Acute Effects of Single Versus Combined Inhaled β2-Agonists Salbutamol and Formoterol on Time Trial Performance, Lung Function, Metabolic and Endocrine Variables

Background High prevalence rates of β2-agonist use among athletes in competitive sports makes it tempting to speculate that illegitimate use of β2-agonists boosts performance. However, data regarding the potential performance-enhancing effects of inhaled β2-agonists and its underlying molecular basis are scarce. Methods In total, 24 competitive endurance athletes (12f/12m) participated in a clinical double-blinded balanced four-way block cross-over trial to investigate single versus combined effects of β2-agonists salbutamol (SAL) and formoterol (FOR), to evaluate the potential performance enhancement of SAL (1200 µg, Cyclocaps, Pb Pharma GmbH), FOR (36 µg, Sandoz, HEXAL AG) and SAL + FOR (1200 µg + 36 µg) compared to placebo (PLA, Gelatine capsules containing lactose monohydrate, Pharmacy of the University Hospital Ulm). Measurements included skeletal muscle gene and protein expression, endocrine regulation, urinary/serum β2-agonist concentrations, cardiac markers, cardiopulmonary and lung function testing and the 10-min time trial (TT) performance on a bicycle ergometer as outcome variables. Blood and urine samples were collected pre-, post-, 3 h post- and 24 h post-TT. Results Mean power output during TT was not different between study arms. Treatment effects regarding lung function (p < 0.001), echocardiographic (left ventricular end-systolic volume p = 0.037; endocardial global longitudinal strain p < 0.001) and metabolic variables (e.g. NR4A2 and ATF3 pathway) were observed without any influence on performance. In female athletes, total serum β2-agonist concentrations for SAL and FOR were higher. Microarray muscle gene analysis showed a treatment effect for target genes in energy metabolism with strongest effect by SAL + FOR (NR4A2; p = 0.001). Of endocrine variables, follicle-stimulating hormone (3 h Post–Post-TT), luteinizing hormone (3 h Post–Pre-TT) and insulin (Post–Pre-TT) concentrations showed a treatment effect (all p < 0.05). Conclusions No endurance performance-enhancing effect for SAL, FOR or SAL + FOR within the permitted dosages compared to PLA was found despite an acute effect on lung and cardiac function as well as endocrine and metabolic variables in healthy participants. The impact of combined β2-agonists on performance and sex-specific thresholds on the molecular and cardiac level and their potential long-term performance enhancing or health effects have still to be determined. Trial registration: Registered at Eudra CT with the number: 2015-005598-19 (09.12.2015) and DRKS with number DRKS00010574 (16.11.2021, retrospectively registered)

Factor VIII/protein C ratio independently predicts liver-related events but does not indicate a hypercoagulable state in ACLD

Background & Aims: It has been suggested that the ratio of procoagulant factor VIII to anticoagulant protein C (FVIII/PC) reflects the hemostatic equilibrium. Moreover, FVIII/PC predicted decompensation/death in a small study not accounting for portal hypertension severity. We investigated (i) the prognostic value of FVIII/PC (outcome-cohort) and (ii) whether FVIII/PC reflects the hypercoagulable state (assessed by thrombomodulin-modified thrombin generation assay [TM-TGA]) or the risk of bleeding/thrombotic events in patients undergoing hepatic venous pressure gradient (HVPG) measurement during follow-up. Methods: (i) The outcome-cohort comprised 576 patients with evidence of advanced chronic liver disease (liver stiffness measurement ≥10 kPa and/or HVPG ≥6 mmHg). (ii) TM-TGA-cohort patients (n = 142) were recruited from the prospective VIenna CIrrhosis Study (VICIS: NCT03267615). Results: (i) FVIII/PC significantly increased across clinical stages (p <0.001) as well as HVPG (p <0.001) and MELD score (p <0.001) strata and remained independently associated with decompensation/liver-related death (adjusted hazard ratio 1.06; 95% CI 1.01–1.11; p = 0.013), even after multivariable adjustment. It was also associated with acute-on-chronic liver failure (ACLF) development (adjusted hazard ratio 1.10; 95% CI 1.02-1.19; p = 0.015) in patients with decompensated cirrhosis. (ii) FVIII/PC showed a weak positive correlation with endogenous thrombin potential (Spearman's ρ = 0.255; p = 0.002), but this association disappeared after adjusting for the severity of liver disease. FVIII/PC was not associated with the development of bleeding (p = 0.272) or thrombotic events (p = 0.269). However, FVIII/PC correlated with biomarkers of different pathophysiological mechanisms that promote liver disease progression. Conclusion: FVIII/PC provides prognostic information regarding hepatic decompensation/death and ACLF, independently of established prognostic indicators. However, this is not evidence that hypercoagulability drives disease progression, as the correlation between FVIII/PC and thrombin generation is confounded by liver disease severity and FVIII/PC was not associated with thrombosis. Therefore, FVIII/PC does not reflect coagulation and results from previous studies on FVIII/PC require re-interpretation. Clinical trial number: NCT03267615 (in part). Lay summary: A balanced coagulation system is essential for preventing bleeding episodes and blood clot formation (thrombosis). Blood of patients with advanced liver disease may have increased coagulation potential, possibly promoting the worsening of liver disease via thrombosis in the blood vessels of the liver. The ratio between the results of 2 blood tests (procoagulant factor VIII to anticoagulant protein C) has been suggested to reflect these increases in coagulation potential. Our study demonstrates, on the one hand, that this ratio is a versatile predictor of the development of complications of cirrhosis, yet on the other hand, that it is unrelated to coagulation

Die „Verfransung" der Künste im Spannungsverhältnis zum Gesamtkunstwerk. Eine theoretische und exemplarische Untersuchung gattungsübergreifender Entwürfe vom 19. Jahrhundert bis heute aus musikwissenschaftlicher Perspektive

Ausgehend von Theodor W. Adornos, in den 1960er Jahren formulierten These der „Verfransung“ der Künste, untersucht die Arbeit Werke vom 19. Jahrhundert bis in die Gegenwart, die transmedial konzipiert sind und die Grenzen zwischen den klassischen Kunstdisziplinen Musik, bildender Kunst, Tanz und Theater, Literatur und Architektur zu überwinden versuchen. Im ersten, theoretischen Teil werden die zentralen Argumente Adornos aus dessen Aufsätzen „Die Kunst und die Künste“ (1967), „Über einige Relationen zwischen Musik und Malerei“ (1967) und „Voraussetzungen“ (1961) eingehend diskutiert. Der zweite Teil der Arbeit befasst sich mit verschiedenen historischen Konzepten des Gesamtkunstwerks: Nach einer Rekapitulation der zentralen ästhetischen Erwägungen Richard Wagners, denen Adorno geschichtsphilosophisch kritisch gegenübersteht, werden Theorien und Werke des 20. Jahrhunderts unter dem Aspekt der Transmedialität beleuchtet – von Arnold Schönberg, Wassily Kandinsky und Alexander Skrjabin über Versuche der historischen Avantgarden (Futurismus, Dada, Surrealismus) zu Joseph Beuys und dessen erweitertem Kunstbegriff. Einige Überlegungen zu Popmusik als Gesamtkunstwerk führen zum dritten Teil der Arbeit, der aus der Analyse von Oh Albert besteht, einem 2016 uraufgeführten Musiktheaters des Basler Künstlers Elia Rediger. Daran wird exemplarisch aufgezeigt, inwiefern die im zweiten Teil behandelten ästhetischen Strategien in der Gegenwart aktualisiert werden und Adornos Beobachtungen aus den 1960er Jahren bis heute relevant bleiben. In einem kurzen Ausblick werden Arbeiten und ästhetische Haltungen von Christoph Schlingensief und Jonathan Meese sowie Simon-Steen Andersen und Johannes Kreidler erörtert, bevor ein Fazit über das in vieler Hinsicht widersprüchliche Verhältnis zwischen Gesamtkunstwerk(en) und Adornos Verfransungsthese gezogen wird

Sex-Related Differences in Metastatic Melanoma Patients Treated with Immune Checkpoint Inhibition

Objectives: We aimed to investigate sex-related differences in patients with advanced melanoma treated with ICI by linking the assessment of inflammatory response in peripheral blood, onset of immune-related adverse events IRAEs during therapy and treatment response in short- and long-term. Methods: For the purpose of this single-center retrospective study metastatic melanoma patients treated with ICI were included. Baseline patient characteristics, blood sample tests and the onset of immune-related adverse events IRAEs were documented based on clinical records. The short-term treatment response was assessed with 18F-2-Fluor-2-desoxy-D-glucose Positron Emission Tomography/Computed Tomography FDG-PET/CT scans performed six months after initiation of ICI. The overall survival OS and progression-free survival PFS were used as endpoints to assess the long-term response to immunotherapy. Results: In total, 103 patients with advanced melanoma (mean age 68 &plusmn; 13.83 years) were included, 29 women (mean age 60.41 &plusmn; 14.57 years) and 74 men (mean age 65.66 &plusmn; 13.34 years). The primary tumor was located on a lower extremity in one out of three women and on the head/neck in one out of three men (p &lt; 0.001). While the superficial spreading (41%) and nodular (36%) melanoma subtypes represented together 77% of the cases in male population, women showed a more heterogenous distribution of melanoma subtypes with the superficial spreading (35%), nodular (23%), acral lentiginous (19%) and mucosal (12%) melanoma subtypes being most frequent in female population (p &lt; 0.001). Most differences between women and men with regards to inflammatory parameters were observed six months after initiation of ICI with a higher median NLR (p = 0.038), lower counts of lymphocytes (p = 0.004) and thrombocytes (p = 0.089) in addition to lower counts of erythrocytes (p &lt; 0.001) and monocytes (p &lt; 0.001) in women towards men. IRAEs were more frequent in women towards men (p = 0.013). Women were more likely to display endocrinological IRAEs, such as thyroiditis being the most frequent adverse event in women. Interestingly IRAEs of the gastrointestinal tract were the most frequent ones in men. Finally, men with advanced melanoma showed a significantly better response to immunotherapy in short- (p = 0.015) and long-term (OS p = 0.015 and PFS p &lt; 0.001) than women. In fact, every fourth man died during the course of the disease, while every second woman did not survive. (p = 0.001). Conclusion: Men with advanced melanoma showed a significantly better response to immunotherapy in short- and long-term than women. Higher immune activation in peripheral blood before and after initiation ICI might be linked to favorable treatment response during and after ICI in favor of men and decoupled from the onset of IRAEs. Given the significantly higher immunotoxicity and worse outcome experienced by women compared to men the use of ICI should be chosen carefully in women with advanced melanoma

Inflammatory Blood Parameters as Biomarkers for Response to Immune Checkpoint Inhibition in Metastatic Melanoma Patients

Objectives: We aimed to investigate whether inflammatory parameters in peripheral blood at baseline and during the first six months of treatment could predict the short- and long-term outcomes of metastatic melanoma patients treated with immune checkpoint inhibitors (ICIs). Methods: This single-center retrospective study considered patients with metastatic melanoma treated with either single or dual checkpoint inhibition. Blood sample tests were scheduled together with 18F-2-fluor-2-desoxy-D-glucose positron emission tomography/computed tomography (FDG-PET/CT) scans at baseline and at three and six months after initiation of ICI treatment. The short-term response to ICIs was assessed using FDG-PET/CT scans. The long-term response to ICIs was assessed using the overall survival OS and progression-free survival PFS as endpoints. Results: A total of 100 patients with metastatic melanoma were included (female, n = 31; male, n = 69). The median age was 68 years (interquartile range (IQR): 53–74 years). A total of 82% of the cohort displayed a disease control (DC), while 18% presented a progressive disease (PD) after six months of ICIs. Patients with DC after six months of ICIs showed a lower median of the neutrophils-to-lymphocytes ratio (NLR) toward patients with PD, with no significant prediction power of NLR neither in the short nor in the long term. The count of neutrophils at the baseline time point (TP 0) (p = 0.037) and erythrocytes three months after treatment start (TP 1) (p = 0.010) were strong predictive parameters of a DC six months after treatment start. Erythrocytes (p p = 0.021) were strong biomarkers predictive of a favorable OS. Erythrocytes (p = 0.013) and lymphocytes (p = 0.017) also showed a significant prediction power for a favorable PFS. Conclusions: Inflammatory blood parameters predicted the short- and long-term response to ICIs with a strong predictive power. Our results suggested the validation of inflammatory blood parameters as biomarkers that predict immunotherapies’ efficacity in metastatic melanoma patients. However, confounding factors that interfere with myelopoiesis should also be taken into consideration

Concept and performance evaluation of a novel UAV-borne topo-bathymetric LiDAR sensor

We present the sensor concept and first performance and accuracy assessment results of a novel lightweight topo-bathymetric laser scanner designed for integration on Unmanned Aerial Vehicles (UAVs), light aircraft, and helicopters. The instrument is particularly well suited for capturing river bathymetry in high spatial resolution as a consequence of (i) the low nominal flying altitude of 50-150 m above ground level resulting in a laser footprint diameter on the ground of typically 10-30 cm and (ii) the high pulse repetition rate of up to 200 kHz yielding a point density on the ground of approximately 20-50 points/m2. The instrument features online waveform processing and additionally stores the full waveform within the entire range gate for waveform analysis in post-processing. The sensor was tested in a real-world environment by acquiring data from two freshwater ponds and a 500 m section of the pre-Alpine Pielach River (Lower Austria). The captured underwater points featured a maximum penetration of two times the Secchi depth. On dry land, the 3D point clouds exhibited (i) a measurement noise in the range of 1-3 mm; (ii) a fitting precision of redundantly captured flight strips of 1 cm; and (iii) an absolute accuracy of 2-3 cm compared to terrestrially surveyed checkerboard targets. A comparison of the refraction corrected LiDAR point cloud with independent underwater checkpoints exhibited a maximum deviation of 7.8 cm and revealed a systematic depth-dependent error when using a refraction coefficient of n = 1.36 for time-of-flight correction. The bias is attributed to multi-path effects in the turbid water column (Secchi depth: 1.1 m) caused by forward scattering of the laser signal at suspended particles. Due to the high spatial resolution, good depth performance, and accuracy, the sensor shows a high potential for applications in hydrology, fluvial morphology, and hydraulic engineering, including flood simulation, sediment transport modeling, and habitat mapping.Deutsche ForschungsgemeinschaftAustrian Research Funding Agenc

Integration of historical glacier images into the Euro-Climhist database

Glaciers are excellent climate indicators, and the worldwide glacier retreat serves as a warning signal for the current climate change with its dramatic effects on humans and the environment. Visualizing glacier change by means of images can reach a broad public. Historical glacier images, especially from the so-called Little Ice Age (LIA, approx. AD 1300 to 1850 in the European Alps), show the earlier glacier fluctuations in a particularly impressive way and give us a unique insight into the climatic events of that time. These findings are in turn the key to understand current and possible future climate changes. The long-term research project "Euro-Climhist" is one of the first projects of its kind worldwide to extract historical documentary data on climate and weather from a wide variety of source types, evaluate the data accordingly, and make it generally accessible in an online database (https://www.euroclimhist.unibe.ch). Until now, the Euro-Climhist database consisted mainly of written sources and measurement data. Within this project, the Euro-Climhist database was conceptually extended to include and secure glacier images in the long term, and to make them accessible to researchers and to the public. Around 500 glacier images were specially prepared for the database and provided with the corresponding metadata, i.e., the name of the artist, the original descriptions as well as supplementary descriptions from the literature, the dating of the images, and the image type. In particular, the assignment to one of five image types - drawing, oil painting, print, photograph, or map - allows conclusions to be drawn about the accuracy of the glacier extents depicted. Besides written evidence, historical pictorial representations of glaciers allow us to reconstruct glacier extents in the Alps from the early 17th century onwards. Satisfactory quantities of historical material are only available for those glaciers that achieved the necessary degree of fame early on to attract travellers, scientists, and artists. Pictorial representations in painting and graphic arts date back to the early 17th century, but only appear in large numbers with the emerging popularity of Alpine travel during the 18th century. Photographs are available from the end of the 1840s

Detection and Quantification of Benzothiazoles in Exhaled Breath and Exhaled Breath Condensate by Real-Time Secondary Electrospray Ionization–High-Resolution Mass Spectrometry and Ultra-High Performance Liquid Chromatography

2-Subtituted benzothiazoles are widely used industrial chemicals whose occurrence in environmental samples has been shown to be ubiquitous. However, knowledge about human exposure to these compounds and their excretion route is still scarce. Here, we demonstrate for the first time the detection of benzothiazole derivatives in exhaled breath. Real-time analysis of breath was carried out by means of secondary electrospray ionization coupled to high-resolution mass spectrometry. This coupling allowed not only the detection of these compounds in breath with a sensitivity in the pptv range but also their robust identification by comparing tandem high-resolution mass spectra from breath and standards. For further confirmation, benzothiazoles were also determined in exhaled breath condensate samples by means of ultra high-performance liquid chromatography. This approach strengthened the identification as a result of excellent matches in retention times and also allowed quantification. An estimated total daily exhalation of ca. 20 μg day^–1 was calculated for the six benzothiazole derivatives found in breath

Metabolic effects of inhaled salbutamol determined by exhaled breath analysis

We explore whether real-time breath analysis by high resolution mass spectrometry is suitable to monitor changes at the metabolic level due to inhaling bronchodilator medication. We compared the breath levels of metabolites in a group of patients (n = 50) at baseline and 10 and 30 min after inhalation of 200 μg salbutamol. The same procedure was performed with a group of controls (n = 48) inhaling a placebo spray. A total of 131 mass spectral features were significantly altered as a result of inhaling medication, but not after inhaling placebo. We found that homologous series of chemical classes correlated strongly with each other, strengthening the notion that certain biochemical processes can be monitored. For example, a series of fatty acids was found to be increased after salbutamol intake, suggesting lipolysis stimulation. Peaks corresponding to salbutamol, its main metabolite salbutamol-4-O-sulfate and formoterol were found to be generally increased in patients inhaling the drugs on an as-needed basis, as compared to non-medicated volunteers. Overall, these results suggest such real-time breath analysis is a useful tool for non-invasive therapeutic drug monitoring

Detection and Quantification of Benzothiazoles in Exhaled Breath and Exhaled Breath Condensate by Real-Time Secondary Electrospray Ionization-High-Resolution Mass Spectrometry and Ultra-High Performance Liquid Chromatography

ISSN:0013-936XISSN:1520-585