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Previous spirometric findings among subjects with chronic tetraplegia that reduction in FEV1and maximal forced expiratory flow, mid-expiratory phase (FEF25–75%) correlated with airway hyperresponsiveness to histamine, and that many of these subjects exhibited significant bronchodilator responsiveness, suggested that baseline airway caliber was low in this population. To better evaluate airway dynamics in patients with spinal cord injury, we used body plethysmography to determine specific airway conductance (sGaw), a less effort-dependent and more reflective surrogate marker of airway caliber.

Background: The metabolizing enzyme cytochrome P450 (CYP) 3A5 is polymorphically expressed as a result of genetic variants that do not encode functional protein. Because of overlapping substrate specificity with CYP3A4 and the multidrug efflux pump P-glycoprotein, the importance of CYP3A5 genetic polymorphism for pharmacokinetics is controversial.Objective: Our objective was to determine whether genetic polymorphisms in CYP3A5 or MDR-1 (which encodes P-glycoprotein) influence the drug levels of ABT-773, a ketolide antibiotic that is a substrate for both CYP3A and P-glycoprotein.Methods: Healthy volunteers given 3 different oral dose levels of ABT-773 were genotyped at 2 common CYP3A5 and 7 common MDR-1 polymorphisms. Individuals were categorized as CYP3A5-positive if they carried at least 1 functional CYP3A5*1 allele and as CYP3A5-negative if they did not. Area under the plasma concentration–time curves (AUCs) from 0 to 6 hours (AUCt) and maximum postdose plasma concentration (Cmax) after a single dose and on day 5 of a twice-daily regimen were calculated and correlated with genotypes.Results: ABT-773 AUCtand Cmaxwere, on average, higher in CYP3A5-negative subjects given 450 mg ABT-773 (n = 9) than in CYP3A5-positive subjects with identical doses (n = 8). The relationship for AUCtwas statistically significant both after a single dose (geometric mean and 95% confidence interval [CI], 5.0 μg · h/mL [3.9-6.4 μg · h/mL] versus 2.8 μg · h/mL [1.8-4.3 μg · h/mL]; P = .03) and on the fifth day of twice-daily dosing (12.4 μg · h/mL [8.7-17.6 μg · h/mL] versus 7.4 μg · h/mL [5.5-9.8 μg · h/mL], P = .04). The relationship for Cmaxwas statistically significant after a single dose (1220 μg/mL [867-1167 μg/mL] versus 727 μg/mL [506-1044 μg/mL], P = .04) and showed a trend in the same direction on the fifth day of twice-daily dosing (2566 μg/mL [1813-3631 μg/mL] versus 1621 μg/mL [1122-2343 μg/mL], P = .07). In contrast, AUCtand Cmaxwere not significantly different between CYP3A5-positive and CYP3A5-negative individuals given 150 mg or 300 mg ABT-773. ABT-773 plasma levels did not trend with MDR-1 genotypes.Conclusions: These results suggest that CYP3A5 genotype may be an important determinant of in vivo drug disposition and that this effect may be dose-dependent.Clinical Pharmacology & Therapeutics (2004) 75, 516–528; doi: 10.1016/j.clpt.2004.01.013

This study utilized cytochrome P450 2D6 (CYP2D6) genotypes to explain variability of desipramine pharmacokinetics in a cohort of non-poor metabolizer individuals. In an interaction study utilizing desipramine as a probe, genotyping for the CYP2D63, 4, 5and 6alleles was used to screen out CYP2D6 poor metabolizers. Individuals were categorized according to these and additional alleles (CYP2D62, 9, 10, 17, 41and x2). Genotypes of individuals heterozygous for two or three of 2, 17and 41alleles were confirmed by molecular haplotyping. Pharmacokinetic parameters of desipramine were analysed according to CYP2D6 category. Molecular haplotyping was necessary to definitively categorize four of 16 individuals. A subject who had unusually high plasma elimination half-time, exposure and metabolic ratios carried an intermediate metabolizer (IM) 9allele in combination with a non-functional allele. This combination has a population frequency of less than 1 : 200. Individuals with 1/1, 1/2and 2/2genotypes had lower than average plasma elimination half-time, exposure and metabolic ratios. For desipramine, additional genotyping of CYP2D6IM alleles helped define subgroups of the CYP2D6-positive cohort. This suggests that genotyping for IM alleles will aid in interpretation of clinical trials involving CYP2D6 substrates. Due to the diversity of IM alleles, molecular haplotyping may be necessary to fully characterize CYP2D6genotype–phenotype relationships.

AbstractBackground/Objective: Few detailed studies have been performed among subjects with spinal cord injury (SCI) using whole body plethysmography for measurement of static lung volumes. Because abdominal gas volumes and respiratory patterns among subjects with varying Ieveis of SCI may differ significantly from able-bodied individuals, methodological concerns related to this technique could conceivably Iead to inaccuracies in lung volume measurements. The purpose of this study was to compare lung volume parameters obtained by whole body plethysmography with those determined by the commonly used nitrogen washaut technique among individuals with SCI.Participants: Twenty-nine clinically stable men, 14 with chronic tetraplegia (injury C4-C7) and 15 with paraplegia (injury below T5) participated in the study.Methods: Lung volumes were obtained using whole body plethysmography and the open-circuit nitrogen washout technique. Within both study groups, data were evaluated by the paired Student’st test and by determination of correlation coefficients.Results: No statistically significant differences for any lung volume parameter were found within either group. ln subjects with tetraplegia on paraplegia, respectively, strong correlation coefficients were found for measurements of totallung capacity (.8 6 and .97), functional residual capacity (.87 and .96), and residual volume (.77 and .85).Conclusion: These findings indicate that body plethysmography is a valid technique for determining lung volumes among subjects with SCI. Because airway resistance measurements can also be obtained du ring same study sessions for assessment of airway caliber and bronchial responsiveness, body plethysmography is a useful tool for examining multiple aspects of pulmonary physiology in this population.

AbstractObjective:The relationship of respiratory symptoms to pulmonary function parameters and smoking status was assessed in subjects with chronic (>1 year) spinal cord injury (SCI).Methods and Participants:As part of their annual physical examination, subjects were queried regarding respiratory symptoms and underwent pulmonary function studies. The 180 patients who successfully completed pulmonary function testing were evaluated, including 79 subjects with tetraplegia (56 nonsmokers and 23 smokers) and 101subjects with paraplegia (78 nonsmokers and 23 smokers).Findings:Logistic-regression analysis revealed the following independent predictors of breathlessness: level of injury (tetraplegia, paraplegia, odds ratio = 3.5, P < 0.0015), cough combined with phlegm and/or wheeze (CPWZ, odds ratio = 3.1, P < 0.015), total lung capacity percentage predicted (TLC < 60%, odds ratio = 3.9, P < 0.02), and expiratory reserve volume (ERV < 0.6 L, odds ratio = 2.5, P < 0.05). Independent predictors of CPWZ were current smoking (odds ratio = 3.3, P < 0.004), breathlessness (odds ratio = 2.9, P < 0.03), and forced expiratory volume in 1second (FEV1< 60%, odds ratio = 3.2, P < 0.01).Conclusion:Altered respiratory mechanics associated with tetraplegia contribute to breathlessness, restrictive ventilatory impairment (low TLC%), and reduced expiratory muscle strength (low ERV). These factors apparently overshadow adverse effects caused by smoking. Conversely, smoking and reduction of airflow (low FEV1%) were predictive of CPWZ, symptoms commonly associated with cigarette use.

We administered aerosolized histamine to 32subjects with tetraplegia to determine whether there were differencesin spirometric and/or lung volume parameters between responders andnonresponders.

Aerosolized ipratropium bromide or orally administered baclofen or oxybutynin chloride (Ditropan) block methacholine-associated airway hyperreactivity in subjects with chronic cervical spinal cord injury (SCI), whereas these agents do not inhibit airway hyperreactivity associated with the inhalation of histamine. The present study was performed to determine whether pretreatment with aβ 2-agonist attenuates airway hyperresponsiveness in these subjects.

The majority of otherwise healthy subjects with chronic cervical spinal cord injury (SCI) demonstrate airway hyperresponsiveness to aerosolized methacholine or histamine. The present study was performed to determine whether ultrasonically nebulized distilled water (UNDW) induces airway hyperresponsiveness and to further elucidate potential mechanisms in this population. Fifteen subjects with SCI, nine with tetraplegia (C4–7) and six with paraplegia (T9–L1), were initially exposed to UNDW for 30 s; spirometry was performed immediately and again 2 min after exposure. The challenge continued by progressively increasing exposure time until the forced expiratory volume in 1 s decreased 20% or more from baseline (PD20) or the maximal exposure time was reached. Five subjects responding to UNDW returned for a second challenge 30 min after inhalation of aerosolized ipratropium bromide (2.5 ml of a 0.6% solution). Eight of nine subjects with tetraplegia had significant bronchoconstrictor responses to UNDW (geometric mean PD20= 7.76 ± 7.67 ml), whereas none with paraplegia demonstrated a response (geometric mean PD20= 24 ml). Five of the subjects with tetraplegia who initially responded to distilled water (geometric mean PD20= 5.99 ± 4.47 ml) were not responsive after pretreatment with ipratropium bromide (geometric mean PD20= 24 ml). Findings that subjects with tetraplegia are hyperreactive to UNDW, a physicochemical agent, combined with previous observations of hyperreactivity to methacholine and histamine, suggest that overall airway hyperresponsiveness in these individuals is a nonspecific phenomenon similar to that observed in patients with asthma. The ability of ipratropium bromide to completely block UNDW-induced bronchoconstriction suggests that, in part, airway hyperresponsiveness in subjects with tetraplegia represents unopposed parasympathetic activity.

Previously, we reported that a majority of subjects with chronic cervical spinal cord injury (SCI) demonstrated airway hyperreactivity in response to inhaled methacholine. To further investigate mechanisms of airway hyperreactivity, 15 male subjects with cervical SCI were challenged with aerosolized histamine, and on a separate day responders were rechallenged 30 min after the inhalation of 72 μg of ipratropium bromide. Twelve of 15 subjects demonstrated airway hyper-responsiveness to histamine (geometric mean PC20 of 1.27 mg/ml), which was not blocked by pretreatment with ipratropium bromide (geometric mean PC20 1.50 mg/ml). Baseline forced vital capacity and forced expiratory volume in 1 sec were not significantly different between responders and nonresponders (2.8 ± 0.6 vs. 3.0 ± 0.4 L and 2.3 ± 0.6 vs. 2.4 ± 0.2 L, respectively). Findings that subjects with cervical SCI are hyperresponsive to methacholine and histamine, chemical agents with direct action through distinct receptor systems, suggest that bronchial hyperreactivity in these subjects represents a nonspecific process similar to that observed in patients with asthma.

Presents the short story 'Look/Here.'

Project overview Team resilience is an interactive and dynamic process that develops over time while a team maintains performance. This study aims to empirically investigate systems-level resilience in a Remotely Piloted Aircraft (RPA) System simulated task environment by examining team interaction during novel events. The approach used in the current study to measure systems-level resilience was developed by Hoffman & Hancock (2017). In their conceptual study, resilience was considered a key feature of success in emerging complex sociotechnical systems; in our case, that is applied to Human-Autonomy Teams (HATs). Hoffman and Hancock conceptualized a resilience measure dynamically by means of several components, such as the time it took the system to recognize and characterize anomalies, and the time taken to specify and achieve new goals. In their framework, there were two main sub-events which expressed resilience via time-based measures, and upon which we designed ours in this study: (1) time taken to design a new process and (2) time required to implement it (Hoffman & Hancock, 2017).Design In this current research, there were three heterogeneous team members who used a text-based system to communicate and successfully photograph target waypoints: (1) navigator – provided information regarding a flight plan with speed and altitude restrictions of each waypoint; (2) pilot – controlled the RPA by adjusting its altitude and airspeed through negotiating with the photographer in order to take a good photo of the target waypoints; and (3) photographer – screened camera settings and sent feedback to the other team members regarding the status of target’s photograph. This study followed the Wizard of Oz paradigm wherein the navigator and photographer were seated together in one room and were told that the pilot was a synthetic agent. In actuality, the pilot was a well-trained experimenter who was working from a separate room. This ‘synthetic’ pilot used restricted vocabulary to simulate that of a computer. The main manipulations in this study consisted of three degraded conditions: (1) automation failure - role-level display failures while processing specific targets, (2) autonomy failure - autonomous agent behaved abnormally while processing specific targets (i.e., it provided misinformation to other team members or demonstrated incorrect actions), and (3) malicious cyber-attacks - the hijacking of the synthetic agent, which led to the synthetic agent providing false, detrimental information to the team about the RPA destination. Because the malicious cyber-attack only occurred once (during the final mission), we will focus on the automation and autonomy failures for this study. Each failure was imposed at a selected target waypoint and the teams had to find a solution in a limited amount of time. The time limit for each failure was related to the difficulty of the failure. Each failure was introduced at a pre-selected target waypoint for each team.Method In this experiment, there were 22 teams, with only two participants randomly assigned to the navigator and photographer roles for each team, because the pilot was a highly-trained experimenter. The current task was comprised of ten 40-minute missions in which teams needed to take as many “good” photos as possible of ground targets while avoiding alarms and rule violations. For this study, using the RPAS paradigm, we calculated two team resilience scores (1) time taken to design a new process and (2) time required to implement it (Hoffman & Hancock, 2017). For the calculations, we used the message sent time (in seconds) for each role to express resilience in terms of the proportion of total task time (2400 seconds). As an outcome measure, we used target processing efficiencyas a coordination and time-based performance score, which was based on how quickly teams were able to take a good photo of each target.Results and discussion We found that teams were more resilient during automation failures and progressed toward targets more successfully than during autonomy failures. We see three possible explanations for this: (1) automation failures were more explicit than autonomy failures, since at least one team member interacted with other teammates; (2) autonomy failures took more time for human teammates to identify the failure, because the autonomous agent’s abnormal behavior was not as straight forward; and 3) human teammates overtrusted to the autonomous agent and lack confidence in themselves and let the failure go on.Acknowledgements This research is supported by ONR Award N000141712382 (Program Managers: Marc Steinberg, Micah Clark). We also acknowledge the assistance of Steven M. Shope of Sandia Research Corporation, who integrated the synthetic agent and the testbed.

GNSS receivers provide position information in a convenient way. However, additional orientation information cannot be fulfilled directly by a single antenna receiver up to now. This paper describes an approach for determining the orientation by a single GNSS receiver based only on its own static observations. As estimable base quantity, satellite positions are used as a reference in the moment of measuring. For that purpose the direction of each satellite s signal has to be known in relation to the antenna. In order to obtain this information, the signal strength of each satellite is measured. A systematical modulation of the signal, realized by rotating shading, is able to provide the required direction information approximately.