Growth in Virologically Suppressed HIV Positive Children on Antiretroviral Therapy: Individual and Population-Level References

BACKGROUND Combination antiretroviral therapy (ART) suppresses viral replication in HIV-infected children. The growth of virologically suppressed children on ART has not been well documented. We aimed to develop dynamic reference curves for weight-for-age z scores (WAZ) and height-for-age z scores (HAZ). RESULTS A total of 4,876 children were followed for 7,407 person-years. Analyses were stratified by baseline z-scores and age, which were the most important predictors of growth response. The youngest children showed the most pronounced increase in weight and height initially but catch-up growth stagnated after 1-2 years. Three years after starting ART, WAZ ranged from -2.2 (95% Prediction interval -5.6 to 0.8) in children with baseline age "5 years and z-score "-3 to 0.0 (-2.7 to 2.4) in children with baseline age "2 years and WAZ "-1. For HAZ the corresponding range was -2.3 (-4.9 to 0.3) in children with baseline age"5 years and z-score "-3 to 0.3 (-3.1 to 3.4) in children with baseline age 2-5 years and HAZ "-1. CONCLUSIONS We have developed an online tool to calculate reference trajectories in fully suppressed children. The web application could help to define 'optimal' growth response and identify children with treatment failure.

A Note on Optimal Care by Wealth-Constrained Injurers

This paper clarifies the relationship between an injurer's wealth level and his care choice by highlighting the distinction between monetary and non-monetary care. When care is non-monetary, wealth-constrained injurers generally take less than optimal care, and care is increasing in their wealth level under both strict liability and negligence. In contrast, when care is monetary, injurers may take too much or too little care under strict liability, and care is not strictly increasing in injurer wealth. Under negligence, the relationship between injurer care and wealth is similar in the two formulations. However, when litigation costs are added to the model, the relationship between injurer care and wealth becomes non-monotonic under both liability rules.

Cis-acting elements and developmental regulators govern toxin gene expression in Bacillus anthracis

Expression of the structural genes for the anthrax toxin proteins is coordinately controlled by host-related signals such as elevated CO2 , and the trans-acting positive regulator, AtxA. No specific binding of AtxA to the toxin gene promoters has been demonstrated and no sequence-based similarities are apparent in the promoter regions of toxin genes. We hypothesized that the toxin genes possess common structural features that are required for positive regulation. To test this hypothesis, I performed an extensive characterization of the toxin gene promoters. I determined the minimal sequences required for atxA-mediated toxin gene expression and compared these sequences for structural similarities. In silico modeling and in vitro experiments indicated significant curvature within these regions. Random mutagenesis revealed that point mutations associated with reduced transcriptional activity, mostly mapped to areas of high curvature. This work enabled the identification of two potential cis-acting elements implicated in AtxA-mediated regulation of the toxin genes. In addition to the growth condition requirements and AtxA, toxin gene expression is under growth phase regulation. The transition state regulator AbrB represses atxA expression to influence toxin synthesis. Here I report that toxin gene expression also requires sigH, a gene encoding the RNA polymerase sigma factor associated with development in B. subtilis. In the well-studied B. subtilis system, σH is part of a feedback control pathway that involves AbrB and the major response regulator of sporulation initiation, Spo0A. My data indicate that in B. anthracis, regulatory relationships exist between these developmental regulators and atxA . Interestingly, during growth in toxin-inducing conditions, sigH and abrB expression deviates from that described for B. subtilis, affecting expression of the atxA gene. These findings, combined with previous observations, suggest that the steady state level of atxA expression is critical for optimal toxin gene transcription. I propose a model whereby, under toxin-inducing conditions, control of toxin gene expression is fine-tuned by the independent effects of the developmental regulators on the expression of atxA . The growth condition-dependent changes in expression of these regulators may be crucial for the correct timing and uninterrupted expression of the toxin genes during infection. ^

Control of the master virulence regulatory gene atxA in Bacillus anthracis

Transcription of the Bacillus anthracis structural genes for the anthrax toxin proteins and biosynthetic operon for capsule are positively regulated by AtxA, a transcription regulator with unique properties. Consistent with the role of atxA in virulence factor expression, a B. anthracis atxA-null mutant is avirulent in a murine model for anthrax. In batch culture, multiple signals impact atxA transcript levels, and the timing and steady state level of atxA expression is critical for optimal toxin and capsule synthesis. Despite the apparent complex control of atxA transcription, only one trans-acting protein, the transition state regulator AbrB, has been demonstrated to directly interact with the atxA promoter. The AbrB-binding site has been described, but additional cis-acting control sequences have not been defined. Using transcriptional lacZ fusions, electrophoretic mobility shift assays, and Western blot analysis, the cis-acting elements and trans-acting factors involved in regulation of atxA in B. anthracis strains containing either both virulence plasmids, pXO1 and pXO2, or only one plasmid, pXO1, were studied. This work demonstrates that atxA transcription from the major start site P1 is dependent upon a consensus sequence for the housekeeping sigma factor SigA, and an A+T-rich upstream element (UP-element) for RNA polymerase (RNAP). In addition, the data show that a trans-acting protein(s) other than AbrB negatively impacts atxA transcription when it binds specifically to a 9-bp palindrome within atxA promoter sequences located downstream of P1. Mutation of the palindrome prevents binding of the trans-acting protein(s) and results in a corresponding increase in AtxA and anthrax toxin production in a strain- and culture-dependent manner. The identity of the trans-acting repressor protein(s) remains elusive; however, phenotypes associated with mutation of the repressor binding site have revealed that the trans-acting repressor protein(s) indirectly controls B. anthracis development. Mutation of the repressor binding site results in misregulation and overexpression of AtxA in conditions conducive for development, leading to a marked sporulation defect that is both atxA- and pXO2-61-dependent. pXO2-61 is homologous to the sensor domain of sporulation sensor histidine kinases and is proposed to titrate an activating signal away from the sporulation phosphorelay when overexpressed by AtxA. These results indicate that AtxA is not only a master virulence regulator, but also a modulator of proper B. anthracis development. Also demonstrated in this work is the impact of the developmental regulators AbrB, Spo0A, and SigH on atxA expression and anthrax toxin production in a genetically incomplete (pXO1+, pXO2-) and genetically complete (pXO1+, pXO2+) strain background. AtxA and anthrax toxin production resulting from deletion of the developmental regulators are strain-dependent suggesting that factors on pXO2 are involved in control of atxA. The only developmental deletion mutant that resulted in a prominent and consistent strain-independent increase in AtxA protein levels was an abrB-null mutant. As a result of increased AtxA levels, there is early and increased production of anthrax toxins in an abrB-null mutant. In addition, the abrB-null mutant exhibited an increase in virulence in a murine model for anthrax. In contrast, virulence of the atxA promoter mutant was unaffected in a murine model for anthrax despite the production of 5-fold more AtxA than the abrB-null mutant. These results imply that AtxA is not the only factor impacting pathogenesis in an abrB-null mutant. Overall, this work highlights the complex regulatory network that governs expression of atxA and provides an additional role for AtxA in B. anthracis development.

The number and timing of time -dependent covariate measurements for the Cox regression model

The problem of analyzing data with updated measurements in the time-dependent proportional hazards model arises frequently in practice. One available option is to reduce the number of intervals (or updated measurements) to be included in the Cox regression model. We empirically investigated the bias of the estimator of the time-dependent covariate while varying the effect of failure rate, sample size, true values of the parameters and the number of intervals. We also evaluated how often a time-dependent covariate needs to be collected and assessed the effect of sample size and failure rate on the power of testing a time-dependent effect.^ A time-dependent proportional hazards model with two binary covariates was considered. The time axis was partitioned into k intervals. The baseline hazard was assumed to be 1 so that the failure times were exponentially distributed in the ith interval. A type II censoring model was adopted to characterize the failure rate. The factors of interest were sample size (500, 1000), type II censoring with failure rates of 0.05, 0.10, and 0.20, and three values for each of the non-time-dependent and time-dependent covariates (1/4,1/2,3/4).^ The mean of the bias of the estimator of the coefficient of the time-dependent covariate decreased as sample size and number of intervals increased whereas the mean of the bias increased as failure rate and true values of the covariates increased. The mean of the bias of the estimator of the coefficient was smallest when all of the updated measurements were used in the model compared with two models that used selected measurements of the time-dependent covariate. For the model that included all the measurements, the coverage rates of the estimator of the coefficient of the time-dependent covariate was in most cases 90% or more except when the failure rate was high (0.20). The power associated with testing a time-dependent effect was highest when all of the measurements of the time-dependent covariate were used. An example from the Systolic Hypertension in the Elderly Program Cooperative Research Group is presented. ^

Water Table Level as Influenced by Rainfall, Crop Requirements, and Tiling Method during the past Three Years

In 1979, a portion of the research farm was pattern tiled including the large tillage plots. This was used as an opportunity to compare tile installation methods: a conventional trenching machine (used widely prior to late 70s), and a trenchless “tile plow” machine. The tile plow inserted plastic tile using a mole approach, which is the current primary tiling method. This research showed that plow and trenching tiling methods were not significantly different and both provided adequate drainage. It also showed that water table measurements were influenced more by timing of water needs of the crop being grown and intensity of the rainfall event than tiling method. This report focuses on continued research completed on these trial plots from 2009 to 2011 measuring water table level.

Evaluation of the attack rates and level of damages by the fall armyworm, Spodoptera frugiperda (Lepidoptera: Noctuidae), affecting corn-crops in the northeast of Argentina

The fall armyworm (FAW) is the most important threat to corn crops in Argentina, and there exists very little up-to-date information on its actual pest status because the available literature was published more than 20 years ago. Therefore, field surveys were carried out in the northeast of Argentina, in order to establish the attack rates and injury levels of the pest in relation to the crop phenology. The study was carried out at two localities: Colonia Benítez, an agricultural region, and Tapenagá, a cattle-raising area. At each site two 1-ha plots were sown either with a Bt-corn expressing Cry 1F protein or with an untransformed corn germplasm. Optimal and late sowing was assayed and FAW larval abundance, relative age composition, attack rates and level of damage to corn were recorded. At the moment of the field experiments, Bt-corn was not affected by FAW larvae. However, untransformed germplasms were severely affected by FAW larvae, with an average of attacked plants of 18% or more. In contrast to data obtained 30 years ago, higher values of FAW density were registered. Levels of damage to corn plants were higher after the V4 stage. It was found that the sowing date affected the infestation levels and early seeding avoided high armyworm densities that develop later in the season; in northern Argentina, this was only relevant in agricultural areas.

Probability inundation map for a scenario combining storm surge and sea-level rise

Coastal managers require reliable spatial data on the extent and timing of potential coastal inundation, particularly in a changing climate. Most sea level rise (SLR) vulnerability assessments are undertaken using the easily implemented bathtub approach, where areas adjacent to the sea and below a given elevation are mapped using a deterministic line dividing potentially inundated from dry areas. This method only requires elevation data usually in the form of a digital elevation model (DEM). However, inherent errors in the DEM and spatial analysis of the bathtub model propagate into the inundation mapping. The aim of this study was to assess the impacts of spatially variable and spatially correlated elevation errors in high-spatial resolution DEMs for mapping coastal inundation. Elevation errors were best modelled using regression-kriging. This geostatistical model takes the spatial correlation in elevation errors into account, which has a significant impact on analyses that include spatial interactions, such as inundation modelling. The spatial variability of elevation errors was partially explained by land cover and terrain variables. Elevation errors were simulated using sequential Gaussian simulation, a Monte Carlo probabilistic approach. 1,000 error simulations were added to the original DEM and reclassified using a hydrologically correct bathtub method. The probability of inundation to a scenario combining a 1 in 100 year storm event over a 1 m SLR was calculated by counting the proportion of times from the 1,000 simulations that a location was inundated. This probabilistic approach can be used in a risk-aversive decision making process by planning for scenarios with different probabilities of occurrence. For example, results showed that when considering a 1% probability exceedance, the inundated area was approximately 11% larger than mapped using the deterministic bathtub approach. The probabilistic approach provides visually intuitive maps that convey uncertainties inherent to spatial data and analysis.

Benthic foraminifera and sea level analyses from IODP Hole 310-M0005D

The course of sea-level fluctuations during Termination II (TII; the penultimate deglaciation), which is critical for understanding ice-sheet dynamics and suborbital climate variability, has yet to be established. This is partly because most shallow-water sequences encompassing TII were eroded during sea-level lowstands of the last glacial period or were deposited below the present sea level. Here we report a new sequence recording sea-level changes during TII in the Pleistocene sequence at Hole M0005D (water depth: 59.63 m below sea level [mbsl]) off Tahiti, French Polynesia, which was drilled during Integrated Ocean Drilling Program Expedition 310. Lithofacies variations and stratigraphic changes in the taxonomic composition, preservation states, and intraspecific test morphology of large benthic foraminifers indicate a deepening-upward sequence in the interval from Core 310-M0005D-26R (core depth: 134 mbsl) through -16R (core depth: 106 mbsl). Reconstruction of relative sea levels, based on paleodepth estimations using large benthic foraminifers, indicated a rise in sea level of about 90 m during this interval, suggesting its correlation with one of the terminations. Assuming that this rise in sea level corresponds to that during TII, after correcting for subsidence since the time of deposition, a highstand sea-level position would be 2 ± 15 m above present sea level (masl), which is generally consistent with highstand sea-level positions in MIS 5e (4 ± 2 masl). If this rise in sea level corresponds to that during older terminations, the subsidence-corrected highstand sea-level positions (30 ± 15 masl for Termination III and 54 ± 15 masl for Termination IV) are not consistent with reported ranges of interglacial sea-level highstands (-18 to 15 masl). Therefore, the studied interval likely records the rise in sea level and associated environmental changes during TII. In particular, the intervening cored materials between the two episodes of sea-level rise found in the studied interval might record the sea-level reversal event during TII. This conclusion is consistent with U/Th ages of around 133 ka, which were obtained from slightly diagenetically altered (i.e., < 1% calcite) in situ corals in the studied interval (Core 310-M0005D-20R [core depth: 118 mbsl]). This study also suggests that our inverse approach to correlate a stratigraphic interval with an approximate time frame could be useful as an independent check on the accuracy of uranium-series dating, which has been applied extensively to fossil corals in late Quaternary sea-level studies.

Full scale test for explosion water barriers in small cross-section galleries

Underground coal mines explosions generally arise from the inflammation of a methane/air mixture. This explosion can also generate a subsequent coal dust explosion. Traditionally such explosions have being fought eliminating one or several of the factors needed by the explosion to take place. Although several preventive measures are taken to prevent explosions, other measures should be considered to reduce the effects or even to extinguish the flame front. Unlike other protection methods that remove one or two of the explosion triangle elements, namely; the ignition source, the oxidizing agent and the fuel, explosion barriers removes all of them: reduces the quantity of coal in suspension, cools the flame front and the steam generated by vaporization removes the oxygen present in the flame. Passive water barriers are autonomous protection systems against explosions that reduce to a satisfactory safety level the effects of methane and/or flammable dust explosions. The barriers are activated by the pressure wave provoked in the explosion destroying the barrier troughs and producing a uniform dispersion of the extinguishing agent throughout the gallery section in quantity enough to extinguish the explosion flame. Full scale tests have been carried out in Polish Barbara experimental mine at GIG Central Mining Institute in order to determine the requirements and the optimal installation conditions of these devices for small sections galleries which are very frequent in the Spanish coal mines. Full scale tests results have been analyzed to understand the explosion timing and development, in order to assess on the use of water barriers in the typical small crosssection Spanish galleries. Several arrangements of water barriers have been designed and tested to verify the effectiveness of the explosion suppression in each case. The results obtained demonstrate the efficiency of the water barriers in stopping the flame front even with smaller amounts of water than those established by the European standard. According to the tests realized, water barriers activation times are between 0.52 s and 0.78 s and the flame propagation speed are between 75 m/s and 80 m/s. The maximum pressures (Pmax) obtained in the full scale tests have varied between 0.2 bar and 1.8 bar. Passive barriers protect effectively against the spread of the flame but cannot be used as a safeguard of the gallery between the ignition source and the first row of water troughs or bags, or even after them, as the pressure could remain high after them even if the flame front has been extinguished.

Self-reference Scrubber for TMR Systems Based on Xilinx Virtex FPGAs

SRAM-based FPGAs are sensitive to radiation effects. Soft errors can appear and accumulate, potentially defeating mitigation strategies deployed at the Application Layer. Therefore, Configuration Memory scrubbing is required to improve radiation tolerance of such FPGAs in space applications. Virtex FPGAs allow runtime scrubbing by means of dynamic partial reconfiguration. Even with scrubbing, intra-FPGA TMR systems are subjected to common-mode errors affecting more than one design domain. This is solved in inter-FPGA TMR systems at the expense of a higher cost, power and mass. In this context, a self-reference scrubber for device-level TMR system based on Xilinx Virtex FPGAs is presented. This scrubber allows for a fast SEU/MBU detection and correction by peer frame comparison without needing to access a golden configuration memory

Low-complexity timing synchronization scheme for MB-OFDM UWB receiver based on sign-bit

A unified low complexity sign-bit correlation based symbol timing synchronization scheme for Multiband Orthogonal Frequency Division Multiplexing (MB-OFDM) Ultra Wideband (UWB) receiver system is proposed. By using the time domain sequence of the packet/frame synchronization preamble, the proposed scheme is in charge of detecting the upcoming MB-OFDM symbol and it estimates the exact boundary of the start of Fast Fourier Transform (FFT) window. The proposed algorithm is implemented by using an efficient Hardware-Software co-simulation methodology. The effectiveness of the proposed synchronization scheme and the optimization criteria is confirmed by hardware implementation results.

Optimal polygonal L1 linearization and fast interpolation of nonlinear systems

The analysis of complex nonlinear systems is often carried out using simpler piecewise linear representations of them. A principled and practical technique is proposed to linearize and evaluate arbitrary continuous nonlinear functions using polygonal (continuous piecewise linear) models under the L1 norm. A thorough error analysis is developed to guide an optimal design of two kinds of polygonal approximations in the asymptotic case of a large budget of evaluation subintervals N. The method allows the user to obtain the level of linearization (N) for a target approximation error and vice versa. It is suitable for, but not limited to, an efficient implementation in modern Graphics Processing Units (GPUs), allowing real-time performance of computationally demanding applications. The quality and efficiency of the technique has been measured in detail on two nonlinear functions that are widely used in many areas of scientific computing and are expensive to evaluate.

Assessing the impact of adaptive accessibility on the optimal transport policy implementation by using an integrated land-use/transport model for Madrid

Accessibility is an essential concept widely used to evaluate the impact of land-use and transport strategies in transport and urban planning. Accessibility is typically evaluated by using a transport model or a land-use model independently or successively without a feedback loop, thus neglecting the interaction effects between the two systems and the induced competition effects among opportunities due to accessibility improvements. More than a mere methodological curiosity, failure to account for land- use/transport interactions and the competition effect may result in large underestimation of the policy effects. With the recent development of land-use and transport interaction (LUTI) models, there is a growing interest in using these models to adequately measure accessibility and evaluate its impact. The current study joins this research stream by embedding an accessibility measure in a LUTI model with two main aims. The first aim is to account for adaptive accessibility, namely the adjustment of the potential accessibility due to the effect of competition among opportunities (e.g., workplaces) as a result of improved accessibility. LUTI models are particularly suitable for assessing adaptive accessibility because the competition factor is a function of the number of jobs, which is related to land-use attractiveness and the number of workers which is related, among other factors, to the transport demand. The second aim is to identify the optimal implementation scenario of policy measures on the basis of the potential and adaptive accessibility and analyse the results in terms of social welfare and accessibility. The metropolitan area of Madrid is used as a case-study and two transport policy instruments, namely a cordon toll and bus frequency increase, have been chosen for the simulation study in order to present the usefulness of the approach to urban planners and policy makers. The MARS model (Metropolitan Activity Relocation Simulator) calibrated for Madrid was employed as the analysis tool. The impact of accessibility is embedded in the model through a social welfare function that includes not only costs and benefits to both road users and transport operators, but also costs and benefits for the government and society in general (external costs). An optimisation procedure is performed by the MARS model for maximizing the value of objective function in order to find the best (optimal) policy imp lementations intensity (i.e., price, frequency). Last, the two policy strategies are evaluated in terms of their accessibility. Results show that the accessibility with competition factor influences the optimal policy implementation level and also generates different results in terms of social welfare. In addition, mapping the difference between the potential and the adaptive accessibility indicators shows that the main changes occur in areas where there is a strong competition among land-use opportunities.

Analysis of the geometric altimetry to support aircraft optimal trajectories within the future 4d trajectory management

Over the past few years, the common practice within air traffic management has been that commercial aircraft fly by following a set of predefined routes to reach their destination. Currently, aircraft operators are requesting more flexibility to fly according to their prefer- ences, in order to achieve their business objectives. Due to this reason, much research effort is being invested in developing different techniques which evaluate aircraft optimal trajectory and traffic synchronisation. Also, the inefficient use of the airspace using barometric altitude overall in the landing and takeoff phases or in Continuous Descent Approach (CDA) trajectories where currently it is necessary introduce the necessary reference setting (QNH or QFE). To solve this problem and to permit a better airspace management born the interest of this research. Where the main goals will be to evaluate the impact, weakness and strength of the use of geometrical altitude instead of the use of barometric altitude. Moreover, this dissertation propose the design a simplified trajectory simulator which is able to predict aircraft trajectories. The model is based on a three degrees of freedom aircraft point mass model that can adapt aircraft performance data from Base of Aircraft Data, and meteorological information. A feature of this trajectory simulator is to support the improvement of the strategic and pre-tactical trajectory planning in the future Air Traffic Management. To this end, the error of the tool (aircraft Trajectory Simulator) is measured by comparing its performance variables with actual flown trajectories obtained from Flight Data Recorder information. The trajectory simulator is validated by analysing the performance of different type of aircraft and considering different routes. A fuel consumption estimation error was identified and a correction is proposed for each type of aircraft model. In the future Air Traffic Management (ATM) system, the trajectory becomes the fundamental element of a new set of operating procedures collectively referred to as Trajectory-Based Operations (TBO). Thus, governmental institutions, academia, and industry have shown a renewed interest for the application of trajectory optimisation techniques in com- mercial aviation. The trajectory optimisation problem can be solved using optimal control methods. In this research we present and discuss the existing methods for solving optimal control problems focusing on direct collocation, which has received recent attention by the scientific community. In particular, two families of collocation methods are analysed, i.e., Hermite-Legendre-Gauss-Lobatto collocation and the pseudospectral collocation. They are first compared based on a benchmark case study: the minimum fuel trajectory problem with fixed arrival time. For the sake of scalability to more realistic problems, the different meth- ods are also tested based on a real Airbus 319 El Cairo-Madrid flight. Results show that pseudospectral collocation, which has shown to be numerically more accurate and computa- tionally much faster, is suitable for the type of problems arising in trajectory optimisation with application to ATM. Fast and accurate optimal trajectory can contribute properly to achieve the new challenges of the future ATM. As atmosphere uncertainties are one of the most important issues in the trajectory plan- ning, the final objective of this dissertation is to have a magnitude order of how different is the fuel consumption under different atmosphere condition. Is important to note that in the strategic phase planning the optimal trajectories are determined by meteorological predictions which differ from the moment of the flight. The optimal trajectories have shown savings of at least 500 [kg] in the majority of the atmosphere condition (different pressure, and temperature at Mean Sea Level, and different lapse rate temperature) with respect to the conventional procedure simulated at the same atmosphere condition.This results show that the implementation of optimal profiles are beneficial under the current Air traffic Management (ATM).