TY - JOUR A1 - Düking, Peter A1 - Hotho, Andreas A1 - Holmberg, Hans-Christer A1 - Fuss, Franz Konstantin A1 - Sperlich, Billy T1 - Comparison of Non-Invasive Individual Monitoring of the Training and Health of Athletes with Commercially Available Wearable Technologies JF - Frontiers in Physiology N2 - Athletes adapt their training daily to optimize performance, as well as avoid fatigue, overtraining and other undesirable effects on their health. To optimize training load, each athlete must take his/her own personal objective and subjective characteristics into consideration and an increasing number of wearable technologies (wearables) provide convenient monitoring of various parameters. Accordingly, it is important to help athletes decide which parameters are of primary interest and which wearables can monitor these parameters most effectively. Here, we discuss the wearable technologies available for non-invasive monitoring of various parameters concerning an athlete's training and health. On the basis of these considerations, we suggest directions for future development. Furthermore, we propose that a combination of several wearables is most effective for accessing all relevant parameters, disturbing the athlete as little as possible, and optimizing performance and promoting health. KW - sports technology KW - wearable technologies KW - performance parameters KW - health monitoring KW - performance monitoring Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-165516 VL - 7 IS - 71 ER - TY - THES A1 - Riegler, Christoph Paul T1 - Eine deutschsprachige Variante des Functioning Assessment Short Test (FAST): Übereinstimmung zwischen Selbsteinschätzung und Fremdeinschätzung T1 - A German variant of the Functioning Assessment Short Test (FAST): Agreement of self-assessment with external assessment N2 - Die Erhebung der alltäglichen Funktionsfähigkeit mithilfe von Skalen zu instrumentellen Aktivitäten des täglichen Lebens (IADL) ist essenziell zur Erfassung der individuellen und gesellschaftlichen Konsequenzen von klinischen und subklinischen Erkrankungen. Im deutschsprachigen Raum existieren jedoch nur wenige validierte Instrumente zur Erfassung von IADL. Da all diese Skalen für ein geriatrisches Patientenkollektiv entwickelt wurden, haben sie wichtige Schwächen in der Anwendung bei jüngeren Patientengruppen (insbesondere die fehlende Erfassung beruflicher Funktionsfähigkeit). Aus diesem Grund wurde im Rahmen der vorliegenden Arbeit mit dem Functioning Assessment Short Test (FAST) ein bereits in mehreren Sprachen validiertes, für erwachsene Patienten jedweden Alters konzipiertes Instrument mit sehr guten psychometrischen Kennwerten ins Deutsche übertragen und hinsichtlich Validität und Reliabilität untersucht. Die deutschsprachige Variante des FAST wurde durch standardisierte vorwärts-rückwärts-Übersetzung aus dem Englischen erstellt und ist als Selbstausfüllerfragebogen konzipiert. Die Skala enthält 23 ordinal skalierte Einzelitems, aus denen sich ein Summenscore berechnen lässt, wobei höhere Werte für eine schlechtere alltägliche Funktionsfähigkeit stehen. Der Fragebogen wurde zwischen 2017 und 2018 an insgesamt 120 Teilnehmern in Würzburg und Münster getestet, von denen 60 aus bevölkerungsbasierten Kohortenstudien stammten und je 30 Patienten aufgrund eines ischämischen Schlaganfalls oder einer akuten Depression stationär behandelt wurden. Als Maß für die Reliabilität des Instrumentes wurde die Übereinstimmung zwischen Selbst- und Fremdeinschätzung der alltäglichen Funktionsfähigkeit (Fremdeinschätzung durch Angehörige der Teilnehmer bzw. behandelnde Ärzte / Psychologen) mithilfe des FAST gewählt. Die Validität der Skala wurde durch die Messung von Korrelationen des FAST Summenscores mit gängigen Skalen zu Depressivität (PHQ-D-9, CES-D), Angstsymptomatik (PHQ-GAD-7), gesundheitsbezogener Lebensqualität (SF-12, EQ-5D) und kognitiver Leistungsfähigkeit (MOCA) erhoben. Daneben erfolgte eine uni- und multivariate Regression zur Erhebung des Einflusses der o.g. Skalen und relevanter Vorerkrankungen auf den Summenscore des FAST. Die Reliabilitätsanalyse zeigte für die Probanden aus der Allgemeinbevölkerung ein moderates (ICC 0.50 (95%-CI 0.64 – 0.54), für die Patienten mit akutem ischämischem Schlaganfall ein gutes (ICC 0.65 (95%-CI 0.55 – 0.75) und für die stationär behandelten Patienten mit Depression ein schlechtes Ergebnis (ICC 0.11 (95%-CI 0.02 – 0.20). Hinsichtlich der Konstruktvalidität zeigte sich in der bevölkerungsbasierten Stichprobe eine signifikante Korrelation des FAST Summenscores mit PHQ-D-9, CES-D, PHQ-GAD-7 und psychischer Summenskala der SF-12. In der univariablen Regression waren PHQ-D9, PHQ-GAD-7, psychische Summenskala des SF-12 und das Vorliegen von chronischem Rückenschmerz signifikante Prädiktoren für den FAST Summenscore. In der multivariablen Analyse verblieben SF-12 und chronischer Rückenschmerz als signifikante Einflussfaktoren. In der Stichprobe von Patienten mit akutem ischämischem Schlaganfall zeigte sich eine signifikante, negative Korrelation des FAST Summenscores mit dem MOCA. Zusammenfassend zeigte die deutschsprachige Variante des FAST moderate bis gute psychometrische Kennwerte in der Allgemeinbevölkerung und bei Patienten mit akutem ischämischem Schlaganfall, während die Ergebnisse bei stationär behandelten Patienten mit Depression schlecht waren. Aufgrund der kleinen Fallzahl der untersuchten Stichproben und des fehlenden Assessment von Test-Retest-Reliabilität sollten vor der breiten Anwendung des FAST im deutschsprachigen Raum weitere psychometrische Prüfungen des Instruments erfolgen. N2 - Assessment of functional impairment via IADL scales is crucial in determining the individual and social consequences of clinical and subclinical diseases. There is only a limited number of validated IADL scales in the German-speaking area. Since all these scales were developed to assess functional impairment in geriatric patients, they possess relevant weaknesses when assessing younger individuals, such as a lack of questions on occupational functioning. Therefore, we created a German variant of the Functioning Assessment Short Test (FAST); an IADL scale that has been validated in various languages with excellent psychometric properties and is applicable to patients of all ages. The German variant of the FAST was developed following a standardized forward-backward translation protocol and is designed as a selfadministered questionnaire. The scale contains 23 ordinal-scaled items of which a sum score can be calculated, whereat higher values on the scale account for more difficulties in activities of daily living. Between 2015 and 2016, 120 participants were enrolled and assessed with the FAST questionnaire in Würzburg and Münster. Sixty patients were derived from two ongoing population-based studies, while 30 participants were inpatients treated for depression and 30 participants were inpatients admitted to a neurological clinic due to acute ischemic stroke. To assess reliability of the FAST scale, the agreement between self-assessment and external assessment by relatives (in participants from the general population and stroke patients) or treating physicians / psychologists (in patients treated for acute depression) was calculated. Validity was assessed by conducting correlations with established scales of depression (PHQD- 9, CES-D), anxiety (PHQ-GAD-7), health-related quality of life (SF-12, VAS from EQ-5D) and cognitive functioning (MOCA). Furthermore, uni- and multivariable regression analyses were conducted using the aforementioned scales together with relevant diagnoses from the participants record to identify predictors of higher values of the FAST scale. Reliability was moderate for patients form the general population (ICC 0.50 (95%-CI 0.64 – 0.54), good for inpatients admitted for acute ischemic stroke (ICC 0.65 (95%-CI 0.55 – 0.75) and poor for inpatients admitted for acute depression (ICC 0.11 (95%-CI 0.02 – 0.20). Regarding construct validity, a significant correlation of the FAST scale with PHQ-D-9, CESD, PHQ-GAD-7 and the mental component of the SF-12 was found in patients derived from the general population. In univariable regression analysis the PHQ-D-9, the PHQ-GAD-7, the mental component of the SF-12 and the presence of chronic back pain explained variance of the FAST scale. In multivariable regression, chronic back pain together with SF-12 remained significant predictors. In the sample of patients treated for acute ischemic stroke, a significant negative correlation between FAST score and MOCA score was detected. In conclusion, the German variant of the FAST yielded moderate to good psychometric properties in the general population and patients treated for acute ischemic stroke, while reliability was poor in inpatients with acute depression. Due to the small sample size and the lack of assessment of test-retest-reliability, the German variant of the FAST should be tested in a larger sample before the scale can be broadly used in research and clinical practice. KW - Functioning Assessment Short Test KW - Instrumental Activities of Daily Living KW - Fragebogen KW - alltägliche Funktionsfähigkeit KW - instrumentelle Aktivitäten des täglichen Lebens Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-288931 ER - TY - JOUR A1 - Esnault, Clara A1 - Schrama, David A1 - Houben, Roland A1 - Guyétant, Serge A1 - Desgranges, Audrey A1 - Martin, Camille A1 - Berthon, Patricia A1 - Viaud-Massuard, Marie-Claude A1 - Touzé, Antoine A1 - Kervarrec, Thibault A1 - Samimi, Mahtab T1 - Antibody–drug conjugates as an emerging therapy in oncodermatology JF - Cancers N2 - Antibody–drug conjugates (ADCs) are an emerging class of therapeutics, with twelve FDA- and EMA-approved drugs for hematological and solid cancers. Such drugs consist in a monoclonal antibody linked to a cytotoxic agent, allowing a specific cytotoxicity to tumor cells. In recent years, tremendous progress has been observed in therapeutic approaches for advanced skin cancer patients. In this regard, targeted therapies (e.g., kinase inhibitors) or immune checkpoint-blocking antibodies outperformed conventional chemotherapy, with proven benefit to survival. Nevertheless, primary and acquired resistances as well as adverse events remain limitations of these therapies. Therefore, ADCs appear as an emerging therapeutic option in oncodermatology. After providing an overview of ADC design and development, the goal of this article is to review the potential ADC indications in the field of oncodermatology. KW - antibody–drug conjugates KW - oncodermatology KW - melanoma KW - skin squamous cell carcinoma KW - cutaneous T-cell lymphoma and Merkel cell carcinoma Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-262192 SN - 2072-6694 VL - 14 IS - 3 ER - TY - JOUR A1 - Mrestani, Achmed A1 - Pauli, Martin A1 - Kollmannsberger, Philip A1 - Repp, Felix A1 - Kittel, Robert J. A1 - Eilers, Jens A1 - Doose, Sören A1 - Sauer, Markus A1 - Sirén, Anna-Leena A1 - Heckmann, Manfred A1 - Paul, Mila M. T1 - Active zone compaction correlates with presynaptic homeostatic potentiation JF - Cell Reports N2 - Neurotransmitter release is stabilized by homeostatic plasticity. Presynaptic homeostatic potentiation (PHP) operates on timescales ranging from minute- to life-long adaptations and likely involves reorganization of presynaptic active zones (AZs). At Drosophila melanogaster neuromuscular junctions, earlier work ascribed AZ enlargement by incorporating more Bruchpilot (Brp) scaffold protein a role in PHP. We use localization microscopy (direct stochastic optical reconstruction microscopy [dSTORM]) and hierarchical density-based spatial clustering of applications with noise (HDBSCAN) to study AZ plasticity during PHP at the synaptic mesoscale. We find compaction of individual AZs in acute philanthotoxin-induced and chronic genetically induced PHP but unchanged copy numbers of AZ proteins. Compaction even occurs at the level of Brp subclusters, which move toward AZ centers, and in Rab3 interacting molecule (RIM)-binding protein (RBP) subclusters. Furthermore, correlative confocal and dSTORM imaging reveals how AZ compaction in PHP translates into apparent increases in AZ area and Brp protein content, as implied earlier. KW - active zone KW - Bruchpilot KW - RIM-binding protein KW - compaction KW - homeostasis KW - presynaptic plasticity KW - super-resolution microscopy Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-265497 VL - 37 IS - 1 ER - TY - JOUR A1 - Schmidbauer, Moritz L. A1 - Ferse, Caroline A1 - Salih, Farid A1 - Klingner, Carsten A1 - Musleh, Rita A1 - Kunst, Stefan A1 - Wittstock, Matthias A1 - Neumann, Bernhard A1 - Schebesch, Karl-Michael A1 - Bösel, Julian A1 - Godau, Jana A1 - Lochner, Piergiorgio A1 - Adam, Elisabeth H. A1 - Jahnke, Kolja A1 - Knier, Benjamin A1 - Schirotzek, Ingo A1 - Müllges, Wolfgang A1 - Notz, Quirin A1 - Dengl, Markus A1 - Güldner, Andreas A1 - Onur, Oezguer A. A1 - Garcia Borrega, Jorge A1 - Dimitriadis, Konstantinos A1 - Günther, Albrecht T1 - COVID-19 and intracranial hemorrhage: a multicenter case series, systematic review and pooled analysis JF - Journal of Clinical Medicine N2 - Introduction: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) profoundly impacts hemostasis and microvasculature. In the light of the dilemma between thromboembolic and hemorrhagic complications, in the present paper, we systematically investigate the prevalence, mortality, radiological subtypes, and clinical characteristics of intracranial hemorrhage (ICH) in coronavirus disease (COVID-19) patients. Methods: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we performed a systematic review of the literature by screening the PubMed database and included patients diagnosed with COVID-19 and concomitant ICH. We performed a pooled analysis, including a prospectively collected cohort of critically ill COVID-19 patients with ICH, as part of the PANDEMIC registry (Pooled Analysis of Neurologic Disorders Manifesting in Intensive Care of COVID-19). Results: Our literature review revealed a total of 217 citations. After the selection process, 79 studies and a total of 477 patients were included. The median age was 58.8 years. A total of 23.3% of patients experienced the critical stage of COVID-19, 62.7% of patients were on anticoagulation and 27.5% of the patients received ECMO. The prevalence of ICH was at 0.85% and the mortality at 52.18%, respectively. Conclusion: ICH in COVID-19 patients is rare, but it has a very poor prognosis. Different subtypes of ICH seen in COVID-19, support the assumption of heterogeneous and multifaceted pathomechanisms contributing to ICH in COVID-19. Further clinical and pathophysiological investigations are warranted to resolve the conflict between thromboembolic and hemorrhagic complications in the future. KW - COVID-19 KW - intracranial hemorrhage KW - prognosis KW - anticoagulation Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-255236 SN - 2077-0383 VL - 11 IS - 3 ER - TY - JOUR A1 - Bolm, Louisa A1 - Zemskov, Sergii A1 - Zeller, Maria A1 - Baba, Taisuke A1 - Roldan, Jorge A1 - Harrison, Jon M. A1 - Petruch, Natalie A1 - Sato, Hiroki A1 - Petrova, Ekaterina A1 - Lapshyn, Hryhoriy A1 - Braun, Ruediger A1 - Honselmann, Kim C. A1 - Hummel, Richard A1 - Dronov, Oleksii A1 - Kirichenko, Alexander V. A1 - Klinkhammer-Schalke, Monika A1 - Kleihues-van Tol, Kees A1 - Zeissig, Sylke R. A1 - Rades, Dirk A1 - Keck, Tobias A1 - Fernandez-del Castillo, Carlos A1 - Wellner, Ulrich F. A1 - Wegner, Rodney E. T1 - Concepts and outcomes of perioperative therapy in stage IA-III pancreatic cancer — a cross-validation of the National Cancer Database (NCDB) and the German Cancer Registry Group of the Society of German Tumor Centers (GCRG/ADT) JF - Cancers N2 - (1) Background: The aim of this study is to assess perioperative therapy in stage IA-III pancreatic cancer cross-validating the German Cancer Registry Group of the Society of German Tumor Centers — Network for Care, Quality, and Research in Oncology, Berlin (GCRG/ADT) and the National Cancer Database (NCDB). (2) Methods: Patients with clinical stage IA-III PDAC undergoing surgery alone (OP), neoadjuvant therapy (TX) + surgery (neo + OP), surgery+adjuvantTX (OP + adj) and neoadjuvantTX + surgery + adjuvantTX (neo + OP + adj) were identified. Baseline characteristics, histopathological parameters, and overall survival (OS) were evaluated. (3) Results: 1392 patients from the GCRG/ADT and 29,081 patients from the NCDB were included. Patient selection and strategies of perioperative therapy remained consistent across the registries for stage IA-III pancreatic cancer. Combined neo + OP + adj was associated with prolonged OS as compared to neo + OP alone (17.8 m vs. 21.3 m, p = 0.012) across all stages in the GCRG/ADT registry. Similarly, OS with neo + OP + adj was improved as compared to neo + OP in the NCDB registry (26.4 m vs. 35.4 m, p < 0.001). (4) Conclusion: The cross-validation study demonstrated similar concepts and patient selection criteria of perioperative therapy across clinical stages of PDAC. Neoadjuvant therapy combined with adjuvant therapy is associated with improved overall survival as compared to either therapy alone. KW - pancreatic cancer KW - perioperative therapy KW - neoadjuvant therapy KW - pancreatic surgery Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-262174 SN - 2072-6694 VL - 14 IS - 4 ER - TY - JOUR A1 - Prasse, Tobias A1 - Stratos, Ioannis A1 - Niehoff, Anja A1 - Christ, Hildegard A1 - Heck, Vincent A1 - Meyer, Carolin A1 - Mittlmeier, Thomas T1 - Bisphenol A-related effects on bone morphology and biomechanical properties in an animal model JF - Toxics N2 - Bisphenol A (BPA), which is contained in numerous plastic products, is known to act as an endocrine-disruptive, toxic, and carcinogenic chemical. This experimental series sought to determine the influence of BPA exposure on the femoral bone architecture and biomechanical properties of male and female Wistar rats. BPA was applied subcutaneously by using osmotic pumps. After 12 weeks, the bones were analyzed by micro-computed tomography (micro-CT) and a three-point bending test. Comparing the female low- and high-dose groups, a significantly greater marrow area (p = 0.047) was identified in the group exposed to a higher BPA concentration. In addition, the trabecular number tended to be higher in the female high-dose group when compared to the low-dose group (p > 0.05). The area moment of inertia also tended to be higher in the male high-dose group when compared to the male low-dose group (p > 0.05). Considering our results, BPA-related effects on the bone morphology in female Wistar rats are osteoanabolic after high-dose exposure, while, in male rats, a tendency toward negative effects on the bone morphology in terms of a reduced cross-sectional cortical area and total area could be demonstrated. KW - bisphenol A KW - endocrine disruption KW - bone morphology KW - micro-computed tomography KW - mechanical property KW - three-point bending Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-262216 SN - 2305-6304 VL - 10 IS - 2 ER - TY - JOUR A1 - Grunz, Jan-Peter A1 - Wenig, Andreas Max A1 - Kunz, Andreas Steven A1 - Veyhl-Wichmann, Maike A1 - Schmitt, Rainer A1 - Gietzen, Carsten Herbert A1 - Pennig, Lenhard A1 - Herz, Stefan A1 - Ergün, Süleyman A1 - Bley, Thorsten Alexander A1 - Gassenmaier, Tobias T1 - 3D cone-beam CT with a twin robotic x-ray system in elbow imaging: comparison of image quality to high-resolution multidetector CT JF - European Radiology Experimental N2 - Background Elbow imaging is challenging with conventional multidetector computed tomography (MDCT), while cone-beam CT (CBCT) provides superior options. We compared intra-individually CBCT versus MDCT image quality in cadaveric elbows. Methods A twin robotic x-ray system with new CBCT mode and a high-resolution clinical MDCT were compared in 16 cadaveric elbows. Both systems were operated with a dedicated low-dose (LD) protocol (equivalent volume CT dose index [CTDI\(_{vol(16 cm)}\)] = 3.3 mGy) and a regular clinical scan dose (RD) protocol (CTDI\(_{vol(16 cm)}\) = 13.8 mGy). Image quality was evaluated by two radiologists (R1 and R2) on a seven-point Likert scale, and estimation of signal intensity in cancellous bone was conducted. Wilcoxon signed-rank tests and intraclass correlation coefficient (ICC) statistics were used. Results The CBCT prototype provided superior subjective image quality compared to MDCT scans (for RD, p ≤ 0.004; for LD, p ≤ 0.001). Image quality was rated very good or excellent in 100% of the cases by both readers for RD CBCT, 100% (R1) and 93.8% (R2) for LD CBCT, 62.6% and 43.8% for RD MDCT, and 0.0% and 0.0% for LD MDCT. Single-measure ICC was 0.95 (95% confidence interval 0.91–0.97; p < 0.001). Software-based assessment supported subjective findings with less “undecided” pixels in CBCT than dose-equivalent MDCT (p < 0.001). No significant difference was found between LD CBCT and RD MDCT. Conclusions In cadaveric elbow studies, the tested cone-beam CT prototype delivered superior image quality compared to high-end multidetector CT and showed a potential for considerable dose reduction. KW - Cancellous bone KW - Cone-beam computed tomography KW - Elbow KW - Elbow joint KW - Multidetector computed tomography Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-229877 VL - 4 ER - TY - JOUR A1 - Sogno, Patrick A1 - Traidl-Hoffmann, Claudia A1 - Kuenzer, Claudia T1 - Earth Observation data supporting non-communicable disease research: a review JF - Remote Sensing N2 - A disease is non-communicable when it is not transferred from one person to another. Typical examples include all types of cancer, diabetes, stroke, or allergies, as well as mental diseases. Non-communicable diseases have at least two things in common — environmental impact and chronicity. These diseases are often associated with reduced quality of life, a higher rate of premature deaths, and negative impacts on a countries' economy due to healthcare costs and missing work force. Additionally, they affect the individual's immune system, which increases susceptibility toward communicable diseases, such as the flu or other viral and bacterial infections. Thus, mitigating the effects of non-communicable diseases is one of the most pressing issues of modern medicine, healthcare, and governments in general. Apart from the predisposition toward such diseases (the genome), their occurrence is associated with environmental parameters that people are exposed to (the exposome). Exposure to stressors such as bad air or water quality, noise, extreme heat, or an overall unnatural surrounding all impact the susceptibility to non-communicable diseases. In the identification of such environmental parameters, geoinformation products derived from Earth Observation data acquired by satellites play an increasingly important role. In this paper, we present a review on the joint use of Earth Observation data and public health data for research on non-communicable diseases. We analyzed 146 articles from peer-reviewed journals (Impact Factor ≥ 2) from all over the world that included Earth Observation data and public health data for their assessments. Our results show that this field of synergistic geohealth analyses is still relatively young, with most studies published within the last five years and within national boundaries. While the contribution of Earth Observation, and especially remote sensing-derived geoinformation products on land surface dynamics is on the rise, there is still a huge potential for transdisciplinary integration into studies. We see the necessity for future research and advocate for the increased incorporation of thematically profound remote sensing products with high spatial and temporal resolution into the mapping of exposomes and thus the vulnerability and resilience assessment of a population regarding non-communicable diseases. KW - Earth Observation KW - land surface dynamics KW - atmosphere KW - exposure KW - geoanalysis KW - non-communicable disease KW - public health KW - remote sensing KW - review Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-211113 SN - 2072-4292 VL - 12 IS - 16 ER - TY - JOUR A1 - Liu, Dan A1 - Hu, Kai A1 - Lau, Kolja A1 - Kiwitz, Tobias A1 - Robitzkat, Katharina A1 - Hammel, Clara A1 - Lengenfelder, Björn Daniel A1 - Ertl, Georg A1 - Frantz, Stefan A1 - Nordbeck, Peter T1 - Impact of diastolic dysfunction on outcome in heart failure patients with mid-range or reduced ejection fraction JF - ESC Heart Failure N2 - Aims The role of diastolic dysfunction (DD) in prognostic evaluation in heart failure (HF) patients with impaired systolic function remains unclear. We investigated the impact of echocardiography-defined DD on survival in HF patients with mid-range (HFmrEF, EF 41–49%) and reduced ejection fraction (HFrEF, EF < 40%). Methods and results A total of 2018 consecutive hospitalized HF patients were retrospectively included and divided in two groups based on baseline EF: HFmrEF group (n = 951, aged 69 ± 13 years, 74.2% male) and HFrEF group (n = 1067, aged 68 ± 13 years, 76.3% male). Clinical data were collected and analysed. All patients completed ≥1 year clinical follow-up. The primary endpoint was defined as all-cause death (including heart transplantation) and cardiovascular (CV)-related death. All-cause mortality (30.8% vs. 24.9%, P = 0.003) and CV mortality (19.1% vs. 13.5%, P = 0.001) were significantly higher in the HFrEF group than the HFmrEF group during follow-up [median 24 (13–36) months]. All-cause mortality increased in proportion to DD severity (mild, moderate, and severe) in either HFmrEF (17.1%, 25.4%, and 37.0%, P < 0.001) or HFrEF (18.9%, 30.3%, and 39.2%, P < 0.001) patients. The risk of all-cause mortality [hazard ratio (HR) = 1.347, P = 0.015] and CV mortality (HR = 1.508, P = 0.007) was significantly higher in HFrEF patients with severe DD compared with non-severe DD after adjustment for identified clinical and echocardiographic covariates. For HFmrEF patients, severe DD was independently associated with increased all-cause mortality (HR = 1.358, P = 0.046) but not with CV mortality (HR = 1.155, P = 0.469). Conclusions Echocardiography-defined severe DD is independently associated with increased all-cause mortality in patients with HFmrEF and HFrEF. KW - heart failure with mid-range ejection fraction KW - heart failure with reduced ejection fraction KW - diastolic dysfunction KW - echocardiography KW - prognosis Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-258894 VL - 8 IS - 4 ER - TY - JOUR A1 - Sbiera, Silviu A1 - Kunz, Meik A1 - Weigand, Isabel A1 - Deutschbein, Timo A1 - Dandekar, Thomas A1 - Fassnacht, Martin T1 - The new genetic landscape of Cushing’s disease: deubiquitinases in the spotlight JF - Cancers N2 - Cushing’s disease (CD) is a rare condition caused by adrenocorticotropic hormone (ACTH)-producing adenomas of the pituitary, which lead to hypercortisolism that is associated with high morbidity and mortality. Treatment options in case of persistent or recurrent disease are limited, but new insights into the pathogenesis of CD are raising hope for new therapeutic avenues. Here, we have performed a meta-analysis of the available sequencing data in CD to create a comprehensive picture of CD’s genetics. Our analyses clearly indicate that somatic mutations in the deubiquitinases are the key drivers in CD, namely USP8 (36.5%) and USP48 (13.3%). While in USP48 only Met415 is affected by mutations, in USP8 there are 26 different mutations described. However, these different mutations are clustering in the same hotspot region (affecting in 94.5% of cases Ser718 and Pro720). In contrast, pathogenic variants classically associated with tumorigenesis in genes like TP53 and BRAF are also present in CD but with low incidence (12.5% and 7%). Importantly, several of these mutations might have therapeutic potential as there are drugs already investigated in preclinical and clinical setting for other diseases. Furthermore, network and pathway analyses of all somatic mutations in CD suggest a rather unified picture hinting towards converging oncogenic pathways. KW - Cushing’s disease KW - pathogenesis KW - somatic mutations KW - deubiquitinases Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-193194 SN - 2072-6694 VL - 11 IS - 11 ER - TY - JOUR A1 - Heilig, Philipp A1 - Faerber, Lars-Christopher A1 - Paul, Mila M. A1 - Kupczyk, Eva A1 - Meffert, Rainer H. A1 - Jordan, Martin C. A1 - Hoelscher-Doht, Stefanie T1 - Plate osteosynthesis combined with bone cement provides the highest stability for tibial head depression fractures under high loading conditions JF - Scientific Reports N2 - Older patients sustaining tibial head depression fractures often cannot follow the post-operative rehabilitation protocols with partial weight-bearing of the affected limb, leading to osteosynthesis failure, cartilage step-off and arthritis development. Therefore, the aim of this study was to analyse the biomechanical performance of different types of osteosyntheses alone and in combination with bone cement simulating cyclically high loading conditions of tibial head depression fractures. Lateral tibial head depression fractures (AO: 41-B2.2; Schatzker type III) were created in synthetic bones and stabilized using three different osteosyntheses alone and in combination with a commonly used bone cement (chronOS™): 2 screws, 4 screws in the jail technique and a lateral angle-stable buttress plate. After fixation, the lateral tibial plateau was axially loaded in two, from each other independent testing series: In the first test protocol, 5000 cycles with 500 N and in the end load-to-failure tests were performed. In the second test protocol, the cyclic loading was increased to 1000 N. Parameters of interest were the displacement of the articular fracture fragment, the stiffness and the maximum load. The osteosyntheses revealed a higher stiffness in combination with bone cement compared to the same type of osteosynthesis alone (e.g., 500 N level: 2 screws 383 ± 43 N/mm vs. 2 screws + chronOs 520 ± 108 N/mm, increase by 36%, p < 0.01; 4 screws 368 ± 97 N/mm vs. 4 screws + chronOS 516 ± 109 N/mm, increase by 40%, p < 0.01; plate: 509 ± 73 N/mm vs. plate + chronOs 792 ± 150 N/mm, increase by 56%, p < 0.01). Bone cement reduced the displacement of the plate significantly (500 N level: plate: 8.9 ± 2.8 mm vs. plate + chronOs: 3.1 ± 1.4 mm, reduction by 65%, p < 0.01; 1000 N level: 16.9 ± 3.6 mm vs 5.6 ± 1.3 mm, reduction by 67%, p < 0.01). Thus, the highest stiffness and lowest displacement values were found when using the plate with bone cement in both loading conditions (500 N level: 2 screws + chronOs 3.7 ± 1.3 mm, 4 screws + chronOs 6.2 ± 2.4 mm; 1000 N level: 2 screws + chronOs 6.5 ± 1.2 mm, 4 screws + chronOs 5.7 ± 0.8 mm). From a biomechanical perspective, plate osteosynthesis of tibial head depression fractures should always be combined with bone cement, provides higher stability than 2-screw and 4-screw fixation and is a valid treatment option in cases where extraordinary stability is required. KW - head depression fractures KW - osteosynthesis KW - arthritis Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-299782 VL - 12 IS - 1 ER - TY - JOUR A1 - Szymski, Dominik A1 - Aschenbach, Leonard A1 - Krutsch, Volker A1 - Alt, Volker A1 - Meffert, Rainer A1 - Krutsch, Werner A1 - Fehske, Kai T1 - Injury epidemiology in men's professional team sports: is media analysis helpful? JF - Archives of Orthopaedic and Trauma Surgery N2 - Introduction Epidemiological injury surveillance in professional sports is often based on online media analysis in order to collect necessary data. However, the validation of this study protocol is lacking. Therefore, this study aimed to identify the validity of injury surveillance in men's professional team sports based on media reports. Methods In a retrospective cohort study, the validity of media-data-relating injuries was investigated in participating teams of the highest two German divisions in men's professional basketball (BB) and handball (HB) in the season 2018/2019. Injury protocols completed by the team physicians were compared to those of sports media injury reports. Results The study population was composed of 133 athletes (54 BB and 79 HB). Of 343 injuries reported by the team physicians, 151 (44%) could be identified by means of sports media reports. Severe injuries (n = 75, 72%) were reported more likely in sports media compared to less severe injuries (n = 76, 32%, p < 0.00001). Odds ratio (OR) was 5.33 (95% CI 3.22-8.82). No differences regarding injury reporting could be seen between the two team sports. Conclusion For severe injuries, media analysis may be a sufficient method for data collection in popular men's professional ball sports. An underestimation of true injury prevalence lies within the range of previous reported investigations concerning the validation of injury surveillance methods. Non-severe injuries could not be verified via media analysis in professional handball and basketball. KW - severe injury KW - professional KW - injury KW - media-based KW - evidence KW - validation Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-266690 SN - 1434-3916 VL - 141 IS - 4 ER - TY - JOUR A1 - Huflage, Henner A1 - Karsten, Sebastian A1 - Kunz, Andreas Steven A1 - Conrads, Nora A1 - Jakubietz, Rafael Gregor A1 - Jakubietz, Michael Georg A1 - Pennig, Lenhard A1 - Goertz, Lukas A1 - Bley, Thorsten Alexander A1 - Schmitt, Rainer A1 - Grunz, Jan-Peter T1 - Improved diagnostic accuracy for ulnar-sided TFCC lesions with radial reformation of 3D sequences in wrist MR arthrography JF - European Radiology N2 - Objectives Triangular fibrocartilage complex (TFCC) injuries frequently cause ulnar-sided wrist pain and can induce distal radioulnar joint instability. With its complex three-dimensional structure, diagnosis of TFCC lesions remains a challenging task even in MR arthrograms. The aim of this study was to assess the added diagnostic value of radial reformatting of isotropic 3D MRI datasets compared to standard planes after direct arthrography of the wrist. Methods Ninety-three patients underwent wrist MRI after fluoroscopy-guided multi-compartment arthrography. Two radiologists collectively analyzed two datasets of each MR arthrogram for TFCC injuries, with one set containing standard reconstructions of a 3D thin-slice sequence in axial, coronal and sagittal orientation, while the other set comprised an additional radial plane view with the rotating center positioned at the ulnar styloid. Surgical reports (whenever available) or radiological reports combined with clinical follow-up served as a standard of reference. In addition, diagnostic confidence and assessability of the central disc and ulnar-sided insertions were subjectively evaluated. Results Injuries of the articular disc, styloid and foveal ulnar attachment were present in 20 (23.7%), 10 (10.8%) and 9 (9.7%) patients. Additional radial planes increased diagnostic accuracy for lesions of the styloid (0.83 vs. 0.90; p = 0.016) and foveal (0.86 vs. 0.94; p = 0.039) insertion, whereas no improvement was identified for alterations of the central cartilage disc. Readers' confidence (p < 0.001) and assessability of the ulnar-sided insertions (p < 0.001) were superior with ancillary radial reformatting. Conclusions Access to the radial plane view of isotropic 3D sequences in MR arthrography improves diagnostic accuracy and confidence for ulnar-sided TFCC lesions. KW - joint instability KW - wrist KW - arthrography KW - magnetic resonance imaging KW - triangular fibrocartilage Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-266512 SN - 1432-1084 VL - 31 IS - 12 ER - TY - JOUR A1 - Eckert, Ina N. A1 - Ribechini, Eliana A1 - Jarick, Katja J. A1 - Strozniak, Sandra A1 - Potter, Sarah J. A1 - Beilhack, Andreas A1 - Lutz, Manfred B. T1 - VLA-1 Binding to Collagen IV Controls Effector T Cell Suppression by Myeloid-Derived Suppressor Cells in the Splenic Red Pulp JF - Frontiers in Immunology N2 - Myeloid-derived suppressor cells (MDSCs) represent a major population controlling T cell immune responses. However, little is known about their molecular requirements for homing and T cell interaction to mediate suppression. Here, we investigated the functional role of the homing and collagen IV receptor VLA-1 (α1β1-integrin) on in vitro GM-CSF generated murine MDSCs from wild-type (WT) and CD49a/α1-integrin (Itga1\(^{−/−}\)) gene-deficient mice. Here, we found that effector (Teff) but not naive (Tn) CD4\(^+\) T cells express VLA-1 and monocytes further up-regulated their expression after culture in GM-CSF when they differentiated into the monocytic subset of resting MDSCs (R-MDSCs). Subsequent activation of R-MDSCs by LPS+IFN-γ (A-MDSCs) showed increased in vitro suppressor potential, which was independent of VLA-1. Surprisingly, VLA-1 deficiency did not influence A-MDSC motility or migration on collagen IV in vitro. However, interaction times of Itga1\(^{−/−}\) A-MDSCs with Teff were shorter than with WT A-MDSCs on collagen IV but not on fibronectin substrate in vitro. After injection, A-MDSCs homed to the splenic red pulp where they co-localized with Teff and showed immediate suppression already after 6 h as shown by inhibition of T cell proliferation and induction of apoptosis. Injection of A-MDSCs from Itga1\(^{−/−}\) mice showed equivalent homing into the spleen but a reduced suppressive effect. Interaction studies of A-MDSCs with Teff in the subcapsular red pulp with intravital two-photon microscopy revealed also here that MDSC motility and migration parameters were not altered by VLA-1 deficiency, but the interaction times with Teff were reduced. Together, our data point to a new role of VLA-1 adhesion to collagen IV as a prerequisite for extended contact times with Teff required for suppression. KW - myeloid-derived suppressor cells (MDSCs) KW - T cells KW - VLA-1 KW - homing KW - spleen Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-222671 SN - 1664-3224 VL - 11 ER - TY - JOUR A1 - Heilig, Philipp A1 - Sandner, Phoebe A1 - Jordan, Martin Cornelius A1 - Jakubietz, Rafael Gregor A1 - Meffert, Rainer Heribert A1 - Gbureck, Uwe A1 - Hoelscher-Doht, Stefanie T1 - Experimental drillable magnesium phosphate cement is a promising alternative to conventional bone cements JF - Materials N2 - Clinically used mineral bone cements lack high strength values, absorbability and drillability. Therefore, magnesium phosphate cements have recently received increasing attention as they unify a high mechanical performance with presumed degradation in vivo. To obtain a drillable cement formulation, farringtonite (Mg\(_3\)(PO\(_4\))\(_2\)) and magnesium oxide (MgO) were modified with the setting retardant phytic acid (C\(_6\)H\(_{18}\)O\(_{24}\)P\(_6\)). In a pre-testing series, 13 different compositions of magnesium phosphate cements were analyzed concentrating on the clinical demands for application. Of these 13 composites, two cement formulations with different phytic acid content (22.5 wt% and 25 wt%) were identified to meet clinical demands. Both formulations were evaluated in terms of setting time, injectability, compressive strength, screw pullout tests and biomechanical tests in a clinically relevant fracture model. The cements were used as bone filler of a metaphyseal bone defect alone, and in combination with screws drilled through the cement. Both formulations achieved a setting time of 5 min 30 s and an injectability of 100%. Compressive strength was shown to be ~12–13 MPa and the overall displacement of the reduced fracture was <2 mm with and without screws. Maximum load until reduced fracture failure was ~2600 N for the cements only and ~3800 N for the combination with screws. Two new compositions of magnesium phosphate cements revealed high strength in clinically relevant biomechanical test set-ups and add clinically desired characteristics to its strength such as injectability and drillability. KW - magnesium phosphate cement KW - phytic acid KW - inositol hexaphosphate KW - drillable bone cement KW - tibial head depression fracture KW - synbones KW - artificial bones KW - biomechanical evaluation KW - cyclic testing KW - load to failure testing Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-236633 SN - 1996-1944 VL - 14 IS - 8 ER - TY - JOUR A1 - Grimm, Johannes A1 - Hufnagel, Anita A1 - Wobser, Marion A1 - Borst, Andreas A1 - Haferkamp, Sebastian A1 - Houben, Roland A1 - Meierjohann, Svenja T1 - BRAF inhibition causes resilience of melanoma cell lines by inducing the secretion of FGF1 JF - Oncogenesis N2 - Approximately half of all melanoma patients harbour activating mutations in the serine/threonine kinase BRAF. This is the basis for one of the main treatment strategies for this tumor type, the targeted therapy with BRAF and MEK inhibitors. While the initial responsiveness to these drugs is high, resistance develops after several months, frequently at sites of the previously responding tumor. This indicates that tumor response is incomplete and that a certain tumor fraction survives even in drug-sensitive patients, e.g., in a therapy-induced senescence-like state. Here, we show in several melanoma cell lines that BRAF inhibition induces a secretome with stimulating effect on fibroblasts and naive melanoma cells. Several senescence-associated factors were found to be transcribed and secreted in response to BRAF or MEK inhibition, among them members of the fibroblast growth factor family. We identified the growth factor FGF1 as mediator of resilience towards BRAF inhibition, which limits the pro-apoptotic effects of the drug and activates fibroblasts to secrete HGF. FGF1 regulation was mediated by the PI3K pathway and by FRA1, a direct target gene of the MAPK pathway. When FGFR inhibitors were applied in parallel to BRAF inhibitors, resilience was broken, thus providing a rationale for combined therapeutical application. KW - melanoma KW - senescence KW - BRAF KW - tumor Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-177261 VL - 7 IS - 71 ER - TY - JOUR A1 - Klenk, Christoph A1 - Hommers, Leif A1 - Lohse, Martin J. T1 - Proteolytic cleavage of the extracellular domain affects signaling of parathyroid hormone 1 receptor JF - Frontiers in Endocrinology N2 - Parathyroid hormone 1 receptor (PTH1R) is a member of the class B family of G protein-coupled receptors, which are characterized by a large extracellular domain required for ligand binding. We have previously shown that the extracellular domain of PTH1R is subject to metalloproteinase cleavage in vivo that is regulated by ligand-induced receptor trafficking and leads to impaired stability of PTH1R. In this work, we localize the cleavage site in the first loop of the extracellular domain using amino-terminal protein sequencing of purified receptor and by mutagenesis studies. We further show, that a receptor mutant not susceptible to proteolytic cleavage exhibits reduced signaling to G\(_s\) and increased activation of G\(_q\) compared to wild-type PTH1R. These findings indicate that the extracellular domain modulates PTH1R signaling specificity, and that its cleavage affects receptor signaling. KW - GPCRs KW - parathyroid hormone 1 receptor KW - matrix metalloproteinase KW - ectodomain cleavage KW - biased signaling Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-262055 SN - 1664-2392 VL - 13 ER - TY - JOUR A1 - Kress, Sebastian A1 - Baur, Johannes A1 - Otto, Christoph A1 - Burkard, Natalie A1 - Braspenning, Joris A1 - Walles, Heike A1 - Nickel, Joachim A1 - Metzger, Marco T1 - Evaluation of a miniaturized biologically vascularized scaffold in vitro and in vivo JF - Scientific Reports N2 - In tissue engineering, the generation and functional maintenance of dense voluminous tissues is mainly restricted due to insufficient nutrient supply. Larger three-dimensional constructs, which exceed the nutrient diffusion limit become necrotic and/or apoptotic in long-term culture if not provided with an appropriate vascularization. Here, we established protocols for the generation of a pre-vascularized biological scaffold with intact arterio-venous capillary loops from rat intestine, which is decellularized under preservation of the feeding and draining vascular tree. Vessel integrity was proven by marker expression, media/blood reflow and endothelial LDL uptake. In vitro maintenance persisted up to 7 weeks in a bioreactor system allowing a stepwise reconstruction of fully vascularized human tissues and successful in vivo implantation for up to 4 weeks, although with time-dependent decrease of cell viability. The vascularization of the construct lead to a 1.5× increase in cellular drug release compared to a conventional static culture in vitro. For the first time, we performed proof-of-concept studies demonstrating that 3D tissues can be maintained within a miniaturized vascularized scaffold in vitro and successfully implanted after re-anastomosis to the intrinsic blood circulation in vivo. We hypothesize that this technology could serve as a powerful platform technology in tissue engineering and regenerative medicine. KW - biological models KW - translational research Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-176343 VL - 8 IS - 4719 ER - TY - JOUR A1 - Eckhardt, Carolin A1 - Sbiera, Iuliu A1 - Krebs, Markus A1 - Sbiera, Silviu A1 - Spahn, Martin A1 - Kneitz, Burkhard A1 - Joniau, Steven A1 - Fassnacht, Martin A1 - Kübler, Hubert A1 - Weigand, Isabel A1 - Kroiss, Matthias T1 - High expression of Sterol-O-Acyl transferase 1 (SOAT1), an enzyme involved in cholesterol metabolism, is associated with earlier biochemical recurrence in high risk prostate cancer JF - Prostate Cancer and Prostatic Diseases N2 - Background Prostate cancer (PCa) is the most frequent cancer in men. The prognosis of PCa is heterogeneous with many clinically indolent tumors and rare highly aggressive cases. Reliable tissue markers of prognosis are lacking. Active cholesteryl ester synthesis has been associated with prostate cancer aggressiveness. Sterol-O-Acyl transferases (SOAT) 1 and 2 catalyze cholesterol esterification in humans. Objective To investigate the value of SOAT1 and SOAT2 tissue expression as prognostic markers in high risk PCa. Patients and Methods Formalin-fixed paraffin-embedded tissue samples from 305 high risk PCa cases treated with radical prostatectomy were analyzed for SOAT1 and SOAT2 protein expression by semi-quantitative immunohistochemistry. The Kaplan-Meier method and Cox proportional hazards modeling were used to compare outcome. Main Outcome Measure Biochemical recurrence (BCR) free survival. Results SOAT1 expression was high in 73 (25%) and low in 219 (75%; not evaluable: 13) tumors. SOAT2 was highly expressed in 40 (14%) and at low levels in 249 (86%) samples (not evaluable: 16). By Kaplan-Meier analysis, we found significantly shorter median BCR free survival of 93 months (95% confidence interval 23.6-123.1) in patients with high SOAT1 vs. 134 months (112.6-220.2, Log-rank p < 0.001) with low SOAT1. SOAT2 expression was not significantly associated with BCR. After adjustment for age, preoperative PSA, tumor stage, Gleason score, resection status, lymph node involvement and year of surgery, high SOAT1 but not SOAT2 expression was associated with shorter BCR free survival with a hazard ratio of 2.40 (95% CI 1.57-3.68, p < 0.001). Time to clinical recurrence and overall survival were not significantly associated with SOAT1 and SOAT2 expression CONCLUSIONS: SOAT1 expression is strongly associated with BCR free survival alone and after multivariable adjustment in high risk PCa. SOAT1 may serve as a histologic marker of prognosis and holds promise as a future treatment target. KW - prostate cancer KW - SOAT1 KW - cholesterol metabolism Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-271819 SN - 1476-5608 VL - 25 IS - 3 ER -