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Deuchler, Svenja ; Wagner, Clemens ; Singh, Pankaj ; Müller, Michael ; Al-Dwairi, Rami ; Benjilali, Rachid ; Schill, Markus ; Ackermann, Hanns ; Bon, Dimitra ; Kohnen, Thomas ; Schoene, Benjamin ; Koss, Michael Janusz ; Koch, Frank H.
Purpose: To evaluate the efficacy of the virtual reality training simulator Eyesi to prepare surgeons for performing pars plana vitrectomies and its potential to predict the surgeons’ performance.
Methods: In a preparation phase, four participating vitreoretinal surgeons performed repeated simulator training with predefined tasks. If a surgeon was assigned to perform a vitrectomy for the management of complex retinal detachment after a surgical break of at least 60 hours it was randomly decided whether a warmup training on the simulator was required (n = 9) or not (n = 12). Performance at the simulator was measured using the built-in scoring metrics. The surgical performance was determined by two blinded observers who analyzed the video-recorded interventions. One of them repeated the analysis to check for intra-observer consistency. The surgical performance of the interventions with and without simulator training was compared. In addition, for the surgeries with simulator training, the simulator performance was compared to the performance in the operating room.
Results: Comparing each surgeon’s performance with and without warmup trainingshowed a significant effect of warmup training onto the final outcome in the operating room. For the surgeries that were preceeded by the warmup procedure, the performance at the simulator was compared with the operating room performance. We found that there is a significant relation. The governing factor of low scores in the simulator were iatrogenic retinal holes, bleedings and lens damage. Surgeons who caused minor damage in the simulation also performed well in the operating room.
Conclusions: Despite the large variation of conditions, the effect of a warmup training as well as a relation between the performance at the simulator and in the operating room was found with statistical significance. Simulator training is able to serve as a warmup to increase the average performance.
Singh, Pankaj ; Chedid de Robaulx, Adonis ; Deuchler, Svenja ; Kohnen, Thomas ; Müller, Michael ; Koch, Frank H.
Purpose: There are little or no published data comparing the outcomes of ILUVIEN® (0.19 mg fluocinolone acetonide [FAc]) and OZURDEX® (0.7 mg dexamethasone [DEX]) implants in patients with diabetic macular edema (DME), and this case sought to compare their outcomes.
Methods: This case was extracted from a monocentric audit involving a pool of 25 patients (33 eyes) with DME and treated with a single FAc implant between October 2013 and December 2016. This case, a 61-year-old male with a pseudophakic lens, is from a patient that had received 4 intravitreal injections of a DEX implant prior to FAc implant and then was monitored for 3 years until re-treatment with a second FAc implant. Parameters measured included visual acuity (VA), central retinal thickness (CRT), and intraocular pressure (IOP).
Results: After the DEX implants, CRT transiently improved. In March 2014, the decision was taken to administer an FAc implant, and this led to a reduction in CRT below 300 µm (from a baseline of 748 µm), and this was sustained for 30 months. VA remained above 65 Early Treatment Diabetic Retinopathy Study letters to month 36, after which time a second FAc implant (in April 2017) was administered due to recurrence of edema and CRT decreased to below 300 µm and VA improved to 70 letters. Side effects included elevated IOP, which was effectively managed with IOP-lowering drops.
Conclusion: A single injection of FAc implant led to sustained improvements in CRT and VA that lasted for between 30 and 36 months, which is in contrast to the DEX implant where re-treatment was generally required within 6–7 months. After 36 months, re-treatment with the FAc implant again led to improved VA and CRT, and responses that were similar to those achieved with the first FAc implant.
Griesinger, Frank ; Eberhardt, Wilfried E. E. ; Nusch, Arnd ; Reiser, Marcel ; Zahn, Mark-Oliver ; Maintz, Christoph ; Bernhardt, Christiane ; Losem, Christoph ; Stenzinger, Albrecht ; Heukamp, Lukas ; Büttner, Reinhard ; Marschner, Sebastian ; Jänicke, Martina ; Fleitz, Annette ; Spring, Lisa ; Sahlmann, Jörg ; Karatas, Aysun ; Hipper, Annette ; Weichert, Wilko ; Heilmann, Monika ; Sadjadian, Parvis ; Gleiber, Wolfgang ; Grah, Christian ; Waller, Cornelius ; Reck, Martin ; Rittmeyer, Achim ; Christopoulos, Petros ; Sebastian, Martin ; Thomas, Michael
Objectives: An increasing number of treatment-determining biomarkers has been identified in non-small cell lung cancer (NSCLC) and molecular testing is recommended to enable optimal individualized treatment. However, data on implementation of these recommendations in the “real-world” setting are scarce. This study presents comprehensive details on the frequency, methodology and results of biomarker testing of advanced NSCLC in Germany.
Patients and methods: This analysis included 3,717 patients with advanced NSCLC (2,921 non-squamous; 796 squamous), recruited into the CRISP registry at start of systemic therapy by 150 German sites between December 2015 and June 2019. Evaluated were the molecular biomarkers EGFR, ALK, ROS1, BRAF, KRAS, MET, TP53, RET, HER2, as well as expression of PD-L1.
Results: In total, 90.5 % of the patients were tested for biomarkers. Testing rates were 92.2 % (non-squamous), 70.7 % (squamous) and increased from 83.2 % in 2015/16 to 94.2% in 2019. Overall testing rates for EGFR, ALK, ROS1, and BRAF were 72.5 %, 74.5 %, 66.1 %, and 53.0 %, respectively (non-squamous). Testing rates for PD-L1 expression were 64.5 % (non-squamous), and 58.5 % (squamous). The most common testing methods were immunohistochemistry (68.5 % non-squamous, 58.3 % squamous), and next-generation sequencing (38.7 % non-squamous, 14.4 % squamous). Reasons for not testing were insufficient tumor material or lack of guideline recommendations (squamous). No alteration was found in 37.8 % (non-squamous), and 57.9 % (squamous), respectively. Most common alterations in non-squamous tumors (all patients/all patients tested for the respective biomarker): KRAS (17.3 %/39.2 %), TP53 (14.1 %/51.4 %), and EGFR (11.0 %/15.1 %); in squamous tumors: TP53 (7.0 %/69.1 %), MET (1.5 %/11.1 %), and EGFR (1.1 %/4.4 %). Median PFS (non-squamous) was 8.7 months (95 % CI 7.4–10.4) with druggable EGFR mutation, and 8.0 months (95 % CI 3.9–9.2) with druggable ALK alterations.
Conclusion: Testing rates in Germany are high nationwide and acceptable in international comparison, but still leave out a significant portion of patients, who could potentially benefit. Thus, specific measures are needed to increase implementation.
Griesinger, Frank ; Eberhardt, Wilfried E. E. ; Nusch, Arnd ; Reiser, Marcel ; Zahn, Mark-Oliver ; Maintz, Christoph ; Bernhardt, Christiane ; Losem, Christoph ; Stenzinger, Albrecht ; Heukamp, Lukas ; Büttner, Reinhard ; Marschner, Sebastian ; Jänicke, Martina ; Fleitz, Annette ; Spring, Lisa ; Sahlmann, Jörg ; Karatas, Aysun ; Hipper, Annette ; Weichert, Wilko ; Heilmann, Monika ; Sadjadian, Parvis ; Gleiber, Wolfgang ; Grah, Christian ; Waller, Cornelius ; Reck, Martin ; Rittmeyer, Achim ; Christopoulos, Petros ; Sebastian, Martin ; Thomas, Michael
Pedretti, Roberto F. E. ; Iliou, Marie-Christine ; Israel, Carsten Walter ; Abreu, Ana ; Miljoen, Hielko ; Corrà, Ugo ; Stellbrink, Christoph ; Gevaert, Andreas B. ; Theuns, Dominic A. M. J. ; Piepoli, Massimo F. ; Reibis, Rona Katharina ; Schmid, Jean Paul ; Wilhelm, Matthias ; Heidbuchel, Hein ; Völler, Heinz ; Ambrosetti, Marco ; Deneke, Thomas ; Cornelissen, Veronique ; Heinzel, Frank ; Davos, Constantinos H. ; Kudaiberdieva, Gulmira ; Frederix, Ines ; Svendsen, Jesper Hastrup ; Hansen, Dominique
Cardiac rehabilitation (CR) is a multidisciplinary intervention including patient assessment and medical actions to promote stabilization, management of cardiovascular risk factors, vocational support, psychosocial management, physical activity counselling, and prescription of exercise training. Millions of people with cardiac implantable electronic devices live in Europe and their numbers are progressively increasing, therefore, large subsets of patients admitted in CR facilities have a cardiac implantable electronic device. Patients who are cardiac implantable electronic devices recipients are considered eligible for a CR programme. This is not only related to the underlying heart disease but also to specific issues, such as psychological adaptation to living with an implanted device and, in implantable cardioverter-defibrillator patients, the risk of arrhythmia, syncope, and sudden cardiac death. Therefore, these patients should receive special attention, as their needs may differ from other patients participating in CR. As evidence from studies of CR in patients with cardiac implantable electronic devices is sparse, detailed clinical practice guidelines are lacking. Here, we aim to provide practical recommendations for CR in cardiac implantable electronic devices recipients in order to increase CR implementation, efficacy, and safety in this subset of patients.
Lenz, Maximilian ; Eichler, Amelie ; Kruse, Pia ; Strehl, Andreas ; Rodriguez-Rozada, Silvia ; Goren, Itamar ; Yogev, Nir ; Frank, Stefan ; Waisman, Ari ; Deller, Thomas ; Jung, Steffen ; Maggio, Nicola ; Vlachos, Andreas
Systemic inflammation is associated with alterations in complex brain functions such as learning and memory. However, diagnostic approaches to functionally assess and quantify inflammation-associated alterations in synaptic plasticity are not well-established. In previous work, we demonstrated that bacterial lipopolysaccharide (LPS)-induced systemic inflammation alters the ability of hippocampal neurons to express synaptic plasticity, i.e., the long-term potentiation (LTP) of excitatory neurotransmission. Here, we tested whether synaptic plasticity induced by repetitive magnetic stimulation (rMS), a non-invasive brain stimulation technique used in clinical practice, is affected by LPS-induced inflammation. Specifically, we explored brain tissue cultures to learn more about the direct effects of LPS on neural tissue, and we tested for the plasticity-restoring effects of the anti-inflammatory cytokine interleukin 10 (IL10). As shown previously, 10 Hz repetitive magnetic stimulation (rMS) of organotypic entorhino-hippocampal tissue cultures induced a robust increase in excitatory neurotransmission onto CA1 pyramidal neurons. Furthermore, LPS-treated tissue cultures did not express rMS-induced synaptic plasticity. Live-cell microscopy in tissue cultures prepared from a novel transgenic reporter mouse line [C57BL/6-Tg(TNFa-eGFP)] confirms that ex vivo LPS administration triggers microglial tumor necrosis factor alpha (TNFα) expression, which is ameliorated in the presence of IL10. Consistent with this observation, IL10 hampers the LPS-induced increase in TNFα, IL6, IL1β, and IFNγ and restores the ability of neurons to express rMS-induced synaptic plasticity in the presence of LPS. These findings establish organotypic tissue cultures as a suitable model for studying inflammation-induced alterations in synaptic plasticity, thus providing a biological basis for the diagnostic use of transcranial magnetic stimulation in the context of brain inflammation.
On the robustness of the r-process in neutron-star mergers against variations of nuclear masses
(2016)
Mendoza-Temis, Joel de Jesús ; Wu, Meng-Ru ; Martínez-Pinedo, Gabriel ; Langanke, Karlheinz ; Bauswein, Andreas Ottmar ; Janka, Hans-Thomas ; Frank, Alejandro
r-process calculations have been performed for matter ejected dynamically in neutron star mergers (NSM), such calculations are based on a complete set of trajectories from a three-dimensional relativistic smoothed particle hydrodynamic (SPH) simulation. Our calculations consider an extended nuclear reaction network, including spontaneous, β- and neutron-induced fission and adopting fission yield distributions from the ABLA code. In this contribution we have studied the sensitivity of the r-process abundances to nuclear masses by using diferent mass models for the calculation of neutron capture cross sections via the statistical model. Most of the trajectories, corresponding to 90% of the ejected mass, follow a relatively slow expansion allowing for all neutrons to be captured. The resulting abundances are very similar to each other and reproduce the general features of the observed r-process abundance (the second and third peaks, the rare-earth peak and the lead peak) for all mass models as they are mainly determined by the fission yields. We find distinct differences in the predictions of the mass models at and just above the third peak, which can be traced back to different predictions of neutron separation energies for r-process nuclei around neutron number N = 130.
Uschner, Frank Erhard ; Glückert, Kathleen ; Paternostro, Rafael ; Gnad, Thorsten ; Schierwagen, Robert ; Mandorfer, Mattias ; Magdaleno, Fernando ; Ortiz, Cristina ; Schwarzkopf, Katharina ; Kamath, Patrick S. ; Alessandria, Carlo ; Boesecke, Christoph ; Pfeifer, Alexander ; Reiberger, Thomas ; Kreisel, Wolfgang ; Sauerbruch, Tilman ; Ferlitsch, Arnulf ; Trebicka, Jonel ; Klein, Sabine
Background & Aims: Phosphodiesterase‐5 inhibitors (PDE‐5‐I) are used for treatment of erectile dysfunction (ED), which is common in patients with cirrhosis. They may improve portal hypertension (PH), but contradictory data on efficacy and side‐effects have been reported. Non‐selective beta blockers (NSBB) reduce portal pressure, but might aggravate ED. Thus, we evaluated the combination of PDE‐5‐I with NSBB and its impact on PH and ED in experimental cirrhosis.
Methods: ED was assessed in cirrhotic patients (n = 86) using standardized questionnaire. Experimental cirrhosis was induced by bile‐duct‐ligation or carbon‐tetrachloride intoxication in rats. Corpus cavernosum pressure – a surrogate of ED ‐, as well as systemic and portal haemodynamics, were measured in vivo and in situ after acute administration of udenafil alone or in combination with propranolol. mRNA and protein levels of PDE‐5 signalling were analysed using PCR and western Blot.
Results: ED in humans was related to severity of liver disease and to NSBB treatment. PDE‐5 was mainly expressed in hepatic stellate cells and upregulated in human and experimental cirrhosis. Propranolol reduced corpus cavernosum pressure in cirrhotic rats and it was restored by udenafil. Even though udenafil treatment improved PH, it led to a reduction of mean arterial pressure. The combination of udenafil and propranolol reduced portal pressure and hepatic resistance without systemic side‐effects.
Conclusions: ED is common with advanced cirrhosis and concomitant NSBB treatment. The combination of PDE‐5‐I and NSBB improves ED and PH in experimental cirrhosis.
Casey, Stephen ; Schierwagen, Robert ; Mak, Kai Yan ; Klein, Sabine ; Uschner, Frank Erhard ; Jansen, Christian ; Praktiknjo, Michael ; Meyer, Carsten ; Thomas, Daniel ; Herath, Chandana ; Jones, Robert ; Trebicka, Jonel ; Angus, Peter
Introduction: Recent animal studies have shown that the alternate renin-angiotensin system (RAS) consisting of angiotensin-converting enzyme 2 (ACE2), angiotensin-(1–7) (Ang-(1–7)) and the Mas receptor is upregulated in cirrhosis and contributes to splanchnic vasodilatation and portal hypertension. To determine the potential relevance of these findings to human liver disease, we evaluated its expression and relationship to the patients’ clinical status in subjects with cirrhosis. Methods: Blood sampling from peripheral and central vascular beds was performed intra-operatively for cirrhotic patients at the time of liver transplantation (LT) or trans-jugular intra-hepatic portosystemic shunt (TIPS) procedures to measure angiotensin II (Ang II) and Ang-(1–7) peptide levels and ACE and ACE2 enzyme activity. Relevant clinical and hemodynamic data were recorded pre-operatively for all subjects and peripheral blood sampling was repeated 3 months or later post-operatively. Results: Ang-(1–-7) and ACE2 activity were up-regulated more than twofold in cirrhotic subjects both at the time of LT and TIPS and levels returned to comparable levels as control subjects post-transplantation. Ang-(1–7) levels correlated positively with the degree of liver disease severity, as measured by the model for an end-stage liver disease (MELD) and also with clinical parameters of pathological vasodilatation including cardiac output (CO). There were strong correlations found between the ACE2:ACE and the Ang-(1–7):Ang II ratio highlighting the inter-dependence of the alternate and classical arms of the RAS and thus their potential impact on vascular tone. Conclusions: In human cirrhosis, the alternate RAS is markedly upregulated and the activation of this system is associated strongly with features of the hyperdynamic circulation in advanced human cirrhosis.
Cremonese, Carla-Luisa Elsa ; Schierwagen, Robert ; Uschner, Frank Erhard ; Torres Núñez, Sandra ; Tyc, Olaf ; Ortiz, Cristina ; Schulz, Martin ; Queck, Alexander David Roger ; Kristiansen, Glen ; Bader, Michael ; Sauerbruch, Tilman ; Weiskirchen, Ralf ; Walther, Thomas ; Trebicka, Jonel ; Klein, Sabine
Non-alcoholic fatty liver disease (NAFLD) is gaining in importance and is linked to obesity. Especially,thedevelopmentoffibrosisandportalhypertensioninNAFLDpatientsrequirestreatment. Transgenic TGR(mREN2)27 rats overexpressing mouse renin spontaneously develop NAFLD with portal hypertension but without obesity. This study investigated the additional role of obesity in this model on the development of portal hypertension and fibrosis. Obesity was induced in twelve-week old TGR(mREN2)27 rats after receiving Western diet (WD) for two or four weeks. Liver fibrosis was assessed using standard techniques. Hepatic expression of transforming growth factor-β1 (TGF-β1), collagen type Iα1, α-smooth muscle actin, and the macrophage markers Emr1, as well as the chemoattractant Ccl2, interleukin-1β (IL1β) and tumor necrosis factor-α (TNFα) were analyzed. Assessment of portal and systemic hemodynamics was performed using the colored microsphere technique. Asexpected,WDinducedobesityandliverfibrosisasconfirmedbySiriusRedandOilRed O staining. The expression of the monocyte-macrophage markers, Emr1, Ccl2, IL1β and TNFα were increasedduringfeedingofWD,indicatinginfiltrationofmacrophagesintotheliver,eventhoughthis increase was statistically not significant for the EGF module-containing mucin-like receptor (Emr1) mRNA expression levels. Of note, portal pressure increased with the duration of WD compared to animals that received a normal chow. Besides obesity, WD feeding increased systemic vascular resistance reflecting systemic endothelial and splanchnic vascular dysfunction. We conclude that transgenic TGR(mREN2)27 rats are a suitable model to investigate NAFLD development with liver fibrosis and portal hypertension. Tendency towards elevated expression of Emr1 is associated with macrophage activity point to a significant role of macrophages in NAFLD pathogenesis, probably due to a shift of the renin–angiotensin system towards a higher activation of the classical pathway. The hepatic injury induced by WD in TGR(mREN2)27 rats is suitable to evaluate different stages of fibrosis and portal hypertension in NAFLD with obesity.