1,460 results on '"Herberg, A"'
Search Results
2. Edmond Fischer's kinase legacy: History of the protein kinase inhibitor and protein kinase A
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Susan S. Taylor, Friedrich W Herberg, Gianluigi Veglia, and Jian Wu
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Clinical Biochemistry ,Genetics ,Cell Biology ,Molecular Biology ,Biochemistry - Published
- 2023
3. Case Management für Personen mit Pflegebedarf und gebrechliche ältere Personen
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Stephan Herberg, Frank Teuteberg, and Jürgen Zerth
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Health Policy - Abstract
ZusammenfassungEine wachsende Fallschwere, höheres Lebensalter und teilweise nicht vorhandene familiäre Betreuungsnetze führen dazu, dass die Koordination von medizinisch-pflegerischen Leistungen und sozialen Unterstützungsleistungen nicht in jedem Fall zu einer adäquaten Versorgungssituation beitragen. Um Menschen soweit als möglich im eigenen Lebens- und Betreuungsumfeld zu halten, ist ein adjustierter Care-Mix zwischen Familienpflege und professioneller Pflege notwendig.Die Betreuung eines vulnerablen Personenkreises durch professionelle wie informelle Akteure bedarf allerdings einer professionellen Koordination. Das Prinzip des Case Managements kann in fast idealtypischer Weise eingesetzt werden, um professionelle und informelle Akteure in einen Care-Prozess zu integrieren und sowohl medizinische Leistungen als auch Pflege- und Betreuungsleistungen im dazu nötigen Setting auszubalancieren.Eine stärke Koordination von Pflegeleistungen ist als Notwendigkeit weithin anerkannt. In verschiedenen Projektansätzen werden Ansätze wie Case Management, Pflegelosten, professionelle Krankenhausnachbetreuung und Gemeindeschwesteransätze erprobt und gelebt.Die Auswertung internationaler Studien im Bereich des Case Managements zeigen grundsätzlich eine proaktivere Herangehensweise an, mit der Empfehlung, eine für ein zielführendes Case Management frühzeitigere und spezifischere Fallauswahl vorzunehmen. Die klare Definition der Einschlusskriterien, die Konzentration auf Patient*innen mit einer hohen Wiederaufnahmewahrscheinlichkeit und ein intensives Case Management können so zu effektiveren Versorgungsergebnissen und reduzierten Inanspruchnahmen von Leistungen führen.In diesem Beitrag soll die Frage diskutiert werden, ob die bestehenden Beratungs- und Lotsenangebote gebündelt, fusioniert und zu einer Case Management-Organisation weiterentwickelt werden können. Insbesondere, falls sich die bestehenden Angebote überschneiden und vorhandene Ressourcen nicht ausreichend koordiniert werden.Es sollen insbesondere Organisationsstrukturen aufgezeigt werden, in denen Case Management langfristig verortet werden könnte. Hier gilt es die Bedeutung der eigenständigen pflegeinfrastrukturellen Rolle eines erweiterten Case Managements zu verdeutlichen.
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- 2023
4. TGFβ2 Regulates Human Trabecular Meshwork Cell Contractility
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Haiyan, Li, Jessica L, Henty-Ridilla, Audrey M, Bernstein, Preethi S, Ganapathy, and Samuel, Herberg
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Transforming Growth Factor beta2 ,Trabecular Meshwork ,Humans ,Hydrogels ,Extracellular Signal-Regulated MAP Kinases ,Actins ,Cells, Cultured ,Glaucoma, Open-Angle ,Signal Transduction - Abstract
Transforming growth factor-beta 2 (TGFβ2) is a major contributor to the pathologic changes occurring in human trabecular meshwork (HTM) cells in primary open-angle glaucoma (POAG). TGFβ2 activates extracellular-signal-regulated kinase (ERK) and Rho-associated kinase (ROCK) signaling pathways, both affecting HTM cell behavior. However, exactly how these signaling pathways converge to regulate HTM cell contractility is unclear. Here, we investigated the molecular mechanism underlying TGFβ2-induced pathologic HTM cell contractility, and the crosstalk between ERK and ROCK signaling pathways with different culture substrates.Hydrogels were engineered by mixing collagen type I, elastin-like polypeptide, and hyaluronic acid, each containing photoactive functional groups, followed by UV crosslinking. Primary HTM cells were seeded atop pre-formed hydrogels for comparisons with glass, or encapsulated within the hydrogels. Changes in actin cytoskeleton, extracellular matrix (ECM) production, phospho-myosin light chain (p-MLC) levels, and hydrogel contraction were assessed.HTM cell morphology and filamentous (F)-actin organization were affected by the underlying culture substrates. TGFβ2 increased HTM cell contractilityOur data suggest that ERK signaling negatively regulates ROCK-mediated HTM cell contractility. These findings emphasize the critical importance of using tissue-mimetic ECM substrates for investigating HTM cell physiology and glaucomatous pathophysiology
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- 2023
5. Moral rifts in the coal phase-out-how mayors shape distributive and recognition-based dimensions of a just transition in Lusatia
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Jeremias Herberg and Konrad Gürtler
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Philosophy and Science Studies ,Rift ,Distributive property ,business.industry ,Transition (fiction) ,Phase (matter) ,Political science ,Geometry ,Coal ,Management, Monitoring, Policy and Law ,business - Abstract
Transitions towards low-carbon societies trigger renegotiations of justice concerns in regions that have to abandon unsustainable, fossil-based production patterns. In these transition regions, tensions may appear between inner- and supra-regional justice claims on the one hand, and recognition-based and distributional justice concerns on the other. Intermediary actors such as municipal politicians have to navigate these spatial and moral tensions. Based on qualitative data generated in the German lignite-mining region of Lusatia, ‘moral rifts’ are reconstructed that shape local perceptions of justice. These rifts help elucidate how reconciliation in this region proves to be difficult despite considerable redistributive efforts. Unless patterns of misrecognition are adequately addressed, prospects for a successful transformation of the region remain limited.
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- 2023
6. Variational discretization of one-dimensional elliptic optimal control problems with BV functions based on the mixed formulation
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Evelyn Herberg
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Control and Optimization ,Applied Mathematics - Published
- 2023
7. Energy spaces: bridging scales and standpoints of just energy transitions
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Jeremias Herberg, Emily Drewing, Julia-Lena Reinermann, Jörg Radtke, Michael LaBelle, Ana Stojilovska, and Konrad Gürtler
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Philosophy and Science Studies ,Management, Monitoring, Policy and Law - Abstract
Contains fulltext : 293302.pdf (Publisher’s version ) (Closed access)
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- 2023
8. Pick Your Threshold
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Elisabetta Salvioni, Massimo Mapelli, Alice Bonomi, Damiano Magrì, Massimo Piepoli, Maria Frigerio, Stefania Paolillo, Ugo Corrà, Rosa Raimondo, Rocco Lagioia, Roberto Badagliacca, Pasquale Perrone Filardi, Michele Senni, Michele Correale, Mariantonietta Cicoira, Enrico Perna, Marco Metra, Marco Guazzi, Giuseppe Limongelli, Gianfranco Sinagra, Gianfranco Parati, Gaia Cattadori, Francesco Bandera, Maurizio Bussotti, Federica Re, Carlo Vignati, Carlo Lombardi, Angela B. Scardovi, Susanna Sciomer, Andrea Passantino, Michele Emdin, Claudio Passino, Caterina Santolamazza, Davide Girola, Denise Zaffalon, Fabiana De Martino, Piergiuseppe Agostoni, Stefania Farina, Beatrice Pezzuto, Anna Apostolo, Pietro Palermo, Mauro Contini, Paola Gugliandolo, Irene Mattavelli, Michele Della Rocca, Giovanna Gallo, Federica Moscucci, Anita Iorio, Geza Halasz, Bruno Capelli, Simone Binno, Giuseppe Pacileo, Fabio Valente, Rossella Vastarella, Cosimo Carriere, Marco Masè, Marco Cittar, Andrea Di Lenarda, Sergio Caravita, Elena Viganò, Giovanni Marchese, Roberto Ricci, Luca Arcari, Domenico Scrutinio, Elisa Battaia, Michele Moretti, Maria Vittoria Matassini, Matilda Shkoza, Roland Herberg, Antonio Cittadini, Andrea Salzano, Alberto Marra, Eluisa Lafranca, and Giuseppe Vitale
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Pulmonary and Respiratory Medicine ,Cardiology and Cardiovascular Medicine ,Critical Care and Intensive Care Medicine - Published
- 2022
9. Correction to: Guideline adherence in febrile children below 3 months visiting European Emergency Departments: an observational multicenter study
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Tan, Chantal D, van der Walle, Eline E P L, Vermont, Clementien L, von Both, Ulrich, Carrol, Enitan D, Eleftheriou, Irini, Emonts, Marieke, van der Flier, Michiel, de Groot, Ronald, Herberg, Jethro, Kohlmaier, Benno, Levin, Michael, Lim, Emma, Maconochie, Ian K, Martinon-Torres, Federico, Nijman, Ruud G, Pokorn, Marko, Rivero-Calle, Irene, Tsolia, Maria, Yeung, Shunmay, Zenz, Werner, Zavadska, Dace, Moll, Henriëtte A, University of Zurich, and Moll, Henriëtte A
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Pediatrics, Perinatology and Child Health ,610 Medicine & health ,2735 Pediatrics, Perinatology and Child Health ,Perinatology and Child Health ,10027 Clinic for Neonatology ,Pediatrics - Published
- 2022
10. Atrioventricular Coupling in Infants and Children Assessed by Three-Dimensional Echocardiography
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Katharina Linden, Florian Otte, Christian Winkler, Kai Thorsten Laser, Franziska Goldschmidt, Johannes Breuer, and Ulrike Herberg
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Adult ,Ventricular Dysfunction, Left ,Diastole ,Echocardiography, Three-Dimensional ,Infant, Newborn ,Humans ,Atrial Function, Left ,Stroke Volume ,Radiology, Nuclear Medicine and imaging ,Heart Atria ,Child ,Cardiology and Cardiovascular Medicine ,Ventricular Function, Left - Abstract
Parameters of the interaction of the left atrium and left ventricle, atrioventricular (AV) coupling, are used in the diagnosis and follow-up of diastolic dysfunction in adults. Pediatric parameters of AV coupling have not been evaluated so far. The aim of this multicenter study was to investigate parameters of AV coupling in a large cohort of healthy infants and children using noninvasive real-time three-dimensional echocardiography. The authors hypothesized that the contribution of the different left atrial (LA) volumes to left ventricular (LV) stroke volume differs over a range of different heart rates.Three-dimensional echocardiographic data sets from 332 subjects (ages 0 days to 18.5 years) were analyzed prospectively. Volume-time curves of the left atrium and left ventricle were generated. Conduit volume was calculated and percentiles were established by the lambda-mu-sigma method of Cole and Green. Contributions of active, passive, and conduit volume to LV filling were measured and related to heart rate by linear regression. LV and LA peak filling rates (PFR) and peak emptying rates (PER) and time to PFR and PER normalized to the R-R interval (PFRConduit volume increased with body surface area. The contribution of LA active emptying to LV filling tended to increase with decreasing heart rate, while the contribution of passive emptying decreased. Conduit volume contributed most to LV filling (median, 57.58 %; interquartile range, 12.85%) with a tendency to increase with decreasing heart rate. Close diastolic AV coupling was demonstrated by virtually identical LV PFRAssessment of conduit volume and AV coupling by three-dimensional echocardiography is feasible in infants and children. The references of this study can serve as a basis to further investigate the role of parameters of AV coupling in pediatric patients with heart diseases concerning diastolic and LA function.
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- 2022
11. Segmental and global longitudinal strain differences between Kawasaki disease and multi-system inflammatory syndrome in children
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Enrico Piccinelli, Carles Bautista-Rodriguez, Jethro Herberg, Heechan Kang, Sylvia Krupickova, Ivan B Altamar, Sara Moscatelli, Jolanda Sabatino, Manjit Josen, Josefa Paredes, Elisabeth Whittaker, Yogen Singh, Alain Fraisse, and Giovanni Di Salvo
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COVID-19 ,Kawasaki disease ,Multi-system inflammatory syndrome ,SARS-CoV-2 ,global longitudinal strain ,Pediatrics, Perinatology and Child Health ,General Medicine ,Cardiology and Cardiovascular Medicine - Abstract
Background: Multi-system inflammatory syndrome in children and Kawasaki disease have overlapping clinical features but comparative echocardiographic studies are lacking. Methods: We reviewed echocardiography findings of all multi-system inflammatory syndrome cases between 1st April and 31st July, 2020 and typical Kawasaki disease patients with coronary arteries abnormalities consecutively followed between 1st October, 2016 and June 30th, 2019. Results: We included 40 multi-system inflammatory syndrome children (25 males, 62.5%) and 45 Kawasaki disease patients (31 males, 68.9%) at a mean age of 6.4 years old and 8 years old, respectively. Four out of 40 multi-system inflammatory syndrome children had coronary arteries abnormalities. Left ventricle ejection fraction was normal in both groups. Global longitudinal strain was normal although Kawasaki disease group had significantly lower values (–20.0 versus –21.7%; p = 0.02). Basal segments were the most affected in Kawasaki disease patients with significant differences in the basal anterior, anterolateral, and anteroseptal strain: –18.2 versus –23.0% (p = 0.002), –16.7 versus –22.0% (p < 0.001), –16.7 versus –19.5% (p = 0.034), respectively. The basal anterolateral and anteroseptal segments in Kawasaki disease patients were the only ones with an absolute reduction of longitudinal strain (–16.7% both) consistent with the greater left main coronary involvement in this cohort. Conclusions: Our findings are consistent with the transient cardiac involvement in multi-system inflammatory syndrome, as opposed to the subtle and chronic myocardial involvement in Kawasaki disease children with coronary arteries abnormalities. We speculate that the mechanism of cardiac impairment in the few multi-system inflammatory syndrome children with reduced global longitudinal strain is not related to coronary arteries abnormalities.
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- 2022
12. Relationship between molecular pathogen detection and clinical disease in febrile children across Europe: a multicentre, prospective observational study
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Herberg, J, Shah, P, Voice, M, Calvo-Bado, L, Rivero Calle, I, Morris, S, Nijman, R, Broderick, C, De, T, Eleftheriou, I, Galassini, R, Khanijau, A, Kolberg, L, Kolnik, M, Rudzate, A, Sagmeister, M, Schweintzger, N, Secka, F, Thakker, C, Van der Velden, F, Vermont, C, Vincek, K, Agyeman, P, Cunnington, A, De Groot, R, Emonts, M, Fidler, K, Kuijpers, T, Mommert-Tripon, M, Brengel-Pesce, K, Mallet, F, Moll, H, Paulus, S, Pokorn, M, Pollard, A, Schlapbach, L, Shen, C-F, Tsolia, M, Usuf, E, Van Der Flier, M, Von Both, U, Yeung, S, Zavadska, D, Zenz, W, Wright, V, Carrol, E, Kaforou, M, Martinon-Torres, F, Fink, C, Levin, M, and PERFORM consortium
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The PERFORM study aimed to understand causes of febrile childhood illness by comparing molecular pathogen detection with current clinical practice. Methods. Febrile children and controls were recruited on presentation to hospital in 9 European countries 2016-2020. Each child was assigned a standardized diagnostic category based on retrospective review of local clinical and microbiological data. Subsequently, centralised molecular tests (CMTs) for 19 respiratory and 27 blood pathogens were performed. Findings. Of 4,611 febrile children, 643 (14%) were classified as definite bacterial infection (DB), 491 (11%) as definite viral infection (DV), and 3,477 (75%) had uncertain aetiology. 1,061 controls without infection were recruited. CMTs detected blood bacteria more frequently in DB than DV cases for N.meningitidis (OR: 3.37, 95% CI: 1.92 – 5.99), S.pneumoniae (OR: 3.89, 95% CI: 2.07 – 7.59), Group A streptococcus (OR 2.73, 95% CI 1.13 – 6.09) and E.coli (OR 2.7, 95% CI 1.02 – 6.71). Respiratory viruses were more common in febrile children than controls, but only influenza A (OR 0.24, 95% CI 0.11 – 0.46), Influenza B (OR 0.12, 95% CI 0.02 – 0.37) and RSV (OR 0.16, 95% CI: 0.06 – 0.36) were less common in DB than DV cases. Of 16 blood viruses, enterovirus (OR 0.43, 95% CI 0.23 – 0.72) and EBV (OR 0.71, 95% CI 0.56 – 0.90) were detected less often in DB than DV cases. Combined local diagnostics and CMTs respectively detected blood viruses and respiratory viruses in 360 (56%) and 161 (25%) of DB cases, and virus detection ruled-out bacterial infection poorly, with predictive values of 0.64 and 0.68 respectively. Interpretation. Most febrile children cannot be conclusively defined as having bacterial or viral infection when molecular tests supplement conventional approaches. Viruses are detected in most patients with bacterial infections, and the clinical value of individual pathogen detection in determining treatment is low. New approaches are needed to help determine which febrile children require antibiotics.
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- 2023
13. Diagnosis of Multisystem Inflammatory Syndrome in Children by a Whole-Blood Transcriptional Signature
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Jackson, Heather R, Miglietta, Luca, Habgood-Coote, Dominic, D'Souza, Giselle, Shah, Priyen, Nichols, Samuel, Vito, Ortensia, Powell, Oliver, Davidson, Maisey Salina, Shimizu, Chisato, Agyeman, Philipp K A, Beudeker, Coco R, Brengel-Pesce, Karen, Carrol, Enitan D, Carter, Michael J, De, Tisham, Eleftheriou, Irini, Emonts, Marieke, Epalza, Cristina, Georgiou, Pantelis, De Groot, Ronald, Fidler, Katy, Fink, Colin, van Keulen, Daniëlle, Kuijpers, Taco, Moll, Henriette, Papatheodorou, Irene, Paulus, Stephane, Pokorn, Marko, Pollard, Andrew J, Rivero-Calle, Irene, Rojo, Pablo, Secka, Fatou, Schlapbach, Luregn J, Tremoulet, Adriana H, Tsolia, Maria, Usuf, Effua, Van Der Flier, Michiel, Von Both, Ulrich, Vermont, Clementien, Yeung, Shunmay, Zavadska, Dace, Zenz, Werner, Coin, Lachlan J M, Cunnington, Aubrey, Burns, Jane C, Wright, Victoria, Martinon-Torres, Federico, Herberg, Jethro A, Rodriguez Manzano, Jesus, Kaforou, Myrsini, and Levin, Michael
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Pediatric ,screening and diagnosis ,lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4] ,COVID-19 ,610 Medicine & health ,MIS-C ,Mucocutaneous Lymph Node Syndrome ,Hospitals ,Systemic Inflammatory Response Syndrome ,rapid diagnostics ,4.1 Discovery and preclinical testing of markers and technologies ,transcriptomics ,Detection ,All institutes and research themes of the Radboud University Medical Center ,COVID-19 Testing ,host diagnostics ,Infectious Diseases ,diagnostic signature ,Genetics ,Humans ,host response ,Child ,pediatric infectious diseases - Abstract
Contains fulltext : 294537.pdf (Publisher’s version ) (Open Access) BACKGROUND: To identify a diagnostic blood transcriptomic signature that distinguishes multisystem inflammatory syndrome in children (MIS-C) from Kawasaki disease (KD), bacterial infections, and viral infections. METHODS: Children presenting with MIS-C to participating hospitals in the United Kingdom and the European Union between April 2020 and April 2021 were prospectively recruited. Whole-blood RNA Sequencing was performed, contrasting the transcriptomes of children with MIS-C (n = 38) to those from children with KD (n = 136), definite bacterial (DB; n = 188) and viral infections (DV; n = 138). Genes significantly differentially expressed (SDE) between MIS-C and comparator groups were identified. Feature selection was used to identify genes that optimally distinguish MIS-C from other diseases, which were subsequently translated into RT-qPCR assays and evaluated in an independent validation set comprising MIS-C (n = 37), KD (n = 19), DB (n = 56), DV (n = 43), and COVID-19 (n = 39). RESULTS: In the discovery set, 5696 genes were SDE between MIS-C and combined comparator disease groups. Five genes were identified as potential MIS-C diagnostic biomarkers (HSPBAP1, VPS37C, TGFB1, MX2, and TRBV11-2), achieving an AUC of 96.8% (95% CI: 94.6%-98.9%) in the discovery set, and were translated into RT-qPCR assays. The RT-qPCR 5-gene signature achieved an AUC of 93.2% (95% CI: 88.3%-97.7%) in the independent validation set when distinguishing MIS-C from KD, DB, and DV. CONCLUSIONS: MIS-C can be distinguished from KD, DB, and DV groups using a 5-gene blood RNA expression signature. The small number of genes in the signature and good performance in both discovery and validation sets should enable the development of a diagnostic test for MIS-C.
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- 2023
14. Proof of concept of an accelerometer as a trigger for unilateral diaphragmatic pacing: a porcine model
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Kratz, Tobias, Ruff, Roman, Koch, Timo, Kronberg, Anne-Sophie, Breuer, Johannes, Asfour, Boulos, Herberg, Ulrike, Bierbach, Benjamin, and Publica
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Biomaterials ,Radiological and Ultrasound Technology ,Biomedical Engineering ,Radiology, Nuclear Medicine and imaging ,General Medicine - Abstract
Background Unilateral diaphragmatic paralysis in patients with univentricular heart is a known complication after pediatric cardiac surgery. Because diaphragmatic excursion has a significant influence on perfusion of the pulmonary arteries and hemodynamics in these patients, unilateral loss of function leads to multiple complications. The current treatment of choice, diaphragmatic plication, does not lead to a full return of function. A unilateral diaphragmatic pacemaker has shown potential as a new treatment option. In this study, we investigated an accelerometer as a trigger for a unilateral diaphragm pacemaker (closed-loop system). Methods Seven pigs (mean weight 20.7 ± 2.25 kg) each were implanted with a customized accelerometer on the right diaphragmatic dome. Accelerometer recordings (mV) of the diaphragmatic excursion of the right diaphragm were compared with findings using established methods (fluoroscopy [mm]; ultrasound, M-mode [cm]). For detection of the amplitude of diaphragmatic excursions, the diaphragm was stimulated with increasing amperage by a cuff electrode implanted around the right phrenic nerve. Results Results with the different techniques for measuring diaphragmatic excursions showed correlations between accelerometer and fluoroscopy values (correlation coefficient 0.800, P P P Conclusion The accelerometer is a valid method for detecting diaphragmatic excursion and can be used as a trigger for a unilateral diaphragmatic pacemaker.
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- 2023
15. Capturing the domain crosstalk in full length LRRK2 and LRRK2RCKW
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Störmer, Eliza, Weng, Jui-Hung, Wu, Jian, Bertinetti, Daniela, Kaila Sharma, Pallavi, Ma, Wen, Herberg, Friedrich W, and Taylor, Susan
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Biochemistry & Molecular Biology ,GTPases ,Neurosciences ,Cell Biology ,Neurodegenerative ,Biological Sciences ,Medical and Health Sciences ,Biochemistry ,molecular dynamics ,Brain Disorders ,kinases ,Parkinsons disease ,Neurological ,Chemical Sciences ,leucine rich repeat kinase ,2.1 Biological and endogenous factors ,Aetiology ,Molecular Biology - Abstract
LRRK2 is a multi-domain protein with three catalytically inert N-terminal domains (NtDs) and four C-terminal domains, including a kinase and a GTPase domain. LRRK2 mutations are linked to Parkinson's Disease. Recent structures of LRRK2RCKW and a full-length inactive LRRK2 (fl-LRRK2INACT) monomer revealed that the kinase domain drives LRRK2 activation. The LRR domain and also an ordered LRR- COR linker, wrap around the C-lobe of the kinase domain and sterically block the substrate binding surface in fl-LRRK2INACT. Here we focus on the crosstalk between domains. Our biochemical studies of GTPase and kinase activities of fl-LRRK2 and LRRK2RCKW reveal how mutations influence this crosstalk differently depending on the domain borders investigated. Furthermore, we demonstrate that removing the NtDs leads to altered intramolecular regulation. To further investigate the crosstalk, we used Hydrogen-Deuterium exchange Mass Spectrometry (HDX-MS) to characterize the conformation of LRRK2RCKW and Gaussian Accelerated Molecular Dynamics (GaMD) to create dynamic portraits of fl-LRRK2 and LRRK2RCKW. These models allowed us to investigate the dynamic changes in wild type and mutant LRRK2s. Our data show that the a3ROC helix, the Switch II motif in the ROC domain, and the LRR-ROC linker play crucial roles in mediating local and global conformational changes. We demonstrate how these regions are affected by other domains in fl-LRRK2 and LRRK2RCKW and show how unleashing of the NtDs as well as PD mutations lead to changes in conformation and dynamics of the ROC and kinase domains which ultimately impact kinase and GTPase activities. These allosteric sites are potential therapeutic targets.
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- 2023
16. TGFβ2 Regulates Human Trabecular Meshwork Cell ContractilityviaERK and ROCK Pathways with Distinct Signaling Crosstalk Dependent on the Culture Substrate
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Haiyan Li, Jessica L. Henty-Ridilla, Audrey M. Bernstein, Preethi S. Ganapathy, and Samuel Herberg
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Cellular and Molecular Neuroscience ,Ophthalmology ,Sensory Systems - Published
- 2022
17. Gαs–Protein Kinase A (PKA) Pathway Signalopathies: The Emerging Genetic Landscape and Therapeutic Potential of Human Diseases Driven by Aberrant Gαs-PKA Signaling
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Dana J. Ramms, J. Silvio Gutkind, Francesco Raimondi, Friedrich W. Herberg, Nadia Arang, Susan S. Taylor, Ramms, D. J., Raimondi, F., Arang, N., Herberg, F. W., Taylor, S. S., and Gutkind, J. S.
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Pharmacology ,Regulation of gene expression ,Gs alpha subunit ,biology ,Settore BIO/11 - Biologia Molecolare ,Computational biology ,Disease ,Genomic Medicine ,Infectious disease (medical specialty) ,GTP-Binding Protein alpha Subunits, G ,Mutation ,GNAS complex locus ,biology.protein ,Molecular Medicine ,Cyclic AMP-Dependent Protein Kinase ,Kinase activity ,Signal transduction ,Protein kinase A ,Human ,Signal Transduction - Abstract
Many of the fundamental concepts of signal transduction and kinase activity are attributed to the discovery and crystallization of cAMP-dependent protein kinase, or protein kinase A. PKA is one of the best-studied kinases in human biology, with emphasis in biochemistry and biophysics, all the way to metabolism, hormone action, and gene expression regulation. It is surprising, however, that our understanding of PKA's role in disease is largely underappreciated. Although genetic mutations in the PKA holoenzyme are known to cause diseases such as Carney complex, Cushing syndrome, and acrodysostosis, the story largely stops there. With the recent explosion of genomic medicine, we can finally appreciate the broader role of the Gαs-PKA pathway in disease, with contributions from aberrant functioning G proteins and G protein-coupled receptors, as well as multiple alterations in other pathway components and negative regulators. Together, these represent a broad family of diseases we term the Gαs-PKA pathway signalopathies. The Gαs-PKA pathway signalopathies encompass diseases caused by germline, postzygotic, and somatic mutations in the Gαs-PKA pathway, with largely endocrine and neoplastic phenotypes. Here, we present a signaling-centric review of Gαs-PKA-driven pathophysiology and integrate computational and structural analysis to identify mutational themes commonly exploited by the Gαs-PKA pathway signalopathies. Major mutational themes include hotspot activating mutations in Gαs, encoded by GNAS, and mutations that destabilize the PKA holoenzyme. With this review, we hope to incite further study and ultimately the development of new therapeutic strategies in the treatment of a wide range of human diseases. SIGNIFICANCE STATEMENT: Little recognition is given to the causative role of Gαs-PKA pathway dysregulation in disease, with effects ranging from infectious disease, endocrine syndromes, and many cancers, yet these disparate diseases can all be understood by common genetic themes and biochemical signaling connections. By highlighting these common pathogenic mechanisms and bridging multiple disciplines, important progress can be made toward therapeutic advances in treating Gαs-PKA pathway-driven disease.
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- 2021
18. Plasma neurodegeneration biomarker concentrations associate with glymphatic and meningeal lymphatic measures in neurological disorders
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Per Kristian Eide, Aslan Lashkarivand, Are Pripp, Lars Magnus Valnes, Markus Herberg Hovd, Geir Ringstad, Kaj Blennow, and Henrik Zetterberg
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Multidisciplinary ,General Physics and Astronomy ,General Chemistry ,General Biochemistry, Genetics and Molecular Biology - Abstract
Clearance of neurotoxic brain proteins via cerebrospinal fluid (CSF) to blood has recently emerged to be crucial, and plasma biomarkers of neurodegeneration were newly introduced to predict neurological disease. This study examines in 106 individuals with neurological disorders associations between plasma biomarkers [40 and 42 amino acid-long amyloid-β (Aβ40 and Aβ42), total-tau, glial fibrillary acidic protein (GFAP), and neurofilament light (NfL)] and magnetic resonance imaging measures of CSF-mediated clearance from brain via extra-vascular pathways (proxy of glymphatic function) and CSF-to-blood clearance variables from pharmacokinetic modeling (proxy of meningeal lymphatic egress). We also examine how biomarkers vary during daytime and associate with subjective sleep quality. Plasma concentrations of neurodegeneration markers associate with indices of glymphatic and meningeal lymphatic functions in individual- and disease-specific manners, vary during daytime, but are unaffected by sleep quality. The results suggest that plasma concentrations of neurodegeneration biomarkers associate with measures of glymphatic and meningeal lymphatic function.
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- 2023
19. Immunoglobulin, glucocorticoid, or combination therapy for multisystem inflammatory syndrome in children: a propensity-weighted cohort study
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Channon-Wells, Samuel, Vito, Ortensia, McArdle, Andrew J, Seaby, Eleanor G, Patel, Harsita, Shah, Priyen, Pazukhina, Ekaterina, Wilson, Clare, Broderick, Claire, D'Souza, Giselle, Keren, Ilana, Nijman, Ruud G, Tremoulet, Adriana, Munblit, Daniel, Ulloa-Gutierrez, Rolando, Carter, Michael J, Ramnarayan, Padmanabhan, De, Tisham, Hoggart, Clive, Whittaker, Elizabeth, Herberg, Jethro A, Kaforou, Myrsini, Cunnington, Aubrey J, Blyuss, Oleg, Levin, Michael, and Best Available Treatment Study (BATS) consortium
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Best Available Treatment Study (BATS) consortium ,Comparative Effectiveness Research ,Clinical Research ,6.1 Pharmaceuticals ,Evaluation of treatments and therapeutic interventions - Abstract
BackgroundMultisystem inflammatory syndrome in children (MIS-C), a hyperinflammatory condition associated with SARS-CoV-2 infection, has emerged as a serious illness in children worldwide. Immunoglobulin or glucocorticoids, or both, are currently recommended treatments.MethodsThe Best Available Treatment Study evaluated immunomodulatory treatments for MIS-C in an international observational cohort. Analysis of the first 614 patients was previously reported. In this propensity-weighted cohort study, clinical and outcome data from children with suspected or proven MIS-C were collected onto a web-based Research Electronic Data Capture database. After excluding neonates and incomplete or duplicate records, inverse probability weighting was used to compare primary treatments with intravenous immunoglobulin, intravenous immunoglobulin plus glucocorticoids, or glucocorticoids alone, using intravenous immunoglobulin as the reference treatment. Primary outcomes were a composite of inotropic or ventilator support from the second day after treatment initiation, or death, and time to improvement on an ordinal clinical severity scale. Secondary outcomes included treatment escalation, clinical deterioration, fever, and coronary artery aneurysm occurrence and resolution. This study is registered with the ISRCTN registry, ISRCTN69546370.FindingsWe enrolled 2101 children (aged 0 months to 19 years) with clinically diagnosed MIS-C from 39 countries between June 14, 2020, and April 25, 2022, and, following exclusions, 2009 patients were included for analysis (median age 8·0 years [IQR 4·2-11·4], 1191 [59·3%] male and 818 [40·7%] female, and 825 [41·1%] White). 680 (33·8%) patients received primary treatment with intravenous immunoglobulin, 698 (34·7%) with intravenous immunoglobulin plus glucocorticoids, 487 (24·2%) with glucocorticoids alone; 59 (2·9%) patients received other combinations, including biologicals, and 85 (4·2%) patients received no immunomodulators. There were no significant differences between treatments for primary outcomes for the 1586 patients with complete baseline and outcome data that were considered for primary analysis. Adjusted odds ratios for ventilation, inotropic support, or death were 1·09 (95% CI 0·75-1·58; corrected p value=1·00) for intravenous immunoglobulin plus glucocorticoids and 0·93 (0·58-1·47; corrected p value=1·00) for glucocorticoids alone, versus intravenous immunoglobulin alone. Adjusted average hazard ratios for time to improvement were 1·04 (95% CI 0·91-1·20; corrected p value=1·00) for intravenous immunoglobulin plus glucocorticoids, and 0·84 (0·70-1·00; corrected p value=0·22) for glucocorticoids alone, versus intravenous immunoglobulin alone. Treatment escalation was less frequent for intravenous immunoglobulin plus glucocorticoids (OR 0·15 [95% CI 0·11-0·20]; p
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- 2023
20. Biomechanical analysis of different fixed dental restorations on short implants: a finite element study
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Christian Wagner, Samira Herberg, Christoph Bourauel, Helmut Stark, and Istabrak Dörsam
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Biomedical Engineering - Abstract
Objectives Although the use of short implants is becoming more common for patients with atrophic alveolar ridges, their use is still quite limited. This is due to the lack of data of long-term survival compared to standard-length implants. The aim of this study was to determine the load in the bone and implant system with different superstructures. Methods Three kinds of prosthetic restorations were created on short implants based on CT-Data. Two short implants with different macro-geometries were used. The implants were inserted in idealised posterior lower mandibular segments and afterwards restored with a crown, a double splinted crown, and a bridge. Results The analysis was performed under load of 300 N either divided between a mesial and distal point or as a point load on the pontic/mesial crown. The different design of the implant systems had a noticeable influence on the stress in the cortical bone, in the implant system, and the displacement of the superstructure as well. Conclusions Compared with implants of standard length, higher stresses were observed, which can lead early failure of the implant during the healing period or a late cervical bone resorption. Precise indications are essential for short implants to avoid the failure of short implants.
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- 2023
21. Prediction of postnatal circulation in pulmonary atresia/critical stenosis with intact ventricular septum: systematic review and external validation of models
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C. Villalaín, A. J. Moon‐Grady, U. Herberg, J. Strainic, J. L. Cohen, A. Shah, D. S. Levi, E. Gómez‐Montes, I. Herraiz, and A. Galindo
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Reproductive Medicine ,Radiological and Ultrasound Technology ,Obstetrics and Gynecology ,Radiology, Nuclear Medicine and imaging ,General Medicine - Published
- 2023
22. Fetal Cardiac Cine MRI with Doppler US Gating in Complex Congenital Heart Disease
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Thomas M. Vollbrecht, Christopher Hart, Shuo Zhang, Christoph Katemann, Alexander Isaak, Claus C. Pieper, Daniel Kuetting, Bettina Faridi, Brigitte Strizek, Ulrike Attenberger, Florian Kipfmueller, Ulrike Herberg, Annegret Geipel, and Julian A. Luetkens
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Radiology, Nuclear Medicine and imaging ,Original Research - Abstract
PURPOSE: To apply Doppler US (DUS)–gated fetal cardiac cine MRI in clinical routine and investigate diagnostic performance in complex congenital heart disease (CHD) compared with that of fetal echocardiography. MATERIALS AND METHODS: In this prospective study (May 2021 to March 2022), women with fetuses with CHD underwent fetal echocardiography and DUS-gated fetal cardiac MRI on the same day. For MRI, balanced steady-state free precession cine images were acquired in the axial and optional sagittal and/or coronal orientations. Overall image quality was assessed on a four-point Likert scale (from 1 = nondiagnostic to 4 = good image quality). The presence of abnormalities in 20 fetal cardiovascular features was independently assessed by using both modalities. The reference standard was postnatal examination results. Differences in sensitivities and specificities were determined by using a random-effects model. RESULTS: The study included 23 participants (mean age, 32 years ± 5 [SD]; mean gestational age, 36 weeks ± 1). Fetal cardiac MRI was completed in all participants. The median overall image quality of DUS-gated cine images was 3 (IQR, 2.5–4). In 21 of 23 participants (91%), underlying CHD was correctly assessed by using fetal cardiac MRI. In one case, the correct diagnosis was made by using MRI only (situs inversus and congenitally corrected transposition of the great arteries). Sensitivities (91.8% [95% CI: 85.7, 95.1] vs 93.6% [95% CI: 88.8, 96.2]; P = .53) and specificities (99.9% [95% CI: 99.2, 100] vs 99.9% [95% CI: 99.5, 100]; P > .99) for the detection of abnormal cardiovascular features were comparable between MRI and echocardiography, respectively. CONCLUSION: Using DUS-gated fetal cine cardiac MRI resulted in performance comparable with that of using fetal echocardiography for diagnosing complex fetal CHD. Keywords: Pediatrics, MR-Fetal (Fetal MRI), Cardiac, Heart, Congenital, Fetal Imaging, Cardiac MRI, Prenatal, Congenital Heart Disease Clinical trial registration no. NCT05066399 Supplemental material is available for this article. © RSNA, 2023 See also the commentary by Biko and Fogel in this issue.
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- 2023
23. Febrile illness in high-risk children: a prospective, international observational study
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van der Velden, Fabian J. S., de Vries, Gabriella, Martin, Alexander, Lim, Emma, von Both, Ulrich, Kolberg, Laura, Carrol, Enitan D., Khanijau, Aakash, Herberg, Jethro A., De, Tisham, Galassini, Rachel, Kuijpers, Taco W., Martinón-Torres, Federico, Rivero-Calle, Irene, Vermont, Clementien L., Hagedoorn, Nienke N., Pokorn, Marko, Pollard, Andrew J., Schlapbach, Luregn J., Tsolia, Maria, Elefhteriou, Irini, Yeung, Shunmay, Zavadska, Dace, Fink, Colin, Voice, Marie, Zenz, Werner, Kohlmaier, Benno, Agyeman, Philipp K. A., Usuf, Effua, Secka, Fatou, de Groot, Ronald, Levin, Michael, van der Flier, Michiel, Emonts, Marieke, Cunnington, Aubrey, Herberg, Jethro, Kaforou, Myrsini, Wright, Victoria, Baumard, Lucas, Bellos, Evangelos, D’Souza, Giselle, Habgood-Coote, Dominic, Hamilton, Shea, Hoggart, Clive, Hourmat, Sara, Jackson, Heather, Maconochie, Ian, Menikou, Stephanie, Lin, Naomi, Nichols, Samuel, Nijman, Ruud, Powell, Oliver, Pena Paz, Ivonne, Shah, Priyen, Shen, Ching-Fen, Vito, Ortensia, Wilson, Clare, Abdulla, Amina, Ali, Ladan, Darnell, Sarah, Jorgensen, Rikke, Mustafa, Sobia, Persand, Salina, Stevens, Molly M., Kim, Nayoung, Kim, Eunjung, Fidler, Katy, Dudley, Julia, Richmond, Vivien, Tavliavini, Emma, Liu, Ching-Chuan, Wang, Shih-Min, Salas, Antonio, Álvez González, Fernando, Balo Farto, Cristina, Barral-Arca, Ruth, Barreiro Castro, María, Bello, Xabier, García, Mirian Ben, Carnota, Sandra, Cebey-López, Miriam, Curras-Tuala, María José, Durán Suárez, Carlos, García Vicente, Luisa, Gómez-Carballa, Alberto, Gómez Rial, Jose, Leboráns Iglesias, Pilar, Martinón-Torres, Nazareth, Martinón Sánchez, José María, Mosquera Pérez, Belén, Pardo-Seco, Jacobo, Rodríguez, Lidia Piñeiro, Pischedda, Sara, Vázquez, Sara Rey, Rivero Calle, Irene, Rodríguez-Tenreiro, Carmen, Redondo-Collazo, Lorenzo, Sadiki Ora, Miguel, Serén Fernández, Sonia, Serén Trasorras, Cristina, Vilas Iglesias, Marisol, Balode, Anda, Bārzdiņa, Arta, Deksne, Dārta, Gardovska, Dace, Grāvele, Dagne, Grope, Ilze, Meiere, Anija, Nokalna, Ieva, Pavāre, Jana, Pučuka, Zanda, Selecka, Katrīna, Rudzāte, Aleksandra, Svile, Dace, Urbāne, Urzula Nora, Bojang, Kalifa, Zaman, Syed M. A., Anderson, Suzanne, RocaIsatou Sarr, Anna, Saidykhan, Momodou, Darboe, Saffiatou, Ceesay, Samba, D’alessandro, Umberto, Moll, Henriëtte A., Vermont, Clementien L, Borensztajn, Dorine M., Tan, Chantal, Zachariasse, Joany, Dik, W, Agyeman, Philipp KA, Berger, Christoph, Giannoni, Eric, Stocker, Martin, Posfay-Barbe, Klara M, Heininger, Ulrich, Bernhard-Stirnemann, Sara, Niederer-Loher, Anita, Kahlert, Christian R., Natalucci, Giancarlo, Relly, Christa, Riedel, Thomas, Aebi, Christoph, Schlapbach, Luregn J, Carrol, Enitan D, Cocklin, Elizabeth, Jennings, Rebecca, Johnston, Joanne, Leigh, Simon, Lewis-Burke, Nadia, Newall, Karen, Romaine, Sam, Eleftheriou, Irini, Tambouratzi, Maria, Marmarinos, Antonis, Xagorari, Marietta, Syggelou, Kelly, Calvo-Bado, Leo, Schweintzger, Nina A., Sagmeister, Manfred G., Kohlfürst, Daniela S., Zurl, Christoph, Binder, Alexander, Hösele, Susanne, Leitner, Manuel, Pölz, Lena, Rajic, Glorija, Bauchinger, Sebastian, Baumgart, Hinrich, Benesch, Martin, Ceolotto, Astrid, Eber, Ernst, Gallistl, Siegfried, Gores, Gunther, Haidl, Harald, Hauer, Almuthe, Hude, Christa, Keldorfer, Markus, Krenn, Larissa, Pilch, Heidemarie, Pfleger, Andreas, Pfurtscheller, Klaus, Nordberg, Gudrun, Niedrist, Tobias, Rödl, Siegfried, Skrabl-Baumgartner, Andrea, Sperl, Matthias, Stampfer, Laura, Strenger, Volker, Till, Holger, Trobisch, Andreas, Löffler, Sabine, Dewez, Juan Emmanuel, Hibberd, Martin, Bath, David, Miners, Alec, Fitchett, Elizabeth, de Jonge, Marien I., van Aerde, Koen, Alkema, Wynand, van den Broek, Bryan, Gloerich, Jolein, van Gool, Alain J., Henriet, Stefanie, Huijnen, Martijn, Philipsen, Ria, Willems, Esther, Gerrits, G.P.J.M., van Leur, M., Heidema, J., de Haan, L., Miedema, C.J., Neeleman, C., Obihara, C.C., Tramper-Stranders, G.A., Kandasamy, Rama, Paulus, Stéphane, Carter, Michael J., O’Connor, Daniel, Bibi, Sagida, Kelly, Dominic F., Gurung, Meeru, Thorson, Stephen, Ansari, Imran, Murdoch, David R., Shrestha, Shrijana, Oliver, Zoe, Valentine, Lucille, Allen, Karen, Bell, Kathryn, Chan, Adora, Crulley, Stephen, Devine, Kirsty, Fabian, Daniel, King, Sharon, McAlinden, Paul, McDonald, Sam, McDonnell, Anne, Pickering, Ailsa, Thomson, Evelyn, Wood, Amanda, Wallia, Diane, Woodsford, Phil, Baxter, Frances, Bell, Ashley, Rhodes, Mathew, Agbeko, Rachel, Mackerness, Christine, Baas, Bryan, Kloosterhuis, Lieke, Oosthoek, Wilma, Arif, Tasnim, Bennet, Joshua, Collings, Kalvin, van der Giessen, Ilona, Martin, Alex, Rashid, Aqeela, Rowlands, Emily, van der Velden, Fabian, Soon, Joshua, Martin, Mike, Mistry, Ravi, Zwerenz, Manuela, Buschbeck, Judith, Bidlingmaier, Christoph, Binder, Vera, Danhauser, Katharina, Haas, Nikolaus, Griese, Matthias, Feuchtinger, Tobias, Keil, Julia, Kappler, Matthias, Lurz, Eberhard, Muench, Georg, Reiter, Karl, Schoen, Carola, Mallet, François, Brengel-Pesce, Karen, Pachot, Alexandre, Mommert, Marine, Kolnik, Mojca, Vincek, Katarina, Srovin, Tina Plankar, Bahovec, Natalija, Prunk, Petra, Osterman, Veronika, Avramoska, Tanja, Kuijpers, Taco, Jongerius, Ilse, van den Berg, J. M., Schonenberg, D., Barendregt, A. M., Pajkrt, D., van der Kuip, M., van Furth, A. M., Sprenkeler, Evelien, Zandstra, Judith, van Mierlo, G., Geissler, J., consortium, PERFORM, Paediatric Infectious Diseases / Rheumatology / Immunology, AII - Infectious diseases, ARD - Amsterdam Reproduction and Development, and Pediatrics
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All institutes and research themes of the Radboud University Medical Center ,Fever ,SDG 3 - Good Health and Well-being ,Antibiotics ,Paediatric ,Pediatrics, Perinatology and Child Health ,Vascular damage Radboud Institute for Health Sciences [Radboudumc 16] ,lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4] ,610 Medicine & health ,Infection ,610 Medizin und Gesundheit ,Immunocompromised - Abstract
To assess and describe the aetiology and management of febrile illness in children with primary or acquired immunodeficiency at high risk of serious bacterial infection, as seen in emergency departments in tertiary hospitals. Prospective data on demographics, presenting features, investigations, microbiology, management, and outcome of patients within the ‘Biomarker Validation in HR patients’ database in PERFORM, were analysed. Immunocompromised children (N = 492); 94.3% proven/presumed bacterial (N = 164), 66.1% proven/presumed viral (N = 84), and 93.2% unknown bacterial or viral infections (N = 177). Mortality was 1.9% (N = 11) and 87.1% made full recovery (N = 522). Conclusion: The aetiology of febrile illness in immunocompromised children is diverse. In one-third of cases, no cause for the fever will be identified. Justification for standard intravenous antibiotic treatment for every febrile immunocompromised child is debatable, yet effective. Better clinical decision-making tools and new biomarkers are needed for this population. What is Known:• Immunosuppressed children are at high risk for morbidity and mortality of serious bacterial and viral infection, but often present with fever as only clinical symptom.• Current diagnostic measures in this group are not specific to rule out bacterial infection, and positivity rates of microbiological cultures are low. What is New:• Febrile illness and infectious complications remain a significant cause of mortality and morbidity in HR children, yet management is effective.• The aetiology of febrile illness in immunocompromised children is diverse, and development of pathways for early discharge or cessation of intravenous antibiotics is debatable, and requires better clinical decision-making tools and biomarkers.
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- 2022
24. Multi-centre, randomised, open-label, blinded endpoint assessed, trial of corticosteroids plus intravenous immunoglobulin (IVIG) and aspirin, versus IVIG and aspirin for prevention of coronary artery aneurysms (CAA) in Kawasaki disease (KD): the KD CAA prevention (KD-CAAP) trial protocol
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Despina Eleftheriou, Yolanda Collaco Moraes, Cara Purvis, Molly Pursell, Marta Merida Morillas, Robin Kahn, Maria Mossberg, Filip Kucera, Robert Tulloh, Joseph F. Standing, Veronica Swallow, Rachael McCormack, Jethro Herberg, Michael Levin, Mandy Wan, Nigel Klein, Roisin Connon, Ann Sarah Walker, and Paul Brogan
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Medicine (miscellaneous) ,Pharmacology (medical) - Abstract
Background Kawasaki disease (KD) is an acute self-limiting inflammatory vasculitis affecting predominantly medium-sized arteries, particularly the coronary arteries. A number of recent studies conducted in different European countries have demonstrated alarmingly high coronary complications despite treatment with intravenous immunoglobulin (IVIG). These high complication rates now emphasize the need for an urgent reappraisal of IVIG as the sole primary therapeutic agent for KD. The Kawasaki disease CAA prevention (KD-CAAP) trial will test the hypothesis that immediate adjunctive corticosteroid treatment to standard of care IVIG and aspirin will reduce coronary artery aneurysm (CAA) rates in unselected KD patients across Europe. Methods KD-CAAP is a multicentre, randomised, controlled, open-label, blinded endpoint assessed trial that will be conducted across Europe supported by the conect4children pan-European clinical trials network. Patients with KD who satisfy the eligibility criteria will be randomised (1:1) to receive either oral prednisolone 2 mg/kg/day plus standard of care therapy IVIG (2 g/kg) and aspirin (40 mg/kg/day); or IVIG and aspirin alone. Further management is dictated by temperature and C-reactive protein (CRP) responses. Co-primary outcomes are as follows: (i) any CAA within the 3 months of trial follow-up; (ii) average estimate of maximum coronary Z-score at weeks 1, 2 and 6 adjusting for rescue treatment. Additional outcomes will be assessed including cost effectiveness, quality of life, corticosteroid toxicity and other safety outcomes. Discussion Several recent studies have indicated that coronary complications associated with KD across Europe are much higher than early trials of IVIG had initially suggested. KD-CAAP directly addresses this issue by exploring the therapeutic benefit of adjunctive corticosteroids in unselected KD cases. If we find that corticosteroids prevent CAA and are safe, this is a cheap and widely available intervention that could be implemented immediately for the benefit of children. Trial registration ISRCTN71987471- March 31, 2020; Eudract 2019–004433-17.
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- 2023
25. Systemic ventricular function in Fontan patients at rest and after exercise at altitude
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Quante, Hannah, Müller, Nicole, Härtel, Julian Alexander, Jung, Thomas, Manunzio, Ursula, Breuer, Johannes, and Herberg, Ulrike
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Pediatrics, Perinatology and Child Health - Abstract
ObjectivePhysical activity at high altitude is expected to pose risks for patients with Fontan circulation and to impair systemic ventricular function. This study aims to determine the effect of high-altitude hypoxia on ventricular function in Fontan patients at rest and after exercise. We hypothesize that systemic ventricular function deteriorates under hypoxic conditions in Fontan patients.MethodsIn this prospective study, 21 Fontan patients (NYHA class I-II) and 21 age-, gender- and body mass index-matched healthy controls were enrolled (median age 17.9 and 16.9 years). Transthoracic echocardiography was performed at rest, after peak (PE) and after continuous exercise (CE) in normoxia and hypoxia at simulated altitude (2,500 m above sea level). The effect of hypoxia on echocardiographic parameters was quantified by linear mixed-effects models and the difference between normoxia and hypoxia (Δ= hypoxia-normoxia).ResultsAt rest, cardiac output (CO) estimated by outflow tract velocity time integral × heart rate and annular plane systolic excursion (APSE) were lower in hypoxia compared to normoxia in Fontan patients (CO: Δ = −12.0%, n.s.; APSE: Δ = −9.6%, p Δ = 8.5%, n.s.; APSE: Δ = 2.5%, n.s.). Other parameters of systolic and diastolic function did not show relevant changes. After exercise under hypoxic conditions, Fontan patients did not show relevant deterioration of systolic function compared to normoxia. Late, active diastolic filling reflected by A-wave velocity remained unchanged in Fontan patients, but increased in controls. Under hypoxic conditions, CO and workload were higher after CE than PE in Fontan patients (CO: PE Δ = 1,530 vs. CE 1630), whereas controls showed higher work load and CO estimates after PE than CE as expected (CO: PE Δ = 2,302 vs. CE 2149).ConclusionFontan patients clinically tolerated short-term altitude exposure up to two hours and exercise and showed no consistent deterioration of systolic systemic ventricular function, but parameters of myocardial contractility, heart rate and cardiac output did not increase as observed in controls. This is likely to be multifactorial and may include intrinsic cardiac dysfunction as well as preload inadequacy and the lack of augmented atrial contraction. CE may be better tolerated than PE.
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- 2023
26. Correction to: Febrile illness in high-risk children: a prospective, international observational study
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Van der Velden, FJS, De Vries, G, Martin, A, Lim, E, Von Both, U, Kolberg, L, Carrol, ED, Khanijau, A, Herberg, JA, De, T, Galassini, R, Kuijpers, TW, Martinón-Torres, F, Rivero-Calle, I, Vermont, CL, Hagedoorn, NN, Pokorn, M, Pollard, AJ, Schlapbach, LJ, Tsolia, M, Elefhteriou, I, Yeung, S, Zavadska, D, Fink, C, Voice, M, Zenz, W, Kohlmaier, B, Agyeman, PKA, Usuf, E, Secka, F, De Groot, R, Levin, M, Van der Flier, M, Emonts, M, and PERFORM consortium
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Pediatrics, Perinatology and Child Health ,610 Medicine & health ,610 Medizin und Gesundheit - Published
- 2023
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27. Führung und Soziale Arbeit
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Christian Herberg
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- 2023
28. Soziale Arbeit und Inklusion
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Christian Herberg
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- 2023
29. Are children with prolonged fever at a higher risk for serious illness? A prospective observational study
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Nijman RG, Tan CD, Hagedoorn NN, Nieboer D, Herberg JA, Balode A, Von Both U, Carrol ED, Eleftheriou I, Emonts M, Van Der Flier M, De Groot R, Kohlmaier B, Lim E, Martinon-Torres F, Pokorn M, Strle F, Tsolia M, Yeung S, Zachariasse JM, Zavadska D, Zenz W, Levin M, Vermont CL, Moll HA, MacOnochie IK
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- 2023
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30. European study confirms the combination of fever and petechial rash as an important warning sign for childhood sepsis and meningitis
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Kohlmaier, Benno, Leitner, Manuel, Hagedoorn, Nienke N., Borensztajn, Dorine M., von Both, Ulrich, Carrol, Enitan D., Emonts, Marieke, van der Flier, Michiel, de Groot, Ronald, Herberg, Jethro, Levin, Michael, Lim, Emma, Maconochie, Ian K., Martinon-Torres, Federico, Nijman, Ruud G., Pokorn, Marko, Rivero-Calle, Irene, Tan, Chantal D., Tsolia, Maria, Vermont, Clementien L., Zachariasse, Joany M., Zavadska, Dace, Moll, Henriette A., Zenz, Werner, and Pediatrics
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All institutes and research themes of the Radboud University Medical Center ,Pediatrics, Perinatology and Child Health ,lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4] ,General Medicine - Abstract
Contains fulltext : 291888.pdf (Publisher’s version ) (Open Access) AIM: This study investigated febrile children with petechial rashes who presented to European emergency departments (EDs) and investigated the role that mechanical causes played in diagnoses. METHODS: Consecutive patients with fever presenting to EDs in 11 European emergency departments in 2017-2018 were enrolled. The cause and focus of infection were identified and a detailed analysis was performed on children with petechial rashes. The results are presented as odds ratios (OR) with 95% confidence intervals (CI). RESULTS: We found that 453/34010 (1.3%) febrile children had petechial rashes. The focus of the infection included sepsis (10/453, 2.2%) and meningitis (14/453, 3.1%). Children with a petechial rash were more likely than other febrile children to have sepsis or meningitis (OR 8.5, 95% CI 5.3-13.1) and bacterial infections (OR 1.4, 95% CI 1.0-1.8) as well as need for immediate life-saving interventions (OR 6.6, 95% CI 4.4-9.5) and intensive care unit admissions (OR 6.5, 95% CI 3.0-12.5). CONCLUSION: The combination of fever and petechial rash is still an important warning sign for childhood sepsis and meningitis. Ruling out coughing and/or vomiting was insufficient to safely identify low-risk patients.
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- 2023
31. Time Regularization in Optimal Time Variable Learning
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Herberg, Evelyn, Herzog, Roland, and Köhne, Frederik
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FOS: Computer and information sciences ,Computer Science - Machine Learning ,Optimization and Control (math.OC) ,FOS: Mathematics ,Mathematics - Optimization and Control ,Machine Learning (cs.LG) - Abstract
Recently, optimal time variable learning in deep neural networks (DNNs) was introduced in arXiv:2204.08528. In this manuscript we extend the concept by introducing a regularization term that directly relates to the time horizon in discrete dynamical systems. Furthermore, we propose an adaptive pruning approach for Residual Neural Networks (ResNets), which reduces network complexity without compromising expressiveness, while simultaneously decreasing training time. The results are illustrated by applying the proposed concepts to classification tasks on the well known MNIST and Fashion MNIST data sets. Our PyTorch code is available on https://github.com/frederikkoehne/time_variable_learning.
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- 2023
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32. Additional file 1 of Biobanking and consenting to research: a qualitative thematic analysis of young people’s perspectives in the North East of England
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van der Velden, Fabian J. S., Lim, Emma, Gills, Lily, Broadey, Jasmin, Hayes, Louise, Roberts, Eve, Courtney, Jack, Ball, Joanne, Herberg, Jethro, Galassini, Rachel, and Emonts, Marieke
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Additional file 1.
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- 2023
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33. Key highlights segmentatiestudie Dierzaam: diervriendelijke en duurzame keuze: De verschillende Nederlandse vleeskopers en hun motivatie, gelegenheid en capaciteit om dierzaam vlees te kopen
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Riemsdijk,van, Lenka, Herberg,van der, Eveline, Timmerman, Tijs, Weijschedé, Dies, and Springelkamp, Clara
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Duurzaam gedrag ,Vleesconsumptie ,gedragsbeïnvloeding ,gedragsverandering - Abstract
Vlees eten is geworteld in onze eetcultuur. Het minderen van vlees vraagt tijd. Ondanks campagnes die plantaardige diëten promoten eet volgens CBS nog zo’n 95% Nederlanders vlees, en de meeste daarvan doen dat meerdere keren per week als een stukje vlees bij de maaltijd. Om op kortere termijn een verschil te maken, zal het stimuleren van consumentenkeuzes voor duurzaam geproduceerd vlees in belangrijke mate bijdragen aan ‘minder en beter’. Dit vraagt om specifieke tactieken, wetende dat consumenten in hun gedrag niet altijd doen dan wat hun intentie is met betrekking tot duurzaamheid: de wil is er, maar vertaalt zich onvoldoende in koopgedrag. Om dit te overkomen zijn marketinginterventies nodig die de capaciteit, gelegenheid en motivatie van consumenten verhogen/versterken. Deze rapportage bevat de resultaten – op hoofdlijnen – van een kwantitatieve segmentatiestudie onder Nederlandse vleeskopende consumenten
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- 2023
34. Immunoglobulin, glucocorticoid, or combination therapy for multisystem inflammatory syndrome in children: a propensity-weighted cohort study
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Channon-Wells, Samuel, Vito, Ortensia, McArdle, Andrew J, Seaby, Eleanor G, Patel, Harsita, Shah, Priyen, Pazukhina, Ekaterina, Wilson, Clare, Broderick, Claire, D'Souza, Giselle, Keren, Ilana, Nijman, Ruud G, Tremoulet, Adriana, Munblit, Daniel, Ulloa-Gutierrez, Rolando, Carter, Michael J, Ramnarayan, Padmanabhan, De, Tisham, Hoggart, Clive, Whittaker, Elizabeth, Herberg, Jethro A, Kaforou, Myrsini, Cunnington, Aubrey J, Blyuss, Oleg, Levin, Michael, Best Available Treatment Study (BATS) consortium, et al, Trück, Johannes, University of Zurich, and Levin, Michael
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2403 Immunology ,Rheumatology ,10036 Medical Clinic ,2745 Rheumatology ,Immunology ,2723 Immunology and Allergy ,Immunology and Allergy ,610 Medicine & health - Published
- 2023
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35. Discovery and validation of a three-gene signature to distinguish COVID-19 and other viral infections in emergency infectious disease presentations: a case-control and observational cohort study
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Mahdad Noursadeghi, Laura Shallcross, Ivana Pennisi, Ravi Mehta, Graham S Cooke, Dominique Arancon, Jesus Rodriguez-Manzano, Ewurabena Mills, Luca Miglietta, Nelofar Obaray, Myrsini Kaforou, Jethro Herberg, Samuel Channon-Wells, Shiranee Sriskandan, Alexander J. Mentzer, Jessica Lin, H K Li, Ahmad Moniri, Rishi K Gupta, Dominic Habgood-Coote, Michael Levin, Victoria J. Wright, Pantelis Georgiou, and Yueh-Ho Chiu
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Adult ,Microbiology (medical) ,Medicine (General) ,medicine.medical_specialty ,Adolescent ,Communicable Diseases ,Microbiology ,Cohort Studies ,R5-920 ,Virology ,Internal medicine ,Pandemic ,medicine ,Humans ,Medical diagnosis ,Bacteria ,Receiver operating characteristic ,SARS-CoV-2 ,business.industry ,COVID-19 ,Articles ,Bacterial Infections ,Emergency department ,Gene signature ,QR1-502 ,C-Reactive Protein ,Infectious Diseases ,Virus Diseases ,Infectious disease (medical specialty) ,Case-Control Studies ,Cohort ,business ,Cohort study - Abstract
Summary Background Emergency admissions for infection often lack initial diagnostic certainty. COVID-19 has highlighted a need for novel diagnostic approaches to indicate likelihood of viral infection in a pandemic setting. We aimed to derive and validate a blood transcriptional signature to detect viral infections, including COVID-19, among adults with suspected infection who presented to the emergency department. Methods Individuals (aged ≥18 years) presenting with suspected infection to an emergency department at a major teaching hospital in the UK were prospectively recruited as part of the Bioresource in Adult Infectious Diseases (BioAID) discovery cohort. Whole-blood RNA sequencing was done on samples from participants with subsequently confirmed viral, bacterial, or no infection diagnoses. Differentially expressed host genes that met additional filtering criteria were subjected to feature selection to derive the most parsimonious discriminating signature. We validated the signature via RT-qPCR in a prospective validation cohort of participants who presented to an emergency department with undifferentiated fever, and a second case-control validation cohort of emergency department participants with PCR-positive COVID-19 or bacterial infection. We assessed signature performance by calculating the area under receiver operating characteristic curves (AUROCs), sensitivities, and specificities. Findings A three-gene transcript signature, comprising HERC6, IGF1R, and NAGK, was derived from the discovery cohort of 56 participants with bacterial infections and 27 with viral infections. In the validation cohort of 200 participants, the signature differentiated bacterial from viral infections with an AUROC of 0·976 (95% CI 0·919−1·000), sensitivity of 97·3% (85·8−99·9), and specificity of 100% (63·1−100). The AUROC for C-reactive protein (CRP) was 0·833 (0·694−0·944) and for leukocyte count was 0·938 (0·840−0·986). The signature achieved higher net benefit in decision curve analysis than either CRP or leukocyte count for discriminating viral infections from all other infections. In the second validation analysis, which included SARS-CoV-2-positive participants, the signature discriminated 35 bacterial infections from 34 SARS-CoV-2-positive COVID-19 infections with AUROC of 0·953 (0·893−0·992), sensitivity 88·6%, and specificity of 94·1%. Interpretation This novel three-gene signature discriminates viral infections, including COVID-19, from other emergency infection presentations in adults, outperforming both leukocyte count and CRP, thus potentially providing substantial clinical utility in managing acute presentations with infection. Funding National Institute for Health Research, Medical Research Council, Wellcome Trust, and EU-FP7.
- Published
- 2021
36. Biobanking and Consenting to Research: a Qualitative Thematic Analysis of Young People’s Perspectives
- Author
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Fabian Johannes Stanislaus van der Velden, Emma Lim, Lily Gills, Jasmin Broadey, Louise Hayes, Eve Roberts, Jack Courtney, Joanne Ball, Jethro Herberg, Rachel Galassini, and Marieke Emonts
- Abstract
Background Biobanking biospecimens and consent are common practice in paediatric research. We need to explore children and young people’s (CYP) knowledge and perspectives around the use of and consent to biobanking. This will ensure meaningful informed consent can be obtained and improve current consent procedures. Methods We designed a survey, in co-production with CYP, collecting demographic data, views on biobanking, and consent using three scenarios: 1) prospective consent, 2) deferred consent, and 3) reconsent and assent at age of capacity. The survey was disseminated via the Young Person’s Advisory Group North England (YPAGne) and participating CYP’s secondary schools. Data were analysed using a qualitative thematic approach by three independent reviewers (including CYP) to identify common themes. Data triangulation occurred independently by a fourth reviewer. Results 102 CYP completed the survey. Most were between 16-18 years (63.7%, N=65) and female (66.7%, N=68). 72.3% had no prior knowledge of biobanking (N=73). Acceptability of prospective consent for biobanking was high (91.2%, N=93) with common themes: ‘altruism’, ‘potential benefits outweigh individual risk’, frugality, and ‘(in)convenience’. Deferred consent was also deemed acceptable in the large majority (84.3%, N=86), with common themes: ‘altruism’, ‘body integrity’ and ‘sample frugality’. 76.5% preferred to reconsent when cognitively mature enough to give assent (N=78), even if parental consent was previously in place. 79.2% wanted to be informed if their biobanked biospecimen is reused (N=80). Conclusion Prospective and deferred consent acceptability for biobanking is high among CYP. Altruism, frugality, body integrity, and privacy are the most important themes. Clear communication and justification are paramount to obtain consent. Any CYP with capacity should be part of the consenting procedure, if possible.
- Published
- 2022
37. In-House-Alignertherapie in Verbindung mit Dysgnathiechirurgie - geht das?
- Author
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Max Herberg and Gerhard Polzar
- Published
- 2022
38. Therapeutischer Humor auf einer Demenzstation. Ergebnisse einer ethnografischen Fallstudie
- Author
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Martin Herberg
- Subjects
Gynecology ,medicine.medical_specialty ,Political science ,medicine - Abstract
Humor ist aus dem heutigen Gesundheitssystem nicht wegzudenken. Auch in der Betreuung demenziell erkrankter Menschen stellt Humor eine wichtige therapeutische Ressource dar. Untersucht wird, wie erfahrene Demenzbegleiter*innen in ihrer taglichen Arbeit Humor einsetzen, worauf sie dabei achten, und welche Funktionen Humor in verschiedenen Situationen erfullt. Im Rahmen einer 12-monatigen teilnehmenden Beobachtung auf einer Demenzstation wurden real auftretende Situationen beobachtet, protokolliert und mit der Methode der ethnografischen Interaktionsanalyse ausgewertet. In der Demenzbetreuung erfullt Humor viele Funktionen. Er ist ein Mittel, um die Aktivierungen attraktiv zu gestalten. Ferner hilft Humor, schambesetzte Situationen zu entscharfen. Zudem ist er eine wichtige Bewaltigungsstrategie im Umgang mit herausforderndem Verhalten. Damit dies gelingt, ist es erforderlich, dass die Betreuungskrafte ihr Humorverhalten auf die Humorfahigkeiten und -vorlieben der Bewohner*innen abstimmen. In der Arbeit der Betreuungskrafte, so das Ergebnis, hat Humor seinen festen Platz. Angesichts seiner Bedeutung fur die Praxis sollte das Thema starker in der Ausbildung berucksichtigt werden. Eine wichtige Errungenschaft in institutioneller Hinsicht ware die Formulierung von Handlungsempfehlungen fur den demenzgerechten Einsatz von Humor. Zu wunschen ware ferner, dass Pflegeeinrichtungen ein internes Humor-Management einfuhren.
- Published
- 2021
39. Isolated cytokine‐enriched pericardial effusion: A likely key feature for <scp>Aymé‐Gripp</scp> syndrome
- Author
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Andreas Müller, Eugenia Bernis, Heiko Reutter, Brigitte Stritzek, Ulrike Herberg, Miriam Bertrand, G. Wiegand, Ute Grasshoff, Hemmen Sabir, Ulrich Gembruch, Anna-Lina König, and Cornelia Wiechers
- Subjects
Pathology ,medicine.medical_specialty ,Hearing loss ,business.industry ,medicine.medical_treatment ,medicine.disease ,Pericardial effusion ,Bilateral Cataracts ,Pericarditis ,Cytokine ,Feature (computer vision) ,Genetics ,Congenital cataracts ,medicine ,Sensorineural hearing loss ,medicine.symptom ,business ,Genetics (clinical) - Abstract
Ayme-Gripp syndrome is a multisystemic disorder caused by a heterozygous variation in the MAF gene (OMIM*177075). Key features are congenital cataracts, sensorineural hearing loss, and a characteristic facial appearance. In a proportion of individuals, pericardial effusion or pericarditis has been reported as part of the phenotypic spectrum. In the present case, a large persistent cytokine-enriched pericardial effusion was the main pre- and postnatal symptom that led to the clinical and later molecular diagnosis of Ayme-Gripp syndrome. In the postnatal course, the typical Ayme-Gripp syndrome-associated features bilateral cataracts and hearing loss were diagnosed. We propose that activating dominant variants in the cytokine-modulating transcription factor c-MAF causes cytokine-enriched pericardial effusions possibly representing a key feature of Ayme-Gripp syndrome.
- Published
- 2021
40. Mutant Phosphodiesterase 3A Protects From Hypertension-Induced Cardiac Damage
- Author
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Maria Ercu, Michael B. Mücke, Tamara Pallien, Lajos Markó, Anastasiia Sholokh, Carolin Schächterle, Atakan Aydin, Alexa Kidd, Stephan Walter, Yasmin Esmati, Brandon J. McMurray, Daniella F. Lato, Daniele Yumi Sunaga-Franze, Philip H. Dierks, Barbara Isabel Montesinos Flores, Ryan Walker-Gray, Maolian Gong, Claudia Merticariu, Kerstin Zühlke, Michael Russwurm, Tiannan Liu, Theda U.P. Batolomaeus, Sabine Pautz, Stefanie Schelenz, Martin Taube, Hanna Napieczynska, Arnd Heuser, Jenny Eichhorst, Martin Lehmann, Duncan C. Miller, Sebastian Diecke, Fatimunnisa Qadri, Elena Popova, Reika Langanki, Matthew A. Movsesian, Friedrich W. Herberg, Sofia K. Forslund, Dominik N. Müller, Tatiana Borodina, Philipp G. Maass, Sylvia Bähring, Norbert Hübner, Michael Bader, and Enno Klussmann
- Subjects
Heart Failure ,Physiology (medical) ,Induced Pluripotent Stem Cells ,Hypertension ,Humans ,Animals ,RNA ,Myocytes, Cardiac ,Cardiomegaly ,X-Ray Microtomography ,Cardiology and Cardiovascular Medicine ,Cyclic Nucleotide Phosphodiesterases, Type 3 ,Rats - Abstract
Background: Phosphodiesterase 3A ( PDE3A ) gain-of-function mutations cause hypertension with brachydactyly (HTNB) and lead to stroke. Increased peripheral vascular resistance, rather than salt retention, is responsible. It is surprising that the few patients with HTNB examined so far did not develop cardiac hypertrophy or heart failure. We hypothesized that, in the heart, PDE3A mutations could be protective. Methods: We studied new patients. CRISPR-Cas9–engineered rat HTNB models were phenotyped by telemetric blood pressure measurements, echocardiography, microcomputed tomography, RNA-sequencing, and single nuclei RNA-sequencing. Human induced pluripotent stem cells carrying PDE3A mutations were established, differentiated to cardiomyocytes, and analyzed by Ca 2+ imaging. We used Förster resonance energy transfer and biochemical assays. Results: We identified a new PDE3A mutation in a family with HTNB. It maps to exon 13 encoding the enzyme’s catalytic domain. All hitherto identified HTNB PDE3A mutations cluster in exon 4 encoding a region N-terminally from the catalytic domain of the enzyme. The mutations were recapitulated in rat models. Both exon 4 and 13 mutations led to aberrant phosphorylation, hyperactivity, and increased PDE3A enzyme self-assembly. The left ventricles of our patients with HTNB and the rat models were normal despite preexisting hypertension. A catecholamine challenge elicited cardiac hypertrophy in HTNB rats only to the level of wild-type rats and improved the contractility of the mutant hearts, compared with wild-type rats. The β-adrenergic system, phosphodiesterase activity, and cAMP levels in the mutant hearts resembled wild-type hearts, whereas phospholamban phosphorylation was decreased in the mutants. In our induced pluripotent stem cell cardiomyocyte models, the PDE3A mutations caused adaptive changes of Ca 2+ cycling. RNA-sequencing and single nuclei RNA-sequencing identified differences in mRNA expression between wild-type and mutants, affecting, among others, metabolism and protein folding. Conclusions: Although in vascular smooth muscle, PDE3A mutations cause hypertension, they confer protection against hypertension-induced cardiac damage in hearts. Nonselective PDE3A inhibition is a final, short-term option in heart failure treatment to increase cardiac cAMP and improve contractility. Our data argue that mimicking the effect of PDE3A mutations in the heart rather than nonselective PDE3 inhibition is cardioprotective in the long term. Our findings could facilitate the search for new treatments to prevent hypertension-induced cardiac damage.
- Published
- 2022
41. YAP/TAZ inactivation with simvastatin attenuates glucocorticoid-induced human trabecular meshwork cell dysfunction
- Author
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Hannah Yoo, Ayushi Singh, Haiyan Li, Ana N. Strat, Tyler Bagué, Preethi S. Ganapathy, and Samuel Herberg
- Abstract
PurposeImpairment of the trabecular meshwork (TM) is the principal cause of increased outflow resistance in the glaucomatous eye. Yes-associated protein (YAP) and transcriptional coactivator with PDZ binding motif (TAZ) are emerging as potential mediators of TM cell/tissue dysfunction. Furthermore, YAP/TAZ activity was recently found to be controlled by the mevalonate pathway in non-ocular cells. Clinically-used statins block the mevalonate cascade and were shown to improve TM cell pathobiology; yet, the link to YAP/TAZ signaling was not investigated. In this study, we hypothesized that YAP/TAZ inactivation with simvastatin attenuates glucocorticoid-induced human TM (HTM) cell dysfunction.MethodsPrimary HTM cells were seeded atop or encapsulated within bioengineered extracellular matrix (ECM) hydrogels. Dexamethasone was used to induce a pathologic phenotype in HTM cells in the absence or presence of simvastatin. Changes in YAP/TAZ activity, actin cytoskeletal organization, phospho-myosin light chain levels, hydrogel contraction/stiffness, and fibronectin deposition were assessed.ResultsSimvastatin potently blocked pathologic YAP/TAZ nuclear localization/activity, actin stress fiber formation, and myosin light chain phosphorylation in HTM cells. Importantly, simvastatin co-treatment significantly attenuated dexamethasone-induced ECM contraction/stiffening and extracellular fibronectin deposition. Sequential treatment was similarly effective but did not match clinically-used Rho kinase inhibition.ConclusionsYAP/TAZ inactivation with simvastatin attenuates HTM cell pathobiology in a tissue-mimetic ECM microenvironment. Our data may help explain the association of statin use with a reduced risk of developing glaucoma via indirect YAP/TAZ inhibition as a proposed regulatory mechanism.
- Published
- 2022
42. Short-term outcome of late gadolinium changes detected on cardiovascular magnetic resonance imaging following coronavirus disease 2019 Pfizer/BioNTech vaccine-related myocarditis in adolescents
- Author
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Sylvia Krupickova, Inga Voges, Raad Mohiaddin, Carles Bautista, Wei Li, Jethro Herberg, Piers E. F. Daubeney, Dudley J. Pennell, and Alain Fraisse
- Subjects
Pediatrics, Perinatology and Child Health ,Radiology, Nuclear Medicine and imaging - Abstract
Rare cases of cardiac inflammation following vaccination for severe acute respiratory coronavirus 2 (SARS-CoV-2) have been reported.To study paediatric patients with clinical findings of acute inflammation post coronavirus disease 2019 (COVID-19) Pfizer/BioNTech vaccination using cardiovascular magnetic resonance imaging (MRI) in acute and subacute phases.We enrolled adolescents younger than 18 years who presented at one of two institutions between July 2021 and August 2022 with clinical and laboratory findings of acute myocarditis shortly following COVID-19 Pfizer/BioNTech vaccination. They all underwent cardiovascular MRI using the institutional myocarditis protocol.Five adolescents (four boys) underwent eight scans between 3 days and 109 days (mean 49 days) after the onset of symptoms following COVID-19 vaccination. Myocardial oedema appeared on short tau inversion recovery (STIR) T2-weighted images in three adolescents at presentation (3-12 days after symptom onset). In these children, the myocardial oedema/acute inflammation had resolved at follow-up cardiovascular MRI (53-68 days after first MRI). However, in all three adolescents, a persistent area of late gadolinium enhancement was evident at follow-up, suggesting post-myocarditic fibrosis. One adolescent scanned only once, 66 days after being symptomatic, had no acute inflammation but persistent fibrotic changes. This last adolescent, who underwent the first scan 109 days after symptom onset, had findings compatible with an episode of previous myocarditis, with mild ongoing regional myocardial oedema/inflammation.This study on post-vaccine myocarditis demonstrates residual lesions with persistent areas of late gadolinium enhancement/myocardial fibrosis with ongoing myocardial oedema after resolution of the initial myocardial oedema a few weeks after Pfizer/BioNTech vaccination. There is an urgent need to recognise and fully investigate the outcome of post-vaccination myocarditis.
- Published
- 2022
43. Doppler-Ultraschall (DUS)-getriggerte fetale Herz-MRT zur Diagnose komplexer Herzfehler bei 3 Tesla: Klinische Etablierung und diagnostische Wertigkeit
- Author
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T Vollbrecht, C Hart, U Herberg, C Katemann, S Zhang, A Isaak, N Mesropyan, D Kravchenko, M L Bischoff, C C Pieper, D Kütting, B Faridi, U Attenberger, A Geipel, and A J Luetkens
- Published
- 2022
44. Enhanced protein immobilization efficacy by nanostructuring of ultrananocrystalline diamond surface
- Author
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Daniel Merker, Daniela Bertinetti, Rolf Merz, Michael Kopnarski, Friedrich W. Herberg, and Cyril Popov
- Subjects
Mechanical Engineering ,Materials Chemistry ,General Chemistry ,Electrical and Electronic Engineering ,Electronic, Optical and Magnetic Materials - Published
- 2023
45. There is no Political Democracy without Relational Equality in Society
- Author
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Andreas Herberg-Rothe
- Subjects
Political science ,Political economy ,Political democracy - Published
- 2021
46. Dynamical Basis of Allosteric Activation for the Plasmodium falciparum Protein Kinase G
- Author
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Bryan VanSchouwen, Giuseppe Melacini, Laura-Li Sarmiento Murga, Philipp Henning, Jung Ah Byun, Jinfeng Huang, and Friedrich W. Herberg
- Subjects
Allosteric regulation ,Drug target ,Biophysics ,010402 general chemistry ,digestive system ,01 natural sciences ,03 medical and health sciences ,0302 clinical medicine ,0103 physical sciences ,Materials Chemistry ,Physical and Theoretical Chemistry ,Protein kinase A ,030304 developmental biology ,0303 health sciences ,Activation pathway ,010304 chemical physics ,biology ,Chemistry ,Plasmodium falciparum ,biology.organism_classification ,Nmr data ,digestive system diseases ,0104 chemical sciences ,3. Good health ,Surfaces, Coatings and Films ,Cell biology ,surgical procedures, operative ,Biochemistry ,cGMP-dependent protein kinase ,030217 neurology & neurosurgery - Abstract
The Plasmodium falciparum cGMP-dependent protein kinase (PfPKG) is required for the progression of the Plasmodium's life cycle and is therefore a promising malaria drug target. PfPKG includes four cGMP-binding domains (CBD-A to CBD-D). CBD-D plays a crucial role in PfPKG regulation as it is the primary determinant for the inhibition and cGMP-dependent activation of the catalytic domain. Hence, it is critical to understand how CBD-D is allosterically regulated by cGMP. Although the apo versus holo conformational changes of CBD-D have been reported, information on the intermediates of the activation pathway is currently lacking. Here, we employed molecular dynamics simulations to model four key states along the thermodynamic cycle for the cGMP-dependent activation of the PfPKG CBD-D domain. The simulations were compared to NMR data, and they revealed that the PfPKG CBD-D activation pathway samples a compact intermediate in which the N- and C-terminal helices approach the central β-barrel. In addition, by comparing the cGMP-bound active and inactive states, the essential binding interactions that differentiate these states were identified. The identification of structural and dynamical features unique to the cGMP-bound inactive state provides a promising basis to design PfPKG-selective allosteric inhibitors as a viable treatment for malaria.
- Published
- 2021
47. PKA Cβ: a forgotten catalytic subunit of cAMP-dependent protein kinase opens new windows for PKA signaling and disease pathologies
- Author
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Bjørn Steen Skålhegg, Susan S. Taylor, Lily Vu, Maximilian Wallbott, Jian Wu, Jessica G.H. Bruystens, Friedrich W. Herberg, Erik M F Machal, Blaine Baker, Kristoffer Søberg, Elimelda Moige Ongeri, Francesco Raimondi, and Faihaa Ahmed
- Subjects
Protein subunit ,Sequence Homology ,Biochemistry ,03 medical and health sciences ,Catalytic Domain ,Neoplasms ,PRKACB Gene ,Animals ,Humans ,splice ,Amino Acid Sequence ,Protein kinase A ,Molecular Biology ,Gene ,030304 developmental biology ,Cyclic AMP-Dependent Protein Kinase Catalytic Subunits ,0303 health sciences ,Chemistry ,030302 biochemistry & molecular biology ,Alternative splicing ,Exons ,Cell Biology ,PRKACA ,Cell biology ,Mutation ,Signal transduction ,Signal Transduction - Abstract
3′,5′-cyclic adenosine monophosphate (cAMP) dependent protein kinase or protein kinase A (PKA) has served as a prototype for the large family of protein kinases that are crucially important for signal transduction in eukaryotic cells. The PKA catalytic subunits are encoded by the two major genes PRKACA and PRKACB, respectively. The PRKACA gene encodes two known splice variants, the ubiquitously expressed Cα1 and the sperm-specifically expressed Cα2. In contrast, the PRKACB gene encodes several splice variants expressed in a highly cell and tissue-specific manner. The Cβ proteins are called Cβ1, Cβ2, Cβ3, Cβ4 and so-called abc variants of Cβ3 and Cβ4. Whereas Cβ1 is ubiquitously expressed, Cβ2 is enriched in immune cells and the Cβ3, Cβ4 and their abc variants are solely expressed in neuronal cells. All Cα and Cβ splice variants share a kinase-conserved catalytic core and a C-terminal tail encoded by exons 2 through 10 in the PRKACA and PRKACB genes, respectively. All Cα and Cβ splice variants with the exception of Cα1 and Cβ1 are hyper-variable at the N-terminus. Here, we will discuss how the PRKACA and PRKACB genes have developed as paralogs that encode distinct and functionally non-redundant proteins. The fact that Cα and Cβ splice variant mutations are associated with numerous diseases further opens new windows for PKA-induced disease pathologies.
- Published
- 2021
48. Oncologic outcomes of human papillomavirus–associated oropharynx carcinoma treated with surgery alone: A 12‐institution study of 344 patients
- Author
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Karolina A. Plonowska-Hirschfeld, Patrick K. Ha, Ramez Philips, Aru Panwar, Russell B. Smith, Andrew Coughlin, Jeremy D. Richmon, Edgar Ochoa, Farhoud Faraji, Matthew E. Herberg, Jeffrey J. Houlton, Charles S. Coffey, William R. Ryan, Bridget V. MacDonald, Arnaud F. Bewley, Theodore A Gobillot, Trevor Hackman, Aaron L. Zebolsky, Jonathan Mallen-St. Clair, Mary Jue Xu, Carole Fakhry, Joseph Curry, Arjun S. Joshi, Andrew J Holcomb, and David Cognetti
- Subjects
Cancer Research ,medicine.medical_specialty ,Multivariate analysis ,Population ,Perineural invasion ,Oropharynx ,Alphapapillomavirus ,03 medical and health sciences ,0302 clinical medicine ,Humans ,Medicine ,Oropharynx Carcinoma ,030212 general & internal medicine ,Stage (cooking) ,education ,Papillomaviridae ,Neoplasm Staging ,Retrospective Studies ,education.field_of_study ,business.industry ,Papillomavirus Infections ,Cancer ,Retrospective cohort study ,Prognosis ,medicine.disease ,Surgery ,Oropharyngeal Neoplasms ,Oncology ,Head and Neck Neoplasms ,030220 oncology & carcinogenesis ,Cohort ,Carcinoma, Squamous Cell ,business - Abstract
Background The oncologic outcomes of surgery alone for patients with American Joint Committee on Cancer 7th edition (AJCC 7th) pN2a and pN2b human papillomavirus-associated oropharynx squamous cell carcinoma (HPV+OPSCC) are not clear. Methods The authors performed a 12-institution retrospective study of 344 consecutive patients with HPV+OPSCC (AJCC 7th pT0-3 N3 M0) treated with surgery alone with 6 months or more of follow-up using univariate and multivariate analyses. Results The 2-year outcomes for the entire cohort were 91% (182 of 200) disease-free survival (DFS), 100% (200 of 200) disease-specific survival (DSS), and 98% (200 of 204) overall survival (OS). The 18 recurrences within 2 years were 88.9% (16 of 18) local and/or regional recurrences and 11.1% (2 of 18) distant metastases. Recurrences were not significantly associated with smoking, pT stage, or pN stage. The 16 patients with locoregional recurrences within 2 years all underwent successful salvage treatments (median follow-up after salvage: 13.1 months), 43.8% (7 of 16) of whom underwent salvage surgery alone for a 2-year overall salvage radiation need of 4.5% (9 of 200). The 2-year outcomes for the 59 evaluable patients among the 109 AJCC 7th pT0-2 N2a-N2b patients with 1 to 3 pathologic lymph nodes (LNs) were as follows: local recurrence, 3.4% (2 of 59); regional recurrence, 8.4% (5 of 59); distant metastases, 0%; DFS, 88.1% (52 of 59); DSS, 100% (59 of 59); OS, 96.7% (59 of 61); and salvage radiation, 5.1% (3 of 59). Conclusions With careful selection, surgery alone for AJCC 7th pT0-2N0-N2b HPV+OPSCC with zero to 3 pathologic LNs without perineural invasion, extranodal extension, or positive margins results in high DFS, DSS, OS, and salvage treatment success. Because of the short-term follow-up, these data support further investigation of treatment de-escalation in this population.
- Published
- 2021
49. How legitimate is the German coal compromise? Areas of tension and negotiation dynamics in the Coal Commission
- Author
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Konrad Gürtler, Tobias Haas, David Löw Beer, and Jeremias Herberg
- Subjects
Philosophy and Science Studies ,Political science ,05 social sciences ,050602 political science & public administration ,0507 social and economic geography ,General Medicine ,050703 geography ,Humanities ,0506 political science - Abstract
Die Legitimität von Expert*innenkommissionen in Demokratien ist stets umstritten, weil Aushandlungsprozesse verlagert werden, die eigentlich in demokratisch legitimierten Gremien stattfinden sollten. Zugleich wird ihre Problemlösungsfähigkeit häufig gelobt. Die bisherige politikwissenschaftliche Forschung zur Legitimität von Expert*innenkommissionen konzentriert sich vor allem auf eine Beurteilung ihrer Funktionen im politischen System sowie auf einzelne Aspekte oder Dimensionen von Legitimität. Im vorliegenden Beitrag wird ein umfassendes Kriteriensystem zur Beurteilung der Legitimität der Kommission Wachstum, Strukturwandel und Beschäftigung („Kohlekommission“, KWSB) entwickelt. Es beinhaltet die Input- (Inklusivität, politische Verantwortlichkeit), Throughput- (Accountability im Prozess, Transparenz, deliberative Arbeitsqualität, Inklusivität und Offenheit) und Outputlegitimität (Problemlösungsfähigkeit und Gemeinwohlorientierung). Dabei wird die Legitimität der KWSB auf Basis von Dokumentenanalysen und Interviews mit 14 der 28 Kommissionsmitglieder bzw. deren Stellvertreter*innen beurteilt. Durch die Kommission wurde ein Vorschlag entwickelt, wie ein schrittweiser Kohleausstieg mit erheblichen Unterstützungsleistungen für die betroffenen Regionen, Beschäftigten und Unternehmen aussehen kann. Über den gesamten Kommissionsprozess sind allerdings intransparente Verantwortlichkeiten, eine Privilegierung der Positionen einzelner Mitglieder sowie ein Ergebnis zu bemängeln, dessen Gemeinwohlorientierung wegen der hohen Kosten des Beschlusses und der geringen klimapolitischen Ambition umstritten ist. Zum Schluss des Aufsatzes wird diskutiert, wie die Legitimität vergleichbarer Kommissionen durch Regulierung sowie direktdemokratische Elemente erhöht werden könnte. The legitimacy of expert commissions in democracies is always disputed, given that negotiation processes are shifted that should actually take place in democratically legitimized bodies. At the same time, their problem-solving capacity is often appreciated. Previous political science research on the legitimacy of expert commissions has focused primarily on an assessment of their functions in the political system and on individual aspects or dimensions of legitimacy. In this paper, we develop a comprehensive set of criteria for assessing the legitimacy of the Commission on Growth, Structural Change and Employment (“Coal Commission”, KWSB). It includes input (inclusiveness, political accountability), throughput (accountability in the process, transparency, deliberative quality of work, inclusiveness and openness) and output legitimacy (problem-solving capacity and public good orientation). The legitimacy of the KWSB is assessed on the basis of document analyses as well as interviews with 14 of the 28 commission members or their deputies. The commission developed a proposal for a gradual coal phase-out with considerable support for the affected regions, employees and companies. Throughout the entire commission process, however, non-transparent responsibilities and a privileging of the positions of individual members should be critized. The orientation of the result toward the common good is controversial due to the high costs of the decision and the low climate policy ambition. The paper concludes with a discussion of how the legitimacy of comparable commissions could be increased through regulation as well as elements of direct democracy.
- Published
- 2021
50. Author response: An auto-inhibited state of protein kinase G and implications for selective activation
- Author
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Rajesh Sharma, Jeong Joo Kim, Liying Qin, Philipp Henning, Madoka Akimoto, Bryan VanSchouwen, Gundeep Kaur, Banumathi Sankaran, Kevin R MacKenzie, Giuseppe Melacini, Darren E Casteel, Friedrich W Herberg, and Choel Kim
- Published
- 2022
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