Supply Risk Management in Pharmaceutical

Fast development in the operating environment and fierce competition have driven companies to pursue efficiency and success through lean and global supply chains. At the same time overall uncertainty has increased in the business environment and supply chains have become a priority in risk management since their vulnerability may endanger business continuity. Although risk management should start at procurement strategy development phase, proactive contingency planning is also essential because it enables correct reaction and fast changes in process execution in the case of risk realization. This thesis is a case study conducted in the pharmaceutical industry where purchasing and materials management organizations face a number of challenges and limitations that have to be considered in supply risk management. The goal of the study was to discuss the operating environment, and identify and analyze supply risks and potential risk management practices. The study was concluded with suggestions for purchasing strategy development that take risk management considerations into account. This copy is the public version of the thesis.

Quantum magnetic deflagration in Mn12 acetate

We report controlled ignition of magnetization reversal avalanches by surface acoustic waves in a single crystal of Mn12 acetate. Our data show that the speed of the avalanche exhibits maxima on the magnetic field at the tunneling resonances of Mn12. Combined with the evidence of magnetic deflagration in Mn12 acetate [Y. Suzuki et al., Phys. Rev. Lett. 95, 147201 (2005)], this suggests a novel physical phenomenon: deflagration assisted by quantum tunneling.

A Thermodynamically Consistent Damage Model for Advanced Composites

A continuum damage model for the prediction of damage onset and structural collapse of structures manufactured in fiber-reinforced plastic laminates is proposed. The principal damage mechanisms occurring in the longitudinal and transverse directions of a ply are represented by a damage tensor that is fixed in space. Crack closure under load reversal effects are taken into account using damage variables established as a function of the sign of the components of the stress tensor. Damage activation functions based on the LaRC04 failure criteria are used to predict the different damage mechanisms occurring at the ply level. The constitutive damage model is implemented in a finite element code. The objectivity of the numerical model is assured by regularizing the dissipated energy at a material point using Bazant’s Crack Band Model. To verify the accuracy of the approach, analyses ofcoupon specimens were performed, and the numerical predictions were compared with experimental data

Glicoproteína-P, resistência a múltiplas drogas (MDR) e relação estrutura-atividade de moduladores

Multidrug resistance, MDR is a major obstacle for cancer chemotherapy. MDR can be reversed by drugs that vary in their chemical structure and main biological activity. Many efforts have been done to overcome MDR based on studies of structure-activity relationships and in this review we summarize some aspects of MDR mediated by P-glycoprotein (P-gp), as the most experimentally and clinically tested form of drug resistance. The most significant MDR mechanisms revealed until now are shortly discussed. Physicochemical and structural properties of MDR modulators, measures of the MDR reversal, and QSAR studies are included.

Pienten osakeyhtiöiden verosuunnittelu - empiirinen tutkimus

Tutkimuksen aiheeksi valittiin pienten osakeyhtiöiden verosuunnittelu. Tutkimuksen teoreettinen viitekehys perustui aiempaan laskentatoimen empiiriseen verotutkimukseen sekä laskentatoimen kontingenssiteoreettiseen pk-yritystutkimukseen. Tutkimusaineistoa kerättiin kyselytutkimuksella sekä tilinpaatostietokannasta Voitto+. Kyselytutkimukseen valittiin satunnaisotannalla osakeyhtiötä Etelä Suomen läänistä, joiden liikevaihto oli välillä 1 10 milj. euroa. Kyselytutkimukseen vastasi 216 yritystä, jolloin vastausprosentiksi saatiin 21,3. Kerättyä tutkimusaineistoa analysoitiin kvantitatiivisin menetelmin. Pääasiallisina analysointimenetelminä käytettiin pääkomponentti-, klusteri- ja regressioanalyysiä. Tutkimuksen tavoitteeksi asetettiin kokonaiskuvan muodostaminen pienten osakeyhtiöiden verosuunnittelusta, verosuunnittelun asemointi osaksi yrityksen taloushallintoa sekä yritysten erilaisia verosuunnittelustrategioita selittävien tekijöiden tunnistaminen. Tutkimusaineistosta kyettiin tunnistamaan pääkomponenttianalyysillä neljä erilaista verosuunnitteluorientaatiota: valistunut, resursseja panostava, veroa minimoiva sekä vastuuta ulkoistava. Verosuunnitteluorientaatioita kuvaavien muuttujien avulla yritykset jaettiin klusterianalyysilla neljään ryhmään. Yritykset nimettiin ryhmien luonteidensa mukaisesti verosuunnittelun osalta vastuun ulkoistajiksi, veron minimoijiksi, veroneutraaleiksi sekä valistuneiksi. Verosuunnitteluvastuuta ulkoistavien yritysten ryhmään kuului n. 57 % kyselyyn vastanneista yrityksistä. Tulos osoittaa sen, että yritykset ovat verosuunnittelun osalta paljolti riippuvaisia taloushallinnon sidosryhmistä, tilitoimistoista sekä tilintarkastajista. Tulosta voidaan tulkita myös niin, että taloushallinnon sidosryhmien ammattitaito verosuunnittelun osalta on keskeisessä roolissa, kun arvioidaan, miten yritysten välinen tasapuolisuus verotuksen osalta käytännössä toteutuu. Yritysten erilaisia verosuunnitteluorientaatioita, jotka kuvasivat yritysten verosuunnittelustrategioita, ei kyetty kvantitatiivisilla analyyseilla selittämään samoilla muuttujilla kuin yritysten erilaisia johdon laskentatoimen käytänteitä. Tätä havaintoa tulkittiin siten, että vaikka verosuunnittelu on selkeästi osa yrityksen taloushallintoa, sen asema ei ole johdon laskentatoimen käytänteiden tavoin taloushallinnon ytimessä. Tutkimuksessa kyettiin tuottamaan tuloksia, jotka kontribuoivat aiempia laskentatoimen empiirisiä verotutkimuksia, ja joilla on uutuusarvoa käytännön toimijoiden näkökulmasta.

Spatial and Spectral Separability of Grasslands in the inner Turku Archipelago using Landsat Thematic Mapper Satellite Imagery

The present study investigates the spatial and spectral discrimination potential for grassland patches in the inner Turku Archipelago using Landsat Thematic Mapper satellite imagery. The spatial discrimination potential was computed through overlay analysis using official grassland parcel data and a hypothetical 30 m resolution satellite image capturing the site. It found that Landsat TM imagery’s ability to retrieve pure or near-pure pixels (90% purity or more) from grassland patches smaller than 1 hectare was limited to 13% success, compared to 52% success when upscaling the resolution to 10 x 10 m pixel size. Additionally, the perimeter/area patch metric is proposed as a predictor for the suitability of the spatial resolution of input imagery. Regression analysis showed that there is a strong negative correlation between a patch’s perimeter/area ratio and its pure pixel potential. The study goes on to characterise the spectral response and discrimination potential for the five main grassland types occurring in the study area: recreational grassland, traditional pasture, modern pasture, fodder production grassland and overgrown grassland. This was done through the construction of spectral response curves, a coincident spectral plot and a contingency matrix as well as by calculating the transformed divergence for the spectral signatures, all based on training samples from the TM imagery. Substantial differences in spectral discrimination potential between imagery from the beginning of the growing season and the middle of summer were found. This is because the spectral responses for these five grassland types converge as the peak of the growing season draws nearer. Recreational grassland shows a consistent discrimination advantage over other grassland types, whereas modern pasture is most easily confused. Traditional pasture land, perhaps the most biologically valuable grassland type, can be spectrally discriminated from other grassland types with satisfactory success rates provided early growing season imagery is used.

IDEAS for Strategic Technology Management: Design of an electronically mediated scenario method

The age-old adage goes that nothing in this world lasts but change, and this generation has indeed seen changes that are unprecedented. Business managers do not have the luxury of going with the flow: they have to plan ahead, to think strategies that will meet the changing conditions, however stormy the weather seems to be. This demand raises the question of whether there is something a manager or planner can do to circumvent the eye of the storm in the future? Intuitively, one can either run on the risk of something happening without preparing, or one can try to prepare oneself. Preparing by planning for each eventuality and contingency would be impractical and prohibitively expensive, so one needs to develop foreknowledge, or foresight past the horizon of the present and the immediate future. The research mission in this study is to support strategic technology management by designing an effective and efficient scenario method to induce foresight to practicing managers. The design science framework guides this study in developing and evaluating the IDEAS method. The IDEAS method is an electronically mediated scenario method that is specifically designed to be an effective and accessible. The design is based on the state-of-the-art in scenario planning, and the product is a technology-based artifact to solve the foresight problem. This study demonstrates the utility, quality and efficacy of the artifact through a multi-method empirical evaluation study, first by experimental testing and secondly through two case studies. The construction of the artifact is rigorously documented as justification knowledge as well as the principles of form and function on the general level, and later through the description and evaluation of instantiations. This design contributes both to practice and foundation of the design. The IDEAS method contributes to the state-of-the-art in scenario planning by offering a light-weight and intuitive scenario method for resource constrained applications. Additionally, the study contributes to the foundations and methods of design by forging a clear design science framework which is followed rigorously. To summarize, the IDEAS method is offered for strategic technology management, with a confident belief that it will enable gaining foresight and aid the users to choose trajectories past the gales of creative destruction and off to a brighter future.

Studies on Neuromuscular Blocking Agents and Their Antagonists During Anaesthesia

Neuromuscular blocking agents (NMBAs) are widely used in clinical anaesthesia and emergency medicine. Main objectives are to facilitate endotracheal intubation and to allow surgery by reducing muscle tone and eliminating sudden movements, which may otherwise lead to trauma and complications. The most commonly used NMBAs are non-depolarizing agents with a medium duration of action, such as rocuronium and cisatracurium. They bind to the acetylcholine receptors in the neuromuscular junction, thus inhibiting the depolarization of the postsynaptic (muscular) membrane, which is a prerequisite for muscle contraction to take place. Previously, it has been assumed that nitrous oxide (N2O), which is commonly used in combination with volatile or intravenous anaesthetics during general anaesthesia, has no effect on NMBAs. Several studies have since claimed that N2O in fact does increase the effect of NMBAs when using bolus administration of the relaxant. The effect of N2O on the infusion requirements of two NMBAs (rocuronium and cisatracurium) with completely different molecular structure and pharmacological properties was assessed. A closed-loop feedback controlled infusion of NMBA with duration of at least 90 minutes at a 90% level of neuromuscular block was used. All patients received total intravenous anaesthesia (TIVA) with propofol and remifentanil. In both studies the study group (n=35) received N2O/Oxygen and the control group (n=35) Air/Oxygen. There were no significant differences in the mean steady state infusion requirements of NMBA (rocuronium in Study I; cisatracurium in Study II) between the groups in either study. In Study III the duration of the unsafe period of recovery after reversal of rocuronium-induced neuromuscular block by using neostigmine or sugammadex as a reversal agent was analyzed. The unsafe period of recovery was defined as the time elapsed from the moment of no clinical (visual) fade in the train-of-four (TOF) sequence until an objectively measured TOF-ratio of 0.90 was achieved. The duration of these periods were 10.3 ± 5.5 and 0.3 ± 0.3 min after neostigmine and sugammadex, respectively (P < 0.001). Study IV investigated the possible effect of reversal of a rocuronium NMB by sugammadex on depth of anaesthesia as indicated by the bispectral index and entropy levels in thirty patients. Sugammadex did not affect the level of anaesthesia as determined by EEG-derived indices of anaesthetic depth such as the bispectral index and entropy.

Application of Computational Fluid Dynamics in Modeling Blood Flow in Human Thoracic Aorta

The aim of this study was to simulate blood flow in thoracic human aorta and understand the role of flow dynamics in the initialization and localization of atherosclerotic plaque in human thoracic aorta. The blood flow dynamics in idealized and realistic models of human thoracic aorta were numerically simulated in three idealized and two realistic thoracic aorta models. The idealized models of thoracic aorta were reconstructed with measurements available from literature, and the realistic models of thoracic aorta were constructed by image processing Computed Tomographic (CT) images. The CT images were made available by South Karelia Central Hospital in Lappeenranta. The reconstruction of thoracic aorta consisted of operations, such as contrast adjustment, image segmentations, and 3D surface rendering. Additional design operations were performed to make the aorta model compatible for the numerical method based computer code. The image processing and design operations were performed with specialized medical image processing software. Pulsatile pressure and velocity boundary conditions were deployed as inlet boundary conditions. The blood flow was assumed homogeneous and incompressible. The blood was assumed to be a Newtonian fluid. The simulations with idealized models of thoracic aorta were carried out with Finite Element Method based computer code, while the simulations with realistic models of thoracic aorta were carried out with Finite Volume Method based computer code. Simulations were carried out for four cardiac cycles. The distribution of flow, pressure and Wall Shear Stress (WSS) observed during the fourth cardiac cycle were extensively analyzed. The aim of carrying out the simulations with idealized model was to get an estimate of flow dynamics in a realistic aorta model. The motive behind the choice of three aorta models with distinct features was to understand the dependence of flow dynamics on aorta anatomy. Highly disturbed and nonuniform distribution of velocity and WSS was observed in aortic arch, near brachiocephalic, left common artery, and left subclavian artery. On the other hand, the WSS profiles at the roots of branches show significant differences with geometry variation of aorta and branches. The comparison of instantaneous WSS profiles revealed that the model with straight branching arteries had relatively lower WSS compared to that in the aorta model with curved branches. In addition to this, significant differences were observed in the spatial and temporal profiles of WSS, flow, and pressure. The study with idealized model was extended to study blood flow in thoracic aorta under the effects of hypertension and hypotension. One of the idealized aorta models was modified along with the boundary conditions to mimic the thoracic aorta under the effects of hypertension and hypotension. The results of simulations with realistic models extracted from CT scans demonstrated more realistic flow dynamics than that in the idealized models. During systole, the velocity in ascending aorta was skewed towards the outer wall of aortic arch. The flow develops secondary flow patterns as it moves downstream towards aortic arch. Unlike idealized models, the distribution of flow was nonplanar and heavily guided by the artery anatomy. Flow cavitation was observed in the aorta model which was imaged giving longer branches. This could not be properly observed in the model with imaging containing a shorter length for aortic branches. The flow circulation was also observed in the inner wall of the aortic arch. However, during the diastole, the flow profiles were almost flat and regular due the acceleration of flow at the inlet. The flow profiles were weakly turbulent during the flow reversal. The complex flow patterns caused a non-uniform distribution of WSS. High WSS was distributed at the junction of branches and aortic arch. Low WSS was distributed at the proximal part of the junction, while intermedium WSS was distributed in the distal part of the junction. The pulsatile nature of the inflow caused oscillating WSS at the branch entry region and inner curvature of aortic arch. Based on the WSS distribution in the realistic model, one of the aorta models was altered to induce artificial atherosclerotic plaque at the branch entry region and inner curvature of aortic arch. Atherosclerotic plaque causing 50% blockage of lumen was introduced in brachiocephalic artery, common carotid artery, left subclavian artery, and aortic arch. The aim of this part of the study was first to study the effect of stenosis on flow and WSS distribution, understand the effect of shape of atherosclerotic plaque on flow and WSS distribution, and finally to investigate the effect of lumen blockage severity on flow and WSS distributions. The results revealed that the distribution of WSS is significantly affected by plaque with mere 50% stenosis. The asymmetric shape of stenosis causes higher WSS in branching arteries than in the cases with symmetric plaque. The flow dynamics within thoracic aorta models has been extensively studied and reported here. The effects of pressure and arterial anatomy on the flow dynamic were investigated. The distribution of complex flow and WSS is correlated with the localization of atherosclerosis. With the available results we can conclude that the thoracic aorta, with complex anatomy is the most vulnerable artery for the localization and development of atherosclerosis. The flow dynamics and arterial anatomy play a role in the localization of atherosclerosis. The patient specific image based models can be used to diagnose the locations in the aorta vulnerable to the development of arterial diseases such as atherosclerosis.

Application of electrokinetic Fenton process for the remediation of soil contaminated with HCB

Electrokinetic remediation coupled with Fenton oxidation, widely called as Electrokinetic Fenton process is a potential soil remediation technique used for low permeable soil. The applicability of the process has been proved with soil contaminated with a wide range of organic compounds from phenol to the most recalcitrant ones such as PAHs and POPs. This thesis summarizes the major findings observed during an Electrokinetic Fenton Process study conducted for the remediation of low permeable soil contaminated with HCB, a typical hydrophobic organic contaminant. Model low permeable soil, kaolin, was artificially contaminated with HCB and subjected to Electrokinetic Fenton treatments in a series of laboratory scale batch experiments. The use of cyclodextrins as an enhancement agent to mobilize the sorbed contaminant through the system was investigated. Major process hindrances such as the oxidant availability and treatment duration were also addressed. The HCB degradation along with other parameters like soil pH, redox and cumulative catholyte flow were analyzed and monitored. The results of the experiments strengthen the existing knowledge on electrokinetic Fenton process as a promising technology for the treatment of soil contaminated with hydrophobic organic compounds. It has been demonstrated that HCB sorbed to kaolin can be degraded by the use of high concentrations of hydrogen peroxide during such processes. The overall system performances were observed to be influenced by the point and mode of oxidant delivery. Furthermore, the study contributes to new knowledge in shortening the treatment duration by adopting an electrode polarity reversal during the process.

Influence of preoperative supplementation of omega-3 fatty acid in the healing of colonic anastomoses in malnourished rats receiving paclitaxel

OBJECTIVE: To evaluate the effect of preoperative supplementation of omega-3 fatty acids on the healing of colonic anastomoses in malnourished rats receiving paclitaxel. METHODS: we studied 160 male Wistar rats, divided in two groups: one subjected to malnutrition by pair feeding (M) for four weeks, and another that received food ad libitum (W). In the fourth week, the groups were further divided into two subgroups that received omega-3 or olive oil by gavage. The animals were submitted to colonic transection and end-to-end anastomosis. After the operation, each of the four groups was divided into two subgroups that received intraperitoneal isovolumetric solutions of saline or paclitaxel. RESULTS: mortality was 26.8% higher in the group of animals that received paclitaxel (p = 0.003). The complete rupture strength was greater in well-nourished-oil Paclitaxel group (WOP) compared with the the malnourished-oil Paclitaxel one (MOP). The collagen maturation index was higher in well-nourished-oil saline group (WOS) in relation to the malnutrition-oil-saline group (MOS), lower in malnourished-oil-saline group (MOS) in relation to malnourished-ômega3-saline one (M3S) and lower in the well-nourished-omega3-saline group (W3S) compared with the malnourished-omega3-saline (M3S). The blood vessel count was higher in the malnourished-oil-saline group (MOS) than in the malnourished-oil-paclitaxel group (MOP) and lower in the malnourished-oil-saline group (MOS) in relation to the malnourished-omega3-paclitaxel group (M3P). CONCLUSION: supplementation with omega-3 fatty acids was associated with a significant increase in the production of mature collagen in malnourished animals, with a reversal of the harmful effects caused by malnutrition associated with the use of paclitaxel on the rupture strength, and with a stimulus to neoangiogenesis in the group receiving paclitaxel.

Thymic atrophy in cattle poisoned with Solanum glaucophyllum

Solanum glaucophyllum (Sg) [= S. malacoxylon] is a calcinogenic plant inducing "Enzootic Calcinosis" in cattle. The 1,25-dihydroxyvitamin D3, its main toxic principle, regulates bone and calcium metabolism and also exerts immunomodulatory effects. Thymocyte precursors from bone marrow-derived progenitor cells differentiate into mature T-cells. Differentiation of most T lymphocytes is characterized not only by the variable expression of CD4/CD8 receptor molecules and increased surface density of the T cell antigen receptor, but also by changes in the glycosylation pattern of cell surface glycolipids or glycoproteins. Thymocytes exert a feedback influence on thymic non-lymphoid cells. Sg-induced modifications on cattle thymus T-lymphocytes and on non-lymphoid cells were analysed. Heifers were divided into 5 groups (control, intoxicated with Sg during 15, 30 or 60 days, and probably recovered group). Histochemical, immunohistochemical, lectinhistochemical and morphometric techniques were used to characterize different cell populations of the experimental heifers. Sg-poisoned heifers showed a progressive cortical atrophy that was characterized using the peanut agglutinin (PNA) lectin that recognizes immature thymocytes. These animals also increased the amount of non-lymphoid cells per unit area detected with the Picrosirius technique, WGA and DBA lectins, and pancytokeratin and S-100 antibodies. The thymus atrophy found in intoxicated animals resembled that of the physiological aging process. A reversal effect on these changes was observed after suppression of the intoxication. These findings suggest that Sg-intoxication induces either directly, through the 1,25-dihydroxyvitamin D3 itself, or indirectly through the hypercalcemia, the observed alteration of the thymus.

Clinical characterization of chronic chagasic cardiomyopathy in dogs

On the American continent, almost 15 million people are affected by Chagas disease, resulting in important economic and social damages. Dogs are considered to be an excellent experimental model to study Chagas' disease; as a result, in this research, the characterization of cardiovascular abnormalities was performed in dogs experimentally infected with Trypanosoma cruzi (the Colombian strain) that were at chronic stage. Thirteen adult female dogs were evaluated by electrocardiographic, echocardiographic, hematological and biochemical analyses in the chronic phase. For the electrocardiographic studies, respiratory sinus arrhythmia was the predominant rhythm during the entire research period (49.55% to 67%), with a low prevalence of right bundle branch block (0-13%) and first-degree atrioventricular block (0-14%). The spectral Doppler echocardio-graphy showed E and A mitral wave reversal (0.71±0.17), confirming the diastolic dysfunction present in all dogs. An increase in the enzymes activities was detected in the serum analysis, indicating myocardial injury by the infection. Six dogs died during the follow-up. In this way, the clinical characterization of experimentally infected dogs, as described here, increases the knowledge and allows for recognition of the behavioural modifications present in Chagas' disease in affected dogs.

Knowledge, processes and relationships in organizational change: Understanding how to facilitate management of intellectual capital in diverse organization structures and cultures.

This study examined relationships of organizational dependencies, change management and developed intellectual knowledge resources, in different intellectual capital based development programs on ICT-sector. Study was carried out in a research context, where high degree of external organizational contingencies existed and lots of changes in several development programs had taken place in the last years. From a scientific perspective the main contribution was that evidence between relationships of organizational dependencies, change model portfolio and developed knowledge resources could be suggested. From managerial perspective the primary implication was that in situations where sustainable competitive advantage is pursued by means of increasing knowledge based productivity of labor, firms should seek to pursue organizational settings where external dependencies have minimal amount of effect.

ICT-varautumisen analyysi ja kehittäminen julkisen sektorin virastossa

Lainsäädäntö velvoittaa valtionhallintoa huolehtimaan riittävästä ICT-varautumisesta, jotta yhteiskunnan kriittiset toiminnot ovat turvattu normaaliolojen lisäksi normaaliolojen häiriötilanteissa ja poikkeusoloissa. ICT-varautumisen vaatimukset on määrätty VAHTI ICT-varautumisen vaatimukset - ohjeessa. ICT-varautuminen on riskienhallintaan perustuvaa toimintaa, joka liittyy keskeisesti organisaation kokonaisturvallisuuteen, tietohallintoon ja yleiseen varautumiseen. Tutkielman teoriakatsauksessa perehdytään riskienhallintaan ja kokonaisturvallisuuteen painottaen ICT-varautumisen kannalta tärkeitä osa-alueita tietoturvallisuutta ja IT-riskienhallintaa. Kohdeorganisaation ICT-varautumisen toimintajärjestelmää varten kartoitetaan ICT-varautumisen viitekehys. Empiirisessä osiossa toteutetaan tapaustutkimuksena kohdeorganisaation ICT-varautumisen nykytilan suppea analyysi ja laaditaan kehittämisehdotelmana toimintamalli ICT-varautumisen organisoimiseksi ja käyttöönottamiseksi. Tutkielman tuotoksena kohdeorganisaatiolla on systemaattinen organisaation eri tasot huomioiva toimintamalli ICT-varautumisen toteuttamiseksi.