L'approche qui a été développée dans l'équipe imXgam du CPPM est de combiner sur un unique support rotatif les modules de détection de la caméra pour petit animal ClearPET avec un détecteur de rayons X à comptage de photons dans le but d'acquérir simultanément des images anatomiques (TDM) et fonctionnelles (TEP) du même champ de vue. L'étude préliminaire du système hybride ClearPET/XPAD3 menée en simulation avec Gate a permis d'implémenter une nouvelle géométrie de détection TEP à 21 détecteurs phoswich, de fixer les grandes lignes de l'assemblage TEP/TDM, ainsi que d'étudier et de solutionner les difficultés liées au régime de fonctionnement bimodal. Pour finir, l'outil de simulation a également permis d'imaginer comment un tel système pourrait judicieusement exploiter la corrélation spatiale et temporelle des informations anatomo-fonctionnelles. Du point de vue de l'instrumentation, ce projet a vu la mise en oeuvre du système hybride simultané ClearPET/XPAD3. Une fois les deux systèmes TEP et TDM opérationnels individuellement, il a été démontré, d'une part que le ClearPET est parfaitement capable d'opérer en régime de fonctionnement simultané moyennant un blindage approprié de ses modules de détection, et d'autre part que la nouvelle génération de caméra à pixels hybrides XPAD3-S/Si s'avère très prometteuse compte tenu de la bonne qualité des premières images reconstruites. Finalement, la preuve de concept d'une acquisition TEP/TDM simultanée avec une source de positons scellée et un tube à rayons X a pu être concrètement démontrée.

Background and objectives: Several new psychoactive drugs for the treatment of psychiatric disorders have been introduced onto the market since the late 1980s. Basic aspects of pharmacodynamics and pharmacokinetics (PK) are investigated before approval for general prescription. Thus, a limited number of subjects are exposed to the drug before it is marketed and only sparse measurements of drug concentration are performed during phases II and III of drug development. The objective of this thesis was to provide further descriptive PK and linked patients data in naturalistic clinical settings. The PK of psychoactive drugs was also studied in the elderly and the young, major risk groups that are exposed in normal everyday clinical practice but that are underrepresented in the phases of drug development. The PK-data were to be assessed by samples sent to the Therapeutic Drug Monitoring (TDM) laboratory service. In a subset of individuals, the genotypes of the cytochrome P450 (CYP) enzymes were described. Results: Serum concentration of the parent compound and its metabolites was provided from TDM-data on antidepressant escitalopram (Paper I) and antipsychotic ziprasidone (Paper II). A large interindividual PK variability was found. The daily dose of the drug was higher than the defined daily dose (DDD) for both escitalopram and ziprasidone (median dose 20 mg and 120 mg, respectively). The median number of drugs per patient, apart from the studied drug, was 4 and 3, respectively (range 1-18). If repeated eligible TDM-data were available, change in treatment strategies could be seen between the first and second sample for the patient, and the metabolite/parent compound (M/P) ratio had lower intraindividual than interindividual variation in the escitalopram study but opposite results were found in the ziprasidone study. The prescription of antidepressant drugs (ADs) in the nursing homes studied was 38 % (Paper III). The concentration of the ADs was higher, or much higher, than could be expected from the dose administered in 73 %. The majority of the elderly people were treated with citalopram. No clear time schedule for how long the drug treatment should continue was found in the patients’ current medical record. The median number of drugs per patient apart from the AD was 11 (range 4-19), no monotherapy was found in these patients. The genetically impaired metabolic activity of CYP enzymes correlated to higher drug concentration as expected, in patients medicated with an AD that is substrate for the CYP enzyme genotype. The concentrations of ADs were as expected from the dose administered in 63 % of the children/adolescents evaluated (Paper IV). The majority of TDM samples requested sertraline. PK outcome of sertraline was similar to the results in adult populations. Monotherapy was documented in 49 % (median number of drugs apart from AD was 1 per patient, range 1-7). Changes in treatment strategies were also shown, if repeated TDM-samples were available. The median variation of the M/P ratio for sertraline between the first and the last samples within the same patient was 20 % (the interindividual variation was 37 %). The poor metabolizers (PM) for CYP2D6 medicated with a CYP2D6 substrate had a lower dose than did non-PM for the same drug. Conclusion: These studies provide reference data for the evaluation of the therapeutic response, i.e. a reference range of what is to be expected in a normal clinical setting, as well as the toxicological information concerning the psychoactive drugs studied. When available, the M/P ratio between two patients’ samples may assess patient compliance, as well as drug-drug interactions. Thus, the use of TDM can be beneficial for individual dose optimisation and drug safety, above all in the studied populations, elderly people and children/adolescents, when the selection of doses requires a consideration of PK parameters. TDM may be a tool for research, increasing knowledge of the psychoactive drug in TDM service, as well as toxicology. A more frequent clinical use of TDM and pharmacogenetic testing in clinical practice would contribute to a better quality when treating with psychoactive drugs.

Le facteur pronostic majeur des cancers du col localement avancés (LACC) est le statut ganglionnaire lombo-aortique. Notre travail de thèse a été d'évaluer la lymphadénectomie lombo-aortique (qui représente la technique de référence pour obtenir cette information) à l'ère de la tomographie par émission de positron (TEP) et de la chirurgie par une seule incision (LESS). Les résultats publiés de cette thèse sont: la lymphadénectomie lombo-aortique extrapéritonéale par LESS est faisable. Nous en avons décrit et codifié la technique pour la première fois par une incision iliaque gauche unique ; cette technique que nous avons mise au point est sure, reproductible et équivalente sur le plan carcinologique et ergonomique à la laparoscopie conventionnelle ; la lymphadénectomie lombo-aortique de staging est indispensable dans les LACC compte tenu du taux de faux négatif du TEP-TDM retrouvé dans ce travail de thèse (12% s'élevant à 22 % en cas de fixations ganglionnaires pelviennes suspectes). Nous avons également démontré sur la plus large de la série de littérature que la lymphadénectomie lombo-aortique associée à l'extension des champs d'irradiation en lombo-aortique lors de la radio-chimiothérapie apporte aux patientes présentant des micrométastases une survie identique à celle des patientes négatives histologiquement au niveau lombo-aortique. En revanche, en cas d'atteinte macrométastatique le pronostic demeure péjoratif et nécessite de proposer d'autres options thérapeutiques.

Neste trabalho analisamos e propomos a utilização de TDM (Time Division Multiplexing) nativo canalizado/estruturado em redes PON (Passive Optical Network) com padrão GPON (Gigabit Passive Optical Network), com ênfase na estrutura de transmissão do legado das redes de telefonia. O objetivo principal é obter um aumento na eficiência de banda transmitida através da fragmentação de sinais E1 sem que seja necessário o uso de técnicas de emulação de circuito (que reduzem a eficiência de banda devido à adição de cabeçalhos). Inicialmente, é descrito o transporte TDM em redes GPON, como efetuado pelos equipamentos comerciais atuais através de duas técnicas: CES - Circuit Emulation Service e TDM nativo não estruturado. Em seguida, é introduzido o conceito de comutação digital visando sua aplicação no transporte TDM nativo estruturado em redes GPON. Nesta etapa, é proposta uma solução para este transporte, é descrito o protocolo utilizado bem como seu funcionamento. Por fim, como prova de conceito, é apresentada uma implementação em HDL (Hardware Description Language) para FPGA (Field Programmable Gate Array). / In this work we analyze and propose the use of native channeled /structured TDM (Time Division Multiplexing) in GPON (Gigabit Passive Optical Network), with emphasis on the structure for transmission of the telephone network legacy. The main target is to achieve an increase in transmitted bandwidth efficiency by fragmenting E1 signals, thus avoiding the use of circuit emulation techniques (which reduce the bandwidth efficiency due to overhead addition). Initially, it is described in TDM transport in GPON networks, as it is performed in present commercial equipment by two techniques: CES - Circuit Emulation Service and Native TDM - unstructured. Next, we introduce the concepts of digital switching aiming its application on the transport of native and structured TDM in GPON. At this stage, we propose a transport solution, describe its protocol and functionalities. Finally, for concept proof, we present an implementation in HDL (Hardware Description Language) meant to FPGA (Field Programmable Gate Array) application.

Abstract The present dissertation deals with the evaluation of multiple-input multiple-output (MIMO) radio channel characteristics from time-division multiplexing (TDM)-switched MIMO channel sounding. The research can be divided into three main areas. First, the impacts of phase noise in TDM-switched MIMO channel sounding on channel capacity are studied. Second, we focus on those impacts on channel parameter estimation using the SAGE algorithm. And in the last part, spatial correlation, channel eigenvalue distribution, and ergodic capacity in realistic environments are analyzed. The rationale behind the first two areas is that most advanced MIMO radio channel sounders employ the TDM technique, which has significant problems from phase noise of the TX and RX phase locked loop (PLL) oscillators causing measurement errors in terms of estimated channel capacity and parameters. We propose statistical models that reproduce the capacity estimates. The effects of the sounding mode (SM), the length of pseudo-random noise (PN) sequence L of the sounding signal, and the system size are disclosed. The distinctive basis is to consider the impact of the actual phase noise in TDM switched MIMO channel sounding, instead of assuming white Gaussian-type phase noise. In a reality, the short-term phase noise component affecting one measurement cycle of a MIMO system plays an important role in the traditional estimators of the radio channel parameters and capacity. We show that the performance impairment is less than that been under the hypothesis of uncorrelated white Gaussian phase-noises samples. The difference is due to the non-vanishing correlation of phase-noise within the measurement cycle. Two approaches to mitigating the impact of phase noise are proposed. The former is the simple and efficient sliding averaging method, where the signal-to-noise ratio (SNR) of the channel impulse response can be increased. The latter is the choice of SM and L, which is more thorough. In the second part, two approaches to mitigating its impact on channel parameter estimation using the SAGE algorithm are also discussed. Besides the sliding averaging, which in general can increase the SNR, the new SAGE algorithm based channel parameter estimation based on the improved signal model accounting for the phase noise in the measurement device is proposed. Finally, the channel eigenvalue distribution and ergodic capacity based on complex hypergeometric functions and their asymptotic characteristics are analyzed. It is shown that the derived theoretical expressions closely approximate the simulated results of the measured finite-dimensional MIMO channels. The spatial correlation and the eigenvalue statistics in frequency selective channels for single and dual polarized antennas are investigated. This knowledge is useful when different MIMO and beamforming techniques are applied.

<p>Suboptimal dosing of anti-microbial agents increases the likelihood of therapeutic failure and resistance. Dosing optimization, while an attractive approach to combat these issues, is difficult to implement due to the different pharmacokinetics of each individual. These limitations highlight the inadequacies of a “standardized” dosing strategy. Therapeutic drug monitoring (TDM) provides a tailored treatment for individuals while avoiding adverse side effects from compounds with a narrow therapeutic window where elevated concentrations of a drug cause organ toxicity. This strategy involves accurately measuring the concentration of the analyte and interpreting the results based on pharmacokinetic parameters. Clinicians then draw conclusions regarding dose adjustment for their patient. However, TDM is expensive and difficult to perform because measurements occur in biofluids. Rapid and robust methods are necessary to quantify antimicrobial agents at the institutional level to guide patient care toward improved outcomes in serious infection. Paper spray ionization (PS), an emerging ambient ionization technique for clinical settings, demonstrations a wide versatility both in analyte variety and applications. This technique offers a rapid, accurate method to analyze these compounds with low rates of false positives even when multiplexing.</p><p><br></p><p>The work herein explains the method development of assays for TDM of various antimicrobial agents. Chapters two and three describe ways to improve the quantitative capability of paper spray through substrate pre-treatment, modification, and manipulation of key factors. Chapter four describes real-world applications for paper spray utility in clinical settings with the cross-validation of antifungal agents against a “gold standard” method. The final chapter, while not clinical based, describes the method development process for a LC-MS/MS assay to detect urobilinoids in fly guts.</p>

Indiana University-Purdue University Indianapolis (IUPUI) / Suboptimal dosing of anti-microbial agents increases the likelihood of therapeutic failure and resistance. Dosing optimization, while an attractive approach to combat these issues, is difficult to implement due to the different pharmacokinetics of each individual. These limitations highlight the inadequacies of a “standardized” dosing strategy. Therapeutic drug monitoring (TDM) provides a tailored treatment for individuals while avoiding adverse side effects from compounds with a narrow therapeutic window where elevated concentrations of a drug cause organ toxicity. This strategy involves accurately measuring the concentration of the analyte and interpreting the results based on pharmacokinetic parameters. Clinicians then draw conclusions regarding dose adjustment for their patient. However, TDM is expensive and difficult to perform because measurements occur in biofluids. Rapid and robust methods are necessary to quantify antimicrobial agents at the institutional level to guide patient care toward improved outcomes in serious infection. Paper spray ionization (PS), an emerging ambient ionization technique for clinical settings, demonstrations a wide versatility both in analyte variety and applications. This technique offers a rapid, accurate method to analyze these compounds with low rates of false positives even when multiplexing. The work herein explains the method development of assays for TDM of various antimicrobial agents. Chapters two and three describe ways to improve the quantitative capability of paper spray through substrate pre-treatment, modification, and manipulation of key factors. Chapter four describes real-world applications for paper spray utility in clinical settings with the cross-validation of antifungal agents against a “gold standard” method. The final chapter, while not clinical based, describes the method development process for a LC-MS/MS assay to detect urobilinoids in fly guts.

Project is focused on description DVB broadcasting for hand-held’s. It describes standard DVB-H that is founded on DVB-T and uses its transmission infrastructure. Standard DVB-SH is a hybrid system that adds to terrestrial broadcasting satellite connection. Signal can extend by various environments, therefore it are defined models transmission channel with defined parameters. Simulation of the transmission in both channel are realized in user application created in MATLAB. Finally, obtained results are evaluated and discussed.

Die vorliegende monografische Publikationsschrift gründet sich auf einer retrospektiven Studie von Labordaten, welche in den Jahren 2003-2010 für pädiatrische Patienten am Institut für klinische Pharmakologie Leipzig erhoben, erfasst und ausgewertet wurden. Das Ziel der Studie besteht in der Identifizierung von entbehrlichen Therapeutisches Drug Monitoring (TDM)-Leistungen, der Validierung von nicht-entbehrlichen TDM-Leistungen, sowie der Generierung von Aussagen zur Arzneimittelsicherheit und Bewertung der Gefährdung bei Intoxikationen.:1. Einführung 1.1 Stellenwert der Arzneimitteltherapie in der modernen Medizin 1.2 Gewährleistung einer adäquaten Arzneimittel-Anwendung 1.2.1 Klinisches Monitoring 1.2.2 Therapeutisches Drug-Monitoring (TDM) 1.2.2.1 Therapeutische Bereiche als Zielwerte 1.2.2.2 Durchführung eines Therapeutisches Drug-Monitoring 1.2.2.3 Indikationen für ein Therapeutisches Drug-Monitoring 1.3 Spezifika der pädiatrischen Arzneimitteltherapie 1.3.1 Limitierte Daten und Zulassungen für Arzneimittel in der Pädiatrie 1.3.2 Verwendung von Medikamenten außerhalb der Zulassung 1.3.2.1 Rechtliche Aspekte des off-label-use 1.3.2.2 Dosisfindung bei off-label-use 1.3.3 Physiologische Besonderheiten pädiatrischer Patienten 1.3.3.1 Aufnahme 1.3.3.2 Verteilung 1.3.3.3 Metabolisierung 1.3.3.4 Elimination 1.3.4 Psychosoziale Entwicklung und ihr Einfluss auf die Arzneimitteltherapie 1.3.4.1 Auswirkungen auf die Compliance 1.3.4.2 Anpassung der Arzneimittel-Darreichungsform an den Entwicklungsstand 1.3.4.2 Aufgabenstellung und angestrebter Erkenntnisgewinn 2. 2. Aufgabenstellung und angestrebter Erkenntnisgewinn 2.1 2.1 Sicherheit von Medikamenten und typische Wirkstoffkonzentrationen 2.2 Einschätzung der Gefährdung durch Intoxikationen 2.3 Bewertung valider und Identifizierung potenziell entbehrlicher TDM-Indikationen 3. Material und Methoden 3.1 Organisationsstruktur, Methodik, Leistungsspektrum und Qualitätssicherung 3.2 Methodik der Datenerhebung und Datenanalyse 4. Ergebnisse 4.1 Übersicht über die der Studie zugrundeliegenden Daten und deren Analyse 4.2 Antiepileptika 4.2.1 Oxcarbazepin (OXC) 4.2.2 Levetiracetam (LEV) 4.2.3 Phenobarbital (PB) 4.2.4 Topiramat (TPM) 4.3 Digoxin (DGX) 4.4 Koffein und Theophyllin 4.5 Antimikrobiotika 4.5.1 Glykopeptide 4.5.2 Aminoglykoside 4.5.3 Azol-Antimykotika 4.6 Antipsychotika 4.6.1 Risperidon 4.6.2 Quetiapin 4.6.3 Olanzapin 4.6.4 Weitere (Clozapin, Amisulprid, Ziprasidon) 4.7 Antidepressiva 4.7.1 Fluoxetin 4.7.2 Citalopram 4.7.3 Sertralin 4.7.4 Mirtazapin 4.8 Benzodiazepine 4.8.1 Clobazam 4.8.2 Diazepam/ Nordiazepam 4.8.3 Midazolam 4.9 Paracetamol 4.10 Drogenscreening 5. Diskussion 6. Zusammenfassung 7. Literaturverzeichnis 8. Anhang 9. Selbständigkeitserklärung, Lebenslauf, Danksa

Ces travaux de thèse portent sur la proposition de stratégies de segmentation des tumeurs cancéreuses dans un contexte multimodal et multitemporel. La multimodalité fait référence au couplage de données TEP/TDM pour exploiter conjointement les deux sources d’information pour améliorer les performances de la segmentation. La multitemporalité fait référence à la disposition des images acquises à différents dates, ce qui limite une correspondance spatiale possible entre elles.Dans une première méthode, une structure arborescente est utilisée pour traiter et pour extraire des informations afin d’alimenter une segmentation par marche aléatoire. Un ensemble d'attributs est utilisé pour caractériser les nœuds de l'arbre, puis le filtrer et projeter des informations afin de créer une image vectorielle. Un marcheur aléatoire guidé par les données vectorielles provenant de l'arbre est utilisé pour étiqueter les voxels à des fins de segmentation.La deuxième méthode traite le problème de la multitemporalité en modifiant le paradigme de voxel à voxel par celui de nœud à nœud. Deux arbres sont alors modélisés à partir de la TEP et de la TDM avec injection de contraste pour comparer leurs nœuds par une différence entre leurs attributs et ainsi correspondre à ceux considérés comme similaires en supprimant ceux qui ne le sont pas.Dans une troisième méthode, qui est une extension de la première, l'arbre calculé à partir de l'image est directement utilisé pour mettre en œuvre l'algorithme développé. Une structure arborescente est construite sur la TEP, puis les données TDM sont projetées sur l’arbre en tant qu’informations contextuelles. Un algorithme de stabilité de nœud est appliqué afin de détecter et d'élaguer les nœuds instables. Des graines, extraites de la TEP, sont projetées dans l'arbre pour fournir des étiquettes (pour la tumeur et le fond) à ses nœuds correspondants et les propager au sein de la hiérarchie. Les régions évaluées comme incertaines sont soumises à une méthode de marche aléatoire vectorielle pour compléter l'étiquetage de l'arbre et finaliser la segmentation. / This work focuses on the proposition of cancerous tumor segmentation strategies in a multimodal and multitemporal context. Multimodal scope refers to coupling PET/CT data in order to jointly exploit both information sources with the purpose of improving segmentation performance. Multitemporal scope refers to the use of images acquired at different dates, which limits a possible spatial correspondence between them.In a first method, a tree is used to process and extract information dedicated to feed a random walker segmentation. A set of region-based attributes is used to characterize tree nodes, filter the tree and then project data into the image space for building a vectorial image. A random walker guided by vectorial tree data on image lattice is used to label voxels for segmentation.The second method is geared toward multitemporality problem by changing voxel-to-voxel for node-to-node paradigm. A tree structure is thus applied to model two hierarchical graphs from PET and contrast-enhanced CT, respectively, and compare attribute distances between their nodes to match those assumed similar whereas discarding the others.In a third method, namely an extension of the first one, the tree is directly involved as the data-structure for algorithm application. A tree structure is built on the PET image, and CT data is then projected onto the tree as contextual information. A node stability algorithm is applied to detect and prune unstable attribute nodes. PET-based seeds are projected into the tree to assign node seed labels (tumor and background) and propagate them by hierarchy. The uncertain nodes, with region-based attributes as descriptors, are involved in a vectorial random walker method to complete tree labeling and build the segmentation.