The electrical industry is considered a high-risk industry, with workers constantly working in close relation to high voltages and in a workplace which constantly changes. This emphasizes the need for a proper safety management system, in order to identify and manage risk at each and every workplace. The aim of this study is to explore the safety management dynamics and interplay between management and workers in regard to safety in the electrical grid industry. This, with the purpose of identifying which deficiencies exist in the interaction, and how existing safety management theories can be applied in order to explain the deficiencies identified. This is done though a qualitative, single case study. The research method uses an abductive approach, and data is collected through both participant observations and semi-structured interviews with managers and workers in order to compare the difference in perception of the current safety management system at the studied organization. The result is analyzed using a thematic analysis, in which four different themes are found, communication, organizational culture, organizational dynamics, and safety practices. The study identifies flawed communication as an underlying issue which results in multiple following deficiencies. A lack of organizational transparency and inefficient communication methods, fuels a confusion regarding the purpose and efficiency of safety measures, and undermines the workers trust in management’s commitment to safety. Consequently, workers perceived organizational support decreases, as well as their willingness to engage in constructive voice behavior and following safety protocol. This gap in understanding between management and workers forms organizational silos between the two actors, where not only communication and collaboration further decrease, but also a social identity within the groups where the other side isn’t seen as a collaborator, but rather a hinderance. The study concludes that the deficiencies in the organizational communication has created a downward spiral, exacerbating the gap between management and workers, and hinders the safety management system. Addressing the deficiencies identified in this study, one should focus on enhancing communication, fostering a mutual trust, and actively promote and prioritize workers engagement to safety practices.

Enterococcus faecium è un componente fondamentale del microbiota di diversi alimenti fermentati quali formaggi e salumi e viene spesso isolato in alto numero in alimenti pronti al consumo. É inoltre largamente utilizzato come probiotico sia per l’uomo che per gli animali. Allo stesso tempo, però, questa specie batterica rappresenta una delle cause principali di infezioni nosocomiali quali endocarditi ed infezioni al tratto urinario. Studi recenti hanno dimostato che la specie E. faecium è costituita da due sub-popolazioni principali: la prima è denominate hospital associated (HA) clade “A” ed include la maggior parte dei ceppi responsabili di infezioni umane; la seconda è chiamata community associated (CA) clade “B”, e contiene principalmente ceppi commensali dell’uomo. Analisi più approfondite hanno rivelato un ulteriore suddivisione all’interno del clade A, nel sub-clade A1 (che raggruppa la maggioranza dei ceppi clinici) e nel sub-clade A2, associato agli animali e più sporadicamente ad infezioni umane. Nel 2012, EFSA ha redatto una linea guida per la valutazione della sicurezza di E. faecium usato come probiotico per gli animali, concludendo che i cepi appartenenti all’hospital-associated clade non devono essere utilizzati in nutrizione animale. Comunque, la distinzione tra le due sub-popolazioni è stata fatta utilizzando dati ottenuti prevalentemente da isolati umani e animali e solo un numero limitato di ceppi isolati dagli alimenti è stato considerato. Obiettivo di questa tesi di dottorato è stato quello di valutare la sicurezza di E. faecium negli alimenti fermentati, considerando ceppi isolati da formaggi artigianali e prodotti carnei e utilizzando sia tecniche di genomica che analisi fisiologiche. Nessuno dei ceppi alimentari studiati è risultato parte del clade A1, ma un ceppo isolato da un salame stagionato pronto al consumo ha rivelato diversi tratti tipici dei ceppi A1, tra cui particolari IS, transposase e geni di resistenza agli antibiotici. Questi risultati, così come altri dati, sottolineano la necessità di approfondire le conoscenze circa il ruolo dei ceppi di E. faecium isolati da alimenti come fattore di rischio per la salute umana. / Enterococcus faecium is commonly found in high numbers in ready to eat foods, being a member of the bacterial communities of a variety of fermented foods, including cheese and sausages, and is widely used as human and animal probiotic. However, this bacterial species is a leading cause of nosocomial infection, mainly endocarditis and urinary tract infections. Recent studies have demonstrated that E. faecium species consists of two very distinct clades: the hospital associated (HA) clade “A”, which includes most of the strains responsible for human infections, and the community associated (CA) clade “B”, that contains primarily human commensal isolates. Deeper analysis revealed a further split within clade A into sub-clade A1 (which groups the vast majority of clinical isolates), and sub-clade A2, associated with animals and sporadic human infections. In 2012, the European Food Safety Authority has issued a guideline for the safety assessment of E. faecium used as animal probiotics, concluding the strains belonging to the hospital-associated clade should not be used in animal nutrition. However, the differentiation of the two clades has been performed using data mainly deriving from human and animal isolates, and only a limited number of strains from the food chain were considered. Aim of this doctoral thesis was to assess the safety of E. faecium in fermented food, considering strains isolated from artisanal cheese and meat products, and using both whole genome-based techniques and physiological studies. None of the food isolates studied in this work belong to the epidemic clade A1, however a strain isolated from a ready to eat salami revealed several A1-specific traits, such as specific IS, transposases and antibiotic resistance genes. These results, as well as other data, underline the emergency of deeper understanding the role of E. faecium isolated from fermented foods as risk factor for human health.

With the advent of autonomous systems and deep learning systems, safety pertaining to these systems has become a major concern. The existing failure analysis techniques are not enough to thoroughly analyze the safety in these systems. Moreover, because these systems are created to operate in various conditions, they are susceptible to unknown safety issues. Hence, we need mechanisms which can take into account the complexity of operational design domains, identify safety issues other than failures, and expose unknown safety issues. Moreover, existing safety analysis approaches require a lot of effort and time for analysis and do not consider machine learning (ML) safety. To address these limitations, in this dissertation, we discuss an artificial-intelligence driven model-based methodology that aids in identifying unknown safety issues and analyzing ML safety. Our methodology consists of 4 major tasks: 1) automated model generation, 2) automated analysis of component state transition model specification, 3) undesired states analysis, and 4) causal factor analysis. In our methodology we identify unknown safety issues by finding undesired combinations of components' states and environmental entities' states as well as causes resulting in these undesired combinations. In our methodology, we refer to the behaviors that occur because of undesired combinations as off-nominal behaviors (ONBs). To identify undesired combinations and ONBs that aid in exposing unknown safety issues with less effort and time we proposed various approaches for each of the task and performed corresponding empirical studies. We also discussed machine learning safety analysis from the perspective of machine learning engineers as well as system and software safety engineers. The results of studies conducted as part of our research shows that our proposed methodology helps in identifying unknown safety issues effectively. Our results also show that combinatorial methods are effective in reducing effort and time for analysis of off-nominal behaviors without overlooking any dependencies among components and environmental entities of a system. We also found that safety analysis of machine learning components is different from analysis of conventional software components and detail the aspects we need to consider for ML safety.

Nuclear power plays a crucial role in energy supply in the world: around 15% of the electricity generated worldwide is provided from nuclear stations avoiding around 2.5 billion tonnes of CO2 emissions. As of January 2016, 442 reactors that generated 380+ GW were in operation and 66 new reactors were under construction. The seismic design of new nuclear power plants (NPPs) has gained much interest after the high-profile Fukushima Dai-ichi accident. In the UK, a tectonically stable continental region that possesses medium-to-low seismic activity, strong earthquakes capable of jeopardising the structural integrity of NPPs, although infrequent, can still occur. Despite that no NPP has been built in Great Britain after 1995, a New Build Programme intended to build 16 GW of new nuclear capacity by 2030 is currently under way. This PhD project provides a state-of-the-art framework for seismic probabilistic safety assessment and risk control of NPPs in Northwest Europe with particular application to the British Isles. It includes three progressive levels: (i) seismic input, (ii) seismic risk analysis, and (iii) seismic risk control. For seismic input, a suitable model to rationally define inputs in the context of risk assessments is proposed. Such a model is based on the stochastic simulation of accelerograms that are compatible with seismic scenarios defined by magnitude 4 < Mw < 6.5, epicentral distance 10 km < Repi < 100 km, and different types of soil (rock, stiff soil and soft soil). It was found to be a rational approach that streamlines the simulation of accelerograms to conduct nonlinear dynamic analyses for safety assessments. The model is a function of a few variables customarily known in structural engineering projects. In terms of PGA, PGV and spectral accelerations, the simulated accelerograms were validated by GMPEs calibrated for the UK, Europe and the Middle East, and other stable continental regions. For seismic risk analysis, a straightforward and logical approach to probabilistically assess the risk of NPPs based on the stochastic simulation of accelerograms is studied. It effectively simplifies traditional approaches: for seismic inputs, it avoids the use of selecting/scaling procedures and GMPEs; for structural outputs, it does not use Monte Carlo algorithms to simulate the damage state. However, it demands more expensive computational resources as a large number of nonlinear dynamic analyses are needed. For seismic risk control, strategies to control the risk using seismic protection systems are analysed. This is based on recent experience reported elsewhere of seismically protected nuclear reactor buildings in other areas of medium-to-low seismic activity. Finally, a scenario-based incremental dynamic analysis (IDA) is proposed aimed at the generation of surfaces for unacceptable performance of NPPs as function of earthquake magnitude and distance. It was found that viscous-based devices are more efficient than hysteretic-based devices in controlling the seismic risk of NPPs in the UK. Finally, using the proposed scenario-based IDA, it was found that when considering all controlling scenarios for a representative UK nuclear site, the risk is significantly reduced ranging from 3 to 5 orders of magnitude when using viscous-based devices.

This master‘s thesis is focused on the design of manipulator for crankshaft handling in flexible production lines. The first part describes the types of production lines and possible ways of inter-operative manipulation. With regard to the suitability of their use, a suitable variant is selected, which is then conceptually processed and verified by technical calculations. The final conclusion is the verification of the design in terms of safety. Part of the master‘s thesis is technical drawing documentation.

The diploma’s thesis deals with the current state of requirements for products resulting from directives of the European Parliament and the European Council. The aim of the thesis is a system analysis of the issue, proposal and justification of the chosen procedure for solving the objectives. Furthermore, the analysis of requirements of current standards and safety analysis related to the work of machine operators in the areas of operation, service and maintenance of horizontal boring machine WHN 13 CNC. The analysis is followed by a proposal for preventive measures for hazards where the value of risks and criticality is unacceptable, leading to their reduction.

L'organisation classique en silos disciplinaires des industries atteint ses limites pour maîtriser la complexité. Les problèmes sont découverts trop tard et le manque de communication entre les experts empêche l'émergence précoce de solutions. C'est pourquoi, il est urgent de fournir de nouvelles approches collaboratives et des moyens d' interactions entre les disciplines d'ingénierie, au début et tout au long du cycle de développement. Dans ce contexte, nous avons étudié l'approche synchronisation de modèles entre deux domaines d'ingénierie : la conception d'architecture de systèmes et la sûreté de fonctionnement. Elle a pour but de construire et maintenir la cohérence entre les modèles.Ces travaux proposent, étudient et analysent une démarche collaborative de synchronisation de modèles. Ils tiennent compte des contextes d’études, des processus, des méthodes appliqués et des points de vue produits par les ingénieurs. Les contributions répondent à des problématiques au niveau des pratiques, des concepts, de la mise en œuvre, des applications et l’implémentation de la synchronisation de modèles. / Classical organization in disciplinary silos in the industry reaches its limits to manage and control complexity. Problems are discovered too late and the lack of communication between experts prevents the early emergence of solutions. This is why it is urgent to provide new collaborative approaches and ways to exchange the models contents between various engineering fields, early and all along the development cycle. In this context, we are particularly interested in a synchronization approach of models between two engineering fields: system architecture design and dependability analysis.This work proposes a collaborative approach of synchronization of models. It takes into account the study contexts, applied processes, applied methods and viewpoint produced by engineers. Contributions address issues at levels of practices, concepts, implementation, applications and implementation of model synchronization.

Passive safety systems are increasingly being utilized in prospective nuclear power plant designs. Indeed, the use of safety systems driven by natural phenomena might be seen as an unmitigated virtue. However, the low magnitude of the forces involved in such systems, combined with the uncertainty inherent in the factors which affect them, pose a problem in the assessment of their reliability when compared to their active counterparts. Hence, the purpose of this thesis is to investigate and apply a state-of-the-art technique in passive reliability assessment, known as the Reliability Methods of Passive Systems (RMPS) methodology, to the isolation condenser system (ICS) of the prospective BWRX-300 small modular reactor (SMR) design. The ICS is a safety system driven by natural circulation which provides emergency core cooling, residual heat removal, and pressure control for the BWRX-300. Using RMPS to analyze the effect that uncertainties in thermal characteristics of the fuel have on ICS operation, the reliability of natural circulation was quantified with a confidence of 99%. This yielded an immeasurably small failure probability. Considering residual uncertainty, an engineering judgment assigned a failure probability of 1.00E-07. This finding was integrated into a Level 1 probabilistic safety assessment, involving analysis of initiating events, event tree analysis, and failure mode and effect analysis (FMEA) of safety systems, including natural circulation. Analysis of sequences leading to core damage resulted in a core damage frequency of 1.23E-07 yr-1. / Passiva säkerhetssystem används i allt större utsträckning i innovativa kärnkraftverkskonstruktioner. Faktum är att användningen av säkerhetssystem som drivs av naturfenomen kan ses som en oförminskad dygd. Den låga storleken på de krafter som är involverade i sådana system, i kombination med den osäkerhet som är inneboende i de faktorer som påverkar dem, utgör ett problem vid bedömningen av deras tillförlitlighet jämfört med deras aktiva motsvarigheter. Därför är syftet med denna avhandling att undersöka och tillämpa en toppmodern teknik inom passiv tillförlitlighetsbedömning, känd som Reliability Methods of Passive Systems (RMPS) metodologi, på isolationskondensorsystemet (ICS) hos den potentiella BWRX-300 liten modulär reaktor (SMR) design. ICS är ett säkerhetssystem som drivs av naturlig cirkulation som ger nödkylning av kärnan, avlägsnande av restvärme och tryckkontroll för BWRX-300. Med hjälp av RMPS kvantifierades den naturliga cirkulationens tillförlitlighet med en konfidens på 99 %, vilket gav en omätligt liten sannolikhet för misslyckande. Med hänsyn till kvarvarande osäkerhet tilldelade en teknisk dom en felsannolikhet på 1.00E-07. Detta fynd integrerades i en nivå 1 probabilistisk säkerhetsbedömning, som involverade analys av initierande händelser, händelseträdsanalys och felläges- och effektanalys (FMEA) av säkerhetssystem, inklusive naturlig cirkulation. Analys av sekvenser som leder till härdskada resulterade i en härdskadafrekvens på 1,23E-07 år-1.

Die Therapiemöglichkeiten für Pferde, die an Culicoides-Hypersensitivität (Sommerekzem) leiden, sind heute noch oft unbefriedigend. Sie reduzieren sich größtenteils auf symptomatische Behand-lungen und auf die Vermeidung der allergieauslösenden Allergene. Es existieren Studien, bei denen rekombinante Proteine in ihrer Wirksamkeit auf die Culicoides-Hypersensitivität beim Pferd untersucht wurden. Für die spezifische Immuntherapie gibt es in der Veterinärmedizin bislang keine oralen Präparate für eine mögliche sublinguale Therapie. Am Beispiel der Culicoides-Hypersensitivität soll letztlich ein Verfahren für die spezifische Immuntherapie entwickelt werden, bei dem die Peptide sowohl zur Diagnostik als auch Therapie allergischer Erkrankungen in der Veterinärmedizin genutzt werden können. In der vorliegenden Studie wurden erste Schritte in diese Richtung unternommen. Dafür wurden eine intrakutan zu applizierende Darreichungsform und eine für das Pferd neuartige, sublingual zu applizierende Arzneiform eingesetzt. Ausgewählte, synthetisch hergestellte Peptide von Mücken der Gattung Culicoides wurden bezüglich ihres Potentials für die spezifische Immuntherapie hinsichtlich der Sicherheit bei ihrer Anwendung im Pferd und Nutzung in der serologischen Diagnostik untersucht. Sieben ausgewählte Peptide, bestehend aus 30-35 Aminosäuren, wurden für in-vitro und in-vivo-Untersuchungen an gesunden (n=6) und an Sommerekzem erkrankten (n=12) Pferden eingesetzt. Nach einer Testphase auf die Verträglichkeit an klinisch gesunden Pferden, wurden die an Culicoides-Hypersensitivität erkrankten Tiere randomisiert in zwei Gruppen (intradermale und sublinguale Arzneiform) eingeteilt. Sie bekamen im Sonner, bei möglicher natürlicher Culicoides-Exposition die jeweilige Arzneiform über 21 Wochen hinweg verabreicht. Während dieser Zeit fanden in regelmäßigen Abständen Kontrollen des Gesundheitszustandes der Tiere statt, bei denen insbesondere klinische Symptome, Blutbilder und die Bildung spezifischer Antikörper erfasst wurden. Das Hautbild der Tiere wurde in Woche 1, 13 und 25 mithilfe eines Sommerekzem-Scores beurteilt. Die zwölf häufigsten vom Ekzem betroffenen Stellen am Pferde-körper wurden hierbei unabhängig voneinander bewertet. Die Besitzer der Tiere wurden mithilfe eines Fragebogens nach ihrer Meinung zur Entwicklung bzw. Ausprägung der klinischen Symptome und dem Befinden ihres Pferdes befragt. Zur Detektion spezifischer Antikörper im Serum der Tiere, unter Verwendung rekombinanter Pepti-de als Antigen, konnten für IgE und die IgG-Isotypen IgG1, IgG3/5 und IgG4/7 direkte bzw. indirekte ELISA etabliert werden. Des Weiteren wurde ein kommerzielles ELISA-Kit verwendet, um den Verlauf der IgE-Gesamtkonzentration während der Studienlaufzeit zu untersuchen. Aufgrund der geringen Studienteilnehmerzahl und vieler nicht verwendbarer Daten aus den ELISA Untersuchungen wurde die statistische Auswertung auf deskriptive Analysen beschränkt. Beide Applikationsarten wurden von den Studienteilnehmern gut toleriert und vertragen. Die Verabreichung der Sublingualtablette konnte durch die zuvor geschulten Pferdebesitzer eigenständig durchgeführt werden. Zu Beginn der Studie betrug der Dermatitisgrad 14 Punkte in der intradermalen Gruppe bzw. 13,67 Punkte in der sublingualen Gruppe. Am Ende der Studienlaufzeit lag der durchschnittliche Dermatitisgrad bei 40,33 bzw. 38,50 Punkten. Damit verschlechterte er sich während der Studienlaufzeit. Der Gehalt an gesamtem IgE im Serum der Probanden sank während des Untersuchungszeitraumes über beide Gruppen hinweg von 2,7 U/l auf 2,1 U/l. Bei den Tieren der Intradermalen Applikationsgruppe reduzierte sich das freie IgE dabei um 0,8 U/l und in der Sublingualen Gruppe um 0,3 U/l. Die Peptid-basierten ELISA zur spezifischen Serologie verschiedener Serum-Antikörperklassen waren nicht valide auswertbar. Die Untersuchungen zu peptidspezifischen IgE ergaben individuelle Verlaufsformen. Da keine Kontrollgruppe ohne Peptid-Applikation eingeschlossen wurde und die Studie in der Saison mit unkontrollierter, natürlicher Culicoides-Exposition durchgeführt wurde, ist keine Aussage zur Wirksamkeit der Behandlung auf klinische oder serologische Parameter möglich. Die entwickelte Sublingualtablette war durch ihre Form, Stabilität und Handhabung gut anwendbar und kann als Applikationsmethode in der Veterinärmedizin in Erwägung gezogen werden. Die synthetischen Peptide waren für den Einsatz in-vivo unschädlich und einsetzbar. Es bleibt zukünftigen Untersuchungen vorbehalten, ihr diagnostisches und therapeutisches Potential zur An-wendung bei Culicoides-Hypersensitivität und gegebenenfalls weiteren allergisch bedingten Erkrankungen des Pferdes weiter zu evaluieren. Aufgrund von limitierenden Faktoren, wie der sehr kleinen Zahl an Studienteilnehmern, dem Fehlen einer Placebogruppe und der Durchführung während der Expositionszeit hat die vorliegende Arbeit insgesamt präliminären Charakter.:Inhaltsverzeichnis Verzeichnis der verwendeten Abkürzungen 1 Einleitung 2 Literaturübersicht 2.1 Allergie 2.1.1 Allergene 2.1.1.1 Charakteristika von Allergenen (Was macht eine Substanz zum Allergen) 2.1.1.2 Kreuzreaktivitäten 2.1.2 Typ-I-Allergie 2.1.2.1 Produktion sensibilisierender Antikörper bei Erstkontakt 2.1.2.2 Ausbildung allergischer Reaktionen bei Folgekontakt 2.1.3 Immunglobulin-System des Pferdes 2.1.4 Potenzielle Bedeutung der IgG-Isotypen bei verschiedenen Erkrankungen 2.2 Das Sommerekzem des Pferdes 2.2.1 Epidemiologie, Ätiologie und Pathogenese 2.2.2 Bedeutende Allergene 2.2.3 Diagnostische Ansätze 2.2.3.1 In-vivo-Test (Intradermal Test) 2.2.3.2 In-vitro-Tests 2.2.3.3 Nachweis von IgE 2.2.3.4 Funktionelle in-vitro-Tests 2.2.4 Therapeutische Ansätze 2.2.4.1 Vermeidung Allergenkontakte, medikamentöse Therapieversuche 2.2.4.2 Allergenspezifische Immuntherapie (ASIT) 2.2.4.3 Desensibilisierung mit nativen Allergenextrakten 2.3 Wechsel von Allergenextrakten auf die molekulare Ebene der Allergene - Bedeutung für Diagnostik und Therapie 2.4 Einsatz synthetischer Peptide in der ASIT 3 Geräte, Material und Methoden 3.1 Geräte 3.2 Material 3.2.1 Klinikbedarf 3.2.2 Laborbedarf 3.2.3 Reagenzien, Puffer und Lösungen 3.2.4 Allergene (Peptide) - Auswahl und Synthese 3.2.5 Antikörper 3.3 Tiere 3.3.1 Gesunde Kontrollgruppe 3.3.2 An Sommerekzem erkranke Studienteilnehmer 3.4 Methoden 3.4.1 Blutentnahme und weitere Verarbeitung 3.4.2 Herstellung der arzneilichen Formulierungen 3.4.2.1 Arzneiliche Formulierung für die intradermale Applikation 3.4.2.2 Arzneiliche Formulierung für die orale Applikation 3.4.3 Prüfung der Unbedenklichkeit an klinisch gesunden Pferden 3.4.3.1 Durchführung der Unbedenklichkeitsprüfung 3.4.3.2 Kontrollen des Gesundheitsstatus 3.4.4 Verabreichung der hergestellten Applikationslösungen an Patienten 3.4.4.1 In-Vivo-Test (Intradermaltest) 3.4.4.2 Intradermale Verabreichung der individuellen Peptidlösungen 3.4.4.3 Orale Verabreichung der individuellen Peptidlösungen 3.4.5 Klinische Veränderungen infolge der SIT 3.4.5.1 Dokumentation und klinische Beurteilung der Symptome 3.4.5.2 Fragebogen zur objektiven Einschätzung durch die Patientenbesitzer 3.4.6 In-Vitro-Test (ELISA) 3.4.6.1 Prinzip des ELISA (Enzyme-linked Immunosorbent Assay) 3.4.6.2 Methode des eingesetzten ELISA 3.4.7 Statistik 4 Ergebnisse 4.1 Auswahl und Einsatz synthetischer Peptide für die Diagnostik und Therapie des equinen Sommerekzems 4.1.1 Arzneiliche Formulierung für den Intrakutantest 4.1.2 Arzneiliche Formulierung für die Intradermale Applikation 4.1.3 Arzneiliche Formulierung für die orale Applikation 4.2 Klinische Veränderungen infolge der SIT 4.2.1 Dermatitisgrad– Beurteilung des Hautbildes 4.2.2 Veränderte Symptomatik in der Studienlaufzeit – Einschätzung der Besitzer 4.3 Labordiagnostische Veränderungen infolge der SIT 4.3.1 Differentialblutbild 4.3.2 Ergebnisse des IgE-ELISA 4.3.3 Ergebnisse des IgG-ELISA 4.4 Vergleich der Werte des IgE ELISA mit den klinischen Symptomen (Score) 5 Diskussion 5.1 Einsatz synthetisch hergestellter Peptide in der Diagnostik und Therapie 5.2 Therapeutischer Einsatz synthetisch hergestellter Peptide für die intradermale Applikation 5.3 Etablierung einer Arzneiform für die sublinguale Therapie beim Pferd 5.4 Klinische Veränderungen in Folge der SIT 5.5 Therapiebegleitende Labordiagnostik 6 Zusammenfassung 7 Summary 7 Literaturverzeichnis 8 Anhang 8.1 Tierkarte der Vorstudie mit klinisch gesunden Pferden 8.2 Besitzereinverständniserklärung und Datenschutzerklärung am Beispiel der Intradermalen Verabreichung 8.3 Tierkarte zur Erfassung des Gesundheitsstatus und Symptomentwicklung 8.4 Protokoll zur Durchführung des Intradermaltests 8.5 Protokoll zur Evaluierung des Dermatitisscores der an SE erkankten Pferde 8.6 Fragebogen zur Besitzerbefragung am Ende der Studie 8.7 Protokoll zur Durchführung eines ELISA am Beispiel der Untersuchung auf peptidspezifisches IgE im Patientenserum 9 Danksagung / The treatment options for horses suffering from Culicoides hypersensitivity are still often unsatisfac-tory. They are mainly reduced to symptomatic treatments and avoiding the allergy-triggering aller-gens. In various studies recombinant proteins were examined for their effectiveness on Culicoides hyper-sensitivity in horses. However, there are currently no oral preparations available in veterinary medicine for specific immunotherapy. Using Culicoides hypersensitivity as an example, a process for specific immunotherapy shall ulti-mately be developed in which the peptides can be used for both, the diagnosis and therapy od allergic diseases in veterinary medicine. The present study tool the first steps in this direction. For this purpose, an intracutaneously adminis-tered dosage form and a sublingually administered dosage form, which is new for horses, were used. Selected, synthetically produced peptides from mosquitoes of the genus Culicoides were ex-amined regarding their potential for specific immunotherapy in terms of their safety after application in horses in-vivo and their use in serology. Seven selected peptides, consisting of 30-35 amino acids, were used for in-vitro and in-vivo studies on healthy (n=6) and horses suffering from Culicoides hypersensitivity (n=12). After a test phase for tolerability in clinically healthy horses, the animals suffering from Culicoides hypersensitivity were randomly divided into two groups (intradermal and sublingual dosage forms). They were administered the respective dosage form for 21 weeks during the summer season with possible natural Culicoides exposure. During this time, the animals' health status was checked at regular intervals, in particular clinical symptoms, blood counts and the formation of specific antibodies were recorded. The skin appearance of the animals was assessed at weeks 1, 13 and 25 using a dermatitis score. The twelve most common areas on the horse's body affected by eczema were evaluated inde-pendently of each other. The owners of the animals were asked using a questionnaire about their opinion on the development or severity of their horse's clinical symptoms and well-being. To detect specific antibodies in the serum of the animals, using recombinant peptides as antigen, direct and indirect ELISAs were established for IgE and the IgG isotypes IgG1, IgG3/5 and IgG4/7. Furthermore, a commercial ELISA kit was used to examine the course of the total IgE concentration during the study period. Due to the small number of study participants and numerous invalid data from the ELISA studies, the statistical analysis was limited to descriptive analyses. Both types of application were well tolerated by the study participants. The administration of the sublingual tablet could be carried out by previously trained horse owners. At the start of the study, the dermatitis score was 14 points in the intradermal group and 13.67 points in the sublingual group. At the end of the study period, the average dermatitis grades were 40.33 and 38.50 points, respectively, and deteriorated during the course of this study. The owner survey revealed a slight improvement in symptoms compared to previous years. The level of total, free IgE in the test subjects' serum fell from 2.7 U/l to 2.1 U/l during the study period. In the animals in the intradermal application group, the free IgE was reduced by 0.8 U/l and in the sublingual group by 0.3 U/l. Peptide-based ELISA to determine different serum antibody isotypes binding the peptides could not be evaluated reliably. Peptide-specific IgE revealed individ-ual variations. Due to the lack of a control group without peptide application and conduction of the study during the season with uncontrolled, natural Culicoides exposure conclusions of effectiveness regarding clinical disease or serological effects cannot be drawn. The sublingual tablet developed was easy to use due to its shape, stability and handling and can be considered as an application method in veterinary medicine. The synthetic peptides were harmless and usable for in-vivo application. It remains reserved for future studies to further evaluate its diagnostic and therapeutic potential for use in equine Culicoides hypersensitivity and possibly other allergic diseases in horses. Due to limiting factors such as the very small number of study participants, the lack of a placebo group and the implementation during the exposure period, the present work is of a preliminary nature.:Inhaltsverzeichnis Verzeichnis der verwendeten Abkürzungen 1 Einleitung 2 Literaturübersicht 2.1 Allergie 2.1.1 Allergene 2.1.1.1 Charakteristika von Allergenen (Was macht eine Substanz zum Allergen) 2.1.1.2 Kreuzreaktivitäten 2.1.2 Typ-I-Allergie 2.1.2.1 Produktion sensibilisierender Antikörper bei Erstkontakt 2.1.2.2 Ausbildung allergischer Reaktionen bei Folgekontakt 2.1.3 Immunglobulin-System des Pferdes 2.1.4 Potenzielle Bedeutung der IgG-Isotypen bei verschiedenen Erkrankungen 2.2 Das Sommerekzem des Pferdes 2.2.1 Epidemiologie, Ätiologie und Pathogenese 2.2.2 Bedeutende Allergene 2.2.3 Diagnostische Ansätze 2.2.3.1 In-vivo-Test (Intradermal Test) 2.2.3.2 In-vitro-Tests 2.2.3.3 Nachweis von IgE 2.2.3.4 Funktionelle in-vitro-Tests 2.2.4 Therapeutische Ansätze 2.2.4.1 Vermeidung Allergenkontakte, medikamentöse Therapieversuche 2.2.4.2 Allergenspezifische Immuntherapie (ASIT) 2.2.4.3 Desensibilisierung mit nativen Allergenextrakten 2.3 Wechsel von Allergenextrakten auf die molekulare Ebene der Allergene - Bedeutung für Diagnostik und Therapie 2.4 Einsatz synthetischer Peptide in der ASIT 3 Geräte, Material und Methoden 3.1 Geräte 3.2 Material 3.2.1 Klinikbedarf 3.2.2 Laborbedarf 3.2.3 Reagenzien, Puffer und Lösungen 3.2.4 Allergene (Peptide) - Auswahl und Synthese 3.2.5 Antikörper 3.3 Tiere 3.3.1 Gesunde Kontrollgruppe 3.3.2 An Sommerekzem erkranke Studienteilnehmer 3.4 Methoden 3.4.1 Blutentnahme und weitere Verarbeitung 3.4.2 Herstellung der arzneilichen Formulierungen 3.4.2.1 Arzneiliche Formulierung für die intradermale Applikation 3.4.2.2 Arzneiliche Formulierung für die orale Applikation 3.4.3 Prüfung der Unbedenklichkeit an klinisch gesunden Pferden 3.4.3.1 Durchführung der Unbedenklichkeitsprüfung 3.4.3.2 Kontrollen des Gesundheitsstatus 3.4.4 Verabreichung der hergestellten Applikationslösungen an Patienten 3.4.4.1 In-Vivo-Test (Intradermaltest) 3.4.4.2 Intradermale Verabreichung der individuellen Peptidlösungen 3.4.4.3 Orale Verabreichung der individuellen Peptidlösungen 3.4.5 Klinische Veränderungen infolge der SIT 3.4.5.1 Dokumentation und klinische Beurteilung der Symptome 3.4.5.2 Fragebogen zur objektiven Einschätzung durch die Patientenbesitzer 3.4.6 In-Vitro-Test (ELISA) 3.4.6.1 Prinzip des ELISA (Enzyme-linked Immunosorbent Assay) 3.4.6.2 Methode des eingesetzten ELISA 3.4.7 Statistik 4 Ergebnisse 4.1 Auswahl und Einsatz synthetischer Peptide für die Diagnostik und Therapie des equinen Sommerekzems 4.1.1 Arzneiliche Formulierung für den Intrakutantest 4.1.2 Arzneiliche Formulierung für die Intradermale Applikation 4.1.3 Arzneiliche Formulierung für die orale Applikation 4.2 Klinische Veränderungen infolge der SIT 4.2.1 Dermatitisgrad– Beurteilung des Hautbildes 4.2.2 Veränderte Symptomatik in der Studienlaufzeit – Einschätzung der Besitzer 4.3 Labordiagnostische Veränderungen infolge der SIT 4.3.1 Differentialblutbild 4.3.2 Ergebnisse des IgE-ELISA 4.3.3 Ergebnisse des IgG-ELISA 4.4 Vergleich der Werte des IgE ELISA mit den klinischen Symptomen (Score) 5 Diskussion 5.1 Einsatz synthetisch hergestellter Peptide in der Diagnostik und Therapie 5.2 Therapeutischer Einsatz synthetisch hergestellter Peptide für die intradermale Applikation 5.3 Etablierung einer Arzneiform für die sublinguale Therapie beim Pferd 5.4 Klinische Veränderungen in Folge der SIT 5.5 Therapiebegleitende Labordiagnostik 6 Zusammenfassung 7 Summary 7 Literaturverzeichnis 8 Anhang 8.1 Tierkarte der Vorstudie mit klinisch gesunden Pferden 8.2 Besitzereinverständniserklärung und Datenschutzerklärung am Beispiel der Intradermalen Verabreichung 8.3 Tierkarte zur Erfassung des Gesundheitsstatus und Symptomentwicklung 8.4 Protokoll zur Durchführung des Intradermaltests 8.5 Protokoll zur Evaluierung des Dermatitisscores der an SE erkankten Pferde 8.6 Fragebogen zur Besitzerbefragung am Ende der Studie 8.7 Protokoll zur Durchführung eines ELISA am Beispiel der Untersuchung auf peptidspezifisches IgE im Patientenserum 9 Danksagung

Automated vehicles are assumed to play an important role in the future of mobility, but their operation must be provably safe. They consist of automated driving systems (ADSs) that perform various automated driving tasks without the active participation of a human driver. These automated driving tasks can be mainly categorized as perception, decision-making, and motion control. These tasks must be accomplished by the components of an ADS, which must be seamlessly integrated to ensure safety. The complexity of the ADS architecture makes the safety assessment rather challenging. This complexity is further exacerbated when automated vehicles need to interact in different traffic situations. Design, verification, and testing of ADSs as simulation models provide a safer and cost-efficient early development opportunity compared to real-world testing. To this end, a capable simulation framework that incorporates the simulation models of ADSs must be developed for designing, implementing, and testing these models in a traffic simulation. The main contributions of this thesis are denoted as (i), (ii), and (iii). Safety assessment of ADS can be done either experimentally by (i) simulation-based testing in (ii) a simulation framework or theoretically (iii) using formal methods. Simulation-based testing requires two components: (i) efficient testing strategies for different ADS components and (ii) a simulation framework containing the models of ADS components for applying these testing strategies. Simulation-based testing alone cannot prove or guarantee safety. In order to complement the safety assessment process, whenever applicable, (iii) formal methods must be utilized to derive theoretical safety proofs for certain types of systems for a set of assumptions. Formal methods for synthesis include methods such as correct-by-construction of control protocols and reachability analysis for dynamic systems, which can be used to design provably safe decision-making and control algorithms. The correct-by-construction synthesis of discrete control protocols can be used as safety filters for decision-making algorithms, such as autonomous intersection management algorithms, to verify the safety of taken actions. The reachability analysis is useful for predicting trajectories for possible maneuvers in a finite time horizon for an automated vehicle on a highway. By over-approximating these ego vehicle trajectories, safety verification of possible maneuvers can be done by comparing them to the possible trajectories of other vehicles. A game-theoretical decision-making approach, such as minimax, can augment safety in maneuver planning by considering the worst-case situations up to a finite time horizon. Such an online maneuver planning algorithm reconsiders the maneuvers at each planning cycle in a receding horizon fashion. However, to apply formal methods, certain assumptions must be made about complex parts of ADSs, and therefore, simulation-based testing is still needed to check the validity of these assumptions in simulation models. Safety assessment with a holistic approach is presented that combines the previously mentioned contributions of this thesis (i), (ii), and (iii) into a workflow of modeling, design/synthesis, and testing. Such an approach is essential for developing safe algorithms for ADSs in a simulation framework.:Kurzfassung v Abstract vii Contents ix 1 Introduction 1 1.1 Motivation . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 1.2 Scope of the Thesis . . . . . . . . . . . . . . . . . . . . . . . 1 1.3 Research Questions . . . . . . . . . . . . . . . . . . . . . . . 2 1.4 Structure of the Thesis . . . . . . . . . . . . . . . . . . . . . 3 2 Safety Assessment of Automated Driving Systems - State of the Art 5 2.1 State of the Art . . . . . . . . . . . . . . . . . . . . . . . . . 5 2.1.1 Definition of ADS . . . . . . . . . . . . . . . . . . . . 5 2.1.2 Meaning of Safety for ADS . . . . . . . . . . . . . . . 8 2.1.3 Testing for Safety . . . . . . . . . . . . . . . . . . . . 12 2.1.4 Simulation Frameworks for ADSs and AVs . . . . . . 14 2.1.5 Roles of Formal Methods . . . . . . . . . . . . . . . . 16 2.2 Challenges and Contributions . . . . . . . . . . . . . . . . . 18 2.2.1 Challenges in the State-of-the-Art . . . . . . . . . . . 18 2.2.2 The Contributions . . . . . . . . . . . . . . . . . . . 21 3 Simulation-based Testing using Fault Injection 23 3.1 Related Work and Preliminaries . . . . . . . . . . . . . . . . 24 3.1.1 Fault Injection . . . . . . . . . . . . . . . . . . . . . 24 3.1.2 Fault Types and Parameters . . . . . . . . . . . . . . 27 3.1.3 Testing for ADS safety using FI . . . . . . . . . . . . 30 3.1.4 Metrics and Specifications for Safety Evaluation . . . 33 3.1.5 Simulative Error Propagation Analysis . . . . . . . . 35 3.2 Developing a Testing Strategy using Fault Injection . . . . . 36 3.2.1 Automated Testing . . . . . . . . . . . . . . . . . . . 37 3.2.2 Using Domain-specific Knowledge . . . . . . . . . . . 40 3.2.3 Smart Testing Strategy . . . . . . . . . . . . . . . . . 41 3.3 Application of Testing Strategies . . . . . . . . . . . . . . . 42 3.3.1 Testing of ACC Systems for Fault Tolerance using Fault Injection . . . . . . . . . . . . . . . . . . . . . . . . . 43 3.3.2 Discovering Fault Parameter Space using Smart Testing Strategy . . . . . . . . . . . . . . . . . . . . . . . 48 3.4 General Functionalities for Efficient Tools . . . . . . . . . . . 52 3.5 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53 4 A Framework for Simulating Automated Driving Systems in Traffic 55 4.1 Related Work . . . . . . . . . . . . . . . . . . . . . . . . . . 56 4.1.1 Levels of Detail in Traffic Simulation . . . . . . . . . 56 4.1.2 Traffic Simulations and Scenario-based Testing . . . . 59 4.1.3 Generic ADS Architecture . . . . . . . . . . . . . . . 64 4.2 Preliminaries and Definitions . . . . . . . . . . . . . . . . . . 65 4.2.1 Map and Path Planning . . . . . . . . . . . . . . . . 66 4.2.2 Decision Making and Trajectories . . . . . . . . . . . 67 4.2.3 Vehicle Motion Control . . . . . . . . . . . . . . . . . 68 4.3 Mapping the ADS structure into a Simulation Model . . . . 72 4.3.1 Sensor-based Perception . . . . . . . . . . . . . . . . 72 4.3.2 V2X Communication . . . . . . . . . . . . . . . . . . 73 4.3.3 Global Path Planner . . . . . . . . . . . . . . . . . . 75 4.3.4 Behavioral Planner/Maneuver Planner . . . . . . . . 78 4.3.5 Longitudinal and Lateral Motion Control . . . . . . . 80 4.4 Interfaces and Layering between Modules . . . . . . . . . . . 81 4.4.1 Relations between Discrete Decision-Making and Continuous Control . . . . . . . . . . . . . . . . . . . . . 82 4.4.2 Vehicles and the Infrastructure - Autonomous Intersection Management . . . . . . . . . . . . . . . . . . . . 83 4.5 Instantiating a Model-based Traffic Simulation . . . . . . . . 86 4.5.1 Traffic Simulation Environment Architecture . . . . . 88 4.5.2 Road Network and the Map Format . . . . . . . . . . 91 4.5.3 Scenario-based Traffic Simulation as Test Cases . . . 95 4.5.4 Overview of the Simulation Framework with Fault Injection . . . . . . . . . . . . . . . . . . . . . . . . . . 97 4.6 Case Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . 101 4.6.1 Urban Traffic Simulations . . . . . . . . . . . . . . . 101 4.6.2 Fault-Error-Failure Chain Analysis for Safety Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . 103 4.7 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108 5 Using Formal Methods for Safe Algorithms Design 111 5.1 Control Protocol Synthesis . . . . . . . . . . . . . . . . . . . 111 5.1.1 Related Work and Preliminaries . . . . . . . . . . . . 111 5.1.1.1 Finite State Transition Systems . . . . . . . 112 5.1.1.2 Linear Temporal Logic and Büchi Automaton 113 5.1.1.3 Correct-by-Construction Control Protocol Synthesis . . . . . . . . . . . . . . . . . . . 114 5.1.2 Application in an Autonomous Intersection Management Algorithm . . . . . . . . . . . . . . . . . . . . . 116 5.1.2.1 Modeling the Intersection and the Behaviors of the Vehicles . . . . . . . . . . . . . . . . 116 5.1.2.2 Specifications for Synthesis . . . . . . . . . 120 5.1.2.3 Algorithm for Safe Decision-Making for AIM 122 5.2 Game-Theoretical Decision-Making and Trajectory Verification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125 5.2.1 Related Work and Preliminaries . . . . . . . . . . . . 125 5.2.1.1 Game-Theoretical Minimax Decision-Making 126 5.2.1.2 Reachability Analysis for Trajectory Generation . . . . . . . . . . . . . . . . . . . . . . 127 5.2.1.3 Motion in Frenet Coordinates . . . . . . . . 130 5.2.1.4 Modeling of AVs and Maneuvers . . . . . . 132 5.2.2 Application in a Safe Maneuver Planning Algorithm . 137 5.2.2.1 Fixed Abstraction and the Over- Approximation of Trajectories . . . . . . . . 138 5.2.2.2 Safety Quantification of Maneuvers . . . . . 140 5.2.2.3 Minimax Decision-Making for Safe Maneuver Planning . . . . . . . . . . . . . . . . . . . 143 5.3 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148 6 Safety Assessment with a Holistic Approach 151 6.1 Overview and the Application of the Approach . . . . . . . . 152 6.2 Case Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . 154 6.2.1 Case Study 1: Safety of an Autonomous Intersection Management Algorithm . . . . . . . . . . . . . . . . 155 6.2.1.1 Modeling . . . . . . . . . . . . . . . . . . . 155 6.2.1.2 Design/Synthesis . . . . . . . . . . . . . . . 157 6.2.1.3 Testing and Results . . . . . . . . . . . . . 159 6.2.1.4 Conclusion . . . . . . . . . . . . . . . . . . 161 6.2.2 Case Study 2: Safety of a Maneuver Planning Algorithm for Highway Driving . . . . . . . . . . . . . . . 162 6.2.2.1 Modeling . . . . . . . . . . . . . . . . . . . 163 6.2.2.2 Design/Synthesis . . . . . . . . . . . . . . . 163 6.2.2.3 Testing and Results . . . . . . . . . . . . . 167 6.2.2.4 Conclusion . . . . . . . . . . . . . . . . . . 175 7 Conclusions 177 7.1 Main Findings . . . . . . . . . . . . . . . . . . . . . . . . . . 178 7.2 Answers to the Research Questions . . . . . . . . . . . . . . 179 7.3 Possible Future Directions . . . . . . . . . . . . . . . . . . . 181 Appendix A Additional Details 185 A.1 Rigid Bodies of the Vehicles . . . . . . . . . . . . . . . . . . 185 A.2 Collision Detection . . . . . . . . . . . . . . . . . . . . . . . 186 A.3 Trajectory Tracking in Frenet Coordinates . . . . . . . . . . 187 References 189