A Síndrome dos Ovários Policísticos (PCOS) é a endocrinopatia mais frequente em mulheres na idade reprodutiva, além de ser a causa mais comum de hiperandrogenismo e anovulação crônica. Diferentes fenótipos da PCOS foram identificados, e um melhor entendimento dessas diferentes apresentações clínicas se faz necessário para o reconhecimento de riscos, medidas preventivas e terapêuticas específicas para cada fenótipo. Associações entre polimorfismos de substituição de um único nucleotídeo (SNPs) em genes que codificam enzimas responsáveis pelo metabolismo androgênico e PCOS foram descritos. O anticoncepcional oral (ACO) é utilizado para o tratamento de mulheres com PCOS por seu efeito supressivo na secreção de androgênios ovarianos e melhora do hirsutismo. Entretanto, os dados na literatura são conflitantes quanto aos efeitos do ACO nos parâmetros metabólicos de mulheres com PCOS. Além disso, não está bem estabelecido se a presença de alelos polimórficos está associada com diferenças nos fenótipos da PCOS e se pode influenciar na resposta ao tratamento com ACO. Os objetivos desta tese foram investigar a influência dos SNPs -71 AG no gene AKR1C3 e SNP50 no gene CYP19 gene (substituição de G por A) na resposta de mulheres com PCOS ao tratamento com ACO e verificar se o SNP50 está associado com fenótipos da PCOS. Cento e sessenta e duas mulheres com PCOS foram estratificadas em PCOS clássicas (hiperandrogenismo e disfunção ovulatória, c-PCOS) e PCOS ovulatórias (hiperandrogenismo, ciclos ovulatórios, aparência policística dos ovários, ov-PCOS) e uma subamostra de 51 mulheres (que não apresentavam resistência insulínica evidente) completaram 6 meses de tratamento com ACO (20 ug etinilestradiol e 75 ug gestodeno, 21/28 dias por ciclo). A presença ou ausência dos alelos polimórficos foram consideradas para expressar os resultados que avaliaram os SNPs -71 AG e SNP50. O escore de hirsutismo foi similar em c-PCOS e ov-PCOS, e as diferenças nos parâmetros hormonais e metabólicos observadas foram independentes da presença do alelo A do SNP50. Após os 6 meses de tratamento com ACO, como era esperado, os níveis de testosterona total e o escore clínico de hirsutismo diminuíram, enquanto os níveis da globulina carreadora de hormônios sexuais aumentaram. Houve uma pequena redução da pressão arterial sistólica e do hormônio luteinizante. As medidas de insulina e do índice HOMA permaneceram inalteradas após o tratamento. Houve um aumento dos níveis de lipídios, mas os valores permaneceram dentro dos limites da normalidade. Nenhuma das alterações observadas esteve associada com a presença dos alelos polimórficos dos SNPs -71 AG ou SNP50. As conclusões são de que o ACO é uma alternativa eficaz para o tratamento dos sintomas do hiperandrogenismo, sem comprometimento dos parâmetros metabólicos, pelo menos naquelas mulheres sem resistência insulínica prévia ao tratamento. Os SNPs -71AG no gene AKR1C3 e SNP50 no gene CYP19 não contribuem para as melhoras observadas com o uso do ACO. Além disso, o SNP50 parece não estar associado com as diferenças existentes entre os fenótipos clássico e ovulatório da PCOS. / Polycystic Ovary Syndrome (PCOS) is the most common endocrine disorder in women at reproductive age, and also the most common cause of hyperandrogenism and chronic anovulation. Different phenotypes of PCOS have been identified, and a better knowledge of these clinical symptoms is necessary to recognize risks, prevention, and treatment strategies for each phenotype. Associations between single nucleotide polymorphisms (SNPs) in genes that codify enzymes responsible for the androgenic metabolism and PCOS have been described. The oral contraceptive pill (OCP) is used to treat women with PCOS due to the suppressive effect on ovarian androgen secretion, with consequent amelioration of hirsutism. However, data are conflicting in literature regarding the effects of OCP on metabolic variables in PCOS. Besides that, it is not well established whether the presence of polymorphic alleles is associated with PCOS phenotypes and whether can influence on the response to OCP treatment. The aims of this thesis were to investigate the influence of the SNPs -71 AG at AKR1C3 gene and SNP50 of CYP19 gene (G to A substitution) on the response of PCOS to treatment with oral contraceptive pills and to assess whether the SNP50 is associated with PCOS phenotypes. A hundred sixty two hirsute women were stratified into a classic PCOS group (hyperandrogenism and ovulatory dysfunction, c-PCOS) and an ovulatory PCOS group (hyperandrogenism, ovulatory cycles, polycystic ovaries, ov-PCOS), and a subsample of 51 women (without evidences of insulin resistance) completed a 6-month OCP trial (20 ug ethinylestradiol plus 75 ug gestodene, 21/28 days per cycle). We considered the presence or absence of the polymorphic alleles to express results and to perform the comparisons regarding the SNPs -71 AG and SNP50. Hirsutism score was similar in c-PCOS and ov-PCOS, and the differences in hormone and metabolic variables between phenotypes were independent of the presence of allele A for SNP50. After 6 months of OCP treatment, as expected, total testosterone and hirsutism score declined, while sex hormone binding globulin increased. There was a slight reduction in systolic blood pressure and luteinizing hormone levels. Insulin and homeostasis model assessment remained unchanged after treatment. There was an increase in lipids, but the values remained at the normal range. None of these changes were associated with the presence of polymorphic alleles for -71 AG or SNP50 polymorphisms. We conclude that OCP is an alternative to ameliorate androgenic symptoms without compromising metabolic parameters, at least in women without insulin resistance before treatment. The -71AG SNP of AKR1C3 gene and the SNP50 of CYP19 gene did not contribute to the improvements observed. Besides that, SNP50 may not be associated to the existing differences between classic and ovulatory PCOS phenotypes.

A Síndrome dos Ovários Policísticos (PCOS) é a endocrinopatia mais frequente em mulheres na idade reprodutiva, além de ser a causa mais comum de hiperandrogenismo e anovulação crônica. Diferentes fenótipos da PCOS foram identificados, e um melhor entendimento dessas diferentes apresentações clínicas se faz necessário para o reconhecimento de riscos, medidas preventivas e terapêuticas específicas para cada fenótipo. Associações entre polimorfismos de substituição de um único nucleotídeo (SNPs) em genes que codificam enzimas responsáveis pelo metabolismo androgênico e PCOS foram descritos. O anticoncepcional oral (ACO) é utilizado para o tratamento de mulheres com PCOS por seu efeito supressivo na secreção de androgênios ovarianos e melhora do hirsutismo. Entretanto, os dados na literatura são conflitantes quanto aos efeitos do ACO nos parâmetros metabólicos de mulheres com PCOS. Além disso, não está bem estabelecido se a presença de alelos polimórficos está associada com diferenças nos fenótipos da PCOS e se pode influenciar na resposta ao tratamento com ACO. Os objetivos desta tese foram investigar a influência dos SNPs -71 AG no gene AKR1C3 e SNP50 no gene CYP19 gene (substituição de G por A) na resposta de mulheres com PCOS ao tratamento com ACO e verificar se o SNP50 está associado com fenótipos da PCOS. Cento e sessenta e duas mulheres com PCOS foram estratificadas em PCOS clássicas (hiperandrogenismo e disfunção ovulatória, c-PCOS) e PCOS ovulatórias (hiperandrogenismo, ciclos ovulatórios, aparência policística dos ovários, ov-PCOS) e uma subamostra de 51 mulheres (que não apresentavam resistência insulínica evidente) completaram 6 meses de tratamento com ACO (20 ug etinilestradiol e 75 ug gestodeno, 21/28 dias por ciclo). A presença ou ausência dos alelos polimórficos foram consideradas para expressar os resultados que avaliaram os SNPs -71 AG e SNP50. O escore de hirsutismo foi similar em c-PCOS e ov-PCOS, e as diferenças nos parâmetros hormonais e metabólicos observadas foram independentes da presença do alelo A do SNP50. Após os 6 meses de tratamento com ACO, como era esperado, os níveis de testosterona total e o escore clínico de hirsutismo diminuíram, enquanto os níveis da globulina carreadora de hormônios sexuais aumentaram. Houve uma pequena redução da pressão arterial sistólica e do hormônio luteinizante. As medidas de insulina e do índice HOMA permaneceram inalteradas após o tratamento. Houve um aumento dos níveis de lipídios, mas os valores permaneceram dentro dos limites da normalidade. Nenhuma das alterações observadas esteve associada com a presença dos alelos polimórficos dos SNPs -71 AG ou SNP50. As conclusões são de que o ACO é uma alternativa eficaz para o tratamento dos sintomas do hiperandrogenismo, sem comprometimento dos parâmetros metabólicos, pelo menos naquelas mulheres sem resistência insulínica prévia ao tratamento. Os SNPs -71AG no gene AKR1C3 e SNP50 no gene CYP19 não contribuem para as melhoras observadas com o uso do ACO. Além disso, o SNP50 parece não estar associado com as diferenças existentes entre os fenótipos clássico e ovulatório da PCOS. / Polycystic Ovary Syndrome (PCOS) is the most common endocrine disorder in women at reproductive age, and also the most common cause of hyperandrogenism and chronic anovulation. Different phenotypes of PCOS have been identified, and a better knowledge of these clinical symptoms is necessary to recognize risks, prevention, and treatment strategies for each phenotype. Associations between single nucleotide polymorphisms (SNPs) in genes that codify enzymes responsible for the androgenic metabolism and PCOS have been described. The oral contraceptive pill (OCP) is used to treat women with PCOS due to the suppressive effect on ovarian androgen secretion, with consequent amelioration of hirsutism. However, data are conflicting in literature regarding the effects of OCP on metabolic variables in PCOS. Besides that, it is not well established whether the presence of polymorphic alleles is associated with PCOS phenotypes and whether can influence on the response to OCP treatment. The aims of this thesis were to investigate the influence of the SNPs -71 AG at AKR1C3 gene and SNP50 of CYP19 gene (G to A substitution) on the response of PCOS to treatment with oral contraceptive pills and to assess whether the SNP50 is associated with PCOS phenotypes. A hundred sixty two hirsute women were stratified into a classic PCOS group (hyperandrogenism and ovulatory dysfunction, c-PCOS) and an ovulatory PCOS group (hyperandrogenism, ovulatory cycles, polycystic ovaries, ov-PCOS), and a subsample of 51 women (without evidences of insulin resistance) completed a 6-month OCP trial (20 ug ethinylestradiol plus 75 ug gestodene, 21/28 days per cycle). We considered the presence or absence of the polymorphic alleles to express results and to perform the comparisons regarding the SNPs -71 AG and SNP50. Hirsutism score was similar in c-PCOS and ov-PCOS, and the differences in hormone and metabolic variables between phenotypes were independent of the presence of allele A for SNP50. After 6 months of OCP treatment, as expected, total testosterone and hirsutism score declined, while sex hormone binding globulin increased. There was a slight reduction in systolic blood pressure and luteinizing hormone levels. Insulin and homeostasis model assessment remained unchanged after treatment. There was an increase in lipids, but the values remained at the normal range. None of these changes were associated with the presence of polymorphic alleles for -71 AG or SNP50 polymorphisms. We conclude that OCP is an alternative to ameliorate androgenic symptoms without compromising metabolic parameters, at least in women without insulin resistance before treatment. The -71AG SNP of AKR1C3 gene and the SNP50 of CYP19 gene did not contribute to the improvements observed. Besides that, SNP50 may not be associated to the existing differences between classic and ovulatory PCOS phenotypes.

A Síndrome dos Ovários Policísticos (PCOS) é a endocrinopatia mais frequente em mulheres na idade reprodutiva, além de ser a causa mais comum de hiperandrogenismo e anovulação crônica. Diferentes fenótipos da PCOS foram identificados, e um melhor entendimento dessas diferentes apresentações clínicas se faz necessário para o reconhecimento de riscos, medidas preventivas e terapêuticas específicas para cada fenótipo. Associações entre polimorfismos de substituição de um único nucleotídeo (SNPs) em genes que codificam enzimas responsáveis pelo metabolismo androgênico e PCOS foram descritos. O anticoncepcional oral (ACO) é utilizado para o tratamento de mulheres com PCOS por seu efeito supressivo na secreção de androgênios ovarianos e melhora do hirsutismo. Entretanto, os dados na literatura são conflitantes quanto aos efeitos do ACO nos parâmetros metabólicos de mulheres com PCOS. Além disso, não está bem estabelecido se a presença de alelos polimórficos está associada com diferenças nos fenótipos da PCOS e se pode influenciar na resposta ao tratamento com ACO. Os objetivos desta tese foram investigar a influência dos SNPs -71 AG no gene AKR1C3 e SNP50 no gene CYP19 gene (substituição de G por A) na resposta de mulheres com PCOS ao tratamento com ACO e verificar se o SNP50 está associado com fenótipos da PCOS. Cento e sessenta e duas mulheres com PCOS foram estratificadas em PCOS clássicas (hiperandrogenismo e disfunção ovulatória, c-PCOS) e PCOS ovulatórias (hiperandrogenismo, ciclos ovulatórios, aparência policística dos ovários, ov-PCOS) e uma subamostra de 51 mulheres (que não apresentavam resistência insulínica evidente) completaram 6 meses de tratamento com ACO (20 ug etinilestradiol e 75 ug gestodeno, 21/28 dias por ciclo). A presença ou ausência dos alelos polimórficos foram consideradas para expressar os resultados que avaliaram os SNPs -71 AG e SNP50. O escore de hirsutismo foi similar em c-PCOS e ov-PCOS, e as diferenças nos parâmetros hormonais e metabólicos observadas foram independentes da presença do alelo A do SNP50. Após os 6 meses de tratamento com ACO, como era esperado, os níveis de testosterona total e o escore clínico de hirsutismo diminuíram, enquanto os níveis da globulina carreadora de hormônios sexuais aumentaram. Houve uma pequena redução da pressão arterial sistólica e do hormônio luteinizante. As medidas de insulina e do índice HOMA permaneceram inalteradas após o tratamento. Houve um aumento dos níveis de lipídios, mas os valores permaneceram dentro dos limites da normalidade. Nenhuma das alterações observadas esteve associada com a presença dos alelos polimórficos dos SNPs -71 AG ou SNP50. As conclusões são de que o ACO é uma alternativa eficaz para o tratamento dos sintomas do hiperandrogenismo, sem comprometimento dos parâmetros metabólicos, pelo menos naquelas mulheres sem resistência insulínica prévia ao tratamento. Os SNPs -71AG no gene AKR1C3 e SNP50 no gene CYP19 não contribuem para as melhoras observadas com o uso do ACO. Além disso, o SNP50 parece não estar associado com as diferenças existentes entre os fenótipos clássico e ovulatório da PCOS. / Polycystic Ovary Syndrome (PCOS) is the most common endocrine disorder in women at reproductive age, and also the most common cause of hyperandrogenism and chronic anovulation. Different phenotypes of PCOS have been identified, and a better knowledge of these clinical symptoms is necessary to recognize risks, prevention, and treatment strategies for each phenotype. Associations between single nucleotide polymorphisms (SNPs) in genes that codify enzymes responsible for the androgenic metabolism and PCOS have been described. The oral contraceptive pill (OCP) is used to treat women with PCOS due to the suppressive effect on ovarian androgen secretion, with consequent amelioration of hirsutism. However, data are conflicting in literature regarding the effects of OCP on metabolic variables in PCOS. Besides that, it is not well established whether the presence of polymorphic alleles is associated with PCOS phenotypes and whether can influence on the response to OCP treatment. The aims of this thesis were to investigate the influence of the SNPs -71 AG at AKR1C3 gene and SNP50 of CYP19 gene (G to A substitution) on the response of PCOS to treatment with oral contraceptive pills and to assess whether the SNP50 is associated with PCOS phenotypes. A hundred sixty two hirsute women were stratified into a classic PCOS group (hyperandrogenism and ovulatory dysfunction, c-PCOS) and an ovulatory PCOS group (hyperandrogenism, ovulatory cycles, polycystic ovaries, ov-PCOS), and a subsample of 51 women (without evidences of insulin resistance) completed a 6-month OCP trial (20 ug ethinylestradiol plus 75 ug gestodene, 21/28 days per cycle). We considered the presence or absence of the polymorphic alleles to express results and to perform the comparisons regarding the SNPs -71 AG and SNP50. Hirsutism score was similar in c-PCOS and ov-PCOS, and the differences in hormone and metabolic variables between phenotypes were independent of the presence of allele A for SNP50. After 6 months of OCP treatment, as expected, total testosterone and hirsutism score declined, while sex hormone binding globulin increased. There was a slight reduction in systolic blood pressure and luteinizing hormone levels. Insulin and homeostasis model assessment remained unchanged after treatment. There was an increase in lipids, but the values remained at the normal range. None of these changes were associated with the presence of polymorphic alleles for -71 AG or SNP50 polymorphisms. We conclude that OCP is an alternative to ameliorate androgenic symptoms without compromising metabolic parameters, at least in women without insulin resistance before treatment. The -71AG SNP of AKR1C3 gene and the SNP50 of CYP19 gene did not contribute to the improvements observed. Besides that, SNP50 may not be associated to the existing differences between classic and ovulatory PCOS phenotypes.

Ideally, every person in the world should have access to a safe and clean water supply; if not all sources of water are clean and safe, at the very least, an effective method to detect water contamination should be readily available. An effective detection method should not only be sensitive, rapid, robust, and affordable, but, ideally, it should also be equipment-free and easy to transport and deliver to the end-users. The main goal of this project is to develop a variety of bits and pieces of bioassay systems, with a particular focus on paper-based bioactive devices in order to provide portable and ready-to-use biosensors which can be useable by anyone anywhere around the world without requiring formal training. According to the World Health Organization (WHO), 76,000 people each year die in India alone because of pesticide poisoning. Long term exposure to organophosphate pesticides is known to have adverse effects on neurological function and can lead to Alzheimer's Disease, Attention Deficit Hyperactivity Disorder (ADHD), and reduced Intelligence Quotient (IQ). The likelihood of long term exposure to pesticides is heightened in developing countries, so a reliable and inexpensive pesticide sensor is a much-needed device in the developing world. To address this need, this project reports on the development of a fully-automated bioactive paper-based sensor for the detection of organophosphate pesticides. In the proposed biosensor, two innovations were implemented to achieve a full-automated format for the pesticide sensor: (I) First is a PUMP ON A PAPER (Jahanshahi-Anbuhi et al., LOC, 2012) that increases the flow rate of fluids within paper-based microfluidic analytical devices and sequentially brings two separate liquid streams to the enzyme test zone on the paper sensor, and (II) the second innovation is a PIPETTE ON A PAPER (Jahanshahi-Anbuhi et al., LOC, 2014) that involved the creation of a pullulan (a natural non-ionic polysaccharide) temporary bridge-system to transfer a known amount of solution to the sensing zone that, gives the enzyme zone a chance to dry and accept the substrate solution from the slow channel after a fixed period of time. This proposed format results in a simplified assay that detects the presence of pesticides automatically without any further manipulation from the user. However, the shelf life of this assay kit is challenging due to instability of both enzyme (AChE) and substrate (IDA) at room temperature. AChE loses its enzymatic activity when stored at room temperature and IDA becomes oxidized quickly. This problem is not unique to these two bio reagents, however; almost all bioassays which use bio-reagents (such as enzymes and small-molecular substrates) are unstable to varying degrees and require special shipping and storage. The instability of these molecules can arise from either thermal denaturation or chemical modification, such as oxidation or hydrolysis. Because of these issues, they often have to be shipped on dry ice with special packaging, which is costly. The cost of maintaining a cold chain for distributing bio-reagents accounts for up to 80% of the cost. Aside from the cost, these reagents also have to be stored in bulk in refrigerators or freezers to minimize the loss of activity, but they must be thawed and aliquoted for their intended tests. Repeated freezing and thawing can result in a significant loss of activity, which often leads to less reliable test results. These issues make running such assays in resource-limited settings a significant challenge. There is, therefore, an urgent need for an assay system with stable reagents that is easy to use, simple to read, inexpensive, and that includes a method for the long-term stabilization of enzymes and other unstable reagents in pre-measured quantities. To overcome to all these issues, pullulan is utilized for the development of pill-based-biosensors. Pullulan dissolves quickly in aqueous solutions and shows very high oxygen barrier properties in its film form. Considering the unique properties of pullulan, it is hypothesized that pullulan may be suitable for producing assay pills with encapsulated enzymes or other unstable molecules and may provide a simplified platform for carrying out bioassays in resource-limited settings. The application of these pill-based-biosensors is shown via the entrapment of AChE and IDA for the creation of an assay kit that can detect organophosphate pesticides (Jahanshahi-Anbuhi et al., Angew. Chem., 2014). Moreover, this thesis reports on the stabilization of highly unstable firefly luciferase for the detection of microorganisms and, more particularly, ATP. Through the use of pullulan, this thesis demonstrates that both the enzyme and the substrate can be protected, immobilized, and stabilized at room temperature, instead of the existing storage methods, which require temperatures <-20˚C. This innovation allows for a more convenient method of shipping the bioassay kits around the world without any extra care. Furthermore, pullulan-based films are utilized for the development of a method for controlled multidirectional flow within paper-based biosensors. This method provides the possibility of trapping labile and volatile reagents and stabilizing them by forming thin films with pullulan. The trapped reagents within pullulan films can be strategically stacked and assembled on a paper strip in different directions. Furthermore, should the need arise, these reagents can be released and delivered sequentially or simultaneously in both vertical and lateral directions through the paper. The application of this method is shown for: (I) creation of "ready-to-use" assay kit for the detection of Escherichia coli (E. Coli). This assay kit has the step of cell lysing and proceeds automatically to the step in which enzymes react. The second application (II) shows the trapping of Simon’s reagents, which is widely used for methamphetamine detection. Overall, these unique fabrication techniques can be widely used for the preparation of highly stable, ready-to-use, and user-friendly biosensors. We are currently working on the detection of other contaminants such as heavy metals, and we are starting on vaccine stabilization and delivery, which would have a tremendous impact for society. / Dissertation / Doctor of Engineering (DEng)

Taking medication at the prescribed times is very important for people with mental issues like schizophrenia, dementia Alzheimer’s and depression. But their condition itself keeps them from doing so. They are either forgetful or choose not to take the pills intentionally. This could lead to missing dosage or overdosing both of which are dangerous to the person’s health. Hence a pill box that monitors the dosage and keeps them from being able to access the pills at undesired times is needed. The aim of the thesis is to design such a pill box for the company Victrix AB in Stockholm, Sweden, by expanding on their current pill box, Dosis. In the project, the locking mechanism to keep the lids closed was rigorously designed in phases after understanding the user conditions. The end result is a locked daily pill box that is ergonomic to use for people of all ages, mental and physical conditions. The product sets itself apart from its competitors by being compact, less medical looking and very easy to use. / Att ta mediciner vid föreskrivna tidpunkter är mycket viktigt för personer med psykiska problem som schizofreni, alzheimers, demens och depressioner. Dock kan deras tillstånd hindra dem från att göra det. De är antingen glömska eller så väljer de att inte ta medicinen avsiktligt. Sådant beteende kan leda till saknad dosering eller överdosering, vilka båda är farliga för personens hälsa. Därmed behövs en pillerask som övervakar doseringen och hindrar dem från att komma åt pillerna vid oönskade tidpunkter. Syftet med examensarbetet har varit att designa en sådan pillerask för företaget Victrix AB i Stockholm, Sverige, genom att utöka sin nuvarande ask, Dosis. I projektet designades låsmekanismen noggrant i faser, genom en ökad förståelse av användarförhållandena, för att hålla locken stängda,. Slutresultatet blev en låst daglig pillerask som är ergonomisk för personer i olika åldrar med mentala och fykiska problem. Produkten skiljer sig från dess konkurrenter genom att vara kompact, inte ha ett typiskt medicinskt utseende samt mycket enkel att använda.

The rapid development of technology in the health-care sector has led to the discovery of many new illnesses and improved treatments that were not possible earlier. However, many treatments and medicines for a specific disease often come with several side effects. The accuracy in treatments with an optimal result on specified targets is therefore desired with minimum side effects. This requires that the production and the usage processes should be precise. The scope of this study is not about the medicine production phase but rather on managing a medicine schedule. How many times a medicine should be taken in a day is strongly related to its dosage and following a precise timing plays a crucial role in the individual’s health. As a solution, a pill box based on a low power display (Electronic Paper Display, EPD) together with an embedded system has been introduced by the project owner (Victrix AB, Stockholm) .The pill box should have some different functions like alarms, data logging and wireless reporting. Different types of alarms including ringtone, vibration and voice recording/playing are required as well. To be able to trace the already planned timing for taking medicines, system will be able to save and report history of the past 100 days. Since every single idea for solving different parts of the problem should be tested in real system, a Quantitative Research based on experiments be used and the best possible solution be selected and implemented in the project. Studying technical material and also related works besides analyzing generated data after each experiment were a useful tool for the system integration in this work. As the result, a pill box based on an embedded system was designed and integrated successfully. A hardware platform, in form of a prototype system based on an ARM microcontroller and a compatible embedded software have been designed, improved and tested successfully and are available. At the end of this work, the low power E-paper display works properly, alarms can be set and activated, data can be saved and also sent wirelessly. Basically, the result of this project shows how an embedded system can be specialized and programmed to be able to interact with patients and e.g. nurses in order to make a stable and continuous connection between them. Most of determined goals have been achieved and some of them be changed and modified during the work. Also a few additional functions and improvements be suggested as future work.

Clinical trials are experiments or observations on a patient’s responses of different medical treatments to cure diseases. Such trials are heavily regulated and must achieve a certain quality standard of the trial and clinical adherence is a determining factor on the success of a study. However, it has historically been difficult to systematically follow and understand patient adherence to medical ordinations, predominately due to lack of proper tools. One new type of tools is a digital pillbox that can be used to supply pills to participants in clinical trials. This paper examines implementing two supervised machine learning models to detect if an object (a pill) is found in an encapsulated compartment (pillbox) based on electromagnetic radiation data from a proximity sensor. Support Vector Machine (SVM) and Random Forest (RF) were evaluated on a data set of N=1,485 observations, consisting of five classes: four different pills and ‘no pill’. RF performs best with accuracy of 98.0% and weighted average precision of 98.0%. SVM had 97.3% accuracy and 97.6% weighted average precision. Best performance was achieved at N=1,000 for RF and 1,100 for SVM. The conclusion was that a high accuracy and precision can be achieved using either RF or SVM. The classification model strengthens the value proposition of a digital pillbox and can improve clinical trials to achieve better data quality. However, for the model to contribute actual economical value, digital pillboxes must be a common practice in clinical trials. / Kliniska studier är experiment eller observationer av en patients reaktion på olika typer av medicinsk vård för behandling sjukdomar. Sådana studier är tungt reglerade och behöver uppnå en viss kvalitésstandard och klinisk följsamhet är en avgörande faktor för en studies framgång. Trots det har det historiskt varit svårt att systematiskt mäta och förstå en patients följsamhet av en medicinsk ordination, primärt på grund av brist av användbara verktyg. En ny typ av verktyg är en digital  pillerbox som försörjer piller till deltagare i kliniska studier. Denna studie undersöker implementation av två bevakade maskininlärningsmodeller för detektion om ett objekt (ett piller) befinner sig i ett slutet fack baserad på elektromagnetisk strålning från en närhetssensor. Support Vector Machine (SVM) och Random Forest (RF) utvärderades på ett dataset av N=1 485 observationer utgjort av fem klasser: fyra piller och ’inget piller’. RF presterar bäst med 98,0% i träffsäkerhet och 98,0% i viktad medelprecision. SVM fick 97,3% träffsäkerhet och 97,6% viktad medelprecision. Bäst prestation uppnåddes vid N=1 000 för RF och N=1 100 för SVM. Slutsatsen var att en hög träffsäkerhet och precision kan uppnås genom antingen RF eller SVM. Klassificeringsmodellen förstärker en digital pillerbox värdeerbjudande och kan hjälpa kliniska studier att uppnå högre datakvalité. Däremot, för klassificeringsmodellen ska bidra med faktiskt ekonomiskt värde, behöver digitala pillerboxar vara en vedertagen praxis.

The background and problem statement focuses on antiretroviral therapy (ART) and the use of mobile technology to improve compliance within a primary health care (PHC) context in South Africa. South Africa is one of the countries, globally, with the highest HIV incidence and prevalence and ART enrolled patients visiting PHC facilities. Compliance to ART plays an integral part in effective HIV/AIDS management. HIV/AIDS management entails a complex process of patient education and pharmacological control to improve ART compliance in South Africa. Studies were done in South Africa on reminder messages as most studies focused on chronic conditions in general. A literature review explored what is known about ART and mobile technology to improve compliance. Literature confirmed that compliance through reminder messages were done worldwide and in Sub-Saharan countries. Previous research indicated that the compliance rate of the patients increased through reminder messages. Yet there is a gap in the literature regarding reminder messages combined with health education on ART compliance. The aim of the study was to determine the impact of reminder messages combined with health education on ART compliance among patients receiving ART at a PHC facility Methodology: The study followed a quantitative, experimental, intervention, randomised multi-group, pre- and post measurement design (Creswell, 2012:1, Welman et al., 2012:80). The research design is experimental because the researcher applied an intervention (reminder messages) to two experimental groups. Random sampling was applied and participants were grouped into three groups: Group A, (control group), Group B, (reminder messages only) and Group C (reminder messages combined with health education). A preand post-measurement design is followed as each participant’s pill count and return date were measured before and after the reminder messages with/without health education were given. The sample size was 202 eligible patients receiving Regime 1 and 2 ART’s (Lamuvidine, Tenofovir, Efavirenz, Nevirapine, Alluvia® and Zidovudine) at a PHC facility in the North West, South Africa (N=202). The sample size was determined with guidance of statistical services to ensure that results obtained from the study would be reliable and significant. Data collection was done in three phases. Phase one (1) consisted of collecting the biographical data and a pre-measurement of pill count and return dates for participants in Groups A, B and C. Phase two (2) consisted of sending bi-weekly messages (Group B) via WinSMS and with health education (Group C) for three (3) months. Phase three (3) consisted of post-measurement of participants’ pill count and return date for Groups A,B and C. Data collection stretched over six months (October 2013-March 2014), namely three months pre-measurement, then activation of intervention combined with another three months post-measurement. Descriptive and inferential statistical analysis was conducted through SPSS (SPSS Inc., 2013). Descriptive statistics indicated that more female patients visited the PHC facility for ART on a more regular basis. It was concluded that the experimental group proved a slight increase in compliance with regards to return date after the SMS intervention. No difference was noted in compliance to pill counts. It can also be concluded that pill counts is a complex monitoring procedure with room for error from the patients’ aspect. / MCur, North-West University, Potchefstroom Campus, 2015

The background and problem statement focuses on antiretroviral therapy (ART) and the use of mobile technology to improve compliance within a primary health care (PHC) context in South Africa. South Africa is one of the countries, globally, with the highest HIV incidence and prevalence and ART enrolled patients visiting PHC facilities. Compliance to ART plays an integral part in effective HIV/AIDS management. HIV/AIDS management entails a complex process of patient education and pharmacological control to improve ART compliance in South Africa. Studies were done in South Africa on reminder messages as most studies focused on chronic conditions in general. A literature review explored what is known about ART and mobile technology to improve compliance. Literature confirmed that compliance through reminder messages were done worldwide and in Sub-Saharan countries. Previous research indicated that the compliance rate of the patients increased through reminder messages. Yet there is a gap in the literature regarding reminder messages combined with health education on ART compliance. The aim of the study was to determine the impact of reminder messages combined with health education on ART compliance among patients receiving ART at a PHC facility Methodology: The study followed a quantitative, experimental, intervention, randomised multi-group, pre- and post measurement design (Creswell, 2012:1, Welman et al., 2012:80). The research design is experimental because the researcher applied an intervention (reminder messages) to two experimental groups. Random sampling was applied and participants were grouped into three groups: Group A, (control group), Group B, (reminder messages only) and Group C (reminder messages combined with health education). A preand post-measurement design is followed as each participant’s pill count and return date were measured before and after the reminder messages with/without health education were given. The sample size was 202 eligible patients receiving Regime 1 and 2 ART’s (Lamuvidine, Tenofovir, Efavirenz, Nevirapine, Alluvia® and Zidovudine) at a PHC facility in the North West, South Africa (N=202). The sample size was determined with guidance of statistical services to ensure that results obtained from the study would be reliable and significant. Data collection was done in three phases. Phase one (1) consisted of collecting the biographical data and a pre-measurement of pill count and return dates for participants in Groups A, B and C. Phase two (2) consisted of sending bi-weekly messages (Group B) via WinSMS and with health education (Group C) for three (3) months. Phase three (3) consisted of post-measurement of participants’ pill count and return date for Groups A,B and C. Data collection stretched over six months (October 2013-March 2014), namely three months pre-measurement, then activation of intervention combined with another three months post-measurement. Descriptive and inferential statistical analysis was conducted through SPSS (SPSS Inc., 2013). Descriptive statistics indicated that more female patients visited the PHC facility for ART on a more regular basis. It was concluded that the experimental group proved a slight increase in compliance with regards to return date after the SMS intervention. No difference was noted in compliance to pill counts. It can also be concluded that pill counts is a complex monitoring procedure with room for error from the patients’ aspect. / MCur, North-West University, Potchefstroom Campus, 2015

O presente trabalho cuida das técnicas comumente referidas como cláusula de proteção à dispersão acionária, empregadas pelas companhias brasileiras. Tais técnicas foram apelidadas pela comunidade jurídica nacional de poison pills (pílulas de veneno). A expressão já é utilizada na experiência norte-americana para se referir a um conjunto de medidas defensivas contra a tomada de controle hostil, com as quais a poison pill à brasileira guarda pouca semelhança. O tema insere-se no contexto mais amplo da tomada de controle da companhia aberta (takeover) e as técnicas de defesa usualmente empregadas para impedi-la ou dificultá-la, quando indesejada. Tais técnicas são principalmente empregadas por companhias com capital disperso no mercado mobiliário e cujo poder de controle é exercido com a detenção de parcela reduzida do capital social. A busca pela maior dispersão acionária, bem como a presença apenas de ações votantes, fez com que a pílula brasileira se tornasse especialmente comum nas companhias listadas no Novo Mercado da BM&F-Bovespa S.A. Bolsa de Valores, Mercadorias e Futuros. A análise proposta circunscreve-se a tais companhias e à defesa por elas adotada. Dessa forma, parte-se da análise da disciplina jurídica das ofertas públicas voluntárias (artigo 257 da Lei das Sociedades por Ações), principal instrumento para a tomada de controle da companhia aberta, passa-se pelos dois principais sistemas de regulação da tomada de controle, com destaque para os modelos norte-americanos e inglês/europeu, para enfim chegar à apreciação da medida defensiva denominada poison pill tanto como originalmente concebida, na prática forense norte-americana, quanto em sua versão brasileira. É tema recente na literatura jurídica brasileira, ainda pouco explorado, mas bastante conhecido, estudado e vivenciado pela doutrina e experiência estrangeira, com apoio na qual o presente trabalho foi desenvolvido / Il presente lavoro si occupa delle tecniche comunemente citate come clausola di protezione alla dispersione azionaria, usate dalle società brasiliane. Dette tecniche sono state soprannominate dalla comunità giuridica nazionale di poison pills (pillole di veleno). Lespressione già è utilizzata nellesperienza nordamericana per riferirsi a un insieme di misure difensive contro la scalata ostile, con la quale la poison pill alla brasiliana si somiglia molto poco. Il tema si inserisce nel contesto più ampio della scalata della società cotata (takeover) e le tecniche di difesa usualmente impiegate per impedirla o tornarla più difficile, quando non desiderata. Tali tecniche sono principalmente usate da società con capitale disperso sul mercato mobiliare e il cui potere di controllo è praticato con il controllo di porzione ridotta del capitale sociale. La ricerca per una maggiore dispersione azionaria, così come la presenza solamente di azioni votanti, ha fatto con che la pillola brasiliana si tornassi specialmente comune nelle società elencate nel Nuovo Mercato della BM&F-Bovespa S.A. Borsa Valori, Borsa Merce e Mercato a termine. Lanalisi proposta è circoscritta a dette società e alla difesa da loro adottate. In questo modo, si parte dallanalisi della disciplina giuridica delle offerte pubbliche volontarie (articolo 257 della Legge di Società per Azioni), principale strumento per la scalata del controllo di società cotata, passiamo per i due principali sistemi di regolazione della scalata, con distacco ai modelli nordamericani e inglese/europeo, per infine arrivare alla valutazione della misura difensiva denominata poison pill tanto come originalmente concepita, nella pratica forense nordamericana, quanto nella sua versione brasiliana. È tema recente nella letteratura giuridica brasiliana, ancora poco investigata, ma abbastanza conosciuta, studiata e vissuta dalla dottrina ed esperienza straniera, con base nella quale il presente lavoro è stato sviluppato.