Monitoring drug therapy.

Drug development has improved over recent decades, with refinements in analytical techniques, population pharmacokinetic-pharmacodynamic (PK-PD) modelling and simulation, and new biomarkers of efficacy and tolerability. Yet this progress has not yielded improvements in individualization of treatment and monitoring, owing to various obstacles: monitoring is complex and demanding, many monitoring procedures have been instituted without critical assessment of the underlying evidence and rationale, controlled clinical trials are sparse, monitoring procedures are poorly validated and both drug manufacturers and regulatory authorities take insufficient account of the importance of monitoring. Drug concentration and effect data should be increasingly collected, analyzed, aggregated and disseminated in forms suitable for prescribers, along with efficient monitoring tools and evidence-based recommendations regarding their best use. PK-PD observations should be collected for both novel and established critical drugs and applied to observational data, in order to establish whether monitoring would be suitable. Methods for aggregating PK-PD data in systematic reviews should be devised. Observational and intervention studies to evaluate monitoring procedures are needed. Miniaturized monitoring tests for delivery at the point of care should be developed and harnessed to closed-loop regulated drug delivery systems. Intelligent devices would enable unprecedented precision in the application of critical treatments, i.e. those with life-saving efficacy, narrow therapeutic margins and high interpatient variability. Pharmaceutical companies, regulatory agencies and academic clinical pharmacologists share the responsibility of leading such developments, in order to ensure that patients obtain the greatest benefit and suffer the least harm from their medicines.

Correction of aberration in holographic optical tweezers using a Shack-Hartmann sensor

Optical aberration due to the nonflatness of spatial light modulators used in holographic optical tweezers significantly deteriorates the quality of the trap and may easily prevent stable trapping of particles. We use a Shack-Hartmann sensor to measure the distorted wavefront at the modulator plane; the conjugate of this wavefront is then added to the holograms written into the display to counteract its own curvature and thus compensate the optical aberration of the system. For a Holoeye LC-R 2500 reflective device, flatness is improved from 0.8¿ to ¿/16 (¿=532 nm), leading to a diffraction-limited spot at the focal plane of the microscope objective, which makes stable trapping possible. This process could be fully automated in a closed-loop configuration and would eventually allow other sources of aberration in the optical setup to be corrected for.

Improvement of rehabilitation possibilities with the MotionMaker (TM)

"MotionMaker (TM)" is a stationary programmable test and training system for the lower limbs developed at the 'Ecole Polytechnique Federale de Lausanne' with the 'Fondation Suisse pour les Cybertheses'.. The system is composed of two robotic orthoses comprising motors and sensors, and a control unit managing the trans-cutaneous electrical muscle stimulation with real-time regulation. The control of the Functional Electrical Stimulation (FES) induced muscle force necessary to mimic natural exercise is ensured by the control unit which receives a continuous input from the position and force sensors mounted on the robot. First results with control subjects showed the feasibility of creating movements by such closed-loop controlled FES induced muscle contractions. To make exercising with the MotionMaker (TM) safe for clinical trials with Spinal Cord Injured (SCI) volunteers, several original safety features have been introduced. The MotionMaker (TM) is able to identify and manage the occurrence of spasms. Fatigue can also be detected and overfatigue during exercise prevented.

Robust power allocation algorithms for MIMO OFDM systems with imperfect CSI

This paper presents a Bayesian approach to the design of transmit prefiltering matrices in closed-loop schemes robust to channel estimation errors. The algorithms are derived for a multiple-input multiple-output (MIMO) orthogonal frequency division multiplexing (OFDM) system. Two different optimizationcriteria are analyzed: the minimization of the mean square error and the minimization of the bit error rate. In both cases, the transmitter design is based on the singular value decomposition (SVD) of the conditional mean of the channel response, given the channel estimate. The performance of the proposed algorithms is analyzed,and their relationship with existing algorithms is indicated. As withother previously proposed solutions, the minimum bit error rate algorithmconverges to the open-loop transmission scheme for very poor CSI estimates.

Stability Evaluation of a Paper Machine Wet End

Työssä analysoidaanprosessin vaikutusta paperikoneen stabiiliuteen. Kaksi modernia sanomalehtipaperikonetta analysoitiin ja sen perusteella molemmista prosesseista rakennettiin fysiikan lakeihin perustuvat simulointimallit APROS Paper simulointiohjelmistolla. Työn tavoitteena on selvittää, miten kyseisten koneiden prosessit eroavat toisistaan ja arvioida, miten havaitut erot vaikuttavat prosessien stabiiliuteen. Työssä tarkastellaan periodisten häiriöiden vaimenemista prosessissa. Simuloinnissa herätteenä käytettiin puhdasta valkoista kohinaa, jonka avulla eri taajuistenperiodisten häiriöiden vaimenemista analysoitiin. Prosessien häiriövasteet esitetään taajuuskoordinaatistossa. Suurimmat erot prosessien välillä löytyivät viirakaivosta ja sen sekoitusdynamiikasta. Perinteisen viirakaivon todettiin muistuttavan käyttäytymiseltään sarjaan kytkettyjä ideaalisekoittimia, kun taas pienempitilavuuksisen fluumin todettiin käyttäytyvän lähes kuin putkiviive. Vaikka erotprosessitilavuudessa sekä viirakaivon sekoitusdynamiikassa olivat hyvin selkeät, havaittiin vain marginaalinen ero prosessin välillä periodisten häiriöiden vaimenemisessa, koska erot viiraretentiotasoissa vaikuttivat eniten simulointituloksia. Matalammalla viiraretentiolla operoivan paperikoneen todettiin vaimentavan tehokkaammin prosessihäiriöitä. Samalla retentiotasolla pienempitilavuuksisen prosessin todettiin vaimentavan hitaita prosessihäiriöitä marginaalisesti paremmin. Tutkituista paperikoneista toisella simuloitiin viiraosan vedenpoistomuutoksenvaikutusta viiraretentioon ja paperin koostumukseen. Lisäksi arvioitiin viiraretention säädön toimivuutta. Viiraosan listakengän vedenpoiston todettiin aiheuttavan merkittäviä sakeus- ja retentiohäiriöitä, mikäli sen avulla poistettavan kiintoaineen virtaus tuplaantuisi. Viiraretention säädön todettiin estävän häiriöiden kierron prosessissa, mutta siirtävän ne suoraan rainaan. Retention säädön eikuitenkaan todettu olevan suoranainen häiriön lähde.

Trimmerin kapasiteetin kasvattaminen dynamiikan mallinnuksen avulla

Työn tavoitteena oli kasvattaa sahan dimensiolaitoksella käytettävän trimmerin rakenteellista kapasiteettia. Tavoitteeseen pyrittiin modernisoimalla trimmerin teräyksikköä käyttävää toimilaite ja teräyksikön säätö dynamiikan mallinnuksen avulla. Trimmerin teräyksikön dynamiikka mallinnettiin MATLAB-matematiikkaohjelmistolla kaksiulotteisena kinematiikkamallina ja kolmeulotteisena kinetiikkamallina. Dynamiikkamallien tulosten perusteella valittin teräyksikköä käyttävä toimilaite komponentteineen. Kinetiikkamalliin mallinnettiin trimmeriä käyttävä hydraulipiiri valittuine komponentteineen keskittyneiden paineiden ja puoliempiirisen mallinnuksen periaatteita käyttäen. Teräyksikön työkiertoa säätämään mallinnettiin suljettu takaisinkytketty säätöpiiri. Tuloksien perusteella valittiin optimaalinen toimilaitteen asemointigeometria ja todettiin mallinnetun järjestelmän täyttävän asetetut vaatimukset. Järjestelmää testattiin muuttamalla jarjestelman parametreja ja tutkimalla muutosten vaikutuksia jarjestelman toimintaan. Lisaksi tutkittiin lyhyesti terayksikon rakenteen keventamisen vaikutuksia.

Development of Servo Hydraulics of Veneer Lathe

Diplomityö tehtiin kansainväliseen, mekaanisen puunjalostusteollisuuden koneita, tuotantojärjestelmiä ja tehtaita toimittavaan yritykseen. Diplomityön tarkoituksena oli kartoittaa syitä viilusorvin teräpenkin asemoinnissa esiintyneisiin värähtelyongelmiin ja tutkia ratkaisuja niiden voittamiseksi, sekä sorvausvoimien määrittäminen. Diplomityön teoreettisessa osassa tutustuttiin viilusorvin, erityisesti sen hydraulisten servojärjestelmien rakenteeseen ja toimintaan sekä viilunsorvaukseen. Teräpenkin syötön servojärjestelmää tutkittiin teoreettisesti johtamalla suljetun piirin siirtofunktiot “asema/käsky” ja “virhe/voima” ja tulostamalla niiden taajuusvaste-kuvaajat, joista tutkittiin parametrien vaikutuksia järjestelmän toimintaan. Tulokset vahvistettiin simuloimalla. Todettiin nykyisen järjestelmän värähtelyongelmien johtuvan pääasiassa hydrauliöljyn joustosta sylinterissä. Parannuksina ehdotettiin suurempaa sylinterin halkaisijaa ja viskoosikitkakertoimen suurentamista. Diplomityön kokeellisessa osassa mitattiin viilusorvin servojärjestelmien toimilaitteissa esiintyviä voimia ja niiden perusteella laskettiin varsinaiset sorvausvoimat. Lisäksi tutkittiin teräpenkin syötön ja muiden servojärjestelmien asemointitarkkuutta sorvauksen aikana. Mittauksia varten diplomityössä suunniteltiin ja hankittiin kannettava mittausjärjestelmä.

Novel Robot Solutions for Carrying out Field Joint Welding and Machining in the Assembly of the Vacuum Vessel of ITER

It is necessary to use highly specialized robots in ITER (International Thermonuclear Experimental Reactor) both in the manufacturing and maintenance of the reactor due to a demanding environment. The sectors of the ITER vacuum vessel (VV) require more stringent tolerances than normally expected for the size of the structure involved. VV consists of nine sectors that are to be welded together. The vacuum vessel has a toroidal chamber structure. The task of the designed robot is to carry the welding apparatus along a path with a stringent tolerance during the assembly operation. In addition to the initial vacuum vessel assembly, after a limited running period, sectors need to be replaced for repair. Mechanisms with closed-loop kinematic chains are used in the design of robots in this work. One version is a purely parallel manipulator and another is a hybrid manipulator where the parallel and serial structures are combined. Traditional industrial robots that generally have the links actuated in series are inherently not very rigid and have poor dynamic performance in high speed and high dynamic loading conditions. Compared with open chain manipulators, parallel manipulators have high stiffness, high accuracy and a high force/torque capacity in a reduced workspace. Parallel manipulators have a mechanical architecture where all of the links are connected to the base and to the end-effector of the robot. The purpose of this thesis is to develop special parallel robots for the assembly, machining and repairing of the VV of the ITER. The process of the assembly and machining of the vacuum vessel needs a special robot. By studying the structure of the vacuum vessel, two novel parallel robots were designed and built; they have six and ten degrees of freedom driven by hydraulic cylinders and electrical servo motors. Kinematic models for the proposed robots were defined and two prototypes built. Experiments for machine cutting and laser welding with the 6-DOF robot were carried out. It was demonstrated that the parallel robots are capable of holding all necessary machining tools and welding end-effectors in all positions accurately and stably inside the vacuum vessel sector. The kinematic models appeared to be complex especially in the case of the 10-DOF robot because of its redundant structure. Multibody dynamics simulations were carried out, ensuring sufficient stiffness during the robot motion. The entire design and testing processes of the robots appeared to be complex tasks due to the high specialization of the manufacturing technology needed in the ITER reactor, while the results demonstrate the applicability of the proposed solutions quite well. The results offer not only devices but also a methodology for the assembly and repair of ITER by means of parallel robots.

Supersaturation-controlled crystallization

Identification of product requirements and quality, together with the management of production are key issues in chemical engineering. Quality control of crystalline products is part of the quality of many industrially manufactured products like paper, paintings, medicines and fertilizers. In most crystallization cases, quality is described with the size, polymorph, shape and purity of the crystal. The chemical composition, hydrodynamics and driving force, together with the operating temperature are in a key position when the properties of a crystalline product are controlled with the crystallization process. This study concentrates on managing the identified properties of a crystalline product with the control of a driving force. The controlling of the driving force can be based on the change of solubility or the change of concentration. Solubility can be changed with temperature, pressure and an antisolvent. The concentration of crystallizing compound, the solute can be changed with the evaporation of the solvent and with the addition of a reagent. The present study focuses on reagent addition and temperature change as methods of changing the level of the driving force. Three control structures for direct control of supersaturation are built, one for cooling crystallization and two for reactive crystallization. Closed loop feedback control structures are based on the measurement of the solute concentration with attenuated total reflection - Fourier transform infrared spectrometer. The details of the reagent feed are analyzed with experimental studies and with results of computational fluid dynamic simulations of the inert particle pulse in the premixer and inert particle injection to the mixing tank. Nucleation in conditions of controlled reactive crystallization is analyzed with Nielsen’s equation of homogeneous nucleation. The resulting control systems, based on regulation of supersaturation, can be used to produce the desired polymorph of an organic product. The polymorph composition of product crystals is controlled repeatably with the decision of a set value of supersaturation level.

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.

Auger-type granular fertylizer distributor: matemathical model and dynamic simulation

The objective of this study was to model mathematically and to simulate the dynamic behavior of an auger-type fertilizer applicator (AFA) in order to use the variable-rate application (VRA) and reduce the coefficient of variation (CV) of the application, proposing an angular speed controller θ' for the motor drive shaft. The input model was θ' and the response was the fertilizer mass flow, due to the construction, density of fertilizer, fill factor and the end position of the auger. The model was used to simulate a control system in open loop, with an electric drive for AFA using an armature voltage (V A) controller. By introducing a sinusoidal excitation signal in V A with amplitude and delay phase optimized and varying θ' during an operation cycle, it is obtained a reduction of 29.8% in the CV (constant V A) to 11.4%. The development of the mathematical model was a first step towards the introduction of electric drive systems and closed loop control for the implementation of AFA with low CV in VRA.

Electrically driven fertilizer applicator controlled by fuzzy logic

The present study shows the development, simulation and actual implementation of a closed-loop controller based on fuzzy logic that is able to regulate and standardize the mass flow of a helical fertilizer applicator. The control algorithm was developed using MATLAB's Fuzzy Logic Toolbox. Both open and closed-loop simulations of the controller were performed in MATLAB's Simulink environment. The instantaneous deviation of the mass flow from the set point (SP), its derivative, the equipment´s translation velocity and acceleration were all used as input signals for the controller, whereas the voltage of the applicator's DC electric motor (DCEM) was driven by the controller as output signal. Calibration and validation of the rules and membership functions of the fuzzy logic were accomplished in the computer simulation phase, taking into account the system's response to SP changes. The mass flow variation coefficient, measured in experimental tests, ranged from 6.32 to 13.18%. The steady state error fell between -0.72 and 0.13g s-1 and the recorded average rise time of the system was 0.38 s. The implemented controller was able to both damp the oscillations in mass flow that are characteristic of helical fertilizer applicators, and to effectively respond to SP variations.

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.

Servo drive in hoist application

The objective of this master thesis is to test according to hoisting requirements, a servo drive system and compare its performance with the performance of a drive equipped with a vector controlled frequency converter. Both systems utilize closed-loop vector control based on PCL program control. In order to compare the results of tests both systems were connected to the same motor driving a variable speed electrical chain hoist. Tests were based on requirements to both systems. As requirements of tests zero speed operation, operation in field weakening, positioning accuracy and smoothness of motion are taken into consideration. Both systems demonstrate quite similar performance and meet the requirements. Servo drive system demonstrates a high positioning accuracy and dynamic performance. Frequency converter is not able to provide the same positioning accuracy and dynamic performance as servo drive.

Production of Mg(OH)2 from Mg-silicate rock for CO2 mineral sequestration

Sequestration of carbon dioxide in mineral rocks, also known as CO2 Capture and Mineralization (CCM), is considered to have a huge potential in stabilizing anthropogenic CO2 emissions. One of the CCM routes is the ex situ indirect gas/sold carbonation of reactive materials, such as Mg(OH)2, produced from abundantly available Mg-silicate rocks. The gas/solid carbonation method is intensively researched at Åbo Akademi University (ÅAU ), Finland because it is energetically attractive and utilizes the exothermic chemistry of Mg(OH)2 carbonation. In this thesis, a method for producing Mg(OH)2 from Mg-silicate rocks for CCM was investigated, and the process efficiency, energy and environmental impact assessed. The Mg(OH)2 process studied here was first proposed in 2008 in a Master’s Thesis by the author. At that time the process was applied to only one Mg-silicate rock (Finnish serpentinite from the Hitura nickel mine site of Finn Nickel) and the optimum process conversions, energy and environmental performance were not known. Producing Mg(OH)2 from Mg-silicate rocks involves a two-staged process of Mg extraction and Mg(OH)2 precipitation. The first stage extracts Mg and other cations by reacting pulverized serpentinite or olivine rocks with ammonium sulfate (AS) salt at 400 - 550 oC (preferably < 450 oC). In the second stage, ammonia solution reacts with the cations (extracted from the first stage after they are leached in water) to form mainly FeOOH, high purity Mg(OH)2 and aqueous (dissolved) AS. The Mg(OH)2 process described here is closed loop in nature; gaseous ammonia and water vapour are produced from the extraction stage, recovered and used as reagent for the precipitation stage. The AS reagent is thereafter recovered after the precipitation stage. The Mg extraction stage, being the conversion-determining and the most energy-intensive step of the entire CCM process chain, received a prominent attention in this study. The extraction behavior and reactivity of different rocks types (serpentinite and olivine rocks) from different locations worldwide (Australia, Finland, Lithuania, Norway and Portugal) was tested. Also, parametric evaluation was carried out to determine the optimal reaction temperature, time and chemical reagent (AS). Effects of reactor types and configuration, mixing and scale-up possibilities were also studied. The Mg(OH)2 produced can be used to convert CO2 to thermodynamically stable and environmentally benign magnesium carbonate. Therefore, the process energy and life cycle environmental performance of the ÅAU CCM technique that first produces Mg(OH)2 and the carbonates in a pressurized fluidized bed (FB) were assessed. The life cycle energy and environmental assessment approach applied in this thesis is motivated by the fact that the CCM technology should in itself offer a solution to what is both an energy and environmental problem. Results obtained in this study show that different Mg-silicate rocks react differently; olivine rocks being far less reactive than serpentinite rocks. In summary, the reactivity of Mg-silicate rocks is a function of both the chemical and physical properties of rocks. Reaction temperature and time remain important parameters to consider in process design and operation. Heat transfer properties of the reactor determine the temperature at which maximum Mg extraction is obtained. Also, an increase in reaction temperature leads to an increase in the extent of extraction, reaching a maximum yield at different temperatures depending on the reaction time. Process energy requirement for producing Mg(OH)2 from a hypothetical case of an iron-free serpentine rock is 3.62 GJ/t-CO2. This value can increase by 16 - 68% depending on the type of iron compound (FeO, Fe2O3 or Fe3O4) in the mineral. This suggests that the benefit from the potential use of FeOOH as an iron ore feedstock in iron and steelmaking should be determined by considering the energy, cost and emissions associated with the FeOOH by-product. AS recovery through crystallization is the second most energy intensive unit operation after the extraction reaction. However, the choice of mechanical vapor recompression (MVR) over the “simple evaporation” crystallization method has a potential energy savings of 15.2 GJ/t-CO2 (84 % savings). Integrating the Mg(OH)2 production method and the gas/solid carbonation process could provide up to an 25% energy offset to the CCM process energy requirements. Life cycle inventory assessment (LCIA) results show that for every ton of CO2 mineralized, the ÅAU CCM process avoids 430 - 480 kg CO2. The Mg(OH)2 process studied in this thesis has many promising features. Even at the current high energy and environmental burden, producing Mg(OH)2 from Mg-silicates can play a significant role in advancing CCM processes. However, dedicated future research and development (R&D) have potential to significantly improve the Mg(OH)2 process performance.