A probabilistic neural twin for treatment planning in peripheral pulmonary artery stenosis.

The substantial computational cost of high-fidelity models in numerical hemodynamics has, so far, relegated their use mainly to offline treatment planning. New breakthroughs in data-driven architectures and optimization techniques for fast surrogate modeling provide an exciting opportunity to overcome these limitations, enabling the use of such technology for time-critical decisions. We discuss an application to the repair of multiple stenosis in peripheral pulmonary artery disease through either transcatheter pulmonary artery rehabilitation or surgery, where it is of interest to achieve desired pressures and flows at specific locations in the pulmonary artery tree, while minimizing the risk for the patient. Since different degrees of success can be achieved in practice during treatment, we formulate the problem in probability, and solve it through a sample-based approach. We propose a new offline-online pipeline for probabilistic real-time treatment planning which combines offline assimilation of boundary conditions, model reduction, and training dataset generation with online estimation of marginal probabilities, possibly conditioned on the degree of augmentation observed in already repaired lesions. Moreover, we propose a new approach for the parametrization of arbitrarily shaped vascular repairs through iterative corrections of a zero-dimensional approximant. We demonstrate this pipeline for a diseased model of the pulmonary artery tree available through the Vascular Model Repository.

Cell-intrinsic C5a synergizes with Dectin-1 in macrophages to mediate fungal killing.

The complement factor C5a is a core effector product of complement activation. C5a, acting through its receptors C5aR1 and C5aR2, exerts pleiotropic immunomodulatory functions in myeloid cells, which is vital for host defense against pathogens. Pattern-recognition receptors (PRRs) are similarly expressed by immune cells as detectors of pathogen-associated molecular patterns. Although there is evidence of cross talk between complement and PRR signaling pathways, knowledge of the full potential for C5a-PRR interaction is limited. In this study, we comprehensively investigated how C5a signaling through C5a receptors can modulate diverse PRR-mediated cytokine responses in human primary monocyte-derived macrophages and observed a powerful, concentration-dependent bidirectional effect of C5a on PRR activities. Unexpectedly, C5a synergized with Dectin-1, Mincle, and STING in macrophages to a much greater extent than TLRs. Notably, we also identified that selective Dectin-1 activation using depleted zymosan triggered macrophages to generate cell-intrinsic C5a, which acted on intracellular and cell surface C5aR1, to help sustain mitochondrial ROS generation, up-regulate TNFα production, and enhance fungal killing. This study adds further evidence to the holistic functions of C5a as a central immunomodulator and important orchestrator of pathogen sensing and killing by phagocytes.

TLQP-21 is a low potency partial C3aR activator on human primary macrophages.

TLQP-21 is a 21-amino acid neuropeptide derived from the VGF precursor protein. TLQP-21 is expressed in the nervous system and neuroendocrine glands, and demonstrates pleiotropic roles including regulating metabolism, nociception and microglial functions. Several possible receptors for TLQP-21 have been identified, with complement C3a receptor (C3aR) being the most commonly reported. However, few studies have characterised the activity of TLQP-21 in immune cells, which represent the major cell type expressing C3aR. In this study, we therefore aimed to define the activity of both human and mouse TLQP-21 on cell signalling in primary human and mouse macrophages. We first confirmed that TLQP-21 induced ERK signalling in CHO cells overexpressing human C3aR, and did not activate human C5aR1 or C5aR2. TLQP-21 mediated ERK signalling was also observed in primary human macrophages. However, the potency for human TLQP-21 was 135,000-fold lower relative to C3a, and only reached 45% at the highest dose tested (10 µM). Unlike in humans, mouse TLQP-21 potently triggered ERK signalling in murine macrophages, reaching near full activation, but at ~10-fold reduced potency compared to C3a. We further confirmed the C3aR dependency of the TLQP-21 activities. Our results reveal significant discrepancy in TLQP-21 C3aR activity between human and murine receptors, with mouse TLQP-21 being consistently more potent than the human counterpart in both systems. Considering the supraphysiological concentrations of hTLQP-21 needed to only partially activate macrophages, it is likely that the actions of TLQP-21, at least in these immune cells, may not be mediated by C3aR in humans.

Unexpected Off-Target Activities for Recombinant C5a in Human Macrophages.

The anaphylatoxin C5a is core effector of complement activation. C5a exerts potent proinflammatory and immunomodulatory actions through interacting with its C5a receptors, C5aR1 and C5aR2, modulating multiple signaling and functional activities of immune cells. Native C5a contains a large N-linked glycosylation site at Asn64, which accounts for up to 25% of its m.w. To date, the vast majority of published studies examining C5a are performed using Escherichia coli-generated recombinant C5a, which is readily available from numerous commercial suppliers, but lacks this glycosylation moiety. However, a plasma-purified "native" form of C5a is also commercially available. The different size and glycosylation of these two C5a versions could have functional implications. Therefore, the current study aimed to compare recombinant human C5a to purified plasma-derived human C5a in driving the signaling and functional activities of human primary macrophages. We found that both versions of C5a displayed similar potencies at triggering C5aR1- and C5aR2-mediated cell signaling, but elicited distinct functional responses in primary human monocyte-derived macrophages. Multiple commercial sources of recombinant C5a, but not the plasma-purified or a synthetic C5a version, induced human monocyte-derived macrophages to produce IL-6 and IL-10 in a C5a receptor-independent manner, which was driven through Syk and NF-κB signaling and apparently not due to endotoxin contamination. Our results, therefore, offer caution against the sole use of recombinant human C5a, particularly in functional/cytokine assays conducted in human primary immune cells, and suggest studies using recombinant human C5a should be paired with C5aR1 inhibitors or purified/synthetic human C5a to confirm relevant findings.

Development of Potent and Selective Agonists for Complement C5a Receptor 1 with In Vivo Activity.

The anaphylatoxin C5a is a complement peptide associated with immune-related disorders. C5a binds with equal potency to two GPCRs, C5aR1 and C5aR2. Multiple C5a peptide agonists have been developed to interrogate the C5a receptor function but none show selectivity for C5aR1. To address these limitations, we developed potent and stable peptide C5aR1 agonists that display no C5aR2 activity and over 1000-fold selectivity for C5aR1 over C3aR. This includes BM213, which induces C5aR1-mediated calcium mobilization and pERK1/2 signaling but not ß-arrestin recruitment, and BM221, which exhibits no signaling bias. Both ligands are functionally similar to C5a in human macrophage cytokine release assays and in a murine in vivo neutrophil mobilization assay. BM213 showed antitumor activity in a mouse model of mammary carcinoma. We anticipate that these C5aR1-selective agonists will be useful research tools to investigate C5aR1 function.

The emerging role of complement in neuromuscular disorders.

The complement cascade is a key arm of the immune system that protects the host from exogenous and endogenous toxic stimuli through its ability to potently regulate inflammation, phagocytosis, and cell lysis. Due to recent clinical trial successes and drug approvals for complement inhibitors, there is a resurgence in targeting complement as a therapeutic approach to prevent ongoing tissue destruction in several diseases. In particular, neuromuscular diseases are undergoing a recent focus, with demonstrated links between complement activation and disease pathology. This review aims to provide a comprehensive overview of complement activation and its role during the initiation and progression of neuromuscular disorders including myasthenia gravis, amyotrophic lateral sclerosis, and Duchenne muscular dystrophy. We will review the preclinical and clinical evidence for complement in these diseases, with an emphasis on the complement-targeting drugs in clinical trials for these indications.

Intrinsic bias at non-canonical, ß-arrestin-coupled seven transmembrane receptors.

G-protein-coupled receptors (GPCRs), also known as seven transmembrane receptors (7TMRs), typically interact with two distinct signal-transducers, i.e., G proteins and ß-arrestins (ßarrs). Interestingly, there are some non-canonical 7TMRs that lack G protein coupling but interact with ßarrs, although an understanding of their transducer coupling preference, downstream signaling, and structural mechanism remains elusive. Here, we characterize two such non-canonical 7TMRs, namely, the decoy D6 receptor (D6R) and the complement C5a receptor subtype 2 (C5aR2), in parallel with their canonical GPCR counterparts. We discover that D6R and C5aR2 efficiently couple to ßarrs, exhibit distinct engagement of GPCR kinases (GRKs), and activate non-canonical downstream signaling pathways. We also observe that ßarrs adopt distinct conformations for D6R and C5aR2, compared to their canonical GPCR counterparts, in response to common natural agonists. Our study establishes D6R and C5aR2 as ßarr-coupled 7TMRs and provides key insights into their regulation and signaling with direct implication for biased agonism.

Absence of Receptor for Advanced Glycation End Product (RAGE) Reduces Inflammation and Extends Survival in the hSOD1G93A Mouse Model of Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) is a fatal and rapidly progressing motor neuron degenerative disease that is without effective treatment. The receptor for advanced glycation end products (RAGE) is a major component of the innate immune system that has been implicated in ALS pathogenesis. However, the contribution of RAGE signalling to the neuroinflammation that underlies ALS neurodegeneration remains unknown. The present study therefore generated SOD1G93A mice lacking RAGE and compared them with SOD1G93A transgenic ALS mice in respect to disease progression (i.e. body weight, survival and muscle strength), neuroinflammation and denervation markers in the spinal cord and tibialis anterior muscle. We found that complete absence of RAGE signalling exerted a protective effect on SOD1G93A pathology, slowing disease progression and significantly extending survival by ~ 3 weeks and improving motor function (rotarod and grip strength). This was associated with reduced microgliosis, cytokines, innate immune factors (complement, TLRs, inflammasomes), and oxidative stress in the spinal cord, and a reduction of denervation markers in the tibialis anterior muscle. We also documented that RAGE mRNA expression was significantly increased in the spinal cord and muscles of preclinical SOD1 and TDP43 models of ALS, supporting a widespread involvement for RAGE in ALS pathology. In summary, our results indicate that RAGE signalling drives neuroinflammation and contributes to neurodegeneration in ALS and highlights RAGE as a potential immune therapeutic target for ALS.

Pharmacological characterisation of small molecule C5aR1 inhibitors in human cells reveals biased activities for signalling and function.

The complement fragment C5a is a core effector of complement activation. C5a, acting through its major receptor C5aR1, exerts powerful pro-inflammatory and immunomodulatory functions. Dysregulation of the C5a-C5aR1 axis has been implicated in numerous immune disorders, and the therapeutic inhibition of this axis is therefore imperative for the treatment of these diseases. A myriad of small-molecule C5aR1 inhibitors have been developed and independently characterised over the past two decades, however the pharmacological properties of these compounds has been difficult to directly compare due to the wide discrepancies in the model, read-out, ligand dose and instrumentation implemented across individual studies. Here, we performed a systematic characterisation of the most commonly reported and clinically advanced small-molecule C5aR1 inhibitors (peptidic: PMX53, PMX205 and JPE1375; non-peptide: W545011, NDT9513727, DF2593A and CCX168). Through signalling assays measuring C5aR1-mediated cAMP and ERK1/2 signalling, and ß-arrestin 2 recruitment, this study highlighted the signalling-pathway dependence of the rank order of potencies of the C5aR1 inhibitors. Functional experiments performed in primary human macrophages demonstrated the high insurmountable antagonistic potencies for the peptidic inhibitors as compared to the non-peptide compounds. Finally, wash-out studies provided novel insights into the duration of inhibition of the C5aR1 inhibitors, and confirmed the long-lasting antagonistic properties of PMX53 and CCX168. Overall, this study revealed the potent and prolonged antagonistic activities of selected peptidic C5aR1 inhibitors and the unique pharmacological profile of CCX168, which thus represent ideal candidates to fulfil diverse C5aR1 research and clinical therapeutic needs.

C5a receptors C5aR1 and C5aR2 mediate opposing pathologies in a mouse model of melanoma.

The canonical complement component 5a (C5a) receptor (C5aR) 1 has well-described roles in tumorigenesis but the contribution of the second receptor, C5aR2, is unclear. The present study demonstrates that B16.F0 melanoma cells express mRNA for both C5aR1 and C5aR2 and signal through ERK and p38 MAPKs in response to C5a. Despite this, C5a had no impact on melanoma cell proliferation or migration in vitro. In vivo studies demonstrated that the growth of B16.F0 melanoma tumors was increased in C5aR2-/- mice but reduced in C5aR1-/- mice and wild-type mice treated with a C5aR1 antagonist. Analysis of tumor-infiltrating leukocyte populations showed no significant differences between wild-type and C5aR2-/- mice. Conversely, percentages of myeloid-derived suppressor cells, macrophages, and regulatory T lymphocytes were lower in tumors from C5aR1-/- mice, whereas total (CD3+) T lymphocytes and CD4+ subsets were higher. Analysis of cytokine and chemokine levels also showed plasma IFN-γ was higher and tumor C-C motif chemokine ligand 2 was lower in the absence of C5aR1. The results suggest that C5aR1 signaling supports melanoma growth by promoting infiltration of immunosuppressive leukocyte populations into the tumor microenvironment, whereas C5aR2 has a more restricted but beneficial role in limiting tumor growth. Overall, these data support the potential of C5aR1-inhibitory therapies for melanoma.-Nabizadeh, J. A., Manthey, H. D., Panagides, N., Steyn, F. J., Lee, J. D., Li, X. X., Akhir, F. N. M., Chen, W., Boyle, G. M., Taylor, S. M., Woodruff, T. M., Rolfe, B. E. C5a receptors C5aR1 and C5aR2 mediate opposing pathologies in a mouse model of melanoma.

Therapeutic blockade of HMGB1 reduces early motor deficits, but not survival in the SOD1G93A mouse model of amyotrophic lateral sclerosis.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal and rapidly progressing neurodegenerative disease without effective treatment. The receptor for advanced glycation end products (RAGE) and the toll-like receptor (TLR) system are major components of the innate immune system, which have been implicated in ALS pathology. Extracellularly released high-mobility group box 1 (HMGB1) is a pleiotropic danger-associated molecular pattern (DAMP), and is an endogenous ligand for both RAGE and TLR4. METHODS: The present study examined the effect of HMGB1 inhibition on disease progression in the preclinical SOD1G93A transgenic mouse model of ALS using a potent anti-HMGB1 antibody (2G7), which targets the extracellular DAMP form of HMGB1. RESULTS: We found that chronic intraperitoneal dosing of the anti-HMGB1 antibody to SOD1G93A mice transiently improved hind-limb grip strength early in the disease, but did not extend survival. Anti-HMGB1 treatment also reduced tumour necrosis factor α and complement C5a receptor 1 gene expression in the spinal cord, but did not affect overall glial activation. CONCLUSIONS: In summary, our results indicate that therapeutic targeting of an extracellular DAMP, HMGB1, improves early motor dysfunction, but overall has limited efficacy in the SOD1G93A mouse model of ALS.

How safe is tuning a radio?: using the radio tuning task as a benchmark for distracted driving.

Drivers engage in non-driving tasks while driving, such as interactions entertainment systems. Studies have identified glance patterns related to such interactions, and manual radio tuning has been used as a reference task to set an upper bound on the acceptable demand of interactions. Consequently, some view the risk associated with radio tuning as defining the upper limit of glance measures associated with visual-manual in-vehicle activities. However, we have little knowledge about the actual degree of crash risk that radio tuning poses and, by extension, the risk of tasks that have similar glance patterns as the radio tuning task. In the current study, we use counterfactual simulation to take the glance patterns for manual radio tuning tasks from an on-road experiment and apply these patterns to lead-vehicle events observed in naturalistic driving studies. We then quantify how often the glance patterns from radio tuning are associated with rear-end crashes, compared to driving only situations. We used the pre-crash kinematics from 34 crash events from the SHRP2 naturalistic driving study to investigate the effect of radio tuning in crash-imminent situations, and we also investigated the effect of radio tuning on 2,475 routine braking events from the Safety Pilot project. The counterfactual simulation showed that off-road glances transform some near-crashes that could have been avoided into crashes, and glance patterns observed in on-road radio tuning experiment produced 2.85-5.00 times more crashes than baseline driving.

Complement C5a-C5aR1 signalling drives skeletal muscle macrophage recruitment in the hSOD1G93A mouse model of amyotrophic lateral sclerosis.

BACKGROUND: The terminal pathway of the innate immune complement system is implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). Terminal complement activation leads to generation of C5a, which through its receptor, C5aR1, drives immune cell recruitment and activation. Importantly, genetic or pharmacological blockage of C5aR1 improves motor performance and reduces disease pathology in hSOD1G93A rodent models of ALS. In this study, we aimed to explore the potential mechanisms of C5aR1-mediated pathology in hSOD1G93A mice by examining their skeletal muscles. RESULTS: We found elevated levels of C1qB, C4, fB, C3, C5a, and C5aR1 in tibialis anterior muscles of hSOD1G93A mice, which increased with disease progression. Macrophage cell numbers also progressively increased in hSOD1G93A muscles in line with disease progression. Immuno-localisation demonstrated that C5aR1 was expressed predominantly on macrophages within hSOD1G93A skeletal muscles. Notably, hSOD1G93A × C5aR1-/- mice showed markedly decreased numbers of infiltrating macrophages, along with reduced neuromuscular denervation and improved grip strength in hind limb skeletal muscles, when compared to hSOD1G93A mice. CONCLUSION: These results indicate that terminal complement activation and C5a production occur in skeletal muscle tissue of hSOD1G93A mice, and that C5a-C5aR1 signalling contributes to the recruitment of macrophages that may accelerate muscle denervation in these ALS mice.

Silencing of ghrelin receptor expression inhibits endometrial cancer cell growth in vitro and in vivo.

Ghrelin is a 28-amino acid peptide hormone produced predominantly in the stomach but also in a range of normal cell types and tumors, where it has endocrine, paracrine, and autocrine roles. Previously, we have demonstrated that ghrelin has proliferative and antiapoptotic effects in endometrial cancer cell lines, suggesting a potential role in promoting tumor growth. In the present study, we investigated the effect of ghrelin receptor, GHSR, and gene silencing in vitro and in vivo and characterized ghrelin and GHSR1a protein expression in human endometrial tumors. GHSR gene silencing was achieved in the Ishikawa and KLE endometrial cancer cell lines, using a lentiviral short-hairpin RNA targeting GHSR. The effects of GHSR1a knockdown were further analyzed in vivo using the Ishikawa cell line in a NOD/SCID xenograft model. Cell proliferation was reduced in cultured GHSR1a knockdown Ishikawa and KLE cells compared with scrambled controls in the absence of exogenously applied ghrelin and in response to exogenous ghrelin (1,000 nM). The tumor volumes were reduced significantly in GHSR1a knockdown Ishikawa mouse xenograft tumors compared with scrambled control tumours. Using immunohistochemistry, we demonstrated that ghrelin and GHSR1a are expressed in benign and cancerous glands in human endometrial tissue specimens, although there was no correlation between the intensity of staining and cancer grade. These data indicate that downregulation of GHSR expression significantly inhibits endometrial cancer cell line and mouse xenograft tumour growth. This is the first preclinical evidence that downregulation of GHSR may be therapeutic in endometrial cancer.

Automatic updating of times remaining in surgical cases using bayesian analysis of historical case duration data and "instant messaging" updates from anesthesia providers.

BACKGROUND: Operating room (OR) whiteboards (status displays) communicate times remaining for ongoing cases to perioperative stakeholders (e.g., postanesthesia care unit, anesthesiologists, holding area, and control desks). Usually, scheduled end times are shown for each OR. However, these displays are inaccurate for predicting the time that remains in a case. Once a case scheduled for 2 h has been on-going for 1.5 h, the median time remaining is not 0.5 h but longer, and the amount longer differs among procedures. METHODS: We derived the conditional Bayesian lower prediction bound of a case's duration, conditional on the minutes of elapsed OR time. Our derivations make use of the posterior predictive distribution of OR times following an exponential of a scaled Student t distribution that depends on the scheduled OR time and several parameters calculated from historical case duration data. The statistical method was implemented using Structured Query Language (SQL) running on the anesthesia information management system (AIMS) database server. In addition, AIMS workstations were sent instant messages displaying a pop-up dialog box asking for anesthesia providers' estimates for remaining times. The dialogs caused negotiated interruptions (i.e., the anesthesia provider could reply immediately, keep the dialog displayed, or defer response). There were no announcements, education, or efforts to promote buy-in. RESULTS: After a case had been in the OR longer than scheduled, the median remaining OR time for the case changes little over time (e.g., 35 min left at 2:30 pm and also at 3:00 pm while the case was still on-going). However, the remaining time differs substantially among surgeons and scheduled procedure(s) (16 min longer [10th percentile], 35 min [50th], and 86 min [90th]). We therefore implemented an automatic method to estimate the times remaining in cases. The system was operational for >119 of each day's 120 5-min intervals. When instant message dialogs appearing on AIMS workstations were used to elicit estimates of times remaining from anesthesia providers, acknowledgment was on average within 1.2 min (95% confidence interval [CI] 1.1-1.3 min). The 90th percentile of latencies was 6.5 min (CI: 4.4-7.0 min). CONCLUSIONS: For cases taking nearly as long as or longer than scheduled, each 1 min progression of OR time reduces the median time remaining in a case by <1 min. We implemented automated calculation of times remaining for every case at a 29 OR hospital.

A psychological basis for anesthesiologists' operating room managerial decision-making on the day of surgery.

BACKGROUND: We investigated whether, without prompting, anesthesiologists tend to make managerial decisions to increase the clinical work per unit time of the sites to which they are assigned during their scheduled time present. Although a sound basis for decision-making involving individual ORs, the heuristic is often suboptimal economically when applied to decisions involving multiple ORs. METHODS: Two studies were performed at one hospital. 1) A retrospective analysis was made of anesthesiologists' managerial decisions when caring for sequential lists of patients. 2) Patients' and surgeons' waiting on nights and weekends were studied before/after education on optimal decision-making. RESULTS: 1) Anesthesiologists' decisions resulted in an increase in their clinical work per unit time, not a reduction in patient waiting. 2) Paradoxically, such efforts on nights and weekends caused increased patient and surgeon waiting. Decisions were unchanged after education on a different way to assign cases. CONCLUSIONS: In a companion article, we showed that clinicians tended to make decisions that increased the clinical work per unit time at each moment in each OR, even when doing so resulted in an increase in overutilized OR time, higher staffing costs, unpredictable work hours, and/or mandatory overtime. The current studies show that such efforts to work fast cannot be explained as a consequence of efforts to reduce surgeon and patient waiting. Rather, the heuristic followed is consistent with increasing one's personal clinical work per unit time at one's assigned anesthetizing location.

Operating room managerial decision-making on the day of surgery with and without computer recommendations and status displays.

BACKGROUND: There are three basic types of decision aids to facilitate operating room (OR) management decision-making on the day of surgery. Decision makers can rely on passive status displays (e.g., big screens or whiteboards), active status displays (e.g., text pager notification), and/or command displays (e.g., text recommendations about what to do). METHODS: Anesthesiologists, OR nurses, and housekeepers were given nine simulated scenarios (vignettes) involving multiple ORs to study their decision-making. Participants were randomized to one of four groups, all with an updated paper OR schedule: with/without command display and with/without passive status display. RESULTS: Participants making decisions without command displays performed no better than random chance in terms of increasing the predictability of work hours, reducing over-utilized OR time, and increasing OR efficiency. Status displays had no effect on these end-points, whereas command displays improved the quality of decisions. In the scenarios for which the command displays provided recommendations that adversely affected safety, participants appropriately ignored advice. CONCLUSIONS: Anesthesia providers and nursing staff made decisions that increased clinical work per unit time in each OR, even when doing so resulted in an increase in over-utilized OR time, higher staffing costs, unpredictable work hours, and/or mandatory overtime. Organizational culture and socialization during clinical training may be a cause. Command displays showed promise in mitigating this tendency. Additional investigations are in our companion paper.

Alerts for in-vehicle information systems: annoyance, urgency, and appropriateness.

OBJECTIVE: This study assesses the influence of the auditory characteristics of alerts on perceived urgency and annoyance and whether these perceptions depend on the context in which the alert is received. BACKGROUND: Alert parameters systematically affect perceived urgency, and mapping the urgency of a situation to the perceived urgency of an alert is a useful design consideration. Annoyance associated with environmental noise has been thoroughly studied, but little research has addressed whether alert parameters differentially affect annoyance and urgency. METHOD: Three 2(3) x 3 mixed within/between factorial experiments, with a total of 72 participants, investigated nine alert parameters in three driving contexts. These parameters were formant (similar to harmonic series), pulse duration, interpulse interval, alert onset and offset, burst duty cycle, alert duty cycle, interburst period, and sound type. Imagined collision warning, navigation alert, and E-mail notification scenarios defined the driving context. RESULTS: All parameters influenced both perceived urgency and annoyance (p < .05), with pulse duration, interpulse interval, alert duty cycle, and sound type influencing urgency substantially more than annoyance. There was strong relationship between perceived urgency and rated appropriateness for high-urgency driving scenarios and a strong relationship between annoyance and rated appropriateness for low-urgency driving scenarios. CONCLUSION: Sound parameters differentially affect annoyance and urgency. Also, urgency and annoyance differentially affect perceived appropriateness of warnings. APPLICATION: Annoyance may merit as much attention as urgency in the design of auditory warnings, particularly in systems that alert drivers to relatively low-urgency situations.

Auditory alerts for in-vehicle information systems: the effects of temporal conflict and sound parameters on driver attitudes and performance.

In-vehicle information systems will soon confront drivers with an increasing number of warnings and alerts for situations ranging from imminent collisions to the arrival of e-mail messages. Coordinating these alerts can ensure that they enhance rather than degrade driving safety. Two experiments examined how temporal conflict and sound parameters affect driver performance and acceptance. The temporal conflict of an e-mail alert occurring 300 ms before a collision warning interfered with the response to the collision warning, but an e-mail alert occurring 1000 ms before the collision warning had the opposite effect and enhanced the response to the collision warning. These results emphasize the need to consider how in-vehicle devices influence drivers' strategic anticipation of high-demand situations. Regarding sound parameters, results showed that highly urgent sounds tended to speed drivers' accelerator release, but the annoyance associated with highly urgent sounds increased workload. In fact, there was a strong positive association between ratings of annoyance and subjective workload. Consistent with the urgency mapping principle, there was a slight negative association between the differences in the rated urgency of collision warnings and e-mail alerts and subjective workload. The results suggest that warning and alert design should consider an annoyance trade-off in addition to urgency mapping.