Population pharmacokinetic study to evaluate dosing strategies of imipenem in neonates and infants

Objective: Imipenem is a broad spectrum antibiotic used to treat severe infections in critically ill patients. Imipenem pharmacokinetics (PK) was evaluated in a cohort of neonates treated in the Neonatal Intensive Care Unit of the Lausanne University Hospital. The objective of our study was to identify key demographic and clinical factors influencing imipenem exposure in this population. Method: PK data from neonates and infants with at least one imipenem concentration measured between 2002 and 2013 were analyzed applying population PK modeling methods. Measurement of plasma concentrations were performed upon the decision of the physician within the frame of a therapeutic drug monitoring (TDM) programme. Effects of demographic (sex, body weight, gestational age, postnatal age) and clinical factors (serum creatinine as a measure of kidney function; co-administration of furosemide, spironolactone, hydrochlorothiazide, vancomycin, metronidazole and erythromycin) on imipenem PK were explored. Model-based simulations were performed (with a median creatinine value of 46 μmol/l) to compare various dosing regimens with respect to their ability to maintain drug levels above predefined minimum inhibitory concentrations (MIC) for at least 40 % of the dosing interval. Results: A total of 144 plasma samples was collected in 68 neonates and infants, predominantly preterm newborns, with median gestational age of 27 weeks (24 - 41 weeks) and postnatal age of 21 days (2 - 153 days). A two-compartment model best characterized imipenem disposition. Actual body weight exhibited the greatest impact on PK parameters, followed by age (gestational age and postnatal age) and serum creatinine on clearance. They explain 19%, 9%, 14% and 9% of the interindividual variability in clearance respectively. Model-based simulations suggested that 15 mg/kg every 12 hours maintain drug concentrations over a MIC of 2 mg/l for at least 40% of the dosing interval during the first days of life, whereas neonates older than 14 days of life required a dose of 20 mg/kg every 12 hours. Conclusion: Dosing strategies based on body weight and post-natal age are recommended for imipenem in all critically ill neonates and infants. Most current guidelines seem adequate for newborns and TDM should be restricted to some particular clinical situations.

A evolução da balança analítica

This work intends to describe the historical evolution of the balance based on its technical improvement. This instrument has always been used for commercial and industrial purposes, but its value in research and chemistry was only recognized much later. The classical balance was the two-pan model for about 40 centuries, but when its importance in chemistry was established, particularly beginning at the end of the XVIIIth century, many improvements were made in order to increase sensitivity and shorten the weighing procedure. The balance design greatly changed along the XXth century: the classical two-pan models were replaced by one-pan balances that were replaced by electronic instruments.

Speed of travelling fronts: Two-dimensional and ballistic dispersal probability distributions

The speed of traveling fronts for a two-dimensional model of a delayed reactiondispersal process is derived analytically and from simulations of molecular dynamics. We show that the one-dimensional (1D) and two-dimensional (2D) versions of a given kernel do not yield always the same speed. It is also shown that the speeds of time-delayed fronts may be higher than those predicted by the corresponding non-delayed models. This result is shown for systems with peaked dispersal kernels which lead to ballistic transport

Pencil grip : a descriptive model and four empirical studies

Previous studies on pencil grip have typically dealt with the developmental aspects in young children while handwriting research is mainly concerned with speed and legibility. Studies linking these areas are few. Evaluation of the existing pencil grip studies is hampered by methodological inconsistencies. The operational definitions of pencil grip arerational but tend to be oversimplified while detailed descriptors tend to be impractical due to their multiplicity. The present study introduces a descriptive two-dimensional model for the categorisation of pencil grip suitable for research applications in a classroom setting. The model is used in four empirical studies of children during the first six years of writing instruction. Study 1 describes the pencil grips observed in a large group of pupils in Finland (n = 504). The results indicate that in Finland the majority of grips resemble the traditional dynamic tripod grip. Significant genderrelated differences in pencil grip were observed. Study 2 is a longitudinal exploration of grip stability vs. change (n = 117). Both expected and unexpected changes were observed in about 25 per cent of the children's grips over four years. A new finding emerged using the present model for categorisation: whereas pencil grips would change, either in terms of ease of grip manipulation or grip configuration, no instances were found where a grip would have changed concurrently on both dimensions. Study 3 is a cross-cultural comparison of grips observed in Finland and the USA (n = 793). The distribution of the pencil grips observed in the American pupils was significantly different from those found in Finland. The cross-cultural disparity is most likely related to the differences in the onset of writing instruction. The differences between the boys' and girls' grips in the American group were non-significant.An implication of Studies 2 and 3 is that the initial pencil grip is of foremost importance since pencil grips are largely stable over time. Study 4 connects the pencil grips to assessment of the mechanics of writing (n = 61). It seems that certain previously not recommended pencil grips might nevertheless be includedamong those accepted since they did not appear to hamper either fluency or legibility.

Toimintopohjainen ennustemalli palvelualan yritykselle

Kohdeorganisaatiossa on havaittu tarvetta kustannusten tarkemmalle ennustamiselle liiketoimintaympäristön ja palvelutarjooman muutosten seurauksena. Diplomityön päätavoitteena on selvittää, kuinka palvelualan yritykselle rakennetaan toimintopohjainen kustannusten ennustemalli. Päätavoitetta lähestytään selvittämällä mallin rakennusvaiheet, soveltuvuus kohdeorganisaatiolle ja siitä saatava lisäarvo. Tutkielmassa käytetään konstruktiivista tutkimusotetta. Malli pohjautuu toimintopohjaisen suunnittelun ja budjetoinnin suljetun silmukkamallin teoriaan. Empiriaosassa suoritetaan mallin rakentaminen vaiheittain. Työn tulokset osoittavat toimintopohjaisen suunnittelun ja budjetoinnin suljetun silmukkamallin soveltuvuuden kohdeorganisaation toimintojen mallinnukseen. Toimintopohjaisesta ennustemallista on saatavissa lisäarvoa budjetointiin ja skenaariotyöhön. Mallin avulla voidaan tarkastella budjetoinnin realistisuutta. Skenaariotyöstä voidaan saada tukea päätöksentekoon, koska erilaisten toimenpiteiden vaikutuksia voidaan arvioida resurssitarpeen ja kustannusten näkökulmasta.

Business Intelligence -ohjelmistot päätöksenteon tukena

Työn tavoitteena on tutkia Business Intelligence -ohjelmistojen käyttöä päätöksenteon tukena. Lisäksi tutkitaan näiden ohjelmistojen merkitystä yrityksille. Työssä tarkastellaan myös mahdollisia tulevaisuuden näkymiä. Työ on kirjallisuustyö, joka pohjautuu lähdeaineistoon. Työn tuloksena on huomattu, kuinka tärkeitä Business Intelligence -ohjelmistot ovat yritysten päätöksenteossa. Suuren tietomäärän vuoksi on tärkeää, että yrityksellä on työkalu, jonka avulla kaikki merkityksellinen tieto saadaan välitettyä päätöksentekijöille. Business Intelligence -ohjelmistot tuottavat monenlaisia analyyseja, joiden avulla voidaan tehdä onnistuneita päätöksiä. Mitä tarkempia analyyseja tehdään, sitä enemmän voidaan myös saavuttaa kilpailuetua. Business Intelligence -ohjelmistojen avulla yrityksillä on mahdollisuus saavuttaa monia erilaisia hyötyjä. Hyötyjen mittaaminen on kuitenkin haastavaa, koska osa hyödyistä on aineettomia. Hyötyjen ja liikearvon mittaamiseen on kehitetty mittareita, joiden avulla on tarkoitus pystyä perustelemaan Business Intelligence -ohjelmistoihin investointia. Tulevaisuudessa Business Intelligence -ohjelmistojen merkitys yrityksille kasvaa. Yritysten muuttuvia tarpeita varten kehitetään uudenlaisia Business Intelligence -sovelluksia. Teknologia ja ohjelmistojen innovatiivinen käyttö muokkaavat BI-ohjelmistoja tehokkaammiksi. Jatkuva uusien sovellusten kehittäminen luo myös haasteita ennen niiden laajempaa käyttöönottoa.

Analysis and validation of space averaged drag model for numerical simulations of gas-solid flows in fluidized beds

This thesis presents an approach for formulating and validating a space averaged drag model for coarse mesh simulations of gas-solid flows in fluidized beds using the two-fluid model. Proper modeling for fluid dynamics is central in understanding any industrial multiphase flow. The gas-solid flows in fluidized beds are heterogeneous and usually simulated with the Eulerian description of phases. Such a description requires the usage of fine meshes and small time steps for the proper prediction of its hydrodynamics. Such constraint on the mesh and time step size results in a large number of control volumes and long computational times which are unaffordable for simulations of large scale fluidized beds. If proper closure models are not included, coarse mesh simulations for fluidized beds do not give reasonable results. The coarse mesh simulation fails to resolve the mesoscale structures and results in uniform solids concentration profiles. For a circulating fluidized bed riser, such predicted profiles result in a higher drag force between the gas and solid phase and also overestimated solids mass flux at the outlet. Thus, there is a need to formulate the closure correlations which can accurately predict the hydrodynamics using coarse meshes. This thesis uses the space averaging modeling approach in the formulation of closure models for coarse mesh simulations of the gas-solid flow in fluidized beds using Geldart group B particles. In the analysis of formulating the closure correlation for space averaged drag model, the main parameters for the modeling were found to be the averaging size, solid volume fraction, and distance from the wall. The closure model for the gas-solid drag force was formulated and validated for coarse mesh simulations of the riser, which showed the verification of this modeling approach. Coarse mesh simulations using the corrected drag model resulted in lowered values of solids mass flux. Such an approach is a promising tool in the formulation of appropriate closure models which can be used in coarse mesh simulations of large scale fluidized beds.

From network pictures to network insight in solution business – the role of internal communication

Operating in business-to-business markets requires an in-depth understanding on business networks. Actions and reactions made to compete in markets are fundamentally based on managers‘ subjective perceptions of the network. However, an amalgamation of these individual perceptions, termed a network picture, to a common company level shared understanding on that network, known as network insight, is found to be a substantial challenge for companies. A company‘s capability to enhance common network insight is even argued to lead competitive advantage. Especially companies with value creating logics that require wide comprehension of and collaborating in networks, such as solution business, are necessitated to develop advanced network insight. According to the extant literature, dispersed pieces of atomized network pictures can be unified to a common network insight through a process of amalgamation that comprises barriers/drivers of multilateral exchange, manifold rationality, and recursive time. However, the extant body of literature appears to lack an understanding on the role of internal communication in the development of network insight. Nonetheless, the extant understanding on the amalgamation process indicates that internal communication plays a substantial role in the development of company level network insight. The purpose of the present thesis is to enhance understanding on internal communication in the amalgamation of network pictures to develop network insight in the solution business setting, which was chosen to represent business-to-business value creating logic that emphasizes the capability to understand and utilize networks. Thus, in solution business the role of succeeding in the amalgamation process is expected to emphasize. The study combines qualitative and quantitative research by means of various analytical methods including multiple case analysis, simulation, and social network analysis. Approaching the nascent research topic with differing perspectives and means provides a broader insight on the phenomenon. The study provides empirical evidence from Finnish business-to-business companies which operate globally. The empirical data comprise interviews (n=28) with managers of three case companies. In addition the data includes a questionnaire (n=23) collected mainly for the purpose of social network analysis. In addition, the thesis includes a simulation study more specifically achieved by means of agent based modeling. The findings of the thesis shed light on the role of internal communication in the amalgamation process, contributing to the emergent discussion of network insights and thus to the industrial marketing research. In addition, the thesis increases understanding on internal communication in the change process to solution business, a supplier‘s internal communication in its matrix organization structure during a project sales process, key barriers and drivers that influence internal communication in project sales networks, perceived power within industrial project sales, and the revisioning of network pictures. According to the findings, internal communication is found to play a substantial role in the amalgamation process. First, it is suggested that internal communication is a base of multilateral exchange. Second, it is suggested that internal communication intensifies and maintains manifold rationality. Third, internal communication is needed to explicate the usually differing time perspectives of others and thus it is suggested that internal communication has role as the explicator of recursive time. Furthermore, the role of an efficient amalgamation process is found to be emphasized in solutions business as it requires a more advanced network insight for cross-functional collaboration. Finally, the thesis offers several managerial implications for industrial suppliers to enhance the amalgamation process when operating in solution business.

Gas-solid two-phase flow in the riser of circulating fluidized beds: mathematical modelling and numerical simulation

A mathematical model is developed for gas-solids flows in circulating fluidized beds. An Eulerian formulation is followed based on the two-fluids model approach where both the fluid and the particulate phases are treated as a continuum. The physical modelling is discussed, including the formulation of boundary conditions and the description of the numerical methodology. Results of numerical simulation are presented and discussed. The model is validated through comparison to experiment, and simulation is performed to investigate the effects on the flow hydrodynamics of the solids viscosity.

Valmistavan tehtaan tuotannon tehostaminen reaaliaikaisen tiedon avulla

Teollinen toimintaympäristö on muuttunut globalisaation seurauksena. Sisäisten ja ulkoisten asiakkaiden vaatimukset ovat entistä haastavampia toimitusajan, laadun ja kustannusten suhteen. Yritysten on automatisoitava toimintoja, jotta voidaan saavuttaa kilpailuetua ja parantaa yrityksen tehokkuutta. Diplomityön tarkoitus on kirjallisuus- ja vertailututkimuksen yhteenvetona koostaa asiakasyrityksen tarpeisiin soveltuva toimintomalli reaaliaikaisen tiedon hyödyntä-miseen valmistavan tehtaan tuotannon tehostamisessa. Kirjallisuustutkimusten avulla pyritään analysoimaan valmistavan teollisuuden erityispiirteet toimintaympäristön osalta, kartoittamaan soveltuvin teknologia haastavaan toimintaympäristöön sekä löytää keinot kuinka reaaliaikaista tietoa hyödynnetään tuotannon tehokkuuden toteutumisessa. Vertailututkimuksessa analysoidaan kahta reaaliaikaista tietoa toiminnoissaan hyödyntävää yritystä, joiden tuloksia verrataan kirjallisuustutkimuksen aineistoon. Työn soveltavassa osuudessa luotiin toimintomalli asiakasyrityksen tarpeisiin, huomioiden tehtaan toiminnot kokonaisuutena. Toimintomallin avulla yritys pystyy toteuttamaan reaaliaikaisen tiedon keräämisen sekä hyödyntämisen yrityksen toi-minnoista. Toimintomallin toimivuus todettiin soveltamalla pilot-projekti asiakasyrityksen tuotantoon ja analysoitiin saavutettuja tuloksia haastattelujen sekä kvalitatiivisten tulosten perusteella. Työn tutkimukset osoittivat haasteet valmistavan teollisuuden toimintaympäristön ja automaatioteknologian soveltamisessa. Yritysten tulee suunnitteella toimintamallin kokonaisuus ja pohtia järjestelmän toimivuutta ongelmatilanteissa. Reaaliaikaisen tiedonkeruun soveltaminen onnistuneesti mahdollistaa hyötyjä monella tapaa. Merkittävimmät ovat tehokkuuden kehittyminen toimintojen nopeutumisena sekä resurssisäästöt toimintojen automatisoinnin johdosta. Reaaliaikaista tietoa voidaan hyödyntää myös suorituskyvyn johtamisessa mittariston avulla.

A new model for the population pharmacokinetics of didanosine in healthy subjects

Didanosine (ddI) is a component of highly active antiretroviral therapy drug combinations, used especially in resource-limited settings and in zidovudine-resistant patients. The population pharmacokinetics of ddI was evaluated in 48 healthy volunteers enrolled in two bioequivalence studies. These data, along with a set of co-variates, were the subject of a nonlinear mixed-effect modeling analysis using the NONMEM program. A two-compartment model with first order absorption (ADVAN3 TRANS3) was fitted to the serum ddI concentration data. Final pharmacokinetic parameters, expressed as functions of the co-variates gender and creatinine clearance (CL CR), were: oral clearance (CL = 55.1 + 240 x CL CR + 16.6 L/h for males and CL = 55.1 + 240 x CL CR for females), central volume (V2 = 9.8 L), intercompartmental clearance (Q = 40.9 L/h), peripheral volume (V3 = 62.7 + 22.9 L for males and V3 = 62.7 L for females), absorption rate constant (Ka = 1.51/h), and dissolution time of the tablet (D = 0.43 h). The intraindividual (residual) variability expressed as coefficient of variation was 13.0%, whereas the interindividual variability of CL, Q, V3, Ka, and D was 20.1, 75.8, 20.6, 18.9, and 38.2%, respectively. The relatively high (>30%) interindividual variability for some of these parameters, observed under the controlled experimental settings of bioequivalence trials in healthy volunteers, may result from genetic variability of the processes involved in ddI absorption and disposition.

Why to invest more in women's football for your brand and your business?

The aim of this master’s thesis is to study the role of sponsorship in the business value of companies and clubs. In order to achieve this goal, the French women’s football context is studied. The main research question is formulated as follows: What is the business value in sport sponsorship? The literature and theory part consists of three chapters that clearly follow the theoretical framework: from the sport sponsorship to the sponsor brand, from the sponsor brand to the brand equity, from the brand equity to the business value. The empirical part of the master’s thesis is based on qualitative research method. Face-to-face interviews were conducted with 4 participants who are Sponsorship Manager or General Manager of French women’s football clubs or sponsors and thus considered as specialists of the study context. The results of the study show that the planning process, the objectives, the sponsor brand, the brand equity components such as the customer behaviour, the economic, financial and immaterial values have positive impacts on the business value in sport sponsorship in the French women’s football context.

Variational Ensemble Kalman Filtering in Hydrology

The current thesis manuscript studies the suitability of a recent data assimilation method, the Variational Ensemble Kalman Filter (VEnKF), to real-life fluid dynamic problems in hydrology. VEnKF combines a variational formulation of the data assimilation problem based on minimizing an energy functional with an Ensemble Kalman filter approximation to the Hessian matrix that also serves as an approximation to the inverse of the error covariance matrix. One of the significant features of VEnKF is the very frequent re-sampling of the ensemble: resampling is done at every observation step. This unusual feature is further exacerbated by observation interpolation that is seen beneficial for numerical stability. In this case the ensemble is resampled every time step of the numerical model. VEnKF is implemented in several configurations to data from a real laboratory-scale dam break problem modelled with the shallow water equations. It is also tried in a two-layer Quasi- Geostrophic atmospheric flow problem. In both cases VEnKF proves to be an efficient and accurate data assimilation method that renders the analysis more realistic than the numerical model alone. It also proves to be robust against filter instability by its adaptive nature.

The roles and tasks of salespeople in Software-as-a-Service company's value-based sales process

Recent research in relationships marketing and sales and sales management emphasizes companies’ ability to create customer value as a core of all business-to-business relationships. The role of individual salespeople in business relation-ships is commonly acknowledged, but has been largely neglected in extant literature. This study offers especially more detailed perspective on salespeople’s roles and tasks in business-to-business value-based sales process. It focuses especially on Software-as-a-Service business environment. The objective of the study is to find out how salespeople can create value in Software-as-a-Service value-based sales process. It determines value-based sales process, salespeople’s roles and tasks in it, and combines value assessment in to process. The results indicate that salespeople have to adapt different selling roles and tasks in Software-as-a-Service value-based sales process to be able to support the customer’s value-in-use experience. The process itself is highly complex, consisting of multiple facets and selling behaviors, and involves relevant actors from both parties of relationship. The study concludes with a discussion of possibilities that provide interesting aspects for future research.

Motivational model of problem drinking for men and women /

This thesis tested a path model of the relationships of reasons for drinking and reasons for limiting drinking with consumption of alcohol and drinking problems. It was hypothesized that reasons for drinking would be composed of positively and negatively reinforcing reasons, and that reasons for limiting drinking would be composed of personal and social reasons. Problem drinking was operationalized as consisting of two factors, consumption and drinking problems, with a positive relationship between the two. It was predicted that positively and negatively reinforcing reasons for drinking would be associated with heavier consumption and, in turn, more drinking problems, through level of consumption. Negatively reinforcing reasons were also predicted to be associated with drinking problems directly, independent of level of consumption. It was hypothesized that reasons for limiting drinking would be associated with lower levels of consumption and would be related to fewer drinking problems, through level of consumption. Finally, among women, reasons for limiting drinking were expected to be associated with drinking problems directly, independent of level of consumption. The sample, was taken from the second phase of the Niagara Young Aduh Health Study, a community sample of young adult men and women. Measurement models of reasons for drinking, reasons for limiting drinking, and problem drinking were tested using Confirmatory Factor Analysis. After adequate fit of each measurement model was obtained, the complete structural model, with all hypothesized paths, was tested for goodness of fit. Cross-group equality constraints were imposed on all models to test for gender differences. The results provided evidence supporting the hypothesized structure of reasons for drinking and problem drinking. A single factor model of reasons for limiting drinking was used in the analyses because a two-factor model was inadequate. Support was obtained for the structural model. For example, the resuhs revealed independent influences of Positively Reinforcing Reasons for Drinking, Negatively Reinforcing Reasons for Drinking, and Reasons for Limiting Drinking on consumption. In addition. Negatively Reinforcing Reasons helped to account for Drinking Problems independent of the amount of alcohol consumed. Although an additional path from Reasons for Limiting Drinking to Drinking Problems was hypothesized for women, it was of marginal significance and did not improve the model's fit. As a result, no sex differences in the model were found. This may be a result of the convergence of drinking patterns for men and women. Furthermore, it is suggested that gender differences may only be found in clinical samples of problem drinkers, where the relative level of consumption for women and men is similar.