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Randall, Joshua C. ; Winkler, Thomas W. ; Kutalik, Zoltán ; I. Berndt, Sonja ; Jackson, Anne U. ; Monda, Keri L. ; Kilpeläinen, Tuomas O. ; Esko, Tõnu ; Mägi, Reedik ; Li, Shengxu ; Workalemahu, Tsegaselassie ; Feitosa, Mary F. ; Croteau-Chonka, Damien C. ; Day, Felix R. ; Fall, Tove ; Ferreira, Teresa ; Gustafsson, Stefan ; Locke, Adam E. ; Mathieson, Iain ; Scherag, André ; Vedantam, Sailaja ; Wood, Andrew R. ; Liang, Liming ; Steinthorsdottir, Valgerdur ; Thorleifsson, Gudmar ; Dermitzakis, Emmanouil T. ; Dimas, Antigone S. ; Karpe, Fredrik ; Min, Josine L. ; Nicholson, George ; Clegg, Deborah J. ; Person, Thomas ; Krohn, Jon P. ; Bauer, Sabrina ; Buechler, Christa ; Eisinger, Kristina ; Bonnefond, Amélie ; Froguel, Philippe ; Hottenga, Jouke-Jan ; Prokopenko, Inga ; Waite, Lindsay L. ; Harris, Tamara B. ; Smith, Albert Vernon ; Shuldiner, Alan R. ; McArdle, Wendy L. ; Caulfield, Mark J. ; Munroe, Patricia B. ; Grönberg, Henrik ; Chen, Yii-Der Ida ; Li, Guo ; Beckmann, Jacques S. ; Johnson, Toby ; Thorsteinsdottir, Unnur ; Teder-Laving, Maris ; Khaw, Kay-Tee ; Wareham, Nicholas J. ; Zhao, Jing Hua ; Amin, Najaf ; Oostra, Ben A. ; Kraja, Aldi T. ; Province, Michael A. ; Cupples, L. Adrienne ; Heard-Costa, Nancy L. ; Kaprio, Jaakko ; Ripatti, Samuli ; Surakka, Ida ; Collins, Francis S. ; Saramies, Jouko ; Tuomilehto, Jaakko ; Jula, Antti ; Salomaa, Veikko ; Erdmann, Jeanette ; Hengstenberg, Christian ; Loley, Christina ; Schunkert, Heribert ; Lamina, Claudia ; Wichmann, Heinz Erich ; Albrecht, Eva ; Gieger, Christian ; Hicks, Andrew A. ; Johansson, Åsa ; Pramstaller, Peter P. ; Kathiresan, Sekar ; Speliotes, Elizabeth K. ; Penninx, Brenda W. J. H. ; Hartikainen, Anna-Liisa ; Jarvelin, Marjo-Riitta ; Gyllensten, Ulf ; Boomsma, Dorret I. ; Campbell, Harry ; Wilson, James F. ; Chanock, Stephen J. ; Farrall, Martin ; Goel, Anuj ; Medina-Gomez, Carolina ; Rivadeneira, Fernando ; Estrada, Karol ; Uitterlinden, André G. ; Hofman, Albert ; Zillikens, M. Carola ; Heijer, Martin den ; Kiemeney, Lambertus Adrianus ; Maschio, Andrea ; Hall, Per ; Tyrer, Jonathan ; Teumer, Alexander ; Völzke, Henry ; Kovacs, Peter ; Tönjes, Anke ; Mangino, Massimo ; Spector, Tim D. ; Hayward, Caroline ; Rudan, Igor ; Hall, Alistair S. ; Samani, Nilesh J. ; Attwood, Antony Paul ; Sambrook, Jennifer G. ; Hung, Joseph ; Palmer, Lyle J. ; Lokki, Marja-Liisa ; Sinisalo, Juha ; Boucher, Gabrielle ; Huikuri, Heikki ; Lorentzon, Mattias ; Ohlsson, Claes ; Eklund, Niina ; Eriksson, Johan G. ; Barlassina, Cristina ; Rivolta, Carlo ; Nolte, Ilja M. ; Snieder, Harold ; Klauw, Melanie M. van der ; Vliet-Ostaptchouk, Jana V. van ; Gejman, Pablo V. ; Shi, Jianxin ; Jacobs, Kevin B. ; Wang, Zhaoming ; Bakker, Stephan J. L. ; Mateo Leach, Irene ; Navis, Gerjan ; Harst, Pim van der ; Martin, Nicholas Gordon ; Medland, Sarah E. ; Montgomery, Grant W. ; Yang, Jian ; Chasman, Daniel I. ; Ridker, Paul M. ; Rose, Lynda M. ; Lehtimäki, Terho ; Raitakari, Olli ; Absher, Devin ; Iribarren, Carlos ; Basart, Hanneke ; Hovingh, Kees G. ; Hyppönen, Elina ; Power, Chris ; Power, Chris ; Anderson, Denise ; Beilby, John P. ; Hui, Jennie ; Jolley, Jennifer ; Sager, Hendrik ; Bornstein, Stefan R. ; Schwarz, Peter E. H. ; Kristiansson, Kati ; Perola, Markus ; Lindström, Jaana ; Swift, Amy J. ; Uusitupa, Matti ; Atalay, Mustafa ; Lakka, Timo A. ; Rauramaa, Rainer ; Bolton, Jennifer L. ; Fowkes, Gerry ; Fraser, Ross M. ; Price, Jackie F. ; Fischer, Krista ; KrjutÅ¡kov, Kaarel ; Metspalu, Andres ; Mihailov, Evelin ; Langenberg, Claudia ; Luan, Jian'an ; Ong, Ken K. ; Chines, Peter S. ; Keinanen-Kiukaanniemi, Sirkka M. ; Saaristo, Timo E. ; Edkins, Sarah ; Franks, Paul W. ; Hallmans, Göran ; Shungin, Dmitry ; Morris, Andrew David ; Palmer, Colin N. A. ; Erbel, Raimund ; Moebus, Susanne ; Nöthen, Markus Maria ; Pechlivanis, Sonali ; Hveem, Kristian ; Narisu, Narisu ; Hamsten, Anders ; Humphries, Steve E. ; Strawbridge, Rona J. ; Tremoli, Elena ; Grallert, Harald ; Thorand, Barbara ; Illig, Thomas ; Koenig, Wolfgang ; Müller-Nurasyid, Martina ; Peters, Annette ; Böhm, Bernhard O. ; Kleber, Marcus E. ; März, Winfried ; Winkelmann, Bernhard R. ; Kuusisto, Johanna ; Laakso, Markku ; Arveiler, Dominique ; Cesana, Giancarlo ; Kuulasmaa, Kari ; Virtamo, Jarmo ; Yarnell, John W. G. ; Kuh, Diana ; Wong, Andrew ; Lind, Lars ; Faire, Ulf de ; Gigante, Bruna ; Magnusson, Patrik K. E. ; Pedersen, Nancy L. ; Dedoussis, George ; Dimitriou, Maria ; Kolovou, Genovefa ; Kanoni, Stavroula ; Stirrups, Kathleen ; Bonnycastle, Lori L. ; Njølstad, Inger ; Wilsgaard, Tom ; Ganna, Andrea ; Rehnberg, Emil ; Hingorani, Aroon ; Kivimaki, Mika ; Kumari, Meena ; Assimes, Themistocles L. ; Barroso, Inês ; Boehnke, Michael ; Borecki, Ingrid B. ; Deloukas, Panos ; Fox, Caroline S. ; Frayling, Timothy ; Groop, Leif C. ; Haritunians, Talin ; Hunter, David ; Ingelsson, Erik ; Kaplan, Robert ; Mohlke, Karen L. ; North, Kari E. ; Lindgren, Cecilia M. ; Qi, Lu ; Loos, Ruth J. F. ; Heid, Iris M. ; Hirschhorn, Joel N. ; McCarthy, Mark I. ; Abecasis, Gonçalo R. ; Stefansson, Kari ; Strachan, David P. ; Schlessinger, David ; O'Connell, Jeffrey R. ; Duijn, Cornelia M. van
Men and women differ substantially regarding height, weight, and body fat. Interestingly, previous work detecting genetic effects for waist-to-hip ratio, to assess body fat distribution, has found that many of these showed sex-differences. However, systematic searches for sex-differences in genetic effects have not yet been conducted. Therefore, we undertook a genome-wide search for sexually dimorphic genetic effects for anthropometric traits including 133,723 individuals in a large meta-analysis and followed promising variants in further 137,052 individuals, including a total of 94 studies. We identified seven loci with significant sex-difference including four previously established (near GRB14/COBLL1, LYPLAL1/SLC30A10, VEGFA, ADAMTS9) and three novel anthropometric trait loci (near MAP3K1, HSD17B4, PPARG), all of which were significant in women, but not in men. Of interest is that sex-difference was only observed for waist phenotypes, but not for height or body-mass-index. We found no evidence for sex-differences with opposite effect direction for men and women. The PPARG locus is of specific interest due to its link to diabetes genetics and therapy. Our findings demonstrate the importance of investigating sex differences, which may lead to a better understanding of disease mechanisms with a potential relevance to treatment options.
Ballo, Olivier ; Fleckenstein, Philine ; Eladly, Fagr ; Kreisel, Eva-Maria ; Stratmann, Jan Alexander ; Seifried, Erhard ; Müller, Markus Matthias ; Serve, Hubert ; Bug, Gesine ; Bönig, Halvard-Björn ; Brandts, Christian Hubertus ; Finkelmeier, Fabian
Background and Objectives: Red blood cell (RBC) transfusions are needed by almost every acute myeloid leukaemia (AML) patient undergoing induction chemotherapy and constitute a cornerstone in supportive measures for cancer patients in general. Randomized controlled trials have shown non‐inferiority or even superiority of restrictive transfusion guidelines over liberal transfusion guidelines in specific clinical situations outside of medical oncology. In this study, we analysed whether more restrictive RBC transfusion reduces blood use without affecting hard outcomes.
Materials and Methods: A total of 352 AML patients diagnosed between 2007 and 2018 and undergoing intensive induction chemotherapy were included in this retrospective analysis. In the less restrictive transfusion group, patients received RBC transfusion for haemoglobin levels below 8 g/dl (2007–2014). In the restrictive transfusion group, patients received RBC transfusion for haemoglobin levels below 7 g/dl (2016–2018). Liberal transfusion triggers were never endorsed.
Results: A total of 268 (76·1%) and 84 (23·9%) AML patients fell into the less restrictive and restrictive transfusion groups, respectively. The less restrictive transfusion group had 1 g/dl higher mean haemoglobin levels, received their first RBC transfusions earlier and needed 1·5 more units of RBC during the hospital stay of induction chemotherapy. Febrile episodes, C‐reactive protein levels, admission to the intensive care unit, length of hospital stay as well as response and survival rates did not differ between the two cohorts.
Conclusion: From our retrospective analysis, we conclude that a more restrictive transfusion trigger does not affect important outcomes of AML patients. The opportunity to test possible effects of the more severe anaemia in the restrictive transfusion group on quality of life was missed.
Kramer, Isabelle Marie ; Pfenninger, Markus ; Feldmeyer, Barbara ; Dhimal, Meghnath ; Gautam, Ishan ; Shreshta, Pramod ; Baral, Sunita ; Phuyal, Parbati ; Hartke, Juliane ; Magdeburg, Axel ; Groneberg, Jan David Alexander ; Ahrens, Bodo ; Müller, Ruth ; Waldvogel, Ann-Marie
Driven by globalization, urbanization and climate change, the distribution range of invasive vector species has expanded to previously colder ecoregions. To reduce health-threatening impacts on humans, insect vectors are extensively studied. Population genomics can reveal the genomic basis of adaptation and help to identify emerging trends of vector expansion. By applying whole genome analyses and genotype-environment associations to populations of the main dengue vector Aedes aegypti, sampled along an altitudinal gradient in Nepal (200–1300 m), we identify putatively adaptive traits and describe the species' genomic footprint of climate adaptation to colder ecoregions. We found two differentiated clusters with significantly different allele frequencies in genes associated to climate adaptation between the highland population (1300 m) and all other lowland populations (≤800 m). We revealed nonsynonymous mutations in 13 of the candidate genes associated to either altitude, precipitation or cold tolerance and identified an isolation-by-environment differentiation pattern. Other than the expected gradual differentiation along the altitudinal gradient, our results reveal a distinct genomic differentiation of the highland population. Local high-altitude adaptation could be one explanation of the population's phenotypic cold tolerance. Carrying alleles relevant for survival under colder climate increases the likelihood of this highland population to a worldwide expansion into other colder ecoregions.
Dietrich, Helge Markus ; Righetto, Ricardo Diogo ; Kumar, Anuj ; Wietrzynski, Wojciech ; Trischler, Raphael ; Schuller, Sandra K. ; Wagner, Jonathan ; Schwarz, Fabian M. ; Engel, Benjamin D. ; Müller, Volker ; Schuller, Jan Michael
Filamentous enzymes have been found in all domains of life, but the advantage of filamentation is often elusive1. Some anaerobic, autotrophic bacteria have an unusual filamentous enzyme for CO2 fixation—hydrogen-dependent CO2 reductase (HDCR)2,3—which directly converts H2 and CO2 into formic acid. HDCR reduces CO2 with a higher activity than any other known biological or chemical catalyst4,5, and it has therefore gained considerable interest in two areas of global relevance: hydrogen storage and combating climate change by capturing atmospheric CO2. However, the mechanistic basis of the high catalytic turnover rate of HDCR has remained unknown. Here we use cryo-electron microscopy to reveal the structure of a short HDCR filament from the acetogenic bacterium Thermoanaerobacter kivui. The minimum repeating unit is a hexamer that consists of a formate dehydrogenase (FdhF) and two hydrogenases (HydA2) bound around a central core of hydrogenase Fe-S subunits, one HycB3 and two HycB4. These small bacterial polyferredoxin-like proteins oligomerize through their C-terminal helices to form the backbone of the filament. By combining structure-directed mutagenesis with enzymatic analysis, we show that filamentation and rapid electron transfer through the filament enhance the activity of HDCR. To investigate the structure of HDCR in situ, we imaged T. kivui cells with cryo-electron tomography and found that HDCR filaments bundle into large ring-shaped superstructures attached to the plasma membrane. This supramolecular organization may further enhance the stability and connectivity of HDCR to form a specialized metabolic subcompartment within the cell.
Comprehensive analysis of tumour sub-volumes for radiomic risk modelling in locally advanced HNSCC
(2020)
Leger, Stefan ; Zwanenburg, Alex ; Leger, Karoline ; Lohaus, Fabian ; Linge, Annett ; Schreiber, Andreas ; Kalinauskaite, Goda ; Tinhofer, Inge ; Guberina, Nika ; Guberina, Maja ; Balermpas, Panagiotis ; Müller-von der Grün, Jens ; Ganswindt, Ute ; Belka, Claus ; Peeken, Jan Caspar ; Combs, Stephanie E. ; Boeke, Simon ; Zips, Daniel ; Richter, Christian ; Krause, Mechthild ; Baumann, Michael ; Troost, Esther Gera Cornelia ; Löck, Steffen
Simple Summary: Radiomic risk models are usually based on imaging features, which are extracted from the entire gross tumour volume (GTV entire ). This approach does not explicitly consider the complex biological structure of the tumours. Therefore, in this retrospective study, we investigated the prognostic value of radiomic analyses based on different tumour sub-volumes using computed tomography imaging of patients with locally advanced head and neck squamous cell carcinoma who were treated with primary radio-chemotherapy. The GTV entire was cropped by different margins to define the rim and corresponding core sub-volumes of the tumour. Furthermore, the best performing tumour rim sub-volume was extended into surrounding tissue with different margins. As a result, the models based on the 5 mm tumour rim and on the 3 mm extended rim sub-volume showed an improved performance compared to models based on the corresponding tumour core. This indicates that the consideration of tumour sub-volumes may help to improve radiomic risk models.
Abstract: Imaging features for radiomic analyses are commonly calculated from the entire gross tumour volume (GTVentire). However, tumours are biologically complex and the consideration of different tumour regions in radiomic models may lead to an improved outcome prediction. Therefore, we investigated the prognostic value of radiomic analyses based on different tumour sub-volumes using computed tomography imaging of patients with locally advanced head and neck squamous cell carcinoma. The GTVentire was cropped by different margins to define the rim and the corresponding core sub-volumes of the tumour. Subsequently, the best performing tumour rim sub-volume was extended into surrounding tissue with different margins. Radiomic risk models were developed and validated using a retrospective cohort consisting of 291 patients in one of the six Partner Sites of the German Cancer Consortium Radiation Oncology Group treated between 2005 and 2013. The validation concordance index (C-index) averaged over all applied learning algorithms and feature selection methods using the GTVentire achieved a moderate prognostic performance for loco-regional tumour control (C-index: 0.61 ± 0.04 (mean ± std)). The models based on the 5 mm tumour rim and on the 3 mm extended rim sub-volume showed higher median performances (C-index: 0.65 ± 0.02 and 0.64 ± 0.05, respectively), while models based on the corresponding tumour core volumes performed less (C-index: 0.59 ± 0.01). The difference in C-index between the 5 mm tumour rim and the corresponding core volume showed a statistical trend (p = 0.10). After additional prospective validation, the consideration of tumour sub-volumes may be a promising way to improve prognostic radiomic risk models.
Rabasco Meneghetti, Asier ; Zwanenburg, Alex ; Leger, Stefan ; Leger, Karoline ; Troost, Esther Gera Cornelia ; Linge, Annett ; Lohaus, Fabian ; Schreiber, Andreas ; Kalinauskaite, Goda ; Tinhofer, Inge ; Guberina, Nika ; Guberina, Maja ; Balermpas, Panagiotis ; Müller-von der Grün, Jens ; Ganswindt, Ute ; Belka, Claus ; Peeken, Jan Caspar ; Combs, Stephanie E. ; Böke, Simon ; Zips, Daniel ; Krause, Mechthild ; Baumann, Michael ; Löck, Steffen
Purpose: To develop and validate a CT-based radiomics signature for the prognosis of loco-regional tumour control (LRC) in patients with locally advanced head and neck squamous cell carcinoma (HNSCC) treated by primary radiochemotherapy (RCTx) based on retrospective data from 6 partner sites of the German Cancer Consortium - Radiation Oncology Group (DKTK-ROG).
Material and methods: Pre-treatment CT images of 318 patients with locally advanced HNSCC were collected. Four-hundred forty-six features were extracted from each primary tumour volume and then filtered through stability analysis and clustering. First, a baseline signature was developed from demographic and tumour-associated clinical parameters. This signature was then supplemented by CT imaging features. A final signature was derived using repeated 3-fold cross-validation on the discovery cohort. Performance in external validation was assessed by the concordance index (C-Index). Furthermore, calibration and patient stratification in groups with low and high risk for loco-regional recurrence were analysed.
Results: For the clinical baseline signature, only the primary tumour volume was selected. The final signature combined the tumour volume with two independent radiomics features. It achieved moderately good discriminatory performance (C-Index [95% confidence interval]: 0.66 [0.55–0.75]) on the validation cohort along with significant patient stratification (p = 0.005) and good calibration.
Conclusion: We identified and validated a clinical-radiomics signature for LRC of locally advanced HNSCC using a multi-centric retrospective dataset. Prospective validation will be performed on the primary cohort of the HNprädBio trial of the DKTK-ROG once follow-up is completed.
Koromina, Maria ; Ravi, Ashvin ; Panagiotaropoulou, Georgia ; Schilder, Brian M. ; Humphrey, Jack ; Braun, Alice ; Bidgeli, Tim ; Chatzinakos, Chris ; Coombes, Brandon ; Kim, Jaeyoung ; Liu, Xiaoxi ; Terao, Chikashi ; O'Connell, Kevin S. ; Adams, Mark ; Adolfsson, Rolf ; Alda, Martin ; Alfredsson, Lars ; Andlauer, Till ; Andreassen, Ole A. ; Antoniou, Anastasia ; Baune, Bernhard T. ; Bengesser, Susanne ; Biernacka, Joanna ; Boehnke, Michael ; Bosch, Rosa ; Cairns, Murray ; Carr, Vaughan J. ; Casas Brugué, Miquel ; Catts, Stanley ; Cichon, Sven ; Corvin, Aiden ; Craddock, Nicholas ; Dafnas, Konstantinos ; Dalkner, Nina ; Dannlowski, Udo ; Degenhardt, Franziska ; Di Florio, Arianna ; Dikeos, Dimitris ; Fellendorf, Frederike Tabea ; Ferentinos, Panagiotis ; Forstner, Andreas Josef ; Forty, Liz ; Frye, Mark ; Fullerton, Janice M. ; Gawlik, Micha ; Gizer, Ian R. ; Gordon-Smith, Katherine ; Green, Melissa J. ; Grigoroiu-Serbanescu, Maria ; Guzman-Parra, José ; Hahn, Tim ; Henskens, Frans ; Hillert, Jan ; Jablensky, Assen V. ; Jones, Lisa ; Jones, Ian ; Jonsson, Lina ; Kelsoe, John R. ; Kircher, Tilo ; Kirov, George ; Kittel-Schneider, Sarah ; Kogevinas, Manolis ; Landén, Mikael ; Leboyer, Marion ; Lenger, Melanie ; Lissowska, Jolanta ; Lochner, Christine ; Loughland, Carmel ; MacIntyre, Donald ; Martin, Nicholas G. ; Maratou, Eirini ; Mathews, Carol A. ; Mayoral, Fermı́n ; McElroy, Susan L. ; McGregor, Nathaniel W. ; McIntosh, Andrew M. ; McQuillin, Andrew ; Michie, Patricia ; Milanova, Vihra ; Mitchell, Philip B. ; Moutsatsou, Paraskevi ; Mowry, Bryan ; Müller-Myhsok, Bertram ; Myers, Richard M. ; Nenadić, Igor ; Nöthen, Markus Maria ; O'Donovan, Claire ; O'Donovan, Michael ; Ophoff, Roel André ; Owen, Michael J. ; Pantelis, Christos ; Pato, Carlos ; Pato, Michele T. ; Patrinos, George P. ; Pawlak, Joanna M. ; Perlis, Roy H. ; Porichi, Evgenia ; Posthuma, Danielle ; Ramos-Quiroga, Josep Antoni ; Reif, Andreas ; Reininghaus, Eva Z. ; Ribasés, Marta ; Rietschel, Marcella ; Schall, Ulrich ; Schulze, Thomas Gerd ; Scott, Laura J. ; Scott, Rodney J. ; Serretti, Alessandro ; Shannon Weickert, Cynthia ; Smoller, Jordan W. ; Soler Artigas, Marı́a ; Stein, Dan J. ; Streit, Fabian ; Toma, Claudio ; Tooney, Paul ; Vieta, Eduard ; Vincent, John B. ; Waldman, Irwin D. ; Weickert, Thomas ; Witt, Stephanie H. ; Hong, Kyung Sue ; Ikeda, Masashi ; Iwata, Nakao ; Świątkowska, Beata ; Won, Hong-Hee ; Edenberg, Howard J. ; Ripke, Stephan ; Raj, Towfique ; Coleman, Jonathan R. I. ; Mullins, Niamh
Bipolar disorder (BD) is a heritable mental illness with complex etiology. While the largest published genome-wide association study identified 64 BD risk loci, the causal SNPs and genes within these loci remain unknown. We applied a suite of statistical and functional fine-mapping methods to these loci, and prioritized 22 likely causal SNPs for BD. We mapped these SNPs to genes, and investigated their likely functional consequences by integrating variant annotations, brain cell-type epigenomic annotations, brain quantitative trait loci, and results from rare variant exome sequencing in BD. Convergent lines of evidence supported the roles of SCN2A, TRANK1, DCLK3, INSYN2B, SYNE1, THSD7A, CACNA1B, TUBBP5, PLCB3, PRDX5, KCNK4, AP001453.3, TRPT1, FKBP2, DNAJC4, RASGRP1, FURIN, FES, YWHAE, DPH1, GSDMB, MED24, THRA, EEF1A2, and KCNQ2 in BD. These represent promising candidates for functional experiments to understand biological mechanisms and therapeutic potential. Additionally, we demonstrated that fine-mapping effect sizes can improve performance and transferability of BD polygenic risk scores across ancestrally diverse populations, and present a high-throughput fine-mapping pipeline (https://github.com/mkoromina/SAFFARI).
Willems, Laurent Maximilian ; Rosenow, Felix ; Schubert-Bast, Susanne ; Kurlemann, Gerhard ; Zöllner, Johann Philipp ; Bast, Thomas ; Bertsche, Astrid ; Bettendorf, Ulrich ; Ebrahimi-Fakhari, Daniel ; Grau, Janina ; Hahn, Andreas ; Hartmann, Hans ; Hertzberg, Christoph ; Hornemann, Frauke ; Immisch, Ilka ; Jacobs-LeVan, Julia ; Klein, Karl Martin ; Klotz, Kerstin Alexandra ; Kluger, Gerhard ; Knake, Susanne ; Knuf, Markus ; Marquard, Klaus ; Mayer, Thomas ; Meyer, Sascha ; Muhle, Hiltrud ; Müller-Schlüter, Karen ; Podewils, Felix von ; Ruf, Susanne ; Sauter, Matthias ; Schäfer, Hannah ; Schlump, Jan-Ulrich ; Syrbe, Steffen ; Thiels, Charlotte ; Trollmann, Regina ; Wiemer-Kruel, Adelheid ; Wilken, Bernd ; Zukunft, Bianca ; Strzelczyk, Adam
Background: The approval of everolimus (EVE) for the treatment of angiomyolipoma (2013), subependymal giant cell astrocytoma (2013) and drug-refractory epilepsy (2017) in patients with tuberous sclerosis complex (TSC) represents the first disease-modifying treatment option available for this rare and complex genetic disorder. Objective: The objective of this study was to analyse the use, efficacy, tolerability and treatment retention of EVE in patients with TSC in Germany from the patient’s perspective. Methods: A structured cross-age survey was conducted at 26 specialised TSC centres in Germany and by the German TSC patient advocacy group between February and July 2019, enrolling children, adolescents and adult patients with TSC. Results: Of 365 participants, 36.7% (n = 134) reported the current or past intake of EVE, including 31.5% (n = 115) who were taking EVE at study entry. The mean EVE dosage was 6.1 ± 2.9 mg/m2 (median: 5.6 mg/m2, range 2.0–15.1 mg/m2) in children and adolescents and 4 ± 2.1 mg/m2 (median: 3.7 mg/m2, range 0.8–10.1 mg/m2) in adult patients. An early diagnosis of TSC, the presence of angiomyolipoma, drug-refractory epilepsy, neuropsychiatric manifestations, subependymal giant cell astrocytoma, cardiac rhabdomyoma and overall multi-organ involvement were associated with the use of EVE as a disease-modifying treatment. The reported efficacy was 64.0% for angiomyolipoma (75% in adult patients), 66.2% for drug-refractory epilepsy, and 54.4% for subependymal giant cell astrocytoma. The overall retention rate for EVE was 85.8%. The retention rates after 12 months of EVE therapy were higher among adults (93.7%) than among children and adolescents (88.7%; 90.5% vs 77.4% after 24 months; 87.3% vs 77.4% after 36 months). Tolerability was acceptable, with 70.9% of patients overall reporting adverse events, including stomatitis (47.0%), acne-like rash (7.7%), increased susceptibility to common infections and lymphoedema (each 6.0%), which were the most frequently reported symptoms. With a total score of 41.7 compared with 36.8 among patients not taking EVE, patients currently being treated with EVE showed an increased Liverpool Adverse Event Profile. Noticeable deviations in the sub-items ‘tiredness’, ‘skin problems’ and ‘mouth/gum problems’, which are likely related to EVE-typical adverse effects, were more frequently reported among patients taking EVE. Conclusions: From the patients’ perspective, EVE is an effective and relatively well-tolerated disease-modifying treatment option for children, adolescents and adults with TSC, associated with a high long-term retention rate that can be individually considered for each patient. Everolimus therapy should ideally be supervised by a centre experienced in the use of mechanistic target of rapamycin inhibitors, and adverse effects should be monitored on a regular basis.
Gorges, Martin ; Müller, Hans-Peter ; Liepelt-Scarfone, Inga ; Storch, Alexander ; Dodel, Richard ; Hilker-Roggendorf, Rüdiger ; Berg, Daniela ; Kunz, Martin S. ; Kalbe, Elke ; Baudrexel, Simon ; Kassubek, Jan
Background: The nonmotor symptom spectrum of Parkinson’s disease (PD) includes progressive cognitive decline mainly in late stages of the disease. The aim of this study was to map the patterns of altered structural connectivity of patients with PD with different cognitive profiles ranging from cognitively unimpaired to PD-associated dementia.
Methods: Diffusion tensor imaging and neuropsychological data from the observational multicentre LANDSCAPE study were analyzed. A total of 134 patients with PD with normal cognitive function (56 PD-N), mild cognitive impairment (67 PD-MCI), and dementia (11 PD-D) as well as 72 healthy controls were subjected to whole-brain-based fractional anisotropy mapping and covariance analysis with cognitive performance measures.
Results: Structural data indicated subtle changes in the corpus callosum and thalamic radiation in PD-N, whereas severe white matter impairment was observed in both PD-MCI and PD-D patients including anterior and inferior fronto-occipital, uncinate, insular cortices, superior longitudinal fasciculi, corona radiata, and the body of the corpus callosum. These regional alterations were demonstrated for PD-MCI and were more pronounced in PD-D. The pattern of involved regions was significantly correlated with the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) total score.
Conclusions: The findings in PD-N suggest impaired cross-hemispherical white matter connectivity that can apparently be compensated for. More pronounced involvement of the corpus callosum as demonstrated for PD-MCI together with affection of fronto-parieto-temporal structural connectivity seems to lead to gradual disruption of cognition-related cortico-cortical networks and to be associated with the onset of overt cognitive deficits. The increase of regional white matter damage appears to be associated with the development of PD-associated dementia.
No association between Parkinson disease and autoantibodies against NMDA-type glutamate receptors
(2019)
Hopfner, Franziska ; Müller, Stefanie H. ; Steppat, Dagmar ; Miller, Joanna ; Schmidt, Nele ; Wandinger, Klaus-Peter ; Leypoldt, Frank ; Berg, Daniela ; Franke, Andre ; Lieb, Wolfgang ; Tittmann, Lukas ; Balzer-Geldsetzer, Monika ; Baudrexel, Simon ; Dodel, Richard ; Hilker-Roggendorf, Rüdiger ; Kalbe, Elke ; Kassubek, Jan ; Klockgether, Thomas ; Liepelt-Scarfone, Inga ; Mollenhauer, Brit ; Neuser, Petra ; Reetz, Kathrin ; Riedel, Oliver ; Schulte, Claudia ; Schulz, Jörg B. ; Spottke, Annika ; Storch, Alexander ; Trenkwalder, Claudia ; Wittchen, Hans-Ulrich ; Witt, Karsten ; Wüllner, Ullrich ; Deuschl, Günther ; Kuhlenbäumer, Gregor
Background: IgG-class autoantibodies to N-Methyl-D-Aspartate (NMDA)-type glutamate receptors define a novel entity of autoimmune encephalitis. Studies examining the prevalence of NMDA IgA/IgM antibodies in patients with Parkinson disease with/without dementia produced conflicting results. We measured NMDA antibodies in a large, well phenotyped sample of Parkinson patients without and with cognitive impairment (n = 296) and controls (n = 295) free of neuropsychiatric disease. Detailed phenotyping and large numbers allowed statistically meaningful correlation of antibody status with diagnostic subgroups as well as quantitative indicators of disease severity and cognitive impairment.
Methods: NMDA antibodies were analysed in the serum of patients and controls using well established validated assays. We used anti-NMDA antibody positivity as the main independent variable and correlated it with disease status and phenotypic characteristics.
Results: The frequency of NMDA IgA/IgM antibodies was lower in Parkinson patients (13%) than in controls (22%) and higher than in previous studies in both groups. NMDA IgA/IgM antibodies were neither significantly associated with diagnostic subclasses of Parkinson disease according to cognitive impairment, nor with quantitative indicators of disease severity and cognitive impairment. A positive NMDA antibody status was positively correlated with age in controls but not in Parkinson patients.
Conclusion: It is unlikely albeit not impossible that NMDA antibodies play a significant role in the pathogenesis or progression of Parkinson disease e.g. to Parkinson disease with dementia, while NMDA IgG antibodies define a separate disease of its own.
Brill, Stefan ; Müller, Joachim ; Hagen, Rudolf ; Möltner, Alexander ; Brockmeier, Steffi-Johanna ; Stark, Thomas ; Helbig, Silke ; Maurer, Jan ; Zahnert, Thomas ; Zierhofer, Clemens ; Nopp, Peter ; Anderson, Ilona ; Strahl, Stefan
Background: The standard electrode array for the MED-EL MAESTRO cochlear implant system is 31 mm in length which allows an insertion angle of approximately 720°. When fully inserted, this long electrode array is capable of stimulating the most apical region of the cochlea. No investigation has explored Electrically Evoked Compound Action Potential (ECAP) recordings in this region with a large number of subjects using a commercially available cochlear implant system. The aim of this study is to determine if certain properties of ECAP recordings vary, depending on the stimulation site in the cochlea. Methods: Recordings of auditory nerve responses were conducted in 67 subjects to demonstrate the feasibility of ECAP recordings using the Auditory Nerve Response Telemetry (ART™) feature of the MED-EL MAESTRO system software. These recordings were then analyzed based on the site of cochlear stimulation defined as basal, middle and apical to determine if the amplitude, threshold and slope of the amplitude growth function and the refractory time differs depending on the region of stimulation. Results: Findings show significant differences in the ECAP recordings depending on the stimulation site. Comparing the apical with the basal region, on average higher amplitudes, lower thresholds and steeper slopes of the amplitude growth function have been observed. The refractory time shows an overall dependence on cochlear region; however post-hoc tests showed no significant effect between individual regions. Conclusions :Obtaining ECAP recordings is also possible in the most apical region of the cochlea. However, differences can be observed depending on the region of the cochlea stimulated. Specifically, significant higher ECAP amplitude, lower thresholds and steeper amplitude growth function slopes have been observed in the apical region. These differences could be explained by the location of the stimulating electrode with respect to the neural tissue in the cochlea, a higher density, or an increased neural survival rate of neural tissue in the apex. Trial registration: The Clinical Investigation has the Competent Authority registration number DE/CA126/AP4/3332/18/05.
Höh, Robert Benedikt ; Wenzel, Mike ; Müller, Matthias ; Wittler, Clarissa ; Schlenke, Eva ; Hohenhorst, Jan L. ; Köllermann, Jens ; Steuber, Thomas ; Graefen, Markus ; Tilki, Derya ; Bernatz, Simon ; Karakiewicz, Pierre I. ; Preißer, Felix ; Becker, Andreas ; Kluth, Luis ; Mandel, Philipp ; Chun, Felix
Background: To test the impact of urethral sphincter length (USL) and anatomic variants of prostatic apex (Lee-type classification) in preoperative multiparametric magnet resonance imaging (mpMRI) on mid-term continence in prostate cancer patients treated with radical prostatectomy (RP). Methods: We relied on an institutional tertiary-care database to identify patients who underwent RP between 03/2018 and 12/2019 with preoperative mpMRI and data available on mid-term (>6 months post-surgery) urinary continence, defined as usage 0/1 (-safety) pad/24 h. Univariable and multivariable logistic regression models were fitted to test for predictor status of USL and prostatic apex variants, defined in mpMRI measurements. Results: Of 68 eligible patients, rate of mid-term urinary continence was 81% (n = 55). Median coronal (15.1 vs. 12.5 mm) and sagittal (15.4 vs. 11.1 mm) USL were longer in patients reporting urinary continence in mid-term follow-up (both p < 0.01). No difference was recorded for prostatic apex variants distribution (Lee-type) between continent vs. incontinent patients (p = 0.4). In separate multivariable logistic regression models, coronal (odds ratio (OR): 1.35) and sagittal (OR: 1.67) USL, but not Lee-type, were independent predictors for mid-term continence. Conclusion: USL, but not apex anatomy, in preoperative mpMRI was associated with higher rates of urinary continence at mid-term follow-up.
Gravitational waves from a core g-mode in supernovae as probes of the high-density equation of state
(2023)
Jakobus, Pia ; Müller, Bernhard ; Heger, Alexander ; Zha, Shuai ; Powell, Jade ; Motornenko, Anton ; Steinheimer, Jan ; Stöcker, Horst
Using relativistic supernova simulations of massive progenitor stars with a quark-hadron equation of state (EoS) and a purely hadronic EoS, we identify a distinctive feature in the gravitational-wave signal that originates from a buoyancy-driven mode (g-mode) below the proto-neutron star convection zone. The mode frequency lies in the range 200≲f≲800Hz and decreases with time. As the mode lives in the core of the proto-neutron star, its frequency and power are highly sensitive to the EoS, in particular the sound speed around twice saturation density.
Gravitational waves from a core g-mode in supernovae as probes of the high-density equation of state
(2023)
Jakobus, Pia ; Müller, Bernhard ; Heger, Alexander ; Zha, Shuai ; Powell, Jade ; Motornenko, Anton ; Steinheimer, Jan ; Stöcker, Horst
Using relativistic supernova simulations of massive progenitor stars with a quark-hadron equation of state (EoS) and a purely hadronic EoS, we identify a distinctive feature in the gravitational-wave signal that originates from a buoyancy-driven mode (g-mode) below the proto-neutron star convection zone. The mode frequency lies in the range 200≲f≲800Hz and decreases with time. As the mode lives in the core of the proto-neutron star, its frequency and power are highly sensitive to the EoS, in particular the sound speed around twice saturation density.