Flow in temporally and spatially varying porous media: a model for transport of interstitial fluid in the brain.

Flow in a porous medium can be driven by the deformations of the boundaries of the porous domain. Such boundary deformations locally change the volume fraction accessible by the fluid, creating non-uniform porosity and permeability throughout the medium. In this work, we construct a deformation-driven porous medium transport model with spatially and temporally varying porosity and permeability that are dependent on the boundary deformations imposed on the medium. We use this model to study the transport of interstitial fluid along the basement membranes in the arterial walls of the brain. The basement membrane is modeled as a deforming annular porous channel with the compressible pore space filled with an incompressible, Newtonian fluid. The role of a forward propagating peristaltic heart pulse wave and a reverse smooth muscle contraction wave on the flow within the basement membranes is investigated. Our results identify combinations of wave amplitudes that can induce either forward or reverse transport along these transport pathways in the brain. The magnitude and direction of fluid transport predicted by our model can help in understanding the clearance of fluids and solutes along the Intramural Periarterial Drainage route and the pathology of cerebral amyloid angiopathy.

International collaboration between low-middle-income and high-income institutions to improve radiation therapy care delivery.

INTRODUCTION: The Philippines is a lower-middle-income island country with over 153 000 new cancer diagnosis each year. Despite many patients needing radiotherapy as part of disease management, there remains limitations to access. Currently, the Philippines has 50 linear accelerator facilities serving a population of 110 million. However, given the recommendation of 1 linear accelerator for every 250 thousand people, it is evident that the demand for accessible radiotherapy resources is significantly underserved in the country. This paper outlines the collaboration between GenesisCare Solutions (GCS) and Fairview Cancer Center (FCC) to address efficiency and access within the radiotherapy department at FCC. METHODS: Through international collaboration between GCS and FCC, areas for improvement were identified and categorized into four domains: Dosimetry quality, Patient workflow, Data & Reporting, and Information Technology (IT) Infrastructure. Action plans were developed then implemented. A baseline measurement was obtained for each domain, and post-implementation evaluation undertaken at 3 months, 6 months, and 12 months. Data captured within the electronic medical record system was extrapolated, and average treatment times were established for pre- and post-engagement. A paired, 2-tailed t-test was used for statistical analysis of outcome parameters using IBM SPSS version 23 for all statistics. RESULTS: Twelve months post-initial engagement, all four domains saw positive outcomes. Improved plan quality linked to Intensity Modulated Radiotherapy (IMRT) utilization rates saw an increase from 20% to 54%. A significant reduction in patient average wait times was also observed, from 27 to 17 min (p ≤ 0.001). Prior to engagement, tracking patient demographics and diagnosis was not prioritized, post engagement an average of 92% diagnosis entry compliance was achieved. CONCLUSION: Through the collaboration of GCS and FCC, objectives in all action plan domains were achieved, highlighting the benefits of collaboration between low-middle-income and high-income institutions.

Multiscale computational modeling of aortic valve calcification.

Calcific aortic valve disease (CAVD) is a common cardiovascular disease that affects millions of people worldwide. The disease is characterized by the formation of calcium nodules on the aortic valve leaflets, which can lead to stenosis and heart failure if left untreated. The pathogenesis of CAVD is still not well understood, but involves several signaling pathways, including the transforming growth factor beta (TGF ß ) pathway. In this study, we developed a multiscale computational model for TGF ß -stimulated CAVD. The model framework comprises cellular behavior dynamics, subcellular signaling pathways, and tissue-level diffusion fields of pertinent chemical species, where information is shared among different scales. Processes such as endothelial to mesenchymal transition (EndMT), fibrosis, and calcification are incorporated. The results indicate that the majority of myofibroblasts and osteoblast-like cells ultimately die due to lack of nutrients as they become trapped in areas with higher levels of fibrosis or calcification, and they subsequently act as sources for calcium nodules, which contribute to a polydispersed nodule size distribution. Additionally, fibrosis and calcification processes occur more frequently in regions closer to the endothelial layer where the cell activity is higher. Our results provide insights into the mechanisms of CAVD and TGF ß signaling and could aid in the development of novel therapeutic approaches for CAVD and other related diseases such as cancer. More broadly, this type of modeling framework can pave the way for unraveling the complexity of biological systems by incorporating several signaling pathways in subcellular models to simulate tissue remodeling in diseases involving cellular mechanobiology.

EigenFold: Generative Protein Structure Prediction with Diffusion Models.

Protein structure prediction has reached revolutionary levels of accuracy on single structures, yet distributional modeling paradigms are needed to capture the conformational ensembles and flexibility that underlie biological function. Towards this goal, we develop EigenFold, a diffusion generative modeling framework for sampling a distribution of structures from a given protein sequence. We define a diffusion process that models the structure as a system of harmonic oscillators and which naturally induces a cascading-resolution generative process along the eigenmodes of the system. On recent CAMEO targets, EigenFold achieves a median TMScore of 0.84, while providing a more comprehensive picture of model uncertainty via the ensemble of sampled structures relative to existing methods. We then assess EigenFold's ability to model and predict conformational heterogeneity for fold-switching proteins and ligand-induced conformational change. Code is available at https://github.com/bjing2016/EigenFold.

Probing Colloidal Assembly on Non-Axisymmetric Droplet Surfaces via Electrospray.

Microparticles trapped on the surface of a sessile droplet interact via electrostatic and capillary forces. The assembly of colloids at a fluid-fluid interface is governed by particle size, surface chemistry, and contact line roughness. We created nonspherical droplets using surface energy patterning and delivered microparticles to the liquid-air interface with electrospray atomization. Using a water droplet as the target, the particle assembly was observed over time. We found that the underlying surface energy pattern significantly influenced the colloidal assembly and drove particles toward the center of the droplet. The particles were arranged into a single, non-close-packed cluster with local hexagonal ordering but left a clear region with very few particles near the contact line. This depletion region is attributed to long-range electrostatic repulsion from the photoresist used to create the surface energy pattern, which retained electric charge from the electrospray. To understand the effect of electrostatic interactions, we explored target droplets with dissimilar dielectric properties. Using patterned substrates and electrospray for particle deposition, we can harness the assembly of colloids at a fluid interface to build repeatable monolayer patterns.

Glycosaminoglycans affect endothelial to mesenchymal transformation, proliferation, and calcification in a 3D model of aortic valve disease.

Calcific nodules form in the fibrosa layer of the aortic valve in calcific aortic valve disease (CAVD). Glycosaminoglycans (GAGs), which are normally found in the valve spongiosa, are located local to calcific nodules. Previous work suggests that GAGs induce endothelial to mesenchymal transformation (EndMT), a phenomenon described by endothelial cells' loss of the endothelial markers, gaining of migratory properties, and expression of mesenchymal markers such as alpha smooth muscle actin (α-SMA). EndMT is known to play roles in valvulogenesis and may provide a source of activated fibroblast with a potential role in CAVD progression. In this study, a 3D collagen hydrogel co-culture model of the aortic valve fibrosa was created to study the role of EndMT-derived activated valvular interstitial cell behavior in CAVD progression. Porcine aortic valve interstitial cells (PAVIC) and porcine aortic valve endothelial cells (PAVEC) were cultured within collagen I hydrogels containing the GAGs chondroitin sulfate (CS) or hyaluronic acid (HA). The model was used to study alkaline phosphatase (ALP) enzyme activity, cellular proliferation and matrix invasion, protein expression, and calcific nodule formation of the resident cell populations. CS and HA were found to alter ALP activity and increase cell proliferation. CS increased the formation of calcified nodules without the addition of osteogenic culture medium. This model has applications in the improvement of bioprosthetic valves by making replacements more micro-compositionally dynamic, as well as providing a platform for testing new pharmaceutical treatments of CAVD.

Efficacy evaluation of True Lift®, a nonsurgical facial ligament retightening injection technique: Two case reports.

BACKGROUND: With aging, four major facial retaining ligaments become elongated, leading to facial sagging and wrinkling. Even though synthetic fillers are popular, however, it cannot address the problems of soft tissue descent alone, and injection of these fillers requires knowledge of the injection technique including the selection of injection sites, the amount of filler, and the dosage used per injection site. CASE SUMMARY: This report aimed to assess the safety and efficacy of a nonsurgical retightening technique to lift and tighten the true ligaments of the face, to improve age-related skin sagging and wrinkling. We objectively quantified the aesthetic lifting effect of a nonsurgical facial retightening procedure that strategically injected high G' fillers into the base of the true retaining ligaments of the face in two female patients. Facial images were recorded with a three-dimensional facial imaging system for comparison of the clinical outcome. The primary efficacy outcome was the change in facial anthropometric measurements obtained prior to and after injection. The patients were followed for 6 mo after the procedure. Skin retightening was observed, with an evident lift in the orbital, zygomatic, and mandibular regions, and the lifting effect was still observable at the 6-mo follow-up. Few mild adverse events, such as mild-to-moderate pain, tenderness, and itching, occurred during the 1st week after the procedure. No adverse events were reported 1 mo post-procedure. CONCLUSION: The results of this study demonstrated that our nonsurgical retightening procedure with strategically placed high G' fillers achieved quantifiable aesthetic improvements in the orbital, zygomatic, and mandibular regions of two patients. Future research with a larger sample could provide a more in-depth evaluation and validation of the aesthetic improvements observed in this study.

Shear and endothelial induced late-stage calcific aortic valve disease-on-a-chip develops calcium phosphate mineralizations.

Calcific aortic valve disease (CAVD) is an active pathobiological process leading to severe aortic stenosis, where the only treatment is valve replacement. Late-stage CAVD is characterized by calcification, disorganization of collagen, and deposition of glycosaminoglycans, such as chondroitin sulfate (CS), in the fibrosa. We developed a three-dimensional microfluidic device of the aortic valve fibrosa to study the effects of shear stress (1 or 20 dyne per cm2), CS (1 or 20 mg mL-1), and endothelial cell presence on calcification. CAVD chips consisted of a collagen I hydrogel, where porcine aortic valve interstitial cells were embedded within and porcine aortic valve endothelial cells were seeded on top of the matrix for up to 21 days. Here, we show that this CAVD-on-a-chip is the first to develop human-like calcified nodules varying in calcium phosphate mineralization maturity resulting from high shear and endothelial cells, specifically di- and octa-calcium phosphates. Long-term co-culture microfluidic studies confirmed cell viability and calcium phosphate formations throughout 21 days. Given that CAVD has no targeted therapies, the creation of a physiologically relevant test-bed of the aortic valve could lead to advances in preclinical studies.

Chondroitin Sulfate Promotes Interstitial Cell Activation and Calcification in an In Vitro Model of the Aortic Valve.

PURPOSE: Calcific aortic valve disease (CAVD), has been characterized as a cascade of cellular changes leading to leaflet thickening and valvular calcification. In diseased aortic valves, glycosaminoglycans (GAGs) normally found in the valve spongiosa migrate to the collagen I-rich fibrosa layer near calcified nodules. Current treatments for CAVD are limited to valve replacement or drugs tailored to other cardiovascular diseases. METHODS: Porcine aortic valve interstitial cells and porcine aortic valve endothelial cells were seeded into collagen I hydrogels of varying initial stiffness or initial stiffness-matched collagen I hydrogels containing the glycosaminoglycans chondroitin sulfate (CS), hyaluronic acid (HA), or dermatan sulfate (DS). Assays were performed after 2 weeks in culture to determine cell gene expression, protein expression, protein secretion, and calcification. Multiple regression analyses were performed to determine the importance of initial hydrogel stiffness, GAGs, and the presence of endothelial cells on calcification, both with and without osteogenic medium. RESULTS: High initial stiffness hydrogels and osteogenic medium promoted calcification, while for DS or HA the presence of endothelial cells prevented calcification. CS was found to increase the expression of pro-calcific genes, increase activated myofibroblast protein expression, induce the secretion of collagen I by activated interstitial cells, and increase calcified nodule formation. CONCLUSION: This study demonstrates a more complete model of aortic valve disease, including endothelial cells, interstitial cells, and a stiff and disease-like ECM. In vitro models of both healthy and diseased valves can be useful for understanding the mechanisms of CAVD pathogenesis and provide a model for testing novel therapeutics.

Cephalometric analysis following combined Sub-SMAS hyaluronic acid injection and subdermal and supraperiosteal poly-L-lactic acid injections in Asian women.

BACKGROUND: The aging face is characterized by skin laxity and volume loss. Attenuation of facial retaining ligaments significantly contributes to skin sagginess and soft tissue volume loss. AIMS: We designed a prospective cohort study to quantitatively assess the efficacy of hyaluronic acid (HA) with adjunct poly-L-lactic acid (PLLA) injections in strengthening the retaining ligaments. PATIENTS/METHODS: A total of 12 Asian women were treated with HA injections to the orbital, zygomatic, buccal-maxillary, and mandibular retaining ligaments with adjunct supraperiosteal and subdermal PLLA injections to the temporal region, midface, and lower face. Cephalometric measurements were done before treatment and 2, 4, 12, and 24 weeks post-procedurally. RESULTS: Eyebrow peak and tail angles increased 20.0° ± 3.8° to 21.0° ± 3.8° (p < 0.05) and -2.9° ± 4.2° to -1.3° ± 3.3° (p < 0.001) at week 12. Eyebrow-to-orbital-rim distance increased 1.9 ± 2.0 mm to 3.9 ± 1.5 mm (p < 0.001) at week 12. Eyebrow-to-upper-eyelid distance increased 11.6 ± 3.0 mm to 12.7 ± 3.2 mm (p < 0.001) at week 24. Eyebrow-peak-to-lateral-limbus distance decreased 6.1 ± 3.1 mm to 5.3 ± 2.4 mm (p < 0.05) at week 4. Tragus-oral-commissure length and lower-facial-contouring length decreased 281 ± 11 mm to 275 ± 10 mm (p < 0.01) and 297 ± 14 to 292 ± 11 mm (p < 0.05) at week 12, respectively. CONCLUSION: Hyaluronic acid injection for strengthening of facial retaining ligaments with adjunct PLLA is viable, safe, and effective in facial rejuvenation as supported by quantitative data.

Racial/ethnic differences in eligibility for asthma biologics among pediatric populations.

BACKGROUND: Asthma is a heterogeneous disease. Clinical blood parameters differ by race/ethnicity and are used to distinguish asthma subtypes and inform therapies. Differences in subtypes may explain population-specific trends in asthma outcomes. However, these differences in racial/ethnic minority pediatric populations are unclear. OBJECTIVE: We investigated the association of blood parameters and asthma subtypes with asthma outcomes and examined population-specific eligibility for biologic therapies in minority pediatric populations. METHODS: Using data from 2 asthma case-control studies of pediatric minority populations, we performed case-control (N = 3738) and case-only (N = 2743) logistic regressions to quantify the association of blood parameters and asthma subtypes with asthma outcomes. Heterogeneity of these associations was tested using an interaction term between race/ethnicity and each exposure. Differences in therapeutic eligibility were investigated using chi-square tests. RESULTS: Race/ethnicity modified the association between total IgE and asthma exacerbations. Elevated IgE level was associated with worse asthma outcomes in Puerto Ricans. Allergic asthma was associated with worse outcomes in Mexican Americans, whereas eosinophilic asthma was associated with worse outcomes in Puerto Ricans. A lower proportion of Puerto Ricans met dosing criteria for allergic asthma-directed biologic therapy than other groups. A higher proportion of Puerto Ricans qualified for eosinophilic asthma-directed biologic therapy than African Americans. CONCLUSIONS: We found population-specific associations between blood parameters and asthma subtypes with asthma outcomes. Our findings suggest that eligibility for asthma biologic therapies differs across pediatric racial/ethnic populations. These findings call for more studies in diverse populations for equitable treatment of minority patients with asthma.

Discovery of ZN-c3, a Highly Potent and Selective Wee1 Inhibitor Undergoing Evaluation in Clinical Trials for the Treatment of Cancer.

Wee1 inhibition has received great attention in the past decade as a promising therapy for cancer treatment. Therefore, a potent and selective Wee1 inhibitor is highly desirable. Our efforts to make safer and more efficacious Wee1 inhibitors led to the discovery of compound 16, a highly selective Wee1 inhibitor with balanced potency, ADME, and pharmacokinetic properties. The chiral ethyl moiety of compound 16 provided an unexpected improvement of Wee1 potency. Compound 16, known as ZN-c3, showed excellent in vivo efficacy and is currently being evaluated in phase 2 clinical trials.

Association between common telomere length genetic variants and telomere length in an African population and impacts of HIV and TB.

Prior studies in predominantly European (Caucasian) populations have discovered common genetic variants (single nucleotide polymorphisms, SNPs) associated with leukocyte telomere length (LTL), but whether these same variants affect LTL in non-Caucasian populations are largely unknown. We investigated whether six genetic variants previously associated with LTL (TERC (rs10936599), TERT (rs2736100), NAF1 (7675998), OBFC1 (rs9420907), ZNF208 (rs8105767), and RTEL1 (rs755017)) are correlated with telomere length (TL) in peripheral blood mononuclear cells (PBMCs) in a cohort of Africans living with and without HIV and undergoing evaluation for tuberculosis (TB). We found OBFC1 and the genetic sum score of the effect alleles across all six loci to be associated with shorter TL (adjusted for age, gender, HIV status, and smoking pack-years (p < 0.02 for both OBFC1 and the genetic sum score). In an analysis stratified by HIV status, the genetic sum score is associated with LTL in both groups with and without HIV. On the contrary, a stratified analysis according to TB status revealed that in the TB-positive subgroup, the genetic sum score is not associated with LTL, whereas the relationship remains in the TB-negative subgroup. The different impacts of HIV and TB on the association between the genetic sum score and LTL indicate different modes of modification and suggest that the results found in this cohort with HIV and TB participants may not be applied to the African general population. Future studies need to carefully consider these confounding factors.

Boundary waves in a microfluidic device as a model for intramural periarterial drainage.

The failure to clear amyloid-Beta from an aging brain leads to its accumulation within the walls of arteries and potentially to Alzheimer's disease. However, the clearance mechanism through the intramural periarterial pathway is not well understood. We previously proposed a hydrodynamic reverse transport model for the cerebral arterial basement membrane pathway. In our model, solute transport results from fluidic forcing driven by the superposition of forward and reverse propagating boundary waves. The aim of this study is to experimentally validate this hydrodynamic reverse transport mechanism in a microfluidic device where reverse transport in a rectangular conduit is driven by applying waveforms along its boundaries. Our results support our theory that while the superimposed boundary waves propagate in the forward direction, a reverse flow in the rectangular conduit can be induced by boundary wave reflections. We quantified the fluid transport velocity and direction under various boundary conditions and analyzed numerical simulations that support our experimental findings. We identified a set of boundary wave parameters that achieved reverse transport, which could be responsible for intramural periarterial drainage of cerebral metabolic waste.

The role of shear stress and altered tissue properties on endothelial to mesenchymal transformation and tumor-endothelial cell interaction.

Tumor development is influenced by stromal cells in aspects including invasion, growth, angiogenesis, and metastasis. Activated fibroblasts are one group of stromal cells involved in cancer metastasis, and one source of activated fibroblasts is endothelial to mesenchymal transformation (EndMT). EndMT begins when the endothelial cells delaminate from the cell monolayer, lose cell-cell contacts, lose endothelial markers such as vascular endothelial-cadherin (VE-cadherin), gain mesenchymal markers like alpha-smooth muscle actin (α-SMA), and acquire mesenchymal cell-like properties. A three-dimensional (3D) culture microfluidic device was developed for investigating the role of steady low shear stress (1 dyne/cm2) and altered extracellular matrix (ECM) composition and stiffness on EndMT. Shear stresses resulting from fluid flow within tumor tissue are relevant to both cancer metastasis and treatment effectiveness. Low and oscillatory shear stress rates have been shown to enhance the invasion of metastatic cancer cells through specific changes in actin and tubulin remodeling. The 3D ECM within the device was composed of type I collagen and glycosaminoglycans (GAGs), hyaluronic acid and chondroitin sulfate. An increase in collagen and GAGs has been observed in the solid tumor microenvironment and has been correlated with poor prognosis in many different cancer types. In this study, it was found that ECM composition and low shear stress upregulated EndMT, including upregulation of mesenchymal-like markers (α-SMA and Snail) and downregulated endothelial marker protein and gene expression (VE-cadherin). Furthermore, this novel model was utilized to investigate the role of EndMT in breast cancer cell proliferation and migration. Cancer cell spheroids were embedded within the 3D ECM of the microfluidic device. The results using this device show for the first time that the breast cancer spheroid size is dependent on shear stress and that the cancer cell migration rate, distance, and proliferation are induced by EndMT-derived activated fibroblasts. This model can be used to explore new therapeutics in a tumor microenvironment.

Endothelial to mesenchymal transformation is induced by altered extracellular matrix in aortic valve endothelial cells.

Alterations in shear stress, mechanical deformation, extracellular matrix (ECM) composition and exposure to inflammatory conditions are known to cause endothelial to mesenchymal transformation (EndMT). This change in endothelial phenotype has only recently been linked to adult pathologies such as cancer progression, organ fibrosis, and calcific aortic valve disease; and its function in adult physiology, especially in response to tissue mechanics, has not been rigorously investigated. EndMT is a response to mechanical and biochemical signals that results in the remodeling of underlying tissues. In diseased aortic valves, glycosaminoglycans (GAGs) are present in the collagen-rich valve fibrosa, and are deposited near calcified nodules. In this study, in vitro models of early and late-stage valve disease were developed by incorporating the GAGs chondroitin sulfate (CS), hyaluronic acid, and dermatan sulfate into 3D collagen hydrogels with or without exposure to TGF-ß1 to simulate EndMT in response to microenvironmental changes. High levels of CS induced the highest rate of EndMT and led to the most collagen I and GAG production by mesenchymally transformed cells, which indicates a cell phenotype most likely to promote fibrotic disease. Mesenchymal transformation due to altered ECM was found to depend on cell-ECM bond strength and extracellular signal-regulated protein kinases 1/2 signaling. Determining the environmental conditions that induce and promote EndMT, and the subsequent behavior of mesenchymally transformed cells, will advance understanding on the role of endothelial cells in tissue regeneration or disease progression. © 2017 Wiley Periodicals Inc. J Biomed Mater Res Part A: 105A: 2729-2741, 2017.

A new tool to improve delivery of patient-engaged care and satisfaction in facial treatments: the Aesthetic Global Ranking Scale.

BACKGROUND: Physicians face the challenge of individualizing aesthetic treatments in order to match the aesthetic needs of patients with their expectations. OBJECTIVE: To review issues underlying patient satisfaction with minimally invasive aesthetic treatment and to present a patient-centric assessment tool (the Global Ranking Scale [GRS]) designed to set higher standards for patient consultation and treatment experience; ensure a comprehensive patient-centric aesthetic consultation process; and raise patient satisfaction with facial rejuvenation treatment. METHODS: A review of the design and content of the GRS and its use as part of the wider Galderma Harmony Program. Results of a small survey of clinicians who have switched to the GRS, and case studies of patients who have used the tool, are also presented. RESULTS: The GRS is used in ~500 clinics around the world. In a small survey, physicians who have used the GRS report that it has changed the way that patients are assessed and treated. While no patient survey was conducted, anecdotal evidence suggests that patients are satisfied with the GRS procedure and the outcomes of treatment. CONCLUSIONS: The GRS is a new patient assessment tool that is designed as a guide for clinicians to help ensure consistency in the quality of patient assessment and consultation in their clinics offering minimally invasive facial cosmetic procedures. Qualitative research suggests that it gives patients a better chance to achieve results aligned with their needs resulting in a higher level of satisfaction with aesthetic treatments, but this needs to be confirmed in a formal patient survey.

Consensus Recommendations for Optimal Augmentation of the Asian Face with Hyaluronic Acid and Calcium Hydroxylapatite Fillers.

BACKGROUND: Although the use of filling agents for soft-tissue augmentation has increased worldwide, most consensus statements do not distinguish between ethnic populations. There are, however, significant differences between Caucasian and Asian faces, reflecting not only cultural disparities, but also distinctive treatment goals. Unlike aesthetic patients in the West, who usually seek to improve the signs of aging, Asian patients are younger and request a broader range of indications. METHODS: Members of the Asia-Pacific Consensus group-comprising specialists from the fields of dermatology, plastic surgery, anatomy, and clinical epidemiology-convened to develop consensus recommendations for Asians based on their own experience using cohesive polydensified matrix, hyaluronic acid, and calcium hydroxylapatite fillers. RESULTS: The Asian face demonstrates differences in facial structure and cosmetic ideals. Improving the forward projection of the "T zone" (i.e., forehead, nose, cheeks, and chin) forms the basis of a safe and effective panfacial approach to the Asian face. Successful augmentation may be achieved with both (1) high- and low-viscosity cohesive polydensified matrix/hyaluronic acid and (2) calcium hydroxylapatite for most indications, although some constraints apply. CONCLUSION: The Asia-Pacific Consensus recommendations are the first developed specifically for the use of fillers in Asian populations. CLINCIAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, V.

Effects of intelligent advanced warnings on drivers negotiating the dilemma zone.

OBJECTIVE: We investigated whether intelligent advanced warnings of the end of green traffic signals help drivers negotiate the dilemma zone (DZ) at signalized intersections and sought to identify behavioral mechanisms for any warning-related benefits. BACKGROUND: Prior research suggested that warnings of end of green can increase slowing and stopping frequency given the DZ, but drivers may sometimes respond to warnings by speeding up. METHOD: In two simulator studies, we compared six types of roadway or in-vehicle warnings with a no-warning control condition. Using multilevel modeling, we tested mediation models of the behavioral mechanisms underlying the effects of warnings. RESULTS: In both studies, warnings led to more stopping at DZ intersections and milder decelerations when stopping compared with no warning. Drivers' predominant response to warnings was anticipatory slowing on approaching the intersection, not speeding up. The increased stopping with warning was mediated by increased slowing. In Study I, anticipatory slowing given warnings generalized to green-light intersections where no warning was given. In Study 2, we found that lane-specific warnings (e.g., LED lights embedded in each lane) sometimes led to fewer unsafe emergency stops than did non-lane-specific roadside warnings. CONCLUSION: End-of-green warnings led to safer behavior in the DZ and on the early approach to intersections. The main mechanism for the benefits of warnings was drivers' increased anticipatory slowing on approaching an intersection. Lane-specific warnings may have some benefits over roadside warnings. APPLICATION: Applications include performance models of how drivers use end-of-green warnings, control algorithms and warning displays for intelligent intersections, and statistical methodology in human factors research.