Optimization of the Ion Source-Mass Spectrometry Parameters in Non-Steroidal Anti-Inflammatory and Analgesic Pharmaceuticals Analysis by a Design of Experiments Approach

The flow rates of drying and nebulizing gas, heat block and desolvation line temperatures and interface voltage are potential electrospray ionization parameters as they may enhance sensitivity of the mass spectrometer. The conditions that give higher sensitivity of 13 pharmaceuticals were explored. First, Plackett-Burman design was implemented to screen significant factors, and it was concluded that interface voltage and nebulizing gas flow were the only factors that influence the intensity signal for all pharmaceuticals. This fractionated factorial design was projected to set a full 2(2) factorial design with center points. The lack-of-fit test proved to be significant. Then, a central composite face-centered design was conducted. Finally, a stepwise multiple linear regression and subsequently an optimization problem solving were carried out. Two main drug clusters were found concerning the signal intensities of all runs of the augmented factorial design. p-Aminophenol, salicylic acid, and nimesulide constitute one cluster as a result of showing much higher sensitivity than the remaining drugs. The other cluster is more homogeneous with some sub-clusters comprising one pharmaceutical and its respective metabolite. It was observed that instrumental signal increased when both significant factors increased with maximum signal occurring when both codified factors are set at level +1. It was also found that, for most of the pharmaceuticals, interface voltage influences the intensity of the instrument more than the nebulizing gas flowrate. The only exceptions refer to nimesulide where the relative importance of the factors is reversed and still salicylic acid where both factors equally influence the instrumental signal. Graphical Abstract ᅟ.

Improving photofermentative hydrogen production through metabolic engineering and DOE (Design of Experiments)

A l’heure actuelle, les biocarburants renouvelables et qui ne nuit pas à l'environnement sont à l'étude intensive en raison de l'augmentation des problèmes de santé et de la diminution des combustibles fossiles. H2 est l'un des candidats les plus prometteurs en raison de ses caractéristiques uniques, telles que la densité d'énergie élevée et la génération faible ou inexistante de polluants. Une façon attrayante pour produire la H2 est par les bactéries photosynthétiques qui peuvent capter l'énergie lumineuse pour actionner la production H2 avec leur système de nitrogénase. L'objectif principal de cette étude était d'améliorer le rendement de H2 des bactéries photosynthétiques pourpres non sulfureuses utilisant une combinaison de génie métabolique et le plan des expériences. Une hypothèse est que le rendement en H2 pourrait être améliorée par la redirection de flux de cycle du Calvin-Benson-Bassham envers du système de nitrogénase qui catalyse la réduction des protons en H2. Ainsi, un PRK, phosphoribulose kinase, mutant « knock-out » de Rhodobacter capsulatus JP91 a été créé. L’analyse de la croissance sur des différentes sources de carbone a montré que ce mutant ne peut croître qu’avec l’acétate, sans toutefois produire d' H2. Un mutant spontané, YL1, a été récupéré qui a retenu l'cbbP (codant pour PRK) mutation d'origine, mais qui avait acquis la capacité de se développer sur le glucose et produire H2. Une étude de la production H2 sous différents niveaux d'éclairage a montré que le rendement d’YL1 était de 20-40% supérieure à la souche type sauvage JP91. Cependant, il n'y avait pas d'amélioration notable du taux de production de H2. Une étude cinétique a montré que la croissance et la production d'hydrogène sont fortement liées avec des électrons à partir du glucose principalement dirigés vers la production de H2 et la formation de la biomasse. Sous des intensités lumineuses faibles à intermédiaires, la production d'acides organiques est importante, ce qui suggère une nouvelle amélioration additionnel du rendement H2 pourrait être possible grâce à l'optimisation des processus. Dans une série d'expériences associées, un autre mutant spontané, YL2, qui a un phénotype similaire à YL1, a été testé pour la croissance dans un milieu contenant de l'ammonium. Les résultats ont montré que YL2 ne peut croître que avec de l'acétate comme source de carbone, encore une fois, sans produire de H2. Une incubation prolongée dans les milieux qui ne supportent pas la croissance de YL2 a permis l'isolement de deux mutants spontanés secondaires intéressants, YL3 et YL4. L'analyse par empreint du pied Western a montré que les deux souches ont, dans une gamme de concentrations d'ammonium, l'expression constitutive de la nitrogénase. Les génomes d’YL2, YL3 et YL4 ont été séquencés afin de trouver les mutations responsables de ce phénomène. Fait intéressant, les mutations de nifA1 et nifA2 ont été trouvés dans les deux YL3 et YL4. Il est probable qu'un changement conformationnel de NifA modifie l'interaction protéine-protéine entre NifA et PII protéines (telles que GlnB ou GlnK), lui permettant d'échapper à la régulation par l'ammonium, et donc d'être capable d'activer la transcription de la nitrogénase en présence d'ammonium. On ignore comment le nitrogénase synthétisé est capable de maintenir son activité parce qu’en théorie, il devrait également être soumis à une régulation post-traductionnelle par ammonium. Une autre preuve pourrait être obtenue par l'étude du transcriptome d’YL3 et YL4. Une première étude sur la production d’ H2 par YL3 et YL4 ont montré qu'ils sont capables d’une beaucoup plus grande production d'hydrogène que JP91 en milieu d'ammonium, qui ouvre la porte pour les études futures avec ces souches en utilisant des déchets contenant de l'ammonium en tant que substrats. Enfin, le reformage biologique de l'éthanol à H2 avec la bactérie photosynthétique, Rhodopseudomonas palustris CGA009 a été examiné. La production d'éthanol avec fermentation utilisant des ressources renouvelables microbiennes a été traitée comme une technique mature. Cependant, la plupart des études du reformage de l'éthanol à H2 se sont concentrés sur le reformage chimique à la vapeur, ce qui nécessite généralement une haute charge énergetique et résultats dans les émissions de gaz toxiques. Ainsi le reformage biologique de l'éthanol à H2 avec des bactéries photosynthétiques, qui peuvent capturer la lumière pour répondre aux besoins énergétiques de cette réaction, semble d’être plus prometteuse. Une étude précédente a démontré la production d'hydrogène à partir d'éthanol, toutefois, le rendement ou la durée de cette réaction n'a pas été examiné. Une analyse RSM (méthode de surface de réponse) a été réalisée dans laquelle les concentrations de trois facteurs principaux, l'intensité lumineuse, de l'éthanol et du glutamate ont été variés. Nos résultats ont montré que près de 2 moles de H2 peuvent être obtenus à partir d'une mole d'éthanol, 33% de ce qui est théoriquement possible.

Territorial planning of Juquiá municipality (State of São Paulo, Brazil), using an integrated analysis of the land cover and slope.

2008

Design of experiment in drug development: optimal allocations in multi-arm clinical trials and design space for multi-step processes

In this thesis, we deal with the design of experiments in the drug development process, focusing on the design of clinical trials for treatment comparisons (Part I) and the design of preclinical laboratory experiments for proteins development and manufacturing (Part II). In Part I we propose a multi-purpose design methodology for sequential clinical trials. We derived optimal allocations of patients to treatments for testing the efficacy of several experimental groups by also taking into account ethical considerations. We first consider exponential responses for survival trials and we then present a unified framework for heteroscedastic experimental groups that encompasses the general ANOVA set-up. The very good performance of the suggested optimal allocations, in terms of both inferential and ethical characteristics, are illustrated analytically and through several numerical examples, also performing comparisons with other designs proposed in the literature. Part II concerns the planning of experiments for processes composed of multiple steps in the context of preclinical drug development and manufacturing. Following the Quality by Design paradigm, the objective of the multi-step design strategy is the definition of the manufacturing design space of the whole process and, as we consider the interactions among the subsequent steps, our proposal ensures the quality and the safety of the final product, by enabling more flexibility and process robustness in the manufacturing.

Exact and heuristic algorithms for the integrated planning of multi-energy systems

The aim of this thesis is to present exact and heuristic algorithms for the integrated planning of multi-energy systems. The idea is to disaggregate the energy system, starting first with its core the Central Energy System, and then to proceed towards the Decentral part. Therefore, a mathematical model for the generation expansion operations to optimize the performance of a Central Energy System system is first proposed. To ensure that the proposed generation operations are compatible with the network, some extensions of the existing network are considered as well. All these decisions are evaluated both from an economic viewpoint and from an environmental perspective, as specific constraints related to greenhouse gases emissions are imposed in the formulation. Then, the thesis presents an optimization model for solar organic Rankine cycle in the context of transactive energy trading. In this study, the impact that this technology can have on the peer-to-peer trading application in renewable based community microgrids is inspected. Here the consumer becomes a prosumer and engages actively in virtual trading with other prosumers at the distribution system level. Moreover, there is an investigation of how different technological parameters of the solar Organic Rankine Cycle may affect the final solution. Finally, the thesis introduces a tactical optimization model for the maintenance operations’ scheduling phase of a Combined Heat and Power plant. Specifically, two types of cleaning operations are considered, i.e., online cleaning and offline cleaning. Furthermore, a piecewise linear representation of the electric efficiency variation curve is included. Given the challenge of solving the tactical management model, a heuristic algorithm is proposed. The heuristic works by solving the daily operational production scheduling problem, based on the final consumer’s demand and on the electricity prices. The aggregate information from the operational problem is used to derive maintenance decisions at a tactical level.

Dosimetric optimization of CT protocols for the preoperative planning of hip arthroplasty

Radiation dose in x-ray computed tomography (CT) has become a topic of great interest due to the increasing number of CT examinations performed worldwide. In fact, CT scans are responsible of significant doses delivered to the patients, much larger than the doses due to the most common radiographic procedures. This thesis work, carried out at the Laboratory of Medical Technology (LTM) of the Rizzoli Orthopaedic Institute (IOR, Bologna), focuses on two primary objectives: the dosimetric characterization of the tomograph present at the IOR and the optimization of the clinical protocol for hip arthroplasty. In particular, after having verified the reliability of the dose estimates provided by the system, we compared the estimates of the doses delivered to 10 patients undergoing CT examination for the pre-operative planning of hip replacement with the Diagnostic Reference Level (DRL) for an osseous pelvis examination. Out of 10 patients considered, only for 3 of them the doses were lower than the DRL. Therefore, the necessity to optimize the clinical protocol emerged. This optimization was investigated using a human femur from a cadaver. Quantitative analysis and comparison of 3D reconstructions were made, after having performed manual segmentation of the femur from different CT acquisitions. Dosimetric simulations of the CT acquisitions on the femur were also made and associated to the accuracy of the 3D reconstructions, to analyse the optimal combination of CT acquisition parameters. The study showed that protocol optimization both in terms of Hausdorff distance and in terms of effective dose (ED) to the patient may be realized simply by modifying the value of the pitch in the protocol, by choosing between 0.98 and 1.37.

Sustainable waste recycling solution for the glass fibre reinforced polymer composite materials industry

In this paper the adequacy and the benefit of incorporating glass fibre reinforced polymer (GFRP) waste materials into polyester based mortars, as sand aggregates and filler replacements, are assessed. Different weight contents of mechanically recycled GFRP wastes with two particle size grades are included in the formulation of new materials. In all formulations, a polyester resin matrix was modified with a silane coupling agent in order to improve binder-aggregates interfaces. The added value of the recycling solution was assessed by means of both flexural and compressive strengths of GFRP admixed mortars with regard to those of the unmodified polymer mortars. Planning of experiments and data treatment were performed by means of full factorial design and through appropriate statistical tools based on analyses of variance (ANOVA). Results show that the partial replacement of sand aggregates by either type of GFRP recyclates improves the mechanical performance of resultant polymer mortars. In the case of trial formulations modified with the coarser waste mix, the best results are achieved with 8% waste weight content, while for fine waste based polymer mortars, 4% in weight of waste content leads to the higher increases on mechanical strengths. This study clearly identifies a promising waste management solution for GFRP waste materials by developing a cost-effective end-use application for the recyclates, thus contributing to a more sustainable fibre-reinforced polymer composites industry.

Moisture content and its influence on the roughness and noise emission during wood machining

Numerous factors influencing the surface quality of wood after machining, among them we highlight the machining parameters and the properties of the wood. In the analysis of the influence of these factors on machining and in determining the quality measurement systems are used to obtain surface characteristics, these systems are divided into methods of contact and non-contact. The method for mechanical contact performed with the aid of the surface roughness tester is the most valued in the measurement of roughness of wood, however, aiming at a greater agility in these measurements, there is a need to seek alternatives for evaluation of surface quality, and one of these options is to use the forms of indirect measurements of this quality, as for example, the use of noise emission during the machining process. With this, the aim was to analyze the influence of the moisture content of the wood, at different levels, on surface quality of the species Pinus elliottii, determined by the method of mechanical probing move and relate this roughness with the sound emission issued for each class of humidity, during machining. The planning of experiments and statistical analyses were performed with the help of Taguchi method. The specimens were conditioned in greenhouses climatizadoras automatics for obtaining three classes of humidity. Machining tests of wooden pieces were performed on a machining center specific for this type of material. The roughness values were measured by a roughness verifier and the noise emission values were measured by for a measurer sound pressure level. Statistically significant differences were observed, the significance level of 10 %, on roughness and noise emission between the three levels of moisture. It was observed that with the increase in the moisture content occurred an increase of roughness and a reduction in noise emission. Monitoring of surface quality through noise level is an interesting alternative to the method of mechanical contact.

Utilization of Particle Image velocimetry in PPOOLEX condensation experiments

Particle Image Velocimetry, PIV, is an optical measuring technique to obtain velocity information of a flow in interest. With PIV it is possible to achieve two or three dimensional velocity vector fields from a measurement area instead of a single point in a flow. Measured flow can be either in liquid or in gas form. PIV is nowadays widely applied to flow field studies. The need for PIV is to obtain validation data for Computational Fluid Dynamics calculation programs that has been used to model blow down experiments in PPOOLEX test facility in the Lappeenranta University of Technology. In this thesis PIV and its theoretical background are presented. All the subsystems that can be considered to be part of a PIV system are presented as well with detail. Emphasis is also put to the mathematics behind the image evaluation. The work also included selection and successful testing of a PIV system, as well as the planning of the installation to the PPOOLEX facility. Already in the preliminary testing PIV was found to be good addition to the measuring equipment for Nuclear Safety Research Unit of LUT. The installation to PPOOLEX facility was successful even though there were many restrictions considering it. All parts of the PIV system worked and they were found out to be appropriate for the planned use. Results and observations presented in this thesis are a good background to further PIV use.

Multi-criteria optimization manipulator trajectory planning

In the last twenty years genetic algorithms (GAs) were applied in a plethora of fields such as: control, system identification, robotics, planning and scheduling, image processing, and pattern and speech recognition (Bäck et al., 1997). In robotics the problems of trajectory planning, collision avoidance and manipulator structure design considering a single criteria has been solved using several techniques (Alander, 2003). Most engineering applications require the optimization of several criteria simultaneously. Often the problems are complex, include discrete and continuous variables and there is no prior knowledge about the search space. These kind of problems are very more complex, since they consider multiple design criteria simultaneously within the optimization procedure. This is known as a multi-criteria (or multiobjective) optimization, that has been addressed successfully through GAs (Deb, 2001). The overall aim of multi-criteria evolutionary algorithms is to achieve a set of non-dominated optimal solutions known as Pareto front. At the end of the optimization procedure, instead of a single optimal (or near optimal) solution, the decision maker can select a solution from the Pareto front. Some of the key issues in multi-criteria GAs are: i) the number of objectives, ii) to obtain a Pareto front as wide as possible and iii) to achieve a Pareto front uniformly spread. Indeed, multi-objective techniques using GAs have been increasing in relevance as a research area. In 1989, Goldberg suggested the use of a GA to solve multi-objective problems and since then other researchers have been developing new methods, such as the multi-objective genetic algorithm (MOGA) (Fonseca & Fleming, 1995), the non-dominated sorted genetic algorithm (NSGA) (Deb, 2001), and the niched Pareto genetic algorithm (NPGA) (Horn et al., 1994), among several other variants (Coello, 1998). In this work the trajectory planning problem considers: i) robots with 2 and 3 degrees of freedom (dof ), ii) the inclusion of obstacles in the workspace and iii) up to five criteria that are used to qualify the evolving trajectory, namely the: joint traveling distance, joint velocity, end effector / Cartesian distance, end effector / Cartesian velocity and energy involved. These criteria are used to minimize the joint and end effector traveled distance, trajectory ripple and energy required by the manipulator to reach at destination point. Bearing this ideas in mind, the paper addresses the planning of robot trajectories, meaning the development of an algorithm to find a continuous motion that takes the manipulator from a given starting configuration up to a desired end position without colliding with any obstacle in the workspace. The chapter is organized as follows. Section 2 describes the trajectory planning and several approaches proposed in the literature. Section 3 formulates the problem, namely the representation adopted to solve the trajectory planning and the objectives considered in the optimization. Section 4 studies the algorithm convergence. Section 5 studies a 2R manipulator (i.e., a robot with two rotational joints/links) when the optimization trajectory considers two and five objectives. Sections 6 and 7 show the results for the 3R redundant manipulator with five goals and for other complementary experiments are described, respectively. Finally, section 8 draws the main conclusions.

Planning the medical workforce - an analysis of the third repport of the Medical Workforce Standing Advisory Committee

Arquivos de Medicina 1998; 12(4): 246-248

Planning, operations and data handling of planetary science missions

Dissertação para obtenção do Grau de Mestre em Engenharia Física

A comparative analysis of sustainable tourism, planning and development between Sligo and Donegal County Councils

Sustainable Development requires appropriate and continuous planning and management of economic, socio cultural and environmental resources. Tourism planning calls for continuous collaboration among tourism agencies, local authorities and local communities for success of the industry. While evidence suggests that tourism planning has been extensively documented, it is apparent that Donegal and Sligo County Councils have, in some cases failed to adequately address the significance of planning of the tourism industry for the North West of Ireland. This was investigated through interviews with chief planners of Donegal and Sligo county councils and was conducted in conjunction with the analysis of county development plans; which were formulated by both organisations involved in this study. Evidence suggests that although tourism is extensively documented by Donegal and Sligo county councils, neither of the two local authorities have developed implementation strategies to facilitate the promotion of sustainable tourism development. This research compares and analyses Donegal and Sligo county councils and how they plan for sustainable tourism development. It outlines the role of the county councils in relation to tourism planning and how Donegal and Sligo compare in how they plan for such a significant industry in the North West o f Ireland. It highlights the importance of implementation tools and methods and offers future directions that can assist in the development of sustainable tourism.

The use of contrast-enhanced MRI angiography for planning interventional catheterization

Background: Interventional catheterization is being increasingly used for relief of residual lesions in congenital heart disease. Exact anatomical imaging is crucial in the planning of an intervention. This can be provided non-invasively and without radiation by contrast-enhanced MR angiography (CEMRA). Aim: To evaluate the accuracy of the measurements of the vessels obtained by CEMRA in comparison to those obtained by conventional X-ray angiography (CXA). Methods: Retrospective blinded measurement of the diameters of aorta and pulmonary arteries on the CEMRA and CXA images, in the same locations. Comparison of the results by Pearson correlation and by calculating the limits of agreement. Results: Twenty-one children with congenital heart disease, mean age 5.6 +- 5.2 years, weight 21.1 +- 18.4 kg, underwent CEMRA and catheterization for assessment or treatment of a residual lesion. The time interval between the CEMRA and the CXA examination was 2.6 +- 2.3 months. A total of 98 measurements, 37 of the aorta and 61 of the pulmonary arteries were performed on the images obtained by each technique. The correlation between CEMRA and CXA measurements was excellent, r = 0.97, p < 0.0001. The mean difference between the two techniques was 0.018 +- 1.1mm; the limits of agreement were -2.14 and +2.18mm. Similar agreement was found for measures of the aorta (r +- 0.97, mean difference 0.20 = 1.08 mm) and of the pulmonary arteries (r +- 0.97, mean difference 0.048 = 0.89 mm). Conclusions: CEMRA provide accurate quantitative anatomical information, which highly agrees with CXA data, and can therefore be used for planning interventional catheterization.