Durante a cirurgia de revascularização do miocárdio com circulação extracorpórea e hipotermia (CEC-H) ocorre alteração na efetividade do propofol e na sua farmacocinética realizada a partir das concentrações plasmáticas do propofol total no decurso do tempo. A ligação do propofol à proteína plasmática parece estar alterada em consequência de diversos fatores incluindo a hemodiluição e a heparinização que ocorre no início da circulação extracorpórea, uma vez que se reportou anteriormente que a concentração plasmática do propofol livre aumentou durante a realização da circulação extracorpórea normotérmica. Por outro lado, a infusão alvo controlada é recomendada para manter a concentração plasmática do propofol equivalente ao alvo de 2 &#181g/mL durante a intervenção cirúrgica com CEC-H. Se alterações significativas na hipnose do propofol ocorrem nesses pacientes, então o efeito aumentado desse agente hipnótico poderia estar relacionado à redução na extensão da ligação do fármaco as proteínas plasmáticas; entretanto, o assunto ainda permanece em discussão e necessita de investigações adicionais. Assim, o objetivo do estudo foi investigar as concentrações plasmáticas de propofol livre em pacientes durante a revascularização do miocárdio com e sem o procedimento de CEC-H através da abordagem PK-PD. Dezenove pacientes foram alocados e estratificados para realização de cirurgia de revascularização do miocárdio com circulação extracorpórea (CEC-H, n=10) ou sem circulação extracorpórea (NCEC, n=9). Os pacientes foram anestesiados com sufentanil e propofol alvo de 2 &#181g/mL. Realizou-se coleta seriada de sangue para estudo farmacocinético e o efeito foi monitorado através do índice bispectral (BIS) para medida da profundidade da hipnose no período desde a indução da anestesia até 12 horas após o término da infusão de propofol, em intervalos de tempo pré-determinados no protocolo de estudo. As concentrações plasmáticas foram determinadas através de método bioanalítico pela técnica de cromatografia líquida de alta eficiência. A farmacocinética foi investigada a partir da aplicação do modelo aberto de dois compartimentos, PK Solutions v. 2. A análise PK-PD foi realizada no Graph Pad Prisma v.5.0 após a escolha do modelo do efeito máximo (EMAX sigmóide, slope variável). Os dados foram analisados utilizando o Prisma v. 5.0, p<0,05, significância estatística. As concentrações plasmáticas de propofol total foram comparáveis nos dois grupos (CEC-H e NCEC); entretanto o grupo CEC-H evidenciou aumento na concentração do propofol livre de 2 a 5 vezes em função da redução na ligação do fármaco às proteínas plasmáticas. A farmacocinética do propofol livre mostrou diferença significativa entre os grupos no processo de distribuição pelo prolongamento da meia vida e aumento do volume aparente, e no processo de eliminação em função do aumento na depuração plasmática e redução na meia vida biológica no grupo CEC-H. A escolha do modelo EMAX sigmóide, slope variável foi adequada uma vez que se evidenciou alta correlação entre os valores do índice bispectral e as concentrações plasmáticas do propofol livre (r2>0.90, P<0.001) para os pacientes investigados. / During coronary artery bypass grafting (CABG) surgery with cardiopulmonary bypass (CPB) profound changes occur on propofol effect and on kinetic disposition related to total drug plasma measurements in these patients. It was reported that drug plasma binding could be altered as a consequence of hemodilution and heparinization before starts CPB since free propofol plasma levels was increased by twice under normothermic procedure. In addition, the target controlled infusion (TCI) is recommended to maintain propofol plasma concentration (2 &#181g/mL) during CABG CPB-H intervention. However, whether significant changes that occur in propofol hypnosis in these patients could be related to the reduction on the extension of drug plasma binding remain unclear and under discussion until now. Then, the objective of this study was to investigate propofol free plasma levels in patients undergoing CABG with and without CPB by a pharmacokinetics-pharmacodynamics (PK-PD) approach. Nineteen patients were scheduled for on-pump coronary artery bypass grafting (CABG-CPB, n=10) or off-pump coronary artery bypass grafting (OPCABG, n=9) were anesthetized with sufentanil and propofol TCI (2 &#181g/mL). Blood samples were collected for drug plasma measurements and BIS were applied to access the depth of hypnosis from the induction of anesthesia up to 12 hours after the end of propofol infusion, at predetermined intervals. Plasma drug concentrations were measured using high-performance liquid chromatography, followed by a propofol pharmacokinetic analysis based on two compartment open model, PK Solutions v.2; PK-PD analysis was performed by applying EMAX model, sigmoid shape-variable slope and data were analyzed using Prisma v. 5.0, considering p<0.05 as significant difference between groups. The total propofol plasma concentrations were comparable in both groups during CABG; however it was shown in CPB-group significant increases in propofol free plasma concentration by twice to fivefold occur as a consequence of drug plasma protein binding reduced in these patients. Pharmacokinetics of free propofol in CPB-H group compared to OPCAB group based on two compartment open model was significantly different by the prolongation of distribution half-life, increases on plasma clearance, and biological half-life shortened. In addition, the kinetic disposition of propofol changes in a different manner considering free drug levels in the CPB-H group against OPCAB group as follows: prolongation of distribution half-life and increases on volume of distribution, remaining unchanged biological half-life in spite of plasma clearance increased. BIS values showed a strong correlation with free drug levels (r2>0.90, P<0.001) in CPB-H group and also in OPCAB group by the chosen EMAX model sigmoid shape-variable slope analyzed by GraphPad Prisma v.5.0.

Tuberculosis, the leading cause of death by a single infection disease caused by bacteria, requires long treatments and the bacteria are prone to develop drug resistance. Therefore, new efficient treatment regiments needs developing, which requires new tools for drug development. A major reason for discontinuance of a drug under development is undesired pharmacokinetic properties. Therefore, it is important to have early information of this, preferably the first time the drug is tested in animals. The first in vivo pharmacokinetic experiment is often done in mice and the only information present at this stage are often in vitro values and physicochemical properties. Physiological-based pharmacokinetic modelling can be used to extrapolate from in vitro to in vivo values. From this, the first in vivo pharmacokinetic experiment can be designed, often with the goal of reducing the amount of mice. This goal is one of the three R.s and it is called Reduction. To explore the Reduction of an experiment population pharmacokinetic modelling can be utilized via exploration of the imprecision, bias and probability of an informative experiment to evaluate if a design meets the goal of Reduction. In this report a recommendation of the first in vivo pharmacokinetic experiment is presented. This is based on in vitro values and physicochemical properties that are common in anti-tuberculosis drugs. If the probability of an informative experiment is critical, a terminal sampling of 40 mice is recommended. If imprecision and bias are necessary, zipper sampling of 10 mice is recommended.

Uppsatsen “Nuförtiden får man ju inte säga ett skit” ‘ är en debattanalys av Europaparlamentarikers kritik gentemot politisk korrekthet i EU. Studien tar ett avstamp i tidigare forskning berörande populism, euroscepticism, GAL-TAN dimensionen, och applicerar detta till ett inte tidigare tillämpat teoretiskt perspektiv för denna typ av forskning, politisk korrekthet. Syftet med studien är att beskriva och kategorisera de huvudteser samt argument som förs i kritiken gentemot ett påstått PK-etablissemang i EU:s viktigaste och enda demokratiskt valda organ. De huvudteser som återfanns i argumentationen var följande: att EU består av ett etablissemang som underminerar EU-medborgarnas sanna vilja med PK-het, att EU är i politisk kris då yttrandefriheten förtrycks, att EU bär på en dubbelmoral av vilka åsikter som får uttryckas och inte, att EUs överstatlighet försummar nationernas egna intressen, och att PK- etablissemanget i EU förvrider den objektiva sanningen och kallar sina motståndarna för populister likt ett retoriskt vapen. Det nytillämpade teoretiska perspektivet, PK, bidrar med ett nytt synsätt på den politiska debatten och de dimensioner av sociala normer som tycks styra det politiska talrummet.

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Humour has for a long time been regarded as something unproblematic that in general shouldn’t be taken seriously, and humour research has mainly focused its positive functions and effects. However, humour is indeed a social and discursive practise that, just like others, have social implications. The aim of this essay is, informed by an intersectional perspective, to problematize and critically examine stand-up comedy as discursive practise and to make visible how humour build upon dominating discourses in society. The aim is also to examine the self-contradictory dimension of the jokes. In a critical discourse analysis of Özz Nûjen’s show Dålig stämning (2013), using PC (political correctness) as an overall analytical framework, the analytical categories ‘women’ as well as ‘ethnicity and culture’ are focused. My conclusion is that in all cases of Nûjen’s prerogative of interpretation, ‘stupidity’, as the lowest common denominator, sticks to symbols, bodies and phenomenon that are associated with something deviant or negative. By what is not expressed, a white, normative Swedish PC-identity is constructed as the abstract, preferable subject. Nûjen’s stand-up comedy, i.a. in expressions of self-contradiction, proves to mainly reinforce social norms. Consequently, negative preconceptions and biased representations of reality are cemented. Though Nûjen does contribute to sociocultural change to some extent, the elaborations of the jokes in most cases prove to sustain the social order. A renegotiation of identities is therefore made strictly limited. However, in one case, Nûjen does challenge the notion of identities as fixed and essential, when renegotiating the master status and construction of “The ethnical Other woman”.

Introduction: No Fixed-Dose Combination (FDC) formulations currently exist for pediatric tuberculosis (TB) treatment. Earlier work implemented, in the software NONMEM, a rational method for optimizing design and individualization of pediatric anti-TB FDC formulations based on patient body weight, but issues with parameter estimation, dosage strata heterogeneity and representative pharmacokinetics remained. Aim: To further develop the rational model-based methodology aiding the selection of appropriate FDC formulation designs and dosage regimens, in pediatric TB treatment. Materials and Methods: Optimization of the method with respect to the estimation of body weight breakpoints was sought. Heterogeneity of dosage groups with respect to treatment efficiency was sought to be improved. Recently published pediatric pharmacokinetic parameters were implemented and the model translated to MATLAB, where also the performance was evaluated by stochastic estimation and graphical visualization. Results: A logistic function was found better suited as an approximation of breakpoints. None of the estimation methods implemented in NONMEM were more suitable than the originally used FO method. Homogenization of dosage group treatment efficiency could not be solved. MATLAB translation was successful but required stochastic estimations and highlighted high densities of local minima. Representative pharmacokinetics were successfully implemented. Conclusions: NONMEM was found suboptimal for the task due to problems with discontinuities and heterogeneity, but a stepwise method with representative pharmacokinetics were successfully implemented. MATLAB showed more promise in the search for a method also addressing the heterogeneity issue.

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Abstract This study aims to clarify the early development stages of technology intensive companies. The current literature does not offer an extensive review of stage perspectives for company growth – the overall picture of the field is somewhat vague. The evolution of this field remains unclear as well as the current state. Further, recent empirical stage models focusing on technology intensive companies have not been delineated. As companies move through their early stages, they face events which contribute to or detract from their aim. A study focusing on these events may provide fresh viewpoints for understanding the management processes. This study seeks to clarify how the literature describes the early stages of technology intensive companies, and what viewpoints are highlighted by the management as a company progresses through these sequences. This retrospective multiple case study clarifies the topic with two meta-analyses and a sequential incident study carried out in ten young technology intensive companies in Finland and Thailand. First, well covered areas, trends, and ideas for fresh approaches are studied through a meta-analysis of the past 60 years of literature focusing on stages of development. Based on recent empirical studies, a sequential self assessment framework is formed. Second, it is studied whether the case study methodology could be utilised to further clarify the early stages of technology intensive companies. Third, the experiences of ten case companies are reflected through the framework in order to test the framework, and to study what viewpoints these cases reveal about the early stages of technology intensive companies. This study provided an extensive review of the research focusing on the stages of development. A four-stage framework was found applicable for a self-assessment of the early stages in technology intensive companies, while ten case studies and cross case analysis provided partial support for the framework. In addition, this study provided many potential fresh viewpoints for a theory related to the early stages of technology intensive companies. These viewpoints are considered here as starting points for further research, which is expected to provide sufficient evidence for further modification of the framework. / Tiivistelmä Tämän tutkimuksen tavoitteena on selkeyttää teknologiaintensiivisten yritysten varhaisia kehitysvaiheita. Kirjallisuus ei tarjoa kattavaa katsausta yrityksen kehitysvaiheita käsittelevästä tutkimuksesta – kokonaiskuva aiheesta jää jokseenkin epämääräiseksi samoin kuin alan kehitys ja nykytila. Lisäksi viimeaikaisten empiiristä aineistoa sisältävien vaihemallien tuloksia ei ole koottu yhteen. Varhaisissa kehitysvaiheissaan yritykset kohtaavat sekä tavoitteitaan edistäviä että estäviä tapahtumia. Tapahtumia tutkimalla on mahdollista nostaa esille tuoreita näkökulmia varhaisiin vaiheisiin liittyviin johtamisprosesseihin. Tämä tutkimus pyrkii selvittämään, kuinka teknologiayrityksen varhaiset kehitysvaiheet on kuvattu kirjallisuudessa ja mitä näkökulmia varhaisen kehityksen läpi käyneiden yritysten johto korostaa. Tämä takautuva monitapaustutkimus analysoi aihetta kahden meta-analyysin ja vaiheittain toteutetun kriittiset tapahtumat -menetelmän avulla. Tapaustutkimus suoritettiin kymmenessä suomalaisessa ja thaimaalaisessa yrityksessä. Ensiksi 60 edeltävää vuotta käsittävässä meta-analyysissä analysoitiin vaihemallien historia ja nykytila, trendit ja potentiaaliset ideat uusille lähestymistavoille. Viimeaikaisten empiiristen tutkimusten perusteella muodostettiin synteesi varhaisten kehitysvaiheiden itsearviointikehykseksi. Toiseksi tutkittiin voidaanko tapaustutkimusta hyödyntämällä edelleen selventää teknologiaintensiivisten yritysten varhaisia kehitysvaiheita. Kolmanneksi kymmenen tapausyrityksen kokemuksia peilattiin itsearviointikehykseen tarkoituksena testata kehystä ja analysoida mitä näkökulmia tapaukset paljastavat teknologiaintensiivisten yritysten varhaisista vaiheista. Tutkimus tarjosi laajan katsauksen yrityksen kehitysvaiheisiin keskittyvään tutkimuskenttään. Nelivaiheinen kehys todettiin soveltuvaksi varhaisten kehitysvaiheiden itsearviointiin teknologiaintensiivisissä yrityksissä – kymmenen tapausta ja näiden vertailu antoi osittaisen tuen tälle. Lisäksi tutkimus tarjosi useita uusia näkökulmia teknologiaintensiivisten yritysten varhaisia kehitysvaiheita käsittelevään teoriaan. Nämä näkökulmat toimivat lähtökohtana jatkotutkimuksille, joiden oletetaan tuovan riittävästi todistusaineistoa itsearviointikehyksen edelleenkehittämiseksi.