610 Medizin und Gesundheit
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We previously identified peptides that are actively transported across the intact tympanic membrane (TM) of rats with infected middle ears. To assess the possibility that this transport would also occur across the human TM, we first developed and validated an assay to evaluate transport in vitro using fragments of the TM. Using this assay, we demonstrated the ability of phage bearing a TM-transiting peptide to cross freshly dissected TM fragments from infected rats or from uninfected rats, guinea pigs and rabbits. We then evaluated transport across fragments of the human TM that were discarded during otologic surgery. Human trans-TM transport was similar to that seen in the animal species. Finally, we found that free peptide, unconnected to phage, was transported across the TM at a rate comparable to that seen for peptide-bearing phage. These studies provide evidence supporting the concept of peptide-mediated drug delivery across the intact TM and into the middle ears of patients.
Increased sympathetic noradrenergic signaling is crucially involved in fear and anxiety as defensive states. MicroRNAs regulate dynamic gene expression during synaptic plasticity and genetic variation of microRNAs modulating noradrenaline transporter gene (SLC6A2) expression may thus lead to altered central and peripheral processing of fear and anxiety. In silico prediction of microRNA regulation of SLC6A2 was confirmed by luciferase reporter assays and identified hsa-miR-579-3p as a regulating microRNA. The minor (T)-allele of rs2910931 (MAFcases = 0.431, MAFcontrols = 0.368) upstream of MIR579 was associated with panic disorder in patients (pallelic = 0.004, ncases = 506, ncontrols = 506) and with higher trait anxiety in healthy individuals (pASI = 0.029, pACQ = 0.047, n = 3112). Compared to the major (A)-allele, increased promoter activity was observed in luciferase reporter assays in vitro suggesting more effective MIR579 expression and SLC6A2 repression in vivo (p = 0.041). Healthy individuals carrying at least one (T)-allele showed a brain activation pattern suggesting increased defensive responding and sympathetic noradrenergic activation in midbrain and limbic areas during the extinction of conditioned fear. Panic disorder patients carrying two (T)-alleles showed elevated heart rates in an anxiety-provoking behavioral avoidance test (F(2, 270) = 5.47, p = 0.005). Fine-tuning of noradrenaline homeostasis by a MIR579 genetic variation modulated central and peripheral sympathetic noradrenergic activation during fear processing and anxiety. This study opens new perspectives on the role of microRNAs in the etiopathogenesis of anxiety disorders, particularly their cardiovascular symptoms and comorbidities.
Metastatic pheochromocytoma and paraganglioma: signs and symptoms related to catecholamine secretion
(2021)
Background
The presence or future development of metastatic pheochromocytomas or paragangliomas (mPPGLs) can be difficult to diagnose or predict at initial presentation. Since production of catecholamines from mPPGLs is different from non-metastatic tumors (non-mPPGLs), this study aimed to clarify whether presenting catecholamine-related signs and symptoms (cSS) might also differ.
Methods
The study included 249 patients, 43 with mPPGL and 206 with non-mPPGL. Clinical data at the time of biochemical diagnosis (i.e. at entry into the study) were used to generate a cumulative score of cSS for each patient.
Results
Patients with mPPGL were significantly younger (43.3 ± 14 vs. 48.9 ± 16.1 years) and included a lower proportion of females (39.5% vs. 60.7%) than patients with non-mPPGLs. Frequencies of signs and symptoms did not differ between the two groups. Patients with mPPGLs had lower (P < 0.001) urinary excretion of epinephrine (3.5 (IQR, 1.9—6.5) µg/day) than those with non-mPPGLs (19.1 (IQR, 4.3—70.2) µg/day). There was no difference in urinary excretion of norepinephrine. In patients with mPPGLs a high cSS score was associated with high urinary excretion of norepinephrine and normetanephrine. In contrast, in patients with non-mPPGLs, a high cSS was associated with high urinary excretion of epinephrine and metanephrine.
Conclusion
Although presenting signs and symptoms were associated with production of norepinephrine in patients with mPPGLs and of epinephrine in patients with non-mPPGLs, there were no differences in signs and symptoms between the two groups. Therefore, consideration of signs and symptoms does not appear helpful for distinguishing patients with and without mPPGLs.
Purpose
The subclassification of adrenal cancers according to the WHO classification in ordinary, myxoid, oncocytic, and sarcomatoid as well as pediatric types is well established, but the criteria for each subtype are not sufficiently determined and the relative frequency of the different types of adrenal cancers has not been studied in large cohorts. Therefore, our large collection of surgically removed adrenal cancers should be reviewed o establish the criteria for the subtypes and to find out the frequency of the various types.
Methods
In our series of 521 adrenal cancers the scoring systems of Weiss et al., Hough et al., van Slooten et al. and the new Helsinki score system were used for the ordinary type of cancer (97% of our series) and the myxoid type (0.8%). For oncocytic carcinomas (2%), the scoring system of Bisceglia et al. was applied.
Results
Discrepancies between benign and malignant diagnoses from the first thee classical scoring systems are not rare (22% in our series) and could be resolved by the Helsinki score especially by Ki-67 index (more than 8% unequivocally malignant). Since all our cancer cases are positive in the Helsinki score, this system can replace the three elder systems. For identification of sarcomatoid cancer as rarest type in our series (0.2%), the scoring systems are not practical but additional immunostainings used for soft tissue tumors and in special cases molecular pathology are necessary to differentiate these cancers from adrenal sarcomas. According to the relative frequencies of the different subtypes of adrenal cancers the main type is the far most frequent (97%) followed by the oncocytic type (2%), the myxoid type (0.8%) and the very rare sarcomatoid type (0.2%).
Conclusions
The Helsinki score is the best for differentiating adrenal carcinomas of the main, the oncocytic, and the myxoid type in routine work. Additional scoring systems for these carcinomas are generally not any longer necessary. Signs of proliferation (mitoses and Ki-67 index) and necroses are the most important criteria for diagnosis of malignancy.
Context
Primary aldosteronism (PA) is the most frequent form of endocrine hypertension. Besides its deleterious impact on cardiovascular target organ damage, PA is considered to cause osteoporosis.
Patients and methods
We assessed bone turnover in a subset of 36 postmenopausal women with PA. 18 patients had unilateral PA and were treated by adrenalectomy, whereas 18 patients had bilateral PA and received mineralocorticoid receptor antagonist (MRA) therapy respectively. 18 age- and BMI-matched females served as controls. To estimate bone remodeling, we measured the bone turnover markers intact procollagen 1 N-terminal propeptide, bone alkaline phosphatase, osteocalcin and tartrate resistant acid phosphatase 5b in plasma by chemiluminescent immunoassays at time of diagnosis and one year after initiation of treatment.
Study design
Observational longitudinal cohort study.
Setting
Tertiary care hospital.
Results
Compared with controls, patients with PA had mildly elevated osteocalcin at baseline (p = 0.013), while the other bone markers were comparable between both groups. There were no differences between the unilateral and the bilateral PA subgroup. One year after initiation of MRA treatment with spironolactone bone resorption and bone formation markers had significantly decreased in patients with bilateral PA. In contrast, patients adrenalectomized because of unilateral PA showed no significant change of bone turnover markers.
Conclusion
This study shows that aldosterone excess in postmenopausal women with PA is not associated with a relevant increase of bone turnover markers at baseline. However, we observed a significant decrease of bone markers in patients treated with spironolactone, but not in patients treated by adrenalectomy.
Purpose
Pheochromocytomas and Paragangliomas (PPGL) result in chronic catecholamine excess and serious health complications. A recent study obtained a metabolic signature in plasma from PPGL patients; however, its targeted nature may have generated an incomplete picture and a broader approach could provide additional insights. We aimed to characterize the plasma metabolome of PPGL patients before and after surgery, using an untargeted approach, and to broaden the scope of the investigated metabolic impact of these tumors.
Design
A cohort of 36 PPGL patients was investigated. Blood plasma samples were collected before and after surgical tumor removal, in association with clinical and tumor characteristics.
Methods
Plasma samples were analyzed using untargeted nuclear magnetic resonance (NMR) spectroscopy metabolomics. The data were evaluated using a combination of uni- and multi-variate statistical methods.
Results
Before surgery, patients with a nonadrenergic tumor could be distinguished from those with an adrenergic tumor based on their metabolic profiles. Tyrosine levels were significantly higher in patients with high compared to those with low BMI. Comparing subgroups of pre-operative samples with their post-operative counterparts, we found a metabolic signature that included ketone bodies, glucose, organic acids, methanol, dimethyl sulfone and amino acids. Three signals with unclear identities were found to be affected.
Conclusions
Our study suggests that the pathways of glucose and ketone body homeostasis are affected in PPGL patients. BMI-related metabolite levels were also found to be altered, potentially linking muscle atrophy to PPGL. At baseline, patient metabolomes could be discriminated based on their catecholamine phenotype.
Therapy options for adrenal insufficiency and recommendations for the management of adrenal crisis
(2021)
Adrenal insufficiency (AI) is a life-threatening condition requiring life-long glucocorticoid (GC) substitution therapy, as well as stress adaptation to prevent adrenal crises. The number of individuals with primary and secondary adrenal insufficiency in Europe is estimated to be 20–50/100.000. A growing number of AI cases are due to side effects of GC treatment used in different treatment strategies for cancer and to immunotherapy in cancer treatment. The benefit of hormone replacement therapy is evident but long-term adverse effects may arise due to the non-physiological GC doses and treatment regimens used. Given multiple GC replacement formulations available comprising short-acting, intermediate, long-acting and novel modified-release hydrocortisone as well as subcutaneous formulations, this review offers a concise summary on the latest therapeutic improvements for treatment of AI and prevention of adrenal crises. As availability of various glucocorticoid formulations and access to expert centers across Europe varies widely, European Reference Networks on rare endocrine conditions aim at harmonizing treatment and ensure access to specialized patient care for individual case-by-case treatment decisions. To improve the availability across Europe to cost effective oral and parenteral formulations of hydrocortisone will save lives.
Differences between immunotherapy-induced and primary hypophysitis—a multicenter retrospective study
(2022)
Objective
Immune checkpoint inhibitors can cause various immune-related adverse events including secondary hypophysitis. We compared clinical characteristics of immunotherapy-induced hypophysitis (IIH) and primary hypophysitis (PH)
Design
Retrospective multicenter cohort study including 56 patients with IIH and 60 patients with PH.
Methods
All patients underwent extensive endocrine testing. Data on age, gender, symptoms, endocrine dysfunction, MRI, immunotherapeutic agents and autoimmune diseases were collected.
Results
Median time of follow-up was 18 months in IIH and 69 months in PH. The median time from initiation of immunotherapy to IIH diagnosis was 3 months. IIH affected males more frequently than PH (p < 0.001) and led to more impaired pituitary axes in males (p < 0.001). The distribution of deficient adenohypophysial axes was comparable between both entities, however, central hypocortisolism was more frequent (p < 0.001) and diabetes insipidus considerably less frequent in IIH (p < 0.001). Symptoms were similar except that visual impairment occurred more rarely in IIH (p < 0.001). 20 % of IIH patients reported no symptoms at all. Regarding MRI, pituitary stalk thickening was less frequent in IIH (p = 0.009). Concomitant autoimmune diseases were more prevalent in PH patients before the diagnosis of hypophysitis (p = 0.003) and more frequent in IIH during follow-up (p = 0.002).
Conclusions
Clinically, IIH and PH present with similar symptoms. Diabetes insipidus very rarely occurs in IIH. Central hypocortisolism, in contrast, is a typical feature of IIH. Preexisting autoimmunity seems not to be indicative of developing IIH.
Background: Monitoring the vital signs of delirious patients in an intensive care unit (ICU) is challenging, as they might (un-)intentionally remove devices attached to their bodies. In mock-up scenarios, we systematically assessed whether a motion detector (MD) attached to the bed may help in identifying emergencies. Methods: We recruited 15 employees of the ICU and equipped an ICU bed with an MD (IRON Software GmbH, Grünwald, Germany). Participants were asked to replay 22 mock-up scenes of one-minute duration each: 12 scenes with movements and 10 without movements, of which 5 were emergency scenes (“lying dead-still, with no or very shallow breathing”). Blinded recordings were presented to an evaluation panel consisting of an experienced ICU nurse and a physician, who was asked to assess and rate the presence of motions. Results: Fifteen participants (nine women; 173 ± 7.0 cm; 78 ± 19 kg) joined the study. In total, 286 out of 330 scenes (86.7%) were rated correctly. Ratings were false negative (FN: “no movements detected, but recorded”) in 7 out of 180 motion scenes (3.9%). Ratings were false positive (FP: “movements detected, but not recorded”) in 37 out of 150 scenes (24.7%), more often in men than women (26 out of 60 vs. 11 out of 90, respectively; p < 0.001). Of note, in 16 of these 37 FP-rated scenes, a vibrating mobile phone was identified as a potential confounder. The emergency scenes were correctly rated in 64 of the 75 runs (85.3%); 10 of the 11 FP-rated scenes occurred in male subjects. Conclusions: The MD allowed for identifying motions of test subjects with high sensitivity (96%) and acceptable specificity (75%). Accuracy might increase further if activities are recorded continuously under real-world conditions.
Adrenocortical carcinoma (ACC) represents a rare tumor entity with limited treatment options and usually rapid tumor progression in case of metastatic disease. As further treatment options are needed and ACC metastases are sensitive to external beam radiation, novel theranostic approaches could complement established therapeutic concepts. Recent developments focus on targeting adrenal cortex-specific enzymes like the theranostic twin [\(^{123/131}\)I]IMAZA that shows a good image quality and a promising therapeutic effect in selected patients. But other established molecular targets in nuclear medicine such as the C-X-C motif chemokine receptor 4 (CXCR4) could possibly enhance the therapeutic regimen as well in a subgroup of patients. The aims of this review are to give an overview of innovative radiopharmaceuticals for the treatment of ACC and to present the different molecular targets, as well as to show future perspectives for further developments since a radiopharmaceutical with a broad application range is still warranted.
Serum liquid chromatography–tandem mass spectrometry (LC–MS/MS) steroid profiling is used for the diagnosis of adrenocortical carcinoma (ACC). Guidelines recommend endocrine work-up in addition to radiological imaging for follow-up in ACC, but data on this topic are scarce. Patients were included in this retrospective study if pre-therapeutic hormone values, regular tumour evaluation by imaging, steroid measurements by LC–MS/MS, and details on therapies were available. The utility of steroid profiles in detecting recurrence or disease progression was assessed, whereby “endocrine progress” was defined by an elevation of at least 3 of 13 analysed hormones. Cohort A included 47 patients after R0 resection, of whom 15 experienced recurrence and 32 did not. In cohort B, 52 patients with advanced disease (including 7 patients of cohort A with recurrence) could be evaluated on 74 visits when progressive disease was documented. In 20 of 89 cases with documented disease progression, “endocrine progress” was detectable prior to radiological progress. In these cases, recurrence/progression was detected at a median of 32 days earlier by steroid measurement than by imaging, with 11-deoxycortisol and testosterone being the most sensitive markers. Notably, these patients had significantly larger tumour burden. In conclusion, steroid profiling by LC–MS/MS is of value in detecting recurrent/progressive disease in ACC.
Safety and tolerability of SGLT2 inhibitors in cardiac amyloidosis — a clinical feasibility study
(2024)
Sodium-glucose transport protein 2 inhibitors (SGLT2i) slow the progression of renal dysfunction and improve the prognosis of patients with heart failure. Amyloidosis constitutes an important subgroup for which evidence is lacking. Amyloidotic fibrils originating from misfolded transthyretin and light chains are the causal agents in ATTR and AL amyloidosis. In these most frequent subtypes, cardiac involvement is the most common organ manifestation. Because cardiac and renal function frequently deteriorate over time, even under best available treatment, SGLT2i emerge as a promising treatment option due to their reno- and cardioprotective properties. We retrospectively analyzed patients with cardiac amyloidosis, who received either dapagliflozin or empagliflozin. Out of 79 patients, 5.1% had urinary tract infections; 2 stopped SGLT2i therapy; and 2.5% died unrelated to the intake of SGLT2i. No genital mycotic infections were observed. As expected, a slight drop in the glomerular filtration rate was noted, while the NYHA functional status, cardiac and hepatic function, as well as the 6 min walk distance remained stable over time. These data provide a rationale for the use of SGLT2i in patients with amyloidosis and concomitant cardiac or renal dysfunction. Prospective randomized data are desired to confirm safety and to prove efficacy in this increasingly important group of patients.
Objectives
The spectrum of giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) represents highly inflammatory rheumatic diseases. Patients mostly report severe physical impairment. Possible consequences for mental health have been scarcely studied. The aim of this study was to investigate psychological well-being in the context of GCA and PMR.
Methods
Cross-sectional study with N = 100 patients with GCA and/or PMR (GCA-PMR). Patient-reported outcomes (PROs) were measured using the Short Form 36 Version 2 (SF-36v2) and visual analog scale (VAS) assessment. Moreover, the Patient Health Questionnaire 9 (PHQ-9) was used in 35 of 100 patients to detect depression. To compare PROs with physician assessment, VAS was also rated from physician perspective. To assess a possible association with inflammation itself, serological parameters of inflammation (C-reactive protein [CRP], erythrocyte sedimentation rate [ESR]) were included.
Results
In all scales of the SF-36v2 except General Health (GH) and in the physical and mental sum score (PCS, MCS), a significant impairment compared to the German reference collective was evident (MCS: d = 0.533, p < 0.001). In the PHQ-9 categorization, 14 of the 35 (40%) showed evidence of major depression disorder. VAS Patient correlated significantly with PHQ-9 and SF-36 in all categories, while VAS Physician showed only correlations to physical categories and not in the mental dimensions. Regarding inflammatory parameters, linear regression showed CRP to be a complementary significant positive predictor of mental health subscale score, independent of pain.
Conclusion
PRO show a relevant impairment of mental health up to symptoms of major depression disorder. The degree of depressive symptoms is also distinctly associated with the serological inflammatory marker CRP.
Purpose
Over the course of COVID-19 pandemic, evidence has accumulated that SARS-CoV-2 infections may affect multiple organs and have serious clinical sequelae, but on-site clinical examinations with non-hospitalized samples are rare. We, therefore, aimed to systematically assess the long-term health status of samples of hospitalized and non-hospitalized SARS-CoV-2 infected individuals from three regions in Germany.
Methods
The present paper describes the COVIDOM-study within the population-based cohort platform (POP) which has been established under the auspices of the NAPKON infrastructure (German National Pandemic Cohort Network) of the national Network University Medicine (NUM). Comprehensive health assessments among SARS-CoV-2 infected individuals are conducted at least 6 months after the acute infection at the study sites Kiel, Würzburg and Berlin. Potential participants were identified and contacted via the local public health authorities, irrespective of the severity of the initial infection. A harmonized examination protocol has been implemented, consisting of detailed assessments of medical history, physical examinations, and the collection of multiple biosamples (e.g., serum, plasma, saliva, urine) for future analyses. In addition, patient-reported perception of the impact of local pandemic-related measures and infection on quality-of-life are obtained.
Results
As of July 2021, in total 6813 individuals infected in 2020 have been invited into the COVIDOM-study. Of these, about 36% wished to participate and 1295 have already been examined at least once.
Conclusion
NAPKON-POP COVIDOM-study complements other Long COVID studies assessing the long-term consequences of an infection with SARS-CoV-2 by providing detailed health data of population-based samples, including individuals with various degrees of disease severity.
Trial registration
Registered at the German registry for clinical studies (DRKS00023742).
Ziel dieser Studie war es, zu eruieren, ob die DSE zur Unterscheidung einer TS- von einer PSAS beitragen kann. Ebenfalls untersuchten wir, ob es bestimmte echokardiographische Prädiktoren für eine TS- und eine PSAS gibt und ob die LVEF bei Patienten mit einer LGAS eine entscheidende Rolle spielt. Methoden: Es wurde bei 130 Patienten mit einer asymptomatischen AS im Uniklinikum Würzburg zwischen Januar 2011 und Dezember 2016 sowohl eine TTE als auch eine DSE durchgeführt. Mittels TTE wurden verschiedene echokardiographische Daten erhoben und falls die Patienten eine AVAi 0,6 cm2/m2 und eine PGmean < 40 mmHg aufwiesen, wurden sie in die Studie eingeschlossen. Sie wurden in zwei Gruppen aufgeteilt, je nachdem ob sie eine LGAS mit einer LVEF 50% oder < 50% aufwiesen. Bei allen Patienten wurde in der DSE die AVAproj berechnet und sie wurden daraufhin in zwei Untergruppen aufgeteilt, Patienten mit einer AVAproj 1 cm2 wurden der Gruppe mit einer hochgradigen LGAS (TS-LGAS) und Patienten mit einer AVAproj > 1cm2 der Gruppe mit einer pseudo-hochgradigen LGAS (PS-LGAS) zugeteilt. Alle Patientendaten wurden manuell ausgewertet. Das klinische Follow Up fand frühestens ein Jahr nach der DSE statt und bestand aus einem Telefoninterview oder einer klinischen Untersuchung. Ergebnisse: Die DSE ist zur Diagnose einer TS-LGAS bei Patienten mit einer erhaltenen LVEF von großem Nutzen. Die in der TTE gemessene AVA ist ein unabhängiger Prädiktor für eine TS-LGAS bei Patienten mit erhaltener und reduzierter LVEF. Eine verringerte MAPSE und eine reduzierte TDI-s´ sprechen bei Patienten mit erhaltener LVEF für eine TS-LGAS. Bei Patienten mit reduzierter LVEF weisen ein erhöhter sPAP und eine verringerte AV Geschwindigkeits Ratio auf eine TS-LGAS hin. Bei Zweifeln können weitere bildgebende Verfahren zur Diagnosefindung hinzugezogen werden.
Diese retrospektive Studie an der Universitätsklinik Würzburg diente der Beurteilung der longitudinalen Funktion in Bezug auf die Gesamtmortalität bei Patienten mit HFmrEF und HFrEF. Die Gruppierung erfolgte anhand der jeweiligen Baseline LVEF. Eine weitere Unterteilung erfolgte in eine ischämische oder nicht-ischämische Genese der HF. Die Subgruppen wurden anhand der Baseline klinischen Charakteristika sowie der echokardiographischen Parameter verglichen. Hier ließ sich ein relativ ähnliches Patientenklientel mit vergleichbarem Alter, Geschlecht, BMI sowie kardialen Risikofaktoren zeigen. Signifikante Unterschiede ergab der Vergleich des NYHA-Stadiums, der Nierenfunktion sowie des Auftretens von Myokardinfarkten.
Die Veränderung der LVEF über die Zeit hat einen zentralen Stellenwert zur Evaluation des Outcomes von Patienten mit HFmrEF und HFrEF. Eine Verbesserung der LVEF fand sich signifikant häufiger bei HFrEF Patienten als bei HFmrEF Patienten, welche über die Zeit signifikant häufiger eine stabile LVEF aufwiesen.
Außerdem war nach Auswertung der Überlebenskurven nach Kaplan-Meier in HFmrEF Patienten eine verbesserte oder unveränderte LVEF über die Zeit mit einem besseren Überleben verbunden, vor allem bei Patienten mit ischämischer Ätiologie. In der HFrEF Gruppe konnte gezeigt werden, dass sowohl Patienten mit ischämischer als auch mit nicht-ischämischer Ätiologie bei Vorliegen einer verbesserten oder unveränderten LVEF über die Zeit ein besseres Outcome aufwiesen.
Eine erniedrigte MAPSE bedeutete vor allem bei HFmrEF Patienten mit nicht-ischämischer Ätiologie ein schlechteres Outcome.
Die Ergebnisse dienten unter anderem der weiteren Charakterisierung der HFmrEF und HFrEF Gruppe sowie der Identifikation von Faktoren zur Beurteilung der Veränderung der LVEF über die Zeit und der Prognose des Langzeitüberlebens beider Gruppen. Ziel für die Zukunft sollte sein, auch für HFmrEF Patienten evidenzbasierte Herzinsuffizienz Therapien zu etablieren.
Hintergrund: Die therapeutischen Optionen für das gering differenzierte (PDTC) und anaplastische (ATC) Schilddrüsenkarzinom sind limitiert, weshalb diese Erkrankungen überwiegend mit einer schlechten Prognose einhergehen. Lenvatinib (LEN) ist ein Multityrosinkinase-Inhibitor, der unter anderem die Fibroblasten-Wachstumsfaktor-Rezeptoren (FGFR) 1-4 inhibiert und zur Therapie des fortgeschrittenen radiojodrefraktären Schilddrüsenkarzinoms zugelassen ist. Es zeigt sich nur ein geringes Ansprechen auf die Monotherapie bei ATCs, wobei neuere Studien eine therapeutische Überlegenheit der Kombination aus LEN und dem PD-1-Inhibitor Pembrolizumab (PEM) beschreiben.
Material und Methoden: Die Expression von PD-L1 wurde in ATC (n=93)- und PDTC (n=47)-Primärtumorgewebe von 1997-2019 aus fünf deutschen (Universitäts-)Kliniken mittels Immunhistochemie analysiert und mit dem Tumor Proportion Score (TPS) quantifiziert. Der Nachweis von FGFR1-4-mRNA wurde bei 31 ATC- und 14 PDTC-Gewebeproben mittels RNAscope In-situ-Hybridisierung quantifiziert. Als Kontrollgruppe wurde normales Schilddrüsengewebe (NT) und Gewebe von papillären Schilddrüsenkarzinomen (PTC) verwendet. Der primäre Endpunkt war das krankheitsspezifische Überleben (DSS).
Ergebnisse: Eine PD-L1-Expression mit einem TPS ≥50% konnte in 42% der ATC- und in 26% der PDTC-Proben nachgewiesen werden. Die mediane PD-L1-Expression war in ATC-(TPS 30%) signifikant höher im Vergleich zu PDTC-Proben (5%; p<0,01) und NT (0%; p<0,001). 53% der PDTC-Proben zeigten eine PD-L1-Expression ≤5%. Die Expression von FGFR-mRNA war in allen Proben sehr gering, wobei die kombinierte FGFR1-4-Expression in PDTC- und ATC-Gewebe im Vergleich zu normalem Schilddrüsengewebe signifikant höher war (jeweils p<0,001). Es ergab sich keine Assoziation zwischen der PD-L1- und FGFR1-4-Expression mit dem krankheitsspezifischen Überleben.
Schlussfolgerung: Eine hohe PD-L1-Expression in einem großen Anteil der ATCs und einem Viertel der PDTCs, könnte auf eine Rationale zur Therapieentscheidung für Immuncheckpoint-Inhibioren hinweisen. Die FGFR-Expression war in allen Schilddrüsenkarzinomen sehr gering. Der klinisch beobachtete Synergismus von PEM und LEN könnte durch immunmodulatorische Effekte hervorgerufen werden.
Ultra-high field cardiac MRI in large animals and humans for translational cardiovascular research
(2023)
A key step in translational cardiovascular research is the use of large animal models to better understand normal and abnormal physiology, to test drugs or interventions, or to perform studies which would be considered unethical in human subjects. Ultrahigh field magnetic resonance imaging (UHF-MRI) at 7 T field strength is becoming increasingly available for imaging of the heart and, when compared to clinically established field strengths, promises better image quality and image information content, more precise functional analysis, potentially new image contrasts, and as all in-vivo imaging techniques, a reduction of the number of animals per study because of the possibility to scan every animal repeatedly. We present here a solution to the dual use problem of whole-body UHF-MRI systems, which are typically installed in clinical environments, to both UHF-MRI in large animals and humans. Moreover, we provide evidence that in such a research infrastructure UHF-MRI, and ideally combined with a standard small-bore UHF-MRI system, can contribute to a variety of spatial scales in translational cardiovascular research: from cardiac organoids, Zebra fish and rodent hearts to large animal models such as pigs and humans. We present pilot data from serial CINE, late gadolinium enhancement, and susceptibility weighted UHF-MRI in a myocardial infarction model over eight weeks. In 14 pigs which were delivered from a breeding facility in a national SARS-CoV-2 hotspot, we found no infection in the incoming pigs. Human scanning using CINE and phase contrast flow measurements provided good image quality of the left and right ventricle. Agreement of functional analysis between CINE and phase contrast MRI was excellent. MRI in arrested hearts or excised vascular tissue for MRI-based histologic imaging, structural imaging of myofiber and vascular smooth muscle cell architecture using high-resolution diffusion tensor imaging, and UHF-MRI for monitoring free radicals as a surrogate for MRI of reactive oxygen species in studies of oxidative stress are demonstrated. We conclude that UHF-MRI has the potential to become an important precision imaging modality in translational cardiovascular research.
Purpose: This study analyses a large number of cancer patients with CIEDs for device malfunction and premature battery depletion by device interrogation after each radiotherapy fraction and compares different guidelines in regard to patient safety. Methods: From 2007 to 2022, a cohort of 255 patients was analyzed for CIED malfunctions via immediate device interrogation after every RT fraction. Results: Out of 324 series of radiotherapy treatments, with a total number of 5742 CIED interrogations, nine device malfunctions (2.8%) occurred. Switching into back-up/safety mode and software errors occurred four times each. Once, automatic read-out could not be performed. The median prescribed cumulative dose at planning target volume (PTV) associated with CIED malfunction was 45.0 Gy (IQR 36.0–64.0 Gy), with a median dose per fraction of 2.31 Gy (IQR 2.0–3.0 Gy). The median maximum dose at the CIED at time of malfunction was 0.3 Gy (IQR 0.0–1.3 Gy). No correlation between CIED malfunction and maximum photon energy (p = 0.07), maximum dose at the CIED (p = 0.59) nor treatment localization (p = 0.41) could be detected. After excluding the nine malfunctions, premature battery depletion was only observed three times (1.2%). Depending on the national guidelines, 1–9 CIED malfunctions in this study would have been detected on the day of occurrence and in none of the cases would patient safety have been compromised. Conclusion: Radiation-induced malfunctions of CIEDs and premature battery depletion are rare. If recommendations of national safety guidelines are followed, only a portion of the malfunctions would be detected directly after occurrence. Nevertheless, patient safety would not be compromised.
Air pollution is associated with morbidity and mortality worldwide. We investigated the impact of improved air quality during the economic lockdown during the SARS-Cov2 pandemic on emergency room (ER) admissions in Germany. Weekly aggregated clinical data from 33 hospitals were collected in 2019 and 2020. Hourly concentrations of nitrogen and sulfur dioxide (NO2, SO2), carbon and nitrogen monoxide (CO, NO), ozone (O3) and particulate matter (PM10, PM2.5) measured by ground stations and meteorological data (ERA5) were selected from a 30 km radius around the corresponding ED. Mobility was assessed using aggregated cell phone data. A linear stepwise multiple regression model was used to predict ER admissions. The average weekly emergency numbers vary from 200 to over 1600 cases (total n = 2,216,217). The mean maximum decrease in caseload was 5 standard deviations. With the enforcement of the shutdown in March, the mobility index dropped by almost 40%. Of all air pollutants, NO2 has the strongest correlation with ER visits when averaged across all departments. Using a linear stepwise multiple regression model, 63% of the variation in ER visits is explained by the mobility index, but still 6% of the variation is explained by air quality and climate change.
Psychosocial factors affect mental health and health-related quality of life (HRQL) in a complex manner, yet gender differences in these interactions remain poorly understood. We investigated whether psychosocial factors such as social support and personal and work-related concerns impact mental health and HRQL differentially in women and men during the first year of the COVID-19 pandemic. Between June and October 2020, the first part of a COVID-19-specific program was conducted within the “Characteristics and Course of Heart Failure Stages A-B and Determinants of Progression (STAAB)” cohort study, a representative age- and gender-stratified sample of the general population of Würzburg, Germany. Using psychometric networks, we first established the complex relations between personal social support, personal and work-related concerns, and their interactions with anxiety, depression, and HRQL. Second, we tested for gender differences by comparing expected influence, edge weight differences, and stability of the networks. The network comparison revealed a significant difference in the overall network structure. The male (N = 1370) but not the female network (N = 1520) showed a positive link between work-related concern and anxiety. In both networks, anxiety was the most central variable. These findings provide further evidence that the complex interplay of psychosocial factors with mental health and HRQL decisively depends on gender. Our results are relevant for the development of gender-specific interventions to increase resilience in times of pandemic crisis.
Long-term sequelae in hospitalized Coronavirus Disease 2019 (COVID-19) patients may result in limited quality of life. The current study aimed to determine health-related quality of life (HRQoL) after COVID-19 hospitalization in non-intensive care unit (ICU) and ICU patients. This is a single-center study at the University Hospital of Wuerzburg, Germany. Patients eligible were hospitalized with COVID-19 between March 2020 and December 2020. Patients were interviewed 3 and 12 months after hospital discharge. Questionnaires included the European Quality of Life 5 Dimensions 5 Level (EQ-5D-5L), patient health questionnaire-9 (PHQ-9), the generalized anxiety disorder 7 scale (GAD-7), FACIT fatigue scale, perceived stress scale (PSS-10) and posttraumatic symptom scale 10 (PTSS-10). 85 patients were included in the study. The EQ5D-5L-Index significantly differed between non-ICU (0.78 ± 0.33 and 0.84 ± 0.23) and ICU (0.71 ± 0.27; 0.74 ± 0.2) patients after 3- and 12-months. Of non-ICU 87% and 80% of ICU survivors lived at home without support after 12 months. One-third of ICU and half of the non-ICU patients returned to work. A higher percentage of ICU patients was limited in their activities of daily living compared to non-ICU patients. Depression and fatigue were present in one fifth of the ICU patients. Stress levels remained high with only 24% of non-ICU and 3% of ICU patients (p = 0.0186) having low perceived stress. Posttraumatic symptoms were present in 5% of non-ICU and 10% of ICU patients. HRQoL is limited in COVID-19 ICU patients 3- and 12-months post COVID-19 hospitalization, with significantly less improvement at 12-months compared to non-ICU patients. Mental disorders were common highlighting the complexity of post-COVID-19 symptoms as well as the necessity to educate patients and primary care providers about monitoring mental well-being post COVID-19.
Highlights
• Loss of DNAJC19's DnaJ domain disrupts cardiac mitochondrial structure, leading to abnormal cristae formation in iPSC-CMs.
• Impaired mitochondrial structures lead to an increased mitochondrial respiration, ROS and an elevated membrane potential.
• Mutant iPSC-CMs show sarcomere dysfunction and a trend to more arrhythmias, resembling DCMA-associated cardiomyopathy.
Background
Dilated cardiomyopathy with ataxia (DCMA) is an autosomal recessive disorder arising from truncating mutations in DNAJC19, which encodes an inner mitochondrial membrane protein. Clinical features include an early onset, often life-threatening, cardiomyopathy associated with other metabolic features. Here, we aim to understand the metabolic and pathophysiological mechanisms of mutant DNAJC19 for the development of cardiomyopathy.
Methods
We generated induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) of two affected siblings with DCMA and a gene-edited truncation variant (tv) of DNAJC19 which all lack the conserved DnaJ interaction domain. The mutant iPSC-CMs and their respective control cells were subjected to various analyses, including assessments of morphology, metabolic function, and physiological consequences such as Ca\(^{2+}\) kinetics, contractility, and arrhythmic potential. Validation of respiration analysis was done in a gene-edited HeLa cell line (DNAJC19tv\(_{HeLa}\)).
Results
Structural analyses revealed mitochondrial fragmentation and abnormal cristae formation associated with an overall reduced mitochondrial protein expression in mutant iPSC-CMs. Morphological alterations were associated with higher oxygen consumption rates (OCRs) in all three mutant iPSC-CMs, indicating higher electron transport chain activity to meet cellular ATP demands. Additionally, increased extracellular acidification rates suggested an increase in overall metabolic flux, while radioactive tracer uptake studies revealed decreased fatty acid uptake and utilization of glucose. Mutant iPSC-CMs also showed increased reactive oxygen species (ROS) and an elevated mitochondrial membrane potential. Increased mitochondrial respiration with pyruvate and malate as substrates was observed in mutant DNAJC19tv HeLa cells in addition to an upregulation of respiratory chain complexes, while cellular ATP-levels remain the same. Moreover, mitochondrial alterations were associated with increased beating frequencies, elevated diastolic Ca\(^{2+}\) concentrations, reduced sarcomere shortening and an increased beat-to-beat rate variability in mutant cell lines in response to β-adrenergic stimulation.
Conclusions
Loss of the DnaJ domain disturbs cardiac mitochondrial structure with abnormal cristae formation and leads to mitochondrial dysfunction, suggesting that DNAJC19 plays an essential role in mitochondrial morphogenesis and biogenesis. Moreover, increased mitochondrial respiration, altered substrate utilization, increased ROS production and abnormal Ca\(^{2+}\) kinetics provide insights into the pathogenesis of DCMA-related cardiomyopathy.
Background
Guideline-directed medical therapy (GDMT) is the cornerstone in the treatment of patients with heart failure and reduced ejection fraction (HFrEF) and novel substances such as sacubitril/valsartan (S/V) and sodium-glucose co-transporter-2 inhibitors (SGLT2i) have demonstrated marked clinical benefits. We investigated their implementation into real-world HF care in Germany before, during, and after the COVID-19 pandemic period.
Methods
The IQVIA LRx data set is based on ∼80% of 73 million people covered by the German statutory health insurance. Prescriptions of S/V were used as a proxy for HFrEF. Time trends were analysed between Q1/2016 and Q2/2023 for prescriptions for S/V alone and in combination therapy with SGLT2i.
Findings
The number of patients treated with S/V increased from 5260 in Q1/2016 to 351,262 in Q2/2023. The share of patients with combination therapy grew from 0.6% (29 of 5260) to 14.2% (31,128 of 219,762) in Q2/2021, and then showed a steep surge up to 54.8% (192,429 of 351,262) in Q2/2023, coinciding with the release of the European Society of Cardiology (ESC) guidelines for HF in Q3/2021. Women and patients aged >80 years were treated less often with combined therapy than men and younger patients. With the start of the COVID-19 pandemic, the number of patients with new S/V prescriptions dropped by 17.5% within one quarter, i.e., from 26,855 in Q1/2020 to 22,145 in Q2/2020, and returned to pre-pandemic levels only in Q1/2021.
Interpretation
The COVID-19 pandemic was associated with a 12-month deceleration of S/V uptake in Germany. Following the release of the ESC HF guidelines, the combined prescription of S/V and SGLT2i was readily adopted. Further efforts are needed to fully implement GDMT and strengthen the resilience of healthcare systems during public health crises.
Die Aortenklappenstenose stellt eine der häufigsten Herzklappenerkrankungen der westlichen Welt mit steigender Inzidenz dar. Mithilfe der kathetergestützten Aortenklappenimplantation (TAVI) ist es heutzutage möglich, auch chirurgisch inoperable PatientInnen mit einer Klappenprothese zielgerichtet zu behandeln. Ziel dieser Arbeit war es, klinische und echokardiografische Prädiktoren der Gesamtmortalität sowie des Kurz- (30 Tage) und Langzeitüberlebens (12 Monate) nach TAVI zu ermitteln.
Es wurden zahlreiche klinische und echokardiografische Parameter bei 618 PatientInnen, die zwischen Juli 2009 und Oktober 2018 eine TAVI erhielten, untersucht. Anschließend erfolgte ein Follow-up mittels Telefoninterview oder hausärztlicher Auskunft. Es folgten statistische Analysen zur Ermittlung signifikanter Unterschiede zwischen verstorbenen und lebenden PatientInnen. Abschließend wurden mögliche Prädiktoren der Mortalität mithilfe multivariabler Cox Regressionmodelle identifiziert.
In den Analysen ergaben sich zahlreiche signifikante Unterschiede zwischen Lebenden und Verstorbenen. Klinische Prädiktoren, die ein höheres Risiko der Gesamt- sowie Langzeitmortalität anzeigen, sind der Zugangsweg (transapikal), pAVK, Vorhofflimmern, erhöhte CRP-Level sowie eine Amiodaroneinnahme. Letztere erwies sich als der einzige Prädiktor der Kurzzeitmortalität. Als echokardiografische Prädiktoren (nach Adjustierung bezüglich klinischer Parameter) der Gesamtmortalität präsentieren sich eine erniedrigte TAPSE (≤14mm), erniedrigte septale MAPSE (≤6mm) sowie erhöhtes septales E/e‘ (≥28). Dieses ist auch ein Prädiktor des Lang- und Kurzzeitüberlebens. Zusätzlich zeigt ein sPAP-Anstieg pro 5mmHg eine erhöhte Kurzzeitsterblichkeit an.
Für die Mortalität nach einem TAVI-Eingriff sind neben kardiovaskulären Komorbiditäten auch echokardiografisch messbare kardiale Faktoren entscheidend, insbesondere eine systolische Dysfunktion (erniedrigte TAPSE und MAPSE), diastolische Dysfunktion (erhöhter Füllungsdruckindex E/e‘) sowie erhöhte pulmonalarterielle Drücke (sPAP). Wenn PatientInnen schon vor dem Eingriff diese pathologischen Werte zeigen, sind sie als einem „Hochrisikokollektiv“ zugehörig aufzufassen, was in der Aufklärung wie auch Vor- und in der Nachsorge solcher PatientInnen zukünftig Berücksichtigung finden sollte.
Der kathetergestützte Aortenklappenersatz nimmt auch bei Patienten mit niedrigem OP-Risiko einen zunehmend größeren Stellenwert zur Behandlung der hochgradigen Aortenklappenstenose ein.45 Umso wichtiger ist es, die einzelnen Schritte der Intervention zu optimieren. In einigen Arbeiten wurde bereits die Vordilatation als obsolet bezeichnet, da sie lediglich die OP-Zeit verlängere und Komplikationen wie Schlaganfälle und AV-Blockierungen begünstige.22,52,53,57,59 Ziel dieser Studie war es, die Vor- und Nachteile der Vordilatation zu untersuchen. Hierzu wurden 625 Patienten, die im Zeitraum von 2016-2020 eine TAVI am UKW erhielten, retrospektiv analysiert (323 mit, 302 ohne Vordilatation). Es wurden demographische sowie prä-, peri- und post-interventionelle Daten analysiert. Statistisch signifikante Unterschiede wurden bei den Schlaganfällen beobachtet (p=0,01), die mit 2,2% lediglich bei Patienten mit Vordilatation auftraten, sodass bei einem hohen Schlaganfallrisiko hierauf verzichtet werden sollte. Zusätzlich war in der Gruppe mit Vordilatation die passagere Schrittmacherabhängigkeit signifikant häufiger (p=0,01). Alle anderen Komplikationen waren nicht signifikant. In beiden Gruppen zeigte sich zu >95% ein Device-Success, sodass der Verzicht auf eine Prädilatation nicht mit einem schlechteren Outcome assoziiert und somit sicher ist.53,57,58,59,61
Die Auswertung der TTE-Daten zeigte, dass eine Prädilatation durchgeführt wurde, wenn die Klappe signifikant höhergradig stenosiert war (Pmean 50,17 vs. 46,79mmHG). Ferner wurde bei leichtgradigen Aortenklappeninsuffizienzen signifikant häufiger auf eine Vordilatation verzichtet (p=0,04). Eine Vordilatation kann also bei komplexeren anatomischen Verhältnissen sinnvoll sein, um einen optimalen Klappensitz zu gewährleisten.52,53 Nach TAVI zeigte sich die LV-EF in der Gruppe mit Prädilatation signifikant höher (p=0,002). Höhergradige Aortenklappeninsuffizienzen scheinen nicht durch eine Vordilatation begünstigt zu sein, die AI°II wurde nur bei 4 Patienten ohne Vordilatation beobachtet. In den postinterventionellen EKG-Daten zeigten sich in der Gruppe ohne Vordilatation signifikant häufiger Linksschenkelblöcke sowie ein AVB °II, Typ II, was vermutlich durch die fehlende Vorbereitung der Klappe und den damit assoziierten ungünstigeren Prothesensitz zu erklären ist.53 Die Nachdilatation wurde nicht durch eine vorausgegangene Vordilatation beeinflusst. Bezüglich der implantierten Klappenarten wurde die S3 Ultra signifikant häufiger bei Patienten ohne Vordilatation eingesetzt. Die in vielen Arbeiten beschriebene kürzere OP-Dauer ließ sich in dieser Studie nicht bestätigen.52,53,56 Stattdessen war bei TAVIs ohne Vordilatation die Eingriffsdauer im Schnitt 4min länger (p=0,11). Es bestätigte sich, dass bei einer Prädilatation signifikant mehr Kontrastmittel verwendet wurde (p=0,001) und die Strahlenbelastung höher war. Dies ist insbesondere für Patienten mit einer Niereninsuffizienz von Bedeutung.42 Ob eine Vordilatation durchgeführt wird, sollte also individuell aufgrund der Begleiterkrankungen und Risikofaktoren entschieden werden.
A growing body of literature reports on the upregulation of C-X-C motif chemokine receptor 4 (CXCR4) in a variety of cancer entities, rendering this receptor as suitable target for molecular imaging and endoradiotherapy in a theranostic setting. For instance, the CXCR4-targeting positron emission tomography (PET) agent [\(^{68}\)Ga]PentixaFor has been proven useful for a comprehensive assessment of the current status quo of solid tumors, including adrenocortical carcinoma or small-cell lung cancer. In addition, [\(^{68}\)Ga]PentixaFor has also provided an excellent readout for hematological malignancies, such as multiple myeloma, marginal zone lymphoma, or mantle cell lymphoma. PET-based quantification of the CXCR4 capacities in vivo allows for selecting candidates that would be suitable for treatment using the theranostic equivalent [\(^{177}\)Lu]/[\(^{90}\)Y]PentixaTher. This CXCR4-directed theranostic concept has been used as a conditioning regimen prior to hematopoietic stem cell transplantation and to achieve sufficient anti-lymphoma/-tumor activity in particular for malignant tissues that are highly sensitive to radiation, such as the hematological system. Increasing the safety margin, pretherapeutic dosimetry is routinely performed to determine the optimal activity to enhance therapeutic efficacy and to reduce off-target adverse events. The present review will provide an overview of current applications for CXCR4-directed molecular imaging and will introduce the CXCR4-targeted theranostic concept for advanced hematological malignancies.
Background: Large Cell Neuroendocrine Carcinoma (LCNEC) is a rare subtype of lung cancer with poor clinical outcomes. Data on recurrence-free survival (RFS) in early and locally advanced pure LCNEC after complete resection (R0) are lacking. This study aims to evaluate clinical outcomes in this subgroup of patients and to identify potential prognostic markers. Methods: Retrospective multicenter study including patients with pure LCNEC stage I-III and R0 resection. Clinicopathological characteristics, RFS, and disease-specific survival (DSS) were evaluated. Univariate and multivariate analyses were performed. Results: 39 patients (M:F = 26:13), with a median age of 64 years (44–83), were included. Lobectomy (69.2%), bilobectomy (5.1%), pneumonectomy (18%), and wedge resection (7.7%) were performed mostly associated with lymphadenectomy. Adjuvant therapy included platinum-based chemotherapy and/or radiotherapy in 58.9% of cases. After a median follow-up of 44 (4–169) months, the median RFS was 39 months with 1-, 2- and 5-year RFS rates of 60.0%, 54.6%, and 44.9%, respectively. Median DSS was 72 months with a 1-, 2- and 5-year rate of 86.8, 75.9, and 57.4%, respectively. At multivariate analysis, age (cut-off 65 years old) and pN status were independent prognostic factors for both RFS (HR = 4.19, 95%CI = 1.46–12.07, p = 0.008 and HR = 13.56, 95%CI 2.45–74.89, p = 0.003, respectively) and DSS (HR = 9.30, 95%CI 2.23–38.83, p = 0.002 and HR = 11.88, 95%CI 2.28–61.84, p = 0.003, respectively). Conclusion: After R0 resection of LCNEC, half of the patients recurred mostly within the first two years of follow-up. Age and lymph node metastasis could help to stratify patients for adjuvant therapy.
Das adrenokortikale Karzinom (ACC) ist eine seltene Tumorerkrankung der Nebennierenrinde. Die Prognose ist im Allgemeinen ungünstig und vom Tumorstadium sowie von weiteren tumor- und patientenspezifischen Faktoren abhängig. Die chirurgische Komplettresektion stellt das bisher einzige kurative Behandlungsverfahren dar.
Dabei gibt es bisher für sonstige Lokaltherapien beim fortgeschrittenen bzw. rezidivierten ACC kaum umfangreiche Daten, welche die entsprechende lokale Wirksamkeit belegen. Neben der Operation stellt die Strahlentherapie eine bisher effektive Therapieoption bei verschiedenen anderen Tumorerkrankungen hinsichtlich Tumorkontrolle, Verträglichkeit und Zugänglichkeit dar. Allerdings ist diese Option in der Behandlung des fortgeschrittenen ACC als Lokaltherapie bislang nicht mit zufriedenstellenden Datensätzen umfänglich untersucht.
Ziel dieser Studie war es, anhand einer retrospektiven Datenanalyse aus dem European Network for the Study of Adrenal Tumours (ENSAT) den Stellenwert der Strahlentherapie als Lokaltherapie beim fortgeschrittenen bzw. rezidivierten ACC zu untersuchen. Es wurden insgesamt 132 Fälle hinsichtlich strahlentherapeutischer Dosis, Lokalkontrolle, progressionsfreiem Überleben, Gesamtüberleben, objektivem Ansprechen, Verträglichkeit und Risikofaktoren untersucht.
Hierbei konnte gezeigt werden, dass die Anwendung einer hohen biologischen Effektivdosis mit einer verbesserten lokalen Tumorkontrolle einhergeht. Insgesamt zeigte sich eine gute Verträglichkeit der strahlentherapeutischen Behandlung. Die Ergebnisse dieser Arbeit legen nahe, dass wahrscheinlich weitere Risikofaktoren mit Rezidiven dieser Tumorart einhergehen, allerdings weitere Untersuchungen (z.B. randomisierte prospektive Studien) erfordern. Letztendlich stellt diese Arbeit auch die angewandten Dosis- und Fraktionierungskonzepte der vergangenen Jahrzente bei der Behandlung des ACC dar.
Neurofibromatosis type 1 (NF1) is a genetic multisystemic autosomal dominant disorder determining reduced life expectancy due to higher risk of developing benign and malignant tumors. Low levels of vitamin D and reduced bone mineral density (BMD) have been reported in young patients with NF1. However, correlation between vitamin D and NF1 phenotype needs to be elucidated. Aim of this study was to assess vitamin D levels and bone metabolism in NF1 patients, analyzing potential correlations with clinical phenotype. A cross-sectional study was carried out in a monocentric series of NF1 patients, evaluating genotype, clinical phenotype, BMD, biochemical evaluation with focus on serum 25OH-vitamin D, parathyroid hormone (PTH), calcium and phosphate levels. Correlations between clinical manifestations, neurofibromas, and vitamin D status have been studied in comparison with healthy controls. 31 NF1 adult patients were matched for sex, age and body mass index with 31 healthy controls. A significantly difference in vitamin D level emerged in NF1 patients compared to controls. Interestingly low vitamin D levels correlated with a more aggressive phenotype and with a bigger size of neurofibromas. These data underline that vitamin D deficiency/insufficiency may play a role in clinical severity of neurofibromas in patients with NF1, suggesting the need to check bone status and replace vitamin D in these patients.
Background
CXCR4-directed positron emission tomography/computed tomography (PET/CT) has been used as a diagnostic tool in patients with solid tumors. We aimed to determine a potential correlation between tumor burden and radiotracer accumulation in normal organs.
Methods
Ninety patients with histologically proven solid cancers underwent CXCR4-targeted [\(^{68}\)Ga]Ga-PentixaFor PET/CT. Volumes of interest (VOIs) were placed in normal organs (heart, liver, spleen, bone marrow, and kidneys) and tumor lesions. Mean standardized uptake values (SUV\(_{mean}\)) for normal organs were determined. For CXCR4-positive tumor burden, maximum SUV (SUV\(_{max}\)), tumor volume (TV), and fractional tumor activity (FTA, defined as SUV\(_{mean}\) x TV), were calculated. We used a Spearman's rank correlation coefficient (ρ) to derive correlative indices between normal organ uptake and tumor burden.
Results
Median SUV\(_{mean}\) in unaffected organs was 5.2 for the spleen (range, 2.44 – 10.55), 3.27 for the kidneys (range, 1.52 – 17.4), followed by bone marrow (1.76, range, 0.84 – 3.98), heart (1.66, range, 0.88 – 2.89), and liver (1.28, range, 0.73 – 2.45). No significant correlation between SUV\(_{max}\) in tumor lesions (ρ ≤ 0.189, P ≥ 0.07), TV (ρ ≥ -0.204, P ≥ 0.06) or FTA (ρ ≥ -0.142, P ≥ 0.18) with the investigated organs was found.
Conclusions
In patients with solid tumors imaged with [\(^{68}\)Ga]Ga-PentixaFor PET/CT, no relevant tumor sink effect was noted. This observation may be of relevance for therapies with radioactive and non-radioactive CXCR4-directed drugs, as with increasing tumor burden, the dose to normal organs may remain unchanged.
Background
International guidelines emphasise the role of radiotherapy (RT) for the management of advanced adrenocortical carcinoma (ACC). However, the evidence for this recommendation is very low.
Methods
We retrospectively analysed all patients who received RT for advanced ACC in five European centres since 2000. Primary endpoint: time to progression of the treated lesion (tTTP). Secondary endpoints: best objective response, progression-free survival (PFS), overall survival (OS), adverse events, and the establishment of predictive factors by Cox analyses.
Results
In total, 132 tumoural lesions of 80 patients were treated with conventional RT (cRT) of 50–60 Gy (n = 20) or 20–49 Gy (n = 69), stereotactic body RT of 35–50 Gy (SBRT) (n = 36), or brachytherapy of 12–25 Gy (BT) (n = 7). Best objective lesional response was complete (n = 6), partial (n = 52), stable disease (n = 60), progressive disease (n = 14). Median tTTP was 7.6 months (1.0–148.6). In comparison to cRT\(_{20-49Gy}\), tTTP was significantly longer for cRT\(_{50-60Gy}\) (multivariate adjusted HR 0.10; 95% CI 0.03–0.33; p < 0.001) and SBRT (HR 0.31; 95% CI 0.12–0.80; p = 0.016), but not for BT (HR 0.66; 95% CI 0.22–1.99; p = 0.46). Toxicity was generally mild and moderate with three grade 3 events. No convincing predictive factors could be established.
Conclusions
This largest published study on RT in advanced ACC provides clear evidence that RT is effective in ACC.
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.
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.
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.
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.
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.
Usability of a mHealth solution using speech recognition for point-of-care diagnostic management
(2023)
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.
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.
Background
Patients with coronary heart disease (CHD) with and without diabetes mellitus have an increased risk of recurrent events requiring multifactorial secondary prevention of cardiovascular risk factors. We compared prevalences of cardiovascular risk factors and its determinants including lifestyle, pharmacotherapy and diabetes mellitus among patients with chronic CHD examined within the fourth and fifth EUROASPIRE surveys (EA-IV, 2012–13; and EA-V, 2016–17) in Germany.
Methods
The EA initiative iteratively conducts European-wide multicenter surveys investigating the quality of secondary prevention in chronic CHD patients aged 18 to 79 years. The data collection in Germany was performed during a comprehensive baseline visit at study centers in Würzburg (EA-IV, EA-V), Halle (EA-V), and Tübingen (EA-V).
Results
384 EA-V participants (median age 69.0 years, 81.3% male) and 536 EA-IV participants (median age 68.7 years, 82.3% male) were examined. Comparing EA-IV and EA-V, no relevant differences in risk factor prevalence and lifestyle changes were observed with the exception of lower LDL cholesterol levels in EA-V. Prevalence of unrecognized diabetes was significantly lower in EA-V as compared to EA-IV (11.8% vs. 19.6%) while the proportion of prediabetes was similarly high in the remaining population (62.1% vs. 61.0%).
Conclusion
Between 2012 and 2017, a modest decrease in LDL cholesterol levels was observed, while no differences in blood pressure control and body weight were apparent in chronic CHD patients in Germany. Although the prevalence of unrecognized diabetes decreased in the later study period, the proportion of normoglycemic patients was low. As pharmacotherapy appeared fairly well implemented, stronger efforts towards lifestyle interventions, mental health programs and cardiac rehabilitation might help to improve risk factor profiles in chronic CHD patients.
Background
Remote monitoring of patients with New York Heart Association (NYHA) functional class III heart failure (HF) using daily transmission of pulmonary artery (PA) pressure values has shown a reduction in HF-related hospitalizations and improved quality of life in patients.
Objectives
PASSPORT-HF is a prospective, randomized, open, multicenter trial evaluating the effects of a hemodynamic-guided, HF nurse-led care approach using the CardioMEMS™ HF-System on clinical end points.
Methods and results
The PASSPORT-HF trial has been commissioned by the German Federal Joint Committee (G-BA) to ascertain the efficacy of PA pressure-guided remote care in the German health-care system. PASSPORT-HF includes adult HF patients in NYHA functional class III, who experienced an HF-related hospitalization within the last 12 months. Patients with reduced ejection fraction must be on stable guideline-directed pharmacotherapy. Patients will be randomized centrally 1:1 to implantation of a CardioMEMS™ sensor or control. All patients will receive post-discharge support facilitated by trained HF nurses providing structured telephone-based care. The trial will enroll 554 patients at about 50 study sites. The primary end point is a composite of the number of unplanned HF-related rehospitalizations or all-cause death after 12 months of follow-up, and all events will be adjudicated centrally. Secondary end points include device/system-related complications, components of the primary end point, days alive and out of hospital, disease-specific and generic health-related quality of life including their sub-scales, and laboratory parameters of organ damage and disease progression.
Conclusions
PASSPORT-HF will define the efficacy of implementing hemodynamic monitoring as a novel disease management tool in routine outpatient care.
Trial registration
ClinicalTrials.gov; NCT04398654, 13-MAY-2020.
Begleitend zu einer Herzinsuffizienz vorliegende Komorbiditäten haben sowohl auf den Krankheitsverlauf als auch auf die Behandlung und Prognose solcher Patienten einen entscheidenden Einfluss.
Ziel der vorliegenden Arbeit war es, Patienten mit Herzinsuffizienz mit erhaltener Pumpfunktion (HFpEF) anhand von elf begleitend zur Herzinsuffizienz vorliegenden Komorbiditäten einer von sechs Phänogruppen zuzuteilen und diese Phänogruppen prognostisch einzuschätzen. Dies wurde nach Vorlage der polytomen latenten Klassenanalyse (poLCA) von David Kao et al., veröffentlicht im Jahr 2015 im European Journal of Heart Failure, durchgeführt. Mithilfe einer poLCA können innerhalb einer Population Subgruppen mit ähnlichen Merkmalsausprägungen identifiziert werden. Die Patienten der vorliegenden Arbeit stammten aus dem Kollektiv des AHF (Acute-Heart-Failure-) Registers der Universitätsklinik Würzburg. Zusätzlich wurde mit denselben elf Variablen eine von der Vergleichspublikation unabhängige poLCA für die Patienten des AHF-Registers erstellt, sowie eine dritte poLCA, die zusätzlich die Höhe des NT-proBNP berücksichtigte.
Die Ergebnisse der Arbeit zeigten, dass die poLCA von Kao et al. durchaus auf andere Studienpopulationen übertragen werden kann, um Patienten mit HFpEF im klinischen Alltag mit wenig Aufwand prognostisch einschätzen zu können. Mehr statistisch signifikante Ergebnisse wurden allerdings bei Anwendung einer eigenen poLCA für das AHF-Register erzielt. Die Höhe des NT-proBNP hatte signifikanten Einfluss auf die Prognose und Klassenzuteilung eines Patienten.
Die Letalität des Myokardinfarktes ist in Deutschland rückläufig, die Bedeutung von Folgeerkrankungen des Myokardinfarktes nimmt daher zu. Durch pathologische Umbauprozesse (Remodeling) nach Myokardinfarkten kann die Mechanik des linken Ventrikels beeinträchtigt werden, sodass eine ischämische Kardiomyopathie entsteht. Im Rahmen dieser Arbeit wurde der Einfluss von Myokardinfarkten auf die Wandbewegungsgeschwindigkeit des linken Ventrikels mittels Tissue Phase Mapping untersucht. Tissue Phase Mapping ist eine MRT-basierte Untersuchungstechnik, welche die Wandbewegung des linken Ventrikels als Gewebegeschwindigkeit mit hoher zeitlicher und räumlicher Auflösung in drei Dimensionen quantifiziert. Bisher durchgeführte Tissue Phase Mapping-Studien bei Infarktpatienten werden in ihrer Aussagekraft durch eine veraltete Sequenztechnik und ein heterogenes Patientenkollektiv limitiert. In dieser Arbeit wurden daher selektiv Patienten mit stattgehabtem Vorderwandinfarkt mit einem bisher unveröffentlichten aktuellen Tissue Phase Mapping-Protokoll untersucht und mit einer Kontrollgruppe verglichen. Hierbei wurden statistisch signifikante pathologische Veränderungen der lokalen myokardialen Rotation und der diastolischen Expansion in radialer Richtung in postischämisch vernarbten Segmenten identifiziert. Aus anderen MRT-basierten Messmethoden (unter anderem Strain-Encoded Magnetic Resonance und Displacement Encoding With Stimulated Echos) ist bereits bekannt, dass die Rotationsbewegung in postischämisch vernarbten Segmenten pathologisch verändert ist. In dieser Arbeit wurde jedoch erstmals eine Reduktion und zum Teil eine Umkehr der lokalen myokardialen Rotation in vernarbten Segmenten mittels Tissue Phase Mapping nachgewiesen. Limitationen dieser Arbeit sind insbesondere die hohe Messzeit und die Anfälligkeit der Untersuchungstechnik für Bewegungsartefakte. Zudem konnten in anderen Studien Veränderungen der linksventrikulären Mechanik in vernarbten Segmenten mittels Strain-Parametern mit höherer Sensitivität erfasst werden. Nichtsdestotrotz könnten Weiterentwicklungen des Tissue Phase Mappings in Zukunft dazu beitragen, die linksventrikuläre Mechanik im Rahmen des Remodelings besser zu verstehen und die ischämische Kardiomyopathie früher zu diagnostizieren.
Hintergrund und Fragestellung
Die Entwöhnung von Beatmungsgeräten wird nicht immer auf der primär behandelnden Intensivstation abgeschlossen. Die Weiterverlegung in andere Behandlungseinrichtungen stellt einen sensiblen Abschnitt in der Behandlung und Rehabilitation des Weaningpatienten dar. Ziel der vorliegenden Studie war die Untersuchung des Überleitungsmanagements und des Interhospitaltransfers von Weaningpatienten unter besonderer Berücksichtigung der Dokumentationsqualität.
Methodik
Es erfolge eine retrospektive Datenanalyse eines Jahrs (2018) auf 2 Intensivstationen eines Universitätsklinikums. Eingeschlossen wurden alle beatmeten Patienten mit folgenden Tracerdiagnosen: COPD, Asthma, Polytrauma, Pneumonie, Sepsis, ARDS und Reanimation (Beatmung > 24 h).
Ergebnisse
Insgesamt konnten 750 Patienten in die Untersuchung eingeschlossen werden (Alter 64 [52, 8–76; Median, IQR]; 32 % weiblich). Davon waren 48 (6,4 %) Patienten zum Zeitpunkt der Verlegung nicht entwöhnt (v. a. Sepsis und ARDS). Die Routinedokumentation war bei den Abschnitten „Spontaneous Breathing Trial“, „Bewertung der Entwöhungsbereitschaft“ und „vermutete Entwöhnbarkeit“ ausreichend, um die Erfüllung der Parameter der S2k-Leitlinie „Prolongiertes Weaning“ adäquat zu beurteilen. Vorwiegend wurden diese Patienten mit Tracheostoma (76 %) in Rehabilitationskliniken (44 %) mittels spezialisierten Rettungsmitteln des arztbegleiteten Patiententransports verlegt (75 %).
Diskussion
Die Verlegung nicht entwöhnter Patienten nach initialem Intensivaufenthalt ist ein relevantes Thema für den Interhospitaltransfer. Die Routinedokumentation eines strukturierten Weaningprozesses ist in Kernelementen ausreichend, um den Weaningprozess lückenlos zu beschreiben. Dies ist für die Kontinuität in der Weiterbehandlung dieser Patienten von großer Bedeutung.
Background: Faster rates of cognitive decline are likely to result in earlier onset of cognitive impairment and dementia. d-galactose, a derivative of lactose, is used in animal studies to induce neurodegeneration. Milk is the primary source of lactose in the human diet, and its effects on cognitive decline have not been fully evaluated. Objective: Assess the association of milk intake with change in cognitive function over 20 years. Methods: A total of 13,751 participants of the Atherosclerosis Risk in Communities (ARIC) cohort completed a food frequency questionnaire and three neurocognitive evaluations from 1990 through 2013. Two single nucleotide polymorphisms (SNPs) were used to determine lactase persistence (LCT-13910 C/T for Whites and LCT-14010 G/C for Blacks). Mixed-effects models were used to study the association of milk intake with cognitive change. Multiple imputations by chained equations were used to account for attrition. Results: Milk intake greater than 1 glass/day was associated with greater decline in the global z-score over a 20-year period. The difference in decline was 0.10 (95% CI: 0.16, 0.03) z-scores, or an additional 10% decline, relative to the group reporting “almost never” consuming milk. Conclusions: Replication of these results is warranted in diverse populations with greater milk intake and higher variability of lactase persistence genotype.
Although bariatric surgery is known to change the metabolome, it is unclear if this is specific for the intervention or a consequence of the induced bodyweight loss. As the weight loss after Roux-en-Y Gastric Bypass (RYGB) can hardly be mimicked with an evenly effective diet in humans, translational research efforts might be helpful. A group of 188 plasma metabolites of 46 patients from the randomized controlled Würzburg Adipositas Study (WAS) and from RYGB-treated rats (n = 6) as well as body-weight-matched controls (n = 7) were measured using liquid chromatography tandem mass spectrometry. WAS participants were randomized into intensive lifestyle modification (LS, n = 24) or RYGB (OP, n = 22). In patients in the WAS cohort, only bariatric surgery achieved a sustained weight loss (BMI −34.3% (OP) vs. −1.2% (LS), p ≤ 0.01). An explicit shift in the metabolomic profile was found in 57 metabolites in the human cohort and in 62 metabolites in the rodent model. Significantly higher levels of sphingolipids and lecithins were detected in both surgical groups but not in the conservatively treated human and animal groups. RYGB leads to a characteristic metabolomic profile, which differs distinctly from that following non-surgical intervention. Analysis of the human and rat data revealed that RYGB induces specific changes in the metabolome independent of weight loss.
Ruxolitinib (RUX) is approved for the treatment of steroid-refractory acute and chronic graft versus host disease (GvHD). It is predominantly metabolized via cytochrome P450 (CYP) 3A4. As patients with GvHD have an increased risk of invasive fungal infections, RUX is frequently combined with posaconazole (POS), a strong CYP3A4 inhibitor. Knowledge of RUX exposure under concomitant POS treatment is scarce and recommendations on dose modifications are inconsistent. A physiologically based pharmacokinetic (PBPK) model was developed to investigate the drug–drug interaction (DDI) between POS and RUX. The predicted RUX exposure was compared to observed concentrations in patients with GvHD in the clinical routine. PBPK models for RUX and POS were independently set up using PK-Sim\(^®\) Version 11. Plasma concentration-time profiles were described successfully and all predicted area under the curve (AUC) values were within 2-fold of the observed values. The increase in RUX exposure was predicted with a DDI ratio of 1.21 (C\(_{max}\)) and 1.59 (AUC). Standard dosing in patients with GvHD led to higher RUX exposure than expected, suggesting further dose reduction if combined with POS. The developed model can serve as a starting point for further simulations of the implemented DDI and can be extended to further perpetrators of CYP-mediated PK-DDIs or disease-specific physiological changes.
Der Sechs-Minuten-Gehtest (6-MGT) stellt eine einfache Methode zur Abschätzung der funktionellen Kapazität bei Patienten mit Herz- und Lungenerkrankungen dar. Um das Ausmaß der Belastungseinschränkung von Patienten angemessen beurteilen zu können, benötigt man populationsspezifische Referenzwerte der Sechs-Minuten-Gehstrecke (6-MGSTR), welche bisher nur unzureichend vorliegen. Zudem müssen bei der Interpretation der 6-MGSTR von der jeweiligen Erkrankung unabhängige Einflussfaktoren berücksichtigt werden.
Ziele der vorliegenden Arbeit waren die Ermittlung klinischer, laborchemischer und echokardiographischer Einflussfaktoren auf die 6-MGSTR in der Normalbevölkerung, das Erstellen von in Deutschland anwendbaren Referenzperzentilen der 6-MGSTR an Gesunden und die Untersuchung des Zusammenhangs des selbstberichteten Gesundheitszustands bzw. der selbstberichteten körperlichen Leistungsfähigkeit erhoben anhand des SF-12 (Short Form 12) Fragebogens mit der objektiven körperlichen Leistungsfähigkeit gemessen anhand der 6-MGSTR in der Normalbevölkerung.
Die Ergebnisse der Arbeit zeigen deutliche Zusammenhänge der 6-MGSTR mit objektiven und subjektiven Merkmalen des Gesundheitszustands. Außerdem wurden alters- und größenspezifische Referenzperzentile der 6-MGSTR ermittelt. Es handelt sich hierbei um die ersten in Deutschland anwendbaren Referenzperzentile der 6-MGSTR an gesunden Erwachsenen.