Regulation of vascular endothelial growth factor bioactivity in patients with acute lung injury

Background: Reduced bioactive vascular endothelial growth factor (VEGF) has been demonstrated in several inflammatory lung conditions including the acute respiratory distress syndrome (ARDS). sVEGFR-1, a soluble form of VEGF-1 receptor, is a potent natural inhibitor of VEGF. We hypothesised that sVEGFR-1 plays an important role in the regulation of the bioactivity of VEGF within the lung in patients with ARDS. Methods: Forty one patients with ARDS, 12 at risk of developing ARDS, and 16 normal controls were studied. Bioactive VEGF, total VEGF, and sVEGFR-1 were measured by ELISA in plasma and bronchoalveolar lavage (BAL) fluid. Reverse transcriptase polymerase chain reaction for sVEGFR-1 was performed on BAL cells. Results: sVEGFR-1 was detectable in the BAL fluid of 48% (20/41) of patients with early ARDS (1.4– 54.8 ng/ml epithelial lining fluid (ELF)) compared with 8% (1/12) at risk patients (p = 0.017) and none of the normal controls (p = 0.002). By day 4 sVEGFR-1 was detectable in only 2/18 ARDS patients (p = 0.008). Patients with detectable sVEGFR-1 had lower ELF median (IQR) levels of bioactive VEGF than those without detectable sVEGFR-1 (1415.2 (474.9–3192) pg/ml v 4761 (1349–7596.6) pg/ml, median difference 3346 pg/ml (95% CI 305.1 to 14711.9), p = 0.016), but there was no difference in total VEGF levels. BAL cells expressed mRNA for sVEGFR-1 and produced sVEGFR-1 protein which increased following incubation with tumour necrosis factor a. Conclusion: This study shows for the first time the presence of sVEGFR-1 in the BAL fluid of patients with ARDS. This may explain the presence of reduced bioactive VEGF in patients early in the course of ARDS

The Risk of a Mosquito-Borne Infectionin a Heterogeneous Environment

A common assumption about malaria, dengue, and other mosquito-borne infections is that the two main components of the risk of human infection—the rate at which people are bitten (human biting rate) and the proportion of mosquitoes that are infectious—are positively correlated. In fact, these two risk factors are generated by different processes and may be negatively correlated across space and time in heterogeneous environments. Uneven distribution of blood-meal hosts and larval habitat creates a spatial mosaic of demograPhic sources and sinks. Moreover, mosquito populations fluctuate temporally, forced by environmental variables such as rainfall, temperature, and humidity. These sources of spatial and temporal heterogeneity in the distribution of mosquito populations generate variability in the human biting rate, in the proportion of mosquitoes that are infectious, and in the risk of human infection. To understand how heterogeneity affects the epidemiology of mosquito-borne infections, we developed a set of simple models that incorporate heterogeneity in a stepwise fashion. These models predict that the human biting rate is highest shortly after the mosquito densities peak, near breeding sites where adult mosquitoes emerge, and around the edges of areas where humans are aggregated. In contrast, the proportion of mosquitoes that are infectious reflects the age structure of mosquito populations; it peaks where old mosquitoes are found, far from mosquito breeding habitat, and when mosquito population density is declining. Finally, we show that estimates for the average risk of infection that are based on the average entomological inoculation rate are strongly biased in heterogeneous environments

Preventing childhood malaria in Africa by protecting adults from mosquitoes with insecticide-treated nets

Malaria prevention in Africa merits particular attention as the world strives toward a better life for the poorest. Insecticide-treated nets (ITNs) represent a practical means to prevent malaria in Africa, so scaling up coverage to at least 80% of young children and pregnant women by 2010 is integral to the Millennium Development Goals (MDG). Targeting individual protection to vulnerable groups is an accepted priority, but community-level impacts of broader population coverage are largely ignored even though they may be just as important. We therefore estimated coverage thresholds for entire populations at which individual- and community-level protection are equivalent, representing rational targets for ITN coverage beyond vulnerable groups

A network-based microfoundation of Granovetter's threshold model for social tipping

Social tipping, where minorities trigger larger populations to engage in collective action, has been suggested as one key aspect in addressing contemporary global challenges. Here, we refine Granovetter's widely acknowledged theoretical threshold model of collective behavior as a numerical modelling tool for understanding social tipping processes and resolve issues that so far have hindered such applications. Based on real-world observations and social movement theory, we group the population into certain or potential actors, such that -- in contrast to its original formulation -- the model predicts non-trivial final shares of acting individuals. Then, we use a network cascade model to explain and analytically derive that previously hypothesized broad threshold distributions emerge if individuals become active via social interaction. Thus, through intuitive parameters and low dimensionality our refined model is adaptable to explain the likelihood of engaging in collective behavior where social tipping like processes emerge as saddle-node bifurcations and hysteresis

Systems Modeling to Implement Integrated System Health Management Capability

ISHM capability includes: detection of anomalies, diagnosis of causes of anomalies, prediction of future anomalies, and user interfaces that enable integrated awareness (past, present, and future) by users. This is achieved by focused management of data, information and knowledge (DIaK) that will likely be distributed across networks. Management of DIaK implies storage, sharing (timely availability), maintaining, evolving, and processing. Processing of DIaK encapsulates strategies, methodologies, algorithms, etc. focused on achieving high ISHM Functional Capability Level (FCL). High FCL means a high degree of success in detecting anomalies, diagnosing causes, predicting future anomalies, and enabling health integrated awareness by the user. A model that enables ISHM capability, and hence, DIaK management, is denominated the ISHM Model of the System (IMS). We describe aspects of the IMS that focus on processing of DIaK. Strategies, methodologies, and algorithms require proper context. We describe an approach to define and use contexts, implementation in an object-oriented software environment (G2), and validation using actual test data from a methane thruster test program at NASA SSC. Context is linked to existence of relationships among elements of a system. For example, the context to use a strategy to detect leak is to identify closed subsystems (e.g. bounded by closed valves and by tanks) that include pressure sensors, and check if the pressure is changing. We call these subsystems Pressurizable Subsystems. If pressure changes are detected, then all members of the closed subsystem become suspect of leakage. In this case, the context is defined by identifying a subsystem that is suitable for applying a strategy. Contexts are defined in many ways. Often, a context is defined by relationships of function (e.g. liquid flow, maintaining pressure, etc.), form (e.g. part of the same component, connected to other components, etc.), or space (e.g. physically close, touching the same common element, etc.). The context might be defined dynamically (if conditions for the context appear and disappear dynamically) or statically. Although this approach is akin to case-based reasoning, we are implementing it using a software environment that embodies tools to define and manage relationships (of any nature) among objects in a very intuitive manner. Context for higher level inferences (that use detected anomalies or events), primarily for diagnosis and prognosis, are related to causal relationships. This is useful to develop root-cause analysis trees showing an event linked to its possible causes and effects. The innovation pertaining to RCA trees encompasses use of previously defined subsystems as well as individual elements in the tree. This approach allows more powerful implementations of RCA capability in object-oriented environments. For example, if a pressurizable subsystem is leaking, its root-cause representation within an RCA tree will show that the cause is that all elements of that subsystem are suspect of leak. Such a tree would apply to all instances of leak-events detected and all elements in all pressurizable subsystems in the system. Example subsystems in our environment to build IMS include: Pressurizable Subsystem, Fluid-Fill Subsystem, Flow-Thru-Valve Subsystem, and Fluid Supply Subsystem. The software environment for IMS is designed to potentially allow definition of any relationship suitable to create a context to achieve ISHM capability