e-Learning, defined as the use of information and communications technology (ICT) for supporting the educational process, has motivated Tanzania to apply ICT in its education systems. Tanzanian secondary schools which are geographically and socially isolated face a number of problems, including a way to get learning materials. The impact of these problems is poor performance in National Examinations. This poor performance however is most noted in science and mathematics. The problem in get- ting learning materials can be reduced by employing ICT. This research developed an interactive e-learning management system (e-LMS) to be used by Tanzanian secondary schools. Tanzania Secondary Schools e-Learning (TanSSe-L) system is the name adopted for an interactive e-LMS developed. The re- search is aimed at supporting teaching and learning functions by allowing for the creation and storage of learning materials, making them available, easily accessed and sharable by students from different secondary schools in Tanzania. It is a context- driven research work of knowledge production in a specific context for application. Initially, the research work focused on two selected pilot schools; Kibaha Secondary School and Wali-ul-Asr Girls’ Seminary in Kibaha town, Pwani region. Features of the TanSSe-L system represent the standard form of any secondary school registered by the Ministry of Education and Vocational Training. The development of the TanSSe-L system made use of software engineering discipline. The research used Unified Modelling Language (UML) and integrated Object-Orient- ed System Analysis and Design (OOSA&D) and Model Driven Architecture (MDA) to address the System Development Life Cycle (SLDC) in a systemic way. UML design class diagram (DCD) is a Platform Independent Model (PIM) that was transformed into a Platform Specific Model (PSM) in MDA for implementation. Implementation made use of open source LMS to help generate a timely solution to TanSSe-L system development. In this specific context, focus group discussion as inspired by action re- search methodology was used. The research evolved into a triple helix process in close cooperation with other stakeholders. Finally, it is considered that replication and mirroring will make learning materials highly available to end-users.

Tandem mass spectrometry, also known as MS/MS, is an analytical technique to measure the mass-to-charge ratio of charged ions and widely used in genomics, proteomics and metabolomics areas. There are two types of automatic ways to interpret tandem mass spectra: de novo methods and database searching methods. Both of them need to use massive computational resources and complicated comparison algorithms. The real-time peptide-spectrum matching (RT-PSM) algorithm is a database searching method to interpret tandem mass spectra with strict time constraints. Restricted by the hardware and architecture of an individual workstation the RT-PSM algorithm has to sacrifice the level of accuracy in order to provide prerequisite processing speed. The peptide-spectrum similarity scoring module is the most time-consuming part out of four modules in the RT-PSM algorithm, which is also the core of the algorithm. In this study, a multi-core computing algorithm is developed for individual workstations. Moreover, a distributed computing algorithm is designed for a cluster. The improved algorithms can achieve the speed requirement of RT-PSM without sacrificing the accuracy. With some expansion, this distributed computing algorithm can also support different PSM algorithms. Simulation results show that compared with the original RT-PSM, the parallelization version achieves 25 to 34 times speed-up based on different individual workstations. A cluster with 240 CPU cores could accelerate the similarity score module 210 times compare with the single-thread similarity score module and the whole peptide identification process 85 times compare with the single-thread peptide identification process.

<p>Soft matter systems exhibiting spatially modulated patterns on a mesoscale are characterized by many long-lived metastable phases for which relaxation to equilibrium is difficult and a satisfactory thermodynamic description is missing. Current dynamical theories suffer as well, because they mostly rely on an understanding of the underlying equilibrium behavior. This thesis relates the study of two canonical examples of modulated systems: microphase and cluster crystal formers. Microphases are the counterpart to gas-liquid phase separation in systems with competing short-range attractive and long-range repulsive interactions. Periodic lamellae, cylinders, clusters, etc., are thus observed in a wide variety of physical and chemical systems, such as multiblock copolymers, oil-water surfactant mixtures, charged colloidal suspensions, and magnetic materials. Cluster crystals in which each lattice site is occupied by multiple particles are formed in systems with steep soft-core repulsive interactions. Dendrimers have been proposed as a potential experimental realization. In order to access and understand the equilibrium properties of modulated systems, we here develop novel Monte Carlo simulation methods. A thermodynamic integration scheme allows us to calculate the free energy of specific modulated phases, while a [N]pT ensemble simulation approach, in which both particle number and lattice spacing fluctuate, allows us to explore their phase space more efficiently. With these two methods, we solve the equilibrium phase behavior of five schematic modulated-phase-forming spin and particle models, including the axial next-nearest-neighbor Ising (ANNNI) model, the Ising-Coulomb (IC) model, the square-well linear (SWL) model, the generalized exponential model of index 4 (GEM-4) and the penetrable sphere model (PSM). Interesting new physics ensues. In the ANNNI layered regime, simple phases are not found to play a particularly significant role in the devil's flowers and interfacial roughening plays at most a small role. With the help of generalized order parameters, the paramagnetic-modulated critical transition of the ANNNI model is also studied. We confirm the XY universality of the paramagnetic-modulated transition and its isotropic nature. With our development of novel free energy minimization schemes, the determination of a first phase diagram of a particle-based microphase former SWL is possible. We identify the low temperature GEM-4 phase diagram to be hybrid between the Gaussian core model (GCM) and the PSM. The system additionally exhibits S-shaped doubly reentrant phase sequences as well as critical isostructural transitions between face-centered cubic (FCC) cluster solids of different integer occupancy. The fluid-solid coexistence in the PSM phase diagram presents a crossover behavior around T~0.1, below which the system approaches the hard sphere limit. Studying this regime allows us to correct and reconcile prior DFT and cell theory work around this transition.</p> / Dissertation

Base Teórica: O câncer de mama é provavelmente o mais temido pelas mulheres devido a sua alta freqüência e, sobretudo, pelos seus efeitos psicológicos que afetam a percepção da sexualidade e a própria imagem pessoal. Ele é relativamente raro antes dos 35 anos de idade, mas acima desta faixa etária sua incidência cresce rápida e progressivamente. Estudos indicam que fatores genéticos e ambientais são responsáveis pela incidência do câncer de mama, sendo que a hereditariedade provavelmente tenha participação restrita no desenvolvimento deste tipo de tumor. Os principais genes associados ao desenvolvimento do câncer de mama, BRCA1 e BRCA2, são responsáveis por cerca de 80% desses casos, conferindo um risco de 71 a 85% de chance de desenvolver a neoplasia em alguma fase da vida. Mutações nesses genes, classificados como supressores tumorais, demonstram que a perda de suas funções não pára o ciclo celular, não permite a ação do sistema de reparo, e não estimula a apoptose (morte celular programada), culminando em replicação anormal e câncer. A observação epidemiológica de que mulheres judias de origem Ashkenazi parecem ser mais vulneráveis ao câncer de mama está sendo explicada através de estudos moleculares dos genes BRCA1 e BRCA2, onde encontramos a prevalência de três mutações específicas: 185delAG e 5382insC, no gene BRCA1 e 6174delT, no gene BRCA2. Métodos: Utilizou-se um banco de DNA pré-existente, extraído de 209 mulheres da comunidade judaica Ashkenazi da cidade de Porto Alegre. A amplificação do DNA foi realizada por PCR, através da técnica PSM (PCR Mediated site-direct) seguida de digestão dos produtos de PCR com enzimas de restrição. Os objetivos foram verificar se as freqüências das mutações 185delAG e 5382insC, no gene BRCA1 são significativas nesta população e compará-las com demais freqüências encontradas. Resultados: Foram encontradas três pacientes com a mutação 185delAG e duas pacientes com a mutação 5382insC, com as freqüências de 1,435% (95% IC: 0,366; 3,856) e 0,957% (95% IC: 0,161; 3,125), respectivamente. / Introduction: Breast cancer is probably the worst diagnosed cancer for women due to its high frequency and furthermore by its psychological problems that affect the perception of sexuality and the self image. It is relatively rare before 35 years of age, but beyond this age its incidence increases rapidly and progressively. Studies show that genetic and environmental factors are responsible for breast cancer incidence, but heredity may play a restrict role in the development of this kind of tumor. The main genes associated to the development of breast cancer, BRCA1 and BRCA2, are responsible for almost 80% of these cases, reaching a chance between 71 and 85% of developing the disease at any life stage. Mutations in these genes, classified as tumor suppressors, do not allow the repair mechanisms of DNA to perform its action and do not stimulate apoptosis, culminating in abnormal replication and cancer. The epidemiological observation in which Ashkenazi Jewish women seems to be more vulnerable to breast cancer is explained through molecular studies of BRCA1 and BRCA2 genes, where three specific mutations have been found (185delAG and 5382insC, in the BRCA1 gene and 6174delT, in the BRCA2 gene). Methods: A pre-existent bank of DNA extracted from 209 women of the Ashkenazi Jewish community of Porto Alegre city has been used. The DNA amplification was performed through PCR, using the PSM (PCR Mediated Site-Direct) technique followed by the digestion of PCR products with restriction enzymes. The objectives of this study was to identify the frequencies of mutations 185delAG and 5382insC at the BRCA1 gene and verify if they are significantly different in this population when compared to frequencies found in other studies. Results: We found three patients with 185delAG mutation and two patients with 5382insC mutation, with frequencies of 1.435% (95% CI: 0,366; 3,856) and 0,957% (95% IC: 0,161; 3,125), respectively.

Base Teórica: O câncer de mama é provavelmente o mais temido pelas mulheres devido a sua alta freqüência e, sobretudo, pelos seus efeitos psicológicos que afetam a percepção da sexualidade e a própria imagem pessoal. Ele é relativamente raro antes dos 35 anos de idade, mas acima desta faixa etária sua incidência cresce rápida e progressivamente. Estudos indicam que fatores genéticos e ambientais são responsáveis pela incidência do câncer de mama, sendo que a hereditariedade provavelmente tenha participação restrita no desenvolvimento deste tipo de tumor. Os principais genes associados ao desenvolvimento do câncer de mama, BRCA1 e BRCA2, são responsáveis por cerca de 80% desses casos, conferindo um risco de 71 a 85% de chance de desenvolver a neoplasia em alguma fase da vida. Mutações nesses genes, classificados como supressores tumorais, demonstram que a perda de suas funções não pára o ciclo celular, não permite a ação do sistema de reparo, e não estimula a apoptose (morte celular programada), culminando em replicação anormal e câncer. A observação epidemiológica de que mulheres judias de origem Ashkenazi parecem ser mais vulneráveis ao câncer de mama está sendo explicada através de estudos moleculares dos genes BRCA1 e BRCA2, onde encontramos a prevalência de três mutações específicas: 185delAG e 5382insC, no gene BRCA1 e 6174delT, no gene BRCA2. Métodos: Utilizou-se um banco de DNA pré-existente, extraído de 209 mulheres da comunidade judaica Ashkenazi da cidade de Porto Alegre. A amplificação do DNA foi realizada por PCR, através da técnica PSM (PCR Mediated site-direct) seguida de digestão dos produtos de PCR com enzimas de restrição. Os objetivos foram verificar se as freqüências das mutações 185delAG e 5382insC, no gene BRCA1 são significativas nesta população e compará-las com demais freqüências encontradas. Resultados: Foram encontradas três pacientes com a mutação 185delAG e duas pacientes com a mutação 5382insC, com as freqüências de 1,435% (95% IC: 0,366; 3,856) e 0,957% (95% IC: 0,161; 3,125), respectivamente. / Introduction: Breast cancer is probably the worst diagnosed cancer for women due to its high frequency and furthermore by its psychological problems that affect the perception of sexuality and the self image. It is relatively rare before 35 years of age, but beyond this age its incidence increases rapidly and progressively. Studies show that genetic and environmental factors are responsible for breast cancer incidence, but heredity may play a restrict role in the development of this kind of tumor. The main genes associated to the development of breast cancer, BRCA1 and BRCA2, are responsible for almost 80% of these cases, reaching a chance between 71 and 85% of developing the disease at any life stage. Mutations in these genes, classified as tumor suppressors, do not allow the repair mechanisms of DNA to perform its action and do not stimulate apoptosis, culminating in abnormal replication and cancer. The epidemiological observation in which Ashkenazi Jewish women seems to be more vulnerable to breast cancer is explained through molecular studies of BRCA1 and BRCA2 genes, where three specific mutations have been found (185delAG and 5382insC, in the BRCA1 gene and 6174delT, in the BRCA2 gene). Methods: A pre-existent bank of DNA extracted from 209 women of the Ashkenazi Jewish community of Porto Alegre city has been used. The DNA amplification was performed through PCR, using the PSM (PCR Mediated Site-Direct) technique followed by the digestion of PCR products with restriction enzymes. The objectives of this study was to identify the frequencies of mutations 185delAG and 5382insC at the BRCA1 gene and verify if they are significantly different in this population when compared to frequencies found in other studies. Results: We found three patients with 185delAG mutation and two patients with 5382insC mutation, with frequencies of 1.435% (95% CI: 0,366; 3,856) and 0,957% (95% IC: 0,161; 3,125), respectively.

Base Teórica: O câncer de mama é provavelmente o mais temido pelas mulheres devido a sua alta freqüência e, sobretudo, pelos seus efeitos psicológicos que afetam a percepção da sexualidade e a própria imagem pessoal. Ele é relativamente raro antes dos 35 anos de idade, mas acima desta faixa etária sua incidência cresce rápida e progressivamente. Estudos indicam que fatores genéticos e ambientais são responsáveis pela incidência do câncer de mama, sendo que a hereditariedade provavelmente tenha participação restrita no desenvolvimento deste tipo de tumor. Os principais genes associados ao desenvolvimento do câncer de mama, BRCA1 e BRCA2, são responsáveis por cerca de 80% desses casos, conferindo um risco de 71 a 85% de chance de desenvolver a neoplasia em alguma fase da vida. Mutações nesses genes, classificados como supressores tumorais, demonstram que a perda de suas funções não pára o ciclo celular, não permite a ação do sistema de reparo, e não estimula a apoptose (morte celular programada), culminando em replicação anormal e câncer. A observação epidemiológica de que mulheres judias de origem Ashkenazi parecem ser mais vulneráveis ao câncer de mama está sendo explicada através de estudos moleculares dos genes BRCA1 e BRCA2, onde encontramos a prevalência de três mutações específicas: 185delAG e 5382insC, no gene BRCA1 e 6174delT, no gene BRCA2. Métodos: Utilizou-se um banco de DNA pré-existente, extraído de 209 mulheres da comunidade judaica Ashkenazi da cidade de Porto Alegre. A amplificação do DNA foi realizada por PCR, através da técnica PSM (PCR Mediated site-direct) seguida de digestão dos produtos de PCR com enzimas de restrição. Os objetivos foram verificar se as freqüências das mutações 185delAG e 5382insC, no gene BRCA1 são significativas nesta população e compará-las com demais freqüências encontradas. Resultados: Foram encontradas três pacientes com a mutação 185delAG e duas pacientes com a mutação 5382insC, com as freqüências de 1,435% (95% IC: 0,366; 3,856) e 0,957% (95% IC: 0,161; 3,125), respectivamente. / Introduction: Breast cancer is probably the worst diagnosed cancer for women due to its high frequency and furthermore by its psychological problems that affect the perception of sexuality and the self image. It is relatively rare before 35 years of age, but beyond this age its incidence increases rapidly and progressively. Studies show that genetic and environmental factors are responsible for breast cancer incidence, but heredity may play a restrict role in the development of this kind of tumor. The main genes associated to the development of breast cancer, BRCA1 and BRCA2, are responsible for almost 80% of these cases, reaching a chance between 71 and 85% of developing the disease at any life stage. Mutations in these genes, classified as tumor suppressors, do not allow the repair mechanisms of DNA to perform its action and do not stimulate apoptosis, culminating in abnormal replication and cancer. The epidemiological observation in which Ashkenazi Jewish women seems to be more vulnerable to breast cancer is explained through molecular studies of BRCA1 and BRCA2 genes, where three specific mutations have been found (185delAG and 5382insC, in the BRCA1 gene and 6174delT, in the BRCA2 gene). Methods: A pre-existent bank of DNA extracted from 209 women of the Ashkenazi Jewish community of Porto Alegre city has been used. The DNA amplification was performed through PCR, using the PSM (PCR Mediated Site-Direct) technique followed by the digestion of PCR products with restriction enzymes. The objectives of this study was to identify the frequencies of mutations 185delAG and 5382insC at the BRCA1 gene and verify if they are significantly different in this population when compared to frequencies found in other studies. Results: We found three patients with 185delAG mutation and two patients with 5382insC mutation, with frequencies of 1.435% (95% CI: 0,366; 3,856) and 0,957% (95% IC: 0,161; 3,125), respectively.

This paper is dedicated to the empirical analysis of the pilot trainee project Stáže ve firmách, which is considered as treatment in this analysis. The main objective of the empirical analysis is estimation of average treatment effect(ATE) and average treatment effect on treated(ATET) for characteristics like socioeconomic status and wage. Counterfactual methods for policy impact evaluation like Difference in Differences Estimator(DiD), First Differences Estimator(FD) and Propensity Score Matching(PSM) are used to estimation mentioned effects. This paper contains extension of Assignment Problem that is used for people matching purposes as alternative for PSM. This way of matching provides better control over creation of couples. Resulting pairs are more similar in selected characteristics due to better control during couples creation process.

<p dir="ltr">Plant secondary metabolites (PSMs) are specialized compounds produced in response to a range of insect herbivores and microbes, making them important in shaping tri-trophic interactions. However, despite being well-studied in the context of plant-insect coevolution, it is unclear how PSMs impact microbial communities associated with plants and the insect herbivores that feed on them. The overarching goal of this dissertation was to better understand how variation in plant defensive responses, particularly expression of PSMs, influences the composition and functional potential of microbial communities associated with plant tissues (roots and leaves) and insect herbivores. Monarchs (<i>Danaus plexippus</i>) and their milkweed hosts (<i>Asclepias spp.)</i> are well-studied for mechanisms of plant defense and insect counter defense, but little is known about the role of associated microbial communities in this iconic system. To address this knowledge gap, a combination of metabarcoding and metagenomics was used to characterize the taxonomic composition and functional gene profiles of bacterial communities associated with plant tissues (i.e., phyllosphere and rhizosphere) and monarch caterpillars fed on multiple milkweed species (<i>A. curassavica</i>, <i>A. syriaca</i>, and <i>A. tuberosa</i>). Findings show the composition of phyllosphere, rhizosphere, and monarch microbiomes vary across milkweed species in terms of diversity and relative abundance of bacterial taxa. Furthermore, phyllosphere and rhizosphere microbiomes were shown to have distinct functional gene profiles and presence of potential PSM metabolism genes that also varied across milkweed species. Rhizosphere microbiomes had a greater overall capacity for PSM metabolism compared to the phyllosphere, having more genes, and associated metabolic pathways involved in degradation or detoxification of known classes of PSMs. However, plant associated microbiomes were not generally affected by monarch feeding, evidenced by few changes in taxonomic composition or abundance of genes predicted to be involved in PSM metabolism. Interestingly, monarch microbiomes shared >90% of their taxa with their host plants, but there was little evidence of PSM metabolism genes present in functional gene profiles. Overall, this dissertation lays the foundation for understanding how PSMs shape all the microbial communities associated with monarchs and their milkweed hosts. Findings suggest plant defensive responses affect the assembly, functional potential and ultimately the evolution of plant and insect microbiomes.</p>

Malignome des Peritoneums (peritoneal surface malignancies, PSMs) treten als Mesotheliome oder Metastasen auf. Ihre Diagnose bedeutet häufig eine schlechtere Prognose als bei anderen Fernmetastasen. Die Standardtherapie in palliativer Intention ist in der Regel eine systemische Chemotherapie (sCHT). Intraperitoneale Druck-Aerosol-Chemotherapie (Pressurized intraperitoneal aerosol chemotherapy, PIPAC) ist eine neue, palliative Behandlungsmöglichkeit für ausgewählte Personen mit PSMs. Das Prinzip der laparoskopischen Vernebelung von Chemotherapeutika soll die Bioverfügbarkeit im Vergleich zu und anderen intraabdominellen Applikationen erhöhen. Sie wird meist in Kombination mit sCHT eingesetzt und zielt darauf ab, die Symptom- und Asziteslast der Behandelten zu reduzieren. Diese monozentrische, prospektive Registerstudie untersucht die Sicherheit, Durchführbarkeit und Wirksamkeit der PIPAC. Einschlusskriterien waren ein histologisch gesichertes PSM und eine positive Tumorboard-Entscheidung. Ausschlusskriterien waren extraperitoneale Fernmetastasen und ein Eastern Cooperative Oncology Group (ECOG) Performance Status größer als 2. Vor jeder PIPAC wurde eine strukturierte Anamnese, eine körperliche Untersuchung, sowie eine ausführliche chirurgische und onkologische Aufklärung durchgeführt. Die PIPAC-Prozeduren wurden laparoskopisch in Allgemeinanästhesie gemäß interner Standard Operating Procedure durchgeführt. Zunächst wurde Aszites aspiriert und quantifiziert. Anschließend wurde eine diagnostische Laparoskopie durchgeführt, der Zugang zum Abdomen als „access“ oder „non access“ beschrieben, sowie der peritoneale Adhäsionsindex (peritoneal adhesion index, PAI) nach Coccolini und der peritoneale Krebsindex (peritoneal cancer index, PCI) nach Sugarbaker erhoben. Sechs Peritonealbiopsien wurden standardisiert entnommen. Nach Präparation und Färbung mit Hämatoxylin und Eosin wurde die relative Tumormenge bestimmt. Nacheinander wurden Cisplatin und Doxorubicin in einer an die Körperoberfläche angepassten Dosierung appliziert. Die Chemotherapeutika wurden mit einer Injektionspumpe bei 200 psi und mit einer Flussrate von 0,5 ml/min über einen Hochdruckschlauch zum Vernebler gefördert. Dieser wurde auf dem 12 mm Trokar befestigt und verteilte die Medikamente im Abdomen. Währenddessen befand sich das gesamte Operationspersonal im separaten Einleitungsraum. Die Applikation wurde über einen Fußschalter gesteuert und durch ein Sichtfenster überwacht. Über den Druck im Kapnoperitoneum konnte freiwerdendes Aerosol detektiert werden. Nach 30 min wurde das Aerosol analog zu Narkosegasen in die Krankenhausentlüftung abgeleitet. Anschließend wurden die Behandelten für einige Stunden im Aufwachraum überwacht und dann auf die Normalstation gebracht. Postoperative Komplikationen wurden nach der Clavien Dindo Klassifikation (CDC) dokumentiert. Insgesamt wurden 108 Patient:innen (n = 55 Frauen, n = 53 Männer) mit einem medianen Alter von 60 Jahren (Interquartilsabstand [IQA] 53–‍69 Jahre) eingeschlossen. Sie wiesen Primärtumore verschiedener Entitätsgruppen auf: n = 41 (38 %) gastral, n = 26 (24 %) kolorektal, n = 9 (8 %) gynäkologisch und n = 15 (14 %) weitere (n = 7 Mesotheliome, n = 3 Pseudomyxoma peritonei, n = 5 Krebserkrankungen mit unbekanntem Primärtumor). Im Median wurden zwei PIPAC-Prozeduren pro Patient:in durchgeführt (IQA 1–‍3). Bei 12 Patient:innen wurde zuvor eine zytoreduktive Chirurgie (CRS) mit hyperthermer intraperitonealer Chemoperfusion (HIPEC) durchgeführt. Von 230 geplanten PIPAC-Prozeduren konnten 189 durchgeführt werden. 41 Prozeduren mussten abgebrochen oder storniert werden: 9 Patient:innen zeigten bei der Aufnahmeuntersuchung einen verschlechterten Allgemeinzustand (z. B. neue Fernmetastasen im Computertomogramm). 3 Patient:innen aspirierten während der Narkoseeinleitung. Bei 7 Laparoskopien war makroskopisch kein PSM mehr nachweisbar. In 22 Fällen war das Abdomen nicht zugänglich (non-access) und/oder es kam zu Darmläsionen. Bei der Aufnahmeuntersuchung vor jeder PIPAC-Prozedur wiesen die Patient:innen in den meisten Fällen keine der spezifisch erhobenen Symptome auf. 55 (24 %) klagten über Bauchschmerzen, 47 (21 %) über Übelkeit oder Erbrechen, 16 (7 %) über Obstipation und 4 (2 %) über Dysphagie (mehrere Symptome gleichzeitig möglich). Die folgenden prä- und perioperativ erhobenen Werte änderten sich nicht signifikant mit aufeinanderfolgenden PIPAC-Prozeduren pro Patient:in (Varianzanalyse [analysis of variance, ANOVA], p > 0,1): ECOG Performance Status (Median 1, IQA 0–‍1), American Society of Anesthesiologists Klassifikation (Median 3, IQA 2–‍3), nutritional risk screening (NRS) (Median 2, IQA 2–‍3), global health status der European Organization for Research and Treatment of Cancer (EORTC) (Median 50, IQA 33–‍67), Operationsdauer (Mittelwert 104 min, Standardfehler des Mittelwertes 1,5 min), PCI (Median 15, IQA 6–‍24), PAI (Median 4, IQA 0–‍12) und maximaler histologischer Tumoranteil (Median 24 %, IQA 5–‍60 %). Die ersten drei konsekutiven PIPAC-Prozeduren zeigten eine signifikante Reduktion des Aszitesvolumens (ANOVA, p = 0,016). Die mediane postoperative Liegedauer betrug 4 Tage (IQA 3 4 Tage). Bei 31 von 213 PIPAC-Prozeduren (14,6 %), bei denen die Patient:innen in den Operationstrakt gebracht worden waren, traten postoperative Komplikationen auf (10,8 % Grad II, 2,4 % Grad IV, 1,4 % Grad V nach CDC). Insgesamt wurden 21 non access-Fälle (9,9 % der 213 PIPAC-Prozeduren, bei denen die Patient:innen in den Operationstrakt gebracht worden waren) und 14 intraoperative Komplikationen (6,6 %) dokumentiert. In den 21 non access-Situationen traten 8 Darmläsionen auf (n = 4 Serosaläsionen, n = 4 transmurale Perforationen). Postoperativ kam es bei den non access Fällen zu 4 Komplikationen Grad II nach CDC und keinen höhergradigen Komplikationen. Bei 3 weiteren Prozeduren traten Darmläsionen ohne non access auf (n = 1 Serosa, n = 2 transmural). Ein:e Patient:in verstarb nach Darmläsion mit nachfolgender Nahtinsuffizienz, Peritonitis und Sepsis. Bei 3 Narkoseeinleitungen aspirierten die Patient:innen und entwickelten daraufhin eine Pneumonie. Auf der Intensivstation wurde sofort eine kalkulierte Antibiotikatherapie eingeleitet. Dennoch verstarben 2 von 3 Patient:innen nach 3 bzw. 4 Tagen. Ein:e Patient:in konnte erfolgreich behandelt und nach 15 Tagen entlassen werden. Aufgrund der hohen Inzidenz von non access und Darmläsionen wurde nach prädiktiven Markern gesucht. Patient:innen mit einer CRS mit HIPEC in der Vorgeschichte hatten ein signifikant erhöhtes Risiko für non access (Odds Ratio [OR] 5,9, χ², p < 0,01) und Darmläsionen (OR 6,4, χ², p < 0,01). Patient:innen mit mehr als zwei Voroperationen im Bauchraum wiesen ebenso ein signifikant erhöhtes Risiko für non-access (OR 4,9, χ², p < 0,01) und Darmläsionen (OR 4,9, χ², p = 0,01) auf. Am Ende des Studienzeitraums befanden sich noch 6 Patient:innen in Therapie. Bei den Übrigen (bei denen mindestens eine PIPAC-Prozedur durchgeführt wurde) gab es unterschiedliche Gründe für die Beendigung der Therapie: n = 26 (34 %) verstorben, n = 20 (26 %) Progression der Grunderkrankung, n = 12 (16 %) Regression der Grunderkrankung (n = 7 ohne weitere Therapie, n = 5 anschließend CRS mit HIPEC), n = 6 (8 %) non-access, n = 5 (6 %) Patient:innenwunsch, n = 8 (10 %) kein Grund dokumentiert. Das mediane Gesamtüberleben ab der ersten geplanten PIPAC-Prozedur betrug 264 Tage (IQA 108–‍586). Insgesamt stellt die PIPAC eine neuartige off-label-Therapie für Patient:innen mit PSMs dar, deren Wirksamkeit und Sicherheit untersucht werden muss. Sie sollte daher nur im Rahmen klinischer Studien durchgeführt werden. Die vorliegende Studie liefert eine genaue Dokumentation von Symptomen, Komplikationen und unerwünschten Ereignissen im Zusammenhang mit PIPAC. In Zusammenschau der vorhandenen Studien scheint die PIPAC gut geeignet zu sein, PSMs und Lebensqualität zu stabilisieren. Zum Nachweis eines kausalen Effekts sind jedoch randomisierte, kontrollierte Studien nötig.:Einführung 1 Epidemiologie 1 Magenkarzinom 1 Kolorektales Karzinom 1 Ovarialkarzinom 1 Pankreaskarzinom 2 Mesotheliom 2 Pseudomyxoma peritonei 2 Pathophysiologie 2 Ablösung vitaler Krebszellen 2 Intraperitonealer Transport 3 Adhäsion und Invasion 3 Wachstum und Metastasierung 3 Symptome/Klinik 3 Diagnostik 3 Bildgebende Verfahren 3 Peritonealer Krebsindex 5 Peritonealer Adhäsionsindex 5 Therapie 5 Systemische Therapie 6 Zytoreduktive Chirurgie 6 Hypertherme intraperitoneale Chemoperfusion 6 Intraperitoneale Druck-Aerosol-Chemotherapie 7 Weitere Therapieoptionen 8 Zielsetzung 8 Publikation 9 Zusammenfassung 21 Literaturverzeichnis 24

S. aureus est un pathogène majeur de l’Homme capable de produire une grande variété de facteurs de virulence tels que les phénol-solubles modulines alpha (PSM) et l’hémolysine delta (Hld). La transmission de S. aureus est essentiellement manu-portée mais les éléments favorisant sa dissémination dans la population restent inconnus. Les mastocytes étant connus pour libérer des médiateurs pruritogènes, nous avons suspecté leur implication dans la physiopathologie et la transmission des infections cutanées staphylococciques. Sur une lignée de mastocytes humains, l’Hld et les PSM1, montrés pour être produits in vivo, déclenchaient la libération de tels médiateurs. Chez S. aureus, la production des toxines est sous la dépendance du système de régulation globale Agr. Les souches de S. aureus appartenant au type Agr1, produisant significativement plus d’Hld et de PSM que les autres souches, ont été les plus fréquemment retrouvées au cours de l’année 2017 dans les infections cutanées staphylococciques. Ceci corrobore l’hypothèse selon laquelle une souche de S. aureus produisant des toxines capables d’interagir avec les mastocytes et induisant un prurit, diffuse plus facilement dans la population. Nous avons ensuite étudié la modulation de l’expression des PSM et d’Hld par des concentrations sub-inhibitrices d’antibiotiques. L’oxacilline induisait une inhibition de l’expression des PSM et d’Hld alors que la clindamycine entraînait plus fréquemment une induction de leur expression. Ces observations nous ont interrogé sur l’utilisation de la clindamycine considérée habituellement comme anti-toxinique et sur l’effet bénéfique ou délétère de l’effet inhibiteur de l’oxacilline / S. aureus is a major human pathogen able to produce several virulence factors such as phenol-solublemodulins alpha (PSMalpha) and delta hemolysin (Hld). S. aureus is essentially spread through hand butthe elements promoting its spreading stay unsolved. Mast cells release several soluble mediatorstriggering itching behavior. We suspect the mast cell involvement in spreading of S. aureus strains andin physiopathology of staphylococcal skin infections. Upon human mast cell line, we showed thatPSMalpha1 and Hld induced the release of mediators triggering itching behavior. Moreover, these toxinswere produced in vivo during staphylococcal skin infections. Expression of staphylococcal virulencefactors is regulated by global regulatory system Agr. Interestingly, we observed that S. aureus strainsbelonging in Agr1 produced higher quantity of PSMalpha and Hld than those belonging to Agr2 and Agr3,and were more frequently responsible to skin infections during the last year. This observation supportsour hypothesis whereby a strain producing toxins able to trigger mast cell mediator inducingscratching behavior, spreads electively in the community. Thereafter, we studied modulation of PSMalphaand Hld expression by sub-inhibitory concentration of antibiotics. We reported that oxacillin inducedan inhibitory effect on PSMalpha and Hld expression, while clindamycin resulted in more frequently aninducer effect. These results are discordant with these observed with Panton-Valentine leucocidin andalpha hemolysin and interrogate on clindamycin use for its anti-toxin activity and on benefic ordeleterious effect of oxacillin inhibitory effect