Entrance Capacity of an Automated Highway System

This paper evaluates the entrance capacity and queueing delay for Automated Highway Systems through use of simulations and analytical modeling. Queueing statistics are also used to determine the sustainable capacity of alternative concepts, taking trip length distribution and spacing between ramps into consideration. Based on safety-spacing headways (produced in a separate analysis), the most promising concept utilizes platoons both on the highway and on on-ramps. However, it is unclear whether comparable capacity can be achieved on exit, when vehicles must be decoupled from their platoons, and whether it is safe for vehicles to enter the highway in closely spaced platoons. The analytical evaluation indicates that entrance/exit spacing on the order of one per 2 km or closer would be required to support highways with total capacity on the order of 20,000 vehicles per hour. Most likely, this would be achieved most efficiently if separate dedicated entrances are provided for automated vehicles, to minimize weaving on manual lanes

Analytical Models for Vehicle/Gap Distribution on Automated Highway Systems

Highway congestion has in recent years become a pervasive problem for urban and suburban areas alike. The concept of Automated Highway Systems is based on the belief that integration of sensing, communication, and control technologies into vehicles and highways can lead to a large improvement in capacity and safety without requiring a significant amount of additional highway right-of-way. A fundamental determinant of Automated Highway Systems capacity is the vehicle-following rule, the rule that governs the behavior of vehicles traveling along a common lane (e.g., the spacing between any two longitudinally adjacent vehicles). Vehicle following affects the longitudinal capacity (achievable flow within a lane), the lateral capacity (achievable flow between lanes) and the conflicting relationship between the longitudinal flow and lateral capacity. The issues are investigated by developing probabilistic models for vehicle/platoon and gap distributions, for vehicles that travel in platoons, in slots, or as free-agents. Mathematical models are also developed to estimate the completion time of a lane change, which can be used as a surrogate for the lateral capacity. Numerical results for the three major vehicle-following rules and their comparison are also provided

Environmental-mechanistic modelling of the impact of global change on human zoonotic disease emergence: A case study of Lassa fever

1. Human infectious diseases are a significant threat to global human health and economies (e.g., Ebola, SARs), with the majority of infectious diseases having an animal source (zoonotic). Despite their importance, the lack of a quantitative predictive framework hampers our understanding of how spill-overs of zoonotic infectious diseases into the human population will be impacted by global environmental stressors. 2. Here, we create an environmental-mechanistic model for understanding the impact of global change on the probability of zoonotic disease reservoir host-human spill-over events. As a case study, we focus on Lassa fever virus (LAS). We firstly quantify the spatial determinants of LAS outbreaks, including the phylogeographic distribution of its reservoir host Natal multimammate rat (Mastomys natalensis) (LAS host). Secondly, we use these determinants to inform our environmental-mechanistic model to estimate present day LAS spill-over events and the predicted impact of climate change, human population growth, and land use by 2070. 3. We find phylogeographic evidence to suggest that LAS is confined to only one clade of LAS host (Western clade Mastomys natalensis), and that the probability of its occurrence was a major determinant of the spatial variation in LAS historical outbreaks (69.8%), along with human population density (20.4%). Our estimates for present day LAS spill-over events from our environmental-mechanistic model were consistent with observed patterns, and we predict an increase in events per year by 2070 from 195,125 to 406,725 within the LAS endemic western African region. Of the component drivers, climate change and human population growth are predicted to have the largest effects by increasing landscape suitability for the host and human-host contact rates, while land use change has only a weak impact on the number of future events. 4. LAS spill-over events did not respond uniformly to global environmental stressors, and we suggest that understanding the impact of global change on zoonotic infectious disease emergence requires an understanding of how reservoir host species respond to environmental change. Our environmental-mechanistic modelling methodology provides a novel generalizable framework to understand the impact of global change on the spill-over of zoonotic diseases

Evaluation of Mannose Binding Lectin Gene Variants in Pediatric Influenza Virus-Related Critical Illness

Background: Mannose-binding lectin (MBL) is an innate immune protein with strong biologic plausibility for protecting against influenza virus-related sepsis and bacterial co-infection. In an autopsy cohort of 105 influenza-infected young people, carriage of the deleterious MBL gene MBL2_Gly54Asp(“B”) mutation was identified in 5 of 8 individuals that died from influenza-methicillin-resistant Staphylococcus aureus (MRSA) co-infection. We evaluated MBL2 variants known to influence MBL levels with pediatric influenza-related critical illness susceptibility and/or severity including with bacterial co-infections.Methods: We enrolled children and adolescents with laboratory-confirmed influenza infection across 38 pediatric intensive care units from November 2008 to June 2016. We sequenced MBL2 “low-producer” variants rs11003125(“H/L”), rs7096206(“Y/X”), rs1800450Gly54Asp(“B”), rs1800451Gly57Glu(“C”), rs5030737Arg52Cys(“D”) in patients and biologic parents. We measured serum levels and compared complement activity in low-producing homozygotes (“B/B,” “C/C”) to HYA/HYA controls. We used a population control of 1,142 healthy children and also analyzed family trios (PBAT/HBAT) to evaluate disease susceptibility, and nested case-control analyses to evaluate severity.Results: We genotyped 420 patients with confirmed influenza-related sepsis: 159 (38%) had acute lung injury (ALI), 165 (39%) septic shock, and 30 (7%) died. Although bacterial co-infection was diagnosed in 133 patients (32%), only MRSA co-infection (n = 33, 8% overall) was associated with death (p < 0.0001), present in 11 of 30 children that died (37%). MBL2 variants predicted serum levels and complement activation as expected. We found no association between influenza-related critical illness susceptibility and MBL2 variants using family trios (633 biologic parents) or compared to population controls. MBL2 variants were not associated with admission illness severity, septic shock, ALI, or bacterial co-infection diagnosis. Carriage of low-MBL producing MBL2 variants was not a risk factor for mortality, but children that died did have higher carriage of one or more B alleles (OR 2.3; p = 0.007), including 7 of 11 with influenza MRSA-related death (vs. 2 of 22 survivors: OR 14.5, p = 0.0002).Conclusions:MBL2 variants that decrease MBL levels were not associated with susceptibility to pediatric influenza-related critical illness or with multiple measures of critical illness severity. We confirmed a prior report of higher B allele carriage in a relatively small number of young individuals with influenza-MRSA associated death

Transcriptomic profiles of multiple organ dysfunction syndrome phenotypes in pediatric critical influenza

BackgroundInfluenza virus is responsible for a large global burden of disease, especially in children. Multiple Organ Dysfunction Syndrome (MODS) is a life-threatening and fatal complication of severe influenza infection.MethodsWe measured RNA expression of 469 biologically plausible candidate genes in children admitted to North American pediatric intensive care units with severe influenza virus infection with and without MODS. Whole blood samples from 191 influenza-infected children (median age 6.4 years, IQR: 2.2, 11) were collected a median of 27 hours following admission; for 45 children a second blood sample was collected approximately seven days later. Extracted RNA was hybridized to NanoString mRNA probes, counts normalized, and analyzed using linear models controlling for age and bacterial co-infections (FDR q<0.05).ResultsComparing pediatric samples collected near admission, children with Prolonged MODS for ≥7 days (n=38; 9 deaths) had significant upregulation of nine mRNA transcripts associated with neutrophil degranulation (RETN, TCN1, OLFM4, MMP8, LCN2, BPI, LTF, S100A12, GUSB) compared to those who recovered more rapidly from MODS (n=27). These neutrophil transcripts present in early samples predicted Prolonged MODS or death when compared to patients who recovered, however in paired longitudinal samples, they were not differentially expressed over time. Instead, five genes involved in protein metabolism and/or adaptive immunity signaling pathways (RPL3, MRPL3, HLA-DMB, EEF1G, CD8A) were associated with MODS recovery within a week.ConclusionThus, early increased expression of neutrophil degranulation genes indicated worse clinical outcomes in children with influenza infection, consistent with reports in adult cohorts with influenza, sepsis, and acute respiratory distress syndrome

Low CCR7-Mediated Migration of Human Monocyte Derived Dendritic Cells in Response to Human Respiratory Syncytial Virus and Human Metapneumovirus

Human respiratory syncytial virus (HRSV) and, to a lesser extent, human metapneumovirus (HMPV) and human parainfluenza virus type 3 (HPIV3), can re-infect symptomatically throughout life without significant antigenic change, suggestive of incomplete or short-lived immunity. In contrast, re-infection by influenza A virus (IAV) largely depends on antigenic change, suggestive of more complete immunity. Antigen presentation by dendritic cells (DC) is critical in initiating the adaptive immune response. Antigen uptake by DC induces maturational changes that include decreased expression of the chemokine receptors CCR1, CCR2, and CCR5 that maintain DC residence in peripheral tissues, and increased expression of CCR7 that mediates the migration of antigen-bearing DC to lymphatic tissue. We stimulated human monocyte-derived DC (MDDC) with virus and found that, in contrast to HPIV3 and IAV, HMPV and HRSV did not efficiently decrease CCR1, 2, and 5 expression, and did not efficiently increase CCR7 expression. Consistent with the differences in CCR7 mRNA and protein expression, MDDC stimulated with HRSV or HMPV migrated less efficiently to the CCR7 ligand CCL19 than did IAV-stimulated MDDC. Using GFP-expressing recombinant virus, we showed that the subpopulation of MDDC that was robustly infected with HRSV was particularly inefficient in chemokine receptor modulation. HMPV- or HRSV-stimulated MDDC responded to secondary stimulation with bacterial lipopolysaccharide or with a cocktail of proinflammatory cytokines by increasing CCR7 and decreasing CCR1, 2 and 5 expression, and by more efficient migration to CCL19, suggesting that HMPV and HRSV suboptimally stimulate rather than irreversibly inhibit MDDC migration. This also suggests that the low concentration of proinflammatory cytokines released from HRSV- and HMPV-stimulated MDDC is partly responsible for the low CCR7-mediated migration. We propose that inefficient migration of HRSV- and HMPV-stimulated DC to lymphatic tissue contributes to reduced adaptive responses to these viruses

Interrelationship between Dendritic Cell Trafficking and Francisella tularensis Dissemination following Airway Infection

Francisella tularensis, the etiological agent of the inhalation tularemia, multiplies in a variety of cultured mammalian cells. Nevertheless, evidence for its in vivo intracellular residence is less conclusive. Dendritic cells (DC) that are adapted for engulfing bacteria and migration towards lymphatic organs could serve as potential targets for bacterial residence and trafficking. Here, we focus on the in vivo interactions of F. tularensis with DC following airway infection of mice. Lethal airway infection of mice with the live vaccine strain (LVS) results in trafficking of a CD11bhigh/CD11cmed/autofluorescencelow DC subset from the respiratory tract to the draining mediastinal lymph node (MdLN). Simultaneously, a rapid, massive bacterial colonization of the MdLN occurs, characterized by large bacterial foci formation. Analysis of bacteria in the MdLN revealed a major population of extracellular bacteria, which co-exists with a substantial fraction of intracellular bacteria. The intracellular bacteria are viable and reside in cells sorted for DC marker expression. Moreover, in vivo vital staining experiments indicate that most of these intracellular bacteria (∼75%) reside in cells that have migrated from the airways to the MdLN after infection. The correlation between DC and bacteria accumulation in the MdLN was further demonstrated by manipulating DC migration to the MdLN through two independent pathways. Impairment of DC migration to the MdLN, either by a sphingosine-1-phosphate receptor agonist (FTY720) or by the D prostanoid receptor 1 agonist (BW245C), resulted in reduced bacterial colonization of MdLN. Moreover, BW245C treatment delayed the onset of morbidity and the time to death of the infected mice. Taken together, these results suggest that DC can serve as an inhabitation niche for F. tularensis in the early stages of infection, and that DC trafficking plays a role in pathogen dissemination. This underscores the therapeutic potential of DC migration impairing drugs in tularemia treatment