Design and optimization of selfnanoemulsifying drug delivery systems for enhanced dissolution of gemfibrozil

Self-nanoemulsifying drug delivery systems of gemfibrozil were developed under Quality by Design approach for improvement of dissolution and oral absorption. Preliminary screening was performed to select proper components combination. BoxBehnken experimental design was employed as statistical tool to optimize the formulation variables, X1 (Cremophor® EL), X2 (Capmul® MCM-C8), and X3 (lemon essential oil). Systems were assessed for visual characteristics (emulsification efficacy), turbidity, droplet size, polydispersity index and drug release. Different pH media were also assayed for optimization. Following optimization, the values of formulation components (X1, X2, and X3) were 32.43%, 29.73% and 21.62%, respectively (16.22% of gemfibrozil). Transmission electron microscopy demonstrated spherical droplet morphology. SNEEDS release study was compared to commercial tablets. Optimized SNEDDS formulation of gemfibrozil showed a significant increase in dissolution rate compared to conventional tablets. Both formulations followed Weibull mathematical model release with a significant difference in td parameter in favor of the SNEDDS. Equally amodelistic parameters were calculated being the dissolution efficiency significantly higher for SNEDDS, confirming that the developed SNEDDS formulation was superior to commercial formulation with respect to in vitro dissolution profile. This paper provides an overview of the SNEDDS of the gemfibrozil as a promising alternative to improve oral absorption.

Rapid optimization of drug combinations for the optimal angiostatic treatment of cancer.

Drug combinations can improve angiostatic cancer treatment efficacy and enable the reduction of side effects and drug resistance. Combining drugs is non-trivial due to the high number of possibilities. We applied a feedback system control (FSC) technique with a population-based stochastic search algorithm to navigate through the large parametric space of nine angiostatic drugs at four concentrations to identify optimal low-dose drug combinations. This implied an iterative approach of in vitro testing of endothelial cell viability and algorithm-based analysis. The optimal synergistic drug combination, containing erlotinib, BEZ-235 and RAPTA-C, was reached in a small number of iterations. Final drug combinations showed enhanced endothelial cell specificity and synergistically inhibited proliferation (p < 0.001), but not migration of endothelial cells, and forced enhanced numbers of endothelial cells to undergo apoptosis (p < 0.01). Successful translation of this drug combination was achieved in two preclinical in vivo tumor models. Tumor growth was inhibited synergistically and significantly (p < 0.05 and p < 0.01, respectively) using reduced drug doses as compared to optimal single-drug concentrations. At the applied conditions, single-drug monotherapies had no or negligible activity in these models. We suggest that FSC can be used for rapid identification of effective, reduced dose, multi-drug combinations for the treatment of cancer and other diseases.

Geometric stopping of a random walk and its applications to valuing equity-linked death benefits

We study discrete-time models in which death benefits can depend on a stock price index, the logarithm of which is modeled as a random walk. Examples of such benefit payments include put and call options, barrier options, and lookback options. Because the distribution of the curtate-future-lifetime can be approximated by a linear combination of geometric distributions, it suffices to consider curtate-future-lifetimes with a geometric distribution. In binomial and trinomial tree models, closed-form expressions for the expectations of the discounted benefit payment are obtained for a series of options. They are based on results concerning geometric stopping of a random walk, in particular also on a version of the Wiener-Hopf factorization.

The Optimization of Flotation Process Parameters in the Deinking Plant

Tämän diplomityön tavoitteena oli sekundäärisen esiflotaation optimointi Stora Enso Sachsen GmbH:n tehtaalla. Optimoinnin muuttujana käytettiin vaahdon määrää ja optimointiparametreinä ISO-vaaleutta, saantoja sekä tuhkapitoisuutta. Lisäksi tutkittiin flotaatiosakeuden vaikutusta myös muihin tehtaan flotaatioprosesseihin. Kirjallisuusosassa tarkasteltiin flotaatiotapahtumaa, poistettavien partikkeleiden ja ilmakuplien kontaktia, vaahdon muodostumista sekä tärkeimpiä käytössä olevia siistausflotaattoreiden laiteratkaisuja. Kokeellisessa osassa tutkittiin flotaatiosakeuden pienetämisen vaikutuksia tehtaan flotaatioprosesseihin tuhkapitoisuuden, ISO-vaaleuden, valon sironta- ja valon absorpiokerrointen kannalta. Sekundäärisen esiflotaation optimonti suoritettiin muuttamalla vaahdon määrää kolmella erilaisella injektorin koolla, (8 mm, 10 mm ja 13 mm), joista keskimmäinen kasvattaa 30 % massan tilavuusvirtaa ilmapitoisuuden muodossa. Optimonnin tarkoituksena oli kasvattaa hyväksytyn massajakeen ISO-vaaleutta, sekä kasvattaa kuitu- ja kokonaissaantoa sekundäärisessä esiflotaatiossa. Flotaatiosakeuden pienentämisellä oli edullisia vaikutuksia ISO-vaaleuteen ja valon sirontakertoimeen kussakin flotaatiossa. Tuhkapitoisuus pieneni sekundäärisissä flotaatioissa enemmän sakeuden ollessa pienempi, kun taas primäärisissä flotaatiossa vaikutus oli päinvastainen. Valon absorptiokerroin parani jälkiflotaatioissa alhaisemmalla sakeudella, kun taas esiflotaatioissa vaikutus oli päinvastainen. Sekundäärisen esiflotaation optimoinnin tuloksena oli lähes 5 % parempi ISO-vaaleus hyväksytyssä massajakeessa. Kokonaissaanto parani optimoinnin myötä 5 % ja kuitusaanto 2 %. Saantojen nousu tuottaa vuosittaisia säästöjä siistauslaitoksen tuotantokapasiteetin noustessa 0,5 %. Tämän lisäksi sekundäärisessä esiflotaatiossa rejektoituvan massavirran pienentyminen tuottaa lisäsäästöjä tehtaan voimalaitoksella.

L'exploitation des peintures en spray en criminalistique: mise en place d'une procédure de gestion et de comparaison des spectres infrarouges à l'aide des statistiques multivariées

La spectroscopie infrarouge (FTIR) est une technique de choix dans l'analyse des peintures en spray (traces ou bonbonnes de référence), grâce à son fort pouvoir discriminant, sa sensibilité, et ses nombreuses possibilités d'échantillonnage. La comparaison des spectres obtenus est aujourd'hui principalement faite visuellement, mais cette procédure présente des limitations telles que la subjectivité de la prise de décision car celle-ci dépend de l'expérience et de la formation suivie par l'expert. De ce fait, de faibles différences d'intensités relatives entre deux pics peuvent être perçues différemment par des experts, même au sein d'un même laboratoire. Lorsqu'il s'agit de justifier ces différences, certains les expliqueront par la méthode analytique utilisée, alors que d'autres estimeront plutôt qu'il s'agit d'une variabilité intrinsèque à la peinture et/ou à son vécu (par exemple homogénéité, sprayage, ou dégradation). Ce travail propose d'étudier statistiquement les différentes sources de variabilité observables dans les spectres infrarouges, de les identifier, de les comprendre et tenter de les minimiser. Le deuxième objectif principal est de proposer une procédure de comparaison des spectres qui soit davantage transparente et permette d'obtenir des réponses reproductibles indépendamment des experts interrogés. La première partie du travail traite de l'optimisation de la mesure infrarouge et des principaux paramètres analytiques. Les conditions nécessaires afin d'obtenir des spectres reproductibles et minimisant la variation au sein d'un même échantillon (intra-variabilité) sont présentées. Par la suite une procédure de correction des spectres est proposée au moyen de prétraitements et de sélections de variables, afin de minimiser les erreurs systématiques et aléatoires restantes, et de maximiser l'information chimique pertinente. La seconde partie présente une étude de marché effectuée sur 74 bonbonnes de peintures en spray représentatives du marché suisse. Les capacités de discrimination de la méthode FTIR au niveau de la marque et du modèle sont évaluées au moyen d'une procédure visuelle, et comparées à diverses procédures statistiques. Les limites inférieures de discrimination sont testées sur des peintures de marques et modèles identiques mais provenant de différents lots de production. Les résultats ont montré que la composition en pigments était particulièrement discriminante, à cause des étapes de corrections et d'ajustement de la couleur subies lors de la production. Les particularités associées aux peintures en spray présentes sous forme de traces (graffitis, gouttelettes) ont également été testées. Trois éléments sont mis en évidence et leur influence sur le spectre infrarouge résultant testée : 1) le temps minimum de secouage nécessaire afin d'obtenir une homogénéité suffisante de la peinture et, en conséquence, de la surface peinte, 2) la dégradation initiée par le rayonnement ultra- violet en extérieur, et 3) la contamination provenant du support lors du prélèvement. Finalement une étude de population a été réalisée sur 35 graffitis de la région lausannoise et les résultats comparés à l'étude de marché des bonbonnes en spray. La dernière partie de ce travail s'est concentrée sur l'étape de prise de décision lors de la comparaison de spectres deux-à-deux, en essayant premièrement de comprendre la pratique actuelle au sein des laboratoires au moyen d'un questionnaire, puis de proposer une méthode statistique de comparaison permettant d'améliorer l'objectivité et la transparence lors de la prise de décision. Une méthode de comparaison basée sur la corrélation entre les spectres est proposée, et ensuite combinée à une évaluation Bayesienne de l'élément de preuve au niveau de la source et au niveau de l'activité. Finalement des exemples pratiques sont présentés et la méthodologie est discutée afin de définir le rôle précis de l'expert et des statistiques dans la procédure globale d'analyse des peintures. -- Infrared spectroscopy (FTIR) is a technique of choice for analyzing spray paint speciments (i.e. traces) and reference samples (i.e. cans seized from suspects) due to its high discriminating power, sensitivity and sampling possibilities. The comparison of the spectra is currently carried out visually, but this procedure has limitations such as the subjectivity in the decision due to its dependency on the experience and training of the expert. This implies that small differences in the relative intensity of two peaks can be perceived differently by experts, even between analysts working in the same laboratory. When it comes to justifying these differences, some will explain them by the analytical technique, while others will estimate that the observed differences are mostly due to an intrinsic variability from the paint sample and/or its acquired characteristics (for example homogeneity, spraying, or degradation). This work proposes to statistically study the different sources of variability observed in infrared spectra, to identify them, understand them and try to minimize them. The second goal is to propose a procedure for spectra comparison that is more transparent, and allows obtaining reproducible answers being independent from the expert. The first part of the manuscript focuses on the optimization of infrared measurement and on the main analytical parameters. The necessary conditions to obtain reproducible spectra with a minimized variation within a sample (intra-variability) are presented. Following that a procedure of spectral correction is then proposed using pretreatments and variable selection methods, in order to minimize systematic and random errors, and increase simultaneously relevant chemical information. The second part presents a market study of 74 spray paints representative of the Swiss market. The discrimination capabilities of FTIR at the brand and model level are evaluated by means of visual and statistical procedures. The inferior limits of discrimination are tested on paints coming from the same brand and model, but from different production batches. The results showed that the pigment composition was particularly discriminatory, because of the corrections and adjustments made to the paint color during its manufacturing process. The features associated with spray paint traces (graffitis, droplets) were also tested. Three elements were identified and their influence on the resulting infrared spectra were tested: 1) the minimum shaking time necessary to obtain a sufficient homogeneity of the paint and subsequently of the painted surface, 2) the degradation initiated by ultraviolet radiation in an exterior environment, and 3) the contamination from the support when paint is recovered. Finally a population study was performed on 35 graffitis coming from the city of Lausanne and surroundings areas, and the results were compared to the previous market study of spray cans. The last part concentrated on the decision process during the pairwise comparison of spectra. First, an understanding of the actual practice among laboratories was initiated by submitting a questionnaire. Then, a proposition for a statistical method of comparison was advanced to improve the objectivity and transparency during the decision process. A method of comparison based on the correlation between spectra is proposed, followed by the integration into a Bayesian framework at both source and activity levels. Finally, some case examples are presented and the recommended methodology is discussed in order to define the role of the expert as well as the contribution of the tested statistical approach within a global analytical sequence for paint examinations.

Priming psychic and conjuring abilities of a magic demonstration influences event interpretation and random number generation biases

Magical ideation and belief in the paranormal is considered to represent a trait-like character; people either believe in it or not. Yet, anecdotes indicate that exposure to an anomalous event can turn skeptics into believers. This transformation is likely to be accompanied by altered cognitive functioning such as impaired judgments of event likelihood. Here, we investigated whether the exposure to an anomalous event changes individuals' explicit traditional (religious) and non-traditional (e.g., paranormal) beliefs as well as cognitive biases that have previously been associated with non-traditional beliefs, e.g., repetition avoidance when producing random numbers in a mental dice task. In a classroom, 91 students saw a magic demonstration after their psychology lecture. Before the demonstration, half of the students were told that the performance was done respectively by a conjuror (magician group) or a psychic (psychic group). The instruction influenced participants' explanations of the anomalous event. Participants in the magician, as compared to the psychic group, were more likely to explain the event through conjuring abilities while the reverse was true for psychic abilities. Moreover, these explanations correlated positively with their prior traditional and non-traditional beliefs. Finally, we observed that the psychic group showed more repetition avoidance than the magician group, and this effect remained the same regardless of whether assessed before or after the magic demonstration. We conclude that pre-existing beliefs and contextual suggestions both influence people's interpretations of anomalous events and associated cognitive biases. Beliefs and associated cognitive biases are likely flexible well into adulthood and change with actual life events.

Exit times in non-Markovian drifting continuous-time random-walk processes

By appealing to renewal theory we determine the equations that the mean exit time of a continuous-time random walk with drift satisfies both when the present coincides with a jump instant or when it does not. Particular attention is paid to the corrections ensuing from the non-Markovian nature of the process. We show that when drift and jumps have the same sign the relevant integral equations can be solved in closed form. The case when holding times have the classical Erlang distribution is considered in detail.

Cooling system optimization in medium-speed engines

Tässä työssä optimoidaan keskinopean Wärtsilä 32 -dieselmoottorin jäähdytysjärjestelmää ja tutkitaan taajuusmuuttajien käyttömahdollisuutta kiertopumppujen yhteydessä niin, että järjestelmässä saataisiin kiertämään vain kulloinkin tarvittava määrä vettä. Tutkimuksen mallinnus on toteutettu laatimalla aiemmin käytössä olleista yksinkertaisista simulointimalleista yksi malli, johon on sisällytetty sekä virtauksen että lämmönsiirron laskenta, jotka on aiemmin mallinnettu erillisillä ohjelmilla. Diplomityö on osa projektia, joka on tehty Sähkötekniikan osaston tutkijan Mikko Pääkkösen kanssa yhteistyössä. Tämän diplomityö keskittyy lähinnä virtausteknisiin ja lämmönsiirtoon liittyviin asioihin, kun taas sähkötekniikan osuus on esitetty Mikko Pääkkösen raportissa. Tulosten perustella voidaan sanoa, että taajuusmuuttajakäyttö kannattaa kiertopumppujen yhteydessä. Käyttämällä pumppujen virtaussäätöä voidaan jäähdytysjärjestelmästä jättää monia komponentteja, kuten termostaattiventtiilejä pois. Mallinnetut yksinkertaiset piiriratkaisut näyttävät toimivan ainakin yleisellä tasolla. Tutkimusta pumppujen säädöstä ja tässä projektissa luoduista jäähdytysjärjestelmäkonfiguraatioista kannattaa jatkaa.

Monotonic continuous-time random walks with drift and stochastic reset events

In this paper we consider a stochastic process that may experience random reset events which suddenly bring the system to the starting value and analyze the relevant statistical magnitudes. We focus our attention on monotonic continuous-time random walks with a constant drift: The process increases between the reset events, either by the effect of the random jumps, or by the action of the deterministic drift. As a result of all these combined factors interesting properties emerge, like the existence (for any drift strength) of a stationary transition probability density function, or the faculty of the model to reproduce power-law-like behavior. General formulas for two extreme statistics, the survival probability, and the mean exit time, are also derived. To corroborate in an independent way the results of the paper, Monte Carlo methods were used. These numerical estimations are in full agreement with the analytical predictions.

Prevalence of alcohol-impaired drivers based on random breath tests in a roadside survey

Sobriety checkpoints are not usually randomly located by traffic authorities. As such, information provided by non-random alcohol tests cannot be used to infer the characteristics of the general driving population. In this paper a case study is presented in which the prevalence of alcohol-impaired driving is estimated for the general population of drivers. A stratified probabilistic sample was designed to represent vehicles circulating in non-urban areas of Catalonia (Spain), a region characterized by its complex transportation network and dense traffic around the metropolis of Barcelona. Random breath alcohol concentration tests were performed during spring 2012 on 7,596 drivers. The estimated prevalence of alcohol-impaired drivers was 1.29 PER CENT, which is roughly a third of the rate obtained in non-random tests. Higher rates were found on weekends (1.90 PER CENT on Saturdays, 4.29 PER CENT on Sundays) and especially at night. The rate is higher for men (1.45 PER CENT) than for women (0.64 PER CENT) and the percentage of positive outcomes shows an increasing pattern with age. In vehicles with two occupants, the proportion of alcohol-impaired drivers is estimated at 2.62 PER CENT, but when the driver was alone the rate drops to 0.84 PER CENT, which might reflect the socialization of drinking habits. The results are compared with outcomes in previous surveys, showing a decreasing trend in the prevalence of alcohol-impaired drivers over time.

Persistent random walk model for transport trough thin slabs

We present a model for transport in multiply scattering media based on a three-dimensional generalization of the persistent random walk. The model assumes that photons move along directions that are parallel to the axes. Although this hypothesis is not realistic, it allows us to solve exactly the problem of multiple scattering propagation in a thin slab. Among other quantities, the transmission probability and the mean transmission time can be calculated exactly. Besides being completely solvable, the model could be used as a benchmark for approximation schemes to multiple light scattering.

Optimization of Radiation Dose and Image Quality in Musculoskeletal CT: Emphasis on Iterative Reconstruction Techniques (Part 1).

Computed tomography (CT) is a modality of choice for the study of the musculoskeletal system for various indications including the study of bone, calcifications, internal derangements of joints (with CT arthrography), as well as periprosthetic complications. However, CT remains intrinsically limited by the fact that it exposes patients to ionizing radiation. Scanning protocols need to be optimized to achieve diagnostic image quality at the lowest radiation dose possible. In this optimization process, the radiologist needs to be familiar with the parameters used to quantify radiation dose and image quality. CT imaging of the musculoskeletal system has certain specificities including the focus on high-contrast objects (i.e., in CT of bone or CT arthrography). These characteristics need to be taken into account when defining a strategy to optimize dose and when choosing the best combination of scanning parameters. In the first part of this review, we present the parameters used for the evaluation and quantification of radiation dose and image quality. In the second part, we discuss different strategies to optimize radiation dose and image quality at CT, with a focus on the musculoskeletal system and the use of novel iterative reconstruction techniques.