Prompt-gamma imaging (PGI) was proposed in the 2000s as a promising in vivo range-verification method to maintain the physical advantage of proton beams by reducing unwanted range-uncertainties. Recently, PGI with a slit camera has been successfully implemented in clinical application. Despite its high accuracy and sensitivity to range deviation being shown in several studies, the clinical benefits of PGI have not yet been investigated. Hence, to fully exploit the advantages of PGI, this thesis aims to investigate the feasibility of PGI-based range verification for the automatic classification of treatment deviations and differentiation of relevant from non-relevant changes in the treatment of head-and-neck (H&N) tumors. In the first part of this thesis, the four most common types of treatment deviations in proton therapy (PT) were investigated regarding their PGI signature and by considering clinically relevant and non-relevant scenarios. A heuristic decision tree (DT) model was iteratively developed. To gain understanding of the specific signature of the error sources, different levels of geometrical complexities were explored, from simple to complex. At the simplest level, a phantom with homogeneous density was used to distinguish range-prediction and setup errors. Next, in the intermediate complexity level, a phantom with heterogeneous density was used to inspect the additional error scenarios of anatomical changes. Finally, real patient CT scans were used to investigate the relevance of changes based on clinical constraints. In the final model, a five-step filtering approach was used during pre-processing to select reliable pencil-beam-scanning spots for range verification. In this study, five features extracted from the filtered PGI data were used to classify the treatment deviation. The model is able distinguish four introduced scenarios into six classes as follows: (1) overestimation of range prediction, (2) underestimation of range prediction, (3) setup error with larger air gap, (4) setup error with smaller air gap, (5) anatomical change, and (6) non-relevant change. To ensure the application was effective, independent patient CT datasets were used to test the model. The results yielded an excellent performance of the DT classifier, with high accuracy, sensitivity, and specificity of 96%, 100%, and 85.7%, respectively. According to these findings, this model can sensitively detect treatment deviations in PT based on simulated PGI data. In the second part of this work, an alternative approach based on machine learning (ML) was taken to automatically classify the error sources. In the first stage, the two approaches were compared, using the same features as well as the same training and test datasets. The results show that the ML approach was slightly better than the heuristic DT approach in terms of accuracy. However, the performance of both approaches was excellent for the individual scenarios. Thus, these results confirm that the PGI-based data classification with five features can be applied to detect individual sources of treatment deviation in PT. In the second stage, there was an investigation of more complex and more realistic combinations of error scenarios, which was out of the scope of the DT approach. The results demonstrated that the performance of the ML-based classifiers declined in general. Furthermore, the additional features of the PG shift did not substantially improve the performance of the classifiers. As a consequence, these findings mark important issues for future research. Potentially, usage of the spatial information from the spot-based PGI data and more complex techniques such as deep learning may improve the performance of classifiers with respect to scenarios with multiple error sources. However, regardless of this, it is recommended that these findings be confirmed and validated in simulations under measurement-like conditions or with real PG measurements of H&N patients themselves. Moreover, this classification model could eventually be tested with other body sites and entities in order to assess its compatibility and adaptation requirements. In summary, this study yielded promising results regarding the automatic classification of treatment-deviation sources and the differentiation of relevant and non-relevant changes in H&N-tumor treatment in PT with PGI data. This simulation study marks an important step towards fully automated PGI-based proton-range verification, which could contribute to closing the treatment-workflow loop of adaptive therapy by supporting clinical decision-making and, ultimately, improving clinical PT.:1 Introduction 2 Background 2.1 Proton therapy 2.1.1 Rationale for proton therapy 2.1.2 Uncertainties and their mitigation 2.2 In vivo range-verification techniques 2.2.1 Range probing 2.2.2 Proton tomography 2.2.3 Magnetic resonance imaging 2.2.4 Ionoacoustic detection 2.2.5 Treatment-activated positron-emission tomography imaging 2.2.6 Prompt-gamma based detection 3 Prompt-gamma imaging with a knife-edged slit camera 3.1 Current state-of-the-art 3.2 Prompt-gamma camera system 3.3 Data acquisition and analysis 4 Error-source classification using heuristic decision tree approach 4.1 Study design 4.1.1 Case selection 4.1.2 Investigated scenarios 4.1.3 Prompt-gamma simulation and range shift determination 4.2 Development of the model 4.2.1 First-generation model 4.2.2 Second-generation model 4.2.3 Third-generation model 4.3 Model testing 4.4 Discussion: decision-tree model 5 Error-source classification using a machine-learning approach 5.1 Machine learning for classification 5.1.1 Support-vector-machine algorithm 5.1.2 Ensemble algorithm – random forest 5.1.3 Logistic-regression algorithm 5.2 Study design 5.2.1 Case selection 5.2.2 Feature selection 5.3 Model generation 5.4 Model testing 5.5 Discussion 6 Summary/ Zusammenfassung Bibliography Appendix List of Figures List of Tables List of Abbreviations

Verglichen mit dem Gesamtunfallgeschehen auf deutschen Straßen stellen Wildunfälle nur ein relativ geringes Verletzungsrisiko für Verkehrsteilnehmer dar. Wildunfälle geschehen fast ausschließlich auf Außerortsstraßen. 2017 wurden dort 2.334 Wildunfälle mit Personenschaden polizeilich erfasst, das entspricht rund 2,5 Prozent aller Unfälle mit Personenschaden im Außerortsbereich. Dabei wurden 10 Personen getötet, 561 schwer und 2.121 leicht verletzt. Etwa 96 Prozent dieser Unfälle ereigneten sich auf Landstraßen, also außerhalb des Autobahnnetzes. Wildunfälle sind überwiegend Unfälle mit Sachschaden, die oft nicht polizeilich aufgenommen werden. Es gibt daher eine sehr hohe Dunkelziffer in der amtlichen Statistik. Die Anzahl der bei den Kfz-Kaskoversicherern gemeldeten Schadensfälle infolge von Wildunfällen hat sich in den letzten zehn Jahren um 14 Prozent auf rund 275.000 im Jahr 2017 erhöht; die damit verbundenen Versicherungsleistungen stiegen im selben Zeitraum sogar um rund 50 Prozent auf 744 Millionen Euro (Abbildung 1). Das heißt, der Kostenanstieg der Versicherungsleistungen beträgt das Dreieinhalb-fache des Anstiegs der Wildunfälle im betrachteten Zeitraum. Wildschäden belegen bei den PKW-Schadensfällen in der Kaskoversicherung nach dem Glasbruch den zweiten Rang. Wildschäden an Fahrzeugen ohne Kaskoversicherung werden in der Regel nicht erfasst und sind damit Teil der Dunkelziffer. Nach der Wildunfallstatistik des Deutschen Jagdverbandes werden je nach Wildart bis zu 20 Prozent der Wildtiere nicht durch die Jagd erlegt. Die meisten davon werden vermutlich durch Kollisionen mit Fahrzeugen im Straßenverkehr getötet. Aufgrund des zunehmenden Verkehrs ist anzunehmen, dass diese Anzahl in den kommenden Jahren weiter steigen wird (Bruinderick und Hazebroek 1996, Seiler 2004, Gritzka et al. 2010). Die in den vergangenen Jahren eingesetzten Gegenmaßnahmen sind in der Regel sehr kostenintensiv (z.B. Wildzäune und Wildbrücken) oder hatten wenig Erfolg (z.B. weiße und rote Reflektoren, Wildwechselzeichen; vgl. Bruinderick und Hazebroek 1996). In einer von der Unfallforschung der Versicherer (UDV) bereits 2007 publizierten Untersuchung zur Wirksamkeit von weißen, roten und akustischen Reflektoren konnte keine Wirkung auf die Zahl der Unfälle mit Wildbeteiligung nachgewiesen werden (Voß et al. 2007). Nach der Veröffentlichung dieser Studie mehrten Berichte dass blaue Reflektoren zu einer Verminderung von Wildunfällen führen würden. Allerdings haben die Hersteller dieser Reflektoren bis heute keine breit angelegte wissenschaftliche Studie vorgelegt, die eine statistisch signifikante Reduzierung von Wildunfällen durch ihre Produkte nachweist. Vor diesem Hintergrund hat die UDV die hier vorliegende neue Studie initiiert und finanziert, die durch die Georg-August-Universität Göttingen in Kooperation mit der Universität Zürich durchgeführt wurde. Die zu klärende zentrale Frage war, ob das Anbringen von blauen oder multi-farbigen Reflektoren die Anzahl der Wildunfälle dauerhaft wirksam reduzieren kann. Zudem sollte geklärt werden, inwieweit infrastrukturelle, straßenraumgestalterische, landnutzungs- oder tierspezifische Merkmale einen maßgebenden Einfluss auf das Wildunfallgeschehen haben können.

The Kinaesthetics care conception is a nursing approach for patient handling which aims to prevent work-related complaints and diseases. The evidence about the influence of Kinaesthetics on musculoskeletal disorders among persons who handle patients is unclear to date. The purposes of the scoping review are to gain insight into the current state of research regarding the clinical effectiveness of Kinaesthetics (in terms of perceived exertion and musculoskeletal complaints) among persons who handle patients and to identify potential research gaps. A scoping review was conducted. The search strategy comprised a systematic search in electronic databases (MEDLINE, EMBASE, AMED, CINAHL), a hand search, a fast forward search (Web of Science) and a Google scholar-search. The review process was carried out independently by two reviewers. Methodological quality was assessed for all studies using three methodological main categories (reporting quality, internal validity, external validity). Thirteen studies with different study designs were included. Seven studies investigated musculoskeletal complaints and nine studies the perceived exertion of nursing staff. Most studies were of very low methodology. Most studies reported a decrease of musculoskeletal complaints and perceived exertion due to Kinaesthetics. In conclusion, there is only little evidence of very low quality about the effectiveness of Kinaesthetics. Out of the studies it could be assumed that Kinaesthetics may decrease the patient handling related perceived exertion and musculoskeletal pain of persons who handle patients. But an overestimation of these results is likely, due to inadequate methodology of included studies. As a result, no clear recommendations about the effectiveness of the Kinaesthetics care conception can be made yet. Since a research gap was shown, further high quality intervention studies are necessary for clarifying the effectiveness of Kinaesthetics.

The Kinaesthetics care conception is a nursing approach for patient handling which aims to prevent work-related complaints and diseases. The evidence about the influence of Kinaesthetics on musculoskeletal disorders among persons who handle patients is unclear to date. The purposes of the scoping review are to gain insight into the current state of research regarding the clinical effectiveness of Kinaesthetics (in terms of perceived exertion and musculoskeletal complaints) among persons who handle patients and to identify potential research gaps. A scoping review was conducted. The search strategy comprised a systematic search in electronic databases (MEDLINE, EMBASE, AMED, CINAHL), a hand search, a fast forward search (Web of Science) and a Google scholar-search. The review process was carried out independently by two reviewers. Methodological quality was assessed for all studies using three methodological main categories (reporting quality, internal validity, external validity). Thirteen studies with different study designs were included. Seven studies investigated musculoskeletal complaints and nine studies the perceived exertion of nursing staff. Most studies were of very low methodology. Most studies reported a decrease of musculoskeletal complaints and perceived exertion due to Kinaesthetics. In conclusion, there is only little evidence of very low quality about the effectiveness of Kinaesthetics. Out of the studies it could be assumed that Kinaesthetics may decrease the patient handling related perceived exertion and musculoskeletal pain of persons who handle patients. But an overestimation of these results is likely, due to inadequate methodology of included studies. As a result, no clear recommendations about the effectiveness of the Kinaesthetics care conception can be made yet. Since a research gap was shown, further high quality intervention studies are necessary for clarifying the effectiveness of Kinaesthetics.

Background: We aimed to update the 2010 evidence- and consensus-based national clinical guideline on the diagnosis and management of uncomplicated urinary tract infections (UTIs) in adult patients. Results are published in 2 parts. Part 1 covers methods, the definition of patient groups, and diagnostics. This second publication focuses on treatment of acute episodes of cystitis and pyelonephritis as well as on prophylaxis of recurrent UTIs. Materials and Methods: An interdisciplinary group consisting of 17 representatives of 12 medical societies and a patient representative was formed. Systematic literature searches were conducted in MEDLINE, EMBASE, and the Cochrane Library to identify literature published in 2010–2015. Results: For the treatment of acute uncomplicated cystitis (AUC), fosfomycin-trometamol, nitrofurantoin, nitroxoline, pivmecillinam, and trimethoprim (depending on the local rate of resistance) are all equally recommended. Cotrimoxazole, fluoroquinolones, and cephalosporins are not recommended as antibiotics of first choice, for concern of an unfavorable impact on the microbiome. Mild to moderate uncomplicated pyelonephritis should be treated with oral cefpodoxime, ceftibuten, ciprofloxacin, or levofloxacin. For AUC with mild to moderate symptoms, instead of antibiotics symptomatic treatment alone may be considered depending on patient preference after discussing adverse events and outcomes. Primarily non-antibiotic options are recommended for prophylaxis of recurrent urinary tract infection. Conclusion: In accordance with the global antibiotic stewardship initiative and considering new insights in scientific research, we updated our German clinical UTI guideline to promote a responsible antibiotic use and to give clear hands-on recommendations for the diagnosis and management of UTIs in adults in Germany for healthcare providers and patients.

Background: Dipyrone (metamizole) is one of the most widely used non-opioid analgesics for the treatment of cancer pain. Aim: Because evidence-based recommendations are not yet available, a systematic review was conducted for the German Guideline Program in Oncology to provide recommendations for the use of dipyrone in cancer pain. Design: First, a systematic review for clinical trials assessing dipyrone in adult patients with cancer pain was conducted. Endpoints were pain intensity, opioid-sparing effects, safety, and quality of life. Data sources: The search was performed in MedLine, Embase (via Ovid), and the Cochrane Library (1948–2013) and additional hand search was conducted. Finally, recommendations were developed and agreed in a formal structured consensus process by 53 representatives of scientific medical societies and 49 experts. Results: Of 177 retrieved studies, 4 could be included (3 randomized controlled trials and 1 cohort study, n = 252 patients): dipyrone significantly decreased pain intensity compared to placebo, even if low doses (1.5–2 g/day) were used. Higher doses (3 × 2 g/day) were more effective than low doses (3 × 1 g/day), but equally effective as 60 mg oral morphine/day. Pain reduction of dipyrone and non-steroidal anti-inflammatory drugs did not differ significantly. Compared to placebo, non-steroidal anti-inflammatory drugs, and morphine, the incidence of adverse effects was not increased. Conclusion: Dipyrone can be recommended for the treatment of cancer pain as an alternative to other non-opioids either alone or in combination with opioids. It can be preferred over non-steroidal anti-inflammatory drugs due to the presumably favorable side effect profile in long-term use, but comparative studies are not available for long-term use.

Objective: Prospective study designs ideally allow patients to be followed from the first manifestations of the illness or even from an at-risk stage. It can thus provide data on the predictive value of changes in clinical symptomatology, cognition or further biological markers to broaden our understanding of the etiopathology and symptomatic trajectory of bipolar disorders. The scope of this narrative review is to summarize evidence from prospectively collected data on psychopathological and other clinical and biological changes in the early developmental course of bipolar disorders. Methods: The narrative review was based on a literature search conducted in February 2016 within the PubMed library for prospective study data of persons in antecedent and early manifest stages of manifest bipolar disorder published within the last 15 years. Results: A total of 19 prospective studies were included. Regarding psychopathological features; personality, temperament and character traits as well as changes in sleep and circadian rhythm, the evidence suggests that risk factors for the development of bipolar disorder can already be described and should be studied further to understand their interaction, mediation with other factors and timing in the developmental process of bipolar disorder. Apart from the positive family history, childhood anxiety, sleep problems, subthreshold (hypo)manic symptoms and certain character traits/emotionality should be identified and monitored already in clinical practice as their presence likely increases risk of bipolar disorder. Up to date no substantiated evidence was found from prospective studies addressing cognitive features, life events, immunological parameters and morphological central nervous system changes as potential risk factors for bipolar disorder. Conclusion: For an improved understanding of episodic disorders, longitudinal data collection is essential. Since the etiology of bipolar disorders is complex, a number of potential risk factors have been proposed. Prospective studies addressing this spectrum and resilience factors are critical and will be best conducted within multi-site research networks or initiatives.

Das übergeordnete Ziel der Arbeit war die Überprüfung der Vorhersagbarkeit unterschiedlicher Outcome-Kriterien bei Patienten in stationärer berufsdermatologischer Rehabilitation mithilfe der Rehamotivation und weiterer theoretisch relevanter Variablen. Zur Anwendung kamen der Rehamotivationsfragebogen PAREMO-20, Verfahren zur Erfassung von psychischer Belastung (Marburger Hautfragebogen, MHF), Krankheitsbewältigung, Selbstwirksamkeit und Lebensqualität sowie soziodemographische, krankheits- und behandlungsbezogene Daten. In einem ersten Schritt ging es um die teststatistische Überprüfung der Untersuchungsverfahren, insbesondere des PAREMO-20 bei der vorliegenden Patientengruppe (N=424). Alle Verfahren erwiesen sich als für die Anwendung bei dermatologischen Patienten geeignet. Für den PAREMO-20 ließen sich die aus der allgemeinen Rehabilitationsforschung bekannten teststatistischen Merkmale weitgehend replizieren. Als Nächstes erfolgte die Überprüfung der prädiktiven Validität dieser diagnostischen Informationen bezüglich verschiedener subjektiver und objektiver Kriterien des Behandlungsergebnisses. Im Zentrum standen hierbei deskriptiv ermittelte sowie mithilfe des Reliable Change Index ermittelte Gruppierungen von Patienten hinsichtlich ihrer Behandlungsfortschritte (verbessert, verschlechtert, gleich geblieben). Hierzu wurden Diskriminanzanalysen und logistische Regressionsanalysen durchgeführt. Als Ergebnis zeigte sich, dass Kriterien der objektiven und subjektiven Hautgesundheit mit den eingesetzten Verfahren nicht vorhersagbar sind. Der PAREMO-20 besitzt hier keine prädiktive Validität. Dagegen konnte die Veränderung der Lebensqualität als indirektes Erfolgskriterium durch die psychische Verfassung zu Beginn der 3-wöchigen Maßnahme mit dem Marburger Hautfragebogen vorhergesagt werden. Zudem wurden Möglichkeiten der Weiterentwicklung der Instrumente diskutiert und Implikationen für Forschung und Praxis abgeleitet.

Bei der vorliegenden Studie handelt es sich um die Untersuchung zur psychometrischen und eignungsdiagnostische Qualität des Auswahlverfahrens des Weiterbildungsinstitutes zum psychologischen Psychotherapeuten der Universität Osnabrück. Die Auswahl geeigneter Ausbildungskandidaten hat zwar national als auch international eine langjährige Tradition, dennoch gab es bisher keine systematischen empirischen Überprüfungen der eignungsdiagnostischen Güte der eingesetzten Auswahlverfahren. Im Fokus des Interesses dieser Arbeit stand neben der Überprüfung der psychometrischen Güte vor allem die Überprüfung der prognostischen Validität beider Eignungsprädiktoren. Die Analysen basieren auf den Daten zweier Ausbildungsjahrgänge. Neben den psychometrischen Qualitäten der eingesetzten Eignungsprädiktoren wurde überprüft, zu welchem Ausmaß die Eignungseinstufungen von 40 Ausbildungskandidaten anhand dieser Prädiktoren mit einem breiten Spektrum an Eignungskriterien nach fünfjähriger Qualifikationsphase korrelieren. Die gefundenen Zusammenhänge zwischen den beiden Eignungsprädiktoren und dem eingesetzten Spektrum von Eignungskriterien variieren zwischen 0.3 und 0.5. Im Vergleich zu entsprechenden Koeffizienten in der Literatur sind sie angesichts eines Prognosezeitraums von mehr als 5 Jahren als gut bis sehr gut zu bewerten. Inhaltlich zeigte sich, dass sich diejenigen Ausbildungskandidaten, die bereits im Auswahl¬verfahren im Sinne einer allgemeinen therapeutischen Eignung als auch im Sinne einer spezifischen interpersonalen Eignung als weniger geeignet eingeschätzt wurden, im Verlaufe der Ausbildung weniger kooperativ in Verwaltungsangelegenheiten zeigten, von ihren Supervisoren als weniger therapeutisch kompetent eingeschätzt wurden, sowie zum Abschluss ihrer Ausbildung weniger reguläre Therapiebeendigungen aufwiesen. Daraus abzuleitende Handlungsanweisungen für den Einsatz solcher Verfahren zum Zwecke der Selektion oder Modifikation werden diskutiert.