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Acharya, Shreyasi ; Adamová, Dagmar ; Adler, Alexander ; Adolfsson, Jonatan ; Aglieri Rinella, Gianluca ; Agnello, Michelangelo ; Agrawal, Neelima ; Ahammed, Zubayer ; Ahmad, Shakeel ; Ahn, Sang Un ; Ahuja, Ishaan ; Akbar, Zaenal ; Akindinov, Alexander ; Al-Turany, Mohammad ; Alam, Sk Noor ; Aleksandrov, Dmitry ; Alessandro, Bruno ; Alfanda, Haidar Mas’ud ; Alfaro Molina, Jose Ruben ; Ali, Bushra ; Ali, Yasir ; Alici, Andrea ; Alizadehvandchali, Negin ; Alkin, Anton ; Alme, Johan ; Alocco, Giacomo ; Alt, Torsten ; Altsybeev, Igor ; Anaam, Mustafa Naji ; Andrei, Cristian ; Andreou, Dimitra ; Andronic, Anton ; Anguelov, Venelin ; Antinori, Federico ; Antonioli, Pietro ; Chandra, Anuj ; Apadula, Nicole ; Aphecetche, Laurent Bernard ; Appelshäuser, Harald ; Arcelli, Silvia ; Arnaldi, Roberta ; Arsene, Ionut Cristian ; Arslandok, Mesut ; Augustinus, Andre ; Averbeck, Ralf Peter ; Aziz, Sizar ; Azmi, Mohd Danish ; Badalà, Angela ; Baek, Yong Wook ; Bai, X. ; Bailhache, Raphaëlle ; Bailung, Yoshini ; 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The production of prompt D0, Ds+, and Λc+ hadrons, and their ratios, Ds+/D0 and Λc+/D0, are measured in proton–proton collisions at √s=13 TeV at midrapidity (|y|<0.5) with the ALICE detector at the LHC. The measurements are performed as a function of the charm-hadron transverse momentum (pT) in intervals of charged-particle multiplicity, measured with two multiplicity estimators covering different pseudorapidity regions. While the strange to non-strange Ds+/D0 ratio indicates no significant multiplicity dependence, the baryon-to-meson pT-differential Λc+/D0 ratio shows a multiplicity-dependent enhancement, with a significance of 5.3σ for 1<pT<12 GeV/c, comparing the highest multiplicity interval with respect to the lowest one. The measurements are compared with a theoretical model that explains the multiplicity dependence by a canonical treatment of quantum charges in the statistical hadronisation approach, and with predictions from event generators that implement colour reconnection mechanisms beyond the leading colour approximation to model the hadronisation process. The Λc+/D0 ratios as a function of pT present a similar shape and magnitude as the Λ/KS0 ratios in comparable multiplicity intervals, suggesting a potential common mechanism for light- and charm-hadron formation, with analogous multiplicity dependence. The pT-integrated ratios, extrapolated down to pT=0, do not show a significant dependence on multiplicity within the uncertainties.
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Nellen, Lukas ; Nesbo, Simon Voigt ; Nešković, Gvozden ; Nesterov, Dmitrii ; Nielsen, Borge Svane ; Nielsen, Emil Gorm ; Nikolaev, Sergey ; Nikulin, Sergey ; Nikulin, Vladimir ; Noferini, Francesco ; Noh, Seoyoung ; Nomokonov, Petr V. ; Norman, Jaime ; Novitzky, Norbert ; Nowakowski, Piotr ; Nyanin, Alexander ; Nystrand, Joakim Ingemar ; Ogino, Masanori ; Ohlson, Alice ; Okorokov, Vitaly A. ; Oleniacz, Janusz ; Silva, Antonio Carlos Oliveira da ; Oliver, Michael Henry ; Önnerstad, Anna ; Oppedisano, Chiara ; Ortiz Velasquez, Antonio ; Oskarsson, Anders Nils Erik ; Otwinowski, Jacek Tomasz ; Oya, Motomi ; Oyama, Ken ; Pachmayer, Yvonne C. ; Padhan, Sonali ; Pagano, Davide ; Paic, Guy ; Palasciano, Antonio ; Pan, Jinjin ; Panebianco, Stefano Matthias ; Park, Jonghan ; Parkkila, Jasper Elias ; Pathak, Surya Prakash ; Patra, Rajendra Nath ; Paul, Biswarup ; Pei, Hua ; Peitzmann, Thomas ; Peng, Xinye ; Pereira, Luis Gustavo ; Pereira Da Costa, Hugo ; Peresunko, Dmitry Yurevich ; Mesa Perez, Guillermo ; Perrin, Sébastien ; Pestov, Yury N. ; Petráček, Vojtech ; Petrov, Vitalii ; Petrovici, Mihai A. ; Pezzi, Rafael Peretti ; Piano, Stefano ; Pikna, Miroslav ; Pillot, Philippe ; Pinazza, Ombretta ; Pinsky, Lawrence ; Pinto, Chiara ; Pisano, Silvia ; Płoskoń, Mateusz ; Planinic, Mirko ; Pliquett, Fabian ; Poghosyan, Martin G. ; Polishchuk, Boris ; Politano, Stefano ; Poljak, Nikola ; Pop, Amalia ; Porteboeuf, Sarah Julie ; Porter, R. Jefferson ; Pozdniakov, Valerii ; Prasad, Sidharth Kumar ; Preghenella, Roberto ; Prino, Francesco ; Pruneau, Claude A. ; Pshenichnov, Igor A. ; Puccio, Maximiliano ; Qiu, Shi ; Quaglia, Luca ; Quishpe Quishpe, Raquel Estefania ; Ragoni, Simone ; Rakotozafindrabe, Andry Malala ; Ramello, Luciano ; Rami, Fouad ; Rodríguez Ramírez, Saúl Aníbal ; Rancien, Thibaut Albert ; Raniwala, Rashmi ; Raniwala, Sudhir ; Räsänen, Sami Sakari ; Rath, Rutuparna ; Ravasenga, Ivan ; Read, Kenneth Francis ; Redelbach, Andreas Ralph ; Redlich, Krzysztof ; Rehman, Attiq ur ; Reichelt, Patrick ; Reidt, Felix ; Reme-Ness, Haakon André ; Jakubcinova, Zuzana ; Reygers, Klaus ; Riabov, Andrei ; Riabov, Viktor ; Richert, Tuva Ora Herenui ; Richter, Matthias ; Riegler, Werner ; Riggi, Francesco ; Ristea, Cătălin-Lucian ; Rodrı́guez Cahuantzi, Mario ; Røed, Ketil ; Rogalev, Roman ; Rogochaya, Elena ; Rogoschinski, Tim Sebastian ; Rohr, David ; Röhrich, Dieter ; Fierro Rojas, Pablo ; Rojas Torres, Solangel ; Rokita, Przemyslaw Stefan ; Ronchetti, Federico ; Rosano, Antonina ; Dominguez Rosas, Edgar ; Rossi, Andrea ; Roy, Ankhi ; Roy, Pradip Kumar ; Roy, Subhadeep ; Rubini, Nicola ; Ruggiano, Daniela ; Rui, Rinaldo ; Rumyantsev, Boris ; Russek, Paweł Grzegorz ; Russo, Roberto ; Rustamov, Anar ; Ryabinkin, Evgeny ; Rybicki, Andrzej Krzysztof ; Rytkönen, Heidi Maria ; Rzęsa, Wioleta ; Saarimäki, Oskari Antti Matti ; Sadek, Rita ; Sadovskiy, Sergey ; Sætre, Jon-are ; Šafařík, Karel ; Saha, Sumit Kumar ; Saha, Swati ; Sahoo, Baidyanath ; Sahoo, Pragati ; Sahoo, Raghunath ; Sahoo, Sarita ; Sahu, Dushmanta ; Sahu, Pradip Kumar ; Saini, Jogender ; Sakai, Shingo ; Panikkassery Salvan, Malavika ; Sambyal, Sanjeev Singh ; Samsonov, Vladimir ; Saramela, Thiago Badaró ; Sarkar, Debojit ; Sarkar, Nachiketa ; Sarma, Pranjal ; Mantovani Sarti, Valentina ; Sas, Mike Henry Petrus ; Schambach, Johann Joachim ; Scheid, Horst Sebastian ; Schiaua, Claudiu Cornel ; Schicker, Rainer ; Schmah, Alexander ; Schmidt, Christian Joachim ; Schmidt, Hans Rudolf ; Schmidt, Marten Ole ; Schmidt, Martin ; Schmidt, Nicolas ; Schmier, Austin Robert ; Schotter, Romain ; Schukraft, Jürgen ; Schwarz, Kilian Eberhard ; Schweda, Kai ; Scioli, Gilda ; Scomparin, Enrico ; Seger, Janet Elizabeth ; Sekiguchi, Yuko ; Sekihata, Daiki ; Selyuzhenkov, Ilya ; Senyukov, Serhiy ; Seo, Jin Joo ; Serebryakov, Dmitry ; Šerkšnytė, Laura ; Sevcenco, Adrian ; Shaba, Tebogo Joyce ; Shabanov, Arseniy ; Shabetai, Alexandre ; Shahoyan, Ruben ; Shaikh, Wadut ; Shangaraev, Artem ; Sharma, Anjali ; Sharma, Himanshu ; Sharma, Meenakshi ; Sharma, Natasha ; Sharma, Sheetal ; Sharma, Upasana ; Shatat, Afnan ; Sheibani, Oveis ; Shigaki, Kenta ; Hachiya Shimomura, Maya ; Shirinkin, Sergey ; Shou, Qiye ; Sibiryak, Yury ; Siddhanta, Sabyasachi ; Siemiarczuk, Teodor ; Silva, Tiago Fiorini da ; Silvermyr, David Olle Rickard ; Simantathammakul, Tawanchat ; Simonetti, Giuseppe ; Singh, Bhawani ; Singh, Ranbir ; Singh, Randhir ; Singh, Ravindra ; Singh, Vivek ; Singhal, Vikas ; Sarkar-Sinha, Tinku ; Sitar, Branislav ; Sitta, Mario ; Skaali, Toralf Bernhard ; Skorodumovs, Georgijs ; Slupecki, Maciej ; Smirnov, Nikolai ; Snellings, Raimond ; Soncco Meza, Carlos ; Song, Jihye ; Songmoolnak, Arnon ; Soramel, Francesca ; Sorensen, Soren Pontoppidan ; Soto Camacho, Rabi ; Sputowska, Iwona Anna ; Stachel, Johanna ; Stan, Ionel ; Steffanic, Patrick John ; Stiefelmaier, Stephan ; Stocco, Diego ; Storehaug, Ida ; Storetvedt, Maksim Melnik ; Stratmann, Peter ; Pliatskas Stylianidis, Christos ; Suaide, Alexandre Alarcon do Passo ; Suire, Christophe Pierre ; Sukhanov, Mikhail ; Šuljić, Miljenko ; Sultanov, Rishat ; Sumberia, Vikash ; Sumowidagdo, Suharyo ; Swain, Sagarika ; Szabo, Alexander ; Szarka, Imrich ; Tabassam, Uzma ; Taghavi, Seyed Farid ; Taillepied, Guillaume ; Takahashi, Jun ; Tambave, Ganesh ; Tang, Siyu ; Tang, Zebo ; Tapia Takaki, Jesus Daniel ; Tarasovicova, Lucia Anna ; Tarhini, Mohamad ; Tarzila, Madalina-Gabriela ; Tauro, Arturo ; Tejeda Muñoz, Guillermo ; Telesca, Adriana ; Terlizzi, Livia ; Terrevoli, Cristina ; Tersimonov, Georgy ; Thakur, Sanchari ; Thomas, Deepa ; Tieulent, Raphael Noel ; Tikhonov, Anatoly ; Timmins, Anthony Robert ; Tkacik, Milan ; Toia, Alberica ; Topilskaya, Nataliya ; Toppi, Marco ; Torales Acosta, Fernando ; Tork, Theraa M.A. ; Torres Ramos, Arianna Grisel ; Trifiro, Antonio ; Tripathy, Sushanta ; Tripathy, Tulika ; Trogolo, Stefano ; Trubnikov, Victor ; Trzaska, Wladyslaw Henryk ; Trzcinski, Tomasz Piotr ; Tumkin, Alexandr ; Turrisi, Rosario ; Tveter, Trine Spedstad ; Ullaland, Kjetil ; Uras, Antonio ; Urioni, Marta ; Usai, Gianluca ; Vala, Martin ; Valle, Nicolò ; Vallero, Sara ; Doremalen, Lennart Vincent Rogier van ; Leeuwen, Marco van ; Weelden, Roelof Jan Gijs van ; Vyvre, Pierre vande ; Varga, Dezsö ; Varga, Zoltán ; Varga-Kofarago, Monika ; Vasileiou, Maria ; Vasiliev, Andrey ; Vazquez Doce, Oton ; Vazquez Rueda, Omar ; Vechernin, Vladimir ; Vercellin, Ermanno ; Vergara Limon, Sergio ; Vermunt, Lucas Anne ; Vértesi, Róbert ; Verweij, Marta ; Vicković, Linda ; Vilakazi, Zabulon ; Villalobos Baillie, Orlando ; Vino, Gioacchino ; Vinogradov, Alexander ; Virgili, Tiziano ; Vislavicius, Vytautas ; Vodopyanov, Alexander ; Völkel, Benedikt ; Völkl, Martin Andreas ; Voloshin, Kirill ; Voloshin, Sergei ; Volpe, Giacomo ; Haller, Barthélémy von ; Vorobyev, Ivan ; Vozniuk, Nikita ; Vrlakova, Janka ; Wagner, Boris ; Wang, Chunzheng ; Wang, Dongfang ; Weber, Michael ; Wegrzynek, Adami Tadeusz ; Weiglhofer, Felix Thomas ; Wenzel, Sandro Christian ; Wessels, Johannes P. ; Wiechula, Jens ; Wikne, Jon ; Wilk, Grzegorz Andrzej ; Wilkinson, Jeremy John ; Willems, Guido Alexander ; Windelband, Bernd ; Winn, Michael ; Witt, William Edward ; Wright, Josephina Rae ; Wu, Wenya ; Wu, Yitao ; Xu, Ran ; Yadav, Arun Kumar ; Yalcin Kuzu, Serpil ; Yamaguchi, Yorito ; Yamakawa, Kosei ; Yang, Shiming ; Yano, Satoshi ; Yin, Zhongbao ; Yoo, In-Kwon ; Yoon, Jin Hee ; Yuan, Shiming ; Yüncü, Alperen ; Zaccolo, Valentina ; Zampolli, Chiara ; Correia Zanoli, Henrique Jose ; Zardoshti, Nima ; Zarochentsev, Andrey ; Závada, Petr ; Zavyalov, Nikolay ; Zhalov, Mikhail ; Zhang, Biao ; Zhang, Song ; Zhang, Xiaoming ; Zhang, Yifei ; Zhao, Mingrui ; Zherebchevskii, Vladimir ; Yu, Zhi ; Zhigareva, Natalia ; Zhou, Daicui ; Zhou, You ; Zhu, Jianhui ; Zhu, Ya ; Zinovjev, Gennady M. ; Zurlo, Nicola
Measurements of (anti)proton, (anti)deuteron, and (anti)3He production in the rapidity range −1<y<0 as a function of the transverse momentum and event multiplicity in p-Pb collisions at a center-of-mass energy per nucleon-nucleon pair sNN−−−√=8.16 TeV are presented. The coalescence parameters B2 and B3, measured as a function of the transverse momentum per nucleon and of the mean charged-particle multiplicity density, confirm a smooth evolution from low to high multiplicity across different collision systems and energies. The ratios between (anti)deuteron and (anti)3He yields and those of (anti)protons are also reported as a function of the mean charged-particle multiplicity density. A comparison with the predictions of the statistical hadronization and coalescence models for different collision systems and center-of-mass energies favors the coalescence description for the deuteron-to-proton yield ratio with respect to the canonical statistical model.
Zöllner, Johann Philipp ; Grau, Janina ; Rosenow, Felix ; Sauter, Matthias ; Knuf, Markus ; Kurlemann, Gerhard ; Mayer, Thomas ; Hertzberg, Christoph ; Bertsche, Astrid ; Immisch, Ilka ; Klein, Karl Martin ; Knake, Susanne ; Marquard, Klaus ; Meyer, Sascha ; Noda, Anna ; Podewils, Felix von ; Schäfer, Hannah ; Thiels, Charlotte ; Willems, Laurent Maximilian ; Zukunft, Bianca ; Schubert-Bast, Susanne ; Strzelczyk, Adam
Background: Tuberous sclerosis complex (TSC) is a monogenetic, multisystem disorder characterized by benign growths due to TSC1 or TSC2 mutations. This German multicenter study estimated the costs and related cost drivers associated with organ manifestations in adults with TSC.
Methods: A validated, three-month, retrospective questionnaire assessed the sociodemographic and clinical characteristics, organ manifestations, direct, indirect, out-of-pocket (OOP), and nursing care-level costs among adult individuals with TSC throughout Germany from a societal perspective (costing year: 2019).
Results: We enrolled 192 adults with TSC (mean age: 33.4 ± 12.7 years; range: 18–78 years, 51.6% [n = 99] women). Reported TSC disease manifestations included skin (94.8%) and kidney and urinary tract (74%) disorders, epilepsy (72.9%), structural brain defects (67.2%), psychiatric disorders (50.5%), heart and circulatory system disorders (50.5%), and lymphangioleiomyomatosis (11.5%). TSC1 and TSC2 mutations were reported in 16.7% and 25% of respondents, respectively. Mean direct health care costs totaled EUR 6452 (median EUR 1920; 95% confidence interval [CI] EUR 5533–7422) per patient over three months. Medication costs represented the major direct cost category (77% of total direct costs; mean EUR 4953), and mechanistic target of rapamycin (mTOR) inhibitors represented the largest share (68%, EUR 4358). Mean antiseizure drug (ASD) costs were only EUR 415 (6%). Inpatient costs (8%, EUR 518) and outpatient treatment costs (7%; EUR 467) were important further direct cost components. The mean care grade allowance as an approximator of informal nursing care costs was EUR 929 (median EUR 0; 95% CI EUR 780–1083) over three months. Mean indirect costs totaled EUR 3174 (median EUR 0; 95% CI EUR 2503–3840) among working-age individuals (< 67 years in Germany). Multiple regression analyses revealed mTOR inhibitor use and persistent seizures as independent cost-driving factors for total direct costs. Older age and disability were independent cost-driving factors for total indirect costs, whereas epilepsy, psychiatric disease, and disability were independent cost-driving factors for nursing care costs.
Conclusions: This three-month study revealed substantial direct healthcare, indirect healthcare, and medication costs associated with TSC in Germany. This study highlights the spectrum of organ manifestations and their associated treatment needs in the German healthcare setting. Trial registration: DRKS, DRKS00016045. Registered 01 March 2019, http://www.drks.de/DRKS00016045.
Grau, Janina ; Zöllner, Johann Philipp ; Schubert-Bast, Susanne ; Kurlemann, Gerhard ; Hertzberg, Christoph ; Wiemer-Kruel, Adelheid ; Bast, Thomas ; Bettendorf, Ulrich ; Fiedler, Barbara ; Hahn, Andreas ; Hartmann, Hans ; Hornemann, Frauke ; Immisch, Ilka ; Jacobs, Julia ; Kieslich, Matthias ; Klein, Karl Martin ; Klotz, Kerstin Alexandra ; Kluger, Gerhard ; Knuf, Markus ; Mayer, Thomas ; Marquard, Klaus ; Meyer, Sascha ; Muhle, Hiltrud ; Müller-Schlüter, Karen ; Noda, Anna ; Ruf, Susanne ; Sauter, Matthias ; Schlump, Jan-Ulrich ; Syrbe, Steffen ; Thiels, Charlotte ; Trollmann, Regina ; Wilken, Bernd ; Willems, Laurent Maximilian ; Rosenow, Felix ; Strzelczyk, Adam
Background: Tuberous sclerosis complex (TSC), a multisystem genetic disorder, affects many organs and systems, characterized by benign growths. This German multicenter study estimated the disease-specific costs and cost-driving factors associated with various organ manifestations in TSC patients. Methods: A validated, three-month, retrospective questionnaire was administered to assess the sociodemographic and clinical characteristics, organ manifestations, direct, indirect, out-of-pocket, and nursing care-level costs, completed by caregivers of patients with TSC throughout Germany. Results: The caregivers of 184 patients (mean age 9.8 ± 5.3 years, range 0.7–21.8 years) submitted questionnaires. The reported TSC disease manifestations included epilepsy (92%), skin disorders (86%), structural brain disorders (83%), heart and circulatory system disorders (67%), kidney and urinary tract disorders (53%), and psychiatric disorders (51%). Genetic variations in TSC2 were reported in 46% of patients, whereas 14% were reported in TSC1. Mean total direct health care costs were EUR 4949 [95% confidence interval (95% CI) EUR 4088–5863, median EUR 2062] per patient over three months. Medication costs represented the largest direct cost category (54% of total direct costs, mean EUR 2658), with mechanistic target of rapamycin (mTOR) inhibitors representing the largest share (47%, EUR 2309). The cost of anti-seizure drugs (ASDs) accounted for a mean of only EUR 260 (5%). Inpatient costs (21%, EUR 1027) and ancillary therapy costs (8%, EUR 407) were also important direct cost components. The mean nursing care-level costs were EUR 1163 (95% CI EUR 1027–1314, median EUR 1635) over three months. Total indirect costs totaled a mean of EUR 2813 (95% CI EUR 2221–3394, median EUR 215) for mothers and EUR 372 (95% CI EUR 193–586, median EUR 0) for fathers. Multiple regression analyses revealed polytherapy with two or more ASDs and the use of mTOR inhibitors as independent cost-driving factors of total direct costs. Disability and psychiatric disease were independent cost-driving factors for total indirect costs as well as for nursing care-level costs. Conclusions: This study revealed substantial direct (including medication), nursing care-level, and indirect costs associated with TSC over three months, highlighting the spectrum of organ manifestations and their treatment needs in the German healthcare setting.
Apheresis therapies for NMOSD attacks : a retrospective study of 207 therapeutic interventions
(2018)
Kleiter, Ingo ; Gahlen, Anna ; Borisow, Nadja ; Fischer, Katrin ; Wernecke, Klaus-Dieter ; Hellwig, Kerstin ; Pache, Florence ; Ruprecht, Klemens ; Havla, Joachim ; Kümpfel, Tania ; Aktas, Orhan ; Hartung, Hans-Peter ; Ringelstein, Marius ; Geis, Christian ; Kleinschnitz, Christoph ; Berthele, Achim ; Hemmer, Bernhard ; Angstwurm, Klemens ; Stellmann, Jan-Patrick ; Schuster, Simon ; Stangel, Martin ; Lauda, Florian ; Tumani, Hayrettin ; Mayer, Christoph ; Krumbholz, Markus ; Zeltner, Lena ; Ziemann, Ulf ; Linker, Ralf ; Schwab, Matthias ; Marziniak, Martin ; Then Bergh, Florian ; Hofstadt-van Oy, Ulrich ; Neuhaus, Oliver ; Zettl, Uwe K. ; Faiss, Jürgen Hartmut ; Wildemann, Brigitte ; Paul, Friedemann ; Jarius, Sven ; Trebst, Corinna
Objective: To analyze whether 1 of the 2 apheresis techniques, therapeutic plasma exchange (PE) or immunoadsorption (IA), is superior in treating neuromyelitis optica spectrum disorder (NMOSD) attacks and to identify predictive factors for complete remission (CR).
Methods: This retrospective cohort study was based on the registry of the German Neuromyelitis Optica Study Group, a nationwide network established in 2008. It recruited patients with neuromyelitis optica diagnosed according to the 2006 Wingerchuk criteria or with aquaporin-4 (AQP4-ab)-antibody–seropositive NMOSD treated at 6 regional hospitals and 16 tertiary referral centers until March 2013. Besides descriptive data analysis of patient and attack characteristics, generalized estimation equation (GEE) analyses were applied to compare the effectiveness of the 2 apheresis techniques. A GEE model was generated to assess predictors of outcome.
Results: Two hundred and seven attacks in 105 patients (87% AQP4-ab-antibody seropositive) were treated with at least 1 apheresis therapy. Neither PE nor IA was proven superior in the therapy of NMOSD attacks. CR was only achieved with early apheresis therapy. Strong predictors for CR were the use of apheresis therapy as first-line therapy (OR 12.27, 95% CI: 1.04–144.91, p = 0.047), time from onset of attack to start of therapy in days (OR 0.94, 95% CI: 0.89–0.99, p = 0.014), the presence of AQP4-ab-antibodies (OR 33.34, 95% CI: 1.76–631.17, p = 0.019), and monofocal attack manifestation (OR 4.71, 95% CI: 1.03–21.62, p = 0.046).
Conclusions: Our findings suggest early use of an apheresis therapy in NMOSD attacks, particularly in AQP4-ab-seropositive patients. No superiority was shown for one of the 2 apheresis techniques.
Classification of evidence: This study provides Class IV evidence that for patients with NMOSD, neither PE nor IA is superior in the treatment of attacks.
Koch, Elena ; Freitag, Christine M. ; Mayer, Jutta ; Medda, Juliane ; Reif, Andreas ; Grimm, Oliver ; Ramos-Quiroga, Josep Antoni ; Palacio Sanchez, Judit ; Asherson, Philip ; Kuntsi, Jonna ; Pawley, Adam D. ; Buitelaar, Jan K. ; Bergsma, Douwe ; Ortega, Francisco B. ; Muntaner-Mas, Adrià ; Reinhard, Iris ; Reichert, Markus ; Giurgiu, Marco ; Ebner-Priemer, Ulrich
Exercise interventions in mental disorders have evidenced a mood-enhancing effect. However, the association between physical activity and affect in everyday life has not been investigated in adult individuals with ADHD, despite being important features of this disorder. As physical activity and affect are dynamic processes in nature, assessing those in everyday life with e-diaries and wearables, has become the gold standard. Thus, we used an mHealth approach to prospectively assess physical activity and affect processes in individuals with ADHD and controls aged 14–45 years. Participants wore accelerometers across a four-day period and reported their affect via e-diaries twelve times daily. We used multilevel models to identify the within-subject effects of physical activity on positive and negative affect. We split our sample into three groups: 1. individuals with ADHD who were predominantly inattentive (n = 48), 2. individuals with ADHD having a combined presentation (i.e., being inattentive and hyperactive; n = 95), and 3. controls (n = 42). Our analyses revealed a significant cross-level interaction (F(2, 135.072)=5.733, p = 0.004) of physical activity and group on positive affect. In details, all groups showed a positive association between physical activity and positive affect. Individuals with a combined presentation significantly showed the steepest slope of physical activity on positive affect (slope_inattentive=0.005, p<0.001; slope_combined=0.009, p<0.001; slope_controls=0.004, p = 0.008). Our analyses on negative affect revealed a negative association only in the individuals with a combined presentation (slope=-0.003; p = 0.001). Whether this specifically pronounced association in individuals being more hyperactive might be a mechanism reinforcing hyperactivity needs to be empirically clarified in future studies.
Microscopic transport approaches are the tool to describe the non-equilibrium evolution in low energy collisions as well as in the late dilute stages of high-energy collisions. Here, a newly developed hadronic transport approach, SMASH (Simulating Many Accelerated Strongly-interacting Hadrons) is introduced. The overall bulk dynamics in low energy heavy ion collisions is shown including the excitation function of elliptic flow employing several equations of state. The implications of this new approach for dilepton production are discussed and preliminary results for afterburner calculations at the highest RHIC energy are presented and compared to previous UrQMD results. A detailed understanding of a hadron gas with vacuum properties is required to establish the baseline for the exploration of the transition to the quark-gluon plasma in heavy ion collisions at high net baryon densities.
Haungs, Andreas ; Apel, Wolf-Dieter ; Arteaga-Velázquez, Juan Carlos ; Bekk, Klaus ; Bertaina, Mario Edoardo ; Blümer, Johannes ; Bozdog, Horia ; Brâncuş, Iliana M. ; Cantoni, Elena ; Chiavassa, Andrea ; Cossavella, Fabiana ; Daumiller, Kai ; Souza, Vitor de ; Di Pierro, Federico ; Doll, Paul ; Engel, Ralph ; Fuhrmann, Daniel ; Gherghel-Lascu, Alexandru ; Gils, Hans J. ; Glasstetter, Ralph ; Grupen, Claus ; Heck, Dieter ; Hörandel, Jörg R. ; Huege, Tim ; Kampert, Karl-Heinz ; Kang, Donghwa ; Klages, Hans Otto ; Link, Katrin ; Luczak, Pawel ; Mathes, Hermann-Josef ; Mayer, Hans-Jürgen ; Milke, Jens-Michael ; Mitrica, Bogdan ; Morello, Carlo ; Oehlschläger, Jürgen ; Ostapchenko, Sergey ; Pierog, Tanguy ; Rebel, Heinrich ; Roth, Markus ; Schieler, Harald ; Schoo, Sven ; Schröder, Frank Gerhard ; Sima, Octavian ; Toma, Gabriel ; Trinchero, Gian Carlo ; Ulrich, Holger ; Weindl, Andreas ; Wochele, Jürgen ; Zabierowski, Janusz
The KASCADE-Grande experiment has significantly contributed to the current knowledge about the energy spectrum and composition of cosmic rays for energies between the knee and the ankle. Meanwhile, post-LHC versions of the hadronic interaction models are available and used to interpret the entire data set of KASCADE-Grande. In addition, a new, combined analysis of both arrays, KASCADE and Grande, was developed significantly increasing the accuracy of the shower observables. First results of the new analysis with the entire data set of the KASCADE-Grande experiment will be the focus of this contribution.
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.
Eckardt, Jan-Niklas ; Stasik, Sebastian ; Kramer, Michael ; Röllig, Christoph ; Krämer, Alwin ; Scholl, Sebastian ; Hochhaus, Andreas ; Crysandt, Martina ; Brümmendorf, Tim Henrik ; Naumann, Ralph ; Steffen, Björn ; Kunzmann, Volker ; Einsele, Hermann ; Schaich, Markus ; Burchert, Andreas ; Neubauer, Andreas ; Schäfer-Eckart, Kerstin ; Schliemann, Christoph ; Krause, Stefan W. ; Herbst, Regina ; Hänel, Mathias ; Frickhofen, Norbert ; Noppeney, Richard ; Kaiser, Ulrich ; Baldus, Claudia ; Kaufmann, Martin ; Rácil, Zdenek ; Platzbecker, Uwe ; Berdel, Wolfgang E. ; Mayer, Jiří ; Serve, Hubert ; Müller-Tidow, Carsten ; Ehninger, Gerhard ; Stölzel, Friedrich ; Kroschinsky, Frank ; Schetelig, Johannes ; Bornhäuser, Martin ; Thiede, Christian ; Middeke, Jan Moritz
Simple Summary: Acute myeloid leukemia (AML) is a genetically heterogeneous disease. Clinical phenotypes of frequent mutations and their impact on patient outcome are well established. However, the role of rare mutations often remains elusive. We retrospectively analyzed 1529 newly diagnosed and intensively treated AML patients for mutations of BCOR and BCORL1. We report a distinct co-mutational pattern that suggests a role in disease progression rather than initiation, especially affecting mechanisms of DNA-methylation. Further, we found loss-of-function mutations of BCOR to be independent markers of poor outcomes in multivariable analysis. Therefore, loss-of-function mutations of BCOR need to be considered for AML management, as they may influence risk stratification and subsequent treatment allocation.
Abstract: Acute myeloid leukemia (AML) is characterized by recurrent genetic events. The BCL6 corepressor (BCOR) and its homolog, the BCL6 corepressor-like 1 (BCORL1), have been reported to be rare but recurrent mutations in AML. Previously, smaller studies have reported conflicting results regarding impacts on outcomes. Here, we retrospectively analyzed a large cohort of 1529 patients with newly diagnosed and intensively treated AML. BCOR and BCORL1 mutations were found in 71 (4.6%) and 53 patients (3.5%), respectively. Frequently co-mutated genes were DNTM3A, TET2 and RUNX1. Mutated BCORL1 and loss-of-function mutations of BCOR were significantly more common in the ELN2017 intermediate-risk group. Patients harboring loss-of-function mutations of BCOR had a significantly reduced median event-free survival (HR = 1.464 (95%-Confidence Interval (CI): 1.005–2.134), p = 0.047), relapse-free survival (HR = 1.904 (95%-CI: 1.163–3.117), p = 0.01), and trend for reduced overall survival (HR = 1.495 (95%-CI: 0.990–2.258), p = 0.056) in multivariable analysis. Our study establishes a novel role for loss-of-function mutations of BCOR regarding risk stratification in AML, which may influence treatment allocation.
Stölzel, Friedrich ; Mohr, Brigitte ; Kramer, Michael ; Oelschlägel, Uta ; Bochtler, Tilmann ; Berdel, Wolfgang E. ; Kaufmann, Martin ; Baldus, Claudia ; Schäfer-Eckart, Kerstin ; Stuhlmann, Reingard ; Einsele, Hermann ; Krause, Stefan W. ; Serve, Hubert ; Hänel, Mathias ; Herbst, Regina ; Neubauer, Andreas ; Sohlbach, Kristina ; Mayer, Jiri ; Middeke, Jan Moritz ; Platzbecker, Uwe ; Schaich, Markus ; Krämer, Alwin ; Röllig, Christoph ; Schetelig, Johannes ; Bornhäuser, Martin ; Ehninger, Gerhard
A complex aberrant karyotype consisting of multiple unrelated cytogenetic abnormalities is associated with poor prognosis in patients with acute myeloid leukemia (AML). The European Leukemia Net classification and the UK Medical Research Council recommendation provide prognostic categories that differ in the definition of unbalanced aberrations as well as the number of single aberrations. The aim of this study on 3526 AML patients was to redefine and validate a cutoff for karyotype complexity in AML with regard to adverse prognosis. Our study demonstrated that (1) patients with a pure hyperdiploid karyotype have an adverse risk irrespective of the number of chromosomal gains, (2) patients with translocation t(9;11)(p21~22;q23) have an intermediate risk independent of the number of additional aberrations, (3) patients with greater than or equal to4 abnormalities have an adverse risk per se and (4) patients with three aberrations in the absence of abnormalities of strong influence (hyperdiploid karyotype, t(9;11)(p21~22;q23), CBF-AML, unique adverse-risk aberrations) have borderline intermediate/adverse risk with a reduced overall survival compared with patients with a normal karyotype.
Mayer, Mathias ; Rosinger, Christoph ; Gorfer, Markus ; Berger, Harald ; Deltedesco, Evi ; Bässler, Claus ; Müller, Jörg ; Seifert, Linda ; Rewald, Boris ; Godbold, Douglas Lawrence
Temperate forests are increasingly subject to natural disturbance by stand replacing windthrows or bark-beetle attacks. Forests are commonly salvage logged after disturbance, whereby substantial parts of biological legacies, such as surviving trees and deadwood, are removed. Despite increasing concerns about the ecological consequences of salvage logging operations, our knowledge on the effects on the soil microbiome and associated functioning remains limited.
Here, we studied soil fungal communities, decomposition processes, and soil organic matter dynamics in 21 intact or disturbed, temperate Norway spruce stands about one decade after they were damaged by windthrow or bark-beetle attacks. Disturbed stands comprised different post-disturbance management, i.e. deadwood retention and salvage logged plots. We used high-throughput sequencing and ergosterol measurements to explore fungal communities and biomass, and enzyme assays to study decomposition processes.
Disturbance shifted soil fungal communities from ectomycorrhizal to saprotrophic dominated assemblages. Fungal biomass declined with decreasing tree abundance after disturbance. Activities of organic matter degrading enzymes declined by ca. 30–80% after disturbance. The relative abundance of ectomycorrhizal fungi was positively related to enzymatic activities. Tree biomass parameters and amounts of deadwood retained were positively related to fungal biomass, certain ectomycorrhizal taxa, and relative ectomycorrhizal fungal abundance among disturbed stands, which, in turn, was associated with higher enzymatic activities.
Our findings demonstrate a significant response of soil fungal communities to natural forest disturbance and salvage logging, with consequences for decomposition and soil organic matter dynamics. We conclude that the retention of surviving trees and deadwood as biological legacies attenuated associated changes to a significant extent, highlighting their importance for the preservation of ectomycorrhizal fungi and the maintenance of decomposition processes after disturbance.
Strzelczyk, Adam ; Kalski, Malin ; Bast, Thomas ; Wiemer-Kruel, Adelheid ; Bettendorf, Ulrich ; Kay, Lara ; Kieslich, Matthias ; Kluger, Gerhard ; Kurlemann, Gerhard ; Mayer, Thomas ; Neubauer, Bernd Axel ; Polster, Tilman ; Herting, Arne ; Spiczak Brzezinski, Sarah von ; Trollmann, Regina ; Wolff, Markus ; Irwin, John ; Carroll, Joe ; Macdonald, Daniel ; Pritchard, Clive ; Klein, Karl Martin ; Rosenow, Felix ; Schubert-Bast, Susanne
Introduction: Dravet syndrome (DS) is a rare developmental and epileptic encephalopathy. This study estimated cost, cost-driving factors and quality of life (QoL) in patients with Dravet syndrome and their caregivers in a prospective, multicenter study in Germany.
Methods: A validated 3–12-month retrospective questionnaire and a prospective 3-month diary assessing clinical characteristics, QoL, and direct, indirect and out-of-pocket (OOP) costs were administered to caregivers of patients with DS throughout Germany.
Results: Caregivers of 93 patients (mean age 10.1 years, ±7.1, range 15 months–33.7 years) submitted questionnaires and 77 prospective diaries. The majority of patients (95%) experienced at least one seizure during the previous 12 months and 77% a status epilepticus (SE) at least once in their lives. Over 70% of patients had behavioural problems and delayed speech development and over 80% attention deficit symptoms and disturbance of motor skills and movement coordination. Patient QoL was lower than in the general population and 45% of caregivers had some form of depressive symptoms. Direct health care costs per three months were a mean of €6,043 ± €5,825 (median €4054, CI €4935-€7350) per patient. Inpatient costs formed the single most important cost category (28%, €1,702 ± €4,315), followed by care grade benefits (19%, €1,130 ± €805), anti-epileptic drug (AED) costs (15%, €892 ± €1,017) and ancillary treatments (9%, €559 ± €503). Total indirect costs were €4,399 ±€ 4,989 (median €0, CI €3466-€5551) in mothers and €391 ± €1,352 (median €0, CI €195-€841) in fathers. In univariate analysis seizure frequency, experience of SE, nursing care level and severe additional symptoms were found to be associated with total direct healthcare costs. Severe additional symptoms was the single independently significant explanatory factor in a multivariate analysis.
Conclusions: This study over a period up to 15 months revealed substantial direct and indirect healthcare costs of DS in Germany and highlights the relatively low patient and caregiver QoL compared with the general population.