Resource limitations in bimanual pointing

We thank Moritz Durst for his help with data collection and valuable comments on a previous version of this manuscript.Peer reviewe

Nicht-invasive Beurteilung der Leberfibrose bei Patienten nach Fontan-Operation mithilfe transienter Elastographie und biochemischen Fibrosemarkern : Beziehung zur myokardialen Funktion.

Hintergrund: Frühere Studien haben gezeigt, dass Patienten mit ungenügender Fontan-Zirkulation eine Leberfibrose und deren Spätfolgen entwickeln können. Daher ist die Früherkennung dieser Komplikationen bei Fontan-Patienten von prognostischer Bedeutung. Die transiente Elastographie ist eine nicht-invasive Methode zur Abschätzung der Lebersteifigkeit, die bei erwachsenen Patienten zwischenzeitlich Einzug in die klinische Routine genommen hat und auch bei Kindern in zahlreichen klinischen Studien evaluiert wurde. Studienaufbau: 39 Patienten mit Fontan-Zirkulation nahmen an dieser Studie teil. Alle Patienten bekamen einen konventionellen Abdomenultraschall einschließlich transienter Elastographie und detaillierte Blutwertuntersuchungen. Es wurde zeitgleich eine konventionelle Echokardiographie sowie eine 2D-Strain-Echokardiographie durchgeführt. Die in den folgenden zwei Jahren durchgeführten Herzkatheteruntersuchungsergebnisse flossen in die Auswertung mit ein. Ergebnisse: Bei 36 von 39 untersuchten Kindern zeigte die Elastographie signifikante Leberfibrosezeichen. Die Beurteilung der Leber anhand der Serummarkerauswertung zeigte bei 28 von 39 Patienten eine Fibrose. Die Lebersteifigkeit gemessen mit transienter Elastographie korrelierte hoch signifikant mit dem Zeitintervall seit Fontan-Operation (R = 0,514; p = 0,001). Von den gemessenen Echoparametern korrelierte der systolische Lungenveneneinstrom als Ausdruck veränderter diastolischer Funktion stark mit der Lebersteifigkeit und damit möglichen Leberfibrose (R = -0,571, p < 0,002). Die Morphologie des Systemventrikels scheint bei dieser Kohorte keinen signifikanten Einfluss auf die Leberveränderungen zu haben. Schlussfolgerung: Die vorliegende Studie zeigt, dass Patienten nach Fontan- Prozedur ein erhöhtes Risiko besitzen, Leberfibrose und Leberzirrhose zu entwickeln. Dieses Risiko steigt mit zunehmendem Alter des Patienten und dem Zeitintervall seit Fontan-Operation an. Die Lebersteifigkeit scheint auch mit zunehmender Verschlechterung der diastolischen Funktion des univentrikulären Herzens mit zunehmendem Alter der Kinder zusammenzuhängen. Die nichtinvasive Leberfibrosemessung mittels transienter Elastographie und Fibroseserummarkern kann hilfreich sein, um Risikopatienten zu identifizieren, die möglicherweise im Verlauf eine Leberfibrose und Zirrhose entwickeln könnten.Non-invasive assessement of liver fibrosis in patients undergoing the Fontan procedure using transient elastography and biochemical fibrosis makers. Relationship to myocardial function. Objective: Studies have shown that patients with failing Fontan circulation may develop liver fibrosis with its sequelae. Therefore, the early detection of fibrosis is essential to identify patients at risk. Transient elastography as a non-invasive staging of liver fibrosis has meanwhile become a routine procedure in adult patients and has been evaluated in children in a multitude of clinical studies. Methods: 39 patients following the Fontan procedure were included in the study. All patients received an abdominal ultrasound, transient elastography, and detailed laboratory testing. Conventional echocardiography assessment as well as 2D-strain echocardiography were performed. Cardiac catheterization results performed during the following two years were included in the evaluation. Results: Transient elastography results revealed significant signs of fibrosis in 36/39 children, the fibrosis marker score in 28/39 children, respectively. The Spearman correlation coefficient between the liver stiffness measured with transient elastography and the time interval since the Fontan operation was highly significant with 0.514 (p = 0.001). There was a highly significant correlation between systolic pulmonary vein flow patterns and liver stiffness and possible fibrosis (R = -0.759, p < 0.001). The liver stiffness seems to be influenced by altered diastolic function of the univentricular heart. The morphology of the systemic ventricle does not appear to have a significant effect on liver changes in this cohort. Conclusion: The present study shows that patients following the Fontan procedure are at increased risk to develop liver fibrosis and liver cirrhosis. The risk of liver fibrosis increases with the age of the patient and deterioration of the diastolic function of the univentricular heart. The non-invasive measurement of liver fibrosis using transient elastography and fibrosis marker scores can be a useful tool to identify patients at risk and for non-invasive surveillance

Die Rolle von Gremlin-1 und seiner Bindungspartner im kardiovaskulären System

In den letzten Jahren ist die kardiovaskuläre Grundlagenforschung immer mehr in den Fokus der medizinischen Forschung gerückt. Speziell für die in vitro und in vivo Anwendung sind hierbei die Klasse der Fusionsproteine eine neue innovative therapeutische Möglichkeit, eine gegen Zielstrukturen gerichtete Therapie im kardiovaskulären Bereich durchzuführen. In der hier vorliegenden Arbeit konnte das bisher als BMP-Antagonist bekannte Protein Grem1 im Kontext der Arteriosklerose und des Myokardinfarktes charakterisiert werden. Es wurde gezeigt, dass Grem1 von Monozyten, Makrophagen und Schaumzellen speziell im Bereich von arteriosklerotischen Läsiosbereichen von ApoE-/- Mäusen verstärkt exprimiert wird., was auch unter in vitro Bedingungen durch eine Sekretion von Grem1 aus Monozyten nachgewiesen werden. Anhand der gezeigten Daten kann Grem1 als neuer endogener Antagonist von MIF beschrieben werden. So konnte nachgewiesen werden, dass es zu einer molekularen Interaktion zwischen MIF und Grem1 kommt. Diese Interaktion führte zu einer Inhibierung der Monozytendifferenzierung zu Schaumzellen, und reduzierte die MIF-induzierte TNF-α Sekretion aus Makrophagen. Das Fusionsprotein mGrem1-Fc konnte in einer in vivo Applikation den Anteil der Makrophagen im Plaquegewebe von ApoE-/- Mäusen signifikant reduzieren, sowie die TNF-α Expression in diesem Bereich als inflammatorischen Marker vermindern. Zusätzlich konnte Grem1 als Inhibitor von TGFβ1 indentifiziert und eine neue Rolle der Grem1/TGFb1 Interaktion in myokardialen Inflammations- und Reperaturprozessen beschrieben werden. Unter Verwendung des Ischämie/Reperfusionsmodells in Mäusen konnte eine vermehrte Expression von Grem1 in Infiltraten im ischämischen Myokardgewebe nachgewiesen werden. So konnte verifiziert werden, dass mGrem1-Fc die TGFβ1 in vitro induzierte Expression und Sekretion an Col I von Fibroblasten und die in vivo Expression an EZM Proteinen nach transienter Ligatur reduzieren kann. Durch die in vivo Applikation von mGrem1-Fc konnte die linksventrikuläre Herzfunktion verbessert werden, sowie die Infarktgröße und die myokardiale Fibrose im Ischämie/Reperfusionsmodell verringert werden. Dies beschreibt Grem1 als vielversprechendes neues Zielmolekül, um die Plaquestabilität und Plaqueprogression, aber auch myokardiale Fibrose und Remodelling Prozesse kontrollieren zu können

Primary Treatment Results in Patients with Ovarian, Fallopian or Peritoneal Cancer—Results of a Clinical Cancer Registry Database Analysis in Germany

Simple Summary: Diagnosis and treatment of ovarian cancers has changed significantly over the last years. However, the role of primary surgery and chemotherapy remain important parts of the multimodal treatment. Furthermore, real life data are often lacking but are very important for improving quality indicators and for hypothesis generation for future trials. The present work represents the first major analysis of federal cancer registry data of OC patients in Germany. Overall, 2771 primary OC cases were included. The results clearly elucidate quality measurements and treatment results and show good treatment outcomes in patients with primary OC compared to other internationally reported outcomes. Abstract: Background: The current therapy of ovarian cancer is based on the so-called "Three-Pillar-Model", consisting of surgery, chemotherapy and maintenance therapy. This study represents the first major analysis of a federal cancer database of OC patients from the states Berlin/Brandenburg in Germany. The primary objective was to evaluate the prevailing established quality indicators surgical outcome, adjuvant chemotherapy and integrity of surgical staging in early stages. Methods: Data from the Clinical Cancer Registry for Brandenburg and Berlin of the years 2009-2019 were analyzed. Objectives were defined by a working group of selected physicians. Descriptive statistics were performed, as well as survival analysis. Results: A total of 2771 primary OC cases were included. Results regarding histological subtype met the suspected allocation with predominantly high-grade serous OC in advanced stage. The rate of complete surgical staging in FIGO stages I-IIA was 57%, and the rate of macroscopic complete resection in >FIGO III was 53%. Five-year survival rate varied from 79% (FIGO I) to 40% (FIGO III). Rate of adjuvant chemotherapy was above 50%. Conclusion: The results elucidate quality measurements and treatment results and show good treatment outcomes in patients with primary diagnosis. However, they also indicate deficits and can help to establish new quality indicators to further improve the treatment

Deoxyguanosine kinase mutation F180S is associated with a lean phenotype in mice

Background: Deoxyguanosine kinase (DGUOK) deficiency is one of the genetic causes of mitochondrial DNA depletion syndrome (MDDS) in humans, leading to the hepatocerebral or the isolated hepatic form of MDDS. Mouse models are helpful tools for the improvement of understanding of the pathophysiology of diseases and offer the opportunity to examine new therapeutic options. Methods: Herein, we describe the generation and metabolic characterization of a mouse line carrying a homozygous DguokF180S/F180S mutation derived from an N-ethyl-N-nitrosourea-mutagenesis screen. Energy expenditure (EE), oxygen consumption (VO2) and carbon dioxide production (VCO2) were assessed in metabolic cages. LC-MS/MS was used to quantify plasma adrenal steroids. Plasma insulin and leptin levels were quantified with commercially available assay kits. Results: Mutant animals displayed significantly lower body weights and reduced inguinal fat pad mass, in comparison to unaffected littermates. Biochemically, they were characterized by significantly lower blood glucose levels, accompanied by significantly lower insulin, total cholesterol, high density lipoprotein and triglyceride levels. They also displayed an almost 2-fold increase in transaminases. Moreover, absolute EE was comparable in mutant and control mice, but EE in mutants was uncoupled from their body weights. Histological examination of inguinal white adipose tissue (WAT) revealed adipocytes with multilocular fat droplets reminiscent of WAT browning. In addition, mRNA and protein expression of Ucp1 was increased. Mutant mice also presented differing mitochondrial DNA content in various tissues and altered metabolic activity in mitochondria, but no further phenotypical or behavioral abnormalities. Preliminary data imply normal survival of DguokF180S/F180S mutant animals. Conclusion: Taken together, DGUOK mutation F180S leads to a lean phenotype, with lower glucose, insulin, and lipid levels rendering this mouse model not only useful for the study of MDDS forms but also for deciphering mechanisms resulting in a lean phenotyp

Defect Coverage after Forequarter Amputation—A Systematic Review Assessing Different Surgical Approaches

Autologous fillet flaps are a common reconstructive option for large defects after forequarter amputation (FQA) due to advanced local malignancy or trauma. The inclusion of osseous structures into these has several advantages. This article therefore systematically reviews reconstructive options after FQA, using osteomusculocutaneous fillet flaps, with emphasis on personalized surgical technique and outcome. Additionally, we report on a case with an alternative surgical technique, which included targeted muscle reinnervation (TMR) of the flap. Our literature search was conducted in the PubMed and Cochrane databases. Studies that were identified were thoroughly scrutinized with regard to relevance, resulting in the inclusion of four studies (10 cases). FQA was predominantly a consequence of local malignancy. For vascular supply, the brachial artery was predominantly anastomosed to the subclavian artery and the brachial or cephalic vein to the subclavian or external jugular vein. Furthermore, we report on a case of a large osteosarcoma of the humerus. Extended FQA required the use of the forearm for defect coverage and shoulder contour reconstruction. Moreover, we performed TMR. Follow-up showed a satisfactory result and no phantom limb pain. In case of the need for free flap reconstruction after FQA, this review demonstrates the safety and advantage of osteomusculocutaneous fillet flaps. If the inclusion of the elbow joint into the flap is not possible, we recommend the use of the forearm, as described. Additionally, we advocate for the additional implementation of TMR, as it can be performed quickly and is likely to reduce phantom limb and neuroma pain

The future of the CDM: same same, but differentiated?

Policy-makers and scientists have raised concerns about the functioning of the Clean Development Mechanism (CDM), in particular regarding its low contribution to sustainable development, unbalanced regional and sectoral distribution of projects, and its limited contribution to global emission reductions. Differentiation between countries or project types has been proposed as a possible way forward to address these problems. An overview is provided of the different ways in which CDM differentiation could be implemented. The implications for the actors involved in the CDM are analysed, along with a quantitative assessment of the impacts on the carbon market, using bottom-up marginal abatement cost curves. The discounting of CDM credits, quota systems, or differentiated eligibility of countries could help to address several of the concerns raised. Preferential treatment may also make a limited contribution to achieving the aims of CDM differentiation by increasing opportunities for under-represented host countries. The impact on the carbon market appears to be limited for most options

Selective inactivation of hypomethylating agents by SAMHD1 provides a rationale for therapeutic stratification in AML.

Hypomethylating agents decitabine and azacytidine are regarded as interchangeable in the treatment of acute myeloid leukemia (AML). However, their mechanisms of action remain incompletely understood, and predictive biomarkers for HMA efficacy are lacking. Here, we show that the bioactive metabolite decitabine triphosphate, but not azacytidine triphosphate, functions as activator and substrate of the triphosphohydrolase SAMHD1 and is subject to SAMHD1-mediated inactivation. Retrospective immunohistochemical analysis of bone marrow specimens from AML patients at diagnosis revealed that SAMHD1 expression in leukemic cells inversely correlates with clinical response to decitabine, but not to azacytidine. SAMHD1 ablation increases the antileukemic activity of decitabine in AML cell lines, primary leukemic blasts, and xenograft models. AML cells acquire resistance to decitabine partly by SAMHD1 up-regulation. Together, our data suggest that SAMHD1 is a biomarker for the stratified use of hypomethylating agents in AML patients and a potential target for the treatment of decitabine-resistant leukemia