Diabetes mellitus und seine schwerwiegenden Folgen im Gefäßsystem stellen ein großes Problem der heutigen Gesellschaft dar. Ein wichtiger Aspekt der Erkrankung sind die Mikro- und Makroangiopathien, die im schlimmsten Fall zum Apoplex oder Tod führen. Es existieren bereits Hinweise, dass proinflammatorische Zytokine wie TNFα an der Entstehung des Diabetes mellitus beteiligt sind. TNFα führt zu einer Aktivierung der DLK und ihrer untergeordneten Kinase JNK, was in Betazellen zur Apoptose führt. In der vorliegenden Arbeit sollte die Rolle und Regulation der DLK in Gefäßzellen untersucht werden. Zusätzlich wurde die Angiogenese bei diät-induzierter Adipositas und Diabetes melitus in einem Mausmodell untersucht. Immunhistochemische Untersuchungen zeigen, dass die DLK in Endothelien und in glatten Muskelzellen der Aorta exprimiert wird. Um die Aktivierung und somit die Phosphorylierung der DLK zu untersuchen, wurde ein spezieller Antikörper, der an S-302 der DLK bindet, bei der Immunoblotanalyse verwendet. Eine Phosphorylierung an S-302 entspricht einer Aktivierung der DLK. Eine Behandlung von humanen Endothelzellen aus der Nabelschnurvene (HUVECs) mit TNFα zeigen eine Phosphorylierung der DLK und ihrer untergeordneten Kinase JNK. Eine Aktivierung durch Leptin oder dem vaskulären Wachstumsfaktor (VEGF) konnte hingegen nicht gezeigt werden. Zusätzlich zeigt eine Behandlung mit dem JNK-Inhibitor SP600125 eine verminderteTNFα-induzierte DLK- und JNK-Phosphorylierung, was zu der Annahme führt, dass in HUVECs die Aktivierung von JNK zu einer Phosphorylierung der DLK führt. Die Untersuchungen im Tiermodell lieferten Hinweise, dass die Regulation von TNFα ein entscheidender therapeutischer Ansatzpunkt bei der Entstehung endothelialer Dysfunktion darstellt. Es wurde gezeigt, dass das Ausschalten nur eines Allels der DLK einen messbaren Unterschied in Zusammenhang mit früher Kollateralbildung nach Ischämie erbringt. In Zusammenschau der vorliegenden Ergebnisse kann festgestellt werden, dass die Regulation der DLK durch TNFα in endothlialen Zellen einen wichtigen Aspekt in der Entwicklung der endothelialen Dysfunktion darstellt und dass die DLK als kollateralfördernde Kinase eine wichtige Rolle in der Revaskularisierung nach Ischämie spielt.

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Randomized controlled trials (RCTs) are the hallmark of evidence-based medicine and form the basis for translating research data into clinical practice. This review summarizes commonly applied designs and quality indicators of RCTs to provide guidance in interpreting and critically evaluating clinical research data. It further reflects on the principle of equipoise and its practical applicability to clinical science with an emphasis on critical care and neurological research. We performed a review of educational material, review articles, methodological studies, and published clinical trials using the databases MEDLINE, PubMed, and ClinicalTrials.gov. The most relevant recommendations regarding design, conduction, and reporting of RCTs may include the following: 1) clinically relevant end points should be defined a priori, and an unbiased analysis and report of the study results should be warranted, 2) both significant and nonsignificant results should be objectively reported and published, 3) structured study design and performance as indicated in the Consolidated Standards of Reporting Trials statement should be employed as well as registration in a public trial database, 4) potential conflicts of interest and funding sources should be disclaimed in study report or publication, and 5) in the comparison of experimental treatment with standard care, preplanned interim analyses during an ongoing RCT can aid in maintaining clinical equipoise by assessing benefit, harm, or futility, thus allowing decision on continuation or termination of the trial.

Der Beitrag diskutiert Probleme der raschen Weiterentwicklung von Klinischer Psychologie und der Verhaltenstherapie im besonderen. Dabei werden drei Perspektiven angesprochen: (a) Binnenbeziehungen innerhalb des Fachs Klinische Psychologie sowie zu Nachbardisziplinen, (b) Transferprobleme wissenschaftlicher Erkenntnisse von der Forschung zur Praxis und (c) Probleme der Fort-und Weiterbildung sowie der Qualitätssicherung in der Verhaltenstherapie. Als Beispiele von Fortschritt und Erosion werden diskutiert: (a) die Verhaltensmedizin, als Muster für gut abgestimmte und in die Klinische Psychologie als Fach integrierte Entwicklung, (b) die Gesundheitspsychologie für eine schlechte Interaktionskultur mit mangelhaftem gegenseitigem Informationstransfer und (c) die Psychotherapieszene als Beispiel für Erosionsprozesse in Forschung, Praxis sowie vor allem rort-und Weiterbildung. Der Beitrag fordert eine wesentliche Stärkung des Fachs Klinische Psychologie als fachliche und organisatorische Klammer zwischen den auseinanderdriftenden Entwicklungen. Eine erfolgreiche Übernahme dieser universitär verankerten Koordinations-und Integrations aufgabe erfordert allerdings gleichzeitig auch eine erhebliche Ausweitung personeller Ressourcen und fachlicher Kompetenzen. Eine zentrale neue Herausforderung für klinisch-psychologische Universitätsinstitute besteht auch in der Entwicklung von Qualitätssicherungsmaßnahmen. Der Beitrag empfiehlt in diesem Zusammenhang, vor allem in der Fort-und Weiterbildung den verstärkten Einsatz von Therapiemanualen sowie die lnstitutionalisierung von regelmäßigen Konsensuskonferenzen mit Empfehlungen zur Therapiedurchführung. / This paper discusses progress and erosion aspects of c1inical psychology and behavior therapy in Germany from three interrelated perspectives: (a) the relationship of behavior therapy and c1inical psychology to other basic and applied psychological disciplines as weIl as neighboring disciplines, (b) the transfer problems from the scientific fields to practice, and (c) the problem of quality assurance in practice and postgraduate education. Specific emphasis is laid on a discussion of the field of behavioral medicine, as an example for well-integrated and coordinated research and practice activities; health psychology as an example for deficient communication patterns with clinical psychology and behavior therapy, and psychotherapy as an example for erosion in research, education and practice. The paper strongly recommends a more dominant steering role of clinical psychology as the most comprehensive scientific discipline. This steering role, however, would also require a considerably expanded infrastructure of clinical psychology departments in universities together with several mechanisms (competence enhancement, consensus conferences, development of postgraduate education guidelines, quality assurance activities, coordination) to be able to fulfill this mission. The paper also suggests the more frequent use of standardized treatment manuals in postgraduate courses.

Der Beitrag diskutiert Probleme der raschen Weiterentwicklung von Klinischer Psychologie und der Verhaltenstherapie im besonderen. Dabei werden drei Perspektiven angesprochen: (a) Binnenbeziehungen innerhalb des Fachs Klinische Psychologie sowie zu Nachbardisziplinen, (b) Transferprobleme wissen-schaftlicher Erkenntnisse von der Forschung zur Praxis und (c) Probleme der Fort– und Weiterbildung sowie der Qualitätssicherung in der Verhaltenstherapie. Als Beispiele von Fortschritt und Erosion werden diskutiert: (a) die Verhaltensmedizin, als Muster für gut abgestimmte und in die Klinische Psychologie als Fach integrierte Entwicklung, (b) die Gesundheitspsychologie für eine schlechte Interaktionskultur mit mangelhaftem gegen-seitigem Informatiûnstransfer und (c) die Psychotherapieszene als Beispiel für Erosionsprozesse in Forschung, Praxis sowie vor allem Fort– und Weiterbildung. Der Beitrag fordert eine wesentliche Stärkung des Fachs Klinische Psychologie als fachliche und organisatorische Klammer zwischen den auseinanderdriftenden Entwicklungen. Eine erfolgreiche Übernahme dieser universitär verankerten Koordinations- und Integrationsaufgabe erfordert allerdings gleichzeitig auch eine erhebliche Ausweitung personeller Ressourcen und fachlicher Kompetenzen. Eine zentrale neue Herausforderung für klinisch-psychologische Universitätsinstitute besteht auch in der Entwicklung von Qualitätssicherungsmaβnahmen. Der Beitrag empfiehlt in diesem Zusammenhang, vor allem in der Fort– und Weiterbildung den verstärkten Einsatz von Therapiemanualen sowie die Institutionalisierung von regelmäβigen Konsensuskonferenzen mit Empfehlungen zur Therapiedurchführung. / This paper discusses progress and erosion aspects of c1inical psychology and behavior therapy in Germany from three interrelated perspectives: (a) the relationship of behavior therapy and c1inical psychology to other basic and applied psychological disciplines as weIl as neighboring disciplines, (b) the transfer problems from the scientific fields to practice, and (c) the problem of quality assurance in practice and postgraduate education. Specific emphasis is laid on a discussion of the field of behavioral medicine, as an example for well-integrated and coordinated research and practice activities; health psychology as an example for deficient communication patterns with clinical psychology and behavior therapy, and psychotherapy as an example for erosion in research, education and practice. The paper strongly recommends a more dominant steering role of clinical psychology as the most comprehensive scientific discipline. This steering role, however, would also require a considerably expanded infrastructure of clinical psychology departments in universities together with several mechanisms (competence enhancement, consensus conferences, development of postgraduate education guidelines, quality assurance activities, coordination) to be able to fulfill this mission. The paper also suggests the more frequent use of standardized treatment manuals in postgraduate courses.

Background: Overweight and obesity are significant public health concerns that are prevalent in younger age cohorts. Preventive or therapeutic interventions are difficult to implement and maintain over time. On the other hand, the majority of adolescents in the United States have a smartphone, representing a huge potential for innovative digitized interventions, such as weight loss programs delivered via smartphone applications. Although the number of available smartphone applications is increasing, evidence for their effectiveness in weight loss is insufficient. Therefore, the proposed study aims to assess the efficacy of a gamification-based smartphone application for weight loss in overweight and obese adolescents. The trial is designed to be a phase II, single-centre, two-arm, triple-blinded, randomized controlled trial (RCT) with a duration of 6 months. Method: The intervention consists of a smartphone application that provides both tracking and gamification elements, while the control arm consists of an identically designed application solely with tracking features of health information. The proposed trial will be conducted in an urban primary care clinic of an academic centre in the United States of America, with expertise in the management of overweight and obese adolescents. Eligible adolescents will be followed for 6 months. Changes in body mass index z score from baseline to 6 months will be the primary outcome. Secondary objectives will explore the effects of the gamification-based application on adherence, as well as anthropometric, metabolic and behavioural changes. A required sample size of 108 participants (54 participants per group) was calculated. Discussion: The benefits of the proposed study include mid-term effects in weight reduction for overweight and obese adolescents. The current proposal will contribute to fill a gap in the literature on the mid-term effects of gamification-based interventions to control weight in adolescents. This trial is a well-designed RCT that is in line with the Consolidated Standards of Reporting Trials statement.

Evidence is limited regarding whether periodontal treatment improves hemoglobin A1c (HbA1c) among people with prediabetes and periodontal disease, and it is unknown whether improvement of metabolic status persists >3 mo. In an exploratory post hoc analysis of the multicenter randomized controlled trial “Antibiotika und Parodontitis” (Antibiotics and Periodontitis)—a prospective, stratified, double-blind study—we assessed whether nonsurgical periodontal treatment with or without an adjunctive systemic antibiotic treatment affects HbA1c and high-sensitivity C-reactive protein (hsCRP) levels among periodontitis patients with normal HbA1c (≤5.7%, n = 218), prediabetes (5.7% < HbA1c < 6.5%, n = 101), or unknown diabetes (HbA1c ≥ 6.5%, n = 8) over a period of 27.5 mo. Nonsurgical periodontal treatment reduced mean pocket probing depth by >1 mm in both groups. In the normal HbA1c group, HbA1c values remained unchanged at 5.0% (95% CI, 4.9% to 6.1%) during the observation period. Among periodontitis patients with prediabetes, HbA1c decreased from 5.9% (95% CI, 5.9% to 6.0%) to 5.4% (95% CI, 5.3% to 5.5%) at 15.5 mo and increased to 5.6% (95% CI, 5.4% to 5.7%) after 27.5 mo. At 27.5 mo, 46% of periodontitis patients with prediabetes had normal HbA1c levels, whereas 47.9% remained unchanged and 6.3% progressed to diabetes. Median hsCRP values were reduced in the normal HbA1c and prediabetes groups from 1.2 and 1.4 mg/L to 0.7 and 0.7 mg/L, respectively. Nonsurgical periodontal treatment may improve blood glucose values among periodontitis patients with prediabetes (ClinicalTrials.gov NCT00707369).

Objective: Lack of insight into illness is common in patients with schizophrenia diagnoses. It is supposed to reflect deficits of executive functioning that are frequently assessed with the Wisconsin Card Sorting Test. Studies on the remediability of WCST deficits in schizophrenia, however, raise doubts about its construct validity and suggest the use of a dynamic pretest-training-posttest paradigm (WCSTdyn) and single-case analysis (Reliable Change Index, RCI) in studies on insight. Moreover, a multifactorial etiology with neurocognitive and motivational factors, as suggested by Startup's (1996) model, has to be taken into consideration. The model hypothesizes a quadratic function of the relationship between insight and cognition, which means that both cognitively impaired and cognitively intact patients with low insight are to be expected. Method: Three interrelated studies on WCSTdyn and insight were conducted. In study 1, the split-half reliability of the WCST-128 was investigated in a non-psychiatric sample (N = 110). Study 2 compared different RCI single-case tests of significance of intraindividual change on data from N = 400 patients with schizophrenia diagnoses. Furthermore, a typology with three homogenous subgroups was developed and first steps toward an external validation were taken. In study 3, the three types of test-takers were compared on two measures of insight (Item G12 of the Positive and Negative Syndrome Scale [PANSS]; Osnabrueck Scale of Therapeutic Attitudes and Identification of Psychological Problems in Schizophrenia [OSSTI]). The model by STARTUP (1996) was tested by means of regression and cluster analyses including scales on coping (Freiburg Questionnaire of Coping with Illness, FKV: MUTHNY, 1989) and defensiveness (Eppendorf Schizophrenia Inventory, ESI-FR: MAß, 2001; N = 85). Results: The WCST-64 was sufficiently stable (r_tt = .70 [Total Number Correct]). Concordances of different RCI methods were high (kappa = .72 - .90). 45 % of the sample consisted of high scorers, in 43 % a low initial score could be normalized by a short training intervention (learners), and in only 12 % of the sample the WCST deficits were not amenable to training (nonlearners). Insight of nonlearners was significantly reduced (G12: g = 0,45). Finally, three clusters were identified with configurations of insight and WCSTdyn scores consistent with the prediction by STARTUP (1996). Patients with intact neurocognition but low insight responded in a significantly more defensive manner (g = 0,38). They did not differ in self-rated coping, however. A quadratic relationship could not be confirmed. Conclusion: The RCI-based performance typology developed in studies 1 and 2 is a universally applicable analytic tool for future studies on insight-limiting neurocognitive deficits with the WCSTdyn. Results from study 3 point in the direction of a multifactorial etiology of lack of insight in schizophrenia with differential contributions of neurocognitive deficits (e.g., interference control) and defensiveness.

Derzeitige Reichweiteunsicherheiten in der Protonentherapie verhindern das vollständige Ausschöpfen ihrer physikalischen Vorteile. Ein wesentlicher Anteil ist dabei auf die Vorhersage der Reichweite mittels Röntgen-Computertomographie (CT) zurückzuführen. Um die CT-bezogene Unsicherheit zu verringern, wird die Zwei-Spektren-Computertomographie (DECT) als vielversprechend angesehen. Innerhalb dieser Arbeit wurde die Anwendbarkeit von DECT in der Protonentherapie untersucht. Zunächst wurde ein CT-Scanprotokoll für die Strahlentherapie hinsichtlich Bildqualität und Konstanz der CT-Zahlen für verschiedene Körperregionen und -größen optimiert. Anschließend wurde die patientenindividuelle DECT- basierte Reichweitevorhersage kalibriert und ihre Genauigkeit in zwei Experimenten mit bekannter Referenz unter Verwendung eines anthropomorphen Phantoms und von homogenen biologischen Geweben verifiziert. Die klinische Relevanz von DECT wurde in einer retrospektiven Analyse von Krebspatienten mit Tumoren im Kopf, Becken oder Thorax nachgewiesen. Die systematischen Reichweiteunterschiede zwischen DECT und dem klinischen Standardverfahren konnten durch die Optimierung der Standardmethode basierend auf zusätzlichen mit DECT erworbenen Patienteninformationen reduziert werden. Somit wurde DECT erstmalig klinisch genutzt, um die Reichweiteberechnung zu verbessern. Die patientenindividuelle DECT-basierte Reichweitevorhersage kann zusätzlich Gewebevariabilitäten innerhalb eines und zwischen Patienten berücksichtigen, wie für Kopftumorpatienten gezeigt wurde. Dies legt den Grundstein für eine genauere Reichweiteberechnung und eröffnet neue Möglichkeiten für die Reduktion klinischer Sicherheitssäume, in denen die CT-bezogenen Unsicherheiten berücksichtigt sind.:1 Introduction 2 Physical Principles of Computed Tomography 2.1 Image Acquisition 2.2 Image Reconstruction 2.3 Dual-Energy Computed Tomography 3 Physical Principles of Proton Therapy 3.1 Treatment Techniques 3.2 Uncertainties in Proton Therapy 4 Principles of Stopping-Power Prediction from Computed Tomography 4.1 Single-Energy Computed Tomography 4.2 Dual-Energy Computed Tomography 5 Experimental Calibration of Stopping-Power Prediction 5.1 Scan Protocol Optimisation in Computed Tomography 5.2 Characterisation of Pseudo-Monoenergetic CT Calculation 5.3 Determination of Proton Stopping Power 5.4 Calibration of Stopping-Power Prediction Methods 6 Experimental Verification of Stopping-Power Prediction 6.1 Anthropomorphic Head Phantom 6.2 Homogeneous Biological Tissue Samples 7 Clinical Translation and Validation of Dual-Energy Computed Tomography 7.1 Feasibility of Dual-Spiral Dual-Energy CT 7.2 Range Prediction in Cerebral and Pelvic Tumour Patients 7.3 Tissue Variability in Brain-Tumour Patients 7.4 Feasibility of 4D Dual-Spiral Dual-Energy CT 7.5 DECT-Based Refinement of the Hounsfield Look-Up Table 8 Summary 9 Zusammenfassung / Range uncertainty in proton therapy currently hampers the full exploitation of its physical advantages. A substantial amount of this uncertainty arises from proton range prediction based on X-ray computed tomography (CT). Dual-energy CT (DECT) has often been suggested as a promising imaging modality to reduce this CT-related range uncertainty. Within this thesis, the translation of DECT into application in proton therapy was evaluated. First, a CT scan protocol was optimised for radiotherapy considering the image quality and CT number stability for various body regions and sizes. The patient-specific DECT-based range prediction was then calibrated and its accuracy validated in two ground-truth experiments using an anthropomorphic phantom and homogeneous biological tissues. Subsequently, the clinical relevance of DECT was demonstrated in a retrospective cohort analysis of cerebral, pelvic and thoracic tumour patients. The systematic range deviations between the DECT and state-of-the-art approach were then reduced by adapting the standard method utilizing additional patient information obtained from DECT. Hence, DECT was clinically applied for the first time to refine proton range calculation. As a further step, the use of patient-specific DECT-based range prediction also considers intra- and inter-patient tissue variabilities as quantified in brain-tumour patients. A future implementation will be an important cornerstone to improve proton range calculation and might open up the possibility to reduce clinical safety margins accounting for the CT-related range uncertainty.:1 Introduction 2 Physical Principles of Computed Tomography 2.1 Image Acquisition 2.2 Image Reconstruction 2.3 Dual-Energy Computed Tomography 3 Physical Principles of Proton Therapy 3.1 Treatment Techniques 3.2 Uncertainties in Proton Therapy 4 Principles of Stopping-Power Prediction from Computed Tomography 4.1 Single-Energy Computed Tomography 4.2 Dual-Energy Computed Tomography 5 Experimental Calibration of Stopping-Power Prediction 5.1 Scan Protocol Optimisation in Computed Tomography 5.2 Characterisation of Pseudo-Monoenergetic CT Calculation 5.3 Determination of Proton Stopping Power 5.4 Calibration of Stopping-Power Prediction Methods 6 Experimental Verification of Stopping-Power Prediction 6.1 Anthropomorphic Head Phantom 6.2 Homogeneous Biological Tissue Samples 7 Clinical Translation and Validation of Dual-Energy Computed Tomography 7.1 Feasibility of Dual-Spiral Dual-Energy CT 7.2 Range Prediction in Cerebral and Pelvic Tumour Patients 7.3 Tissue Variability in Brain-Tumour Patients 7.4 Feasibility of 4D Dual-Spiral Dual-Energy CT 7.5 DECT-Based Refinement of the Hounsfield Look-Up Table 8 Summary 9 Zusammenfassung

Background: Bioprinting is one of the most rapidly developing fields in medicine. Plastic and reconstructive surgery will be affected enormously by bioprinting, due to its original purpose of restoring injured or lost tissue. This article in particular has the purpose to analyze the current state of bioprinted tissues as well as research engagement for its application in plastic and reconstructive surgery. Material and methods: A systematic search for the time span between 2000 and 2022 was performed on EMBASE, Pub-Med, Scopus, and Web of Science databases according to the PRISMA Guidelines. Criteria for the selection of publications were in vitro, animal in vivo, and human in vivo studies where three-dimensional bioprinting of tissue was performed. We extracted data such as (a) author’s country of origin, (b) in vitro study, (c) animal in vivo study, and (d) human in vivo study and categorized the publications by topics such as (1) neural tissue, (2) vascularization, (3) skin, (4) cartilage, (5) bone, and (6) muscle. Additionally, recent discoveries of in vivo animal trials were summarized. - Results: Out of a pool of 1.629 articles, only 29 publications met our criteria. Of these publications, 97% were published by university institutions. Publications from China (28%, n=8), the USA (28%, n=8), and Germany (10%, n=3) led the publication list on 3D bioprinting. Concerning the publications, 45% (n=13) were in vitro studies, 52% (n=15) in vivo studies on animal models, and 3% (n=1) pilot clinical studies on humans as reported by Zhou et al. (EBioMedicine 28: 287–302, 2018). Regarding the classification of topics, our study revealed that publications were mainly in the field of 3D printing of cartilage (n=13, 39%), skin (n=7, 21%), bone (n=6, 18%), and vascularization (n=5, 15%). - Conclusions: To this date, it has not been yet possible to bioprint whole tissue systems. However, the progress in threedimensional bioprinting is rapid. There are still some challenges, which need to be overcome regarding cell survival before and during the printing process, continuation of architecture of bioprinted multilinear cells, and long-term stabilization and survival of complex tissues. Level of evidence: Not ratable.