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Zusammenfassung Hintergrund und Fragestellung Die Entwöhnung von Beatmungsgeräten wird nicht immer auf der primär behandelnden Intensivstation abgeschlossen. Die Weiterverlegung in andere Behandlungseinrichtungen stellt einen sensiblen Abschnitt in der Behandlung und Rehabilitation des Weaningpatienten dar. Ziel der vorliegenden Studie war die Untersuchung des Überleitungsmanagements und des Interhospitaltransfers von Weaningpatienten unter besonderer Berücksichtigung der Dokumentationsqualität. Methodik Es erfolge eine retrospektive Datenanalyse eines Jahrs (2018) auf 2 Intensivstationen eines Universitätsklinikums. Eingeschlossen wurden alle beatmeten Patienten mit folgenden Tracerdiagnosen: COPD, Asthma, Polytrauma, Pneumonie, Sepsis, ARDS und Reanimation (Beatmung > 24 h). Ergebnisse Insgesamt konnten 750 Patienten in die Untersuchung eingeschlossen werden (Alter 64 [52, 8–76; Median, IQR]; 32 % weiblich). Davon waren 48 (6,4 %) Patienten zum Zeitpunkt der Verlegung nicht entwöhnt (v. a. Sepsis und ARDS). Die Routinedokumentation war bei den Abschnitten „Spontaneous Breathing Trial“, „Bewertung der Entwöhungsbereitschaft“ und „vermutete Entwöhnbarkeit“ ausreichend, um die Erfüllung der Parameter der S2k-Leitlinie „Prolongiertes Weaning“ adäquat zu beurteilen. Vorwiegend wurden diese Patienten mit Tracheostoma (76 %) in Rehabilitationskliniken (44 %) mittels spezialisierten Rettungsmitteln des arztbegleiteten Patiententransports verlegt (75 %). Diskussion Die Verlegung nicht entwöhnter Patienten nach initialem Intensivaufenthalt ist ein relevantes Thema für den Interhospitaltransfer. Die Routinedokumentation eines strukturierten Weaningprozesses ist in Kernelementen ausreichend, um den Weaningprozess lückenlos zu beschreiben. Dies ist für die Kontinuität in der Weiterbehandlung dieser Patienten von großer Bedeutung.

ZusammenfassungÜber die letzten Jahre gewann die außerklinische Langzeitbeatmung zunehmend an Bedeutung. Auch wenn Akutkomplikationen im außerstationären Setting nur selten auftreten, sind diese oft mit dramatischen Folgen verbunden. Bislang ist unbekannt, wie hoch die Einsatzerfahrung von Notärzten in der präklinischen Behandlung von heimbeatmeten Patienten ist, mit welchen Problemen sie sich im Einsatz konfrontiert sehen und wo Verbesserungspotenzial liegt.In dieser retrospektiven Beobachtungsstudie wurde allen in Bayern tätigen Notärzten ein elektronischer Fragebogen übermittelt. Circa 7–8% (n = 264) der Notärzte sendeten eine Antwort.Von den an der Versorgung von langzeitbeatmeten Patienten beteiligten Notärzten sahen sich 66,9% (n = 121) mit Versorgungsproblemen konfrontiert. Insbesondere Probleme mit dem Atemweg oder dem Beatmungsgerät sind besonders kritisch. Um dem vermehrten Aufkommen von Notfalleinsätzen bei langzeitbeatmeten Patienten gerecht zu werden, sollten spezifische Problemfelder dieser Patientengruppe stärker in der Ausbildung von ärztlichem und nicht ärztlichem Rettungsdienstfachpersonal berücksichtigt werden.

Background Numerous predictive clinical scores with varying discriminatory performance have been developed in the context of the current coronavirus disease 2019 (COVID-19) pandemic. To support clinical application, we test the transferability of the frequently applied 4C mortality score (4C score) to the German prospective Cross-Sectoral Platform (SUEP) of the National Pandemic Cohort Network (NAPKON) compared to the non COVID-19 specific quick sequential organ failure assessment score (qSOFA). Our project aims to externally validate these two scores, stratified for the most prevalent variants of concerns (VOCs) of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) in Germany. Methods A total of 685 adults with polymerase chain reaction (PCR)-detected SARS-CoV-2 infection were included from NAPKON-SUEP. Patients were recruited from 11/2020 to 03/2022 at 34 university and non-university hospitals across Germany. Missing values were complemented using multiple imputation. Predictive performance for in-hospital mortality at day of baseline visit was determined by area under the curve (AUC) with 95%-confidence interval (CI) stratified by VOCs of SARS-CoV-2 (alpha, delta, omicron) (Figure 1). Figure 1:Study flow chart with inclusion criteria and methodological workflow. Results Preliminary results suggest a high predictive performance of the 4C score for in-hospital mortality (Table 1). This applies for the overall cohort (AUC 0.813 (95%CI 0.738-0.888)) as well as the VOC-strata (alpha: AUC 0.859 (95%CI 0.748-0.970); delta: AUC 0.769 (95%CI 0.657-0.882); omicron: AUC 0.866 (95%CI 0.724-1.000)). The overall mortality rates across the defined 4C score risk groups are 0.3% (low), 3.2% (intermediate), 11.6% (high), and 49.5% (very high). The 4C score performs significantly better than the qSOFA (Chi2-test: p=0.001) and the qSOFA does not seem to be a suitable tool in this context. Table 1:Discriminatory performance of the 4C Mortality Score and the qSOFA score within the validation cohort NAPKON-SUEP stratified by the Variant of Concerns of SARS-CoV-2. Conclusion Despite its development in the early phase of the pandemic and improved treatment, external validation of the 4C score in NAPKON-SUEP indicates a high predictive performance for in-hospital mortality across all VOCs. However, since the qSOFA was not specifically designed for this predictive issue, it shows low discriminatory performance, as in other validation studies. Any interpretations regarding the omicron stratum are limited due to the sample size. Disclosures Daniel Pape, Dr., Advanz Pharma Germany: Support for attending meetings and/or travel for ECCMID 2021 Martin Hower, n/a, MSD: Advisor/Consultant|Trogarzo: Advisor/Consultant|ViiV Healthcare: Advisor/Consultant Björn-Erik O. Jensen, Dr. med., GILEAD: Advisor/Consultant|GILEAD: Lectures, Travel|GSK: Lectures, Travel Jörg J. Vehreschild, Univ.-Prof. Dr. med., Ärztekammer Nordrhein: Honoraria|Academy for Infectious Medicine, University Manchester: Honoraria|Astellas Pharma: Grant/Research Support|Astellas Pharma: Honoraria|Back Bay Strategies: Honoraria|Basilea: Grant/Research Support|Basilea: Honoraria|Deutsches Zetrum für Luft- und Raumfahrt (DLR): Grant/Research Support|German Centre for Infection Research (DZIF): Grant/Research Support|German Centre for Infection Research (DZIF): Honoraria|German Federal Ministry of Education and Research (BMBF): Grant/Research Support|German Society for Infectious Diseases (DGI): Honoraria|German Society for Internal Medicine (DGIM): Honoraria|GILEAD: Advisor/Consultant|GILEAD: Grant/Research Support|GILEAD: Honoraria|Janssen: Honoraria|Merck / MSD: Grant/Research Support|Merck / MSD: Honoraria|Molecular Health: Honoraria|Netzwerk Universitätsmedizin: Honoraria|NordForsk: Honoraria|Pfizer: Advisor/Consultant|Pfizer: Grant/Research Support|Pfizer: Honoraria|Rigshospitalet Copenhagen: Grant/Research Support|Shionogi: Advisor/Consultant|Shionogi: Honoraria|University Hospital Aachen: Honoraria|University Hospital Freiburg/ Congress and Communication: Honoraria|University of Bristol: Grant/Research Support.

Complexity of outpatient intensive care for ventilated people: Cross-mapping into the standardised NNN-taxonomy

Zusammenfassung. Hintergrund: Zur Abbildung des Pflegeprozesses wird in der außerstationären Intensivpflege in Deutschland bevorzugt im Freitext dokumentiert, obwohl Klassifikationssysteme eine genauere Beschreibung ermöglichen könnten. Fragestellung: Wie lässt sich die pflegerische Versorgung außerstationär beatmeter Menschen mit der NNN-Taxonomie darstellen und welche Empfehlungen ergeben sich daraus für die Pflegepraxis? Methoden: Angewendet wurde ein qualitatives „multiple Case“ Design. Mittels deduktiver Inhaltsanalyse (Datenquellen: Pflegedokumentation und Sekundäranalyse von Interviews mit Betroffenen) wurden mehrere Fälle sowohl individuell als auch über alle Fälle hinweg mit den Pflegediagnosen, -interventionen und -ergebnissen der NNN-Taxonomie verknüpft (Cross-Mapping). Ergebnisse: Insgesamt wurde die Pflegedokumentation von 16 invasiv beatmete Personen mit einem Durchschnittsalter von 58,4 Jahren ( SD = 16,3) analysiert. Sieben Personen steuerten zusätzlich Interviewdaten bei. Dokumentiert wurde überwiegend nach dem „Strukturmodell“ (14/16) mit einer mittleren bis hohen Genauigkeit (D-Catch Score: 16,6; SD = 4,1). Beim Cross-Mapping wurden 4016 Codes vergeben: 618 Pflegediagnosen, 1956 -interventionen und 1442 -ergebnisse. Es wurde stark maßnahmenorientiert, wenig personenzentriert und mit mangelnder Differenzierung zwischen Diagnostik und Intervention dokumentiert. Schlussfolgerungen: Zur Verbesserung der Pflegepraxis sollen eine personenzentrierte Grundhaltung und die Fähigkeit zwischen pflegerischen Diagnosen, Interventionen und Ergebnissen zu unterscheiden gefördert werden.

Zusammenfassung Hintergrund und Fragestellung Die Anzahl der invasiven und nicht-invasiven außerklinischen Langzeitbeatmungen steigt seit Jahren stark an. Gleichzeitig gibt es nur wenige Informationen über die Versorgungsqualität von außerstationär beatmeten Patienten. Die vorliegende Untersuchung erfolgte im Rahmen der OVER-BEAS-Studie. Ziel dieser Untersuchung war es, die Versorgungssituation von Weaning-Patienten von der Aufnahme bis zur Entlassung aus dem Weaning-Zentrum anhand der vorhandenen Routinedokumentation abzubilden. Material und Methoden In unsere retrospektive Analyse schlossen wir alle Patienten ein, die 2018 über die Weaning-Station des Thoraxzentrums Münnerstadt aufgenommen wurden. Es erfolgte die deskriptive Auswertung der im Rahmen des Qualitätsmanagements erhobenen Routinedaten. Datenquellen waren die WeanNet-Datenbank, der Entlassbrief des Weaning-Zentrums sowie der Verlegungsbericht der zuverlegenden Klinik. Ergebnisse Im untersuchten Weaningz-Zentrum konnten 50,8 % der Patienten (n = 31) vollständig vom Respirator entwöhnt und extubiert bzw. dekanüliert werden (Kategorie 3aI). Gelang keine vollständige Entwöhnung, so war im weiteren Verlauf bei 75,0 % (n = 21) die ständige Anwesenheit von speziell geschultem Personal oder einer Fachpflegekraft erforderlich. Hier erfolgte die Weiterversorgung meist in stationären Pflegeeinrichtungen (z. B. Beatmungs-WG). Schlussfolgerung Anhand der Routinedokumentation lässt sich die Versorgungssituation von Weaning-Patienten darstellen und mit bekannten Daten vergleichen. So kann die Ergebnisqualität eines Weaning-Zentrums vergleichbar gemacht werden.

Fur die Behandlung von M. Parkinson in Deutschland sind je nach Krankheitsstadium und Symptomstarke verschiedene Therapien (z. B. orale medikamentose Gabe von Levodopa oder tiefe Hirnstimulation) sowie auch multidisziplinare bis hin zu sektorubergreifenden Versorgungsansatze (z. B. Parkinson-Komplextherapie oder integrierte Versorgung) verfugbar. Dennoch fehlt es in der Versorgung von M.-Parkinson-Patienten bisher neben flachendeckenden Angeboten auch an einer bundesweit standardisierten Erfassung der Behandlungsqualitat, v. a. bei technisch aufwendigen Verfahren, welche eine hohe Expertise des Behandlers bedingen. Einige dieser Herausforderungen konnten durch eine Ausweitung digitaler Ansatze (z. B. teleneurologische Sprechstunde oder Wearables) und mithilfe von Registern zur Qualitatssicherung in Angriff genommen werden.

Background: In patients with intracerebral hemorrhage (ICH) and prevalent atrial fibrillation (AF), the optimal stroke prevention strategy is unclear. We sought to estimate the risk of cerebrovascular events among ICH survivors with AF. Methods: We used the Danish Stroke Registry to identify patients with incident ICH and prevalent AF between 2003 and 2018. Key inclusion/exclusion criteria of the PRESTIGE-AF (Prevention of Stroke in Intracerebral hemorrhage Survivors With Atrial Fibrillation) trial were applied. Cumulative incidence of recurrent ICH, cerebrovascular ischemic event, and all-cause death were investigated after one year. Results: A total of 1885 patients (median age 80.0 years; 47.6% females) were included in the study. We observed 191 cerebrovascular events and 650 all-cause deaths, and more cerebrovascular ischemic events (N=63) than recurrent ICH events (N=40). Risks of recurrent ICH, cerebrovascular ischemic event, and all-cause death were 1.5%, 3.2%, and 30.3%, respectively, among patients not exposed to OAC during follow-up. The cumulative incidences were 2.8% for recurrent ICH, 3.2% for cerebrovascular ischemic events, and 22.0% for all-cause death among patients initiating/resuming OAC during follow-up. Conclusions: We observed a high risk of cerebrovascular ischemic events and a very high risk of all-cause death at one year after the incident ICH. The results of ongoing clinical trials are warranted to determine optimal stroke prevention treatment among ICH survivors with concomitant AF.

Weaning from ventilators is not always finished in the primary intensive care unit (ICU) setting. Transfer to other treatment facilities is a sensitive stage in the treatment and rehabilitation of the weaning patient. The aim of the present study was to investigate transition management and interhospital transfer of weaning patients, with special emphasis on documentation quality.A retrospective data analysis of one year (2018) in two ICUs of a university hospital was performed. All ventilated patients with the following tracer diagnoses were included: chronic obstructive pulmonary disease (COPD), asthma, patients with multiple injuries, pneumonia, sepsis, acute respiratory distress syndrome (ARDS), and cardiac arrest (ventilation 24 h).A total of 750 patients were included in the study (median age 64 [IQR 52.8-76]; 32% female). In all, 48 (6.4%) patients were not weaned at the time of transfer (especially sepsis and ARDS). Routine documentation was sufficient for the sections "spontaneous breathing trial", "assessment of readiness to wean" and "presumed weanability" to adequately assess the parameters of the German S2k guideline "prolonged weaning". Predominantly, these patients were transferred with tracheostoma (76%) to rehabilitation units (44%) by specialized physician-assisted patient transport ambulances (75%).The transfer of ventilated patients after initial ICU stay is a relevant issue for interhospital transfer. Routine documentation of a structured weaning process is sufficient in core elements to describe the weaning process. This is of great importance for continuity in the further treatment of these patients.HINTERGRUND UND FRAGESTELLUNG: Die Entwöhnung von Beatmungsgeräten wird nicht immer auf der primär behandelnden Intensivstation abgeschlossen. Die Weiterverlegung in andere Behandlungseinrichtungen stellt einen sensiblen Abschnitt in der Behandlung und Rehabilitation des Weaningpatienten dar. Ziel der vorliegenden Studie war die Untersuchung des Überleitungsmanagements und des Interhospitaltransfers von Weaningpatienten unter besonderer Berücksichtigung der Dokumentationsqualität.Es erfolge eine retrospektive Datenanalyse eines Jahrs (2018) auf 2 Intensivstationen eines Universitätsklinikums. Eingeschlossen wurden alle beatmeten Patienten mit folgenden Tracerdiagnosen: COPD, Asthma, Polytrauma, Pneumonie, Sepsis, ARDS und Reanimation (Beatmung 24 h).Insgesamt konnten 750 Patienten in die Untersuchung eingeschlossen werden (Alter 64 [52, 8–76; Median, IQR]; 32 % weiblich). Davon waren 48 (6,4 %) Patienten zum Zeitpunkt der Verlegung nicht entwöhnt (v. a. Sepsis und ARDS). Die Routinedokumentation war bei den Abschnitten „Spontaneous Breathing Trial“, „Bewertung der Entwöhungsbereitschaft“ und „vermutete Entwöhnbarkeit“ ausreichend, um die Erfüllung der Parameter der S2k-Leitlinie „Prolongiertes Weaning“ adäquat zu beurteilen. Vorwiegend wurden diese Patienten mit Tracheostoma (76 %) in Rehabilitationskliniken (44 %) mittels spezialisierten Rettungsmitteln des arztbegleiteten Patiententransports verlegt (75 %).Die Verlegung nicht entwöhnter Patienten nach initialem Intensivaufenthalt ist ein relevantes Thema für den Interhospitaltransfer. Die Routinedokumentation eines strukturierten Weaningprozesses ist in Kernelementen ausreichend, um den Weaningprozess lückenlos zu beschreiben. Dies ist für die Kontinuität in der Weiterbehandlung dieser Patienten von großer Bedeutung.

Orphanet journal of rare diseases : OJRD 17(1), 47 (2022). doi:10.1186/s13023-022-02176-1, Published by BioMed Central, London

Purpose Over the course of COVID-19 pandemic, evidence has accumulated that SARS-CoV-2 infections may affect multiple organs and have serious clinical sequelae, but on-site clinical examinations with non-hospitalized samples are rare. We, therefore, aimed to systematically assess the long-term health status of samples of hospitalized and non-hospitalized SARS-CoV-2 infected individuals from three regions in Germany. Methods The present paper describes the COVIDOM-study within the population-based cohort platform (POP) which has been established under the auspices of the NAPKON infrastructure (German National Pandemic Cohort Network) of the national Network University Medicine (NUM). Comprehensive health assessments among SARS-CoV-2 infected individuals are conducted at least 6 months after the acute infection at the study sites Kiel, Würzburg and Berlin. Potential participants were identified and contacted via the local public health authorities, irrespective of the severity of the initial infection. A harmonized examination protocol has been implemented, consisting of detailed assessments of medical history, physical examinations, and the collection of multiple biosamples (e.g., serum, plasma, saliva, urine) for future analyses. In addition, patient-reported perception of the impact of local pandemic-related measures and infection on quality-of-life are obtained. Results As of July 2021, in total 6813 individuals infected in 2020 have been invited into the COVIDOM-study. Of these, about 36% wished to participate and 1295 have already been examined at least once. Conclusion NAPKON-POP COVIDOM-study complements other Long COVID studies assessing the long-term consequences of an infection with SARS-CoV-2 by providing detailed health data of population-based samples, including individuals with various degrees of disease severity. Trial registration Registered at the German registry for clinical studies (DRKS00023742).

Background and Purpose: Quality indicators (QI) are an accepted tool to measure performance of hospitals in routine care. We investigated the association between quality of acute stroke care defined by overall adherence to evidence-based QI and early outcome in German acute care hospitals. Methods: Patients with ischemic stroke admitted to one of the hospitals cooperating within the ADSR (German Stroke Register Study Group) were analyzed. The ADSR is a voluntary network of 9 regional stroke registers monitoring quality of acute stroke care across 736 hospitals in Germany. Quality of stroke care was defined by adherence to 11 evidence-based indicators of early processes of stroke care. The correlation between overall adherence to QI with outcome was investigated by assessing the association between 7-day in-hospital mortality with the proportion of QI fulfilled from the total number of QI the individual patient was eligible for. Generalized linear mixed model analysis was performed adjusted for the variables age, sex, National Institutes of Health Stroke Scale and living will and as random effect for the variable hospital. Results: Between 2015 and 2016, 388 012 patients with ischemic stroke were reported (median age 76 years, 52.4% male). Adherence to distinct QI ranged between 41.0% (thrombolysis in eligible patients) and 95.2% (early physiotherapy). Seven-day in-hospital mortality was 3.4%. The overall proportion of QI fulfilled was median 90% (interquartile range, 75%–100%). In multivariable analysis, a linear association between overall adherence to QI and 7-day in-hospital-mortality was observed (odds ratio adherence P Conclusions: Higher quality of care measured by adherence to a set of evidence-based process QI for the early phase of stroke treatment was associated with lower in-hospital mortality.

Hintergrund und Stand (inter)nationaler Forschung: Die außerklinische Intensivversorgung langzeitbeatmeter Menschen ist ein stark anwachsender Bereich mit vielseitigen Versorgungsbedarfen. Der rasante Anstieg beatmeter, intensiv-pflegebedürftiger Menschen stellt das Gesundheitssystem vor enorme[zum vollständigen Text gelangen Sie über die oben angegebene URL], 19. Deutscher Kongress für Versorgungsforschung (DKVF)

In Germany various concepts for treating patients with Parkinson's disease (PD) are available, e.g. oral medication with levodopa or deep brain stimulation (DBS), depending on the stage and severity of symptoms and also multidisciplinary management up to intersectoral treatment approaches (e.g. complex PD treatment and integrative care concepts). Nevertheless, in the treatment of patients with PD a comprehensive provision of services and a nationwide standardized collation of treatment quality are so far lacking. This is particularly true for technically complicated procedures, which necessitate a high standard of expertise by the treating physician. Some of these challenges could be overcome by expanding digital approaches (e.g. teleneurological consultation and wearables) and by introducing quality assurance initiatives (e.g. comprehensive registries and certification programs).

The usual approach in hernia surgery is to select the ideal repair method independent of the patient’s characteristics. In the present study, we change the approach to ask which technique is best for the individual patient`s risk profile. For this, two criteria are important: does the patient need reconstruction of the abdominal wall? or does he or she need treatment of symptoms without being exposed to unnecessarily high perioperative risks? In a heuristic selection procedure, 486 consecutive patients were classified according to their characteristics as low-risk or high-risk for postoperative complications. Low-risk patients preferentially underwent open abdominal wall reconstruction with mesh (MFR + mesh), high-risk patients mainly a bridging-mesh procedure, either by laparoscopic (Lap.-IPOM) or open approach (Open-IPOM). Primary outcome was the incidence of postoperative complications. Secondary outcome was the recurrence-free interval. The propensity score was used for covariate adjustment analyzing recurrence rate as well as postoperative complications using Cox regression and logistic regression, respectively. Comparison of all surgical procedures showed risk factors had no independent influence on occurrence of complications (p = 0.110). Hernial gap width was an independent factor for occurrence of complications (p = 0.002). Propensity score adjustment revealed Lap.-IPOM to have a significantly higher recurrence rate than MFR + mesh (HR 2.367, 95% CI 1.123–4.957, p = 0.024). Three or more risk factors were protective against recurrence (HR 0.454, 95% CI 0.221–0.924, p = 0.030). In the univariate Cox regression analysis for recurrence, age >50 years was a protective prognostic factor (HR 0.412, 95% CI 0.245–0.702, p = 0.002). The classification criteria applied were internally validated. The heuristic algorithm ensured that patients at high-risk of complications did not have a higher perioperative complication rate than patients at low-risk.

BACKGROUND The number of invasive and non-invasive long-term out-of-hospital ventilations has been increasing rapidly for years. At the same time, there is poor information on the quality of care of out-of-hospital ventilated patients. The present investigation was conducted as part of the OVER-BEAS study. The aim of this study was to describe the care situation of weaning patients from admission to discharge from the weaning center using existing routine documentation. MATERIAL AND METHODS In our retrospective analysis, we included all patients admitted in 2018 via the weaning ward of the Thorax Center Munnerstadt. Descriptive analysis of routine data collected as part of quality management was performed. Data sources were the WeanNet database, the discharge letter of the weaning center, and the transfer report of the referring hospital. RESULTS In the studied weaning center, 50.8 % of the patients (n = 31) could be completely weaned from the respirator and extubated or decannulated (category 3aI). If complete weaning was not successful, 75.0 % (n = 21) required the constant presence of specially trained staff or a specialist nurse in the further course. In this case, further care was mostly provided in inpatient care facilities (e. g., ventilator shared living community). CONCLUSION Based on routine documentation, the care situation of weaning patients can be presented and compared with known data. In this way, the outcome quality of a weaning center can be made comparable.

Introduction Deep Brain Stimulation (DBS) is a complex, invasive and cost-intensive therapy that requires a high level of expertise. To date, data on quality of DBS in clinical routine in the German health care system are lacking. Methods The development of evidence-based QIs for DBS in PD patients was performed following a standardized process by a multidisciplinary board between 2014 and 2016. The process was initiated by the German Parkinson Society and followed international recommendations for developing QIs including: a systematic literature search; an appraisal of the published evidence; a consensus-based selection of the QI set; and a pilot study to assess the feasibility in implementing the QIs in clinical routine. Results A set of 28 QIs for determining the quality of DBS in PD was established by the board covering different dimensions of health care quality (structure, process, and outcome) in different treatment phases of DBS care (pre-operative, peri-operative, and post-operative). Implementation in clinical practice was tested in a pilot study comprising three hospitals delivering DBS care. The feasibility of the QI set was evaluated positively by the participating physicians and hospitals. Mean time to document one patient was 25 min. The German-wide implementation of the defined indicator set within a dedicated quality registry (QualiPa) started in June 2016. Conclusion QIs are a necessary requirement to monitor hospital performance in DBS care. The evidence-based approach to develop the proposed indicator set is expected to assure transparency, acceptance and long-term applicability of the QI set in Germany.

Background Anticoagulation with vitamin K antagonists and non-vitamin K antagonists oral anticoagulants (NOAC) is effective in stroke prevention in patients with atrial fibrillation. However, anticoagulation also poses a major challenge for emergency treatment of patients suffering ischaemic stroke or intracerebral haemorrhage. Aim The registry RASUNOA-prime is designed to describe current patterns of emergency management, clinical course and outcome of patients with atrial fibrillation experiencing an acute ischaemic stroke or intracerebral haemorrhage under different anticoagulation schemes prior to stroke (NOAC, vitamin K antagonists or no anticoagulation). Methods and design RASUNOA-prime (ClinicalTrials.gov, NCT02533960) is a prospective, investigator-initiated, multicentre, observational cohort study aiming to recruit 3000 patients with acute ischaemic stroke and atrial fibrillation, and 1000 patients with acute intracerebral haemorrhage and atrial fibrillation with different anticoagulation schemes pre-stroke. It is a non-interventional triple-armed study aiming at a balanced inclusion of ischaemic stroke and intracerebral haemorrhage patients according to the different anticoagulation schemes. Patients will be followed up for clinical course, management and outcome up to three months after the event. Findings in ischaemic stroke and intracerebral haemorrhage patients on NOAC will be compared with patients taking vitamin K antagonists or no anticoagulant pre-stroke. Study outcomes Primary endpoint for ischaemic stroke patients: occurrence of symptomatic intracerebral haemorrhage, for intracerebral haemorrhage patients: occurrence of secondary haematoma expansion. Secondary endpoints include assessment of coagulation, use of thrombolysis and/or mechanical thrombectomy, occurrence of complications, implementation of secondary prevention. Summary Describing the current patterns of early management as well as outcome of stroke patients with atrial fibrillation will help guide physicians to develop recommendations for emergency treatment of stroke patients under different anticoagulation schemes.

OBJECTIVES To identify differences in clinical characteristics and severity of cerebral small vessel disease (CSVD) including cerebral microbleeds (CMBs), between patients suffering ischemic stroke (IS) or intracerebral hemorrhage (ICH) while taking novel (non-vitamin K antagonists) oral anticoagulants (NOACs). METHODS Multicenter, prospective, observational cohort study performed at 38 centers between 2012 and 2015. We compared demographics, comorbidity, and functional status (before and after stroke) between NOAC-IS and NOAC-ICH patients. Extent of white matter lesions (WML), and location and counts of CMBs were analyzed in a subgroup of patients for whom MRI including hemorrhage-sensitive sequences was available. RESULTS A total of 351 patients were included (290 NOAC-IS, 61 NOAC-ICH). Functional status was worse in NOAC-ICH patients before and after stroke. No significant differences were found for demographic variables and cardiovascular comorbidity. In the subgroup with available MRI (n = 116), the proportion of patients with at least one CMB was higher in NOAC-ICH than in NOAC-IS (15/19 [79%] vs 36/97 [37%], P

BACKGROUND: Intracerebral hemorrhage (ICH) is a life-threatening complication of non-vitamin K antagonist oral anticoagulants (NOAC). Little is known about the effect of intensity of anticoagulation on NOAC-ICH. We describe the current use of coagulation testing in the emergency setting and explore associations with baseline size and expansion of hematoma as determined in a previous study. METHODS: Data from the prospective multicenter RASUNOA registry were analyzed. Patients with NOAC-ICH were enrolled between February 2012 and December 2014. Frequency of local test performance of specific (anti-factor Xa tests, diluted thrombin time) and non-specific tests (international normalized ratio (INR), activated partial thromboplastin time (aPTT), thrombin time) was analyzed. The association of anticoagulation intensity at admission with hematoma volume and hematoma expansion was explored. RESULTS: In 61 NOAC-ICH patients enrolled at 21 centers, drug-specific coagulation testing was performed in 16 cases (26%), and only 29% of centers appeared to use drug-specific tests in NOAC-ICH at all. In some cases, INR and aPTT values were normal despite drug concentrations in the peak range. In patients with available drug-specific concentrations, 50% had drug levels in the peak range at admission. Higher intensity of anticoagulation was not associated with higher hematoma volume at admission or with subsequent hematoma expansion. CONCLUSION: Drug-specific tests are only infrequently used in NOAC-ICH. Normal results in non-specific coagulation do not reliably rule out peak range concentrations. Anticoagulation intensity at admission does not predict baseline hematoma volume or subsequent hematoma expansion.

Outpatient intensive care for people with long-term mechanical ventilation is a rapidly growing area with a wide range of care demands. The aim of this Scoping Review is to present the current state of research on the quality of care for people with home mechanical ventilation in Germany and to identify research gaps.Based on predefined inclusion criteria, 4 databases were searched for publications dealing with the care of people with home ventilation in Germany. The method of "data driven thematic analysis" led the data extraction and analysis. Distinction was made between research and expert opinion.The search resulted in 493 matches of which 68 publications were included in the this study: two guidelines (3%), 45 (66%) research papers and 21 (31%) expert opinions. The following topics were identified: Organization and control of ventilation (n=43; 63%), nursing (n=23; 34%), medical (n=39; 57%), therapeutic (n=7; 10%) and assistive technologies care (n=24; 35%), as well as the perspective of people with home mechanical ventilation and their relatives (n=33; 49%) and other topics (n=13; 19%).Although the debate on the quality of care for people living with home mechanical ventilation is conducted broadly, studies focusing on individual care demands, autonomy and participation depending on the living situation or on the role of specific health professionals within the interprofessional team are missing.Die außerklinische Intensivversorgung von Menschen mit Langzeitbeatmung ist ein stark anwachsender Bereich mit vielseitigen Versorgungsbedarfen. Ziel dieses Scoping Reviews ist es, den aktuellen Forschungsstand zur Qualität der Versorgung beatmeter Menschen in der außerstationären Intensivpflege in Deutschland darzustellen und Forschungslücken aufzudecken.Anhand definierter Einschlusskriterien wurden 4 Datenbanken nach Publikationen zur Versorgung von außerklinisch beatmeten Menschen in Deutschland durchsucht. Datenextraktion und Synthese erfolgten nach der Methode der „data driven thematic analysis“. Eine Differenzierung zwischen Forschung und Expertenmeinung fand statt.Die Suche ergab 493 Treffer, von denen insgesamt 68 Publikationen eingeschlossen wurden, darunter 2 Leitlinien (3%), 45 (66%) Forschungsarbeiten und 21 (31%) Expertenmeinungen. Inhaltlich konnten folgende Themenfelder identifiziert werden: Organisation und Steuerung der Beatmung (n=43; 63%), pflegerische (n=23; 34%), medizinische (n=39; 57%), therapeutische (n=7; 10%) und Hilfsmittelversorgung (n=24; 35%), sowie die Sicht beatmeter Personen und deren Angehörigen (n=33; 49%) und weitere Themen (n=13; 19%).Obwohl der Qualitätsdiskurs zur Versorgung beatmeter Personen in der außerklinischen Intensivpflege breit geführt wird, fehlen Studien zur Bedarfsgerechtigkeit von Versorgungsleistungen, zu Selbstbestimmung und Teilhabe in Abhängigkeit der Wohnform oder zur Rolle einzelner ‚Health Professionals‘ im interprofessionellen Team.

Erhebungsinstrumente, die sich mit der Erfassung psychosozialer Risiken in der Arbeitswelt beschaftigen, entstehen haufig in einem theoretischen Kontext, der einen ubergeordneten Vergleich der Inhalte dieser erschwert. Dieser Beitrag beschreibt die Entwicklung einer vorlaufigen Taxonomie fur eine theorieubergreifende Ordnungsstruktur der Frageninhalte verschiedener standardisierter Erhebungsverfahren. Die Anwendbarkeit der Taxonomie wurde anhand einer Konkordanzuntersuchung mit zwei Urteilern gepruft, die 2883 Items aus 38 Erhebungsinstrumenten insgesamt 31 Kategorien mit einer Konkordanz von Kappa =.77 zuordneten. Trotz dieser hohen Ubereinstimmung ergaben sich Schwierigkeiten bei der Zuordnung einzelner Frageinhalte (Items): Haufig sind diese nicht auf eine einfache Beschreibung singularer Arbeitsexpositionen ausgerichtet, sondern zielen auf eine Passung von Umweltanforderungen und Personenvariablen und den damit einhergehenden Auswirkungen.

Background and Purpose— In patients who present with acute ischemic stroke while on treatment with non–vitamin K antagonist oral anticoagulants (NOACs), coagulation testing is necessary to confirm the eligibility for thrombolytic therapy. We evaluated the current use of coagulation testing in routine clinical practice in patients who were on NOAC treatment at the time of acute ischemic stroke. Methods— Prospective multicenter observational RASUNOA registry (Registry of Acute Stroke Under New Oral Anticoagulants; February 2012–2015). Results of locally performed nonspecific (international normalized ratio, activated partial thromboplastin time, and thrombin time) and specific (antifactor Xa tests, hemoclot assay) coagulation tests were documented. The implications of test results for thrombolysis decision-making were explored. Results— In the 290 patients enrolled, nonspecific coagulation tests were performed in ≥95% and specific coagulation tests in 26.9% of patients. Normal values of activated partial thromboplastin time and international normalized ratio did not reliably rule out peak drug levels at the time of the diagnostic tests (false-negative rates 11%–44% [95% confidence interval 1%–69%]). Twelve percent of patients apparently failed to take the prescribed NOAC prior to the acute event. Only 5.7% (9/159) of patients in the 4.5-hour time window received thrombolysis, and NOAC treatment was documented as main reason for not administering thrombolysis in 52.7% (79/150) of patients. Conclusions— NOAC treatment currently poses a significant barrier to thrombolysis in ischemic stroke. Because nonspecific coagulation test results within normal range have a high false-negative rate for detection of relevant drug concentrations, rapid drug-specific tests for thrombolysis decision-making should be established. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01850797.

J Stroke > Volume 19(1); 2017 > Article Original Article Journal of Stroke 2017;19(1):67-76. Published online: January 31, 2017 DOI: https://doi.org/10.5853/jos.2016.00542 Haemorrhagic Transformation after Ischaemic Stroke in Patients Taking Non-vitamin K Antagonist Oral Anticoagulants Jan C. Purruckera, Kirsten Haasb, Marcel Wolfc, Timolaos Rizosa, Shujah Khana, Peter Kraftd, Sven Polie, Rainer Dziewasf, Johannes Meyneg, Frederick Palmh, Sebastian Janderi, Markus Möhlenbruchc, Peter U. Heuschmannb,j, Roland Veltkampa,k, on behalf of the, RASUNOA investigators aDepartment of Neurology, Heidelberg University Hospital, Heidelberg, Germany bInstitute of Clinical Epidemiology and Biometry, University Würzburg, Germany cDepartment of Neuroradiology, Heidelberg University Hospital, Heidelberg, Germany dDepartment of Neurology, University Hospital Würzburg, Würzburg, Germany eDepartment of Neurology, Tübingen University, Tübingen, Germany fDepartment of Neurology, University Hospital Münster, Germany gDepartment of Neurology, University Hospital Schleswig-Holstein, Kiel, Germany hDepartment of Neurology, Klinikum Ludwigshafen, Ludwigshafen, Germany iDepartment of Neurology, Heinrich-Heine-University, Medical Faculty, Düsseldorf, Germany jComprehensive Heart Failure Center, and Clinical Trial Center, University Hospital Würzburg, Würzburg, Germany kDepartment of Stroke Medicine, Imperial College London, London, United Germany Correspondence: Roland Veltkamp Department of Stroke Medicine, Imperial College London, Charing Cross Campus, 3 East 6, Fulham Palace Road, London, W6 8RF, United Kingdom Phone: +44-20-33130133, Fax: +44-20-83833309, E-mail: r.veltkamp@imperial.ac.uk Received June 16, 2016 Revised October 11, 2016 Accepted November 28, 2016 Copyright © 2017 Korean Stroke Society This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Background and Purpose To evaluate the frequency and outcome of haemorrhagic transformation (HT) after ischaemic stroke in patients treated with non-vitamin K antagonist oral anticoagulants (NOACs). Methods Patients with stroke on treatment with a NOAC were prospectively enrolled in this multicentre observational study between February 2012 and 2015. Brain imaging at admission and follow-up imaging until day 7 were reviewed for HT. Functional outcome was assessed by the modified Rankin scale (mRS) before the index event, at discharge, and at 3-months. Results 231 patients without recanalisation therapy (no-RT), and 32 patients with RT were eligible for analysis. Any HT was present at admission in 9/231 no-RT patients (3.9%, 95% CI 2.0 to 7.3) and in none of the patients with RT. In patients with follow-up imaging (no-RT, n=129, and RT, n=32), HT was present in 14.0% (no-RT; 95% CI, 8.9 to 21.1), and 40.6% (RT, 95% CI, 25.5 to 57.8), respectively. After adjustment for stroke severity, this difference between the no-RT and RT groups became non-significant. Symptomatic ICH was observed in 1 patient per group. HT was not associated with unfavourable outcome (mRS 3-6) at 3-months in multivariable analysis. Resumption of OAC after stroke was delayed in patients with HT compared to those without (15 d [IQR, 5–26] vs. 1 d [0–4], P

Background and Purpose— Prospective data on the safety of endovascular thrombectomy in acute stroke patients on non–vitamin K antagonist oral anticoagulants are lacking. Methods— Prospective multicenter observational study. Patients with ischemic stroke undergoing thrombectomy with or without preceding thrombolysis were enrolled into the Registry of Acute Ischemic Stroke Under New Oral Anticoagulants. Baseline characteristics and functional outcome at 3 months were assessed. Hemorrhagic transformation and symptomatic intracranial hemorrhage were analyzed. Reperfusion was graded using the modified Thrombolysis in Cerebral Infarction score. Results— Of 28 patients treated with thrombectomy, 5 had received also systemic thrombolysis (18%). Intracranial hemorrhage was observed in 46%, but symptomatic intracranial hemorrhage occurred only in 1 patient. Successful reperfusion (Thrombolysis in Cerebral Infarction score, 2b–3) was achieved in 59%. At 3 months, 19% had a modified Rankin Scale score of 0 to 2, and mortality was 26%. Conclusions— Thrombectomy in non–vitamin K antagonist oral anticoagulant patients seems safe although a comparatively high rate of asymptomatic hemorrhagic transformation was noted. Confirmation in larger prospective controlled cohorts is necessary. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01850797.

Importance Intracerebral hemorrhage (ICH) is the most devastating adverse event in patients receiving oral anticoagulation. There is only sparse evidence regarding ICH related to the use of non–vitamin K antagonist oral anticoagulant (NOAC) agents. Objective To evaluate the early clinical and radiological course, acute management, and outcome of ICH related to NOAC use. Design, Setting, and Participants Prospective investigator-initiated, multicenter observational study. All diagnostic and treatment decisions, including administration of hemostatic factors (eg, prothrombin complex concentrate), were left to the discretion of the treating physicians. The setting was 38 stroke units across Germany (February 1, 2012, to December 31, 2014). The study included 61 consecutive patients with nontraumatic NOAC-associated ICH, of whom 45 (74%) qualified for the hematoma expansion analysis. Main Outcomes and Measures Hematoma expansion, intraventricular hemorrhage, and reversal of anticoagulation during the acute phase. Recorded were the 3-month functional outcome, factors associated with an unfavorable outcome (modified Rankin Scale score, 3-6), any new intraventricular extension or an increase in the modified Graeb score by at least 2 points, and the frequency of substantial hematoma expansion (defined as relative [≥33%] or absolute [≥6-mL] volume increase). Results In total, 41% (25 of 61) of patients with NOAC-associated ICH were female, and the mean (SD) patient age was 76.1 (11.6) years. At admission, the median National Institutes of Health Stroke Scale score was 10 (interquartile range, 4-18). The mean (SD) baseline hematoma volume was 23.7 (31.3) mL. In patients with sequential imaging for the hematoma expansion analysis, substantial hematoma expansion occurred in 38% (17 of 45). New or increased intraventricular hemorrhage was observed in 18% (8 of 45). Overall mortality was 28% (17 of 60 [follow-up data were missing in 1 patient]) at 3 months, and 65% (28 of 43) of survivors had an unfavorable outcome (modified Rankin Scale score, 3-6). Overall, 57% (35 of 61) of the patients received prothrombin complex concentrate, with no statistically significant effect on the frequency of substantial hematoma expansion (43% [12 of 28] for prothrombin complex concentrate vs 29% [5 of 17] for no prothrombin complex concentrate, P = .53), or on the occurrence of an unfavorable outcome (modified Rankin Scale score, 3-6) (odds ratio, 1.20; 95% CI, 0.37-3.87; P = .76). Conclusions and Relevance Non–vitamin K antagonist oral anticoagulant–associated ICH has a high mortality and an unfavorable outcome, and hematoma expansion is frequent. Larger-scale prospective studies are needed to determine whether the early administration of specific antidotes can improve the poor prognosis of NOAC-associated ICH.

To study the oncogenic activity of cyclin E in an in vivo system we generated transgenic mice expressing high levels of cyclin E in T-lymphocytes by using a construct containing the CD2 locus control region. These animals were neither predisposed to develop any tumors spontaneously nor showed an increased incidence when crossbred with Emu L-myc transgenic mice but developed hyperplasia in peripheral lymphoid organs at later age with an incidence of 27%. When treated with the DNA methylating carcinogen N-methylnitrosourea (MNU) that provokes the development of T-cell lymphomas, CD2-cyclin E transgenic animals came down with T-cell neoplasia showing a significant higher incidence (54%) than normal non transgenic controls (31%). In one of eight tumors that arose in normal MNU treated mice we could find an expected activating point mutation in the Ki-ras gene (12.5%). In contrast, the same mutation occurred in five of 16 tumors from CD2-cyclin E transgenic mice (31.2%). Whereas cyclin E overexpression alone did not lead to an increased CDK2 activity we observed in all tumors that emerged from either MNU treated normal mice or treated CD2-cyclin E transgenics a downregulation of p27KIP1 and a higher histone H1 kinase activity in CDK2 immunoprecipitates compared to normal tissue. These findings demonstrate that high level expression of cyclin E can predispose T-cells for hyperplasia and malignant transformation. However, the results also suggest that this activity of cyclin E is manifest only when other cooperating oncogenes in particular ras genes are present and activated. This would be consistent with our previous finding that cyclin E and Ha-Ras cooperate in focus formation assays in rat embryo fibroblasts.

We demonstrate in this paper that the G1 phase specific cell cycle regulator cyclin E is able to provoke focus formation when cotransfected with activated Ha-ras into primary rat embryo fibroblasts (REFs). Cyclin E/Ha-ras transformed cells are highly tumorigenic in synergeneic rats, are able to form colonies in soft agar and show protection towards apoptosis upon serum starvation or DNA damage compared to cells transformed by the combination of Myc, cyclin D1 or SV40 large T-antigen and Ha-ras. Lines that were established after cyclin E/Ha-ras or cyclin D1/Ha-ras transformation contain a large percentage of polyploid cells. This was not observed in cells transformed with other oncoproteins and Ha-ras pointing to an involvement of D- and E type cyclins in genomic instability. The cyclin dependent kinase inhibitors p21 and p27 but also p16 completely abrogate focus formation by cyclin E and Ha-ras suggesting that the oncogenic activity of cyclin E still requires functional G1 specific cyclin/CDK complexes. Moreover, inhibition of Myc function also blocks the oncogenic activity of cyclin E indicating a requirement of Myc for cyclin E function. The findings presented here demonstrate that cyclin E can act as an oncoprotein with a potential involvement in genomic instability and the prevention of cell death. Our data also present more evidence for a strict functional interdependency between G1 cyclin/CDK complexes and c-Myc.

Cyclin E is the regulatory subunit of the cdc2-related protein kinase cdk2 and is a rate limiting factor for the entry into S phase. To date, cyclin E is the only cyclin for which alternative splicing has been described. We report here the isolation of a new splice variant of cyclin E, termed cyclin ET, which has an internal deletion of 45 amino acids compared with the full-length cyclin E protein. Even though cyclin ETcontains an intact cyclin box, it is unable to complement a triple cln mutant strain of Saccharomyces cerevisiae or to interfere with rescue by cyclin E, indicating that an intact cyclin box is functionally insufficient. The expression pattern of cyclin ET during cell cycle entry, progression and differentiation differs from that of cyclin E. Thus, ET expression precedes that of the other isoforms during the G0-->S progression; it shows a sharp peak in early G1 in cells released from a mitotic block and is strongly down-regulated in terminally differentiated myeloid cells. These observations point to different functions for cyclin ET and E and show for the first time that the alternative splicing of cyclin E is a regulated mechanism governed by the cell cycle and differentiation.

Lipoprotein lipase (LPL) supplies brown adipose tissue with fatty acids for nonshivering thermogenesis. In brown adipose tissue of the Djungarian hamster we studied i) the molecular mechanisms involved in cold-induced stimulation of LPL activity, ii) the adrenergic control of LPL expression, and iii) compared LPL expression in brown and white adipose tissue. i) After 8 h cold exposure we detected a 2-fold increase in LPL activity and protein level in brown adipose tissue, whereas LPL mRNA level remained unchanged. A cold-induced increase (1.5-fold) in LPL activity was observed in brown adipose tissue of hamsters treated with actinomycin D prior to 4 h cold exposure, whereas cycloheximide treatment completely abolished LPL stimulation. Thus, these data suggest that during the initial phase (< 24 h) of cold exposure the stimulation of LPL activity in brown adipose tissue is most likely due to increased translation. In contrast, during prolonged cold exposure, we detected a maximal 7-fold increase in LPL activity and a 2- to 3-fold increase in LPL mRNA level in brown adipose tissue indicating LPL regulation at the pretranslational level. Furthermore, comparison of LPL protein and activity in brown adipose tissue during prolonged (> 24 h) cold exposure provides some evidence that the active fraction of the enzyme pool in brown adipose tissue is increased in response to cold. ii) Surgical denervation and noradrenaline treatment revealed a complex role of the sympathetic innervation in the control of LPL expression in brown adipose tissue. Denervation decreased LPL mRNA level, but increased LPL activity. Noradrenaline treatment stimulated LPL activity to a similar extent as cold exposure. However, cold-induced stimulation of LPL activity was not impaired by denervation. iii) Cold exposure significantly elevated LPL mRNA content of inguinal white adipose tissue, although LPL activity was not affected. Posttranscriptional mechanisms appear to be involved in the tissue specific control of LPL expression.

The goal was to analyze the link between blood levels of calcidiol and all-cause, cardiac and infectious diseases, and mortality due to cancer in hemodialysis patients.This study retrospectively evaluated a representative sub-cohort (n=6,518) of German hemodialysis patients from the incidence cohorts 1997-2006.Most (58.8%) were found to be vitamin D deficient (25(OH)D20 ng/ml), with 41.2% being severely deficient (25(OH)D12.5 ng/ml). All-cause mortality risk more than doubled in patients with severe deficiency (adjusted odds ratio (aOR)=2.67; 95% confidence interval (CI)=2.30-3.10; p0.0001). Comparable data were obtained for mortality from cardiac disease (aOR=1.57; 95% CI=1.30-1.88; p0.0001), infectious disease (aOR=1.48; 95% CI=1.15-1.90; p=0.0026), and cancer (aOR=1.51; 95% CI=1.09-2.08; p=0.0121), respectively.These data highlight the need to ensure primarily adequate 25(OH)D levels in dialysis patients for an advantage of survival.

Neue direkte orale Antikoagulanzien (NOAK) sind eine effektive therapeutische Option, um Schlaganfallen bei Patienten mit Vorhofflimmern (VHF) vorzubeugen, bei gleichzeitig guter Vertraglichkeit. Die Behandlung von Schlaganfallen unter Antikoagulanzien insgesamt, aber insbesondere unter den erst seit 2011 zugelassenen NOAK, stellt eine Herausforderung fur die Notfalltherapie dar. Beim ischamischen Schlaganfall ist die Moglichkeit der Thrombolyse unter NOAK ungeklart.

The non-steroidal anti-inflammatory drug sulindac is used in cancer prevention and therapy, but the molecular aspects of its anti-tumor effect remain unresolved. In vivo the prodrug sulindac, is converted into the metabolite sulindac sulfide. We found that sulindac sulfide strongly inhibits Ras induced malignant transformation and Ras/Raf dependent transactivation. Sulindac sulfide decreases the Ras induced activation of its main effector, the c-Raf-1 kinase. In vitro sulindac sulfide directly binds to the Ras gene product p21ras in a non-covalent manner. Moreover, we can show that sulindac sulfide inhibits the interaction of p21ras with the p21ras binding domain of the Raf protein. In addition, sulindac sulfide can impair the nucleotide exchange on p21ras by CDC25 as well as the acceleration of the p21ras GTPase reaction by p120GAP. Due to its action at the most critical site in Ras signaling we propose sulindac sulfide as a lead compound in the search for novel anti-cancer drugs which directly inhibit Ras mediated cell proliferation and malignant transformation.

We demonstrate in this paper that CDK4 which is a G1 phase specific cell cycle regulator and catalytic subunit of D-type cyclins has oncogenic activity similar to D-type cyclins themselves and is able to provoke focus formation when cotransfected with activated Ha-ras into primary rat embryo fibroblasts. Surprisingly, using two different mutants we show that CDK4's ability to bind to p16INK4a and not its kinase activity is important for its transforming potential. In addition, p16INK4a but not a mutant form that is found in human tumours can completely abrogate focus formation by CDK4 suggesting that CDK4 can malignantly transform cells by sequestering p16INK4a or other CKIs. We demonstrate that both cyclin D1 and CDK4 functionally depend on active Myc to exert their potential as oncogenes and vice versa that the transforming ability of Myc requires functional cyclin D/CDK complexes. Moreover, we find that p16INK4a and the Rb related protein p107 which releases Myc after phosphorylation by cyclin D1/CDK4 efficiently block Myc's activity as a transcriptional transactivator and as an oncogene. We conclude that both p16INK4a and cyclin D/CDK4 complexes are upstream regulators of Myc and directly govern Myc function in transcriptional transactivation and transformation via the pocket protein p107.