Hibernating female big brown bats (Eptesicus fuscus) adjust huddling and drinking behaviour, but not arousal frequency, in response to low humidity.

Many mammals hibernate during winter, reducing energy expenditure via bouts of torpor. The majority of a hibernator's energy reserves are used to fuel brief, but costly, arousals from torpor. Although arousals likely serve multiple functions, an important one is to restore water stores depleted during torpor. Many hibernating bat species require high humidity, presumably to reduce torpid water loss, but big brown bats (Eptesicus fuscus) appear tolerant of a wide humidity range. We tested the hypothesis that hibernating female E. fuscus use behavioural flexibility during torpor and arousals to maintain water balance and reduce energy expenditure. We predicted: (1) E. fuscus hibernating in dry conditions would exhibit more compact huddles during torpor and drink more frequently than bats in high humidity conditions; and (2) the frequency and duration of torpor bouts and arousals, and thus total loss of body mass would not differ between bats in the two environments. We housed hibernating E. fuscus in temperature- and humidity-controlled incubators at 50% or 98% relative humidity (8°C, 110 days). Bats in the dry environment maintained a more compact huddle during torpor and drank more frequently during arousals. Bats in the two environments had a similar number of arousals, but arousal duration was shorter in the dry environment. However, total loss of body mass over hibernation did not differ between treatments, indicating that the two groups used similar amounts of energy. Our results suggest that behavioural flexibility allows hibernating E. fuscus to maintain water balance and reduce energy costs across a wide range of hibernation humidities.

Exploration of the MCMC Wald test with linear regression.

Recently, Asparouhov and Muthén Structural Equation Modeling: A Multidisciplinary Journal, 28, 1-14, (2021a, 2021b) proposed a variant of the Wald test that uses Markov chain Monte Carlo machinery to generate a chi-square test statistic for frequentist inference. Because the test's composition does not rely on analytic expressions for sampling variation and covariation, it potentially provides a way to get honest significance tests in cases where the likelihood-based test statistic's assumptions break down (e.g., in small samples). The goal of this study is to use simulation to compare the new MCM Wald test to its maximum likelihood counterparts, with respect to both their type I error rate and power. Our simulation examined the test statistics across different levels of sample size, effect size, and degrees of freedom (test complexity). An additional goal was to assess the robustness of the MCMC Wald test with nonnormal data. The simulation results uniformly demonstrated that the MCMC Wald test was superior to the maximum likelihood test statistic, especially with small samples (e.g., sample sizes less than 150) and complex models (e.g., models with five or more predictors). This conclusion held for nonnormal data as well. Lastly, we provide a brief application to a real data example.

White-Nose Syndrome Disrupts the Splenic Lipidome of Little Brown Bats (Myotis lucifugus) at Early Disease Stages.

White-nose syndrome (WNS)-positive little brown bats (Myotis lucifugus) may exhibit immune responses including increased cytokine and pro-inflammatory mediator gene levels. Bioactive lipid mediators (oxylipins) formed by enzymatic oxidation of polyunsaturated fatty acids can contribute to these immune responses, but have not been investigated in WNS pathophysiology. Nonenzymatic conversion of polyunsaturated fatty acids can also occur due to reactive oxygen species, however, these enantiomeric isomers will lack the same signaling properties. In this study, we performed a series of targeted lipidomic approaches on laboratory Pseudogymnoascus destructans-inoculated bats to assess changes in their splenic lipidome, including the formation of lipid mediators at early stages of WNS. Hepatic lipids previously identified were also resolved to a higher structural detail. We compared WNS-susceptible M. lucifugus to a WNS-resistant species, the big brown bat (Eptesicus fuscus). Altered splenic lipid levels were only observed in M. lucifugus. Differences in splenic free fatty acids included both omega-3 and omega-6 compounds. Increased levels of an enantiomeric monohydroxy DHA mixture were found, suggesting nonenzymatic formation. Changes in previously identified hepatic lipids were confined to omega-3 constituents. Together, these results suggest that increased oxidative stress, but not an inflammatory response, is occurring in bats at early stages of WNS that precedes fat depletion. These data have been submitted to metabolomics workbench and assigned a study number ST002304.

Optimizing the Pairs of Radiologists That Double Read Screening Mammograms.

Background Despite variation in performance characteristics among radiologists, the pairing of radiologists for the double reading of screening mammograms is performed randomly. It is unknown how to optimize pairing to improve screening performance. Purpose To investigate whether radiologist performance characteristics can be used to determine the optimal set of pairs of radiologists to double read screening mammograms for improved accuracy. Materials and Methods This retrospective study was performed with reading outcomes from breast cancer screening programs in Sweden (2008-2015), England (2012-2014), and Norway (2004-2018). Cancer detection rates (CDRs) and abnormal interpretation rates (AIRs) were calculated, with AIR defined as either reader flagging an examination as abnormal. Individual readers were divided into performance categories based on their high and low CDR and AIR. The performance of individuals determined the classification of pairs. Random pair performance, for which any type of pair was equally represented, was compared with the performance of specific pairing strategies, which consisted of pairs of readers who were either opposite or similar in AIR and/or CDR. Results Based on a minimum number of examinations per reader and per pair, the final study sample consisted of 3 592 414 examinations (Sweden, n = 965 263; England, n = 837 048; Norway, n = 1 790 103). The overall AIRs and CDRs for all specific pairing strategies (Sweden AIR range, 45.5-56.9 per 1000 examinations and CDR range, 3.1-3.6 per 1000; England AIR range, 68.2-70.5 per 1000 and CDR range, 8.9-9.4 per 1000; Norway AIR range, 81.6-88.1 per 1000 and CDR range, 6.1-6.8 per 1000) were not significantly different from the random pairing strategy (Sweden AIR, 54.1 per 1000 examinations and CDR, 3.3 per 1000; England AIR, 69.3 per 1000 and CDR, 9.1 per 1000; Norway AIR, 84.1 per 1000 and CDR, 6.3 per 1000). Conclusion Pairing a set of readers based on different pairing strategies did not show a significant difference in screening performance when compared with random pairing. © RSNA, 2023.

An Investigation of Factored Regression Missing Data Methods for Multilevel Models with Cross-Level Interactions.

A growing body of literature has focused on missing data methods that factorize the joint distribution into a part representing the analysis model of interest and a part representing the distributions of the incomplete predictors. Relatively little is known about the utility of this method for multilevel models with interactive effects. This study presents a series of Monte Carlo computer simulations that investigates Bayesian and multiple imputation strategies based on factored regressions. When the model's distributional assumptions are satisfied, these methods generally produce nearly unbiased estimates and good coverage, with few exceptions. Severe misspecifications that arise from substantially non-normal distributions can introduce biased estimates and poor coverage. Follow-up simulations suggest that a Yeo-Johnson transformation can mitigate these biases. A real data example illustrates the methodology, and the paper suggests several avenues for future research.

Attenuation of Response to Repeated Drug Administration: A Proposal for Differentiating Tachyphylaxis and Tolerance.

Attenuation of drug response with repeated administration is referred to as tachyphylaxis or tolerance, though the distinction between these two is obscured through both their usage in the literature and imprecise definitions in common pharmacology texts. In this perspective, I propose that these terms be distinguished by the mechanisms underlying the attenuation of drug response. Specifically, tachyphylaxis should be reserved for attenuation that occurs in response to cellular depletion, whereas tolerance should be used to describe attenuation that arises from cellular adaptations. A framework for understanding behavioral tolerance, physiologic tolerance, and dispositional tolerance as distinct phenomena is also discussed. Using this framework, a classification of drugs exhibiting attenuation of drug response with repeated administration is presented. SIGNIFICANCE STATEMENT: Distinction between tachyphylaxis and tolerance is unclear in the literature. Nonetheless, a mechanistic basis for distinguishing these important terms has practical implications for managing or preventing attenuation of drug response with repeated administration.

Does scent attractiveness reveal women's ovulatory timing? Evidence from signal detection analyses and endocrine predictors of odour attractiveness.

Odour cues associated with shifts in ovarian hormones indicate ovulatory timing in females of many nonhuman species. Although prior evidence supports women's body odours smelling more attractive on days when conception is possible, that research has left ambiguous how diagnostic of ovulatory timing odour cues are, as well as whether shifts in odour attractiveness are correlated with shifts in ovarian hormones. Here, 46 women each provided six overnight scent and corresponding day saliva samples spaced five days apart, and completed luteinizing hormone tests to determine ovulatory timing. Scent samples collected near ovulation were rated more attractive, on average, relative to samples from the same women collected on other days. Importantly, however, signal detection analyses showed that rater discrimination of fertile window timing from odour attractiveness ratings was very poor. Within-women shifts in salivary oestradiol and progesterone were not significantly associated with within-women shifts in odour attractiveness. Between-women, mean oestradiol was positively associated with mean odour attractiveness. Our findings suggest that raters cannot reliably detect women's ovulatory timing from their scent attractiveness. The between-women effect of oestradiol raises the possibility that women's scents provide information about overall cycle fecundity, though further research is necessary to rigorously investigate this possibility.

Combination treatment with varenicline and naltrexone reduces World Health Organization risk drinking levels.

BACKGROUND: The U.S. Food and Drug Administration identifies abstinence and the absence of heavy drinking days as outcomes for pharmacotherapy trials for alcohol use disorder (AUD). However, many individuals with AUD struggle to achieve these outcomes, which may discourage them from seeking treatment. World Health Organization (WHO) risk drinking levels have garnered attention in the alcohol field as potential non-abstinent outcomes for AUD medication trials. Further, testing combination pharmacotherapy for AUD represents an important direction in the field, particularly using medications such as naltrexone and varenicline, which are approved for treating AUD and smoking, respectively. The objective of the current study was to test the utility of the WHO risk drinking levels as a drinking outcome in a randomized clinical trial of combined varenicline and naltrexone for smoking cessation and drinking reduction. These analyses provide additional tests of the efficacy of this combination treatment. METHODS: The current study is a secondary analysis of a phase 2, randomized, double-blind clinical trial, wherein participants (N = 165) who were daily smokers and heavy drinkers were randomly assigned to receive either 2 mg/day of varenicline plus 50 mg/day of naltrexone or 2 mg/day of varenicline plus placebo for 12 weeks. Medication effects on 1- and 2-level reductions in WHO risk drinking levels were assessed at 4, 8, and 12 weeks into the active medication period. RESULTS: In logistic growth curve models individuals receiving the combined treatment had greater reductions in WHO risk drinking levels than individuals taking varenicline alone when assessed at 4 weeks into the active medication period. Among individuals who were WHO high and very high risk drinkers at baseline, the largest effect sizes favoring combination treatment were at Week 4 for the WHO 2-level reduction outcome (Cohen's h = 0.202) and Week 12 for the WHO 1-level reduction outcome (Cohen's h = 0.244), although these effects did not reach statistical significance. CONCLUSIONS: These findings provide evidence that combined varenicline plus naltrexone treatment is effective at reducing WHO risk drinking levels, particularly among individuals who smoke cigarettes daily and drink heavily. These results add to a growing body of literature validating reductions in WHO risk drinking levels as outcomes of alcohol medication trials.

Evaluation of reader performance during interpretation of breast cancer screening: the Recall and detection Of breast Cancer in Screening (ROCS) trial study design.

The magnitude of the tradeoff between recall rate (RR) and cancer detection rate (CDR) in breast-cancer screening is not clear, and it is expected to depend on target population and screening program characteristics. Multi-reader multi-case research studies, which may be used to estimate this tradeoff, rely on enriched datasets with artificially high prevalence rates, which may bias the results. Furthermore, readers participating in research studies are subject to "laboratory" effects, which can alter their performance relative to actual practice. The Recall and detection Of breast Cancer in Screening (ROCS) trial uses a novel data acquisition system that minimizes these limitations while obtaining an estimate of the RR-CDR curve during actual practice in the Dutch National Breast Cancer Screening Program. ROCS involves collection of at least 40,000 probability-of-malignancy ratings from at least 20 radiologists during interpretation of approximately 2,000 digital mammography screening cases each. With the use of custom-built software on a tablet, and a webcam, this data was obtained in the usual reading environment with minimal workflow disruption and without electronic access to the review workstation software. Comparison of the results to short- and medium-term follow-up allows for estimation of the RR-CDR and receiver operating characteristics curves, respectively. The anticipated result of the study is that performance-based evidence from practice will be available to determine the optimal operating point for breast-cancer screening. In addition, this data will be useful as a benchmark when evaluating the impact of potential new screening technologies, such as digital breast tomosynthesis or artificial intelligence. KEY POINTS: • The ROCS trial aims to estimate the recall rate-cancer detection rate curve during actual screening practice in the Dutch National Breast Cancer Screening Program. • The study design is aimed at avoiding the influence of the "laboratory effect" in usual observer performance studies. • The use of a tablet and a webcam allows for the acquisition of probability of malignancy ratings without access to the review workstation software.

Automated prediction of the Thoracolumbar Injury Classification and Severity Score from CT using a novel deep learning algorithm.

OBJECTIVE: Damage to the thoracolumbar spine can confer significant morbidity and mortality. The Thoracolumbar Injury Classification and Severity Score (TLICS) is used to categorize injuries and determine patients at risk of spinal instability for whom surgical intervention is warranted. However, calculating this score can constitute a bottleneck in triaging and treating patients, as it relies on multiple imaging studies and a neurological examination. Therefore, the authors sought to develop and validate a deep learning model that can automatically categorize vertebral morphology and determine posterior ligamentous complex (PLC) integrity, two critical features of TLICS, using only CT scans. METHODS: All patients who underwent neurosurgical consultation for traumatic spine injury or degenerative pathology resulting in spine injury at a single tertiary center from January 2018 to December 2019 were retrospectively evaluated for inclusion. The morphology of injury and integrity of the PLC were categorized on CT scans. A state-of-the-art object detection region-based convolutional neural network (R-CNN), Faster R-CNN, was leveraged to predict both vertebral locations and the corresponding TLICS. The network was trained with patient CT scans, manually labeled vertebral bounding boxes, TLICS morphology, and PLC annotations, thus allowing the model to output the location of vertebrae, categorize their morphology, and determine the status of PLC integrity. RESULTS: A total of 111 patients were included (mean ± SD age 62 ± 20 years) with a total of 129 separate injury classifications. Vertebral localization and PLC integrity classification achieved Dice scores of 0.92 and 0.88, respectively. Binary classification between noninjured and injured morphological scores demonstrated 95.1% accuracy. TLICS morphology accuracy, the true positive rate, and positive injury mismatch classification rate were 86.3%, 76.2%, and 22.7%, respectively. Classification accuracy between no injury and suspected PLC injury was 86.8%, while true positive, false negative, and false positive rates were 90.0%, 10.0%, and 21.8%, respectively. CONCLUSIONS: In this study, the authors demonstrate a novel deep learning method to automatically predict injury morphology and PLC disruption with high accuracy. This model may streamline and improve diagnostic decision support for patients with thoracolumbar spinal trauma.

Predicting and mitigating failures on the flight deck: an aircraft engine bird strike scenario.

Engine damage as a consequence of foreign object debris (FOD) during flight is frequently caused by birds. One approach to minimising disruption caused by this damage is to provide flight crew with accurate information relating to the continuing operational status of the aircraft's engines. Before designing such avionic systems however, understanding of current procedures is needed. Hierarchical Task Analysis (HTA) and Systematic Human Error Reduction and Prediction Approach (SHERPA) were used to identify potential failures that flight crew may make when managing an engine bird strike. Workshops with commercial pilots generated insights into current practice and a commercial pilot SME reviewed outputs for accuracy. Over 200 potential failures were identified, most commonly related to communication. Remedial measures, considering future avionic systems, are proposed to mitigate identified failures. This analysis provides a starting point for future design concepts for assisting flight crew in dealing with engine malfunction due to FOD strikes. Practitioner summary: Hierarchical Task Analysis was conducted to show all tasks involved in dealing with an in-flight aircraft engine bird strike. Systematic Human Error Reduction and Prediction Approach analysis was performed and over 200 possible failures were identified when managing this event. Remedial measures are proposed to help mitigate possible failures.

An Inducible and Vascular Smooth Muscle Cell-Specific Pink1 Knockout Induces Mitochondrial Energetic Dysfunction during Atherogenesis.

DNA damage and mitochondrial dysfunction are defining characteristics of aged vascular smooth muscle cells (VSMCs) found in atherosclerosis. Pink1 kinase regulates mitochondrial homeostasis and recycles dysfunctional organelles critical for maintaining energetic homeostasis. Here, we generated a new vascular-specific Pink1 knockout and assessed its effect on VSMC-dependent atherogenesis in vivo and VSMC energetic metabolism in vitro. A smooth muscle cell-specific and MHC-Cre-inducible flox'd Pink1f/f kinase knockout was made on a ROSA26+/0 and ApoE-/- C57Blk6/J background. Mice were high fat fed for 10 weeks and vasculature assessed for physiological and pathogical changes. Mitochondrial respiratory activity was then assessed in wild-type and knockout animals vessels and isolated cells for their reliance on oxidative and glycolytic metabolism. During atherogenesis, we find that Pink1 knockout affects development of plaque quality rather than plaque quantity by decreasing VSMC and extracellular matrix components, collagen and elastin. Pink1 protein is important in the wild-type VSMC response to metabolic stress and induced a compensatory increase in hexokinase II, which catalyses the first irreversible step in glycolysis. Pink1 appears to play an important role in VSMC energetics during atherogenesis but may also provide insight into the understanding of mitochondrial energetics in other diseases where the regulation of energetic switching between oxidative and glycolytic metabolism is found to be important.

Inducing Energetic Switching Using Klotho Improves Vascular Smooth Muscle Cell Phenotype.

The cardiovascular disease of atherosclerosis is characterised by aged vascular smooth muscle cells and compromised cell survival. Analysis of human and murine plaques highlights markers of DNA damage such as p53, Ataxia telangiectasia mutated (ATM), and defects in mitochondrial oxidative metabolism as significant observations. The antiageing protein Klotho could prolong VSMC survival in the atherosclerotic plaque and delay the consequences of plaque rupture by improving VSMC phenotype to delay heart attacks and stroke. Comparing wild-type VSMCs from an ApoE model of atherosclerosis with a flox'd Pink1 knockout of inducible mitochondrial dysfunction we show WT Pink1 is essential for normal cell viability, while Klotho mediates energetic switching which may preserve cell survival. METHODS: Wild-type ApoE VSMCs were screened to identify potential drug candidates that could improve longevity without inducing cytotoxicity. The central regulator of cell metabolism AMP Kinase was used as a readout of energy homeostasis. Functional energetic switching between oxidative and glycolytic metabolism was assessed using XF24 technology. Live cell imaging was then used as a functional readout for the WT drug response, compared with Pink1 (phosphatase-and-tensin-homolog (PTEN)-induced kinase-1) knockout cells. RESULTS: Candidate drugs were assessed to induce pACC, pAMPK, and pLKB1 before selecting Klotho for its improved ability to perform energetic switching. Klotho mediated an inverse dose-dependent effect and was able to switch between oxidative and glycolytic metabolism. Klotho mediated improved glycolytic energetics in wild-type cells which were not present in Pink1 knockout cells that model mitochondrial dysfunction. Klotho improved WT cell survival and migration, increasing proliferation and decreasing necrosis independent of effects on apoptosis. CONCLUSIONS: Klotho plays an important role in VSMC energetics which requires Pink1 to mediate energetic switching between oxidative and glycolytic metabolism. Klotho improved VSMC phenotype and, if targeted to the plaque early in the disease, could be a useful strategy to delay the effects of plaque ageing and improve VSMC survival.

Adjusting the need for speed: assessment of a visual interface to reduce fuel use.

Previous research has identified that fuel consumption and emissions can be considerably reduced if drivers engage in eco-driving behaviours. However, the literature suggests that individuals struggle to maintain eco-driving behaviours without support. This paper evaluates an in-vehicle visual interface system designed to support eco-driving through recommendations based on both feedforward and feedback information. A simulator study explored participants' fuel usage, driving style, and cognitive workload driving normally, when eco-driving without assistance and when using a visual interface. Improvements in fuel-efficiency were observed for both assisted (8.5%) and unassisted eco-driving (11%), however unassisted eco-driving also induced a significantly greater rating of self-reported effort. In contrast, using the visual interface did not induce the same increase of reported effort compared to everyday driving, but itself did not differ from unassisted driving. Results hold positive implications for the use of feedforward in-vehicle interfaces to improve fuel efficiency. Accordingly, directions are suggested for future research. Practitioner Summary: Results from a simulator study comparing fuel usage from normal driving, engaging in unassisted eco-driving, or using a novel speed advisory interface, designed to reduce fuel use, are presented. Whilst both unassisted and assisted eco-driving reduced fuel use, assisted eco-driving did not induce workload changes, unlike unassisted eco-driving. Abbreviations: CO-2: carbon dioxide; NASA-TLX: NASA task load index; RMS: root-mean-square; MD: mean difference.

Disease recovery in bats affected by white-nose syndrome.

Processes associated with recovery of survivors are understudied components of wildlife infectious diseases. White-nose syndrome (WNS) in bats provides an opportunity to study recovery of disease survivors, understand implications of recovery for individual energetics, and assess the role of survivors in pathogen transmission. We documented temporal patterns of recovery from WNS in little brown bats (Myotis lucifugus) following hibernation to test the hypotheses that: (1) recovery of wing structure from WNS matches a rapid time scale (i.e. approximately 30 days) suggested by data from free-ranging bats; (2) torpor expression plays a role in recovery; (3) wing physiological function returns to normal alongside structural recovery; and (4) pathogen loads decline quickly during recovery. We collected naturally infected bats at the end of hibernation, brought them into captivity, and quantified recovery over 40 days by monitoring body mass, wing damage, thermoregulation, histopathology of wing biopsies, skin surface lipids and fungal load. Most metrics returned to normal within 30 days, although wing damage was still detectable at the end of the study. Torpor expression declined overall throughout the study, but bats expressed relatively shallow torpor bouts - with a plateau in minimum skin temperature - during intensive healing between approximately days 8 and 15. Pathogen loads were nearly undetectable after the first week of the study, but some bats were still detectably infected at day 40. Our results suggest that healing bats face a severe energetic imbalance during early recovery from direct costs of healing and reduced foraging efficiency. Management of WNS should not rely solely on actions during winter, but should also aim to support energy balance of recovering bats during spring and summer.

CBD for the treatment of pain: What is the evidence?

Cannabidiol (CBD) has become widely available owing to recent changes in federal and state regulations. Although it is marketed for many health conditions, a recent survey found that the most common reason for taking CBD was for the treatment of pain. The endocannabinoid system (ECS) is present at essentially all levels of the anterolateral system, which is responsible for the perception and modulation of pain. In addition to its effects on the ECS, CBD interacts with other important signaling systems involved in the regulation of pain. Thus, there is a physiological basis to investigate CBD for the treatment of pain. Although CBD has been found to reduce pain in several animal models of inflammatory and neuropathic pain, studies to date lack sufficient rigor to provide more than modest evidence for the analgesic activity of CBD. To date, only 1 controlled clinical study has been published evaluating the effect of CBD in the treatment of pain. This study was fraught with numerous deficiencies in design, such that the results are uninformative. Because studies to date have found a high level of variability in the content of CBD products, product quality is a major concern. Although limited preclinical studies suggest that CBD may alter the metabolism of drugs metabolized by cytochromes P450, the lack of clinical studies makes it impossible to assess the clinical significance of these observations. At present, there is insufficient evidence to recommend CBD for the treatment of pain. The safety of the compound in patients with chronic illness remains untested, and pharmacists should caution patients about its use in the absence of clinical supervision.

Higher fat stores contribute to persistence of little brown bat populations with white-nose syndrome.

The persistence of populations declining from novel stressors depends, in part, on their ability to respond by trait change via evolution or plasticity. White-nose syndrome (WNS) has caused rapid declines in several North America bat species by disrupting hibernation behaviour, leading to body fat depletion and starvation. However, some populations of Myotis lucifugus now persist with WNS by unknown mechanisms. We examined whether persistence of M. lucifigus with WNS could be explained by increased body fat in early winter, which would allow bats to tolerate the increased energetic costs associated with WNS. We also investigated whether bats were escaping infection or resistant to infection as an alternative mechanism explaining persistence. We measured body fat in early and late winter during initial WNS invasion and 8 years later at six sites where bats are now persisting. We also measured infection prevalence and intensity in persisting populations. Infection prevalence was not significantly lower than observed in declining populations. However, at two sites, infection loads were lower than observed in declining populations. Body fat in early winter was significantly higher in four of the six persisting populations than during WNS invasion. Physiological models of energy use indicated that these higher fat stores could reduce WNS mortality by 58%-70%. These results suggest that differences in fat storage and infection dynamics have reduced the impacts of WNS in many populations. Increases in body fat provide a potential mechanism for management intervention to help conserve bat populations.

Use of Highways in the Sky and a virtual pad for landing Head Up Display symbology to enable improved helicopter pilots situation awareness and workload in degraded visual conditions.

Flight within degraded visual conditions is a great challenge to pilots of rotary-wing craft. Environmental cues typically used to guide interpretation of speed, location and approach can become obscured, forcing the pilots to rely on data available from in-cockpit instrumentation. To ease the task of flight during degraded visual conditions, pilots require easy access to flight critical information. The current study examined the effect of 'Highways in the Sky' symbology and a conformal virtual pad for landing presented using a Head Up Display (HUD) on pilots' workload and situation awareness for both clear and degraded conditions across a series of simulated rotary-wing approach and landings. Results suggest that access to the HUD lead to significant improvements to pilots' situation awareness, especially within degraded visual conditions. Importantly, access to the HUD facilitated pilot awareness in all conditions. Results are discussed in terms of future HUD development. Practitioner Summary: This paper explores the use of a novel Heads Up Display, to facilitate rotary-wing pilots' situation awareness and workload for simulated flights in both clear and degraded visual conditions. Results suggest that access to HUD facilitated pilots' situation awareness, especially when flying in degraded conditions.

Role of the Aryl Hydrocarbon Receptor in Sugen 5416-induced Experimental Pulmonary Hypertension.

Rats dosed with the vascular endothelial growth factor inhibitor Sugen 5416 (Su), subjected to hypoxia, and then restored to normoxia have become a widely used model of pulmonary arterial hypertension (PAH). However, the mechanism by which Su exacerbates pulmonary hypertension is unclear. We investigated Su activation of the aryl hydrocarbon receptor (AhR) in human pulmonary artery smooth muscle cells (hPASMCs) and blood outgrowth endothelial cells (BOECs) from female patients with PAH. We also examined the effect of AhR on aromatase and estrogen levels in the lung. Protein and mRNA analyses demonstrated that CYP1A1 was very highly induced in the lungs of Su/hypoxic (Su/Hx) rats. The AhR antagonist CH223191 (8 mg/kg/day) reversed the development of PAH in this model in vivo and normalized lung CYP1A1 expression. Increased lung aromatase and estrogen levels in Su/Hx rats were also normalized by CH223191, as was AhR nuclear translocator (ARNT [HIF-1ß]), which is shared by HIF-1α and AhR. Su reduced HIF-1α expression in hPASMCs. Su induced proliferation in BOECs and increased apoptosis in human pulmonary microvascular ECs and also induced translocation of AhR to the nucleus in hPASMCs. Under normoxic conditions, hPASMCs did not proliferate to Su. However, when grown in hypoxia (1%), Su induced hPASMC proliferation. In combination with hypoxia, Su is proliferative in hPASMCs and BOECs from patients with PAH, and Su/Hx-induced PAH in rats may be facilitated by AhR-induced CYP1A1, ARNT, and aromatase. Inhibition of AhR may be a novel approach to the treatment of pulmonary hypertension.

The Role of Sex in the Pathophysiology of Pulmonary Hypertension.

Pulmonary arterial hypertension (PAH) is a progressive disease characterised by increased pulmonary vascular resistance and pulmonary artery remodelling as result of increased vascular tone and vascular cell proliferation, respectively. Eventually, this leads to right heart failure. Heritable PAH is caused by a mutation in the bone morphogenetic protein receptor-II (BMPR-II). Female susceptibility to PAH has been known for some time, and most recent figures show a female-to-male ratio of 4:1. Variations in the female sex hormone estrogen and estrogen metabolism modify FPAH risk, and penetrance of the disease in BMPR-II mutation carriers is increased in females. Several lines of evidence point towards estrogen being pathogenic in the pulmonary circulation, and thus increasing the risk of females developing PAH. Recent studies have also suggested that estrogen metabolism may be crucial in the development and progression of PAH with studies indicating that downstream metabolites such as 16α-hydroxyestrone are upregulated in several forms of experimental pulmonary hypertension (PH) and can cause pulmonary artery smooth muscle cell proliferation and subsequent vascular remodelling. Conversely, other estrogen metabolites such as 2-methoxyestradiol have been shown to be protective in the context of PAH. Estrogen may also upregulate the signalling pathways of other key mediators of PAH such as serotonin.