Online verfügbar: 13. Februar 2025 ; Gesehen am 10.09.2025
Background - In the ESCAPE-NA1 trial, treatment with nerinetide, an eicosapeptide that interferes with post-synaptic density protein 95, was associated with improved functional outcome among patients with acute ischaemic stroke due to large vessel occlusion undergoing endovascular thrombectomy without co-treatment with an intravenous thrombolytic agent. There was no benefit when intravenous thrombolytic agent co-treatment was used. We sought to confirm the clinical benefit of nerinetide in the absence of previous intravenous thrombolytic drug treatment. - Methods - In this multicentre, randomised, double-blind, placebo-controlled study, done in 77 centres in Canada (16), the USA (16), Germany (21), Italy (four), the Netherlands (three), Norway (four), Switzerland (three), Australia (eight), and Singapore (two), we enrolled patients with acute ischaemic stroke due to anterior circulation large vessel occlusion within 12 h from onset. Eligible patients were aged 18 years or older with a disabling ischaemic stroke at the time of randomisation (baseline National Institutes of Health Stroke Scale [NIHSS] score >5), who had been functioning independently in the community (Barthel Index score >90) before the stroke, had Alberta Stroke Program Early CT Score (ASPECTS) greater than 4, and who were not treated with a plasminogen activator. Patients were randomly allocated (1:1) to receive intravenous infusion of nerinetide in a single dose of 2·6 mg/kg, up to a maximum dose of 270 mg, based upon estimated or actual weight (if known) or saline placebo using a real-time, dynamic, internet-based, stratified randomised minimisation procedure. All patients underwent endovascular thrombectomy. The primary outcome was a favourable functional outcome 90 days from randomisation, defined as a modified Rankin Scale (mRS) score of 0-2. The analysis was by intention to treat and adjusted for time from stroke onset to randomisation (≤4·5 h [yes or no]), age, sex, baseline NIHSS score, occlusion location, time from qualifying imaging to randomisation, baseline ASPECTS, and region. Secondary outcomes were measures of mortality, worsening of stroke, improved functional independence, and measures of neurological disability. This trial is registered with ClinicalTrials.gov, NCT04462536. - Findings - From Dec 6, 2020, to Jan 31, 2023, 850 patients were assigned to receive nerinetide (n=454) or placebo (n=396). 206 (45%) participants in the nerinetide group and 181 (46%) participants in the placebo group achieved an mRS score of 0-2 at 90 days (odds ratio 0·97, 95% CI 0·72-1·30; p=0·82). Serious adverse events occurred equally between groups. - Interpretation - While nerinetide did not improve outcomes in patients with acute ischaemic stroke, it was not associated with excess adverse events. Further study is needed to identify the ideal timing of treatment and the sub-population of stroke patients who might benefit from treatment combined with current reperfusion therapies. - Funding - Canadian Institutes for Health Research and NoNO.
The lancet London [u.a.] : Elsevier, 1823 405(2025), 10478 vom: Feb., Seite 560-570 Online-Ressource
von Julie George ; Lukas Maas ; Nima Abedpour ; Maria Cartolano ; Laura Kaiser ; Rieke Nila Fischer ; Andreas H. Scheel ; Jan-Philipp Weber ; Martin Hellmich ; Graziella Bosco ; Caroline Volz ; Christian Müller ; Ilona Dahmen ; Felix John ; Cleidson Padua Alves ; Lisa Werr ; Jens Peter Panse ; Martin Kirschner ; Walburga Engel-Riedel ; Jessica Jürgens ; Erich Stoelben ; Michael Brockmann ; Stefan Grau ; Martin Sebastian ; Jan Alexander Stratmann ; Jens Kern ; Horst-Dieter Hummel ; Balazs Hegedus ; Martin Schuler ; Till Plönes ; Clemens Aigner ; Thomas Elter ; Karin Toepelt ; Yon-Dschun Ko ; Sylke Kurz ; Christian Grohé ; Monika Serke ; Katja Anne Höpker ; Lars Gerd Hagmeyer ; Fabian Doerr ; Khosro Hekmath ; Judith Strapatsas ; Karl-Otto Kambartel ; Geothy Chakupurakal ; Annette Hülsmeyer ; Franz-Georg Bauernfeind ; Frank Griesinger ; Anne Lüers ; Wiebke Dirks ; Rainer Gerhard Wiewrodt ; Andrea Luecke ; Ernst Michael Rodermann ; Andreas Diel ; Volker Hagen ; Kai Severin ; Roland Ullrich ; Christian Reinhardt ; Alexander Quaas ; Magdalena Bogus ; Cornelius Courts ; Peter Nürnberg ; Kerstin Becker ; Viktor Achter ; Reinhard Büttner ; Jürgen Wolf ; Martin Peifer ; Roman Thomas
HochschulschriftEthanAromatisierungCarbon dioxide capture and utilizationOxidansAntioxidansEmissionsverringerungRecyclingCarbon dioxide capture and storageAlkane
Im Fokus dieser Dissertationsschrift steht die Aromatisierung von Ethan, die durch die Zugabe von Oxidationsmitteln wie Kohlenstoffdioxid und Luftsauerstoff untersucht wurde. Als Katalysatoren wurden kommerzielle Zeolithkatalysatoren durch Festkörper-Ionenaustausch und Imprägnierung erhalten. Die Katalysatoren wurden nach der Modifikation und nach der Katalyse jeweils charakterisiert, um Deaktivierungsprozesse zu beleuchten. Bei der nicht-oxidativen Aromatisierung von Ethan konnte die Wasserstoffbilanz durch experimentelle Daten abgebildet und näher untersucht werden. Bei der Zugabe von Kohlenstoffdioxid konnten Deaktivierungsprozesse in der Aromatisierung beobachtet wird, die auf die Bildung von Wasser zurückgeführt wurde. Die oxidative Aromatisierung mit Luftsauerstoff konnte durch physisches Mischen von H-ZSM-5 und M1-Mischoxidkatalysator realisiert werden. Dabei wurden die Prozessparameter systematisch variiert und der Einfluss von verschiedenen Modifikationen betrachtet.
This dissertation focuses on the aromatization of ethane, which was investigated by the addition of oxidants such as carbon dioxide and atmospheric oxygen. Commercial zeolite catalysts were modified by solid-state ion exchange and impregnation. The catalysts were characterized after modification and after catalysis, respectively, to shed light on deactivation processes. For the non-oxidative aromatization of ethane, the hydrogen balance could be mapped by experimental data and studied in more detail. When carbon dioxide was added, deactivation processes in the aromatization could be observed, which was attributed to the formation of water. Oxidative aromatization with atmospheric oxygen could be realized by physically mixing H-ZSM-5 and M1 mixed oxide catalysts. The process parameters were systematically varied and the influence of different modifications was considered.
VIII, 330 Seiten Illustrationen (überwiegend farbig), Diagramme 24 cm x 17 cm.
Zusatz auf dem Cover: ideale Ergänzung zu Rettungssanitäter Heute ; Titelzusatz auf dem Cover: Fragen - Fallbeispiele - kommentierte Lösungen ; Verlagsangabe auf dem Umschlag: Elsevier, Urban & Fischer
Lithium is regarded as the first-line treatment for bipolar disorder (BD), a severe and disabling mental health disorder that affects about 1% of the population worldwide. Nevertheless, lithium is not consistently effective, with only 30% of patients showing a favorable response to treatment. To provide personalized treatment options for bipolar patients, it is essential to identify prediction biomarkers such as polygenic scores. In this study, we developed a polygenic score for lithium treatment response (Li+PGS) in patients with BD. To gain further insights into lithium’s possible molecular mechanism of action, we performed a genome-wide gene-based analysis. Using polygenic score modeling, via methods incorporating Bayesian regression and continuous shrinkage priors, Li+PGS was developed in the International Consortium of Lithium Genetics cohort (ConLi+Gen: N = 2367) and replicated in the combined PsyCourse (N = 89) and BipoLife (N = 102) studies. The associations of Li+PGS and lithium treatment response — defined in a continuous ALDA scale and a categorical outcome (good response vs. poor response) were tested using regression models, each adjusted for the covariates: age, sex, and the first four genetic principal components. Statistical significance was determined at P < 0.05. Li+PGS was positively associated with lithium treatment response in the ConLi+Gen cohort, in both the categorical (P = 9.8 × 10−12, R2 = 1.9%) and continuous (P = 6.4 × 10−9, R2 = 2.6%) outcomes. Compared to bipolar patients in the 1st decile of the risk distribution, individuals in the 10th decile had 3.47-fold (95%CI: 2.22-5.47) higher odds of responding favorably to lithium. The results were replicated in the independent cohorts for the categorical treatment outcome (P = 3.9 × 10−4, R2 = 0.9%), but not for the continuous outcome (P = 0.13). Gene-based analyses revealed 36 candidate genes that are enriched in biological pathways controlled by glutamate and acetylcholine. Li+PGS may be useful in the development of pharmacogenomic testing strategies by enabling a classification of bipolar patients according to their response to treatment.
von Julia Roeper ; Nikolaj Frost ; Martin Wermke ; Felix Saalfeld ; Daniel Heudobler ; Tobias Pukrop ; Melanie Janning ; Jonas Kuon ; Rieke Kempfer ; Lucia Nogová ; Petros Christopoulos ; Frank Griesinger
von Nikolaj Frost ; Petros Christopoulos ; Diego Kauffmann-Guerrero ; Jan Stratmann ; Richard Riedel ; Monica Schaefer ; Jürgen Alt ; Sylvia Gütz ; Daniel C. Christoph ; Eckart Laack ; Martin Faehling ; Richard Fischer ; Klaus Fenchel ; Sebastian Haen ; Lukas Heukamp ; Christian Schulz ; Frank Griesinger
ALK; brain metastases; early access program; lorlatinib; NSCLC; ROS1; TP53
Introduction:We report on the results of the German early access program (EAP) with the third-generation ALK- and ROS1-inhibitor lorlatinib.Patients and Methods:Patients with documented treatment failure of all approved ALK/ROS1-specific therapies or with resistance mutations not covered by approved inhibitors or leptomeningeal carcinomatosis were enrolled and analyzed.Results:In total, 52 patients were included [median age 57?years (range 32?81), 54% female, 62% never smokers, 98% adenocarcinoma]; 71% and 29% were ALK- and ROS1-positive, respectively. G1202R and G2032R resistance mutations prior to treatment with lorlatinib were observed in 10 of 26 evaluable patients (39%), 11 of 39 patients showed TP53 mutations (28%). Thirty-six patients (69%) had active brain metastases (BM) and nine (17%) leptomeningeal carcinomatosis when entering the EAP. Median number of prior specific TKIs was 3 (range 1?4). Median duration of treatment, progression-free survival (PFS), response rate and time to treatment failure were 10.4?months, 8.0?months, 54% and 13.0?months. Calculated 12-, 18- and 24-months survival rates were 65, 54 and 47%, overall survival since primary diagnosis (OS2) reached 79.6?months. TP53 mutations were associated with a substantially reduced PFS (3.7 versus 10.8?month, HR 3.3, p?=?0.003) and were also identified as a strong prognostic biomarker (HR for OS2 3.0 p?=?0.02). Neither prior treatments with second-generation TKIs nor BM had a significant influence on PFS and OS.Conclusions:Our data from real-life practice demonstrate the efficacy of lorlatinib in mostly heavily pretreated patients, providing a clinically meaningful option for patients with resistance mutations not covered by other targeted therapies and those with BM or leptomeningeal carcinomatosis.
Therapeutic advances in medical oncology Thousand Oaks, Calif. : Sage, 2009 13(2021) vom: Jan., Artikel-ID 1758835920980558, Seite 1-15 Online-Ressource
