Effect of constant and variable domain glycosylation on pharmacokinetics of therapeutic antibodies in mice

Previous studies on the effect of glycosylation on the elimination rate of antibodies have produced conflicting results. Here, we performed pharmacokinetic studies in mice with two preparations of a monoclonal IgG1 antibody enriched for complex type or high mannose type oligosaccharides at the Fc glycosylation site. No significant difference in the serum half-life was found between the two antibody glycoforms, nor was any difference observed in the serum half-lives of different complex type glycoforms. To evaluate the influence of glycosylation within the variable domain, a second monoclonal antibody, glycosylated in both the Fc and Fv domains, was separated into fractions containing different amounts of Fv-associated sialic acid and administered to mice. Again, no significant difference was found in the clearance rates of variants carrying different amounts of Fv-associated sialic acid or lacking Fv-glycosylation. These results suggest that glycosylation has little or no impact on the pharmacokinetic behavior of these two monoclonal antibodies in mice.

Open top chambers and infrared lamps : a comparison of heating efficacy and CO₂/CH₄ dynamics in a Lake Superior coastal peatland

Experimental warming provides a method to determine how an ecosystem will respond to increased temperatures. Northern peatland ecosystems, sensitive to changing climates, provide an excellent setting for experimental warming. Storing great quantities of carbon, northern peatlands play a critical role in regulating global temperatures. Two of the most common methods of experimental warming include open top chambers (OTCs) and infrared (IR) lamps. These warming systems have been used in many ecosystems throughout the world, yet their efficacy to create a warmer environment is variable and has not been widely studied. To date, there has not been a direct, experimentally controlled comparison of OTCs and IR lamps. As a result, a factorial study was implemented to compare the warming efficacy of OTCs and IR lamps and to examine the resulting carbon dioxide (CO2) and methane (CH4) flux rates in a Lake Superior peatland. IR lamps warmed the ecosystem on average by 1-2 #°C, with the majority of warming occurring during nighttime hours. OTC's did not provide any long-term warming above control plots, which is contrary to similar OTC studies at high latitudes. By investigating diurnal heating patterns and micrometeorological variables, we were able to conclude that OTCs were not achieving strong daytime heating peaks and were often cooler than control plots during nighttime hours. Temperate day-length, cloudy and humid conditions, and latent heat loss were factors that inhibited OTC warming. There were no changes in CO2 flux between warming treatments in lawn plots. Gross ecosystem production was significantly greater in IR lamp-hummock plots, while ecosystem respiration was not affected. CH4 flux was not significantly affected by warming treatment. Minimal daytime heating differences, high ambient temperatures, decay resistant substrate, as well as other factors suppressed significant gas flux responses from warming treatments.

Modeling and classifying variable width riparian zones utilizing digital elevation models, flood height data, digital soil data and national wetlands inventory : a new approach for riparian zone delineation

Riparian zones are dynamic, transitional ecosystems between aquatic and terrestrial ecosystems with well defined vegetation and soil characteristics. Development of an all-encompassing definition for riparian ecotones, because of their high variability, is challenging. However, there are two primary factors that all riparian ecotones are dependent on: the watercourse and its associated floodplain. Previous approaches to riparian boundary delineation have utilized fixed width buffers, but this methodology has proven to be inadequate as it only takes the watercourse into consideration and ignores critical geomorphology, associated vegetation and soil characteristics. Our approach offers advantages over other previously used methods by utilizing: the geospatial modeling capabilities of ArcMap GIS; a better sampling technique along the water course that can distinguish the 50-year flood plain, which is the optimal hydrologic descriptor of riparian ecotones; the Soil Survey Database (SSURGO) and National Wetland Inventory (NWI) databases to distinguish contiguous areas beyond the 50-year plain; and land use/cover characteristics associated with the delineated riparian zones. The model utilizes spatial data readily available from Federal and State agencies and geospatial clearinghouses. An accuracy assessment was performed to assess the impact of varying the 50-year flood height, changing the DEM spatial resolution (1, 3, 5 and 10m), and positional inaccuracies with the National Hydrography Dataset (NHD) streams layer on the boundary placement of the delineated variable width riparian ecotones area. The result of this study is a robust and automated GIS based model attached to ESRI ArcMap software to delineate and classify variable-width riparian ecotones.

Distinguishing phenotypes of childhood wheeze and cough using latent class analysis

Airway disease in childhood comprises a heterogeneous group of disorders. Attempts to distinguish different phenotypes have generally considered few disease dimensions. The present study examines phenotypes of childhood wheeze and chronic cough, by fitting a statistical model to data representing multiple disease dimensions. From a population-based, longitudinal cohort study of 1,650 preschool children, 319 with parent-reported wheeze or chronic cough were included. Phenotypes were identified by latent class analysis using data on symptoms, skin-prick tests, lung function and airway responsiveness from two preschool surveys. These phenotypes were then compared with respect to outcome at school age. The model distinguished three phenotypes of wheeze and two phenotypes of chronic cough. Subsequent wheeze, chronic cough and inhaler use at school age differed clearly between the five phenotypes. The wheeze phenotypes shared features with previously described entities and partly reconciled discrepancies between existing sets of phenotype labels. This novel, multidimensional approach has the potential to identify clinically relevant phenotypes, not only in paediatric disorders but also in adult obstructive airway diseases, where phenotype definition is an equally important issue.

Computational simulations of latent heat thermal energy storage systems - with innovative and first-principles based simulation for the underlying unsteady melting (and solidification) processes

This thesis develops an effective modeling and simulation procedure for a specific thermal energy storage system commonly used and recommended for various applications (such as an auxiliary energy storage system for solar heating based Rankine cycle power plant). This thermal energy storage system transfers heat from a hot fluid (termed as heat transfer fluid - HTF) flowing in a tube to the surrounding phase change material (PCM). Through unsteady melting or freezing process, the PCM absorbs or releases thermal energy in the form of latent heat. Both scientific and engineering information is obtained by the proposed first-principle based modeling and simulation procedure. On the scientific side, the approach accurately tracks the moving melt-front (modeled as a sharp liquid-solid interface) and provides all necessary information about the time-varying heat-flow rates, temperature profiles, stored thermal energy, etc. On the engineering side, the proposed approach is unique in its ability to accurately solve – both individually and collectively – all the conjugate unsteady heat transfer problems for each of the components of the thermal storage system. This yields critical system level information on the various time-varying effectiveness and efficiency parameters for the thermal storage system.

Implementation of a Variable Compression Ratio Mechanism in a Four Cylinder Engine

Ever since the invention of the internal combustion engine, generating more power and achieving better efficiency has been a major goal for the designers. Variable compression ratio technology is way to achieve those goals. This paper will discuss the method of varying the compression ratio of an inline 4-cylinder engine through the use of a 4-bar linkage and gear mechanism. This mechanism was proven to easily vary the compression ratio of the engine and shows promise of becoming a technology used for future engine designer.

DEVELOPMENT OF A PREDICTIVE COMBUSTION MODEL OF A SPARK IGNITED ENGINE WITH GASOLINE DIRECT INJECTION, VARIABLE VALVE TIMING, DURATION AND LIFT TECHNOLOGIES

There is a need by engine manufactures for computationally efficient and accurate predictive combustion modeling tools for integration in engine simulation software for the assessment of combustion system hardware designs and early development of engine calibrations. This thesis discusses the process for the development and validation of a combustion modeling tool for Gasoline Direct Injected Spark Ignited Engine with variable valve timing, lift and duration valvetrain hardware from experimental data. Data was correlated and regressed from accepted methods for calculating the turbulent flow and flame propagation characteristics for an internal combustion engine. A non-linear regression modeling method was utilized to develop a combustion model to determine the fuel mass burn rate at multiple points during the combustion process. The computational fluid dynamic software Converge ©, was used to simulate and correlate the 3-D combustion system, port and piston geometry to the turbulent flow development within the cylinder to properly predict the experimental data turbulent flow parameters through the intake, compression and expansion processes. The engine simulation software GT-Power © is then used to determine the 1-D flow characteristics of the engine hardware being tested to correlate the regressed combustion modeling tool to experimental data to determine accuracy. The results of the combustion modeling tool show accurate trends capturing the combustion sensitivities to turbulent flow, thermodynamic and internal residual effects with changes in intake and exhaust valve timing, lift and duration.

Space trajectories optimization using variable-chromosome-length genetic algorithms

The problem of optimal design of a multi-gravity-assist space trajectories, with free number of deep space maneuvers (MGADSM) poses multi-modal cost functions. In the general form of the problem, the number of design variables is solution dependent. To handle global optimization problems where the number of design variables varies from one solution to another, two novel genetic-based techniques are introduced: hidden genes genetic algorithm (HGGA) and dynamic-size multiple population genetic algorithm (DSMPGA). In HGGA, a fixed length for the design variables is assigned for all solutions. Independent variables of each solution are divided into effective and ineffective (hidden) genes. Hidden genes are excluded in cost function evaluations. Full-length solutions undergo standard genetic operations. In DSMPGA, sub-populations of fixed size design spaces are randomly initialized. Standard genetic operations are carried out for a stage of generations. A new population is then created by reproduction from all members based on their relative fitness. The resulting sub-populations have different sizes from their initial sizes. The process repeats, leading to increasing the size of sub-populations of more fit solutions. Both techniques are applied to several MGADSM problems. They have the capability to determine the number of swing-bys, the planets to swing by, launch and arrival dates, and the number of deep space maneuvers as well as their locations, magnitudes, and directions in an optimal sense. The results show that solutions obtained using the developed tools match known solutions for complex case studies. The HGGA is also used to obtain the asteroids sequence and the mission structure in the global trajectory optimization competition (GTOC) problem. As an application of GA optimization to Earth orbits, the problem of visiting a set of ground sites within a constrained time frame is solved. The J2 perturbation and zonal coverage are considered to design repeated Sun-synchronous orbits. Finally, a new set of orbits, the repeated shadow track orbits (RSTO), is introduced. The orbit parameters are optimized such that the shadow of a spacecraft on the Earth visits the same locations periodically every desired number of days.

COMPUTATIONAL ANALYSIS OF THE AEROELASTIC DYNAMICS OF A WIND TURBINE BLADE WITH VARIABLE-SPEED STALL CONTROL

The accuracy of simulating the aerodynamics and structural properties of the blades is crucial in the wind-turbine technology. Hence the models used to implement these features need to be very precise and their level of detailing needs to be high. With the variety of blade designs being developed the models should be versatile enough to adapt to the changes required by every design. We are going to implement a combination of numerical models which are associated with the structural and the aerodynamic part of the simulation using the computational power of a parallel HPC cluster. The structural part models the heterogeneous internal structure of the beam based on a novel implementation of the Generalized Timoshenko Beam Model Technique.. Using this technique the 3-D structure of the blade is reduced into a 1-D beam which is asymptotically equivalent. This reduces the computational cost of the model without compromising its accuracy. This structural model interacts with the Flow model which is a modified version of the Blade Element Momentum Theory. The modified version of the BEM accounts for the large deflections of the blade and also considers the pre-defined structure of the blade. The coning, sweeping of the blade, tilt of the nacelle and the twist of the sections along the blade length are all computed by the model which aren’t considered in the classical BEM theory. Each of these two models provides feedback to the other and the interactive computations lead to more accurate outputs. We successfully implemented the computational models to analyze and simulate the structural and aerodynamic aspects of the blades. The interactive nature of these models and their ability to recompute data using the feedback from each other makes this code more efficient than the commercial codes available. In this thesis we start off with the verification of these models by testing it on the well-known benchmark blade for the NREL-5MW Reference Wind Turbine, an alternative fixed-speed stall-controlled blade design proposed by Delft University, and a novel alternative design that we proposed for a variable-speed stall-controlled turbine, which offers the potential for more uniform power control and improved annual energy production.. To optimize the power output of the stall-controlled blade we modify the existing designs and study their behavior using the aforementioned aero elastic model.

IMPROVING STARTABILITY AND REDUCING EMISSIONS IN FLEXFUEL SPARK IGNITION DIRECT INJECTION VARIABLE CAM TIMING ENGINE

Experimental work and analysis was done to investigate engine startup robustness and emissions of a flex-fuel spark ignition (SI) direct injection (DI) engine. The vaporization and other characteristics of ethanol fuel blends present a challenge at engine startup. Strategies to reduce the enrichment requirements for the first engine startup cycle and emissions for the second and third fired cycle at 25°C ± 1°C engine and intake air temperature were investigated. Research work was conducted on a single cylinder SIDI engine with gasoline and E85 fuels, to study the effect on first fired cycle of engine startup. Piston configurations that included a compression ratio change (11 vs 15.5) and piston geometry change (flattop vs bowl) were tested, along with changes in intake cam timing (95,110,125) and fuel pressure (0.4 MPa vs 3 MPa). The goal was to replicate the engine speed, manifold pressure, fuel pressure and testing temperature from an engine startup trace for investigating the first fired cycle for the engine. Results showed bowl piston was able to enable lower equivalence ratio engine starts with gasoline fuel, while also showing lower IMEP at the same equivalence ratio compared to flat top piston. With E85, bowl piston showed reduced IMEP as compression ratio increased at the same equivalence ratio. A preference for constant intake valve timing across fuels seemed to indicate that flattop piston might be a good flex-fuel piston. Significant improvements were seen with higher CR bowl piston with high fuel pressure starts, but showed no improvement with low fuel pressures. Simulation work was conducted to analyze initial three cycles of engine startup in GT-POWER for the same set of hardware used in the experimentations. A steady state validated model was modified for startup conditions. The results of which allowed an understanding of the relative residual levels and IMEP at the test points in the cam phasing space. This allowed selecting additional test points that enable use of higher residual levels, eliminating those with smaller trapped mass incapable of producing required IMEP for proper engine turnover. The second phase of experimental testing results for 2nd and 3rd startup cycle revealed both E10 and E85 prefer the same SOI of 240°bTDC at second and third startup cycle for the flat top piston and high injection pressures. E85 fuel optimal cam timing for startup showed that it tolerates more residuals compared to E10 fuel. Higher internal residuals drives down the Ø requirement for both fuels up to their combustion stability limit, this is thought to be direct benefit to vaporization due to increased cycle start temperature. Benefits are shown for an advance IMOP and retarded EMOP strategy at engine startup. Overall the amount of residuals preferred by an engine for E10 fuel at startup is thought to be constant across engine speed, thus could enable easier selection of optimized cam positions across the startup speeds.

Variable impact on mortality of AIDS-defining events diagnosed during combination antiretroviral therapy: not all AIDS-defining conditions are created equal

BACKGROUND: The extent to which mortality differs following individual acquired immunodeficiency syndrome (AIDS)-defining events (ADEs) has not been assessed among patients initiating combination antiretroviral therapy. METHODS: We analyzed data from 31,620 patients with no prior ADEs who started combination antiretroviral therapy. Cox proportional hazards models were used to estimate mortality hazard ratios for each ADE that occurred in >50 patients, after stratification by cohort and adjustment for sex, HIV transmission group, number of antiretroviral drugs initiated, regimen, age, date of starting combination antiretroviral therapy, and CD4+ cell count and HIV RNA load at initiation of combination antiretroviral therapy. ADEs that occurred in <50 patients were grouped together to form a "rare ADEs" category. RESULTS: During a median follow-up period of 43 months (interquartile range, 19-70 months), 2880 ADEs were diagnosed in 2262 patients; 1146 patients died. The most common ADEs were esophageal candidiasis (in 360 patients), Pneumocystis jiroveci pneumonia (320 patients), and Kaposi sarcoma (308 patients). The greatest mortality hazard ratio was associated with non-Hodgkin's lymphoma (hazard ratio, 17.59; 95% confidence interval, 13.84-22.35) and progressive multifocal leukoencephalopathy (hazard ratio, 10.0; 95% confidence interval, 6.70-14.92). Three groups of ADEs were identified on the basis of the ranked hazard ratios with bootstrapped confidence intervals: severe (non-Hodgkin's lymphoma and progressive multifocal leukoencephalopathy [hazard ratio, 7.26; 95% confidence interval, 5.55-9.48]), moderate (cryptococcosis, cerebral toxoplasmosis, AIDS dementia complex, disseminated Mycobacterium avium complex, and rare ADEs [hazard ratio, 2.35; 95% confidence interval, 1.76-3.13]), and mild (all other ADEs [hazard ratio, 1.47; 95% confidence interval, 1.08-2.00]). CONCLUSIONS: In the combination antiretroviral therapy era, mortality rates subsequent to an ADE depend on the specific diagnosis. The proposed classification of ADEs may be useful in clinical end point trials, prognostic studies, and patient management.

Multivariate modelling of responses to conditional items: New possibilities for latent class analysis

Questionnaire data may contain missing values because certain questions do not apply to all respondents. For instance, questions addressing particular attributes of a symptom, such as frequency, triggers or seasonality, are only applicable to those who have experienced the symptom, while for those who have not, responses to these items will be missing. This missing information does not fall into the category 'missing by design', rather the features of interest do not exist and cannot be measured regardless of survey design. Analysis of responses to such conditional items is therefore typically restricted to the subpopulation in which they apply. This article is concerned with joint multivariate modelling of responses to both unconditional and conditional items without restricting the analysis to this subpopulation. Such an approach is of interest when the distributions of both types of responses are thought to be determined by common parameters affecting the whole population. By integrating the conditional item structure into the model, inference can be based both on unconditional data from the entire population and on conditional data from subjects for whom they exist. This approach opens new possibilities for multivariate analysis of such data. We apply this approach to latent class modelling and provide an example using data on respiratory symptoms (wheeze and cough) in children. Conditional data structures such as that considered here are common in medical research settings and, although our focus is on latent class models, the approach can be applied to other multivariate models.

Randomized controlled trial comparing a variable-thread novel tapered and a standard tapered implant: interim one-year results

STATEMENT OF PROBLEM: A tapered implant with continuously changing threads purported to provide stable tissue support and allow immediate function has been developed. Treatment success and stabilization of supporting tissues over time require documentation. PURPOSE: The purpose of this prospective, randomized, controlled, multicenter study was to evaluate changes in bone level and soft tissue behavior between the novel implant (NobelActive/NA) and a standard tapered implant (NobelReplace Tapered Groovy/NR) with regard to immediate function. MATERIAL AND METHODS: A total of 177 patients randomly allocated to 3 treatment groups (2 different test implant groups: NA Internal (n=117; internal connection) and External (n=82), and 1 standard treatment group, NR (n=126)) received 325 implants. Implants were placed into healed sites, and all but 6 implants were immediately nonocclusally loaded. Clinical and radiographic evaluations of treatment success, crestal bone levels, and soft tissue changes were performed at the time of placement and after 3, 6, and 12 months. Log-Rank test was used to analyze the differences in survival rate. Marginal bone level was compared using the Kruskal-Wallis test and Mann-Whitney U-test (alpha=.05). RESULTS: One-year cumulative survival rates were comparable (96.6% for NA Internal; 96.3% for NA External; 97.6% for NR; P=.852; Log-Rank). Mean (SD) change in bone level was -0.95 mm (1.37) for NA Internal, -0.64 mm (0.97) for NA External, and -0.63 mm (1.18) for NR (P=.589; Kruskal-Wallis). Stable soft tissues and significantly increased papilla scores (P<.001; Wilcoxon signed-rank) were observed for all implant types. CONCLUSIONS: The novel implants showed high survival rates as well as stable bone and soft tissue levels after 1 year, and may be recommended for clinical use, even under immediate function.

Novel screening tools for latent tuberculosis: time to leave an old friend?

PURPOSE OF REVIEW: Therapeutic inhibition of tumour necrosis factor-alpha strongly increases the risk of reactivation in latent tuberculosis infection. Recent blood tests based on antigen-specific T cell response and measuring production of interferon-gamma, so called interferon-gamma release assays (IGRAs), are promising novel tools to identify infected patients. The performance of diagnostic testing for latent tuberculosis infection in patients with rheumatic diseases will be discussed. RECENT FINDINGS: In patients with rheumatoid arthritis, IGRAs are more sensitive and more specific than traditional tuberculin skin testing. They are unaffected by Bacillus-Calmette-Guérin vaccination and most nontuberculous mycobacteria. Most comparative studies show a better performance of the IGRAs than tuberculin skin testing in terms of a higher specificity. The rate of indeterminate results may be affected by glucocorticoids and the underlying disease but appears independent of disease-modifying antirheumatic drugs. Despite using identical Mycobacterium tuberculosis antigens, the two commercially available tests show differences in clinical performance. SUMMARY: The current information about the performance of the tuberculin skin testing and the IGRAs in the detection of latent tuberculosis infection in patients with rheumatic diseases strongly suggest a clinically relevant advantage of the IGRAs. Their use will help to reduce overuse and underuse of preventive treatment in tumour necrosis factor inhibition.