TY - JOUR A1 - Tamburello, Mariangela A1 - Altieri, Barbara A1 - Sbiera, Iuliu A1 - Sigala, Sandra A1 - Berruti, Alfredo A1 - Fassnacht, Martin A1 - Sbiera, Silviu T1 - FGF/FGFR signaling in adrenocortical development and tumorigenesis: novel potential therapeutic targets in adrenocortical carcinoma JF - Endocrine N2 - FGF/FGFR signaling regulates embryogenesis, angiogenesis, tissue homeostasis and wound repair by modulating proliferation, differentiation, survival, migration and metabolism of target cells. Understandably, compelling evidence for deregulated FGF signaling in the development and progression of different types of tumors continue to emerge and FGFR inhibitors arise as potential targeted therapeutic agents, particularly in tumors harboring aberrant FGFR signaling. There is first evidence of a dual role of the FGF/FGFR system in both organogenesis and tumorigenesis, of which this review aims to provide an overview. FGF-1 and FGF-2 are expressed in the adrenal cortex and are the most powerful mitogens for adrenocortical cells. Physiologically, they are involved in development and maintenance of the adrenal gland and bind to a family of four tyrosine kinase receptors, among which FGFR1 and FGFR4 are the most strongly expressed in the adrenal cortex. The repeatedly proven overexpression of these two FGFRs also in adrenocortical cancer is thus likely a sign of their participation in proliferation and vascularization, though the exact downstream mechanisms are not yet elucidated. Thus, FGFRs potentially offer novel therapeutic targets also for adrenocortical carcinoma, a type of cancer resistant to conventional antimitotic agents. KW - FGF-pathway KW - FGFR KW - FGFR-inhibitors KW - adrenocortical development KW - adrenocortical tumors Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-324420 VL - 77 IS - 3 ER - TY - THES A1 - Cejka, Vladimir T1 - Prognostische Relevanz von Fettgewebesurrogaten bei Patienten mit chronischer Niereninsuffizienz – Auswertungen der prospektiven German Chronic Kidney Disease Studie T1 - Prognostic relevance of adiposity measures in patients with chronic kidney disease - analyses from the prospective German Chronic Kidney Disease study N2 - Einleitung: In dieser Arbeit wurde die Auswirkung der Fettgewebesurrogate Halsumfang (HU), Taillenumfang (TU) und Body Mass Index (BMI) auf die Prognose bei Patienten mit chronischer Niereninsuffizienz untersucht. Methoden: Datengrundlage dieser Arbeit war die German Chronic Kidney Disease (GCKD) Beobachtungsstudie. Eingeschlossen wurden Erwachsene mit GFR 30-60 ml/min/1,73m² oder GFR > 60 ml/min/1,73m² mit offensichtlicher Proteinurie. Ausschlusskriterien waren: nicht-kaukasische Ethnie, Organtransplantation, Malignome und Herzinsuffizienz NYHA IV. Untersuchte kombinierte Endpunkte (EP) waren: 1) 4P-MACE (Herzinfarkt, Schlaganfall, kardiovaskulärer Tod, pAVK-Ereignis) 2) Tod jeglicher Ursache 3) Nierenversagen (Dialyse, Transplantation). Es wurden Cox-Regressionen mit HU, TU, und BMI für jeden EP, adjustiert für Alter, Geschlecht, Nikotinkonsum, Diabetes mellitus, arterielle Hypertonie, LDL-Cholesterin, GFR, Urin-Albumin/Kreatinin Ratio (UACR) und CRP berechnet. Interaktionsterme des jeweiligen Surrogats mit dem Geschlecht wurden eingeschlossen. Ergebnisse: Von den 4537 analysierten Studienteilnehmern, waren 59% Männer mit einem Durchschnittsalter von 60 (±12) Jahren, einer mittleren GFR von 50 (±18) ml/min/1,73m² und einem UACR-Median von 49 (10–374) mg/g. Der mittlere HU war 42,7 (±3,6) cm bei Männern und 37,2 (±3,7) cm bei Frauen, der mittlere TU 107,6 (±13,6) cm bei Männern und 97,0 (±16,3) cm bei Frauen und der mittlere BMI 29,7 (±5,9) kg/m². Die mittlere Beobachtungszeit betrug 6,5 Jahre. Der TU war signifikant mit Tod assoziiert, mit einer HR von 1,014 pro cm (95% KI 1,005–1,024). HU war signifikant mit Tod bei Frauen assoziiert, Interaktionsterm HR 1,080 pro cm (95% KI 1,009–1,155). Der BMI hatte keinen signifikanten Einfluss auf untersuchte EP. Schlussfolgerung: Bei Patienten mit mittel- bis schwergradig eingeschränkter Nierenfunktion steigern ein erhöhter TU (bei beiden Geschlechtern), sowie bei Frauen ein erhöhter HU das Risiko für Tod jeglicher Ursache. N2 - Introduction: Adiposity alters the risk of adverse outcome in chronic kidney disease. This work investigates the prognostic impact of the adiposity measures neck circumference (NC), waist circumference (WC) and body mass index (BMI). Methods: This study is based on data from the prospective observational German Chronic Kidney study which included adults with chronic kidney disease, defined as estimated glomerular filtration rate (GFR) 30–60 ml/min/1.73 m² or GFR > 60 ml/min/1.73 m² with overt proteinuria. Exclusion criteria were non-Caucasian ethnicity, solid organ transplant, active malignancy and heart failure NYHA IV. Investigated composite outcomes were: 1) 4P-MACE (stroke, myocardial infarction, cardiovascular death, peripheral artery disease event) 2) all-cause death 3) kidney failure (dialysis, transplantation). Cox-models for each outcome and adiposity measure, adjusted for age, sex, smoking, diabetes, hypertension, LDL-cholesterol, GFR, urine-albumin-creatinine ratio (UACR) and CRP, were calculated. Interaction terms of adiposity measures with sex were included. Results: Of the 4537 analysed participants, 59% were men with a mean age of 60 (±12) years, a mean GFR of 50 (±18) ml/min/1.73m² and a median UACR of 49 (10–374) mg/g. Mean NC was 42.7 (±3.6) cm in men and 37.2 (±3.7) cm in women, mean WC was 107.6 (±13.6) cm in men and 97.0 ± 16.3 cm in women, mean BMI was 29.7 (±5.9) kg/m². The mean follow-up time was 6.5 years. WC was associated with death, HR 1.014 per cm (95%CI: 1.005–1.024). NC in women was associated with death, interaction HR 1.080 per cm (95%CI: 1.009–1.155). No significant association of the BMI with the analysed outcomes was observed. Conclusion: In patients with moderate to moderately severe chronic kidney disease, WC in both sexes and NC in women were independently associated with death. BMI was not a relevant prognostic factor in these patients. KW - Fettsucht KW - Chronische Niereninsuffizienz KW - Body-Mass-Index KW - Fettgewebe KW - chronic kidney disease KW - neck circumference KW - waist circumference KW - body mass index KW - Ersatzstoff KW - Surrogat Y1 - 2024 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-349266 ER - TY - THES A1 - Weber, Justus C. T1 - Development and preclinical assessment of ROR2-specific CAR-T cells for the treatment of clear cell renal cell carcinoma and multiple myeloma T1 - Entwicklung und präklinische Evaluation ROR2-spezifischer CAR-T Zellen zur Behandlung des klarzelligen Nierenzellkarzinoms und des Multiplen Myeloms N2 - Adoptive immunotherapy using chimeric antigen receptor (CAR)-modified T cells is an effective treatment for hematological malignancies that are refractory to conventional chemotherapy. To address a wider variety of cancer entities, there is a need to identify and characterize additional target antigens for CAR-T cell therapy. The two members of the receptor tyrosine kinase-like orphan receptor family, ROR1 and ROR2, have been found to be overexpressed on cancer cells and to correlate with aggressive cancer phenotypes. Recently, ROR1-specific CAR-T cells have entered testing in phase I clinical trials, encouraging us to assess the suitability of ROR2 as a novel target for CAR-T cell therapy. To study the therapeutic potential of targeting ROR2 in solid and hematological malignancies, we selected two representative cancer entities with high unmet medical need: renal cell carcinoma and multiple myeloma. Our data show that ROR2 is commonly expressed on primary samples and cell lines of clear cell renal cell carcinoma and multiple myeloma. To study the efficacy of ROR2-specific CAR T cell therapy, we designed two CAR constructs with 10-fold binding affinity differences for the same epitope of ROR2. We found both cell products to exhibit antigen-specific anti-tumor reactivity in vitro, including tumor cell lysis, secretion of the effector cytokines interleukin-2 (IL-2) and interferon-gamma (IFNγ), and T cell proliferation. In vivo studies revealed ROR2 specific CAR-T cells to confer durable responses, significant survival benefits and long-term persistence of CAR-expressing T cells. Overall, there was a trend towards more potent anti-tumor efficacy upon treatment with T cells that expressed the CAR with higher affinity for ROR2, both in vitro and in vivo. We performed a preclinical safety and toxicology assessment comprising analyses of ROR2 expression in healthy human and murine tissues, cross-reactivity, and adoptive T cell transfer in immunodeficient mice. We found ROR2 expression to be conserved in mice, and low-level expression was detectable in the male and female reproductive system as well as parts of the gastrointestinal tract. CAR-T cells targeting human ROR2 were found to elicit similarly potent reactivity upon recognition of murine ROR2. In vivo analyses showed transient tissue-specific enrichment and activation of ROR2-specific CAR-T cells in organs with high blood circulation, such as lung, liver, or spleen, without evidence for clinical toxicity or tissue damage as determined by histological analyses. Furthermore, we humanized the CAR binding domain of ROR2-specific CAR-T cells to mitigate the risk of adverse immune reactions and concomitant CAR-T cell rejection. Functional analyses confirmed that humanized CARs retained their specificity and functionality against ROR2-positive tumor cells in vitro. In summary, we show that ROR2 is a prevalent target in RCC and MM, which can be addressed effectively with ROR2-specific CAR-T cells in preclinical models. Our preliminary toxicity studies suggest a favorable safety profile for ROR2-specific CAR-T cells. These findings support the potential to develop ROR2-specific CAR-T cells clinically to obtain cell products with broad utility. N2 - Adoptive Immuntherapie mit T-Zellen, die chimäre Antigenrezeptoren (CAR) exprimieren, ist ein effektiver Behandlungsansatz für Chemotherapie-resistente Blutkrebserkrankungen. Die Übertragung dieses Konzepts auf weitere Krebsarten erfordert die Identifikation und Charakterisierung neuer Zielstrukturen für die CAR-T Zelltherapie. ROR1 und ROR2, die beiden Mitglieder der Familie der Rezeptortyrosinkinase-ähnlichen Orphan-Rezeptoren, werden auf einer Vielzahl von Tumoren überexprimiert und korrelieren mit einer schlechten Prognose und höherer Krebs-Invasivität. Kürzlich konnte ROR1 als Zielstruktur für die CAR-T Zelltherapie bestätigt werden und die Effektivität und Sicherheit ROR1 spezifischer CAR-T Zellen wird derzeit im Rahmen klinischer Phase-I Studien näher untersucht. Aus diesem Grund waren wir daran interessiert, das therapeutische Potenzial ROR2-spezifischer Zelltherapie zu untersuchen. Als Modellsysteme hierfür wählten wir das Nierenzellkarzinom und das Multiple Myelom als repräsentative hämatologische und solide Krebserkrankungen mit hohem medizinischem Bedarf aus. Unsere Daten zeigen, dass ROR2 häufig auf Zelllinien und primären Tumorproben des klarzelligen Nierenzellkarzinoms und des Multiplen Myeloms vorkommt. Um die Effektivität ROR2-spezifischer CAR-T Zellen zu untersuchen, wurden zwei CAR Konstrukte mit zehnfach unterschiedlichen Bindungsaffinitäten für dasselbe Epitop von ROR2 hergestellt. Beide Zellprodukte zeigten hohe, antigen-spezifische Antitumor-Reaktivität in vitro – insbesondere im Hinblick auf Tumorzell-Lyse, Sekretion der Zytokine Interleukin-2 (IL-2) und Interferon gamma (IFNγ) und T-Zell Proliferation. In vivo beobachteten wir langanhaltende Antitumor-Effektivität durch ROR2-spezifische CAR-T Zellen, sowie signifikante Überlebensvorteile und langfristige T-Zell Persistenz. Außerdem beobachteten wir, sowohl in vitro als auch in vivo, einen Trend zu stärkerer Antitumor-Effektivität von T-Zellen, die den CAR mit höherer Affinität für ROR2 exprimierten. Im Rahmen einer präklinischen Toxikologie-Studie analysierten wir die Expression von ROR2 im gesunden Gewebe, die Kreuz-Reaktivität ROR2-spezifischer CAR-T Zellen und deren Sicherheit durch adoptiven T-Zell Transfer in immun-defiziente Mäuse. Unsere Daten zeigen, dass ROR2 in H. sapiens und M. musculus gleichermaßen exprimiert wird und ROR2 Expression war insbesondere in den weiblichen und männlichen Reproduktionsorganen und Teilen des Gastrointestinaltrakts detektierbar. Wir konnten außerdem zeigen, dass CAR-T Zellen, die menschliches ROR2 erkennen, vergleichbare Antitumor-Reaktivität gegen Zellen, die murines ROR2 exprimieren, auslösen. Unsere in vivo Analysen zeigten temporäre Anreicherung und Aktivierung ROR2-spezifischer CAR-T Zellen in gut durchbluteten Geweben, wie Lunge, Leber und Milz, in der Abwesenheit klinischer Anzeichen für Toxizität oder histologisch nachweisbarer Gewebsschädigungen. Um die Risiken immunologischer Nebenwirkungen und die damit einhergehende Abstoßung ROR2-spezifischer CAR-T Zellen zu reduzieren, humanisierten wir die CAR Bindedomäne. Unsere Daten zeigen, dass humanisierte ROR2-spezifische CAR-T Zellen vergleichbare Spezifität und Funktionalität gegen ROR2-positive Tumorzellen in vitro aufweisen. Insgesamt zeigen unsere Daten, dass ROR2 eine häufig auftretende Zielstruktur auf der Oberfläche von RCC und MM Zellen ist und diese in präklinischen Modellen effektiv mittels ROR2-spezifischer CAR-T Zellen adressiert werden kann. Unsere vorläufigen Toxizitätsdaten deuten darauf hin, dass ROR2-spezifische CAR-T Zellen ein vorteilhaftes Sicherheitsprofil aufweisen. Alles in allem unterstützen diese Daten das Potenzial der klinischen Entwicklung ROR2-spezifischer CAR-T Zellen als Zellprodukte mit breit gefächerter Anwendbarkeit. KW - CAR-T-Zell-Therapie KW - Immuntherapie KW - CAR-T cell KW - ROR2 KW - cell therapy KW - cancer therapy Y1 - 2024 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-310399 ER - TY - JOUR A1 - Traub, Jan A1 - Frey, Anna A1 - Störk, Stefan T1 - Chronic neuroinflammation and cognitive decline in patients with cardiac disease: evidence, relevance, and therapeutic implications JF - Life N2 - Acute and chronic cardiac disorders predispose to alterations in cognitive performance, ranging from mild cognitive impairment to overt dementia. Although this association is well-established, the factors inducing and accelerating cognitive decline beyond ageing and the intricate causal pathways and multilateral interdependencies involved remain poorly understood. Dysregulated and persistent inflammatory processes have been implicated as potentially causal mediators of the adverse consequences on brain function in patients with cardiac disease. Recent advances in positron emission tomography disclosed an enhanced level of neuroinflammation of cortical and subcortical brain regions as an important correlate of altered cognition in these patients. In preclinical and clinical investigations, the thereby involved domains and cell types of the brain are gradually better characterized. Microglia, resident myeloid cells of the central nervous system, appear to be of particular importance, as they are extremely sensitive to even subtle pathological alterations affecting their complex interplay with neighboring astrocytes, oligodendrocytes, infiltrating myeloid cells, and lymphocytes. Here, we review the current evidence linking cognitive impairment and chronic neuroinflammation in patients with various selected cardiac disorders including the aspect of chronic neuroinflammation as a potentially druggable target. KW - neuroinflammation KW - cognitive impairment KW - dementia KW - myocardial infarction KW - heart failure KW - hypertension KW - coronary artery disease KW - atrial fibrillation KW - cardiac arrest KW - aortic valve stenosis Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-304869 SN - 2075-1729 VL - 13 IS - 2 ER - TY - THES A1 - Liebner, Felix T1 - Linksschenkelblock als Prognosemarker für das Mortalitätsrisiko bei Herzinsuffizienz-PatientInnen mit mittelgradiger oder reduzierter Ejektionsfraktion und normaler Nierenfunktion T1 - Left bundle branch block as a prognostic marker for mortality risk in heart failure patients with moderate or reduced ejection fraction and normal renal function N2 - Wie diese und auch weitere Studien gezeigt haben, ist die Prävalenz der PatientInnen mit einer LVEF zwischen 36-49% und einem begleitenden LSB nicht zu unterschätzen. Ziel der vorliegenden Arbeit war es zum einen, zu untersuchen, ob ein LSB einen signifikanten Einfluss auf die Mortalität und kardiovaskuläre Sterblichkeit bei sowohl HFmrEF- als auch HFrEF-PatientInnen hat und zum anderen, ob es einen Zusammenhang zwischen einem LSB und der Nierenfunktion gibt. Methoden: Unsere retrospektive Studie untersuchte 2152 PatientInnen mit echokardiographisch bestätigter HI, die sich zwischen 2009 und 2017 in der Universitätsklinik Würzburg vorstellten. Das mittleres Alter betrug 69 Jahre (±13 Jahre) und 72,5% der HFmrEF-Gruppe und 75,7% der HFrEF-Gruppe waren männlich. Jeder Patient erhielt ein durchschnittliches Follow-Up-von 25 Monaten (13-39 Monate). Zunächst wurden beide Gruppen direkt bezüglich des Vorhandenseins eines LSB miteinander verglichen. Die mit in die Studie aufgenommenen PatientInnen wurden anschließend in zwei größere Gruppen eingeteilt. Dabei konnten 1011 PatientInnen der HFmrEF-Gruppe zugeteilt werden, 125 PatientInnen mit und 886 ohne LSB. In der HFrEF-Gruppe befanden sich 1141 PatientInnen, 281 mit und 860 ohne LSB. Die HFrEF-Gruppe wurde zudem erneut hinsichtlich der Nierenfunktion aufgeteilt. Von den 1141 HFrEF-PatientInnen wurden 648 in die Gruppe mit erhaltener Nierenfunktion aufgeteilt und 493 HFrEF-PatientInnen in die Gruppe mit eingeschränkter Nierenfunktion. Ergebnisse: In der HFmrEF-Subgruppe zeigten sich keine relevanten Auswirkungen durch das Vorhandensein oder Fehlen eines LSB auf die Gesamtmortalität und die kardiovaskuläre Mortalität. Auch in der HFrEF-Gruppe hatte das Vorhandensein eines LSB keine signifikante Relevanz für die Gesamtmortalität (34,5% vs. 31,6%, p=0,165). Das Risiko an einem kardiovaskulären Ereignis zu versterben war allerdings für HFrEF-PatientInnen mit LSB deutlich höher als für PatientInnen ohne LSB (86,3% vs. 82,2%, p=0,041). Nach Adjustierung von Alter, Geschlecht, BMI, KHK sowie Schlaganfall war der Einfluss eines LSB nicht mehr signifikant. Es zeigte sich jedoch, dass HFrEF-PatientInnen mit LSB und normaler Nierenfunktion eine mehr als zweifach erhöhte kardiovaskuläre Sterblichkeit haben (8,2% vs. 16,2%, p=0,002). Nach dieser Feststellung wurde gesondert auf weitere Komorbiditäten als mögliche Einflussfaktoren eingegangen. Unabhängig von dem Vorhandensein eines LSB hatten PatientInnen mit eingeschränkter Nierenfunktion eine deutlich erhöhte Mortalität verglichen mit PatientInnen ohne Nierendysfunktion. Hingegen beeinflusste ein LSB bei HFrEF-PatientInnen mit erhaltener Nierenfunktion das Überleben deutlich. LSB-PatientInnen mit erhaltener Nierenfunktion verstarben häufiger an einem kardiovaskulären Ereignis als HFrEF-PatientInnen mit normaler Nierenfunktion ohne LSB (86,3% vs. 82,2%, p=0,041). Um diese Untersuchung weiter zu vertiefen, wurde die HFrEF-Gruppe anhand der EF erneut in drei Subgruppen eingeteilt. Hierbei konnte eindeutig festgestellt werden, dass PatientInnen mit LSB, erhaltener Nierenfunktion und einer BLEF ≤ 30% vor Adjustierung von Alter, Geschlecht, BMI, Schlaganfall und KHK signifikant häufiger kardiovaskulär verstarben als PatientInnen ohne LSB. Des Weiteren fiel besonders die Subgruppe mit einer BLEF zwischen 36 und 39% auf. Denn vor Adjustierung der kardiovaskulären Mortalität zeigte sich ein signifikant erhöhte Mortalitätsrate für PatientInnen mit LSB. Nach Adjustierung der Einflussfaktoren war der prozentuale Anteil immer noch erhöht, lediglich nicht mehr signifikant. Somit gibt diese Studie den Anreiz, weitere prospektive Studien mit einem größeren Stichprobenumfang durchzuführen, um diese Annahme zu bestätigen. Zudem sollte in weiteren Studien untersucht werden, ob speziell für HFrEF-PatientInnen mit LSB und einer EF zwischen 36 und 39% eine CRT einen positiven therapeutischen Effekt bringen könnte. N2 - As these and other studies have shown, the prevalence of patients with an left ventricular ejection fraction (LVEF) between 36-49% and a concomitant left bundle branch block (LBBB) should not be underestimated. The aim of the present study was to investigate whether LBBB has a significant impact on mortality and cardiovascular mortality in both heart failure with midrange ejection fraction (HFmrEF) and heart failure with reduced ejection fraction (HFrEF) patients and whether there is an association between LBBB and renal function. Methods: Our retrospective study examined 2152 patients with echocardiographically confirmed heart failure (HI) who presented to the University Hospital of Würzburg between 2009 and 2017. The mean age was 69 years (±13 years) and 72.5% of the HFmrEF group and 75.7% of the HFrEF group were male. Each patient received an average follow-up of 25 months (13-39 months). Initially, both groups were directly compared for the presence of LBBB. The patients included in the study were then divided into two larger groups. A total of 1011 patients were assigned to the HFmrEF group, 125 patients with and 886 without LBBB. There were 1141 patients in the HFrEF group, 281 with and 860 without LBBB. The HFrEF group was also divided again according to renal function. Of the 1141 HFrEF patients, 648 were divided into the group with preserved renal function and 493 HFrEF patients into the group with impaired renal function. Results: In the HFmrEF subgroup, there were no relevant effects of the presence or absence of LBBB on all-cause mortality and cardiovascular mortality. In the HFrEF group, the presence of an LBBB also had no significant relevance for all-cause mortality (34.5% vs. 31.6%, p=0.165). However, the risk of dying from a cardiovascular event was significantly higher for HFrEF patients with LBBB than for patients without LBBB (86.3% vs. 82.2%, p=0.041). After adjustment for age, gender, body mass index, coronary heart disease (CHD) and stroke, the influence of LBBB was no longer significant. However, it was found that HFrEF patients with LBBB and normal renal function had a more than two-fold increase in cardiovascular mortality (8.2% vs. 16.2%, p=0.002). After this finding, further comorbidities were separately discussed as possible influencing factors. Regardless of the presence of LBBB, patients with impaired renal function had a significantly higher mortality rate compared to patients without renal dysfunction. In contrast, an LBBB in HFrEF patients with preserved renal function had a significant impact on survival. LBBB patients with preserved renal function were more likely to die from a cardiovascular event than HFrEF patients with normal renal function without LBBB (86.3% vs. 82.2%, p=0.041). To further investigate this study, the HFrEF group was again divided into three subgroups based on ejection fraction. It was clearly established that patients with LBBB, preserved renal function and a BLEF ≤ 30% before adjustment for age, gender, BMI, stroke and CHD died significantly more frequently from cardiovascular causes than patients without LBBB. Furthermore, the subgroup with a baseline ejection fraction between 36 and 39% was particularly striking. Before adjustment for cardiovascular mortality, the mortality rate for patients with LBBB was significantly higher. After adjustment of the influencing factors, the percentage was still increased, but no longer significantly. This study therefore provides an incentive to conduct further prospective studies with a larger sample size in order to confirm this assumption. In addition, further studies should investigate whether cardiac resynchronization therapy (CRT) could have a positive therapeutic effect specifically for HFrEF patients with LBBB and an EF between 36 and 39%. KW - Herzinsuffizienz KW - Linksschenkelblock KW - Schenkelblock KW - Nierenfunktion KW - Kardiale Resynchronisationstherapie KW - CRT Y1 - 2024 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-348487 ER - TY - JOUR A1 - Gelbrich, Götz A1 - Morbach, Caroline A1 - Deutschbein, Timo A1 - Fassnacht, Martin A1 - Störk, Stefan A1 - Heuschmann, Peter U. T1 - The population comparison index: an intuitive measure to calibrate the extent of impairments in patient cohorts in relation to healthy and diseased populations JF - International Journal of Environmental Research and Public Health N2 - We assume that a specific health constraint, e.g., a certain aspect of bodily function or quality of life that is measured by a variable X, is absent (or irrelevant) in a healthy reference population (Ref0), and it is materially present and precisely measured in a diseased reference population (Ref1). We further assume that some amount of this constraint of interest is suspected to be present in a population under study (SP). In order to quantify this issue, we propose the introduction of an intuitive measure, the population comparison index (PCI), that relates the mean value of X in population SP to the mean values of X in populations Ref0 and Ref1. This measure is defined as PCI[X] = (mean[X|SP] − mean[X|Ref0])/(mean[X|Ref1] − mean[X|Ref0]) × 100[%], where mean[X|.] is the average value of X in the respective group of individuals. For interpretation, PCI[X] ≈ 0 indicates that the values of X in the population SP are similar to those in population Ref0, and hence, the impairment measured by X is not materially present in the individuals in population SP. On the other hand, PCI[X] ≈ 100 means that the individuals in SP exhibit values of X comparable to those occurring in Ref1, i.e., the constraint of interest is equally present in populations SP and Ref1. A value of 0 < PCI[X] < 100 indicates that a certain percentage of the constraint is present in SP, and it is more than in Ref0 but less than in Ref1. A value of PCI[X] > 100 means that population SP is even more affected by the constraint than population Ref1. KW - reference data KW - normal values KW - disease severity KW - disease score KW - comparability Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-304933 SN - 1660-4601 VL - 20 IS - 3 ER - TY - JOUR A1 - Kerwagen, Fabian A1 - Fuchs, Konrad F. A1 - Ullrich, Melanie A1 - Schulze, Andres A1 - Straka, Samantha A1 - Krop, Philipp A1 - Latoschik, Marc E. A1 - Gilbert, Fabian A1 - Kunz, Andreas A1 - Fette, Georg A1 - Störk, Stefan A1 - Ertl, Maximilian T1 - Usability of a mHealth solution using speech recognition for point-of-care diagnostic management JF - Journal of Medical Systems N2 - The administrative burden for physicians in the hospital can affect the quality of patient care. The Service Center Medical Informatics (SMI) of the University Hospital Würzburg developed and implemented the smartphone-based mobile application (MA) ukw.mobile1 that uses speech recognition for the point-of-care ordering of radiological examinations. The aim of this study was to examine the usability of the MA workflow for the point-of-care ordering of radiological examinations. All physicians at the Department of Trauma and Plastic Surgery at the University Hospital Würzburg, Germany, were asked to participate in a survey including the short version of the User Experience Questionnaire (UEQ-S) and the Unified Theory of Acceptance and Use of Technology (UTAUT). For the analysis of the different domains of user experience (overall attractiveness, pragmatic quality and hedonic quality), we used a two-sided dependent sample t-test. For the determinants of the acceptance model, we employed regression analysis. Twenty-one of 30 physicians (mean age 34 ± 8 years, 62% male) completed the questionnaire. Compared to the conventional desktop application (DA) workflow, the new MA workflow showed superior overall attractiveness (mean difference 2.15 ± 1.33), pragmatic quality (mean difference 1.90 ± 1.16), and hedonic quality (mean difference 2.41 ± 1.62; all p < .001). The user acceptance measured by the UTAUT (mean 4.49 ± 0.41; min. 1, max. 5) was also high. Performance expectancy (beta = 0.57, p = .02) and effort expectancy (beta = 0.36, p = .04) were identified as predictors of acceptance, the full predictive model explained 65.4% of its variance. Point-of-care mHealth solutions using innovative technology such as speech-recognition seem to address the users’ needs and to offer higher usability in comparison to conventional technology. Implementation of user-centered mHealth innovations might therefore help to facilitate physicians’ daily work. KW - mHealth KW - digital Health KW - speech recognition KW - usability KW - user-centered design KW - clinical systems Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-324002 VL - 47 IS - 1 ER - TY - JOUR A1 - Gerhardt, Louisa M. S. A1 - Kordsmeyer, Maren A1 - Sehner, Susanne A1 - Güder, Gülmisal A1 - Störk, Stefan A1 - Edelmann, Frank A1 - Wachter, Rolf A1 - Pankuweit, Sabine A1 - Prettin, Christiane A1 - Ertl, Georg A1 - Wanner, Christoph A1 - Angermann, Christiane E. T1 - Prevalence and prognostic impact of chronic kidney disease and anaemia across ACC/AHA precursor and symptomatic heart failure stages JF - Clinical Research in Cardiology N2 - Background The importance of chronic kidney disease (CKD) and anaemia has not been comprehensively studied in asymptomatic patients at risk for heart failure (HF) versus those with symptomatic HF. We analysed the prevalence, characteristics and prognostic impact of both conditions across American College of Cardiology/American Heart Association (ACC/AHA) precursor and HF stages A–D. Methods and results 2496 participants from three non-pharmacological German Competence Network HF studies were categorized by ACC/AHA stage; stage C patients were subdivided into C1 and C2 (corresponding to NYHA classes I/II and III, respectively). Overall, patient distribution was 8.1%/35.3%/32.9% and 23.7% in ACC/AHA stages A/B/C1 and C2/D, respectively. These subgroups were stratified by the absence ( – ) or presence ( +) of CKD (estimated glomerular filtration rate [eGFR] < 60 mL/min/1.73m2) and anaemia (haemoglobin in women/men < 12/ < 13 g/dL). The primary outcome was all-cause mortality at 5-year follow-up. Prevalence increased across stages A/B/C1 and C2/D (CKD: 22.3%/23.6%/31.6%/54.7%; anaemia: 3.0%/7.9%/21.7%/33.2%, respectively), with concordant decreases in median eGFR and haemoglobin (all p < 0.001). Across all stages, hazard ratios [95% confidence intervals] for all-cause mortality were 2.1 [1.8–2.6] for CKD + , 1.7 [1.4–2.0] for anaemia, and 3.6 [2.9–4.6] for CKD + /anaemia + (all p < 0.001). Population attributable fractions (PAFs) for 5-year mortality related to CKD and/or anaemia were similar across stages A/B, C1 and C2/D (up to 33.4%, 30.8% and 34.7%, respectively). Conclusions Prevalence and severity of CKD and anaemia increased across ACC/AHA stages. Both conditions were individually and additively associated with increased 5-year mortality risk, with similar PAFs in asymptomatic patients and those with symptomatic HF. KW - anaemia KW - ACC/AHA classification KW - chronic kidney disease KW - comorbidity KW - heart failure KW - mortality Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-323990 VL - 112 IS - 7 ER - TY - JOUR A1 - Lenschow, Christina A1 - Wennmann, Andreas A1 - Hendricks, Anne A1 - Germer, Christoph-Thomas A1 - Fassnacht, Martin A1 - Buck, Andreas A1 - Werner, Rudolf A. A1 - Plassmeier, Lars A1 - Schlegel, Nicolas T1 - Questionable value of [\(^{99m}\)Tc]-sestamibi scintigraphy in patients with pHPT and negative ultrasound JF - Langenbeck’s Archives of Surgery N2 - Purpose A successful focused surgical approach in primary hyperparathyroidism (pHPT) relies on accurate preoperative localization of the parathyroid adenoma (PA). Most often, ultrasound is followed by [\(^{99m}\)Tc]-sestamibi scintigraphy, but the value of this approach is disputed. Here, we evaluated the diagnostic approach in patients with surgically treated pHPT in our center with the aim to further refine preoperative diagnostic procedures. Methods A single-center retrospective analysis of patients with pHPT from 01/2005 to 08/2021 was carried out followed by evaluation of the preoperative imaging modalities to localize PA. The localization of the PA had to be confirmed intraoperatively by the fresh frozen section and significant dropping of the intraoperative parathyroid hormone (PTH) levels. Results From 658 patients diagnosed with pHPT, 30 patients were excluded from the analysis because of surgery for recurrent or persistent disease. Median age of patients was 58.0 (13–93) years and 71% were female. Neck ultrasound was carried out in 91.7% and localized a PA in 76.6%. In 23.4% (135/576) of the patients, preoperative neck ultrasound did not detect a PA. In this group, [\(^{99m}\)Tc]-sestamibi correctly identified PA in only 25.4% of patients. In contrast, in the same cohort, the use of [\(^{11}\)C]-methionine or [\(^{11}\)C]-choline PET resulted in the correct identification of PA in 79.4% of patients (OR 13.23; 95% CI 5.24–33.56). Conclusion [\(^{11}\)C]-Methionine or [\(^{11}\)C]-choline PET/CT are superior second-line imaging methods to select patients for a focused surgical approach when previous ultrasound failed to identify PA. KW - primary hyperparathyroidism KW - parathyroid adenoma KW - [99mTc]-Sestamibi scan KW - [11C]-Methionine KW - [11C]-Choline PET/CT KW - focused surgical approach Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-323926 VL - 407 IS - 8 ER - TY - JOUR A1 - Hering, Ilona A1 - Dörries, Luise A1 - Flemming, Sven A1 - Krietenstein, Laura A1 - Koschker, Ann-Kathrin A1 - Fassnacht, Martin A1 - Germer, Christoph-Thomas A1 - Hankir, Mohammed K. A1 - Seyfried, Florian T1 - Impact of preoperative weight loss achieved by gastric balloon on peri- and postoperative outcomes of bariatric surgery in super-obese patients: a retrospective matched-pair analysis JF - Langenbeck’s Archives of Surgery N2 - Background An intragastric balloon is used to cause weight loss in super-obese patients (BMI > 60 kg/m\(^2\)) prior to bariatric surgery. Whether weight loss from intragastric balloon influences that from bariatric surgery is poorly studied. Methods In this retrospective, single-center study, the effects of intragastric balloon in 26 patients (BMI 69.26 ± 6.81) on weight loss after bariatric surgery (primary endpoint), postoperative complications within 30 days, hospital readmission, operation time, and MTL30 (secondary endpoints) were evaluated. Fifty-two matched-pair patients without intragastric balloon prior to bariatric surgery were used as controls. Results Intragastric balloon resulted in a weight loss of 17.3 ± 14.1 kg (BMI 5.75 ± 4.66 kg/m\(^2\)) with a nadir after 5 months. Surgical and postoperative outcomes including complications were comparable between both groups. Total weight loss was similar in both groups (29.0% vs. 32.2%, p = 0.362). Direct postoperative weight loss was more pronounced in the control group compared to the gastric balloon group (29.16 ± 7.53% vs 23.78 ± 9.89% after 1 year, p < 0.05 and 32.13 ± 10.5% vs 22.21 ± 10.9% after 2 years, p < 0.05), who experienced an earlier nadir and started to regain weight during the follow-up. Conclusion A multi-stage therapeutic approach with gastric balloon prior to bariatric surgery in super-obese patients may be effective to facilitate safe surgery. However, with the gastric balloon, pre-treated patients experienced an attenuated postoperative weight loss with an earlier nadir and earlier body weight regain. This should be considered when choosing the appropriate therapeutic regime and managing patients’ expectations. KW - obesity KW - super-obesity KW - intragastric balloon KW - sleeve gastrectomy KW - Roux-en-Y gastric bypass Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-323909 VL - 407 IS - 5 ER -