Activities of clotting factor VIII and IX in healthy controls and patients with venous thromboembolism

Erhöhte Faktorenaktivitäten der Gerinnungsfaktoren VIII und IX standen seit längerer Zeit in dem Verdacht, unabhängige thrombophile Risikofaktoren darzustellen. Die Studienlage hierzu ist bzgl. der Wahl der untersuchten Kollektive, der Messmethoden, sowie der berücksichtigten Einflussgrößen uneinheitlich. Daher wurde die vorliegende Studie durchgeführt, um zum einen in einem Normalkollektiv die die Faktorenaktivität möglicherweise beeinflussenden Störgrössen wie Body Mass Index (BMI) oder ein steigendes Lebensalter zu definieren, und um andererseits die Häufigkeit erhöhter Faktor VIII und IX Aktivitäten bei Patienten mit venösen Thrombosen unter Berücksichtigung dieser Störgrössen im Vergleich zum Normalkollektiv exakt zu analysieren. Es wurden 500 Blutspender konsekutiv als Normalkollektiv eingeschlossen. Diesem wurde ein Patientenkollektiv von 374 konsekutiven Patienten mit venösen Thrombosen gegenübergestellt. Beide Kollektive wurden an Hand eines einheitlichen, standardisierten Fragebogens bezüglich ihrer Eigen- und Familienanamnese befragt. Darüber hinaus erfolgte eine Blutentnahme unter standardisierten Bedingungen. Als Messmethode für die Faktorenaktivität von Faktor VIII und IX wurde ein Einstufengerinnungstest verwendet, hierbei wird die Aktivität eines einzelnen Gerinnungsfaktors gemessen. Alle zu untersuchenden Plasmen wurden auf Lupusantikoagulantien getestet, um Probanden und Patienten mit positiven Lupusantikoagulantien von den weiteren Berechnungen ausschließen zu können, da Lupusantikoagulantien die Faktorenmessergebnisse verfälschen können. Dies wurde in den bisherigen Veröffentlichungen nicht berücksichtigt. Mit Hilfe des Normalkollektives wurde die 90% Perzentile als Cut Off für erhöhte Faktorenwerte definiert (FVIII = 158%; FIX = 151%). Bei Analyse des Faktors VIII konnten mit Hilfe einer linearen Regressionsanalyse folgende Störgrössen als relevant für die Faktorenaktivität innerhalb des Normalkollektives beschrieben werden: Raucher wiesen signifikant niedrigere Faktor VIII – Aktivitäten als Nichtraucher auf, während ein steigender BMI und ein steigendes Lebensalter zu signifikant höheren Faktor VIII -Aktivitäten führten. Ein Einfluss des Geschlechtes, sowie ein signifikanter Einfluss oraler Kontrazeptiva auf die Faktor VIII - Aktivitäten konnte nicht nachgewiesen werden. Die Aktivitäten des Faktor IX zeigten im Normalkollektiv ebenfalls eine Abhängigkeit von steigendem Lebensalter, höheren BMI Werten sowie im Gegensatz zur Faktor VIII – Aktivität auch von der Einnahme oraler Kontrazeptiva, wobei alle diese Zustände zu signifikant höheren Faktor IX Aktivitäten führten. Ein Vergleich der Höhe der Faktor VIII – Aktivitäten der Patienten mit venösen Thrombosen zum Normalkollektiv konnte leider nicht durchgeführt werden, da festgestellt wurde, dass eine unterschiedlich lange Lagerzeit der tiefgefrorenen Plasmaproben der Patienten zu einem Absinken von erhöhten Faktor VIII – Aktivitäten führen kann. Dies wurde in der Literatur bisher nicht beschrieben und war daher zu Beginn der Studie nicht bekannt. Im Gegensatz hierzu blieben die erhöht gemessenen Faktor IX – Aktivitäten auch nach einer längeren Lagerzeit stabil, so dass hier eine Risikoberechnung für erhöhte Faktor IX – Aktivitäten in Bezug auf das Auftreten venöser Thrombosen mit einer korrigierten Odds – Ratio erfolgen konnte. Die für BMI, Alter und Geschlecht korrigierte Odds Ratio betrugt 3,98 mit einem 95% Konfidenzintervall von 2,5 – 6,3. Es ist somit von einem ca. 4 fach erhöhten relativen Risiko für venöse Thrombosen bei erhöhten Faktor IX – Aktivitäten auszugehen, so dass diese einen neuen thrombophilen Risikofaktor für venöse Thrombosen darstellen.Elevated activities of clotting factor VIII and IX are suspected to be relevant and independent risk factors for venous thromboembolism. The literature on this topic is differing in terms of study population, the measurement methods and the considered confounders on clotting factor activity. This study was planned and carried out to define the influence of suspected confounders like Body Mass index (BMI) and increasing age on clotting factor activities. The second aim was to perform an exact analysis of the incidence of elevated clotting factor VIII and IX activities in patients and controls by considering the previously observed confounders. The study population consisted of 500 consecutive blood donors as controls and 374 consecutive patients that had suffered from venous thromboembolism. The medical history of both groups was taken by the same standardized questionnaire. The collection of blood samples was also standardized and identical in both groups. The activities of clotting factor VIII and IX were determined by an one stage clotting assay. All plasma samples were tested for lupus anticoagulants to detect patients and controls with positive testing and exclude them from further analysis because lupus anticoagulants can falsify the clotting factor measurements. The cut off values for elevated clotting factor activities were defined as the 90th percentile of control subjects (F VIII = 158%; F IX 151%). We could describe the following confounders of clotting factor VIII activities as relevant by linear regression analysis among control subjects: smoking caused significant lower factor VIII activities, while higher BMI values and an increasing age lead to significant higher factor VIII activities. We could not find a significant influence by gender or the use of oral contraceptives on the activities of clotting factor VIII. The activities of clotting factor IX among control subjects were also influenced by rising age and BMI values and in contrast to factor VIII also by the use of oral contraceptives in women. All the described confounders lead to higher activities of factor IX. We could not perform the planned analysis between controls and patients concerning activities of clotting factor – VIII because a lowering in the activities of clotting factor VIII could be found the longer the samples were stored frozen. This is not described in the existing literature, and thus was not known when starting the study. In contrast to the factor VIII activities the activities of clotting factor IX remained constant over time and the planned analysis could be performed. We performed a risk stratification concerning elevated factor IX – activities and the incidence of venous thromboembolism by calculating corrected odds ratios. We included BMI, age and sex in our correction. The corrected odds ratio is 3,98 and its 95% confidence interval ranges from 2.5 to 6.3. This predicts an approximately 4 times higher risk for venous thromboembolism with elevated activitites of clotting factor IX. Factor IX therefore is a new and independent risk factor for venous thromboembolism

Manned and Unmanned Space Vehicles: Air Traffic Insertion & SESAR Requirements

Space Traffic Management, SESA

CDO1 Promoter Methylation is a Biomarker for Outcome Prediction of Anthracycline Treated, Estrogen Receptor-Positive, Lymph Node-Positive Breast Cancer Patients

<p>Abstract</p> <p>Background</p> <p>Various biomarkers for prediction of distant metastasis in lymph-node negative breast cancer have been described; however, predictive biomarkers for patients with lymph-node positive (LNP) disease in the context of distinct systemic therapies are still very much needed. DNA methylation is aberrant in breast cancer and is likely to play a major role in disease progression. In this study, the DNA methylation status of 202 candidate loci was screened to identify those loci that may predict outcome in LNP/estrogen receptor-positive (ER+) breast cancer patients with adjuvant anthracycline-based chemotherapy.</p> <p>Methods</p> <p>Quantitative bisulfite sequencing was used to analyze DNA methylation biomarker candidates in a retrospective cohort of 162 LNP/ER+ breast cancer patients, who received adjuvant anthracycline-based chemotherapy. First, twelve breast cancer specimens were analyzed for all 202 candidate loci to exclude genes that showed no differential methylation. To identify genes that predict distant metastasis, the remaining loci were analyzed in 84 selected cases, including the 12 initial ones. Significant loci were analyzed in the remaining 78 independent cases. Metastasis-free survival analysis was conducted by using Cox regression, time-dependent ROC analysis, and the Kaplan-Meier method. Pairwise multivariate regression analysis was performed by linear Cox Proportional Hazard models, testing the association between methylation scores and clinical parameters with respect to metastasis-free survival.</p> <p>Results</p> <p>Of the 202 loci analysed, 37 showed some indication of differential DNA methylation among the initial 12 patient samples tested. Of those, 6 loci were associated with outcome in the initial cohort (n = 84, log rank test, p < 0.05).</p> <p>Promoter DNA methylation of cysteine dioxygenase 1 (CDO1) was confirmed in univariate and in pairwise multivariate analysis adjusting for age at surgery, pathological T stage, progesterone receptor status, grade, and endocrine therapy as a strong and independent biomarker for outcome prediction in the independent validation set (log rank test p-value = 0.0010).</p> <p>Conclusions</p> <p>CDO1 methylation was shown to be a strong predictor for distant metastasis in retrospective cohorts of LNP/ER+ breast cancer patients, who had received adjuvant anthracycline-based chemotherapy.</p

Wie sehen Kinder digitale Medien? Vorschlag und Diskussion einer spielbasierten Methode für Forschung und Praxis

In diesem Beitrag wird eine Methode zur Eruierung der Perspektiven von Kindern auf digitale Medien in der Kindertageseinrichtung sowie auf ihre Mediennutzung in der Familie vorgestellt. Hierzu wurde auf ein dialoggestütztes Gruppeninterview zurückgegriffen, das durch einen Kitarundgang und spielerische Elemente in Form eines Memo-Spiels ergänzt wurde. Der Fokus des Beitrags liegt auf der Beschreibung der Methode. Diese soll für den Einsatz in der Praxis zur Verfügung gestellt werden mit dem Ziel, dass Fachkräfte mit den Kindern zum Thema Medien ins Gespräch kommen und auf dieser Basis deren Perspektiven in ihre pädagogische Planung einbeziehen, indem sie ihr eigenes medienpädagogisches Handeln reflektieren und ggf. anpassen. Erste Erprobungen bestätigten die Praxistauglichkeit, es wurde aber auch deutlich, dass je nach Situation flexible Anpassungen sinnvoll sein können und darauf zu achten ist, dass die Auswertung im Rahmen der zeitlichen Ressourcen der Fachkräfte leistbar ist

Impact of lockdown during Covid‐19 pandemic on physical activity and arrhythmia burden in heart failure patients

Background Restricted outdoor activity during COVID-19 related lockdown may accelerate heart failure (HF) progression and thereby increase cardiac arrhythmias. We analyzed the impact of March/April 2020 lockdown on physical activity and arrhythmia burden in HF patients treated with cardiac resynchronization therapy (CRT) devices with daily, automatic remote monitoring (RM) function. Methods The study cohort included 405 HF patients enrolled in Observation of Clinical Routine Care for Heart Failure Patients Implanted with BIOTRONIK CRT Devices (BIO|STREAM.HF) registry in 16 countries, who had left ventricular ejection fraction (LVEF) = 8 min/day in 46.5% of patients; predictors were higher LVEF, lower NYHA class, no defibrillator indication, and more activity before lockdown. AHRE burden increased by >= 17 min/day in 4.7% of patients; predictors were history of atrial fibrillation, higher LVEF, higher body mass index, and activity decrease during lockdown. Conclusion Unfavorable changes in physical activity, AHRE burden, and follow-up rate were observed during lockdown, but not in ventricular arrhythmia

Risk for life-threatening arrhythmia in newly diagnosed peripartum cardiomyopathy with low ejection fraction: a German multi-centre analysis

Introduction Peripartum cardiomyopathy (PPCM) is a rare cardiomyopathy characterized by an acute reduction in left ventricular ejection fraction (LVEF). Sudden deaths during the course of PPCM are reported to be elevated, the underlying mechanisms remains unknown. The aim of the present multi-centre study was to evaluate the arrhythmia burden in a multi-centre approach in patients with PPCM using a wearable cardioverter/defibrillator (WCD). Methods and results Forty-nine patients from 16 German centres with newly diagnosed PPCM and LVEF <= 35% receiving a WCD were included in this retrospective analysis. Mean follow-up was 15 +/- 10 months. At diagnosis, mean age was 33 +/- 5 years, parity was 2.1 +/- 1.6, LVEF was 21 +/- 7%, NYHA functional class was 3.4 +/- 0.7. Mean wear time was 120 +/- 106 days, mean wear time per day was 21.4 +/- 3.3 h. Six (12%) patients presented eight ventricular tachyarrhythmias during WCD period: five episodes of VF, two sustained ventricular tachycardia (VT) and one non-sustained VT occurred. Conclusion This multicentre study underpins the elevated risk for ventricular tachyarrhythmias in patients with newly diagnosed PPCM and reduced LVEF. A WCD should be considered for 3-6 months in these patients to prevent sudden cardiac death from ventricular tachyarrhythmias

Molecular Characterization of Cancer Associated Fibroblasts in Prostate Cancer

Background: Stromal components surrounding epithelial cancer cells seem to play a pivotal role during epithelial-to-mesenchymal transition (EMT), tumor invasion, and metastases. To identify the molecular mechanisms underlying tumor–stroma interactions may yield novel therapeutic targets for prostate cancer. Methods: Gene expression profile of prostate-cancer associated fibroblast (PCAF) and prostate non-cancer associated fibroblast (PNAF) cells isolated from radical prostatectomy was performed by Illumina, analyzed, and further processed by Ingenuity®: IPA® software. qRT-PCR was performed on an independent set of 17 PCAF, 12 PNAF, and 12 fibroblast cell lines derived from patients with benign prostatic hyperplasia (BPHF). Results: Using microarray analysis, we found six upregulated genes and two downregulated genes in PCAFs compared to PNAFs. To validate microarray results, we performed qRT-PCR for the most significantly regulated genes involved in the modulation of proliferation and androgen resistance on an independent set of PNAF, PCAF, and BHPF samples. We confirmed the increased expression of SCARB1, MAPK3K1, and TGF-β as well as the decreased expression of S100A10 in PCAFs compared to PNAFs and BPHFs. Conclusions: These results provide strong evidence that the observed changes in the gene expression profile of PCAFs can contribute to functional alteration of adjacent prostate cancer cells

Megapixels @ Megahertz -- The AGIPD High-Speed Cameras for the European XFEL

The European XFEL is an extremely brilliant Free Electron Laser Source with a very demanding pulse structure: trains of 2700 X-Ray pulses are repeated at 10 Hz. The pulses inside the train are spaced by 220 ns and each one contains up to $10^{12}$ photons of 12.4 keV, while being $\le 100$ fs in length. AGIPD, the Adaptive Gain Integrating Pixel Detector, is a hybrid pixel detector developed by DESY, PSI, and the Universities of Bonn and Hamburg to cope with these properties. It is a fast, low noise integrating detector, with single photon sensitivity (for $\text{E}_{\gamma} \ge 6$ keV) and a large dynamic range, up to $10^4$ photons at 12.4 keV. This is achieved with a charge sensitive amplifier with 3 adaptively selected gains per pixel. 352 images can be recorded at up to 6.5 MHz and stored in the in-pixel analogue memory and read out between pulse trains. The core component of this detector is the AGIPD ASIC, which consists of $64 \times 64$ pixels of $200 {\mu}\text{m} \times 200 {\mu}\text{m}$. Control of the ASIC's image acquisition and analogue readout is via a command based interface. FPGA based electronic boards, controlling ASIC operation, image digitisation and 10 GE data transmission interface AGIPD detectors to DAQ and control systems. An AGIPD 1 Mpixel detector has been installed at the SPB experimental station in August 2017, while a second one is currently commissioned for the MID endstation. A larger (4 Mpixel) AGIPD detector and one to employ Hi-Z sensor material to efficiently register photons up to $\text{E}_{\gamma} \approx 25$ keV are currently under construction.Comment: submitted to the proceedings of the ULITIMA 2018 conference, to be published in NIM

Protecting Important Sites for Biodiversity Contributes to Meeting Global Conservation Targets

Protected areas (PAs) are a cornerstone of conservation efforts and now cover nearly 13% of the world's land surface, with the world's governments committed to expand this to 17%. However, as biodiversity continues to decline, the effectiveness of PAs in reducing the extinction risk of species remains largely untested. We analyzed PA coverage and trends in species' extinction risk at globally significant sites for conserving birds (10,993 Important Bird Areas, IBAs) and highly threatened vertebrates and conifers (588 Alliance for Zero Extinction sites, AZEs) (referred to collectively hereafter as ‘important sites’). Species occurring in important sites with greater PA coverage experienced smaller increases in extinction risk over recent decades: the increase was half as large for bird species with>50% of the IBAs at which they occur completely covered by PAs, and a third lower for birds, mammals and amphibians restricted to protected AZEs (compared with unprotected or partially protected sites). Globally, half of the important sites for biodiversity conservation remain unprotected (49% of IBAs, 51% of AZEs). While PA coverage of important sites has increased over time, the proportion of PA area covering important sites, as opposed to less important land, has declined (by 0.45–1.14% annually since 1950 for IBAs and 0.79–1.49% annually for AZEs). Thus, while appropriately located PAs may slow the rate at which species are driven towards extinction, recent PA network expansion has under-represented important sites. We conclude that better targeted expansion of PA networks would help to improve biodiversity trends