective in-vehicle FCWs. Application Results from this study have implications for the design of auditory FCWs and in-vehicle display design.

Positive valence music restores executive control over sustained attention.

Music sometimes improves performance in sustained attention tasks. But the type of music employed in previous investigations has varied considerably, which can account for equivocal results. Progress has been hampered by lack of a systematic database of music varying in key characteristics like tempo and valence. The aims of this study were to establish a database of popular music varying along the dimensions of tempo and valence and to examine the impact of music varying along these dimensions on restoring attentional resources following performance of a sustained attention to response task (SART) vigil. Sixty-nine participants rated popular musical selections that varied in valence and tempo to establish a database of four musical types: fast tempo positive valence, fast tempo negative valence, slow tempo positive valence, and slow tempo negative valence. A second group of 89 participants performed two blocks of the SART task interspersed with either no break or a rest break consisting of 1 of the 4 types of music or silence. Presenting positive valence music (particularly of slow tempo) during an intermission between two successive blocks of the SART significantly decreased miss rates relative to negative valence music or silence. Results support an attentional restoration theory of the impact of music on sustained attention, rather than arousal theory and demonstrate a means of restoring sustained attention. Further, the results establish the validity of a music database that will facilitate further investigations of the impact of music on performance.

Impact of prior flavivirus immunity on Zika virus infection in rhesus macaques.

Studies have demonstrated cross-reactivity of anti-dengue virus (DENV) antibodies in human sera against Zika virus (ZIKV), promoting increased ZIKV infection in vitro. However, the correlation between in vitro and in vivo findings is not well characterized. Thus, we evaluated the impact of heterotypic flavivirus immunity on ZIKV titers in biofluids of rhesus macaques. Animals previously infected (≥420 days) with DENV2, DENV4, or yellow fever virus were compared to flavivirus-naïve animals following infection with a Brazilian ZIKV strain. Sera from DENV-immune macaques demonstrated cross-reactivity with ZIKV by antibody-binding and neutralization assays prior to ZIKV infection, and promoted increased ZIKV infection in cell culture assays. Despite these findings, no significant differences between flavivirus-naïve and immune animals were observed in viral titers, neutralizing antibody levels, or immune cell kinetics following ZIKV infection. These results indicate that prior infection with heterologous flaviviruses neither conferred protection nor increased observed ZIKV titers in this non-human primate ZIKV infection model.

Perceived urgency mapping across modalities within a driving context.

Hazard mapping is essential to effective driver-vehicle interface (DVI) design. Determining which modality to use for situations of different criticality requires an understanding of the relative impact of signal parameters within each modality on perceptions of urgency and annoyance. Towards this goal we obtained psychometric functions for visual, auditory and tactile interpulse interval (IPI), visual color, signal word, and auditory fundamental frequency on perceptions of urgency, annoyance, and acceptability. Results indicate that manipulation of IPI in the tactile modality, relative to visual and auditory, has greater utility (greater impact on urgency than annoyance). Manipulations of color were generally rated as less annoying and more acceptable than auditory and tactile stimuli; but they were also rated as lower in urgency relative to other modality manipulations. Manipulation of auditory fundamental frequency resulted in high ratings of both urgency and annoyance. Results of the current investigation can be used to guide DVI design and evaluation.

Multimodal urgency coding: auditory, visual, and tactile parameters and their impact on perceived urgency.

Through a series of investigations involving different levels of contextual fidelity we developed scales of perceived urgency for several dimensions of the auditory, visual, and tactile modalities. Psychophysical ratings of perceived urgency, annoyance, and acceptability as well as behavioral responses to signals in each modality were obtained and analyzed using Steven's Power Law to allow comparison across modalities. Obtained results and their implications for use as in-vehicle alerts and warnings are discussed.

Protective effect of two recombinant ricin subunit vaccines in the New Zealand white rabbit subjected to a lethal aerosolized ricin challenge: survival, immunological response, and histopathological findings.

Ricin, isolated from the castor bean plant Ricinus communis, is included on the Centers for Disease Control and Prevention Category B list of bioterrorism agents, indicating that the toxin is moderately easy to disseminate and could result in moderate morbidity rates. This study evaluated two promising recombinant ricin subunit vaccines, one made using an Escherichia coli codon-optimized gene and the other using a yeast codon-optimized gene in E. coli-based fermentations. Rabbits were vaccinated four times over a period of 6 months and challenged with ∼10 to 30 times the median lethal dose of aerosolized ricin. All unvaccinated control rabbits were either found dead or humanely euthanized within 30 h postchallenge, while the rabbits vaccinated with either vaccine survived the exposure without adverse clinical signs. When the protective antibody responses were analyzed, no significant difference was seen between the two vaccines. However, there was a significant difference in the immune response over time for both vaccines tested. Although clinical pathology was unremarkable, significant histological lesions in the control animals included fibrinonecrotic pneumonia, acute necrotizing lesions in the upper respiratory tract, and necrotizing lymphadenitis in the lymph nodes draining the upper and lower respiratory tract. Vaccine-treated rabbits exhibited resolving lesions associated with ricin exposure, namely chronic inflammation in the upper respiratory tract and lungs, fibrosis, type II pneumocyte hyperplasia, and bronchiolitis obliterans. This study confirmed the safety and efficacy of two recombinant ricin subunit vaccines in rabbits, offering potential protection to warfighters and select populations.

Development of a novel nonhuman primate model for Rift Valley fever.

Rift Valley fever (RVF) virus (RVFV) can cause severe human disease characterized by either acute-onset hepatitis, delayed-onset encephalitis, retinitis and blindness, or a hemorrhagic syndrome. The existing nonhuman primate (NHP) model for RVF utilizes an intravenous (i.v.) exposure route in rhesus macaques (Macaca mulatta). Severe disease in these animals is infrequent, and large cohorts are needed to observe significant morbidity and mortality. To overcome these drawbacks, we evaluated the infectivity and pathogenicity of RVFV in the common marmoset (Callithrix jacchus) by i.v., subcutaneous (s.c.), and intranasal exposure routes to more closely mimic natural exposure. Marmosets were more susceptible to RVFV than rhesus macaques and experienced higher rates of morbidity, mortality, and viremia and marked aberrations in hematological and chemistry values. An overwhelming infection of hepatocytes was a major consequence of infection of marmosets by the i.v. and s.c. exposure routes. Additionally, these animals displayed signs of hemorrhagic manifestations and neurological impairment. Based on our results, the common marmoset model more closely resembles severe human RVF disease and is therefore an ideal model for the evaluation of potential vaccines and therapeutics.

Interposition grafts for rectovaginal fistula repair in the New Zealand white rabbit.

INTRODUCTION AND HYPOTHESIS: The objective was to use an animal model to study different types of interposition grafts for rectovaginal fistula repair. METHODS: Twelve New Zealand white rabbits underwent surgical creation of a rectovaginal fistula, followed by repair. Four repair techniques were studied; three with interposition grafts and one control group without a graft. Animals were euthanized at 4-week intervals and underwent gross and histologic analysis. RESULTS: The mean rectovaginal wall thickness was greatest in the control group (5.6 mm) and thinnest in the autologous rectus fascia (4.2 mm) and porcine small intestine submucosa (5.1 mm) groups. The polypropylene graft had a mean thickness of 5.4 mm and elicited a strong, protracted inflammatory response. All fistulas were successfully closed except one porcine small intestine submucosa repair. CONCLUSIONS: There is no benefit from interposition graft use for rectovaginal fistula repair in our New Zealand white rabbit model.