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Application-based remote interstage home monitoring for infants with shunt- or duct-dependent pulmonary perfusion
Get PDFObjective: Interstage home monitoring (IHM) programs are considered standard of care after Norwood palliation and have led to substantial improvements in clinical outcomes. This study aims to evaluate an application-based remote IHM program for infants with shunt- or duct-dependent pulmonary circulation. The primary goals were to discharge infants from the hospital while minimizing mortality, optimizing somatic growth, and enhancing caregivers' confidence in the clinical management at home.
Methods: Infants with shunt-dependent single ventricle physiology or complex biventricular physiology requiring staged palliation with aortopulmonary shunt were enrolled for the study. Caregivers completed a comprehensive education program on the clinical management of their child at home and were asked to remotely send monitoring data using an application. We analyzed demographic data and clinical outcomes; evaluated patient acceptance and adherence, as well as data entry patterns and metrics; and compared these to a historical control group monitored in a non-remote IHM program and with a propensity score-matched cohort adjusted for baseline characteristics.
Results: We enrolled 30 infants in the remote IHM program between July 2021 and May 2024. The median duration of IHM was 110 days (IQR 75–140). A median of 353 (IQR 351–743) data entries were sent per patient during IHM of which 0.8% (IQR 0.3–1.9) were pathological. Readmissions (63%) and interventions (57%) were common, mainly due to cyanosis and infections. As all infants survived stage II palliation, interstage mortality could be reduced to 0% compared to 10.3% in the historical control group and was significantly lower compared to the propensity score-matched cohort with 14% (P = 0.032).
Conclusion: Application-based remote IHM for infants with duct- or shunt-dependent pulmonary perfusion is feasible, with high acceptance and adherence. The program significantly reduced interstage mortality compared to traditional monitoring methods. Remote patient monitoring (RPM) improves communication between caregivers and healthcare teams, allowing for early intervention and optimized patient outcomes. RPM has the potential to improve outcomes, enhance patient safety, and reduce family burden in this high-risk population
Decoding the role of PHF13 in genome regulation and chromatin organization
Get PDFPHF13 is an H3K4me3 epigenetic reader that participates in important biological processes, including transcription, DNA damage response, and the organization of chromatin structure. Aberrant regulation of PHF13 disrupts the epigenetic landscape of key transcription factors involved in the epithelial-to-mesenchymal transition and is linked to various cancers.
This thesis reveals that PHF13 employs alternative mechanisms to differentially regulate chromatin organization, highlighting its diverse biological roles. I demonstrate that PHF13 can oligomerize through conserved structured regions in its N- and C-terminal domains, which enhances its chromatin affinity, leading to chromatin condensation and transcriptional changes. Remarkably, I discovered that PHF13 can also self-associate independently of these regulatory domains via intrinsically disordered regions. This alternative mechanism reduces its chromatin affinity, facilitating the formation of liquid- liquid phase separation-like foci and activating distinct transcriptional programs. Finally, I developed two PHF13 cell lines to fine-tune its expression, allowing for a more thorough exploration of its role in chromatin organization.
My findings suggest that the intrinsic balance between PHF13’s structured and disordered regions plays a critical role in regulating its chromatin affinity, chromatin condensation, and transcriptional outcomes. Moreover, I propose that PHF13 can employ distinct mechanisms to modulate its chromatin functions in different biological processes.PHF13 ist ein epigenetischer H3K4me3-Leser, der an wichtigen biologischen Prozessen wie Transkription, der Antwort auf DNA-Schäden und der Organisation der Chromatinstruktur beteiligt ist. Eine gestörte Regulierung von PHF13 stört die epigenetischen Prozesse wichtiger Transkriptionsfaktoren, die am Übergang vom Epithel zum Mesenchym beteiligt sind, und wird mit verschiedenen Krebsarten in Verbindung gebracht.
In dieser Dissertation zeige ich, dass PHF13 verschiedene Mechanismen nutzt, um die Chromatinorganisation unterschiedlich zu regulieren, wodurch seine vielfältigen zellulären Rollen hervorgehoben werden. Ich weise nach, dass PHF13, mittels konservierter strukturierter Regionen in seinen N- und C-terminalen Domänen, Oligomere bildet und damit seine Chromatinaffinität erhöht, zu Chromatinkondensation beiträgt und zu transkriptionellen Veränderungen der Zelle führt. Zudem entdeckte ich, dass PHF13 sich unabhängig von diesen regulatorischen Domänen über intrinsisch ungeordnete Regionen selbst assoziieren kann. Diese alternative Assoziation reduziert die Chromatinaffinität, erleichtert die Bildung von flüssig-flüssig-phasentrennungsähnlichen Zuständen und aktiviert unterschiedliche transkriptionelle Programme. Schließlich habe ich zwei PHF13- Zellliniensysteme entwickelt, um seine Expression gezielt zu steuern und so eine detailliertere Untersuchung seiner Rolle in der Chromatinorganisation zu ermöglichen.
Meine Ergebnisse deuten darauf hin, dass das intrinsische Gleichgewicht zwischen den strukturierten und ungeordneten Regionen von PHF13 eine entscheidende Rolle bei der Regulation seiner Chromatinaffinität, der Chromatinkondensation und transkriptionellen Ergebnisse spielt. Darüber hinaus schlage ich vor, dass PHF13 unterschiedliche Mechanismen einsetzen kann, um seine Chromatinfunktionen in verschiedenen biologischen Prozessen zu modulieren
Portrayals of the Shero: a critical discourse analysis on the representation of Wonder Woman and Captain Marvel
Get PDFSuperhero films are currently the most commercially successful action films. They long relied on classical gender role divisions, representing physically strong male heroes. However, especially films published in the second decade of the 21st century have also shown women in more active roles. Wonder Woman (2017) and Captain Marvel (2019) were the first superhero films in which superheroines saved the world as protagonists. In this paper, I apply critical discourse analysis to investigate the contemporary film representations of Wonder Woman and Captain Marvel. My results suggest that both films depict female empowerment and address their superheroines’ struggles in rejecting women’s social roles and focusing on the pursuit of activities traditionally perceived as masculine. Both films also emphasize their superheroines’ womanhood; however, they represent these characters differently. Wonder Woman strongly emphasizes its superheroine’s feminine traits and shows her engaging in a heterosexual romantic relationship. Conversely, Captain Marvel depicts an obstinate woman whose psychological strength derives from her perseverance and support from a close female friend. I discuss my results with reference to the contemporary feminist movements postfeminism, neoliberal feminism and popular feminism
Novel coronaviruses identified in livestock: The urgent need to enhance coronavirus surveillance to mitigate zoonotic risks
Get PDFDevelopment of a Phase-Sensitive Sum Frequency Generation Microscope for the Investigation of Molecular Structures at Interfaces
No full textMolecular assemblies at interfaces are fundamental to natural and industrial applications,
with prominent examples including biological membranes and functionalized sensors, where
they play key roles in processes like selective transport and signal detection. Understanding
their molecular structure, arrangement, and orientation is crucial in biophysics, along with
applications in materials science and nanophotonics. While techniques like atomic force
microscopy, Brewster angle microscopy, or fluorescence microscopy have provided valuable
insights, elucidating molecular conformations and order remains a formidable challenge.
Vibrational sum-frequency generation (vSFG) microscopy complements these methods,
offering features such as label-free detection and unique sensitivity to molecular order and
orientation under ambient conditions. However, existing implementations face limitations,
including low signal-to-noise ratios, complex geometries, and challenges in characterizing
thin films on dielectric substrates.
In this thesis, a newly designed phase-resolved vSFG microscope is presented, which ad-
dresses challenges in characterizing molecular assemblies. The system integrates a collinear
beam geometry and a reflective objective with a custom-drilled hole for distortion-free
imaging at the sub-micron scale. To enhance signal quality, a paired pixel balanced imag-
ing technique was developed, achieving a „10-fold improvement in signal-to-noise ratio.
Interferometric time-domain scans with femtosecond laser pulses provide phase-resolved
vibrational spectra for each pixel, ensuring high spectral resolution. Proof-of-principle
measurements on a TEM grid validated its performance, confirming high sensitivity, im-
proved signal quality, and the system’s capability for detailed molecular characterization.
The microscope was applied to chiral phospholipid monolayers as model systems for biolog-
ical membranes. At specific surface pressures, mixed lipid monolayers coexist in condensed
and expanded phases, with the condensed lipids forming micron scale domains with nearly
circular shape. The SFG microscopy shows that these domains exhibit curved molecular
directionality and spiraling mesoscopic organization, providing new insights into their hier-
archical structural features. Enantiomeric substitution experiments uncovered deviations
from mirror symmetry, providing insights into enantioselective interactions and offering
new perspectives on the evolution of homochirality. Furthermore, the visualization and
investigation of phase-separated lipid domains enabled the extraction of molecular com-
positions and out-of-plane orientational order in both condensed and expanded phases.
In conclusion, this thesis work overcomes key limitations of SFG microscopy by various
technical achievements mentioned above. The performance of the newly designed phase-
resolved vSFG microscope was demonstrated by the study of the molecular packing struc-
ture in lipid monolayers, uncovering its potential to study diverse molecular assemblies,
paving the way for advancements in interfacial science
An overlooked morphological feature in the genus Rhodospatha (Araceae, Monsteroideae, Anepsiadeae) revealed through international collaboration, with the description of a new endemic species from Costa Rica
Get PDFA recent floristic survey in the Pacific slope of the Talamanca Mountain (Costa Rica), has revealed a new species of Rhodospatha, characterised by a bracteolate inflorescence. We describe and fully illustrate Rhodospatha rubrinervis from the Cloudbridge Nature Reserve. A detailed taxonomic description, as well as its distribution, ecology, phenology and conservation assessment are provided, along with a comparative discussion of its morphological affinities with R. forgetii and R. wendlandii. In addition, we present a brief discussion on the presence of a bracteole in Rhodospatha, a morphological character that, although illustrated by H.W. Schott 160 years ago, has not previously been described in detail
Reconstructing the distribution of relaxation times with analytical basis functions
Get PDFThe present work proposes the implementation of non-singular basis functions into the algorithm for reconstructing the distribution of relaxation times (DRT) function of impedance data. These functions reflect the dispersed and asymmetrical nature of non-ideal capacitive–resistive processes. Inclusion is achieved by combining the singular Debye distribution basis with distributed relaxation functions, such as those derived from the analytical models of Cole–Cole and Havriliak–Negami.
The shapes of the introduced basis functions are described by constant parameters, for which an empirical optimization approach is provided alongside. Using synthetic impedance data of non-ideal capacitive–resistive processes subjected to white noise, it is shown that the demand for regularization can be reduced significantly by using distributed bases. To underline the practical relevance of non-singular basis functions in DRT reconstruction, an experimental study comprising 100 sodium-ion and 80 lithium-ion commercial cells is presented. In this context, it is shown that auxiliary information from the non-ideal nature of real-world electrochemical processes is outsourced into the basis and, hence, easily filtered out of the resulting DRT. This facilitates the separation of single processes without post-DRT curve fitting and thus improves the interpretation and classification of impedance data significantly
Receptor Tyrosine Kinase Axl and Therapy Resistance in Glioblastoma
Get PDFFragestellung: Die RTK Axl spielt eine bedeutende Rolle in der Pathogenese des Glioblastoms und ist unter anderem für Angiogenese, Tumorzellproliferation und -migration sowie Immunosuppression und Chemoresistenz in verschiedenen Tumorentitäten verantwortlich. In der vorliegenden Arbeit sollte die Rolle Axl’s im Rahmen unterschiedlicher Pathomechanismen des Glioblastoms (unter RTK-Inhibition, Bestrahlung und in hypoxischen Tumorarealen) untersucht werden. Zunächst erfolgte die Inhibition der Axl-Aktivierung durch den hoch spezifischen SMI R428. Anschließend wurde die Rolle Axl’s bei Inhibition der RTK MET mit dem Inhibitor ARQ197 studiert, um festzustellen, ob Axl unter MET-Inhibition als Ausweichsignalkaskade genutzt wird. Danach untersuchten wir die Rolle Axl’s im Rahmen der – standardmäßig beim Glioblastom durchgeführten – Radiotherapie. Hierbei gingen wir davon aus, dass die Axl-Signalkaskade in strahlenresistenteren Zellen überaktiviert ist. Zuletzt sollte noch Axl’s Bedeutung in hypoxischen Tumorarealen analysiert werden, da Vorstudien zeigen konnten, dass die Rezeptordichte in diesen Arealen besonders hoch ist.
Methodik: Die beiden Glioblastom-Zelllinien SF126 und U118MG (in einzelnen Expe-rimenten auch weitere Zelllinien) wurden in jeweils unterschiedlichen Experimenten mit den Inhibitoren R428 oder ARQ197 behandelt, bestrahlt oder in einer Hypoxiekammer inkubiert. Anschließend wurden MTT-Assays und Colony Formation-Assays durchgeführt und RNA bzw. Proteine isoliert und hieraus qPCRs (Zielgene: Axl, MET, EGFR, Snail, Slug, TWIST, HIF1α) bzw. Western Blots (für Axl, Phospho-Axl779, MET, HIF1α) sowie Phospho-RTK-Arrays erstellt.
Ergebnisse: Die Behandlung der Zellen mit R428 führt zu einer verminderten Zellviabilität sowie zu einer vermehrten Axl-Expression und zu vermehrtem Axl-Shedding. In unbehandelten U118MG-Zellen sind zahlreiche RTKs überexprimiert. Die Behandlung mit R428 führt zu einer verminderten Axl-Phosphorylierung. Unter der Therapie mit ARQ197 konnten wir keine erhöhte Axl-Transkription (Kinasen-Switch) nachweisen. Die Radiosensitivität unterschiedlicher Glioblastom-Zelllinien variiert stark. Die Axl-Expression spielt hierbei in genetisch veränderten SF126-Zellen eine Rolle: Axl-Überexpression führt zu einer höheren Strahlenresistenz und ein Axl-Knockdown zu mehr Strahlensensitivität. Axl ist in der strahlenresistenteren Zelllinie SF126 unter Bestrahlung hyperphosphoryliert und eine Kombination von Bestrahlung und Axl-Inhibition hat hier einen synergistischen Effekt. Unter Hypoxie kommt es zu vermehrtem Axl-Shedding.
Fazit: Die Axl-Signalkaskade kann im Glioblastom Strahlenresistenz induzieren und scheint in hypoxischen, besonders malignen Tumorarealen überexprimiert zu sein. Die spezifische Axl-Inhibition kann diese Mechanismen teilweise umkehren, wobei Wechselwirkungen mit anderen RTK-Signalkaskaden – z.B. MET – bedacht werden müssen. Weitere translationale Modelle sind notwendig, um dies genauer zu studieren.Purpose: The receptor tyrosine kinase Axl plays an important role in the pathogenesis of glioblastoma and is responsible for angiogenesis, tumor cell proliferation and migration, immunosuppression and chemoresistance in different tumor entities. Here, we want to examine Axl’s role in different pathophysiological situations (RTK-inhibtion, radiation and hypoxic tumorniches). First, we applied the highly specific Axl-small molecule inhibitor R428 and studied the effects. We then were interested in the role of Axl as a bypass mechanism under MET-inhibition with ARQ197. Next, we investigated the role of Axl in the standard-of-care radiotherapy in glioblastoma, assuming an activation of the Axl signaling cascade in radioresistant cell lines. Lastly, we analyzed Axl’s function in hypoxic tumor zones since precedent studies showed a high receptor prevalence in these regions.
Methods: The two glioblastoma cell lines SF126 and U118MG (in some experiments additional cell lines have been used) were in individual experiments either treated with the inhibitors R428 or ARQ197, irradiated or incubated in a hypoxia chamber. We then performed MTT-assays, colony formation assays and isolated RNA and proteins. After which we performed qPCRs (targets: Axl, MET, EGFR, Snail, Slug, TWIST, HIF1α), Western Blots (for Axl, Phospho-Axl779, MET, HIF1α) and phospho-receptor tyrosine kinase-arrays.
Results: Treatment of the cells with R428 lead to a decrease of cell viability and an increase in Axl-expression and -shedding. Untreated U118MG cells overexpress numerous receptor tyrosine kinases. R428 treatment leads to a decrease in Axl-phosphorylation. Under the treatment with ARQ197 we could not find a decreased Axl-transcription (kinase switch). The radiosensitivity of different glioblastoma cell lines varies. The expression of Axl in genetically modified SF126 cells impacted the radiosensitivity: Axl overexpression leads to an increased radio resistance and Axl-knockdown leads to more radiosensitivity. Axl is hyperphosphorylated in the radioresistant cell line SF126 and a combination of radiation and Axl-inhibition has a synergistic effect in this cell line. Under hypoxia we found increased Axl-shedding.
Conclusion: The Axl signaling cascade can induce radio resistance and seems to be overexpressed in hypoxic – especially malignant – tumor areas. A specific Axl-inhibition can in part reverse these mechanisms but interactions with other RTK signal-ing cascades – for example MET – have to be kept in mind. Further translational re-search is necessary to further understand the importance
Perioperative non-invasive advanced hemodynamic monitoring of patients with primary ovarian cancer undergoing multivisceral debulking surgery
Get PDFHintergrund: Patienten, die sich einer Hochrisiko-Operation unterziehen, zeigen häufig hämodynamische Instabilitäten und haben ein erhöhtes Morbiditäts- und Mortalitätsrisiko. Eine frühe Detektion von Veränderungen im kardiozirkulatorischen Fluss mittels hämodynamischen Monitorings ist die Grundlage für eine adäquate Therapie. Die meisten verfügbaren Daten konzentrieren sich jedoch nur auf den intraoperativen Zeitraum. Das Ziel der Studie ist es, Patienten mittels perioperativer Messungen der thorakalen Bioimpedanz (Elektrische Kardiometrie, EC) im gesamten perioperativen Verlauf zu charakterisieren und zu erforschen, ob damit eine frühzeitige Risikostratifikation von Patienten, die Komplikationen erleiden, möglich ist.
Methodik: In einer prospektiven, monozentrischen Beobachtungsstudie wurden an 29 Patientinnen mit primärem Ovarialkarzinom EC-Messungen vor, während und wiederholt nach der zytoreduktiven Operation durchgeführt. Perioperativ wurden Interleukin-6 (IL-6) und das interzelluläre Adhäsionsmolekül-1 (ICAM-1) analysiert. Schwere postoperative Komplikationen wurden nach Clavien-Dindo klassifiziert und dienten als Gruppierungskriterium.
Ergebnisse: Ein relativer Vergleich der ersten intraoperativen mit der präoperativen Messung zeigte eine verminderte Herzfrequenz (HR, Median -19 % [Q25 -26 %; Q75 -10 %], p < 0.0001), einen verminderten Index des Schlag- (SVI, Median -9.5 [-15,3; 3,2] %, p = 0,0038) und des Herzminutenvolumens (CI, -24,5 [-32; -13] %, p < 0,0001) sowie der Kontraktilität (ICON, -17,5 [-35,3; -0,8] %, p < 0,0001). Intraoperativ hatten die Patientinnen verminderte HR und CI, postoperativ hingegen erhöhte Werte für HR und CI, wobei der SVI perioperativ unverändert war. Der thorakale Flüssigkeitsgehalt (TFC) stieg im Vergleich zu präoperativ im Verlauf kontinuierlich an. Patientinnen mit postoperativen Komplikationen unterschieden sich von Patientinnen ohne Komplikationen im Verlauf in niedrigeren Werten des ICON und einem verlängerten systolischem Zeitverhältnis (STR), wobei der CI zwischen den Gruppen vergleichbar war. Zudem waren die inflammatorischen Marker IL-6 und ICAM-1 im perioperativen Verlauf bei Patientinnen mit postoperativen Komplikationen höher.
Schlussfolgerungen: Vom Tag vor der Operation bis zu den ersten intraoperativen Werten nach der Narkoseeinleitung und dem Beginn der Operation kam es zu einem wesentlichen Abfall von HR, SVI, CI und ICON. Patientinnen mit postoperativen Komplikationen unterschieden sich von Patientinnen ohne Komplikationen in den kardialen Funktionsmarkern, ICON (vermindert) und STR (verlängert), sowie einem niedrigeren SVI. Die Analyse von Trends über den gesamten perioperativen Verlauf mittels nicht-invasiver Technologien wie der EC scheint nützlich, um Patienten mit veränderten hämodynamischen Parametern und damit einem erhöhten Risiko für postoperative Komplikationen nach Hochrisiko-Operationen zu identifizieren.Background: Patients undergoing high-risk surgery often show hemodynamic instability and have an increased risk of morbidity and mortality. The early detection of changes in cardiocirculatory flow by means of hemodynamic monitoring is the basis for an adequate therapy. However, most of the available data concentrate only on the intraoperative period. This study aims to characterize patients with advanced hemodynamic monitoring throughout the whole perioperative period using thoracic bioimpedance (electrical cardiometry, EC) and to explore if it allows for early risk stratification of patients sustaining perioperative hemodynamic complications.
Methods: In a prospective, observational, monocentric study, EC measurements were obtained before, during and repeatedly after surgery on 29 patients with primary ovarian cancer undergoing cytoreductive surgery. Interleukine-6 (IL-6) and intercellular adhesion molecule-1 (ICAM-1) were analyzed perioperatively. Severe postoperative complications were classified according to Clavien-Dindo and used as a grouping criterion.
Results: The relative comparison of the preoperative baseline to the first intraoperative timepoint showed a reduced heart rate (HR, median -19 % [Q25 -26 %; Q75 -10 %], p < 0.0001), stroke volume index (SVI, -9.5 [-15.3; 3.2] %, p = 0.0038), cardiac index (CI, -24.5 [-32; -13] %, p < 0.0001) and index of contractility (ICON, -17.5 [-35.3; -0.8] %, p < 0.0001). Throughout the perioperative course, patients had intraoperatively a reduced HR and CI and postoperatively an increased HR and CI, whereas the SVI was unchanged. The thoracic fluid volume (TFC) increased continuously in comparison to the preoperative values. Patients having postoperative complications showed lower values of the ICON and a higher systolic time ratio (STR) over the perioperative course in comparison to patients without complications, whereas the CI was comparable between groups. Also, the markers IL-6 and ICAM-1 were higher over the perioperative course for patients with postoperative complications.
Conclusions: Substantial decreases in HR, SVI, CI, and ICON occurred from the day before surgery to the first intraoperative values after induction of anesthesia and the start of surgery. HR and CI were altered throughout the perioperative course. Patients with postoperative complications differed from patients without complications in the markers of cardiac function, a lower ICON, a higher STR, as well as a lower SVI. The analyses of trends over the whole perioperative time course by using non‐invasive technologies like EC seem to be useful to identify patients with altered hemodynamic parameters and therefore at an increased risk for postoperative complications after major surgery
Timing of oral anticoagulation in atrial fibrillation and outcome after ischemic stroke Data from the Berlin Atrial Fibrillation Registry
Get PDFHintergrund Eine orale Antikoagulation ist in der Sekundärprävention des ischämischen Schlaganfalls bei Patient:innen mit Vorhofflimmern wirksam und wird von Leitlinien empfohlen. Der ideale Startzeitpunkt einer Antikoagulation nach akutem ischämischen Schlaganfall ist nicht abschließend geklärt. Eine in der klinischen Praxis verwendete Empfehlung ist die „1-3-6-12-Tage Regel“, die anhand der klinischen Schwere des Schlaganfalls den Zeitpunkt festlegt.
Methoden Wir analysierten Daten des prospektiven, multizentrischen Berliner Vorhofflimer Registers, das Patient:innen nach akutem ischämischen Schlaganfall einschloss, sofern ein Vorhofflimmern vorbekannt war oder stationär diagnostiziert wurde. Analysiert wurde der Einfluss des Startzeitpunktes der Antikoagulation auf den kombinierten Endpunkt (ischämischer Schlaganfall, systemische Embolie, Myokardinfarkt, schwere Blutung oder Tod) innerhalb von 90 Tagen.
Ergebnisse Es wurden 978 Registerpatient:innen (mittleres Alter 72 Jahre, 48.9% weiblich, mittlerer NIHSS-Score 2) berücksichtigt, von denen 241 (24.6%) eine TIA erlitten hatten. Eine Antikoagulation wurde bei 917 (93.7%) innerhalb von 90 Tagen begonnen/fortgesetzt. Insgesamt 79 (8.0%) Patient:innen erreichten den klinischen Endpunkt, 48 (4.9%) erlitten eine ischämische, 13 (1.3%) eine hämorrhagische Komplikation und 18 (1.8%) verstarben. Ein neues neurologisches Defizit [HR 3.3 (95%CI 1.8-5.8)], ein kardialer Thrombus [HR 4.6 (95%CI 1.6-12.8)], keine Antikoagulation (HR 3.7 (95%CI 1.9-7.2)] und eine intravenöse Thrombolyse [HR 0.29 (95%CI 0.10-0.79)] korrelierte mit dem kombinierten Endpunkt. Der Startzeitpunkt der Antikoagulation entsprach der „1-3-6-12-Tage Regel“ bei 39% aller Patient:innen. Ein mindestens mittelgroßer Infarkt [OR 2.6 (95%CI 1.1-6.5)], ein neues neurologisches Defizit [OR 3.5 (95%CI 1.4-10.8)] und keine Antikoagulation bei Auftreten des Schlaganfalls [OR 0.46 (95%CI 0.31-0.66)] korrelierte mit einer fehlenden Einhaltung der „1-3-6-12-Tage-Regel“. Eine Abweichung von der „1-3-6-12-Tage-Regel“ korrelierte nicht mit dem Auftreten des kombinierten Endpunkts. Den Ein- und Ausschlusskriterien der nach Ende des Registers publizierten randomisierten TIMING- und ELAN-Studie entsprachen 29% beziehungsweise 8% der Registerpatient:innen. Das Auftreten des klinischen Endpunkts variierte nicht bei Übertragung der Studienkriterien auf die Registerkohorte.
Schlussfolgerungen Die überwiegende Mehrzahl der Registerpatient:innen erhielt eine Sekundärprävention mittels oraler Antikoagulation, die mit einer Reduktion des klinischen Endpunktes assoziiert war. Der Startzeitpunkt der Antikoagulation entsprach bei etwa 40% der Patient:innen den Empfehlungen. Eine orale Antikoagulation bei Auftreten des Schlaganfalls korrelierte mit der Einhaltung dieser. Die im Nachgang der Rekrutierung veröffentlichten randomisierten Studien berücksichtigen nur einen geringen Teil der Registerpatient:innen, so dass weitere Studien angezeigt sind.Background Oral anticoagulation is effective in the secondary prevention of ischemic stroke in patients with atrial fibrillation and is recommended by guidelines. The ideal time to start anticoagulation after acute ischemic stroke has not been conclusively determined. One recommendation used in clinical practice is the "1-3-6-12 day rule", which determines the timing based on the clinical severity of the stroke.
Methods We analyzed data from the prospective, multicenter Berlin Atrial Fibrillation Registry, which included patients after acute ischemic stroke if atrial fibrillation was previously known or diagnosed as an inpatient. The influence of the start time of anticoagulation on the combined endpoint (ischemic stroke, systemic embolism, myocardial infarction, major bleeding or death) within 90 days was analyzed.
Results A total of 978 registry patients (mean age 72 years, 48.9% female, mean NIHSS score 2) were included, of whom 241 (24.6%) had suffered a TIA. Anticoagulation was started/continued within 90 days in 917 (93.7%). A total of 79 (8.0%) patients reached the clinical endpoint, 48 (4.9%) suffered an ischemic complication, 13 (1.3%) a hemorrhagic complication and 18 (1.8%) died. New neurological deficit [HR 3.3 (95%CI 1.8-5.8)], cardiac thrombus [HR 4.6 (95%CI 1.6-12.8)], no anticoagulation (HR 3.7 (95%CI 1.9-7.2)] and intravenous thrombolysis [HR 0.29 (95%CI 0.10-0.79)] correlated with the combined endpoint. The start time of anticoagulation corresponded to the "1-3-6-12-day rule" in 39% of all patients. An infarction of at least moderate size [OR 2.6 (95%CI 1.1-6.5)], a new neurological deficit [OR 3.5 (95%CI 1.4-10.8)] and no anticoagulation at stroke onset [OR 0.46 (95%CI 0.31-0.66)] correlated with a lack of adherence to the "1-3-6-12 day rule". A deviation from the "1-3-6-12-day rule" did not correlate with the occurrence of the combined endpoint. The inclusion and exclusion criteria of the randomized TIMING and ELAN studies published after the end of the registry were met by 29% and 8% of registry patients, respectively. The occurrence of the clinical endpoint did not vary when the
study criteria were applied to the registry cohort.
Conclusions The vast majority of registry patients received secondary prevention by means of oral anticoagulation, which was associated with a reduction in the clinical endpoint. The start time of anticoagulation corresponded to the recommendations in around 40% of patients. Oral
anticoagulation at the onset of stroke correlated with adherence. The randomized studies published after recruitment only include a small proportion of the registry patients, so that further studies are indicated