495 results on '"Schmidt, Wolfgang"'
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2. Sex-specific cardiovascular remodeling leads to a divergent sex-dependent development of heart failure in aged hypertensive rats
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Kovács, Árpád, Zhazykbayeva, Saltanat, Herwig, Melissa, Fülöp, Gábor Á., Csípő, Tamás, Oláh, Nikolett, Hassoun, Roua, Budde, Heidi, Osman, Hersh, Kaçmaz, Mustafa, Jaquet, Kornelia, Priksz, Dániel, Juhász, Béla, Akin, Ibrahim, Papp, Zoltán, Schmidt, Wolfgang E., Mügge, Andreas, El-Battrawy, Ibrahim, Tóth, Attila, and Hamdani, Nazha
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Introduction: The prevalence of heart failure with preserved ejection fraction (HFpEF) is continuously rising and predominantly affects older women often hypertensive and/or obese or diabetic. Indeed, there is evidence on sex differences in the development of HF. Hence, we studied cardiovascular performance dependent on sex and age as well as pathomechanisms on a cellular and molecular level. Methods: We studied 15-week- and 1-year-old female and male hypertensive transgenic rats carrying the mouse Ren-2 renin gene (TG) and compared them to wild-type (WT) controls at the same age. We tracked blood pressure and cardiac function via echocardiography. After sacrificing the 1-year survivors we studied vascular smooth muscle and endothelial function. Isolated single skinned cardiomyocytes were used to determine passive stiffness and Ca
2+ -dependent force. In addition, Western blots were applied to analyse the phosphorylation status of sarcomeric regulatory proteins, titin and of protein kinases AMPK, PKG, CaMKII as well as their expression. Protein kinase activity assays were used to measure activities of CaMKII, PKG and angiotensin-converting enzyme (ACE). Results: TG male rats showed significantly higher mortality at 1 year than females or WT male rats. Left ventricular (LV) ejection fraction was specifically reduced in male, but not in female TG rats, while LV diastolic dysfunction was evident in both TG sexes, but LV hypertrophy, increased LV ACE activity, and reduced AMPK activity as evident from AMPK hypophosphorylation were specific to male rats. Sex differences were also observed in vascular and cardiomyocyte function showing different response to acetylcholine and Ca2+ -sensitivity of force production, respectively cardiomyocyte functional changes were associated with altered phosphorylation states of cardiac myosin binding protein C and cardiac troponin I phosphorylation in TG males only. Cardiomyocyte passive stiffness was increased in TG animals. On a molecular level titin phosphorylation pattern was altered, though alterations were sex-specific. Thus, also the reduction of PKG expression and activity was more pronounced in TG females. However, cardiomyocyte passive stiffness was restored by PKG and CaMKII treatments in both TG sexes. Conclusion: Here we demonstrated divergent sex-specific cardiovascular adaptation to the over-activation of the renin-angiotensin system in the rat. Higher mortality of male TG rats in contrast to female TG rats was observed as well as reduced LV systolic function, whereas females mainly developed HFpEF. Though both sexes developed increased myocardial stiffness to which an impaired titin function contributes to a sex-specific molecular mechanism. The functional derangements of titin are due to a sex-specific divergent regulation of PKG and CaMKII systems.- Published
- 2024
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3. Geometric domain adaptation for CBCT segmentation
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Chen, Weijie, Astley, Susan M., Querfurth, Anne, Rohleder, Maximilian, Maier, Andreas, Hohenforst Schmidt, Wolfgang, and Kunze, Holger
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- 2024
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4. The Novel OMERACT Ultrasound Scoring System for Salivary Gland Changes in Patients With Sjögren Syndrome Is Associated With MRI and Salivary Flow Rates.
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Inanc, Nevsun, Jousse-Joulin, Sandrine, Abacar, Kerem, Cimşit, Çagatay, Cimşit, Canan, D'Agostino, Maria-Antonietta, Naredo, Esperanza, Hocevar, Alojzija, Finzel, Stephanie, Pineda, Carlos, Keen, Helen, Iagnocco, Annamaria, Hanova, Petra, Schmidt, Wolfgang A., Mumcu, Gonca, Terslev, Lene, and Bruyn, George A.
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- 2024
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5. Giant magnetocaloric effect in spin supersolid candidate Na2BaCo(PO4)2
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Xiang, Junsen, Zhang, Chuandi, Gao, Yuan, Schmidt, Wolfgang, Schmalzl, Karin, Wang, Chin-Wei, Li, Bo, Xi, Ning, Liu, Xin-Yang, Jin, Hai, Li, Gang, Shen, Jun, Chen, Ziyu, Qi, Yang, Wan, Yuan, Jin, Wentao, Li, Wei, Sun, Peijie, and Su, Gang
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Supersolid, an exotic quantum state of matter that consists of particles forming an incompressible solid structure while simultaneously showing superfluidity of zero viscosity1, is one of the long-standing pursuits in fundamental research2,3. Although the initial report of 4He supersolid turned out to be an artefact4, this intriguing quantum matter has inspired enthusiastic investigations into ultracold quantum gases5–8. Nevertheless, the realization of supersolidity in condensed matter remains elusive. Here we find evidence for a quantum magnetic analogue of supersolid—the spin supersolid—in the recently synthesized triangular-lattice antiferromagnet Na2BaCo(PO4)2(ref. 9). Notably, a giant magnetocaloric effect related to the spin supersolidity is observed in the demagnetization cooling process, manifesting itself as two prominent valley-like regimes, with the lowest temperature attaining below 100 mK. Not only is there an experimentally determined series of critical fields but the demagnetization cooling profile also shows excellent agreement with the theoretical simulations with an easy-axis Heisenberg model. Neutron diffractions also successfully locate the proposed spin supersolid phases by revealing the coexistence of three-sublattice spin solid order and interlayer incommensurability indicative of the spin superfluidity. Thus, our results reveal a strong entropic effect of the spin supersolid phase in a frustrated quantum magnet and open up a viable and promising avenue for applications in sub-kelvin refrigeration, especially in the context of persistent concerns about helium shortages10,11.
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- 2024
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6. The Novel OMERACT Ultrasound Scoring System for Salivary Gland Changes in Patients With Sjo¨gren Syndrome Is Associated With MRI and Salivary Flow Rates
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Inanc, Nevsun, Jousse-Joulin, Sandrine, Abacar, Kerem, Cimsit, Cagatay, Cimsit, Canan, D’Agostino, Maria-Antonietta, Naredo, Esperanza, Hocevar, Alojzija, Finzel, Stephanie, Pineda, Carlos, Keen, Helen, Iagnocco, Annamaria, Hanova, Petra, Schmidt, Wolfgang A., Mumcu, Gonca, Terslev, Lene, and Bruyn, George A.
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ObjectiveTo assess the construct validity of the novel Outcome Measures in Rheumatology (OMERACT) ultrasound (US) semiquantitative scoring system for morphological lesions in major salivary glands by comparing it with magnetic resonance imaging (MRI) and unstimulated whole salivary flow rates (U-WSFRs) in patients with primary Sjo¨gren syndrome (pSS).MethodsNine sonographers applied the OMERACT 0-3 grayscale scoring system for parotid (PGs) and submandibular glands (SMGs) in 11 patients with pSS who also had MRIs performed. These were evaluated by 2 radiologists using a semiquantitative 0-3 scoring system for morphological lesions. The agreement between US and MRI and the association between U-WSFRs and imaging structural lesions was determined. A score ≥ 2 for both US and MRI was defined as gland pathology.ResultsThe prevalence of US morphological lesions in 11 patients with a score ≥ 2 was 58% for PGs and 76% for SMGs, and 46% and 41% for PGs and SMGs, respectively, for MRI. The agreement between OMERACT US scores and MRI scores was 73-91% (median 82%) in the right PG and 73-91% (median 91%) in the left PG, 55-91% (median 55%) in the right SMG and 55-82% (median 55%) in the left SMG. When relations between the presence of hyposalivation and an US score ≥ 2 were examined, agreement was 91-100% (median 83%) in both PGs and 55-91% (median 67%) in both SMGs.ConclusionThere is moderate to strong agreement between the OMERACT US and MRI scores for major salivary glands in patients with pSS. Similar agreement ratios were observed between the higher OMERACT US scores and presence of hyposalivation.
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- 2024
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7. Architects, Urban Planners and Further Development of the 3D City Model Kassel
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Meise, Christoph, Schmidt, Wolfgang, and Rus, Sandra
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In the last years, 3D city models have become an important topic in the Geoinformation Departments of many German cities. The city of Kassel began building such a database more than 10 years ago. The most important application area of the now quite extensive database is the support of urban development processes as well as a visually sustainable improvement in the preparation and integration of construction projects. Kassel relies on the three platforms “Desktop Scene” (exe-files), Online-Viewer and the output of analogue Haptic Models.
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- 2024
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8. The Mechanism and Pathway of Selective Partial Oxidation of n‑Butane to Maleic Anhydride Studied on Titanium Phosphate Catalysts.
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Stegmann, Niklas, Ochoa-Hernández, Cristina, Truong, Khai-Nghi, Petersen, Hilke, Weidenthaler, Claudia, and Schmidt, Wolfgang
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- 2023
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9. Superfast Synthesis of Carbon Xerogels.
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Bilican, Abdurrahman, Sharma, Priyanka, Tran, Nguyen Khang, Weidenthaler, Claudia, and Schmidt, Wolfgang
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- 2023
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10. IRON MAN is a jack of all trades
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Vélez-Bermúdez, Isabel Cristina and Schmidt, Wolfgang
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The functions of a small family of non-secreted peptides, originally identified as critical communicators of the plant’s iron status, have expanded. The involvement of these effectors in disparate signalling cascades underlines the pivotal role peptides have in responses to the environment.
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- 2024
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11. Episignature analysis of moderate effects and mosaics
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Oexle, Konrad, Zech, Michael, Stühn, Lara G., Siegert, Sandy, Brunet, Theresa, Schmidt, Wolfgang M., Wagner, Matias, Schmidt, Axel, Engels, Hartmut, Tilch, Erik, Monestier, Olivier, Destrėe, Anne, Hanker, Britta, Boesch, Sylvia, Jech, Robert, Berutti, Riccardo, Kaiser, Frank, Haslinger, Bernhard, Haack, Tobias B., Garavaglia, Barbara, Krawitz, Peter, Winkelmann, Juliane, and Mirza-Schreiber, Nazanin
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DNA methylation classifiers (“episignatures”) help to determine the pathogenicity of variants of uncertain significance (VUS). However, their sensitivity is limited due to their training on unambiguous cases with strong-effect variants so that the classification of variants with reduced effect size or in mosaic state may fail. Moreover, episignature evaluation of mosaics as a function of their degree of mosaicism has not been developed so far. We improved episignatures with respect to three categories. Applying (i) minimum-redundancy-maximum-relevance feature selection we reduced their length by up to one order of magnitude without loss of accuracy. Performing (ii) repeated re-training of a support vector machine classifier by step-wise inclusion of cases in the training set that reached probability scores larger than 0.5, we increased the sensitivity of the episignature-classifiers by 30%. In the newly diagnosed patients we confirmed the association between DNA methylation aberration and age at onset of KMT2B-deficient dystonia. Moreover, we found evidence for allelic series, including KMT2B-variants with moderate effects and comparatively mild phenotypes such as late-onset focal dystonia. Retrained classifiers also can detect mosaics that previously remained below the 0.5-threshold, as we showed for KMT2D-associated Kabuki syndrome. Conversely, episignature-classifiers are able to revoke erroneous exome calls of mosaicism, as we demonstrated by (iii) comparing presumed mosaic cases with a distribution of artificial in silico-mosaics that represented all the possible variation in degree of mosaicism, variant read sampling and methylation analysis.
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- 2023
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12. Light Olefins from Acetylene under Pressurized Conditions.
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Agbaba, Özgül, Trotuş, Ioan-Teodor, Schmidt, Wolfgang, and Schüth, Ferdi
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- 2023
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13. Growth and Oxygen Stoichiometry Control of High-Quality La2CoO4+δ Single Crystals (δ = 0.25).
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De Barros, Ruben, Ceretti, Monica, Schmidt, Wolfgang, Pomjakushin, Vladimir Y., and Paulus, Werner
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- 2022
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14. Discovery of Clinical Candidate CHF-6366: A Novel Super-soft Dual Pharmacology Muscarinic Antagonist and β2 Agonist (MABA) for the Inhaled Treatment of Respiratory Diseases.
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Carzaniga, Laura, Linney, Ian D., Rizzi, Andrea, Delcanale, Maurizio, Schmidt, Wolfgang, Knight, Christopher K., Pastore, Fiorella, Miglietta, Daniela, Carnini, Chiara, Cesari, Nicola, Riccardi, Benedetta, Mileo, Valentina, Venturi, Luca, Moretti, Elisa, Blackaby, Wesley P., Patacchini, Riccardo, Accetta, Alessandro, Biagetti, Matteo, Bassani, Franco, and Tondelli, Marina
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- 2022
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15. Genomically Hardwired Regulation of Gene Activity Orchestrates Cellular Iron Homeostasis in Arabidopsis
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Hsieh, En-Jung, Lin, Wen-Dar, and Schmidt, Wolfgang
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ABSTRACTIron (Fe) is an essential micronutrient which plays pivotal roles as electron donor and catalyst across organisms. In plants, variable, often insufficient Fe supply necessitates mechanisms that constantly attune Fe uptake rates and recalibrate cellular Fe homoeostasis. Here, we show that short-term (0.5, 6, and 12 h) exposure of Arabidopsis thalianaplants to Fe deficiency triggered massive changes in gene activity governed by transcription and alternative splicing (AS), regulatory layers that were to a large extent mutually exclusive. Such preclusion was not observed for genes that are directly involved in the acquisition of Fe, which appears to be concordantly regulated by both expression and AS. Generally, genes with lower splice site strengths and higher intron numbers were more likely to be regulated by AS, no dependence on gene architecture was observed for transcriptionally controlled genes. Conspicuously, specific processes were associated with particular genomic features and biased towards either regulatory mode, suggesting that genomic hardwiring is functionally biased. Early changes in splicing patterns were, in many cases, congruent with later changes in transcript or protein abundance, thus contributing to the pronounced transcriptome-proteome discordance observed in plants.
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- 2022
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16. More losses than gains during one century of plant biodiversity change in Germany
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Jandt, Ute, Bruelheide, Helge, Jansen, Florian, Bonn, Aletta, Grescho, Volker, Klenke, Reinhard A., Sabatini, Francesco Maria, Bernhardt-Römermann, Markus, Blüml, Volker, Dengler, Jürgen, Diekmann, Martin, Doerfler, Inken, Döring, Ute, Dullinger, Stefan, Haider, Sylvia, Heinken, Thilo, Horchler, Peter, Kuhn, Gisbert, Lindner, Martin, Metze, Katrin, Müller, Norbert, Naaf, Tobias, Peppler-Lisbach, Cord, Poschlod, Peter, Roscher, Christiane, Rosenthal, Gert, Rumpf, Sabine B., Schmidt, Wolfgang, Schrautzer, Joachim, Schwabe, Angelika, Schwartze, Peter, Sperle, Thomas, Stanik, Nils, Storm, Christian, Voigt, Winfried, Wegener, Uwe, Wesche, Karsten, Wittig, Burghard, and Wulf, Monika
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Long-term analyses of biodiversity data highlight a ‘biodiversity conservation paradox’: biological communities show substantial species turnover over the past century1,2, but changes in species richness are marginal1,3–5. Most studies, however, have focused only on the incidence of species, and have not considered changes in local abundance. Here we asked whether analysing changes in the cover of plant species could reveal previously unrecognized patterns of biodiversity change and provide insights into the underlying mechanisms. We compiled and analysed a dataset of 7,738 permanent and semi-permanent vegetation plots from Germany that were surveyed between 2 and 54 times from 1927 to 2020, in total comprising 1,794 species of vascular plants. We found that decrements in cover, averaged across all species and plots, occurred more often than increments; that the number of species that decreased in cover was higher than the number of species that increased; and that decrements were more equally distributed among losers than were gains among winners. Null model simulations confirmed that these trends do not emerge by chance, but are the consequence of species-specific negative effects of environmental changes. In the long run, these trends might result in substantial losses of species at both local and regional scales. Summarizing the changes by decade shows that the inequality in the mean change in species cover of losers and winners diverged as early as the 1960s. We conclude that changes in species cover in communities represent an important but understudied dimension of biodiversity change that should more routinely be considered in time-series analyses.
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- 2022
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17. Standardized 18F-FDG PET/CT radiomic features provide information on PD-L1 expression status in treatment-naïve patients with non-small cell lung cancer
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Zhang, Ruiyun, Hohenforst-Schmidt, Wolfgang, Steppert, Claus, Sziklavari, Zsolt, Schmidkonz, Christian, Atzinger, Armin, Kuwert, Torsten, Klink, Thorsten, Sterlacci, William, Hartmann, Arndt, Vieth, Michael, and Förster, Stefan
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- 2022
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18. Chemical Affinity of Ag-Exchanged Zeolites for Efficient Hydrogen Isotope Separation.
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Zhang, Linda, Wulf, Toshiki, Baum, Florian, Schmidt, Wolfgang, Heine, Thomas, and Hirscher, Michael
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- 2022
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19. Nitrogen doping in carbon xerogels via ammonia pyrolysis: A case study
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Sharma, Priyanka, Bilican, Abdurrahman, Schmidt, Wolfgang, Ochoa-Hernández, Cristina, Etter, Martin, and Weidenthaler, Claudia
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Nitrogen-doped carbon xerogels (CXNs) were carbonized across a range of temperatures (400 °C–800 °C) using sol-gel derived resorcinol-formaldehyde xerogel to elucidate their structural evolution during carbonization in ammonia. The investigation extensively probed chemical and structural changes in CXNs at varying carbonization temperatures, employing analytical methods such as X-ray photoelectron spectroscopy, infrared spectroscopy, and energy-dispersive X-ray spectroscopy. These findings were thoroughly compared with the local structure derived from total X-ray scattering and Raman spectroscopy. The results showed a transformation in the local ordering and chemical structure of CXNs, characterized by a reduction in oxidation sites, expansion of C sp2network structures, leading to the growth of aromatic domains, and the incorporation of nitrogen into the carbon backbone structure. Pyrolysis in ammonia notably influenced the textural structure, resulting in a partial loss of mesopores and an increased micropore volume.
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- 2024
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20. Crystal Structures of Two Titanium Phosphate-Based Proton Conductors: Ab Initio Structure Solution and Materials Properties.
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Petersen, Hilke, Stegmann, Niklas, Fischer, Michael, Zibrowius, Bodo, Radev, Ivan, Philippi, Wladimir, Schmidt, Wolfgang, and Weidenthaler, Claudia
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- 2022
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21. Contrast-Enhanced Ultrasound for Monitoring Takayasu Arteritis.
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Schmidt, Wolfgang Andreas
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- 2022
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22. From 1D to 3D Graphitic Carbon Nitride (Melon): A Bottom-Up Route via Crystalline Microporous Templates.
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Stegmann, Niklas, Dai, Yitao, Nürenberg, Edward, and Schmidt, Wolfgang
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- 2021
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23. OMERACT definition and reliability assessment of chronic ultrasound lesions of the axillary artery in giant cell arteritis.
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Schäfer, Valentin Sebastian, Chrysidis, Stavros, Schmidt, Wolfgang A., Duftner, Christina, Iagnocco, Annamaria, Bruyn, George A., Carrara, Greta, De Miguel, Eugenio, Diamantopoulos, Andreas P., Nielsen, Berit Dalsgaard, Fredberg, Ulrich, Hartung, Wolfgang, Hanova, Petra, Hansen, Ib Tønder, Hocevar, Alojzija, Juche, Aaron, Kermani, Tanaz A., Lorenzen, Tove, Macchioni, Pierluigi, and Milchert, Marcin
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To define chronic ultrasound lesions of the axillary artery (AA) in long-standing giant cell arteritis (GCA) and to evaluate the reliability of the new ultrasound definition in a web-based exercise. A structured Delphi, involving an expert panel of the Large Vessel Vasculitis subgroup of the Outcome Measures in Rheumatology (OMERACT) Ultrasound Working Group was carried out. The reliability of the new definition was tested in a 2-round web-based exercise involving 23 experts and using 50 still images each from AA of long-standing and acute GCA patients, as well as 50 images from healthy individuals. The final OMERACT ultrasound definition of chronic changes was based on measurement and appearance of the intima-media complex. The overall reliability of the new definition for chronic ultrasound changes in longstanding GCA of the AA was good to excellent with Light's kappa values of 0.79-0.80 for inter-reader reliability and mean Light's-kappa of 0.88 for intra-reader reliability. The mean inter-rater and intra-rater agreements were 86-87% and 92%, respectively. Good reliabilities were observed comparing the vessels with longstanding versus acute GCA with a mean agreement and kappa values of 81% and 0.63, respectively. The new OMERACT ultrasound definition for chronic vasculitis of the AA in GCA revealed a good to excellent inter- and intra-reader reliability in a web-based exercise of experts. [ABSTRACT FROM AUTHOR]
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- 2021
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24. Diagnosing vasculitis with ultrasound: findings and pitfalls
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Schmidt, Wolfgang A. and Schäfer, Valentin S.
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Rheumatologists are increasingly utilizing ultrasound for suspected giant cell arteritis (GCA) or Takayasu arteritis (TAK). This enables direct confirmation of a suspected diagnosis within the examination room without further referrals. Rheumatologists can ask additional questions and explain findings to their patients while performing ultrasound, preferably in fast-track clinics to prevent vision loss. Vascular ultrasound for suspected vasculitis was recently integrated into rheumatology training in Germany. New European Alliance of Associations for Rheumatology recommendations prioritize ultrasound as the first imaging tool for suspected GCA and recommend it as an imaging option for suspected TAK alongside magnetic resonance imaging, positron emission tomography and computed tomography. Ultrasound is integral to the new classification criteria for GCA and TAK. Diagnosis is based on consistent clinical and ultrasound findings. Inconclusive cases require histology or additional imaging tests. Robust evidence establishes high sensitivities and specificities for ultrasound. Reliability is good among experts. Ultrasound reveals a characteristic non-compressible ‘halo sign’ indicating intima-media thickening (IMT) and, in acute disease, artery wall oedema. Ultrasound can further identify stenoses, occlusions and aneurysms, and IMT can be measured. In suspected GCA, ultrasound should include at least the temporal and axillary arteries bilaterally. Nearly all other arteries are accessible except the descending thoracic aorta. TAK mostly involves the common carotid and subclavian arteries. Ultrasound detects subclinical GCA in over 20% of polymyalgia rheumatica (PMR) patients without GCA symptoms. Patients with silent GCA should be treated as GCA because they experience more relapses and require higher glucocorticoid doses than PMR patients without GCA. Scores based on intima-thickness (IMT) of temporal and axillary arteries aid follow-up of GCA, particularly in trials. The IMT decreases more rapidly in temporal than in axillary arteries. Ascending aorta ultrasound helps monitor patients with extracranial GCA for the development of aneurysms. Experienced sonologists can easily identify pitfalls, which will be addressed in this article.
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- 2024
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25. Crystal Structures of Two Titanium Phosphate-Based Proton Conductors: Ab Initio Structure Solution and Materials Properties
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Petersen, Hilke, Stegmann, Niklas, Fischer, Michael, Zibrowius, Bodo, Radev, Ivan, Philippi, Wladimir, Schmidt, Wolfgang, and Weidenthaler, Claudia
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Transition-metal phosphates show a wide range of chemical compositions, variations of the valence states, and crystal structures. They are commercially used as solid-state catalysts, cathode materials in rechargeable batteries, or potential candidates for proton-exchange membranes in fuel cells. Here, we report on the successful ab initio structure determination of two novel titanium pyrophosphates, Ti(III)p and Ti(IV)p, from powder X-ray diffraction (PXRD) data. The low-symmetry space groups P21/cfor Ti(III)p and P1̅ for Ti(IV)p required the combination of spectroscopic and diffraction techniques for structure determination. In Ti(III)p, trivalent titanium ions occupy the center of TiO6polyhedra, coordinated by five pyrophosphate groups, one of them as a bidentate ligand. This secondary coordination causes the formation of one-dimensional six-membered ring channels with a diameter dmaxof 3.93(2) Å, which is stabilized by NH4+ions. Annealing Ti(III)p in inert atmospheres results in the formation of a new compound, denoted as Ti(IV)p. The structure of this compound shows a similar three-dimensional framework consisting of [PO4]3–tetrahedra and TiIV+O6octahedra and an empty one-dimensional channel with a diameter dmaxof 5.07(1) Å. The in situPXRD of the transformation of Ti(III)p to Ti(IV)p reveals a two-step mechanism, i.e., the decomposition of NH4+ions in a first step and subsequent structure relaxation. The specific proton conductivity and activation energy of the proton migration of Ti(III)p, governed by the Grotthus mechanism, belong to the highest and lowest, respectively, ever reported for this class of materials, which reveals its potential application in electrochemical devices like fuel cells and water electrolyzers in the intermediate temperature range.
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- 2022
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26. SUFUhaploinsufficiency causes a recognisable neurodevelopmental phenotype at the mild end of the Joubert syndrome spectrum
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Serpieri, Valentina, D’Abrusco, Fulvio, Dempsey, Jennifer C, Cheng, Yong-Han Hank, Arrigoni, Filippo, Baker, Janice, Battini, Roberta, Bertini, Enrico Silvio, Borgatti, Renato, Christman, Angela K, Curry, Cynthia, D'Arrigo, Stefano, Fluss, Joel, Freilinger, Michael, Gana, Simone, Ishak, Gisele E, Leuzzi, Vincenzo, Loucks, Hailey, Manti, Filippo, Mendelsohn, Nancy, Merlini, Laura, Miller, Caitlin V, Muhammad, Ansar, Nuovo, Sara, Romaniello, Romina, Schmidt, Wolfgang, Signorini, Sabrina, Siliquini, Sabrina, Szczałuba, Krzysztof, Vasco, Gessica, Wilson, Meredith, Zanni, Ginevra, Boltshauser, Eugen, Doherty, Dan, and Valente, Enza Maria
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BackgroundJoubert syndrome (JS) is a recessively inherited ciliopathy characterised by congenital ocular motor apraxia (COMA), developmental delay (DD), intellectual disability, ataxia, multiorgan involvement, and a unique cerebellar and brainstem malformation. Over 40 JS-associated genes are known with a diagnostic yield of 60%–75%.In 2018, we reported homozygous hypomorphic missense variants of the SUFUgene in two families with mild JS. Recently, heterozygous truncating SUFUvariants were identified in families with dominantly inherited COMA, occasionally associated with mild DD and subtle cerebellar anomalies.MethodsWe reanalysed next generation sequencing (NGS) data in two cohorts comprising 1097 probands referred for genetic testing of JS genes.ResultsHeterozygous truncating and splice-site SUFUvariants were detected in 22 patients from 17 families (1.5%) with strong male prevalence (86%), and in 8 asymptomatic parents. Patients presented with COMA, hypotonia, ataxia and mild DD, and only a third manifested intellectual disability of variable severity. Brain MRI showed consistent findings characterised by vermis hypoplasia, superior cerebellar dysplasia and subtle-to-mild abnormalities of the superior cerebellar peduncles. The same pattern was observed in two out of three tested asymptomatic parents.ConclusionHeterozygous truncating or splice-site SUFUvariants cause a novel neurodevelopmental syndrome encompassing COMA and mild JS, which likely represent overlapping entities. Variants can arise de novo or be inherited from a healthy parent, representing the first cause of JS with dominant inheritance and reduced penetrance. Awareness of this condition will increase the diagnostic yield of JS genetic testing, and allow appropriate counselling about prognosis, medical monitoring and recurrence risk.
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- 2022
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27. From 1D to 3D Graphitic Carbon Nitride (Melon): A Bottom-Up Route via Crystalline Microporous Templates
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Stegmann, Niklas, Dai, Yitao, Nürenberg, Edward, and Schmidt, Wolfgang
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Herein, we present a novel bottom-up preparation route for heptazine-based polymers (melon), also known as graphitic carbon nitride. The growth characteristics of isolated 1D melon strings in microporous templates are presented and studied in detail. Removal of the microporous silicate template via etching is accompanied by the self-assembly of a 1D melon to stacked 3D structures. The advantages and limitations of the bottom-up approach are shown by using microporous templates with different pore sizes (ETS-10, ZSM-5, and zeolite Y). In accordance with the molecular size of the heptazine units (0.67 nm), a 1D melon can be deposited in ETS-10 with a pore width of about 0.78 nm, whereas its formation in the smaller 0.47 nm pores of ZSM-5 is sterically impeded. The self-assembly of isolated 1D melon to stacked 3D structures offers a novel experimental perspective to the controversial debate on the polymerization degree in 2D sheets of graphitic carbon nitride as micropore sizes below 1 nm confine the condensation degree of heptazine to isolated 1D strands at a molecular level. The growth characteristics and structural features were investigated by X-ray diffraction, N2physisorption, scanning transmission electron microscopy/energy-dispersive X-ray analysis, 13C CP-NMR spectroscopy, and attenuated total reflection–infrared spectroscopy.
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- 2021
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28. Nutrition and NSCLC; Should We Administer Food Supplements?
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Zarogoulidis, Paul, Kosmidis, Christoforos, Kesisoglou, Isaak, Tsakiridis, Kosmas, Hohenforst-Schmidt, Wolfgang, Huang, Haidong, Romanidis, Konstantinos, Vagionas, Anastasios, and Sapalidis, Konstantinos
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Non-small cell lung cancer is usually diagnosed at the advanced stage of the disease. We have novel diagnostic tools. However, prevention is still the best way to deal with this disease. Patients receive different treatments with different adverse effects. Targeted treatment with tyrosine kinase inhibitors and immunotherapy have entered everyday clinical practice. The nutritional status of a patient plays a crucial role in the treatment of the patient. Cachexia is observed in most cancer patients, and it has been identified as an independent factor in the overall survival of the patient. The improvement of nutritional status and metabolism directly impacts the quality of life, daily living, and overall survival of a lung cancer patient. We conducted a search on PubMed and Scopus and identified relevant publications. In this review, we will focus on the nutritional status of NSCLC patients and how food supplements assist in the QoL based on published literature. Additional information from other cancer types will be included where necessary.
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- 2021
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29. Imaging of vasculitis: State of the art
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Muratore, Francesco, Pipitone, Nicolò, Salvarani, Carlo, and Schmidt, Wolfgang A.
- Abstract
The increasing availability and improvement of imaging techniques are making a profound impact in the evaluation and management of patients with vasculitis, particularly for those with large vessel vasculitis, and will most likely play an ever more important role in the future. Deep, large vessels can be examined by CT or MRI, while ultrasound is the method of choice for the evaluation of superficial vessels (such as temporal, carotid, and axillary arteries). PET is very sensitive in detecting large vessel inflammation, but it does not delineate the vessel wall. Imaging studies can also be used to monitor the disease course and the development of late vascular complication. This review will focus on the role of imaging studies in diagnosing and monitoring LVV, but will also mention their principal applications in medium and small-sized vessel vasculitis. Indications and limitations of the available imaging modalities will be discussed as well.
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- 2024
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30. Discovery, Multiparametric Optimization, and Solid-State Driven Identification of CHF-6550, a Novel Soft Dual Pharmacology Muscarinic Antagonist and β2Agonist (MABA) for the Inhaled Treatment of Respiratory Diseases
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Carzaniga, Laura, Linney, Ian D., Rizzi, Andrea, Schmidt, Wolfgang, Knight, Christopher K., Mileo, Valentina, Amadei, Francesco, Pastore, Fiorella, Miglietta, Daniela, Cesari, Nicola, Riccardi, Benedetta, Mazzucato, Roberta, Ghidini, Eleonora, Blackaby, Wesley P., Patacchini, Riccardo, Battipaglia, Loredana, Villetti, Gino, Puccini, Paola, Catinella, Silvia, Civelli, Maurizio, and Rancati, Fabio
- Abstract
Clinical guidelines for COPD and asthma recommend inhaled β-adrenergic agonists, muscarinic antagonists, and, for frequent exacerbators, inhaled corticosteroids, with the challenge of combining them into a single device. The MABA (muscarinic antagonist and β2agonist) concept has the potential to simplify this complexity while increasing the efficacy of both pharmacologies. In this article, we report the outcome of our solid-state driven back-up program that led to the discovery of the MABA compound CHF-6550. A soft drug approach was applied, aiming at high plasma protein binding and high hepatic clearance, concurrently with an early stage assessment of crystallinity through a dedicated experimental workflow. A new chemotype was identified, the diphenyl hydroxyacetic esters, able to generate crystalline material. Among this class, CHF-6550demonstrated in vivoefficacy, suitability for dry powder inhaler development, favorable pharmacokinetics, and safety in preclinical settings and was selected as a back-up candidate, fulfilling the desired pharmacological and solid-state profile.
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- 2024
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31. OMERACT Definitions for Ultrasonographic Pathologies and Elementary Lesions of Rheumatic Disorders 15 Years On.
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Bruyn, George A., Iagnocco, Annamaria, Naredo, Esperanza, Balint, Peter V., Gutierrez, Marwin, Hammer, Hilde B., Collado, Paz, Filippou, Georgios, Schmidt, Wolfgang A., Jousse-Joulin, Sandrine, Mandl, Peter, Conaghan, Philip G., Wakefield, Richard J., Keen, Helen I., Terslev, Lene, D'Agostino, Maria Antonietta, and OMERACT Ultrasound Working Group
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- 2019
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32. Contrast-Enhanced Ultrasound for Monitoring Takayasu Arteritis
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Schmidt, Wolfgang Andreas
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- 2022
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33. A Multicentre, Randomised, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Efficacy and Safety of Sirukumab in the Treatment of Giant Cell Arteritis
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Schmidt, Wolfgang A., Dasgupta, Bhaskar, Luqmani, Raashid, Unizony, Sebastian H., Blockmans, Daniel, Lai, Zhihong, Kurrasch, Regina H., Lazic, Ivana, Brown, Kurt, and Rao, Ravi
- Abstract
Introduction: To evaluate the efficacy and safety of sirukumab in giant cell arteritis (GCA). Methods: In this multicentre, randomised, double-blind, placebo-controlled, two-part phase 3 trial (NCT02531633; Part A [52-week double-blind treatment]; Part B [104-week follow-up]), patients with GCA were randomised (3:3:2:2:2) to sirukumab 100 mg every 2 weeks plus 6-month or 3-month prednisone taper, sirukumab 50 mg every 4 weeks plus 6-month prednisone taper, or placebo every 2 weeks plus 6-month or 12-month prednisone taper. The primary endpoint was the proportion of patients in sustained remission at week 52. Secondary endpoints included disease flare and safety. The study was terminated early (October 2017; sponsor decision). Results: Of 161 patients randomised (sirukumab: n?=?107; placebo: n?=?54), 28 (17.4%) completed week 52 (median treatment duration: 24–30 weeks). In a revised intent-to-treat (ITT) subgroup (completed week 52 or discontinued before study termination [n?=?55]); six patients (all receiving sirukumab) achieved the primary endpoint. In the ITT population (n?=?161), the proportion of patients with flares (week 2–52) was lower with sirukumab (18.4–30.8%) than placebo (37.0–40.0%). The proportion of patients with flares (week 2–12) was highest with sirukumab 100 mg every 2 weeks plus 3-month prednisone taper (23.1%). In Part A, 94.4% of patients reported?=?1 treatment-emergent adverse event (TEAE); 19.3% reported serious TEAEs. The proportions of patients with TEAEs were generally similar across treatment arms. No deaths occurred. Conclusions: Although data were limited due to early termination and shortened treatment duration, sirukumab treatment resulted in numerically lower proportions of patients with flare by week 52 versus placebo, with no unexpected safety findings. Trial Registration: Clinicaltrials.gov: NCT02531633.
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- 2020
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34. High Dynamics of Vapor Adsorption in Ordered Mesoporous Carbon CMK-5: A Small Angle X-ray Scattering Study
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Schmidt, Wolfgang and Amenitsch, Heinz
- Abstract
Adsorption of dichloromethane in CMK-5 is a highly dynamic process going along with substantial rearrangement of both the adsorbent phase and the adsorbate phase. The carbon nanotubes of CMK-5 expand and contract during the process which is accompanied by increase and decrease in average distances between the tubes. Adsorption starts preferentially within the interstitial pores and then continues in the tubular ones. The complete process was monitored by small-angle X-ray diffraction. The SAXS data provided structural information on the carbon material and quantitative information on the adsorption process, which allowed drawing a precise picture of the complete adsorption process.
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- 2020
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35. Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial
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Younossi, Zobair M, Ratziu, Vlad, Loomba, Rohit, Rinella, Mary, Anstee, Quentin M, Goodman, Zachary, Bedossa, Pierre, Geier, Andreas, Beckebaum, Susanne, Newsome, Philip N, Sheridan, David, Sheikh, Muhammad Y, Trotter, James, Knapple, Whitfield, Lawitz, Eric, Abdelmalek, Manal F, Kowdley, Kris V, Montano-Loza, Aldo J, Boursier, Jerome, Mathurin, Philippe, Bugianesi, Elisabetta, Mazzella, Giuseppe, Olveira, Antonio, Cortez-Pinto, Helena, Graupera, Isabel, Orr, David, Gluud, Lise Lotte, Dufour, Jean-Francois, Shapiro, David, Campagna, Jason, Zaru, Luna, MacConell, Leigh, Shringarpure, Reshma, Harrison, Stephen, Sanyal, Arun J, Abdelmalek, Manal, Abrams, Gary, Aguilar, Humberto, Ahmed, Aijaz, Aigner, Elmar, Aithal, Guruprasad, Ala, Aftab, Alazawi, William, Albillos, Agustin, Allison, Michael, Al-Shamma, Sfa, Andrade, Raul, Andreone, Pietro, Angelico, Mario, Ankoma-Sey, Victor, Anstee, Quentin, Anty, Rodolphe, Araya, Victor, Arenas Ruiz, Juan Ignacio, Arkkila, Perttu, Arora, Marty, Asselah, Tarik, Au, Jennifer, Ayonrinde, Oyekoya, Bailey, Robert James, Balakrishnan, Maya, Bambha, Kiran, Bansal, Meena, Barritt, Sidney, Bate, John, Beato, Jorge, Beckebaum, Susanne, Behari, Jaideep, Bellot, Pablo, Ben Ari, Ziv, Bennett, Michael, Berenguer, Marina, Beretta-Piccoli, Benedetta Terziroli, Berg, Thomas, Bonacini, Maurizio, Bonet, Lucia, Borg, Brian, Bourliere, Marc, Boursier, Jerome, Bowman, William, Bradley, David, Brankovic, Marija, Braun, Marius, Bronowicki, Jean-Pierre, Bruno, Savino, Bugianesi, Elisabetta, Cai, Cindy, Calderon, Amy, Calleja Panero, José Luis, Carey, Elizabeth, Carmiel, Michal, Carrión, Jose Antonio, Cave, Matthew, Chagas, Cristina, Chami, Tawfik, Chang, Alan, Coates, Allan, Cobbold, Jeremy, Costentin, Charlote, Corey, Kathleen, Corless, Lynsey, Cortez-Pinto, Helena, Crespo, Javier, Cruz Pereira, Oscar, de Ledinghen, Victor, deLemos, Andrew, Diago, Moises, Dong, Mamie, Dufour, Jean-François, Dugalic, Predrag, Dunn, Winston, Elkhashab, Magby, Epstein, Michael, Escudero-Garcia, Maria Desamparados, Etzion, Ohad, Evans, Larry, Falcone, Robert, Fernandez, Conrado, Ferreira, Jose, Fink, Scott, Finnegan, Kevin, Firpi-Morell, Roberto, Floreani, Annarosa, Fontanges, Thierry, Ford, Ryan, Forrest, Ewan, Fowell, Andrew, Fracanzani, Anna Ludovica, Francque, Sven, Freilich, Bradley, Frias, Juan, Fuchs, Michael, Fuentes, Javier, Galambos, Michael, Gallegos, Juan, Geerts, Anja, Geier, Andreas, George, Jacob, Ghali, Maged, Ghalib, Reem, Gholam, Pierre, Gines, Pere, Gitlin, Norman, Gluud, Lise Lotte, Goeser, Tobias, Goff, John, Gordon, Stuart, Gordon, Frederic, Goria, Odile, Greer, Shaun, Grigorian, Alla, Gronbaek, Henning, Guillaume, Maeva, Gunaratnam, Naresh, Halegoua-De Marzio, Dina, Hameed, Bilal, Hametner, Stephanie, Hamilton, James, Harrison, Stephen, Hartleb, Marek, Hassanein, Tarek, Häussinger, Dieter, Hellstern, Paul, Herring, Robert, Heurich, Eva, Hezode, Christophe, Hinrichsen, Holger, Holland Fischer, Peter, Horsmans, Yves, Huang, Jonathan, Hussaini, Hyder, Jakiche, Antoine, Jeffers, Lennox, Jones, Blake, Jorge, Rosa, Jorquera, Francisco, Joshi, Shoba, Kahraman, Alisan, Kaita, Kelly, Karyotakis, Nicholas, Kayali, Zeid, Kechagias, Stergios, Kepczyk, Thomas, Khalili, Mandana, Khallafi, Hicham, Kluwe, Johannes, Knapple, Whitfield, Kohli, Anita, Korenblat, Kevin, Kowdley, Kris, Krag, Aleksander, Krause, Richard, Kremer, Andreas, Krok, Karen, Krstic, Miodrag, Kugelmas, Marcelo, Kumar, Sonal, Kuwada, Scott, Labarriere, Damien, Lai, Michelle, Laleman, Wim, Lampertico, Pietro, Lawitz, Eric, Lee, Alice, Leroy, Vincent, Lidofsky, Steven, Lim, Tina Huey, Lim, Joseph, Lipkis, Donald, Little, Ester, Lonardo, Amadeo, Long, Michelle, Loomba, Rohit, Luketic, Velimir Anthony Christopher, Lurie, Yoav, Macedo, Guilherme, Magalhaes, Joana, Makara, Mihály, Maliakkal, Benedict, Manns, Michael, Manousou, Pinelopi, Mantry, Parvez, Marchesini, Giulio, Marinho, Carla, Marotta, Paul, Marschall, Hanns-Ulrich, Martinez, Linda, Mathurin, Philippe, Mayo, Marlyn, Mazzella, Giuseppe, McCullen, Mark, McLaughlin, William, Merle, Uta, Merriman, Raphael, Modi, Apurva, Molina, Esther, Montano-Loza, Aldo, Monteverde, Carlos, Morales Cardona, Amilcar, Moreea, Sulleman, Moreno, Christophe, Morisco, Filomena, Mubarak, Abdullah, Muellhaupt, Beat, Mukherjee, Sandeep, Müller, Tobias, Nagorni, Aleksandar, Naik, Jahnavi, Neff, Guy, Nevah, Moises, Newsome, Philip, Nguyen-Khac, Eric, Noureddin, Mazen, Oben, Jude, Olveira, Antonio, Orlent, Hans, Orr, David, Orr, James, Ortiz-Lasanta, Grisell, Ozenne, Violaine, Pandya, Prashant, Paredes, Angelo, Park, James, Patel, Joykumar, Patel, Keyur, Paul, Sonali, Patton, Heather, Peck-Radosavljevic, Markus, Petta, Salvatore, Pianko, Stephen, Piekarska, Anna, Pimstone, Neville, Pisegna, Joseph, Pockros, Paul, Pol, Stanislas, Porayko, Michael, Poulos, John, Pound, David, Pouzar, Joe, Presa Ramos, Jose, Pyrsopoulos, Nikolaos, Rafiq, Nila, Muller, Kate, Ramji, Alnoor, Ratziu, Vlad, Ravinuthala, Ravi, Reddy, Chakradhar, Reddy K G, Gautham, Reddy K R, K. Rajender, Regenstein, Frederic, Reindollar, Robert, Reynolds, Justin, Riera, Andres, Rinella, Mary, Rivera Acosta, Jose, Robaeys, Geert, Roberts, Stuart, Rodriguez-Perez, Federico, Romero, Sandor, Romero-Gomez, Manuel, Rubin, Raymond, Rumi, Mariagrazia, Rushbrook, Simon, Rust, Christian, Ryan, Michael, Safadi, Rifaat, Said, Adnan, Salminen, Kimmo, Samuel, Didier, Santoro, John, Sanyal, Arun, Sarkar, Souvik, Schaeffer, Cynthia, Schattenberg, Jörn, Schiefke, Ingolf, Schiff, Eugene, Schmidt, Wolfgang, Schneider, Jeffrey, Schouten, Jeoffrey, Schultz, Michael, Sebastiani, Giada, Semela, David, Sepe, Thomas, Sheikh, Aasim, Sheikh, Muhammad, Sheridan, David, Sherman, Kenneth, Shibolet, Oren, Shiffman, Mitchell, Siddique, Asma, Sieberhagen, Cyril, Sigal, Samuel, Sikorska, Katarzyna, Simon, Krzysztof, Sinclair, Marie, Skoien, Richard, Solis, Joel, Sood, Siddharth, Souder, Bob, Spivey, James, Stal, Per, Stinton, Laura, Strasser, Simone, Svorcan, Petar, Szabo, Gyongzi, Talal, Andrew, Tam, Edward, Tetri, Brent, Thuluvath, Paul, Tobias, Hillel, Tomasiewicz, Krzysztof, Torres, Dawn, Tran, Albert, Trauner, Michael, Trautwein, Christian, Trotter, James, Tsochatzis, Emanuel, Unitt, Esther, Vargas, Victor, Varkonyi, Istvan, Veitsman, Ella, Vespasiani Gentilucci, Umberto, Victor, David, Vierling, John, Vincent, Catherine, Vincze, Aron, von der Ohe, Manfred, Von Roenn, Natasha, Vuppalanchi, Raj, Waters, Michael, Watt, Kymberly, Wattacheril, Julia, Weltman, Martin, Wieland, Amanda, Wiener, Gregory, Williams A, Alonzo, Williams J, Jeffrey, Wilson, Jason, Yataco, Maria, Yoshida, Eric, Younes, Ziad, Yuan, Liyun, Zivony, Adam, Zogg, Donald, Zoller, Heinz, Zoulim, Fabien, Zuckerman, Eli, and Zuin, Massimo
- Abstract
Non-alcoholic steatohepatitis (NASH) is a common type of chronic liver disease that can lead to cirrhosis. Obeticholic acid, a farnesoid X receptor agonist, has been shown to improve the histological features of NASH. Here we report results from a planned interim analysis of an ongoing, phase 3 study of obeticholic acid for NASH.
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- 2019
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36. COSY catalyses trans–cisisomerization and lactonization in the biosynthesis of coumarins
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Vanholme, Ruben, Sundin, Lisa, Seetso, Keletso Carol, Kim, Hoon, Liu, Xinyu, Li, Jin, De Meester, Barbara, Hoengenaert, Lennart, Goeminne, Geert, Morreel, Kris, Haustraete, Jurgen, Tsai, Huei-Hsuan, Schmidt, Wolfgang, Vanholme, Bartel, Ralph, John, and Boerjan, Wout
- Abstract
Coumarins, also known as 1,2-benzopyrones, comprise a large class of secondary metabolites that are ubiquitously found throughout the plant kingdom. In many plant species, coumarins are particularly important for iron acquisition and plant defence. Here, we show that COUMARIN SYNTHASE (COSY) is a key enzyme in the biosynthesis of coumarins. Arabidopsis thaliana cosymutants have strongly reduced levels of coumarin and accumulate o-hydroxyphenylpropanoids instead. Accordingly, cosymutants have reduced iron content and show growth defects when grown under conditions in which there is a limited availability of iron. Recombinant COSY is able to produce umbelliferone, esculetin and scopoletin from their respective o-hydroxycinnamoyl-CoA thioesters by two reaction steps—a trans–cisisomerization followed by a lactonization. This conversion happens partially spontaneously and is catalysed by light, which explains why the need for an enzyme for this conversion has been overlooked. The combined results show that COSY has an essential function in the biosynthesis of coumarins in organs that are shielded from light, such as roots. These findings provide routes to improving coumarin production in crops or by microbial fermentation.
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- 2019
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37. Modular Pd/Zeolite Composites Demonstrating the Key Role of Support Hydrophobic/Hydrophilic Character in Methane Catalytic Combustion.
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Losch, Pit, Huang, Weixin, Vozniuk, Olena, Goodman, Emmett D., Schmidt, Wolfgang, and Cargnello, Matteo
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- 2019
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38. Ozone Treatment: A Versatile Tool for the Postsynthesis Modification of Porous Silica-Based Materials.
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Joshi, Hrishikesh, Jalalpoor, Daniel, Ochoa-Hernández, Cristina, Schmidt, Wolfgang, and Schüth, Ferdi
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- 2018
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39. Proton Mobility, Intrinsic Acid Strength, and Acid Site Location in Zeolites Revealed by Varying Temperature Infrared Spectroscopy and Density Functional Theory Studies.
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Losch, Pit, Joshi, Hrishikesh R., Vozniuk, Olena, Grünert, Anna, Ochoa-Hernández, Cristina, Jabraoui, Hicham, Badawi, Michael, and Schmidt, Wolfgang
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- 2018
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40. Evidence of mild founder mutations causing nemaline myopathy 10 in Germany and Austria.
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Schatz, Ulrich A., Weiss, Simone, Wenninger, Stephan, Schoser, Benedikt, Muss, Wolfgang H., Bittner, Reginald E., Schmidt, Wolfgang M., Schossig, Anna S., Rudnik-Schöneborn, Sabine, and Baumann, Matthias
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- 2018
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41. A phase 3 randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of sarilumab in patients with giant cell arteritis
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Schmidt, Wolfgang A., Dasgupta, Bhaskar, Sloane, Jennifer, Giannelou, Angeliki, Xu, Yuqing, Unizony, Sebastian H., Mackie, Sarah L., Gonzalez-Gay, Miguel A., Spiera, Robert, Warrington, Kenneth J., Villiger, Peter M., Nivens, Michael C., Akinlade, Bolanle, Lin, Yong, Buttgereit, Frank, and Stone, John H.
- Abstract
Background: Giant cell arteritis (GCA) is primarily treated with glucocorticoids (GCs), which have substantial toxicity. Tocilizumab, an interleukin-6-receptor inhibitor (IL-6Ri), showed beneficial effects in GCA, leading to its approval. This study investigated the efficacy and safety of sarilumab (another IL-6Ri) in GCA. Methods: This Phase 3, double-blind study comprised a 52-week treatment period and a 24-week follow-up phase. Eligible GCA patients were randomized to receive sarilumab 200 mg (SAR200 + 26W) or 150 mg (SAR150 + 26W) with a 26-week GC taper, or placebo with a 52-week (PBO + 52W) or 26-week (PBO + 26W) GC taper. The primary efficacy endpoint was sustained remission (SR) at week 52. Additional endpoints were SR at week 24, cumulative GC dose, and safety. The study was discontinued prematurely due to protracted recruitment timelines, because of the impact of COVID-19. Therefore, only descriptive statistics were summarized. Results: Of the planned 360 subjects, only 83 were randomized and 36 were included in the week 52 analysis. At week 52, 46% (n= 6/13) of patients in SAR200 + 26W, 43% (n= 3/7) in SAR150 + 26W, 30% (n= 3/10) in PBO + 52W, and 0 (n= 0/6) in PBO + 26W taper groups achieved SR. Sensitivity analyses, excluding acute-phase reactants from the SR definition, showed similar results for SAR groups, but 60% (n= 6/10) in PBO + 52W and 17% (n= 1/6) in PBO + 26W taper groups achieved SR at week 52. Similar findings were noted at week 24. The proportions of patients who adhered to GC taper from week 12 through week 52 in each group were as follows: 46% (n= 6/13, SAR200 + 26W), 43% (n= 3/7, SAR150 + 26W), 60% (n= 6/10, PBO + 52W), and 33% (n= 2/6, PBO + 26W). The median actual cumulative GC dose received in the SAR200 + 26W group was lower than other groups. Most patients (80–100%) experienced treatment-emergent adverse events, with similar incidences reported across groups. Conclusions: Owing to the small sample size due to the early termination, it is difficult to draw clear conclusions from this study. There were no unexpected safety findings. Trial registration: ClinicalTrials.gov NCT03600805. Registered on July 26, 2018.
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- 2023
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42. Unraveling Direct Formation of Hierarchical Zeolite Beta by Dynamic Light Scattering, Small Angle X-ray Scattering, and Liquid and Solid-State NMR: Insights at the Supramolecular Level.
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Castro, Maria, Losch, Pit, Woojin Park, Haouas, Mohamed, Taulelle, Francis, Loerbroks, Claudia, Brabants, Gert, Breynaert, Eric, Kirschhock, Christine E. A., Ryong Ryoo, and Schmidt, Wolfgang
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- 2018
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43. Scalable One-Pot Synthesis of Yolk-Shell Carbon Nanospheres with Yolk-Supported Pd Nanoparticles for Size-Selective Catalysis.
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Guang-Hui Wang, Kun Chen, Engelhardt, Jan, Tüysüz, Harun, Bongard, Hans-Josef, Schmidt, Wolfgang, and Schüth, Ferdi
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- 2018
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44. New hybrid method for trachea dilatation with rigid and flexible tools.
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Sapalidis, Konstantinos, Laskou, Stella, Amaniti, Aikaterini, Koulouris, Charilaos, Giannakidis, Dimitrios, Mantalovas, Stylianos, Karapantzos, Ilias, Karapantzou, Chrysa, Zarogoulidis, Paul, Arapakis, Iakovos, Huang, Haidong, Bai, Chong, Kougioumtzi, Ioanna, Katsikogiannis, Nikolaos, Sarika, Eirini, Konstantinou, Fotis, Hohenforst-Schmidt, Wolfgang, and Kesisoglou, Isaak
- Abstract
Trachea stenosis is observed either in benign or malignant situations. In cancer malignancy a tumor might obstruct the central airway in three different ways. Again granuloma tissue is usually observed after intubation or stent placement in order to manage a benign malformation of the trachea. In any case there are several tools and techniques that can be used either with surgery or endoscopically to manage such situation. We will focus on a hybrid technique in order to ventilate the patient while performing endoscopic management of granuloma tissue. [ABSTRACT FROM AUTHOR]
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- 2018
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45. A new mode of ventilation for interventional pulmonology. A case with EBUS-TBNA and debulking.
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Zarogoulidis, Paul, Huang, Haidong, Bai, Chong, Kosmidis, Christoforos, Porpodis, Konstantinos, Kallianos, Anastasios, Veletza, Lemonia, Trakada, Georgia, Benhassen, Naim, and Hohenforst-Schmidt, Wolfgang
- Abstract
Lung cancer is still underdiagnosed mainly due to lack of symptoms. Most patients are diagnosed in a late stage where unfortunately only systematic therapy can be applied. Fortunately in the last five years several novel therapies and combinations have emerged. However; in certain situations local therapeutics modalities have to be applied in order to solve emergency problems as in the case that we will present. Convex-EBUS probe was used along with a novel method of ventilation which keeps PCO 2 concentration satisfyingly low. [ABSTRACT FROM AUTHOR]
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- 2018
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46. Psoriatic arthritis due to nivolumab administration a case report and review of the literature.
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Sapalidis, Konstantinos, Kosmidis, Christoforos, Michalopoulos, Nikolaos, Koulouris, Charilaos, Mantalobas, Stylianos, Giannakidis, Dimitrios, Munteanu, Alexandru, Surlin, Valeriu, Laskou, Stella, Zarogoulidis, Paul, Drougas, Dimitrios, Sardeli, Crysanthi, Karapantzou, Chrysanthi, Karapantzos, Ilias, Hohenforst-Schmidt, Wolfgang, Huang, Haidong, and Kesisoglou, Isaak
- Abstract
Nowadays we have novel equipment for lung cancer diagnosis, however; due to lack of symptoms, lung cancer is still diagnosed at a late stage. Currently we have the following therapies for non-small cell lung cancer: a) non-specific cytotoxic agents, b) targeted therapies and c) immunotherapy. Each therapy has its own advantages and adverse effects. In the current case we will present a rare case of psoriacic arthritis that was presented after two cycles of nivolumab administration and we will also present a review of the literature. [ABSTRACT FROM AUTHOR]
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- 2018
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47. Definition and Reliability Assessment of Elementary Ultrasonographic Findings in Calcium Pyrophosphate Deposition Disease: A Study by the OMERACT Calcium Pyrophosphate Deposition Disease Ultrasound Subtask Force.
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Filippou, Georgios, Scirè, Carlo A., Damjanov, Nemanja, Adinolfi, Antonella, Carrara, Greta, Picerno, Valentina, Toscano, Carmela, Bruyn, George A., D'Agostino, Maria Antonietta, Sedie, Andrea Delle, Filippucci, Emilio, Gutierrez, Marwin, Micu, Mihaela, Möller, Ingrid, Naredo, Esperanza, Pineda, Carlos, Porta, Francesco, Schmidt, Wolfgang A., Terslev, Lene, and Vlad, Violeta
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- 2017
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48. Sarcoidosis of the Intra- and Extrahepatic Bile Ducts with Concomitant Cholangitis in a Patient with Ulcerative Colitis
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Jebran, Ahmad Fasel, Schmidt, Wolfgang E., Kahraman, Alisan, Canbay, Ali, and Bulut, Kerem
- Abstract
Cholangitis in patients with ulcerative colitis (UC) can lead to misdiagnosis of primary sclerosing cholangitis (PSC). Furthermore, it can mimic cholangiocellular carcinoma, which also can lead to inappropriate and potentially harmful treatment of the patient. An 18-year-old male patient with known UC presented with pain in his right upper abdomen and elevation of the cholestatic liver enzymes (alkaline phosphatase: 197 U/L, γ-glutamyltransferase: 229 U/L) and increased inflammatory parameters (leukocytosis and CrP of 13.6 mg/L). Magnetic resonance cholangiopancreatography revealed unclear stenosis in the bifurcation of the main hepatic bile duct as well as in the prepapillary bile duct. Ultrasound (US) examination and endoscopic retrograde cholangiopancreatography showed dilatation of the intra -and extrahepatic bile ducts, which raised the suspicion of PSC. US image with dilated intra- and extrahepatic dilatation of the bile duct was also suggestive for autoimmune cholangitis. However, serum analysis revealed an elevated soluble interleukin-II receptor (1,305 U/mL), while immunoglobulin G4 was within normal ranges. Liver biopsy demonstrated hepatic inflammation and presence of granulomatous cells within the portal fields – convenient to sarcoidosis. After starting treatment with steroids, we observed a rapid clinical response with improvement of the dilated bile ducts and decrease of the initially elevated cholestatic liver enzymes. Sarcoidosis within the bile duct is a rare condition. Steroids are the treatment of choice and – along with the histology – are furthermore helpful to differentiate between several potential differential diagnoses like IgG4 cholangitis, primary biliary cholangitis, or PSC.
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- 2019
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49. OMERACT Definitions for Ultrasonographic Pathologies and Elementary Lesions of Rheumatic Disorders 15 Years On
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Bruyn, George A., Iagnocco, Annamaria, Naredo, Esperanza, Balint, Peter V., Gutierrez, Marwin, Hammer, Hilde B., Collado, Paz, Filippou, Georgios, Schmidt, Wolfgang A., Jousse-Joulin, Sandrine, Mandl, Peter, Conaghan, Philip G., Wakefield, Richard J., Keen, Helen I., Terslev, Lene, and D’Agostino, Maria Antonietta
- Abstract
Objective.The Outcome Measures in Rheumatology (OMERACT) Ultrasound (US) Working Group (WG) operates research activities for the validation of US as an outcome measurement instrument according to the Filter 2.0 framework.Methods.Original publications on definitions and scoring systems for pathophysiological manifestations and elementary lesions of various rheumatic disorders were reviewed from the onset of the WG research in 2005.Results.Definitions and scoring systems according to new terminology are provided.Conclusion.We have redefined OMERACT US pathology and elementary lesions as well as scoring systems, which are now proposed for OMERACT approval for application in clinical trials.
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- 2019
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50. Proton Mobility, Intrinsic Acid Strength, and Acid Site Location in Zeolites Revealed by Varying Temperature Infrared Spectroscopy and Density Functional Theory Studies
- Author
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Losch, Pit, Joshi, Hrishikesh R., Vozniuk, Olena, Grünert, Anna, Ochoa-Hernández, Cristina, Jabraoui, Hicham, Badawi, Michael, and Schmidt, Wolfgang
- Abstract
The intrinsic Brønsted acid strength in solid acids relates to the energy required to separate a proton from a conjugate base, for example a negatively charged zeolite framework. The reliable characterization of zeolites’ intrinsic acidity is fundamental to the understanding of acid catalysis and setting in relation solid Brønsted acids with their activity and selectivity. Here, we report an infrared spectroscopic study with partial isotopic deuterium exchange of a series of 15 different acidic aluminosilicate materials, including ZSM-5 zeolites with very few defects. Varying Temperature Infrared spectroscopy (VTIR) permitted estimating activation energies for proton diffusion. Two different proton transfer mechanisms have been distinguished for two different temperature ranges. Si-rich zeolites appeared to be promising proton-transfer materials (Eact.< 40 kJ mol–1) at temperatures above 150 °C (423 K). Further, a linear bathochromic shift of the Si–(OD)–Al stretching vibration as a function of temperature was observed. It can be assumed that this red-shift is related to the intrinsic O–(H/D) bond strength. This observation allowed the extrapolation and estimation of precise v(O–D)@0 K values, which could be attributed to distinct crystallographic locations through Density Functional Theory (DFT) calculations. The developed method was used to reliably determine the likelihood of the position of a proton in ZSM-5 zeolites under catalytically relevant conditions (T> 423 K), which has so far never been achieved by any other technique.
- Published
- 2018
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