TY - JOUR A1 - Stoppe, Christian A1 - Patel, Jayshil J. A1 - Zarbock, Alex A1 - Lee, Zheng-Yii A1 - Rice, Todd W. A1 - Mafrici, Bruno A1 - Wehner, Rebecca A1 - Chan, Man Hung Manuel A1 - Lai, Peter Chi Keung A1 - MacEachern, Kristen A1 - Myrianthefs, Pavlos A1 - Tsigou, Evdoxia A1 - Ortiz-Reyes, Luis A1 - Jiang, Xuran A1 - Day, Andrew G. A1 - Hasan, M. Shahnaz A1 - Meybohm, Patrick A1 - Ke, Lu A1 - Heyland, Daren K. T1 - The impact of higher protein dosing on outcomes in critically ill patients with acute kidney injury: a post hoc analysis of the EFFORT protein trial JF - Critical Care N2 - Background Based on low-quality evidence, current nutrition guidelines recommend the delivery of high-dose protein in critically ill patients. The EFFORT Protein trial showed that higher protein dose is not associated with improved outcomes, whereas the effects in critically ill patients who developed acute kidney injury (AKI) need further evaluation. The overall aim is to evaluate the effects of high-dose protein in critically ill patients who developed different stages of AKI. Methods In this post hoc analysis of the EFFORT Protein trial, we investigated the effect of high versus usual protein dose (≥ 2.2 vs. ≤ 1.2 g/kg body weight/day) on time-to-discharge alive from the hospital (TTDA) and 60-day mortality and in different subgroups in critically ill patients with AKI as defined by the Kidney Disease Improving Global Outcomes (KDIGO) criteria within 7 days of ICU admission. The associations of protein dose with incidence and duration of kidney replacement therapy (KRT) were also investigated. Results Of the 1329 randomized patients, 312 developed AKI and were included in this analysis (163 in the high and 149 in the usual protein dose group). High protein was associated with a slower time-to-discharge alive from the hospital (TTDA) (hazard ratio 0.5, 95% CI 0.4–0.8) and higher 60-day mortality (relative risk 1.4 (95% CI 1.1–1.8). Effect modification was not statistically significant for any subgroup, and no subgroups suggested a beneficial effect of higher protein, although the harmful effect of higher protein target appeared to disappear in patients who received kidney replacement therapy (KRT). Protein dose was not significantly associated with the incidence of AKI and KRT or duration of KRT. Conclusions In critically ill patients with AKI, high protein may be associated with worse outcomes in all AKI stages. Recommendation of higher protein dosing in AKI patients should be carefully re-evaluated to avoid potential harmful effects especially in patients who were not treated with KRT. Trial registration: This study is registered at ClinicalTrials.gov (NCT03160547) on May 17th 2017. KW - acute kidney injury KW - critical illness KW - nutrition support KW - protein KW - randomized trial KW - registry trial Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-357221 VL - 27 ER - TY - JOUR A1 - Hecker, Katharina A1 - Grüner, Julia A1 - Hartmannsberger, Beate A1 - Appeltshauser, Luise A1 - Villmann, Carmen A1 - Sommer, Claudia A1 - Doppler, Kathrin T1 - Different binding and pathogenic effect of neurofascin and contactin–1 autoantibodies in autoimmune nodopathies JF - Frontiers in Immunology N2 - Introduction IgG4 autoantibodies against paranodal proteins are known to induce acute-onset and often severe sensorimotor autoimmune neuropathies. How autoantibodies reach their antigens at the paranode in spite of the myelin barrier is still unclear. Methods We performed in vitro incubation experiments with patient sera on unfixed and unpermeabilized nerve fibers and in vivo intraneural and intrathecal passive transfer of patient IgG to rats, to explore the access of IgG autoantibodies directed against neurofascin-155 and contactin-1 to the paranodes and their pathogenic effect. Results We found that in vitro incubation resulted in weak paranodal binding of anti-contactin-1 autoantibodies whereas anti-neurofascin-155 autoantibodies bound to the nodes more than to the paranodes. After short-term intraneural injection, no nodal or paranodal binding was detectable when using anti-neurofascin-155 antibodies. After repeated intrathecal injections, nodal more than paranodal binding could be detected in animals treated with anti-neurofascin-155, accompanied by sensorimotor neuropathy. In contrast, no paranodal binding was visible in rats intrathecally injected with anti-contactin-1 antibodies, and animals remained unaffected. Conclusion These data support the notion of different pathogenic mechanisms of anti-neurofascin-155 and anti-contactin-1 autoantibodies and different accessibility of paranodal and nodal structures. KW - autoimmune nodopathy KW - IgG4 KW - neurofascin KW - contactin KW - node of ranvier KW - inflammatory neuropathy KW - passive transfer Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-320395 VL - 14 ER - TY - JOUR A1 - Schmid, Benedikt A1 - Eckert, Dominik A1 - Meixner, Andreas A1 - Pistner, Paul A1 - Malzahn, Uwe A1 - Berberich, Monika A1 - Happel, Oliver A1 - Meybohm, Patrick A1 - Kranke, Peter T1 - Conventional versus video-assisted laryngoscopy for perioperative endotracheal intubation (COVALENT) - a randomized, controlled multicenter trial JF - BMC Anesthesiology N2 - Background Data on the routine use of video-assisted laryngoscopy in peri-operative intubations are rather inconsistent and ambiguous, in part due to small populations and non-uniform outcome measures in past trials. Failed or prolonged intubation procedures are a reason for relevant morbidity and mortality. This study aims to determine whether video-assisted laryngoscopy (with both Macintosh-shaped and hyperangulated blades) is at least equal to the standard method of direct laryngoscopy with respect to the first-pass success rate. Furthermore, validated tools from the field of human factors will be applied to examine within-team communication and task load during this critical medical procedure. Methods In this randomized, controlled, three-armed parallel group design, multi-centre trial, a total of more than 2500 adult patients scheduled for perioperative endotracheal intubation will be randomized. In equally large arms, video-assisted laryngoscopy with a Macintosh-shaped or a hyperangulated blade will be compared to the standard of care (direct laryngoscopy with Macintosh blade). In a pre-defined hierarchical analysis, we will test the primary outcome for non-inferiority first. If this goal should be met, the design and projected statistical power also allow for subsequent testing for superiority of one of the interventions. Various secondary outcomes will account for patient safety considerations as well as human factors interactions within the provider team and will allow for further exploratory data analysis and hypothesis generation. Discussion This randomized controlled trial will provide a solid base of data in a field where reliable evidence is of major clinical importance. With thousands of endotracheal intubations performed every day in operating rooms around the world, every bit of performance improvement translates into increased patient safety and comfort and may eventually prevent significant burden of disease. Therefore, we feel confident that a large trial has the potential to considerably benefit patients and anaesthetists alike. Trial registration ClincalTrials.gov NCT05228288. Protocol version 1.1, November 15, 2021. KW - anaesthesiology KW - laryngoscopy KW - video-assisted laryngoscopy KW - intubation KW - airway management KW - patient safety KW - human factors Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-357207 VL - 23 ER - TY - JOUR A1 - Radakovic, Dejan A1 - Penov, Kiril A1 - Lazarus, Marc A1 - Madrahimov, Nodir A1 - Hamouda, Khaled A1 - Schimmer, Christoph A1 - Leyh, Rainer G. A1 - Bening, Constanze T1 - The completeness of the left atrial appendage amputation during routine cardiac surgery JF - BMC Cardiovascular Disorders N2 - Background Left atrial appendage (LAA) is the origin of most heart thrombi which can lead to stroke or other cerebrovascular event in patients with non-valvular atrial fibrillation (AF). This study aimed to prove safety and low complication rate of surgical LAA amputation using cut and sew technique with control of its effectiveness. Methods 303 patients who have undergone selective LAA amputation were enrolled in the study in a period from 10/17 to 08/20. The LAA amputation was performed concomitant to routine cardiac surgery on cardiopulmonary bypass with cardiac arrest with or without previous history of AF. The operative and clinical data were evaluated. Extent of LAA amputation was examined intraoperatively by transoesophageal echocardiography (TEE). Six months in follow up, the patients were controlled regarding clinical status and episodes of strokes. Results Average age of study population was 69.9 ± 19.2 and 81.9% of patients were male. In only three patients was residual stump after LAA amputation larger than 1 cm with average stump size 0.28 ± 0.34 cm. 3 patients (1%) developed postoperative bleeding. Postoperatively 77 (25.4%) patients developed postoperative AF (POAF), of which 29 (9.6%) still had AF at discharge. On 6 months follow up only 5 patients had NYHA class III and 1 NYHA class IV. Seven patients reported with leg oedema and no patient experienced any cerebrovascular event in early postoperative follow up. Conclusion LAA amputation can be performed safely and completely leaving minimal to no LAA residual stump. KW - left atrial appendage occlusion KW - cut and sew technique KW - atrial fibrillation Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-357376 VL - 23 ER - TY - JOUR A1 - Zeiner, Carsten A1 - Schröder, Malte A1 - Metzner, Selina A1 - Herrmann, Johannes A1 - Notz, Quirin A1 - Hottenrott, Sebastian A1 - Röder, Daniel A1 - Meybohm, Patrick A1 - Lepper, Philipp M. A1 - Lotz, Christopher T1 - High-dose methylprednisolone pulse therapy during refractory COVID-19 acute respiratory distress syndrome: a retrospective observational study JF - BMC Pulmonary Medicine N2 - Background Current COVID-19 guidelines recommend the early use of systemic corticoids for COVID-19 acute respiratory distress syndrome (ARDS). It remains unknown if high-dose methylprednisolone pulse therapy (MPT) ameliorates refractory COVID-19 ARDS after many days of mechanical ventilation or rapid deterioration with or without extracorporeal membrane oxygenation (ECMO). Methods This is a retrospective observational study. Consecutive patients with COVID-19 ARDS treated with a parenteral high-dose methylprednisolone pulse therapy at the intensive care units (ICU) of two University Hospitals between January 1st 2021 and November 30st 2022 were included. Clinical data collection was at ICU admission, start of MPT, 3-, 10- and 14-days post MPT. Results Thirty-seven patients (mean age 55 ± 12 years) were included in the study. MPT started at a mean of 17 ± 12 days after mechanical ventilation. Nineteen patients (54%) received ECMO support when commencing MPT. Mean paO2/FiO2 significantly improved 3- (p = 0.034) and 10 days (p = 0.0313) post MPT. The same applied to the necessary FiO2 10 days after MPT (p = 0.0240). There were no serious infectious complications. Twenty-four patients (65%) survived to ICU discharge, including 13 out of 20 (65%) needing ECMO support. Conclusions Late administration of high-dose MPT in a critical subset of refractory COVID-19 ARDS patients improved respiratory function and was associated with a higher-than-expected survival of 65%. These data suggest that high-dose MPT may be a viable salvage therapy in refractory COVID-19 ARDS. KW - corticoid KW - methylprednisolone KW - pulse therapy KW - SARS-CoV2 KW - ECMO KW - salvage therapy Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-357231 VL - 23 ER - TY - JOUR A1 - Döhler, Ida A1 - Röder, Daniel A1 - Schlesinger, Tobias A1 - Nassen, Christian Alexander A1 - Germer, Christoph-Thomas A1 - Wiegering, Armin A1 - Lock, Johan Friso T1 - Risk-adjusted perioperative bridging anticoagulation reduces bleeding complications without increasing thromboembolic events in general and visceral surgery JF - BMC Anesthesiology N2 - Background Perioperative bridging of oral anticoagulation increases the risk of bleeding complications after elective general and visceral surgery. The aim of this study was to explore, whether an individual risk-adjusted bridging regimen can reduce bleeding events, while still protecting against thromboembolic events. Methods We performed a quality improvement study comparing bridging parameters and postoperative outcomes before (period 1) and after implementation (period 2) of a new risk-adjusted bridging regimen. The primary endpoint of the study was overall incidence of postoperative bleeding complications during 30 days postoperatively. Secondary endpoints were major postoperative bleeding, minor bleeding, thromboembolic events, postoperative red blood cell transfusion, perioperative length-of-stay (LOS) and in-hospital mortality. Results A total of 263 patients during period 1 and 271 patients during period 2 were compared. The included elective operations covered the entire field of general and visceral surgery. The overall incidence of bleeding complications declined from 22.1% during period 1 to 10.3% in period 2 (p < 0.001). This reduction affected both major as well as minor bleeding events (8.4% vs. 4.1%; p = 0.039; 13.7% vs. 6.3%; p = 0.004). The incidence of thromboembolic events remained low (0.8% vs. 1.1%). No changes in mortality or length-of-stay were observed. Conclusion It is important to balance the individual thromboembolic and bleeding risks in perioperative bridging management. The risk adjusted bridging regimen reduces bleeding events in general and visceral surgery while the risk of thromboembolism remains comparably low. KW - low-molecular heparin KW - atrial fibrillation KW - postoperative bleeding KW - thromboembolism KW - anticoagulation KW - bridging Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-357305 VL - 23 ER - TY - JOUR A1 - Notz, Quirin A1 - Heyland, Daren K. A1 - Lee, Zheng-Yii A1 - Menger, Johannes A1 - Herrmann, Johannes A1 - Chillon, Thilo S. A1 - Fremes, Stephen A1 - Mohammadi, Siamak A1 - Elke, Gunnar A1 - Mazer, C. David A1 - Hill, Aileen A1 - Velten, Markus A1 - Ott, Sascha A1 - Kleine-Brueggeney, Maren A1 - Meybohm, Patrick A1 - Schomburg, Lutz A1 - Stoppe, Christian T1 - Identifying a target group for selenium supplementation in high-risk cardiac surgery: a secondary analysis of the SUSTAIN CSX trial JF - Intensive Care Medicine Experimental N2 - Background Recent data from the randomized SUSTAIN CSX trial could not confirm clinical benefits from perioperative selenium treatment in high-risk cardiac surgery patients. Underlying reasons may involve inadequate biosynthesis of glutathione peroxidase (GPx3), which is a key mediator of selenium's antioxidant effects. This secondary analysis aimed to identify patients with an increase in GPx3 activity following selenium treatment. We hypothesize that these responders might benefit from perioperative selenium treatment. Methods Patients were selected based on the availability of selenium biomarker information. Four subgroups were defined according to the patient's baseline status, including those with normal kidney function, reduced kidney function, selenium deficiency, and submaximal GPx3 activity. Results Two hundred and forty-four patients were included in this analysis. Overall, higher serum concentrations of selenium, selenoprotein P (SELENOP) and GPx3 were correlated with less organ injury. GPx3 activity at baseline was predictive of 6-month survival (AUC 0.73; p = 0.03). While selenium treatment elevated serum selenium and SELENOP concentrations but not GPx3 activity in the full patient cohort, subgroup analyses revealed that GPx3 activity increased in patients with reduced kidney function, selenium deficiency and low to moderate GPx3 activity. Clinical outcomes did not vary between selenium treatment and placebo in any of these subgroups, though the study was not powered to conclusively detect differences in outcomes. Conclusions The identification of GPx3 responders encourages further refined investigations into the treatment effects of selenium in high-risk cardiac surgery patients. KW - selenium KW - glutathione peroxidase KW - cardiac surgery KW - critical care KW - oxidative stress KW - SUSTAIN CSX Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-357196 VL - 11 ER - TY - JOUR A1 - García-Fernández, Patricia A1 - Höfflin, Klemens A1 - Rausch, Antonia A1 - Strommer, Katharina A1 - Neumann, Astrid A1 - Cebulla, Nadine A1 - Reinhold, Ann-Kristin A1 - Rittner, Heike A1 - Üçeyler, Nurcan A1 - Sommer, Claudia T1 - Systemic inflammatory markers in patients with polyneuropathies JF - Frontiers in Immunology N2 - Introduction In patients with peripheral neuropathies (PNP), neuropathic pain is present in 50% of the cases, independent of the etiology. The pathophysiology of pain is poorly understood, and inflammatory processes have been found to be involved in neuro-degeneration, -regeneration and pain. While previous studies have found a local upregulation of inflammatory mediators in patients with PNP, there is a high variability described in the cytokines present systemically in sera and cerebrospinal fluid (CSF). We hypothesized that the development of PNP and neuropathic pain is associated with enhanced systemic inflammation. Methods To test our hypothesis, we performed a comprehensive analysis of the protein, lipid and gene expression of different pro- and anti-inflammatory markers in blood and CSF from patients with PNP and controls. Results While we found differences between PNP and controls in specific cytokines or lipids, such as CCL2 or oleoylcarnitine, PNP patients and controls did not present major differences in systemic inflammatory markers in general. IL-10 and CCL2 levels were related to measures of axonal damage and neuropathic pain. Lastly, we describe a strong interaction between inflammation and neurodegeneration at the nerve roots in a specific subgroup of PNP patients with blood-CSF barrier dysfunction. Conclusion In patients with PNP systemic inflammatory, markers in blood or CSF do not differ from controls in general, but specific cytokines or lipids do. Our findings further highlight the importance of CSF analysis in patients with peripheral neuropathies. KW - cytokines KW - polyneuropathy KW - cerebrospinal fluid KW - neurofilament light chain KW - blood CSF barrier Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-304217 VL - 14 ER - TY - JOUR A1 - Shityakov, Sergey A1 - Nagai, Michiaki A1 - Ergün, Süleyman A1 - Braunger, Barbara M. A1 - Förster, Carola Y. T1 - The protective effects of neurotrophins and microRNA in diabetic retinopathy, nephropathy and heart failure via regulating endothelial function JF - Biomolecules N2 - Diabetes mellitus is a common disease affecting more than 537 million adults worldwide. The microvascular complications that occur during the course of the disease are widespread and affect a variety of organ systems in the body. Diabetic retinopathy is one of the most common long-term complications, which include, amongst others, endothelial dysfunction, and thus, alterations in the blood-retinal barrier (BRB). This particularly restrictive physiological barrier is important for maintaining the neuroretina as a privileged site in the body by controlling the inflow and outflow of fluid, nutrients, metabolic end products, ions, and proteins. In addition, people with diabetic retinopathy (DR) have been shown to be at increased risk for systemic vascular complications, including subclinical and clinical stroke, coronary heart disease, heart failure, and nephropathy. DR is, therefore, considered an independent predictor of heart failure. In the present review, the effects of diabetes on the retina, heart, and kidneys are described. In addition, a putative common microRNA signature in diabetic retinopathy, nephropathy, and heart failure is discussed, which may be used in the future as a biomarker to better monitor disease progression. Finally, the use of miRNA, targeted neurotrophin delivery, and nanoparticles as novel therapeutic strategies is highlighted. KW - diabetic retinopathy KW - diabetes mellitus KW - microvascular complications KW - diabetic nephropathy KW - heart failure KW - microRNA KW - neurotrophins Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-285966 SN - 2218-273X VL - 12 IS - 8 ER - TY - JOUR A1 - Salvador, Ellaine A1 - Kessler, Almuth F. A1 - Domröse, Dominik A1 - Hörmann, Julia A1 - Schaeffer, Clara A1 - Giniunaite, Aiste A1 - Burek, Malgorzata A1 - Tempel-Brami, Catherine A1 - Voloshin, Tali A1 - Volodin, Alexandra A1 - Zeidan, Adel A1 - Giladi, Moshe A1 - Ernestus, Ralf-Ingo A1 - Löhr, Mario A1 - Förster, Carola Y. A1 - Hagemann, Carsten T1 - Tumor Treating Fields (TTFields) reversibly permeabilize the blood–brain barrier in vitro and in vivo JF - Biomolecules N2 - Despite the availability of numerous therapeutic substances that could potentially target CNS disorders, an inability of these agents to cross the restrictive blood–brain barrier (BBB) limits their clinical utility. Novel strategies to overcome the BBB are therefore needed to improve drug delivery. We report, for the first time, how Tumor Treating Fields (TTFields), approved for glioblastoma (GBM), affect the BBB’s integrity and permeability. Here, we treated murine microvascular cerebellar endothelial cells (cerebEND) with 100–300 kHz TTFields for up to 72 h and analyzed the expression of barrier proteins by immunofluorescence staining and Western blot. In vivo, compounds normally unable to cross the BBB were traced in healthy rat brain following TTFields administration at 100 kHz. The effects were analyzed via MRI and immunohistochemical staining of tight-junction proteins. Furthermore, GBM tumor-bearing rats were treated with paclitaxel (PTX), a chemotherapeutic normally restricted by the BBB combined with TTFields at 100 kHz. The tumor volume was reduced with TTFields plus PTX, relative to either treatment alone. In vitro, we demonstrate that TTFields transiently disrupted BBB function at 100 kHz through a Rho kinase-mediated tight junction claudin-5 phosphorylation pathway. Altogether, if translated into clinical use, TTFields could represent a novel CNS drug delivery strategy. KW - blood–brain barrier KW - TTFields KW - CNS disorders Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-288057 SN - 2218-273X VL - 12 IS - 10 ER - TY - JOUR A1 - Liu, Sheng A1 - Bonalume, Veronica A1 - Gao, Qi A1 - Chen, Jeremy Tsung-Chieh A1 - Rohr, Karl A1 - Hu, Jing A1 - Carr, Richard T1 - Pre-synaptic GABA\(_A\) in NaV1.8\(^+\) primary afferents is required for the development of punctate but not dynamic mechanical allodynia following CFA inflammation JF - Cells N2 - Hypersensitivity to mechanical stimuli is a cardinal symptom of neuropathic and inflammatory pain. A reduction in spinal inhibition is generally considered a causal factor in the development of mechanical hypersensitivity after injury. However, the extent to which presynaptic inhibition contributes to altered spinal inhibition is less well established. Here, we used conditional deletion of GABA\(_A\) in NaV1.8-positive sensory neurons (Scn10a\(^{Cre}\);Gabrb3\(^{fl/fl}\)) to manipulate selectively presynaptic GABAergic inhibition. Behavioral testing showed that the development of inflammatory punctate allodynia was mitigated in mice lacking pre-synaptic GABA\(_A\). Dorsal horn cellular circuits were visualized in single slices using stimulus-tractable dual-labelling of c-fos mRNA for punctate and the cognate c-Fos protein for dynamic mechanical stimulation. This revealed a substantial reduction in the number of cells activated by punctate stimulation in mice lacking presynaptic GABA\(_A\) and an approximate 50% overlap of the punctate with the dynamic circuit, the relative percentage of which did not change following inflammation. The reduction in dorsal horn cells activated by punctate stimuli was equally prevalent in parvalbumin- and calretinin-positive cells and across all laminae I–V, indicating a generalized reduction in spinal input. In peripheral DRG neurons, inflammation following complete Freund’s adjuvant (CFA) led to an increase in axonal excitability responses to GABA, suggesting that presynaptic GABA effects in NaV1.8\(^+\) afferents switch from inhibition to excitation after CFA. In the days after inflammation, presynaptic GABA\(_A\) in NaV1.8\(^+\) nociceptors constitutes an “open gate” pathway allowing mechanoreceptors responding to punctate mechanical stimulation access to nociceptive dorsal horn circuits. KW - GABA\(_A\) KW - presynaptic inhibition KW - NaV1.8 KW - spinal dorsal horn KW - punctate mechanical allodynia KW - c-fos KW - electrical excitability KW - activity-dependent slowing Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-286081 SN - 2073-4409 VL - 11 IS - 15 ER - TY - JOUR A1 - Salvador, Ellaine A1 - Köppl, Theresa A1 - Hörmann, Julia A1 - Schönhärl, Sebastian A1 - Bugaeva, Polina A1 - Kessler, Almuth F. A1 - Burek, Malgorzata A1 - Ernestus, Ralf-Ingo A1 - Löhr, Mario A1 - Hagemann, Carsten T1 - Tumor Treating Fields (TTFields) induce cell junction alterations in a human 3D in vitro model of the blood-brain barrier JF - Pharmaceutics N2 - In a recent study, we showed in an in vitro murine cerebellar microvascular endothelial cell (cerebEND) model as well as in vivo in rats that Tumor-Treating Fields (TTFields) reversibly open the blood–brain barrier (BBB). This process is facilitated by delocalizing tight junction proteins such as claudin-5 from the membrane to the cytoplasm. In investigating the possibility that the same effects could be observed in human-derived cells, a 3D co-culture model of the BBB was established consisting of primary microvascular brain endothelial cells (HBMVEC) and immortalized pericytes, both of human origin. The TTFields at a frequency of 100 kHz administered for 72 h increased the permeability of our human-derived BBB model. The integrity of the BBB had already recovered 48 h post-TTFields, which is earlier than that observed in cerebEND. The data presented herein validate the previously observed effects of TTFields in murine models. Moreover, due to the fact that human cell-based in vitro models more closely resemble patient-derived entities, our findings are highly relevant for pre-clinical studies. KW - blood-brain barrier KW - Tumor-Treating Fields (TTFields) KW - CNS disorders KW - human brain microvascular endothelial cells (HBMVEC) KW - human cells KW - 3D in vitro model Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-304830 SN - 1999-4923 VL - 15 IS - 1 ER - TY - JOUR A1 - Schmitt, Elke A1 - Meybohm, Patrick A1 - Neef, Vanessa A1 - Baumgarten, Peter A1 - Bayer, Alexandra A1 - Choorapoikayil, Suma A1 - Friederich, Patrick A1 - Friedrich, Jens A1 - Geisen, Christof A1 - Güresir, Erdem A1 - Grünewald, Matthias A1 - Gutjahr, Martin A1 - Helmer, Philipp A1 - Herrmann, Eva A1 - Müller, Markus A1 - Narita, Diana A1 - Raadts, Ansgar A1 - Schwendner, Klaus A1 - Seifried, Erhard A1 - Stark, Patrick A1 - Steinbicker, Andrea U. A1 - Thoma, Josef A1 - Velten, Markus A1 - Weigt, Henry A1 - Wiesenack, Christoph A1 - Wittmann, Maria A1 - Zacharowski, Kai A1 - Piekarski, Florian T1 - Preoperative anaemia and red blood cell transfusion in patients with aneurysmal subarachnoid and intracerebral haemorrhage - a multicentre subanalysis of the German PBM Network Registry JF - Acta Neurochirurgica N2 - Purpose Anaemia is common in patients presenting with aneurysmal subarachnoid (aSAH) and intracerebral haemorrhage (ICH). In surgical patients, anaemia was identified as an idenpendent risk factor for postoperative mortality, prolonged hospital length of stay (LOS) and increased risk of red blood cell (RBC) transfusion. This multicentre cohort observation study describes the incidence and effects of preoperative anaemia in this critical patient collective for a 10-year period. Methods This multicentre observational study included adult in-hospital surgical patients diagnosed with aSAH or ICH of 21 German hospitals (discharged from 1 January 2010 to 30 September 2020). Descriptive, univariate and multivariate analyses were performed to investigate the incidence and association of preoperative anaemia with RBC transfusion, in-hospital mortality and postoperative complications in patients with aSAH and ICH. Results A total of n = 9081 patients were analysed (aSAH n = 5008; ICH n = 4073). Preoperative anaemia was present at 28.3% in aSAH and 40.9% in ICH. RBC transfusion rates were 29.9% in aSAH and 29.3% in ICH. Multivariate analysis revealed that preoperative anaemia is associated with a higher risk for RBC transfusion (OR = 3.25 in aSAH, OR = 4.16 in ICH, p < 0.001), for in-hospital mortality (OR = 1.48 in aSAH, OR = 1.53 in ICH, p < 0.001) and for several postoperative complications. Conclusions Preoperative anaemia is associated with increased RBC transfusion rates, in-hospital mortality and postoperative complications in patients with aSAH and ICH. KW - aneurysmal subarachnoid haemorrhage KW - intracerebral haemorrhage KW - anaemia KW - red blood cell transfusion KW - patient blood management Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-346754 VL - 164 ER - TY - JOUR A1 - Herrmann, Johannes A1 - Adam, Elisabeth Hannah A1 - Notz, Quirin A1 - Helmer, Philipp A1 - Sonntagbauer, Michael A1 - Ungemach-Papenberg, Peter A1 - Sanns, Andreas A1 - Zausig, York A1 - Steinfeldt, Thorsten A1 - Torje, Iuliu A1 - Schmid, Benedikt A1 - Schlesinger, Tobias A1 - Rolfes, Caroline A1 - Reyher, Christian A1 - Kredel, Markus A1 - Stumpner, Jan A1 - Brack, Alexander A1 - Wurmb, Thomas A1 - Gill-Schuster, Daniel A1 - Kranke, Peter A1 - Weismann, Dirk A1 - Klinker, Hartwig A1 - Heuschmann, Peter A1 - Rücker, Viktoria A1 - Frantz, Stefan A1 - Ertl, Georg A1 - Muellenbach, Ralf Michael A1 - Mutlak, Haitham A1 - Meybohm, Patrick A1 - Zacharowski, Kai A1 - Lotz, Christopher T1 - COVID-19 Induced Acute Respiratory Distress Syndrome — A Multicenter Observational Study JF - Frontiers in Medicine N2 - Background: Proportions of patients dying from the coronavirus disease-19 (COVID-19) vary between different countries. We report the characteristics; clinical course and outcome of patients requiring intensive care due to COVID-19 induced acute respiratory distress syndrome (ARDS). Methods: This is a retrospective, observational multicentre study in five German secondary or tertiary care hospitals. All patients consecutively admitted to the intensive care unit (ICU) in any of the participating hospitals between March 12 and May 4, 2020 with a COVID-19 induced ARDS were included. Results: A total of 106 ICU patients were treated for COVID-19 induced ARDS, whereas severe ARDS was present in the majority of cases. Survival of ICU treatment was 65.0%. Median duration of ICU treatment was 11 days; median duration of mechanical ventilation was 9 days. The majority of ICU treated patients (75.5%) did not receive any antiviral or anti-inflammatory therapies. Venovenous (vv) ECMO was utilized in 16.3%. ICU triage with population-level decision making was not necessary at any time. Univariate analysis associated older age, diabetes mellitus or a higher SOFA score on admission with non-survival during ICU stay. Conclusions: A high level of care adhering to standard ARDS treatments lead to a good outcome in critically ill COVID-19 patients. KW - COVID-19 KW - ARDS (acute respiratory distress syndrome) KW - intensive care medicine KW - pandemia KW - Germany Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-219834 SN - 2296-858X VL - 7 ER - TY - JOUR A1 - Riemer, Manuel A1 - Kranke, Peter A1 - Helf, Antonia A1 - Mayer, Debora A1 - Popp, Maria A1 - Schlesinger, Tobias A1 - Meybohm, Patrick A1 - Weibel, Stephanie T1 - Trial registration and selective outcome reporting in 585 clinical trials investigating drugs for prevention of postoperative nausea and vomiting JF - BMC Anesthesiology N2 - Background: Selective outcome reporting in clinical trials introduces bias in the body of evidence distorting clinical decision making. Trial registration aims to prevent this bias and is suggested by the International Committee of Medical Journal Editors (ICMJE) since 2004. Methods: The 585 randomized controlled trials (RCTs) published between 1965 and 2017 that were included in a recently published Cochrane review on antiemetic drugs for prevention of postoperative nausea and vomiting were selected. In a retrospective study, we assessed trial registration and selective outcome reporting by comparing study publications with their registered protocols according to the ‘Cochrane Risk of bias’ assessment tool 1.0. Results: In the Cochrane review, the first study which referred to a registered trial protocol was published in 2004. Of all 585 trials included in the Cochrane review, 334 RCTs were published in 2004 or later, of which only 22% (75/334) were registered. Among the registered trials, 36% (27/75) were pro- and 64% (48/75) were retrospectively registered. 41% (11/27) of the prospectively registered trials were free of selective outcome reporting bias, 22% (6/27) were incompletely registered and assessed as unclear risk, and 37% (10/27) were assessed as high risk. Major outcome discrepancies between registered and published high risk trials were a change from the registered primary to a published secondary outcome (32%), a new primary outcome (26%), and different outcome assessment times (26%). Among trials with high risk of selective outcome reporting 80% favoured at least one statistically significant result. Registered trials were assessed more often as ‘overall low risk of bias’ compared to non-registered trials (64% vs 28%). Conclusions: In 2017, 13 years after the ICMJE declared prospective protocol registration a necessity for reliable clinical studies, the frequency and quality of trial registration in the field of PONV is very poor. Selective outcome reporting reduces trustworthiness in findings of clinical trials. Investigators and clinicians should be aware that only following a properly registered protocol and transparently reporting of predefined outcomes, regardless of the direction and significance of the result, will ultimately strengthen the body of evidence in the field of PONV research in the future. KW - clinical trial KW - postoperative nausea and vomiting KW - selective outcome reporting KW - systematic review KW - trial registration Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-265518 VL - 21 ER - TY - JOUR A1 - Nowacka-Chmielewska, Marta A1 - Grabowska, Konstancja A1 - Grabowski, Mateusz A1 - Meybohm, Patrick A1 - Burek, Malgorzata A1 - Małecki, Andrzej T1 - Running from stress: neurobiological mechanisms of exercise-induced stress resilience JF - International Journal of Molecular Sciences N2 - Chronic stress, even stress of a moderate intensity related to daily life, is widely acknowledged to be a predisposing or precipitating factor in neuropsychiatric diseases. There is a clear relationship between disturbances induced by stressful stimuli, especially long-lasting stimuli, and cognitive deficits in rodent models of affective disorders. Regular physical activity has a positive effect on the central nervous system (CNS) functions, contributes to an improvement in mood and of cognitive abilities (including memory and learning), and is correlated with an increase in the expression of the neurotrophic factors and markers of synaptic plasticity as well as a reduction in the inflammatory factors. Studies published so far show that the energy challenge caused by physical exercise can affect the CNS by improving cellular bioenergetics, stimulating the processes responsible for the removal of damaged organelles and molecules, and attenuating inflammation processes. Regular physical activity brings another important benefit: increased stress robustness. The evidence from animal studies is that a sedentary lifestyle is associated with stress vulnerability, whereas a physically active lifestyle is associated with stress resilience. Here, we have performed a comprehensive PubMed Search Strategy for accomplishing an exhaustive literature review. In this review, we discuss the findings from experimental studies on the molecular and neurobiological mechanisms underlying the impact of exercise on brain resilience. A thorough understanding of the mechanisms underlying the neuroprotective potential of preconditioning exercise and of the role of exercise in stress resilience, among other things, may open further options for prevention and therapy in the treatment of CNS diseases. KW - stress KW - stress resilience KW - anxiety KW - depression KW - neuropsychiatric disorders KW - physical activity KW - exercise Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-297407 SN - 1422-0067 VL - 23 IS - 21 ER - TY - JOUR A1 - Feldheim, Jonas A1 - Wend, David A1 - Lauer, Mara J. A1 - Monoranu, Camelia M. A1 - Glas, Martin A1 - Kleinschnitz, Christoph A1 - Ernestus, Ralf-Ingo A1 - Braunger, Barbara M. A1 - Meybohm, Patrick A1 - Hagemann, Carsten A1 - Burek, Malgorzata T1 - Protocadherin Gamma C3 (PCDHGC3) is strongly expressed in glioblastoma and its high expression is associated with longer progression-free survival of patients JF - International Journal of Molecular Sciences N2 - Protocadherins (PCDHs) belong to the cadherin superfamily and represent the largest subgroup of calcium-dependent adhesion molecules. In the genome, most PCDHs are arranged in three clusters, α, β, and γ on chromosome 5q31. PCDHs are highly expressed in the central nervous system (CNS). Several PCDHs have tumor suppressor functions, but their individual role in primary brain tumors has not yet been elucidated. Here, we examined the mRNA expression of PCDHGC3, a member of the PCDHγ cluster, in non-cancerous brain tissue and in gliomas of different World Health Organization (WHO) grades and correlated it with the clinical data of the patients. We generated a PCDHGC3 knockout U343 cell line and examined its growth rate and migration in a wound healing assay. We showed that PCDHGC3 mRNA and protein were significantly overexpressed in glioma tissue compared to a non-cancerous brain specimen. This could be confirmed in glioma cell lines. High PCDHGC3 mRNA expression correlated with longer progression-free survival (PFS) in glioma patients. PCDHGC3 knockout in U343 resulted in a slower growth rate but a significantly faster migration rate in the wound healing assay and decreased the expression of several genes involved in WNT signaling. PCDHGC3 expression should therefore be further investigated as a PFS-marker in gliomas. However, more studies are needed to elucidate the molecular mechanisms underlying the PCDHGC3 effects. KW - glioblastoma multiforme KW - glioma KW - astrocytoma KW - recurrence KW - relapse KW - mRNA KW - protein KW - brain KW - expression KW - PCDHGC3 KW - WNT signaling Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-284433 SN - 1422-0067 VL - 23 IS - 15 ER - TY - JOUR A1 - Gabbert, Lydia A1 - Dilling, Christina A1 - Meybohm, Patrick A1 - Burek, Malgorzata T1 - Deletion of Protocadherin Gamma C3 Induces Phenotypic and Functional Changes in Brain Microvascular Endothelial Cells In Vitro JF - Frontiers in Pharmacology N2 - Inflammation of the central nervous system (CNS) is associated with diseases such as multiple sclerosis, stroke and neurodegenerative diseases. Compromised integrity of the blood-brain barrier (BBB) and increased migration of immune cells into the CNS are the main characteristics of brain inflammation. Clustered protocadherins (Pcdhs) belong to a large family of cadherin-related molecules. Pcdhs are highly expressed in the CNS in neurons, astrocytes, pericytes and epithelial cells of the choroid plexus and, as we have recently demonstrated, in brain microvascular endothelial cells (BMECs). Knockout of a member of the Pcdh subfamily, PcdhgC3, resulted in significant changes in the barrier integrity of BMECs. Here we characterized the endothelial PcdhgC3 knockout (KO) cells using paracellular permeability measurements, proliferation assay, wound healing assay, inhibition of signaling pathways, oxygen/glucose deprivation (OGD) and a pro-inflammatory cytokine tumor necrosis factor alpha (TNFα) treatment. PcdhgC3 KO showed an increased paracellular permeability, a faster proliferation rate, an altered expression of efflux pumps, transporters, cellular receptors, signaling and inflammatory molecules. Serum starvation led to significantly higher phosphorylation of extracellular signal-regulated kinases (Erk) in KO cells, while no changes in phosphorylated Akt kinase levels were found. PcdhgC3 KO cells migrated faster in the wound healing assay and this migration was significantly inhibited by respective inhibitors of the MAPK-, β-catenin/Wnt-, mTOR- signaling pathways (SL327, XAV939, or Torin 2). PcdhgC3 KO cells responded stronger to OGD and TNFα by significantly higher induction of interleukin 6 mRNA than wild type cells. These results suggest that PcdhgC3 is involved in the regulation of major signaling pathways and the inflammatory response of BMECs. KW - blood-brain barrier KW - protocadherin gamma C3 KW - inflammation KW - oxygen/glucose deprivation KW - stroke KW - tumor necrosis factor-α KW - proliferation Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-219828 SN - 1663-9812 VL - 11 ER - TY - JOUR A1 - Hill, Aileen A1 - Dossow, Vera von A1 - Heyland, Daren K. A1 - Rossaint, Rolf A1 - Meybohm, Patrick A1 - Fox, Henrik A1 - Morshuis, Michiel A1 - Elke, Gunnar A1 - Panholzer, Bernd A1 - Haneya, Assad A1 - Böning, Andreas A1 - Niemann, Bernd A1 - Zayat, Rashad A1 - Moza, Ajay A1 - Stoppe, Christian T1 - Preoperative nutritional optimization and physical exercise for patients scheduled for elective implantation for a left-ventricular assist device — The PROPER-LVAD study JF - Surgeries N2 - Background: Prehabilitation is gaining increasing interest and shows promising effects on short- and long-term outcomes among patients undergoing major surgery. The effect of multimodal, interdisciplinary prehabilitation has not yet been studied in patients with severe heart failure scheduled for the implantation of a left-ventricular assist device (LVAD). Methods: This randomized controlled multi-center study evaluates the effect of preoperative combined optimization of nutritional and functional status. Patients in the intervention group are prescribed daily in-bed cycling and oral nutrition supplements (ONS) from study inclusion until the day before LVAD-implantation. Patients in the control group receive standard of care treatment. The primary outcomes for the pilot study that involves 48 patients are safety (occurrence of adverse events), efficacy (group separation regarding the intake of macronutrients), feasibility of the trial protocol (compliance (percentage of received interventions) and confirmation of recruitment rates. Secondary outcomes include longitudinal measurements of muscle mass, muscle strength, physical function and quality of life, next to traditional clinical outcomes (30-day mortality, hospital and ICU length of stay, duration of mechanical ventilation and number of complications and infections). If the pilot study is successful, a larger confirmatory, international multicenter study is warranted. KW - prehabilitation KW - medical nutrition therapy KW - in-bed cycling KW - left-ventricular assist device KW - trial protocol KW - clinical trial KW - oral nutrition supplements Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-288317 SN - 2673-4095 N1 - Funding: This investigator-initiated trial is supported by a grant from Fresenius Kabi Deutschland (Fresenius Kabi Deutschland GmbH, Else-Kröner-Straße 1, 61352 Bad Homburg). The oral nutrition supplements (Fresubin PRO®) are provided by Fresenius Kabi Germany. VL - 3 IS - 4 SP - 284 EP - 296 ER - TY - JOUR A1 - Helmer, Philipp A1 - Helf, Daniel A1 - Sammeth, Michael A1 - Winkler, Bernd A1 - Hottenrott, Sebastian A1 - Meybohm, Patrick A1 - Kranke, Peter T1 - The use of non-invasive continuous blood pressure measuring (ClearSight\(^®\)) during central neuraxial anaesthesia for caesarean section — a retrospective validation study JF - Journal of Clinical Medicine N2 - Background: The close monitoring of blood pressure during a caesarean section performed under central neuraxial anaesthesia should be the standard of safe anaesthesia. As classical oscillometric and invasive blood pressure measuring have intrinsic disadvantages, we investigated a novel, non-invasive technique for continuous blood pressure measuring. Methods: In this monocentric, retrospective data analysis, the reliability of continuous non-invasive blood pressure measuring using ClearSight\(^®\) (Edwards Lifesciences Corporation) is validated in 31 women undergoing central neuraxial anaesthesia for caesarean section. In addition, patients and professionals evaluated ClearSight\(^®\) through questioning. Results: 139 measurements from 11 patients were included in the final analysis. Employing Bland–Altman analyses, we identified a bias of −10.8 mmHg for systolic, of −0.45 mmHg for diastolic and of +0.68 mmHg for mean arterial blood pressure measurements. Pooling all paired measurements resulted in a Pearson correlation coefficient of 0.7 for systolic, of 0.67 for diastolic and of 0.75 for mean arterial blood pressure. Compensating the interindividual differences in linear regressions of the paired measurements provided improved correlation coefficients of 0.73 for systolic, of 0.9 for diastolic and of 0.89 for mean arterial blood pressure measurements. Discussion: Diastolic and mean arterial blood pressure are within an acceptable range of deviation from the reference method, according to the Association for the Advancement of Medical Instrumentation (AAMI) in the patient collective under study. Both patients and professionals prefer ClearSight\(^®\) to oscillometric blood pressure measurement in regard of comfort and handling. KW - volume clamp KW - epidural anaesthesia KW - supine hypotensive syndrome KW - ClearSight\(^®\) KW - Bland–Altman KW - Fisher Z-score transformation KW - Pearson correlation coefficient Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-286042 SN - 2077-0383 VL - 11 IS - 15 ER - TY - JOUR A1 - Herrmann, Johannes A1 - Notz, Quirin A1 - Schlesinger, Tobias A1 - Stumpner, Jan A1 - Kredel, Markus A1 - Sitter, Magdalena A1 - Schmid, Benedikt A1 - Kranke, Peter A1 - Schulze, Harald A1 - Meybohm, Patrick A1 - Lotz, Christopher T1 - Point of care diagnostic of hypercoagulability and platelet function in COVID-19 induced acute respiratory distress syndrome: a retrospective observational study JF - Thrombosis Journal N2 - Background Coronavirus disease 2019 (COVID-19) associated coagulopathy (CAC) leads to thromboembolic events in a high number of critically ill COVID-19 patients. However, specific diagnostic or therapeutic algorithms for CAC have not been established. In the current study, we analyzed coagulation abnormalities with point-of-care testing (POCT) and their relation to hemostatic complications in patients suffering from COVID-19 induced Acute Respiratory Distress Syndrome (ARDS). Our hypothesis was that specific diagnostic patterns can be identified in patients with COVID-19 induced ARDS at risk of thromboembolic complications utilizing POCT. Methods This is a single-center, retrospective observational study. Longitudinal data from 247 rotational thromboelastometries (Rotem®) and 165 impedance aggregometries (Multiplate®) were analysed in 18 patients consecutively admitted to the ICU with a COVID-19 induced ARDS between March 12th to June 30th, 2020. Results Median age was 61 years (IQR: 51–69). Median PaO2/FiO2 on admission was 122 mmHg (IQR: 87–189), indicating moderate to severe ARDS. Any form of hemostatic complication occurred in 78 % of the patients with deep vein/arm thrombosis in 39 %, pulmonary embolism in 22 %, and major bleeding in 17 %. In Rotem® elevated A10 and maximum clot firmness (MCF) indicated higher clot strength. The delta between EXTEM A10 minus FIBTEM A10 (ΔA10) > 30 mm, depicting the sole platelet-part of clot firmness, was associated with a higher risk of thromboembolic events (OD: 3.7; 95 %CI 1.3–10.3; p = 0.02). Multiplate® aggregometry showed hypoactive platelet function. There was no correlation between single Rotem® and Multiplate® parameters at intensive care unit (ICU) admission and thromboembolic or bleeding complications. Conclusions Rotem® and Multiplate® results indicate hypercoagulability and hypoactive platelet dysfunction in COVID-19 induced ARDS but were all in all poorly related to hemostatic complications.. KW - COVID-19 KW - acute Respiratory Distress Syndrome KW - point of care testing KW - thromboelastometry KW - impedance aggregometry; WHOLE-BLOOD THROMBOELASTOMETRY; DEFINITION; DISEASE Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-260739 VL - 19 IS - 1 ER - TY - JOUR A1 - Fiedler, Mascha O. A1 - Muellenbach, Ralf M. A1 - Rolfes, Caroline A1 - Lotz, Christopher A1 - Nickel, Felix A1 - Müller-Stich, Beat P. A1 - Supady, Alexander A1 - Lepper, Philipp M. A1 - Weigand, Markus A. A1 - Meybohm, Patrick A1 - Kalenka, Armin A1 - Reyher, Christian T1 - Pumpless extracorporeal hemadsorption technique (pEHAT): a proof-of-concept animal study JF - Journal of Clinical Medicine N2 - Background: Extracorporeal hemadsorption eliminates proinflammatory mediators in critically ill patients with hyperinflammation. The use of a pumpless extracorporeal hemadsorption technique allows its early usage prior to organ failure and the need for an additional medical device. In our animal model, we investigated the feasibility of pumpless extracorporeal hemadsorption over a wide range of mean arterial pressures (MAP). Methods: An arteriovenous shunt between the femoral artery and femoral vein was established in eight pigs. The hemadsorption devices were inserted into the shunt circulation; four pigs received CytoSorb\(^®\) and four Oxiris\(^®\) hemadsorbers. Extracorporeal blood flow was measured in a range between mean arterial pressures of 45–85 mmHg. Mean arterial pressures were preset using intravenous infusions of noradrenaline, urapidil, or increased sedatives. Results: Extracorporeal blood flows remained well above the minimum flows recommended by the manufacturers throughout all MAP steps for both devices. Linear regression resulted in CytoSorb\(^®\) blood flow [mL/min] = 4.226 × MAP [mmHg] − 3.496 (R-square 0.8133) and Oxiris\(^®\) blood flow [mL/min] = 3.267 × MAP [mmHg] + 57.63 (R-square 0.8708), respectively. Conclusion: Arteriovenous pumpless extracorporeal hemadsorption resulted in sufficient blood flows through both the CytoSorb\(^®\) and Oxiris\(^®\) devices over a wide range of mean arterial blood pressures and is likely an intriguing therapeutic option in the early phase of septic shock or hyperinflammatory syndromes. KW - blood purification KW - extracorporeal hemadsorption KW - cytokines KW - adsorption KW - animal model KW - immunosorbents KW - septic shock KW - endotoxin KW - extracorporeal techniques in hemadsorption therapy KW - arteriovenous extracorporeal hemadsorption technique Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-297347 SN - 2077-0383 VL - 11 IS - 22 ER - TY - JOUR A1 - Notz, Quirin A1 - Lotz, Christopher A1 - Herrmann, Johannes A1 - Vogt, Marius A1 - Schlesinger, Tobias A1 - Kredel, Markus A1 - Muellges, Wolfgang A1 - Weismann, Dirk A1 - Westermaier, Thomas A1 - Meybohm, Patrick A1 - Kranke, Peter T1 - Severe neurological complications in critically ill COVID‑19 patients JF - Journal of Neurology N2 - No abstract available. KW - COVID-19 KW - neurological complications Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-232429 SN - 0340-5354 ER - TY - JOUR A1 - Schmid, Benedikt A1 - Kredel, Markus A1 - Ullrich, Roman A1 - Krenn, Katharina A1 - Lucas, Rudolf A1 - Markstaller, Klaus A1 - Fischer, Bernhard A1 - Kranke, Peter A1 - Meybohm, Patrick A1 - Zwißler, Bernhard A1 - Frank, Sandra T1 - Safety and preliminary efficacy of sequential multiple ascending doses of solnatide to treat pulmonary permeability edema in patients with moderate-to-severe ARDS - a randomized, placebo-controlled, double-blind trial JF - Trials N2 - Background Acute respiratory distress syndrome (ARDS) is a complex clinical diagnosis with various possible etiologies. One common feature, however, is pulmonary permeability edema, which leads to an increased alveolar diffusion pathway and, subsequently, impaired oxygenation and decarboxylation. A novel inhaled peptide agent (AP301, solnatide) was shown to markedly reduce pulmonary edema in animal models of ARDS and to be safe to administer to healthy humans in a Phase I clinical trial. Here, we present the protocol for a Phase IIB clinical trial investigating the safety and possible future efficacy endpoints in ARDS patients. Methods This is a randomized, placebo-controlled, double-blind intervention study. Patients with moderate to severe ARDS in need of mechanical ventilation will be randomized to parallel groups receiving escalating doses of solnatide or placebo, respectively. Before advancing to a higher dose, a data safety monitoring board will investigate the data from previous patients for any indication of patient safety violations. The intervention (application of the investigational drug) takes places twice daily over the course of 7 days, ensued by a follow-up period of another 21 days. Discussion The patients to be included in this trial will be severely sick and in need of mechanical ventilation. The amount of data to be collected upon screening and during the course of the intervention phase is substantial and the potential timeframe for inclusion of any given patient is short. However, when prepared properly, adherence to this protocol will make for the acquisition of reliable data. Particular diligence needs to be exercised with respect to informed consent, because eligible patients will most likely be comatose and/or deeply sedated at the time of inclusion. Trial registration This trial was prospectively registered with the EU Clinical trials register (clinicaltrialsregister.eu). EudraCT Number: 2017-003855-47. KW - acute respiratory distress syndrome KW - solnatide KW - extravascular lung water KW - pulmonary edema KW - critical care Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-258783 VL - 22 IS - 1 ER - TY - JOUR A1 - Helmer, Philipp A1 - Hottenrott, Sebastian A1 - Steinisch, Andreas A1 - Röder, Daniel A1 - Schubert, Jörg A1 - Steigerwald, Udo A1 - Choorapoikayil, Suma A1 - Meybohm, Patrick T1 - Avoidable blood loss in critical care and patient blood management: scoping review of diagnostic blood loss JF - Journal of Clinical Medicine N2 - Background: Anemia remains one of the most common comorbidities in intensive care patients worldwide. The cause of anemia is often multifactorial and triggered by underlying disease, comorbidities, and iatrogenic factors, such as diagnostic phlebotomies. As anemia is associated with a worse outcome, especially in intensive care patients, unnecessary iatrogenic blood loss must be avoided. Therefore, this scoping review addresses the amount of blood loss during routine phlebotomies in adult (>17 years) intensive care patients and whether there are factors that need to be improved in terms of patient blood management (PBM). Methods: A systematic search of the Medline Database via PubMed was conducted according to PRISMA guidelines. The reported daily blood volume for diagnostics and other relevant information from eligible studies were charted. Results: A total of 2167 studies were identified in our search, of which 38 studies met the inclusion criteria (9 interventional studies and 29 observational studies). The majority of the studies were conducted in the US (37%) and Canada (13%). An increasing interest to reduce iatrogenic blood loss has been observed since 2015. Phlebotomized blood volume per patient per day was up to 377 mL. All interventional trials showed that the use of pediatric-sized blood collection tubes can significantly reduce the daily amount of blood drawn. Conclusion: Iatrogenic blood loss for diagnostic purposes contributes significantly to the development and exacerbation of hospital-acquired anemia. Therefore, a comprehensive PBM in intensive care is urgently needed to reduce avoidable blood loss, including blood-sparing techniques, regular advanced training, and small-volume blood collection tubes. KW - PBM KW - critically ill KW - intensive care KW - iatrogenic anemia KW - avoidable blood loss KW - diagnostic blood loss Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-255145 SN - 2077-0383 VL - 11 IS - 2 ER - TY - JOUR A1 - Schrader, Nikolas A1 - Riese, Thorsten A1 - Kurlbaum, Max A1 - Meybohm, Patrick A1 - Kredel, Markus A1 - Surat, Güzin A1 - Scherf-Clavel, Oliver A1 - Strate, Alexander A1 - Pospiech, Andreas A1 - Hoppe, Kerstin T1 - Personalized antibiotic therapy for the critically ill: Implementation strategies and effects on clinical outcome of piperacillin therapeutic drug monitoring — a descriptive retrospective analysis JF - Antibiotics N2 - Therapeutic drug monitoring (TDM) is increasingly relevant for an individualized antibiotic therapy and subsequently a necessary tool to reduce multidrug-resistant pathogens, especially in light of diminishing antimicrobial capabilities. Critical illness is associated with profound pharmacokinetic and pharmacodynamic alterations, which challenge dose finding and the application of particularly hydrophilic drugs such as β-lactam antibiotics. Methods: Implementation strategy, potential benefit, and practicability of the developed standard operating procedures were retrospectively analyzed from January to December 2020. Furthermore, the efficacy of the proposed dosing target of piperacillin in critically ill patients was evaluated. Results: In total, 160 patients received piperacillin/tazobactam therapy and were subsequently included in the study. Of them, 114 patients received piperacillin/tazobactam by continuous infusion and had at least one measurement of piperacillin serum level according to the standard operating procedure. In total, 271 measurements were performed with an average level of 79.0 ± 46.0 mg/L. Seventy-one piperacillin levels exceeded 100 mg/L and six levels were lower than 22.5 mg/L. The high-level and the low-level group differed significantly in infection laboratory parameters (CRP (mg/dL) 20.18 ± 11.71 vs. 5.75 ± 5.33) and renal function [glomerular filtration rate (mL/min/1.75 m2) 40.85 ± 26.74 vs. 120.50 ± 70.48]. Conclusions: Piperacillin levels are unpredictable in critically ill patients. TDM during piperacillin/tazobactam therapy is highly recommended for all patients. Although our implementation strategy was effective, further strategies implemented into the daily clinical workflow might support the health care staff and increase the clinicians' alertness. KW - therapeutic drug monitoring KW - piperacillin/tazobactam KW - personalized antimicrobial therapy KW - antimicrobial stewardship Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-250052 SN - 2079-6382 VL - 10 IS - 12 ER - TY - JOUR A1 - Sitter, Magdalena A1 - Pecks, Ulrich A1 - Rüdiger, Mario A1 - Friedrich, Sabine A1 - Fill Malfertheiner, Sara A1 - Hein, Alexander A1 - Königbauer, Josefine T. A1 - Becke-Jakob, Karin A1 - Zöllkau, Janine A1 - Ramsauer, Babett A1 - Rathberger, Katharina A1 - Pontones, Constanza A. A1 - Kraft, Katrina A1 - Meybohm, Patrick A1 - Härtel, Christoph A1 - Kranke, Peter T1 - Pregnant and postpartum women requiring intensive care treatment for COVID-19 — first data from the CRONOS-registry JF - Journal of Clinical Medicine N2 - (1) Background: Data on coronavirus 2 infection during pregnancy vary. We aimed to describe maternal characteristics and clinical presentation of SARS-CoV-2 positive women requiring intensive care treatment for COVID-19 during pregnancy and postpartum period based on data of a comprehensive German surveillance system in obstetric patients. (2) Methods: Data from COVID-19 Related Obstetric and Neonatal Outcome Study (CRONOS), a prospective multicenter registry for SARS-CoV-2 positive pregnant women, was analyzed with respect to ICU treatment. All women requiring intensive care treatment for COVID-19 were included and compared regarding maternal characteristics, course of disease, as well as maternal and neonatal outcomes. (3) Results: Of 2650 cases in CRONOS, 101 women (4%) had a documented ICU stay. Median maternal age was 33 (IQR, 30–36) years. COVID-19 was diagnosed at a median gestational age of 33 (IQR, 28–35) weeks. As the most invasive form of COVID-19 treatment interventions, patients received either continuous monitoring of vital signs without further treatment requirement (n = 6), insufflation of oxygen (n = 30), non-invasive ventilation (n = 22), invasive ventilation (n = 28), or escalation to extracorporeal membrane oxygenation (n = 15). No significant clinical differences were identified between patients receiving different forms of ventilatory support for COVID-19. Prevalence of preterm delivery was significantly higher in women receiving invasive respiratory treatments. Four women died of COVID-19 and six fetuses were stillborn. (4) Conclusions: Our cohort shows that progression of COVID-19 is rare in pregnant and postpartum women treated in the ICU. Preterm birth rate is high and COVID-19 requiring respiratory support increases the risk of poor maternal and neonatal outcome. KW - maternal critical care KW - COVID-19 KW - ARDS KW - SARS-CoV-2 KW - pregnancy KW - obstetrics Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-255257 SN - 2077-0383 VL - 11 IS - 3 ER - TY - JOUR A1 - Weibel, Stephanie A1 - Pace, Nathan L. A1 - Schaefer, Maximilian S. A1 - Raj, Diana A1 - Schlesinger, Tobias A1 - Meybohm, Patrick A1 - Kienbaum, Peter A1 - Eberhart, Leopold H. J. A1 - Kranke, Peter T1 - Drugs for preventing postoperative nausea and vomiting in adults after general anesthesia: An abridged Cochrane network meta-analysis JF - Journal of Evidence-Based Medicine N2 - Objective In this abridged version of the recently published Cochrane review on antiemetic drugs, we summarize its most important findings and discuss the challenges and the time needed to prepare what is now the largest Cochrane review with network meta-analysis in terms of the number of included studies and pages in its full printed form. Methods We conducted a systematic review with network meta-analyses to compare and rank single antiemetic drugs and their combinations belonging to 5HT₃-, D₂-, NK₁-receptor antagonists, corticosteroids, antihistamines, and anticholinergics used to prevent postoperative nausea and vomiting in adults after general anesthesia. Results 585 studies (97 516 participants) testing 44 single drugs and 51 drug combinations were included. The studies’ overall risk of bias was assessed as low in only 27% of the studies. In 282 studies, 29 out of 36 drug combinations and 10 out of 28 single drugs lowered the risk of vomiting at least 20% compared to placebo. In the ranking of treatments, combinations of drugs were generally more effective than single drugs. Single NK1 receptor antagonists were as effective as other drug combinations. Of the 10 effective single drugs, certainty of evidence was high for aprepitant, ramosetron, granisetron, dexamethasone, and ondansetron, while moderate for fosaprepitant and droperidol. For serious adverse events (SAEs), any adverse event (AE), and drug-class specific side effects evidence for intervention effects was mostly not convincing. Conclusions There is high or moderate evidence for at least seven single drugs preventing postoperative vomiting. However, there is still considerable lack of evidence regarding safety aspects that does warrant investigation. KW - systematic review, KW - antiemetics KW - network meta-analysis KW - postoperative nausea and vomiting KW - vomiting Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-259470 VL - 14 IS - 3 ER - TY - JOUR A1 - Schlesinger, Tobias A1 - Weibel, Stephanie A1 - Steinfeldt, Thorsten A1 - Sitter, Magdalena A1 - Meybohm, Patrick A1 - Kranke, Peter T1 - Intraoperative management of combined general anesthesia and thoracic epidural analgesia: A survey among German anesthetists JF - Acta Anaesthesiologica Scandinavica N2 - Background Evidence concerning combined general anesthesia (GA) and thoracic epidural analgesia (EA) is controversial and the procedure appears heterogeneous in clinical implementation. We aimed to gain an overview of different approaches and to unveil a suspected heterogeneity concerning the intraoperative management of combined GA and EA. Methods This was an anonymous survey among Members of the Scientific working group for regional anesthesia within the German Society of Anaesthesiology and Intensive Care Medicine (DGAI) conducted from February 2020 to August 2020. Results The response rate was 38%. The majority of participants were experienced anesthetists with high expertise for the specific regimen of combined GA and EA. Most participants establish EA in the sitting position (94%), prefer early epidural initiation (prior to skin incision: 80%; intraoperative: 14%) and administer ropivacaine (89%) in rather low concentrations (0.2%: 45%; 0.375%: 30%; 0.75%: 15%) mostly with an opioid (84%) in a bolus-based mode (95%). The majority reduce systemic opioid doses intraoperatively if EA works sufficiently (minimal systemic opioids: 58%; analgesia exclusively via EA: 34%). About 85% manage intraoperative EA insufficiency with systemic opioids, 52% try to escalate EA, and only 25% use non-opioids, e.g. intravenous ketamine or lidocaine. Conclusions Although, consensus seems to be present for several aspects (patient's position during epidural puncture, main epidural substance, application mode), there is considerable heterogeneity regarding systemic opioids, rescue strategies for insufficient EA, and hemodynamic management, which might explain inconsistent results of previous trials and meta-analyses. KW - analgesics KW - enhanced recovery after surgery KW - multimodal treatments KW - perioperative care KW - epidural analgesia Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-258286 VL - 65 IS - 10 ER - TY - JOUR A1 - Lotz, Christopher A1 - Notz, Quirin A1 - Kranke, Peter A1 - Kredel, Markus A1 - Meybohm, Patrick T1 - Unconventional approaches to mechanical ventilation - step-by-step through the COVID-19 crisis JF - Critical Care N2 - No abstract available. KW - COVID 19 KW - mechanical ventilation Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-229868 VL - 24 ER - TY - JOUR A1 - Averdunk, Luisa A1 - Bernhagen, Jürgen A1 - Fehnle, Karl A1 - Surowy, Harald A1 - Lüdecke, Hermann-Josef A1 - Mucha, Sören A1 - Meybohm, Patrick A1 - Wieczorek, Dagmar A1 - Leng, Lin A1 - Marx, Gernot A1 - Leaf, David E. A1 - Zarbock, Alexander A1 - Zacharowski, Kai A1 - Bucala, Richard A1 - Stoppe, Christian T1 - The Macrophage Migration Inhibitory Factor (MIF) promoter polymorphisms (rs3063368, rs755622) predict acute kidney injury and death after cardiac surgery JF - Journal of Clinical Medicine N2 - Background: Macrophage Migration Inhibitory Factor (MIF) is highly elevated after cardiac surgery and impacts the postoperative inflammation. The aim of this study was to analyze whether the polymorphisms CATT\(_{5–7}\) (rs5844572/rs3063368,“-794”) and G>C single-nucleotide polymorphism (rs755622,-173) in the MIF gene promoter are related to postoperative outcome. Methods: In 1116 patients undergoing cardiac surgery, the MIF gene polymorphisms were analyzed and serum MIF was measured by ELISA in 100 patients. Results: Patients with at least one extended repeat allele (CATT\(_7\)) had a significantly higher risk of acute kidney injury (AKI) compared to others (23% vs. 13%; OR 2.01 (1.40–2.88), p = 0.0001). Carriers of CATT\(_7\) were also at higher risk of death (1.8% vs. 0.4%; OR 5.12 (0.99–33.14), p = 0.026). The GC genotype was associated with AKI (20% vs. GG/CC:13%, OR 1.71 (1.20–2.43), p = 0.003). Multivariate analyses identified CATT\(_7\) predictive for AKI (OR 2.13 (1.46–3.09), p < 0.001) and death (OR 5.58 (1.29–24.04), p = 0.021). CATT\(_7\) was associated with higher serum MIF before surgery (79.2 vs. 50.4 ng/mL, p = 0.008). Conclusion: The CATT\(_7\) allele associates with a higher risk of AKI and death after cardiac surgery, which might be related to chronically elevated serum MIF. Polymorphisms in the MIF gene may constitute a predisposition for postoperative complications and the assessment may improve risk stratification and therapeutic guidance. KW - acute kidney injury KW - genetic polymorphisms KW - risk prediction KW - (cardiac) surgery KW - inflammatory cytokines KW - clinical studies Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-213126 SN - 2077-0383 VL - 9 IS - 9 ER - TY - JOUR A1 - Fischer, Dania A1 - Thies, Fabian A1 - Awad, Omar A1 - Brat, Camilla A1 - Meybohm, Patrick A1 - Baer, Patrick C. A1 - Müller, Markus M. A1 - Urbschat, Anja A1 - Maier, Thorsten J. A1 - Zacharowski, Kai A1 - Roos, Jessica T1 - Red blood cell-derived microparticles exert no cancer promoting effects on colorectal cancer cells in vitro JF - International Journal of Molecular Sciences N2 - The biomedical consequences of allogeneic blood transfusions and the possible pathomechanisms of transfusion-related morbidity and mortality are still not entirely understood. In retrospective studies, allogeneic transfusion was associated with increased rates of cancer recurrence, metastasis and death in patients with colorectal cancer. However, correlation does not imply causation. The purpose of this study was to elucidate this empirical observation further in order to address insecurity among patients and clinicians. We focused on the in vitro effect of microparticles derived from red blood cell units (RMPs). We incubated different colon carcinoma cells with RMPs and analyzed their effects on growth, invasion, migration and tumor marker expression. Furthermore, effects on Wnt, Akt and ERK signaling were explored. Our results show RMPs do not seem to affect functional and phenotypic characteristics of different colon carcinoma cells and did not induce or inhibit Wnt, Akt or ERK signaling, albeit in cell culture models lacking tumor microenvironment. Allogeneic blood transfusions are associated with poor prognosis, but RMPs do not seem to convey tumor-enhancing effects. Most likely, the circumstances that necessitate the transfusion, such as preoperative anemia, tumor stage, perioperative blood loss and extension of surgery, take center stage. KW - transfusion KW - red blood cells KW - microparticles KW - colorectal carcinoma Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-286018 SN - 1422-0067 VL - 23 IS - 16 ER - TY - JOUR A1 - Reis, Stefanie A1 - Popp, Maria A1 - Schmid, Benedikt A1 - Stegemann, Miriam A1 - Metzendorf, Maria-Inti A1 - Kranke, Peter A1 - Meybohm, Patrick A1 - Weibel, Stephanie T1 - Safety and efficacy of intermediate- and therapeutic-dose anticoagulation for hospitalised patients with COVID-19: a systematic review and meta-analysis JF - Journal of Clinical Medicine N2 - Background: COVID-19 patients are at high thrombotic risk. The safety and efficacy of different anticoagulation regimens in COVID-19 patients remain unclear. Methods: We searched for randomised controlled trials (RCTs) comparing intermediate- or therapeutic-dose anticoagulation to standard thromboprophylaxis in hospitalised patients with COVID-19 irrespective of disease severity. To assess efficacy and safety, we meta-analysed data for all-cause mortality, clinical status, thrombotic event or death, and major bleedings. Results: Eight RCTs, including 5580 patients, were identified, with two comparing intermediate- and six therapeutic-dose anticoagulation to standard thromboprophylaxis. Intermediate-dose anticoagulation may have little or no effect on any thrombotic event or death (RR 1.03, 95% CI 0.86–1.24), but may increase major bleedings (RR 1.48, 95% CI 0.53–4.15) in moderate to severe COVID-19 patients. Therapeutic-dose anticoagulation may decrease any thrombotic event or death in patients with moderate COVID-19 (RR 0.64, 95% CI 0.38–1.07), but may have little or no effect in patients with severe disease (RR 0.98, 95% CI 0.86–1.12). The risk of major bleedings may increase independent of disease severity (RR 1.78, 95% CI 1.15–2.74). Conclusions: Certainty of evidence is still low. Moderately affected COVID-19 patients may benefit from therapeutic-dose anticoagulation, but the risk for bleeding is increased. KW - anticoagulant therapy KW - coronavirus disease 2019 KW - thrombosis KW - bleeding KW - death Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-252285 SN - 2077-0383 VL - 11 IS - 1 ER - TY - JOUR A1 - Curtaz, Carolin J. A1 - Schmitt, Constanze A1 - Herbert, Saskia-Laureen A1 - Feldheim, Jonas A1 - Schlegel, Nicolas A1 - Gosselet, Fabien A1 - Hagemann, Carsten A1 - Roewer, Norbert A1 - Meybohm, Patrick A1 - Wöckel, Achim A1 - Burek, Malgorzata T1 - Serum-derived factors of breast cancer patients with brain metastases alter permeability of a human blood-brain barrier model JF - Fluids and Barriers of the CNS N2 - Background The most threatening metastases in breast cancer are brain metastases, which correlate with a very poor overall survival, but also a limited quality of life. A key event for the metastatic progression of breast cancer into the brain is the migration of cancer cells across the blood-brain barrier (BBB). Methods We adapted and validated the CD34\(^+\) cells-derived human in vitro BBB model (brain-like endothelial cells, BLECs) to analyse the effects of patient serum on BBB properties. We collected serum samples from healthy donors, breast cancer patients with primary cancer, and breast cancer patients with, bone, visceral or cerebral metastases. We analysed cytokine levels in these sera utilizing immunoassays and correlated them with clinical data. We used paracellular permeability measurements, immunofluorescence staining, Western blot and mRNA analysis to examine the effects of patient sera on the properties of BBB in vitro. Results The BLECs cultured together with brain pericytes in transwells developed a tight monolayer with a correct localization of claudin-5 at the tight junctions (TJ). Several BBB marker proteins such as the TJ proteins claudin-5 and occludin, the glucose transporter GLUT-1 or the efflux pumps PG-P and BCRP were upregulated in these cultures. This was accompanied by a reduced paracellular permeability for fluorescein (400 Da). We then used this model for the treatment with the patient sera. Only the sera of breast cancer patients with cerebral metastases had significantly increased levels of the cytokines fractalkine (CX3CL1) and BCA-1 (CXCL13). The increased levels of fractalkine were associated with the estrogen/progesterone receptor status of the tumour. The treatment of BLECs with these sera selectively increased the expression of CXCL13 and TJ protein occludin. In addition, the permeability of fluorescein was increased after serum treatment. Conclusion We demonstrate that the CD34\(^+\) cell-derived human in vitro BBB model can be used as a tool to study the molecular mechanisms underlying cerebrovascular pathologies. We showed that serum from patients with cerebral metastases may affect the integrity of the BBB in vitro, associated with elevated concentrations of specific cytokines such as CX3CL1 and CXCL13. KW - Metastatic breast cancer KW - Blood–brain barrier KW - In vitro models KW - CX3CL1 KW - CXCL13 Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-229940 VL - 17 ER - TY - JOUR A1 - Schlesinger, Tobias A1 - Weißbrich, Benedikt A1 - Wedekink, Florian A1 - Notz, Quirin A1 - Herrmann, Johannes A1 - Krone, Manuel A1 - Sitter, Magdalena A1 - Schmid, Benedikt A1 - Kredel, Markus A1 - Stumpner, Jan A1 - Dölken, Lars A1 - Wischhusen, Jörg A1 - Kranke, Peter A1 - Meybohm, Patrick A1 - Lotz, Christpher T1 - Biodistribution and serologic response in SARS-CoV-2 induced ARDS: A cohort study JF - PLoS One N2 - Background The viral load and tissue distribution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remain important questions. The current study investigated SARS-CoV-2 viral load, biodistribution and anti-SARS-CoV-2 antibody formation in patients suffering from severe corona virus disease 2019 (COVID-19) induced acute respiratory distress syndrome (ARDS). Methods This is a retrospective single-center study in 23 patients with COVID-19-induced ARDS. Data were collected within routine intensive care. SARS-CoV-2 viral load was assessed via reverse transcription quantitative polymerase chain reaction (RT-qPCR). Overall, 478 virology samples were taken. Anti-SARS-CoV-2-Spike-receptor binding domain (RBD) antibody detection of blood samples was performed with an enzyme-linked immunosorbent assay. Results Most patients (91%) suffered from severe ARDS during ICU treatment with a 30-day mortality of 30%. None of the patients received antiviral treatment. Tracheal aspirates tested positive for SARS-CoV-2 in 100% of the cases, oropharyngeal swabs only in 77%. Blood samples were positive in 26% of the patients. No difference of viral load was found in tracheal or blood samples with regard to 30-day survival or disease severity. SARS-CoV-2 was never found in dialysate. Serologic testing revealed significantly lower concentrations of SARS-CoV-2 neutralizing IgM and IgA antibodies in survivors compared to non-survivors (p = 0.009). Conclusions COVID-19 induced ARDS is accompanied by a high viral load of SARS-CoV-2 in tracheal aspirates, which remained detectable in the majority throughout intensive care treatment. Remarkably, SARS-CoV-2 RNA was never detected in dialysate even in patients with RNAemia. Viral load or the buildup of neutralizing antibodies was not associated with 30-day survival or disease severity. KW - viral load Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-231348 VL - 15, 2020 IS - 11 ER - TY - JOUR A1 - Menger, Johannes A1 - Lee, Zheng-Yii A1 - Notz, Quirin A1 - Wallqvist, Julia A1 - Hasan, M. Shahnaz A1 - Elke, Gunnar A1 - Dworschak, Martin A1 - Meybohm, Patrick A1 - Heyland, Daren K. A1 - Stoppe, Christian T1 - Administration of vitamin D and its metabolites in critically ill adult patients: an updated systematic review with meta-analysis of randomized controlled trials JF - Critical Care N2 - Background The clinical significance of vitamin D administration in critically ill patients remains inconclusive. The purpose of this systematic review with meta-analysis was to investigate the effect of vitamin D and its metabolites on major clinical outcomes in critically ill patients, including a subgroup analysis based on vitamin D status and route of vitamin D administration. Methods Major databases were searched through February 9, 2022. Randomized controlled trials of adult critically ill patients with an intervention group receiving vitamin D or its metabolites were included. Random-effect meta-analyses were performed to estimate the pooled risk ratio (dichotomized outcomes) or mean difference (continuous outcomes). Risk of bias assessment included the Cochrane tool for assessing risk of bias in randomized trials. Results Sixteen randomized clinical trials with 2449 patients were included. Vitamin D administration was associated with lower overall mortality (16 studies: risk ratio 0.78, 95% confidence interval 0.62–0.97, p = 0.03; I2 = 30%), reduced intensive care unit length of stay (12 studies: mean difference − 3.13 days, 95% CI − 5.36 to − 0.89, n = 1250, p = 0.006; I2 = 70%), and shorter duration of mechanical ventilation (9 studies: mean difference − 5.07 days, 95% CI − 7.42 to − 2.73, n = 572, p < 0.0001; I2 = 54%). Parenteral administration was associated with a greater effect on overall mortality than enteral administration (test of subgroup differences, p = 0.04), whereas studies of parenteral subgroups had lower quality. There were no subgroup differences based on baseline vitamin D levels. Conclusions Vitamin D supplementation in critically ill patients may reduce mortality. Parenteral administration might be associated with a greater impact on mortality. Heterogeneity and assessed certainty among the studies limits the generalizability of the results. KW - critically ill KW - vitamin D KW - nutrition KW - meta-analysis KW - mortality KW - mechanical ventilator weaning Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-299700 VL - 26 IS - 1 ER - TY - JOUR A1 - Judd, L. A1 - Hof, L. A1 - Beladdale, L. A1 - Friederich, P. A1 - Thoma, J. A1 - Wittmann, M. A1 - Zacharowski, K. A1 - Meybohm, P. A1 - Choorapoikayil, S. T1 - Prevalence of pre-operative anaemia in surgical patients: a retrospective, observational, multicentre study in Germany JF - Anaesthesia N2 - Anaemia is a risk factor for several adverse postoperative outcomes. Detailed data about the prevalence of anaemia are not available over a long time-period in Germany. In this retrospective, observational, multicentre study, patients undergoing surgery in March in 2007, 2012, 2015, 2017 and 2019 were studied. The primary objective was the prevalence of anaemia at hospital admission. The secondary objectives were the association between anaemia and the number of units of red blood cells transfused, length of hospital stay and in-hospital mortality. A total of 23,836 patients were included from eight centres. The prevalence of pre-operative anaemia in patients aged ≥ 18 years decreased slightly from 37% in 2007 to 32.5% in 2019 (p = 0.01) and increased in patients aged ≤ 18 years from 18.8% in 2007 to 26.4% in 2019 (p > 0.001). The total amount of blood administered per 1000 patients decreased from 671.2 units in 2007 to 289.0 units in 2019. Transfusion rates in anaemic patients declined from 33.8% in 2007 to 19.1% in 2019 (p < 0.001) and in non-anaemic patients from 8.4% in 2007 to 3.4% in 2019 (p < 0.001). Overall, the mortality rate remained constant over the years: 2.9% in 2007, 2.1% in 2012, 2.5% in 2015, 1.9% in 2017 and 2.5% in 2019. In the presence of anaemia, mortality was significantly increased compared with patients without anaemia (OR 5.27 (95%CI 4.13–6.77); p < 0.001). Red blood cell transfusion was associated with an increased risk of mortality (OR 14.98 (95%CI 11.83–19.03); p < 0.001). Using multivariable linear regression analysis with fixed effects, we found that pre-operative anaemia (OR 2.08 (95%CI 1.42–3.05); p < 0.001) and red blood cell transfusion (OR 4.29 (95%CI 3.09–5.94); p < 0.001) were predictors of mortality but not length of stay (0.99 (95%CI 0.98–1.00) days; p = 0.12) and analysed years (2007 vs. 2019: OR 1.49 (95%CI 0.86–2.69); p = 0.07). Pre-operative anaemia affects more than 30% of surgical patients in Germany and multidisciplinary action is urgently required to reduce adverse outcomes. KW - anaemia KW - surgery KW - prevalence Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-318199 VL - 77 IS - 11 SP - 1209 EP - 1218 ER - TY - JOUR A1 - Flemming, S. A1 - Hankir, M. A1 - Ernestus, R.-I. A1 - Seyfried, F. A1 - Germer, C.-T. A1 - Meybohm, P. A1 - Wurmb, T. A1 - Vogel, U. A1 - Wiegering, A. T1 - Surgery in times of COVID-19 — recommendations for hospital and patient management JF - Langenbeck's Archives of Surgery N2 - Background The novel coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2), has escalated rapidly to a global pandemic stretching healthcare systems worldwide to their limits. Surgeonshave had to immediately react to this unprecedented clinical challenge by systematically repurposing surgical wards. Purpose To provide a detailed set of guidelines developed in a surgical ward at University Hospital Wuerzburg to safelyaccommodate the exponentially rising cases of SARS-CoV-2 infected patients without compromising the care of emergencysurgery and oncological patients or jeopardizing the well-being of hospital staff. Conclusions The dynamic prioritization of SARS-CoV-2 infected and surgical patient groups is key to preserving life whilemaintaining high surgical standards. Strictly segregating patient groups in emergency rooms, non-intensive care wards andoperating areas prevents viral spread while adequately training and carefully selecting hospital staff allow them to confidentlyand successfully undertake their respective clinical duties. KW - SARS-CoV-2 KW - COVID-19 KW - Surgery Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-231766 SN - 1435-2443 VL - 405 ER - TY - JOUR A1 - Notz, Quirin A1 - Schmalzing, Marc A1 - Wedekink, Florian A1 - Schlesinger, Tobias A1 - Gernert, Michael A1 - Herrmann, Johannes A1 - Sorger, Lena A1 - Weismann, Dirk A1 - Schmid, Benedikt A1 - Sitter, Magdalena A1 - Schlegel, Nicolas A1 - Kranke, Peter A1 - Wischhusen, Jörg A1 - Meybohm, Patrick A1 - Lotz, Christopher T1 - Pro- and Anti-Inflammatory Responses in Severe COVID-19-Induced Acute Respiratory Distress Syndrome—An Observational Pilot Study JF - Frontiers in Immunology N2 - Objectives The severity of Coronavirus Disease 2019 (COVID-19) is largely determined by the immune response. First studies indicate altered lymphocyte counts and function. However, interactions of pro- and anti-inflammatory mechanisms remain elusive. In the current study we characterized the immune responses in patients suffering from severe COVID-19-induced acute respiratory distress syndrome (ARDS). Methods This was a single-center retrospective study in patients admitted to the intensive care unit (ICU) with confirmed COVID-19 between March 14th and May 28th 2020 (n = 39). Longitudinal data were collected within routine clinical care, including flow-cytometry of lymphocyte subsets, cytokine analysis and growth differentiation factor 15 (GDF-15). Antibody responses against the receptor binding domain (RBD) of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Spike protein were analyzed. Results All patients suffered from severe ARDS, 30.8% died. Interleukin (IL)-6 was massively elevated at every time-point. The anti-inflammatory cytokine IL-10 was concomitantly upregulated with IL-6. The cellular response was characterized by lymphocytopenia with low counts of CD8+ T cells, natural killer (NK) and naïve T helper cells. CD8+ T and NK cells recovered after 8 to 14 days. The B cell system was largely unimpeded. This coincided with a slight increase in anti-SARS-CoV-2-Spike-RBD immunoglobulin (Ig) G and a decrease in anti-SARS-CoV-2-Spike-RBD IgM. GDF-15 levels were elevated throughout ICU treatment. Conclusions Massively elevated levels of IL-6 and a delayed cytotoxic immune defense characterized severe COVID-19-induced ARDS. The B cell response and antibody production were largely unimpeded. No obvious imbalance of pro- and anti-inflammatory mechanisms was observed, with elevated GDF-15 levels suggesting increased tissue resilience. KW - Coronavirus Disease 2019 KW - acute respiratory distress syndrome KW - Severe Acute Respiratory Syndrome Coronavirus 2 KW - cytokines KW - inflammation KW - growth differentiation factor 15 KW - immune response Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-212815 SN - 1664-3224 VL - 11 ER - TY - JOUR A1 - Notz, Quirin A1 - Herrmann, Johannes A1 - Schlesinger, Tobias A1 - Helmer, Philipp A1 - Sudowe, Stephan A1 - Sun, Qian A1 - Hackler, Julian A1 - Roeder, Daniel A1 - Lotz, Christopher A1 - Meybohm, Patrick A1 - Kranke, Peter A1 - Schomburg, Lutz A1 - Stoppe, Christian T1 - Clinical Significance of Micronutrient Supplementation in Critically Ill COVID-19 Patients with Severe ARDS JF - Nutrients N2 - The interplay between inflammation and oxidative stress is a vicious circle, potentially resulting in organ damage. Essential micronutrients such as selenium (Se) and zinc (Zn) support anti-oxidative defense systems and are commonly depleted in severe disease. This single-center retrospective study investigated micronutrient levels under Se and Zn supplementation in critically ill patients with COVID-19 induced acute respiratory distress syndrome (ARDS) and explored potential relationships with immunological and clinical parameters. According to intensive care unit (ICU) standard operating procedures, patients received 1.0 mg of intravenous Se daily on top of artificial nutrition, which contained various amounts of Se and Zn. Micronutrients, inflammatory cytokines, lymphocyte subsets and clinical data were extracted from the patient data management system on admission and after 10 to 14 days of treatment. Forty-six patients were screened for eligibility and 22 patients were included in the study. Twenty-one patients (95%) suffered from severe ARDS and 14 patients (64%) survived to ICU discharge. On admission, the majority of patients had low Se status biomarkers and Zn levels, along with elevated inflammatory parameters. Se supplementation significantly elevated Se (p = 0.027) and selenoprotein P levels (SELENOP; p = 0.016) to normal range. Accordingly, glutathione peroxidase 3 (GPx3) activity increased over time (p = 0.021). Se biomarkers, most notably SELENOP, were inversely correlated with CRP (r\(_s\) = −0.495), PCT (r\(_s\) = −0.413), IL-6 (r\(_s\) = −0.429), IL-1β (r\(_s\) = −0.440) and IL-10 (r\(_s\) = −0.461). Positive associations were found for CD8\(^+\) T cells (r(_s\) = 0.636), NK cells (r\(_s\) = 0.772), total IgG (r\(_s\) = 0.493) and PaO\(_2\)/FiO\(_2\) ratios (r\(_s\) = 0.504). In addition, survivors tended to have higher Se levels after 10 to 14 days compared to non-survivors (p = 0.075). Sufficient Se and Zn levels may potentially be of clinical significance for an adequate immune response in critically ill patients with severe COVID-19 ARDS. KW - acute respiratory distress syndrome KW - selen KW - zinc KW - critical care KW - oxidative stress KW - nutrient supplementation Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-241112 SN - 2072-6643 VL - 13 IS - 6 ER - TY - JOUR A1 - Beierle, Felix A1 - Schobel, Johannes A1 - Vogel, Carsten A1 - Allgaier, Johannes A1 - Mulansky, Lena A1 - Haug, Fabian A1 - Haug, Julian A1 - Schlee, Winfried A1 - Holfelder, Marc A1 - Stach, Michael A1 - Schickler, Marc A1 - Baumeister, Harald A1 - Cohrdes, Caroline A1 - Deckert, Jürgen A1 - Deserno, Lorenz A1 - Edler, Johanna-Sophie A1 - Eichner, Felizitas A. A1 - Greger, Helmut A1 - Hein, Grit A1 - Heuschmann, Peter A1 - John, Dennis A1 - Kestler, Hans A. A1 - Krefting, Dagmar A1 - Langguth, Berthold A1 - Meybohm, Patrick A1 - Probst, Thomas A1 - Reichert, Manfred A1 - Romanos, Marcel A1 - Störk, Stefan A1 - Terhorst, Yannik A1 - Weiß, Martin A1 - Pryss, Rüdiger T1 - Corona Health — A Study- and Sensor-Based Mobile App Platform Exploring Aspects of the COVID-19 Pandemic JF - International Journal of Environmental Research and Public Health N2 - Physical and mental well-being during the COVID-19 pandemic is typically assessed via surveys, which might make it difficult to conduct longitudinal studies and might lead to data suffering from recall bias. Ecological momentary assessment (EMA) driven smartphone apps can help alleviate such issues, allowing for in situ recordings. Implementing such an app is not trivial, necessitates strict regulatory and legal requirements, and requires short development cycles to appropriately react to abrupt changes in the pandemic. Based on an existing app framework, we developed Corona Health, an app that serves as a platform for deploying questionnaire-based studies in combination with recordings of mobile sensors. In this paper, we present the technical details of Corona Health and provide first insights into the collected data. Through collaborative efforts from experts from public health, medicine, psychology, and computer science, we released Corona Health publicly on Google Play and the Apple App Store (in July 2020) in eight languages and attracted 7290 installations so far. Currently, five studies related to physical and mental well-being are deployed and 17,241 questionnaires have been filled out. Corona Health proves to be a viable tool for conducting research related to the COVID-19 pandemic and can serve as a blueprint for future EMA-based studies. The data we collected will substantially improve our knowledge on mental and physical health states, traits and trajectories as well as its risk and protective factors over the course of the COVID-19 pandemic and its diverse prevention measures. KW - mobile health KW - ecological momentary assessment KW - digital phenotyping KW - longitudinal studies KW - mobile crowdsensing Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-242658 SN - 1660-4601 VL - 18 IS - 14 ER - TY - JOUR A1 - Curtaz, Carolin J. A1 - Reifschläger, Leonie A1 - Strähle, Linus A1 - Feldheim, Jonas A1 - Feldheim, Julia J. A1 - Schmitt, Constanze A1 - Kiesel, Matthias A1 - Herbert, Saskia-Laureen A1 - Wöckel, Achim A1 - Meybohm, Patrick A1 - Burek, Malgorzata T1 - Analysis of microRNAs in exosomes of breast cancer patients in search of molecular prognostic factors in brain metastases JF - International Journal of Molecular Sciences N2 - Brain metastases are the most severe tumorous spread during breast cancer disease. They are associated with a limited quality of life and a very poor overall survival. A subtype of extracellular vesicles, exosomes, are sequestered by all kinds of cells, including tumor cells, and play a role in cell-cell communication. Exosomes contain, among others, microRNAs (miRs). Exosomes can be taken up by other cells in the body, and their active molecules can affect the cellular process in target cells. Tumor-secreted exosomes can affect the integrity of the blood-brain barrier (BBB) and have an impact on brain metastases forming. Serum samples from healthy donors, breast cancer patients with primary tumors, or with brain, bone, or visceral metastases were used to isolate exosomes and exosomal miRs. Exosomes expressed exosomal markers CD63 and CD9, and their amount did not vary significantly between groups, as shown by Western blot and ELISA. The selected 48 miRs were detected using real-time PCR. Area under the receiver-operating characteristic curve (AUC) was used to evaluate the diagnostic accuracy. We identified two miRs with the potential to serve as prognostic markers for brain metastases. Hsa-miR-576-3p was significantly upregulated, and hsa-miR-130a-3p was significantly downregulated in exosomes from breast cancer patients with cerebral metastases with AUC: 0.705 and 0.699, respectively. Furthermore, correlation of miR levels with tumor markers revealed that hsa-miR-340-5p levels were significantly correlated with the percentage of Ki67-positive tumor cells, while hsa-miR-342-3p levels were inversely correlated with tumor staging. Analysis of the expression levels of miRs in serum exosomes from breast cancer patients has the potential to identify new, non-invasive, blood-borne prognostic molecular markers to predict the potential for brain metastasis in breast cancer. Additional functional analyzes and careful validation of the identified markers are required before their potential future diagnostic use. KW - breast cancer KW - breast cancer metastases KW - blood-brain barrier KW - patient serum KW - exosomes KW - microRNA KW - gene expression KW - prognostic marker Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-284476 SN - 1422-0067 VL - 23 IS - 7 ER - TY - JOUR A1 - Herrmann, Johannes A1 - Lotz, Christopher A1 - Karagiannidis, Christian A1 - Weber-Carstens, Steffen A1 - Kluge, Stefan A1 - Putensen, Christian A1 - Wehrfritz, Andreas A1 - Schmidt, Karsten A1 - Ellerkmann, Richard K. A1 - Oswald, Daniel A1 - Lotz, Gösta A1 - Zotzmann, Viviane A1 - Moerer, Onnen A1 - Kühn, Christian A1 - Kochanek, Matthias A1 - Muellenbach, Ralf A1 - Gaertner, Matthias A1 - Fichtner, Falk A1 - Brettner, Florian A1 - Findeisen, Michael A1 - Heim, Markus A1 - Lahmer, Tobias A1 - Rosenow, Felix A1 - Haake, Nils A1 - Lepper, Philipp M. A1 - Rosenberger, Peter A1 - Braune, Stephan A1 - Kohls, Mirjam A1 - Heuschmann, Peter A1 - Meybohm, Patrick T1 - Key characteristics impacting survival of COVID-19 extracorporeal membrane oxygenation JF - Critical Care N2 - Background Severe COVID-19 induced acute respiratory distress syndrome (ARDS) often requires extracorporeal membrane oxygenation (ECMO). Recent German health insurance data revealed low ICU survival rates. Patient characteristics and experience of the ECMO center may determine intensive care unit (ICU) survival. The current study aimed to identify factors affecting ICU survival of COVID-19 ECMO patients. Methods 673 COVID-19 ARDS ECMO patients treated in 26 centers between January 1st 2020 and March 22nd 2021 were included. Data on clinical characteristics, adjunct therapies, complications, and outcome were documented. Block wise logistic regression analysis was applied to identify variables associated with ICU-survival. Results Most patients were between 50 and 70 years of age. PaO\(_{2}\)/FiO\(_{2}\) ratio prior to ECMO was 72 mmHg (IQR: 58–99). ICU survival was 31.4%. Survival was significantly lower during the 2nd wave of the COVID-19 pandemic. A subgroup of 284 (42%) patients fulfilling modified EOLIA criteria had a higher survival (38%) (p = 0.0014, OR 0.64 (CI 0.41–0.99)). Survival differed between low, intermediate, and high-volume centers with 20%, 30%, and 38%, respectively (p = 0.0024). Treatment in high volume centers resulted in an odds ratio of 0.55 (CI 0.28–1.02) compared to low volume centers. Additional factors associated with survival were younger age, shorter time between intubation and ECMO initiation, BMI > 35 (compared to < 25), absence of renal replacement therapy or major bleeding/thromboembolic events. Conclusions Structural and patient-related factors, including age, comorbidities and ECMO case volume, determined the survival of COVID-19 ECMO. These factors combined with a more liberal ECMO indication during the 2nd wave may explain the reasonably overall low survival rate. Careful selection of patients and treatment in high volume ECMO centers was associated with higher odds of ICU survival. KW - Covid-19 KW - extracorporeal membrane oxygenation (ECMO) KW - intensive care unit Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-299686 VL - 26 IS - 1 ER - TY - JOUR A1 - Hottenrott, Sebastian A1 - Schlesinger, Tobias A1 - Helmer, Philipp A1 - Meybohm, Patrick A1 - Alkatout, Ibrahim A1 - Kranke, Peter T1 - Do small incisions need only minimal anesthesia? — anesthetic management in laparoscopic and robotic surgery JF - Journal of Clinical Medicine N2 - Laparoscopic techniques have established themselves as a major part of modern surgery. Their implementation in every surgical discipline has played a vital part in the reduction of perioperative morbidity and mortality. Precise robotic surgery, as an evolution of this, is shaping the present and future operating theatre that an anesthetist is facing. While incisions get smaller and the impact on the organism seems to dwindle, challenges for anesthetists do not lessen and could even become more demanding than in open procedures. This review focuses on the pathophysiological effects of contemporary laparoscopic and robotic procedures and summarizes anesthetic challenges and strategies for perioperative management. KW - general anesthesia KW - anesthetics KW - perioperative care KW - minimally invasive surgery KW - laparoscopic surgery KW - robotic surgery Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-220039 SN - 2077-0383 VL - 9 IS - 12 ER - TY - JOUR A1 - Notz, Quirin A1 - Lee, Zheng-Yii A1 - Menger, Johannes A1 - Elke, Gunnar A1 - Hill, Aileen A1 - Kranke, Peter A1 - Roeder, Daniel A1 - Lotz, Christopher A1 - Meybohm, Patrick A1 - Heyland, Daren K. A1 - Stoppe, Christian T1 - Omega-6 sparing effects of parenteral lipid emulsions-an updated systematic review and meta-analysis on clinical outcomes in critically ill patients JF - Critical Care N2 - Background Parenteral lipid emulsions in critical care are traditionally based on soybean oil (SO) and rich in pro-inflammatory omega-6 fatty acids (FAs). Parenteral nutrition (PN) strategies with the aim of reducing omega-6 FAs may potentially decrease the morbidity and mortality in critically ill patients. Methods A systematic search of MEDLINE, EMBASE, CINAHL and CENTRAL was conducted to identify all randomized controlled trials in critically ill patients published from inception to June 2021, which investigated clinical omega-6 sparing effects. Two independent reviewers extracted bias risk, treatment details, patient characteristics and clinical outcomes. Random effect meta-analysis was performed. Results 1054 studies were identified in our electronic search, 136 trials were assessed for eligibility and 26 trials with 1733 critically ill patients were included. The median methodologic score was 9 out of 14 points (95% confidence interval [CI] 7, 10). Omega-6 FA sparing PN in comparison with traditional lipid emulsions did not decrease overall mortality (20 studies; risk ratio [RR] 0.91; 95% CI 0.76, 1.10; p = 0.34) but hospital length of stay was substantially reduced (6 studies; weighted mean difference [WMD] − 6.88; 95% CI − 11.27, − 2.49; p = 0.002). Among the different lipid emulsions, fish oil (FO) containing PN reduced the length of intensive care (8 studies; WMD − 3.53; 95% CI − 6.16, − 0.90; p = 0.009) and rate of infectious complications (4 studies; RR 0.65; 95% CI 0.44, 0.95; p = 0.03). When FO was administered as a stand-alone medication outside PN, potential mortality benefits were observed compared to standard care. Conclusion Overall, these findings highlight distinctive omega-6 sparing effects attributed to PN. Among the different lipid emulsions, FO in combination with PN or as a stand-alone treatment may have the greatest clinical impact. KW - omega-6 fatty acid KW - parenteral nutrition KW - critical illness KW - immunonutrition KW - fish oil KW - omega-3 fatty acid Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-299710 VL - 26 IS - 1 ER - TY - JOUR A1 - Neef, Vanessa A1 - Meisenzahl, David A1 - Kessler, Paul A1 - Raimann, Florian J. A1 - Piekarski, Florian A1 - Choorapoikayil, Suma A1 - Fleege, Christoph A1 - Zacharowski, Kai D. A1 - Meybohm, Patrick A1 - Meurer, Andrea T1 - Implementation of an anaemia walk‐in clinic: Feasibility and preliminary data from the Orthopedic University Hospital JF - Transfusion Medicine N2 - Background Approximately one in three patients suffers from preoperative anaemia. Even though haemoglobin is measured before surgery, anaemia management is not implemented in every hospital. Objective Here, we demonstrate the implementation of an anaemia walk‐in clinic at an Orthopedic University Hospital. To improve the diagnosis of iron deficiency (ID), we examined whether reticulocyte haemoglobin (Ret‐He) could be a useful additional parameter. Material and Methods In August 2019, an anaemia walk‐in clinic was established. Between September and December 2019, major orthopaedic surgical patients were screened for preoperative anaemia. The primary endpoint was the incidence of preoperative anaemia. Secondary endpoints included Ret‐He level, red blood cell (RBC) transfusion rate, in‐hospital length of stay and anaemia at hospital discharge. Results A total of 104 patients were screened for anaemia. Preoperative anaemia rate was 20.6%. Intravenous iron was supplemented in 23 patients. Transfusion of RBC units per patient (1.7 ± 1.2 vs. 0.2 ± 0.9; p = 0.004) and hospital length of stay (13.1 ± 4.8 days vs. 10.6 ± 5.1 days; p = 0.068) was increased in anaemic patients compared to non‐anaemic patients. Ret‐He values were significantly lower in patients with ID anaemia (33.3 pg [28.6–40.2 pg]) compared to patients with ID (35.3 pg [28.9–38.6 pg]; p = 0.015) or patients without anaemia (35.4 pg [30.2–39.4 pg]; p = 0.001). Conclusion Preoperative anaemia is common in orthopaedic patients. Our results proved the feasibility of an anaemia walk‐in clinic to manage preoperative anaemia. Furthermore, our analysis supports the use of Ret‐He as an additional parameter for the diagnosis of ID in surgical patients. KW - anaemia walk‐in clinic KW - blood transfusion KW - iron deficiency KW - orthopaedic patients KW - patient blood management KW - reticulocyte haemoglobin Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-224594 VL - 30 IS - 6 SP - 467 EP - 474 ER - TY - JOUR A1 - Curtaz, Carolin J. A1 - Kiesel, Ludwig A1 - Meybohm, Patrick A1 - Wöckel, Achim A1 - Burek, Malgorzata T1 - Anti-hormonal therapy in breast cancer and its effect on the blood-brain barrier JF - Cancers N2 - Simple Summary Anti-hormonal therapie regimes are well established in oncological treatments in breast cancer. In contrast there is limited knowledge of their effects on metastatic brain metastases in advanced breast cancer and their ability to cross the blood brain-barrier. In this review, we point out the usual antihormonal therapy options in the primary disease, but also in metastatic breast cancer. In addition, we explain the epidemiological facts of brain metastases, as well as the basics of the blood-brain barrier and how this is overcome by metastase. Last but not least, we deal with the known anti-hormonal therapy options and present clinical studies on their intracerebral effect, as well as the known basics of their blood-brain barrier penetration. Not all common anti-hormonal therapeutics are able to penetrate the CNS. It is therefore important for the treating oncologists to use substances that have been proven to cross the BBB, despite the limited data available. Aromataseinhibitors, especially letrozole, probably also tamoxifen, everolimus and CDK4/6 inhibitors, especially abemaciclib, appear to act intracerebrally by overcoming the blood-brain barrier. Nevertheless, further data must be obtained in basic research, but also health care research in relation to patients with brain metastases. Abstract The molecular receptor status of breast cancer has implications for prognosis and long-term metastasis. Although metastatic luminal B-like, hormone-receptor-positive, HER2−negative, breast cancer causes brain metastases less frequently than other subtypes, though tumor metastases in the brain are increasingly being detected of this patient group. Despite the many years of tried and tested use of a wide variety of anti-hormonal therapeutic agents, there is insufficient data on their intracerebral effectiveness and their ability to cross the blood-brain barrier. In this review, we therefore summarize the current state of knowledge on anti-hormonal therapy and its intracerebral impact and effects on the blood-brain barrier in breast cancer. KW - anti-hormonal therapy KW - brain-metastasis KW - blood-brain barrier KW - breast cancer Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-290320 SN - 2072-6694 VL - 14 IS - 20 ER - TY - JOUR A1 - Sun, Aili A1 - Blecharz-Lang, Kinga G. A1 - Małecki, Andrzej A1 - Meybohm, Patrick A1 - Nowacka-Chmielewska, Marta M. A1 - Burek, Malgorzata T1 - Role of microRNAs in the regulation of blood-brain barrier function in ischemic stroke and under hypoxic conditions in vitro JF - Frontiers in Drug Delivery N2 - The blood-brain barrier (BBB) is a highly specialized structure that separates the brain from the blood and allows the exchange of molecules between these two compartments through selective channels. The breakdown of the BBB is implicated in the development of severe neurological diseases, especially stroke and traumatic brain injury. Oxygen-glucose deprivation is used to mimic stroke and traumatic brain injury in vitro. Pathways that trigger BBB dysfunction include an imbalance of oxidative stress, excitotoxicity, iron metabolism, cytokine release, cell injury, and cell death. MicroRNAs are small non-coding RNA molecules that regulate gene expression and are emerging as biomarkers for the diagnosis of central nervous system (CNS) injuries. In this review, the regulatory role of potential microRNA biomarkers and related therapeutic targets on the BBB is discussed. A thorough understanding of the potential role of various cellular and linker proteins, among others, in the BBB will open further therapeutic options for the treatment of neurological diseases. KW - blood-brain barrier KW - microRNA KW - stroke KW - traumatic brain injury KW - tight junctions KW - transporter Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-291423 SN - 2674-0850 VL - 2 ER - TY - JOUR A1 - Lotz, Christopher A1 - Herrmann, Johannes A1 - Notz, Quirin A1 - Meybohm, Patrick A1 - Kehl, Franz T1 - Mitochondria and pharmacologic cardiac conditioning — At the heart of ischemic injury JF - International Journal of Molecular Sciences N2 - Pharmacologic cardiac conditioning increases the intrinsic resistance against ischemia and reperfusion (I/R) injury. The cardiac conditioning response is mediated via complex signaling networks. These networks have been an intriguing research field for decades, largely advancing our knowledge on cardiac signaling beyond the conditioning response. The centerpieces of this system are the mitochondria, a dynamic organelle, almost acting as a cell within the cell. Mitochondria comprise a plethora of functions at the crossroads of cell death or survival. These include the maintenance of aerobic ATP production and redox signaling, closely entwined with mitochondrial calcium handling and mitochondrial permeability transition. Moreover, mitochondria host pathways of programmed cell death impact the inflammatory response and contain their own mechanisms of fusion and fission (division). These act as quality control mechanisms in cellular ageing, release of pro-apoptotic factors and mitophagy. Furthermore, recently identified mechanisms of mitochondrial regeneration can increase the capacity for oxidative phosphorylation, decrease oxidative stress and might help to beneficially impact myocardial remodeling, as well as invigorate the heart against subsequent ischemic insults. The current review highlights different pathways and unresolved questions surrounding mitochondria in myocardial I/R injury and pharmacological cardiac conditioning. KW - cardioprotection KW - preconditioning KW - ischemia/reperfusion injury KW - volatile anesthetics Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-285368 SN - 1422-0067 VL - 22 IS - 6 ER - TY - JOUR A1 - Teles, Ramon Handerson Gomes A1 - Yano, Rafael Sussumu A1 - Villarinho, Nicolas Jones A1 - Yamagata, Ana Sayuri A1 - Jaeger, Ruy Gastaldoni A1 - Meybohm, Patrick A1 - Burek, Malgorzata A1 - Freitas, Vanessa Morais T1 - Advances in breast cancer management and extracellular vesicle research, a bibliometric analysis JF - Current Oncology N2 - Extracellular vesicles transport variable content and have crucial functions in cell–cell communication. The role of extracellular vesicles in cancer is a current hot topic, and no bibliometric study has ever analyzed research production regarding their role in breast cancer and indicated the trends in the field. In this way, we aimed to investigate the trends in breast cancer management involved with extracellular vesicle research. Articles were retrieved from Scopus, including all the documents published concerning breast cancer and extracellular vesicles. We analyzed authors, journals, citations, affiliations, and keywords, besides other bibliometric analyses, using R Studio version 3.6.2. and VOSviewer version 1.6.0. A total of 1151 articles were retrieved, and as the main result, our analysis revealed trending topics on biomarkers of liquid biopsy, drug delivery, chemotherapy, autophagy, and microRNA. Additionally, research related to extracellular vesicles in breast cancer has been focused on diagnosis, treatment, and mechanisms of action of breast tumor-derived vesicles. Future studies are expected to explore the role of extracellular vesicles on autophagy and microRNA, besides investigating the application of extracellular vesicles from liquid biopsies for biomarkers and drug delivery, enabling the development and validation of therapeutic strategies for specific cancers. KW - breast cancer KW - metastasis KW - exosomes KW - extracellular vesicles KW - bibliometrics Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-284321 SN - 1718-7729 VL - 28 IS - 6 SP - 4504 EP - 4520 ER - TY - JOUR A1 - Helmer, Philipp A1 - Hottenrott, Sebastian A1 - Rodemers, Philipp A1 - Leppich, Robert A1 - Helwich, Maja A1 - Pryss, Rüdiger A1 - Kranke, Peter A1 - Meybohm, Patrick A1 - Winkler, Bernd E. A1 - Sammeth, Michael T1 - Accuracy and Systematic Biases of Heart Rate Measurements by Consumer-Grade Fitness Trackers in Postoperative Patients: Prospective Clinical Trial JF - Journal of Medical Internet Research N2 - Background: Over the recent years, technological advances of wrist-worn fitness trackers heralded a new era in the continuous monitoring of vital signs. So far, these devices have primarily been used for sports. Objective: However, for using these technologies in health care, further validations of the measurement accuracy in hospitalized patients are essential but lacking to date. Methods: We conducted a prospective validation study with 201 patients after moderate to major surgery in a controlled setting to benchmark the accuracy of heart rate measurements in 4 consumer-grade fitness trackers (Apple Watch 7, Garmin Fenix 6 Pro, Withings ScanWatch, and Fitbit Sense) against the clinical gold standard (electrocardiography). Results: All devices exhibited high correlation (r≥0.95; P<.001) and concordance (rc≥0.94) coefficients, with a relative error as low as mean absolute percentage error <5% based on 1630 valid measurements. We identified confounders significantly biasing the measurement accuracy, although not at clinically relevant levels (mean absolute error<5 beats per minute). Conclusions: Consumer-grade fitness trackers appear promising in hospitalized patients for monitoring heart rate. KW - Withings ScanWatch KW - health tracker KW - smartwatch KW - internet of things KW - personalized medicine KW - photoplethysmography KW - wearable KW - Garmin Fenix 6 Pro KW - Apple Watch 7 KW - Fitbit Sense Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-299679 VL - 24 IS - 12 ER - TY - JOUR A1 - Lindhoff-Last, Edelgard A1 - Birschmann, Ingvild A1 - Bidenharn, Antonia J. A1 - Kuhn, Joachim A1 - Lindau, Simone A1 - Konstantinides, Stavros A1 - Grottke, Oliver A1 - Nowak-Göttl, Ulrike A1 - Lucks, Jessica A1 - Zydek, Barbara A1 - Heymann, Christian von A1 - Sümnig, Ariane A1 - Beyer-Westendorf, Jan A1 - Schellong, Sebastian A1 - Meybohm, Patrick A1 - Greinacher, Andreas A1 - Herrmann, Eva T1 - Pharmacokinetics of phenprocoumon in emergency situations – results of the prospective observational RADOA-registry (reversal agent use in patients treated with direct oral anticoagulants or vitamin K antagonists registry) JF - Pharmaceuticals N2 - Background: Phenprocoumon has been used as an oral anticoagulant in patients with thromboembolic disease for more than 40 years. So far its pharmacokinetics have not been analyzed in emergency situations. Methods: Phenprocoumon-treated patients with major bleeding or urgent surgery were included in a prospective, observational registry. Phenprocoumon drug concentrations were analyzed in samples, collected as part of routine care using ultraperformance liquid chromatography tandem mass spectrometry. Moreover, anticoagulant intensity and drug half-life (t1/2) were calculated. Results: 115 patients were included. Phenprocoumon levels declined over time with a half-life of 5.27 and 5.29 days in patients with major bleedings (n = 82) and with urgent surgery (n = 33). Baseline phenprocoumon levels were 2.2 times higher in the bleeding group compared to the surgery group (1.92 vs. 0.87 ng/mL, p < 0.0001). International normalized ratio (INR) values decreased rapidly during the first 24 h. In 27.6% of patients a rebound of INR (recurrent increase > 1.5) was observed which was associated with significantly increased bleeding rates (22% vs. 4.2% in patients with or without INR rebound, p = 0.012). Conclusions: In emergency situations, the long half-life of phenprocoumon may cause INR rebound and associated recurrent bleedings. Optimal management may need to include repeated vitamin K supplementation over days. KW - phenprocoumon KW - pharmacokinetics KW - emergency KW - major bleeding KW - urgent surgery KW - INR rebound Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-297226 SN - 1424-8247 VL - 15 IS - 11 ER - TY - JOUR A1 - Hackenbroich, Samantha A1 - Kranke, Peter A1 - Meybohm, Patrick A1 - Weibel, Stephanie T1 - Include or not to include conference abstracts in systematic reviews? Lessons learned from a large Cochrane network meta-analysis including 585 trials JF - Systematic Reviews N2 - Background Systematic reviews attempt to gather all available evidence. Controversy exists regarding effort and benefit of including study results presented at conferences only. We recently published a Cochrane network meta-analysis (NMA) including 585 randomized controlled trials comparing drugs for prevention of postoperative nausea and vomiting (PONV). Studies published as conference abstracts only were excluded. This study aimed to include all eligible studies published as abstracts only, assessing their added value regarding reporting quality and effect on the review’s interpretation. Methods Conference abstracts were searched in the review’s excluded studies and conference proceedings of anaesthesiologic societies. We assessed their reporting quality regarding review’s eligibility criteria, Cochrane ‘risk of bias’ assessment tool 1.0, and adherence to CONSORT (Consolidated Standards of Reporting Trials) for abstracts. Abstracts were included in sensitivity NMA, and impact on the NMA structure was investigated. Results We identified 90 abstracts. A total of 14% (13/90) were eligible. A total of 86% (77/90) are awaiting classification due to insufficient reporting of review’s eligibility criteria. In abstracts awaiting classification, sufficient information was missing on standardization of anaesthesia in 71% (55/77), age of participants in 56% (43/77), and outcome details in 46% (36/77). A total of 73% (66/90) of abstracts lacked sufficient information on 15/25 data extraction items. Reported study characteristics of abstracts were comparable to included studies of the review. A total of 62% (56/90) of abstract trials were assessed as overall high risk of bias due to poor reporting. Median adherence to CONSORT for abstracts was 24% (IQR, 18 to 29%). Six of the 13 eligible abstracts reported relevant outcome data in sufficient detail for NMA on seven outcomes of the Cochrane review. Inclusion of abstracts did not substantially change the network structure, network effect estimates, ranking of treatments, or the conclusion. Certainty of evidence for headache on palonosetron use was upgraded from very low to low. Conclusions Most conference abstracts on PONV were insufficiently reported regarding review’s narrow inclusion criteria and could not be included in NMA. The resource-intensive search and evaluation of abstracts did not substantially extent the full-text evidence base of the review, given the few adequately reported abstracts. Conferences should oblige authors to adhere to CONSORT for abstracts. KW - systemic reviews KW - conference abstracts KW - meta-analysis Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-299660 VL - 11 IS - 1 ER - TY - JOUR A1 - Kippnich, Maximilian A1 - Duempert, Maximilian A1 - Schorscher, Nora A1 - Jordan, Martin C. A1 - Kunz, Andreas S. A1 - Meybohm, Patrick A1 - Wurmb, Thomas T1 - Simultaneous treatment of trauma patients in a dual room trauma suite with integrated movable sliding gantry CT system: an observational study JF - Scientific Reports N2 - The trauma center of the University Hospital Wuerzburg has developed an advanced trauma pathway based on a dual-room trauma suite with an integrated movable sliding gantry CT-system. This enables simultaneous CT-diagnostics and treatment of two trauma patients. The focus of this study was to investigate the quality of the concept based on defined outcome criteria in this specific setting (time from arrival to initiation of CT scan: tCT; time from arrival to initiation of emergency surgery: tES). We analyzed all trauma patients admitted to the hospital’s trauma suite from 1st May 2019 through 29th April 2020. Two subgroups were defined: trauma patients, who were treated without a second trauma patient present (group 1) and patients, who were treated simultaneously with another trauma patient (group 2). Simultaneous treatment was defined as parallel arrival within a period of 20 min. Of 423 included trauma patients, 46 patients (10.9%) were treated simultaneously. Car accidents were the predominant trauma mechanism in this group (19.6% vs. 47.8%, p < 0.05). Prehospital life-saving procedures were performed with comparable frequency in both groups (intubation 43.5% vs. 39%, p = 0.572); pleural drainage 3.2% vs. 2.2%, p = 0.708; cardiopulmonary resuscitation 5% vs. 2.2%, p = 0.387). At hospital admission, patients in group 2 suffered significantly more pain (E-problem according to Advanced Trauma Life Support principles©; 29.2% vs. 45.7%, p < 0.05). There were no significant differences in the clinical treatment (emergency procedures, vasopressor and coagulant therapy, and transfusion of red blood cells). tCT was 6 (4–10) minutes (median and IQR) in group 1 and 8 (5–15.5) minutes in group 2 (p = 0.280). tES was 90 (78–106) minutes in group 1 and 99 (97–108) minutes in group 2 (p = 0.081). The simultaneous treatment of two trauma patients in a dual-room trauma suite with an integrated movable sliding gantry CT-system requires a medical, organizational, and technical concept adapted to this special setting. Despite the oftentimes serious and life-threatening injuries, optimal diagnostic and therapeutic procedures can be guaranteed for two simultaneous trauma patients at an individual medical level in consistent quality. KW - dual-room trauma suite KW - movable sliding gantry KW - CT Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-299695 VL - 12 IS - 1 ER - TY - JOUR A1 - Schorscher, Nora A1 - Kippnich, Maximilian A1 - Meybohm, Patrick A1 - Wurmb, Thomas T1 - Lessons learned from terror attacks: thematic priorities and development since 2001 - results from a systematic review JF - European Journal of Trauma and Emergency Surgery N2 - PURPOSE The threat of national and international terrorism remains high. Preparation is the key requirement for the resilience of hospitals and out-of-hospital rescue forces. The scientific evidence for defining medical and tactical strategies often feeds on the analysis of real incidents and the lessons learned derived from them. This systematic review of the literature aims to identify and systematically report lessons learned from terrorist attacks since 2001. METHODS PubMed was used as a database using predefined search strategies and eligibility criteria. All countries that are part of the Organization for Economic Cooperation and Development (OECD) were included. The time frame was set between 2001 and 2018. RESULTS Finally 68 articles were included in the review. From these, 616 lessons learned were extracted and summarized into 15 categories. The data shows that despite the difference in attacks, countries, and casualties involved, many of the lessons learned are similar. We also found that the pattern of lessons learned is repeated continuously over the time period studied. CONCLUSIONS The lessons from terrorist attacks since 2001 follow a certain pattern and remained constant over time. Therefore, it seems to be more accurate to talk about lessons identified rather than lessons learned. To save as many victims as possible, protect rescue forces from harm, and to prepare hospitals at the best possible level it is important to implement the lessons identified in training and preparation. KW - terror attacks KW - evaluation KW - lessons learned KW - emergency preparedness KW - public health preparedness KW - mass casualties Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-264862 SN - 1863-9941 VL - 48 ER - TY - JOUR A1 - Holzmann-Littig, Christopher A1 - Stadler, David A1 - Popp, Maria A1 - Kranke, Peter A1 - Fichtner, Falk A1 - Schmaderer, Christoph A1 - Renders, Lutz A1 - Braunisch, Matthias Christoph A1 - Assali, Tarek A1 - Platen, Louise A1 - Wijnen-Meijer, Marjo A1 - Lühnen, Julia A1 - Steckelberg, Anke A1 - Pfadenhauer, Lisa A1 - Haller, Bernhard A1 - Fuetterer, Cornelia A1 - Seeber, Christian A1 - Schaaf, Christian T1 - Locating medical information during an infodemic: information seeking behavior and strategies of health-care workers in Germany JF - Healthcare N2 - Background: The COVID-19 pandemic has led to a flood of — often contradictory — evidence. HCWs had to develop strategies to locate information that supported their work. We investigated the information-seeking of different HCW groups in Germany. Methods: In December 2020, we conducted online surveys on COVID-19 information sources, strategies, assigned trustworthiness, and barriers — and in February 2021, on COVID-19 vaccination information sources. Results were analyzed descriptively; group comparisons were performed using χ\(^2\)-tests. Results: For general COVID-19-related medical information (413 participants), non-physicians most often selected official websites (57%), TV (57%), and e-mail/newsletters (46%) as preferred information sources — physicians chose official websites (63%), e-mail/newsletters (56%), and professional journals (55%). Non-physician HCWs used Facebook/YouTube more frequently. The main barriers were insufficient time and access issues. Non-physicians chose abstracts (66%), videos (45%), and webinars (40%) as preferred information strategy; physicians: overviews with algorithms (66%), abstracts (62%), webinars (48%). Information seeking on COVID-19 vaccination (2700 participants) was quite similar, however, with newspapers being more often used by non-physicians (63%) vs. physician HCWs (70%). Conclusion: Non-physician HCWs more often consulted public information sources. Employers/institutions should ensure the supply of professional, targeted COVID-19 information for different HCW groups. KW - COVID-19 KW - infodemic KW - health-care workers KW - HCW KW - information strategies KW - emergency information Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-319306 SN - 2227-9032 VL - 11 IS - 11 ER - TY - JOUR A1 - Sammeth, Michael A1 - Ursache, Nicu-Cosmin A1 - Alboaie, Sînică T1 - OpenDSU: digital sovereignty in PharmaLedger JF - Frontiers in Blockchain N2 - Introduction: Distributed ledger networks, chiefly those based on blockchain technologies, currently are heralding a next-generation of computer systems that aims to suit modern users’ demands. Over the recent years, several technologies for blockchains, off-chaining strategies, as well as decentralised and respectively self-sovereign identity systems have shot up so fast that standardisation of the protocols is lagging behind, severely hampering the interoperability of different approaches. Moreover, most of the currently available solutions for distributed ledgers focus on either home users or enterprise use case scenarios, failing to provide integrative solutions addressing the needs of both. Methods: Herein, we introduce the OpenDSU platform that allows to interoperate generic blockchain technologies, organised–and possibly cascaded in a hierarchical fashion–in domains. To achieve this flexibility, we seamlessly integrated a set of well conceived components that orchestrate off-chain data and provide granularly resolved and cryptographically secure access levels, intrinsically nested with sovereign identities across the different domains. The source code and extensive documentation of all OpenDSU components described herein are publicly available under the MIT open-source licence at https://opendsu.com. Results: Employing our platform to PharmaLedger, an inter-European network for the standardisation of data handling in the pharmaceutical industry and in healthcare, we demonstrate that OpenDSU can cope with generic demands of heterogeneous use cases in both, performance and handling substantially different business policies. Discussion: Importantly, whereas available solutions commonly require a predefined and fixed set of components, no such vendor lock-in restrictions on the blockchain technology or identity system exist in OpenDSU, making systems built on it flexibly adaptable to new standards evolving in the future. KW - opendsu KW - blockchain interoperability KW - off-chain data KW - blockchain anchoring KW - self-sovereign identities KW - pharmaledger KW - blockchain in healthcare KW - blockchain in the pharmaceutical industry Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-320458 SN - 2624-7852 VL - 6 ER - TY - JOUR A1 - Herrmann, Johannes A1 - Müller, Kerstin A1 - Notz, Quirin A1 - Hübsch, Martha A1 - Haas, Kirsten A1 - Horn, Anna A1 - Schmidt, Julia A1 - Heuschmann, Peter A1 - Maschmann, Jens A1 - Frosch, Matthias A1 - Deckert, Jürgen A1 - Einsele, Hermann A1 - Ertl, Georg A1 - Frantz, Stefan A1 - Meybohm, Patrick A1 - Lotz, Christopher T1 - Prospective single-center study of health-related quality of life after COVID-19 in ICU and non-ICU patients JF - Scientific Reports N2 - Long-term sequelae in hospitalized Coronavirus Disease 2019 (COVID-19) patients may result in limited quality of life. The current study aimed to determine health-related quality of life (HRQoL) after COVID-19 hospitalization in non-intensive care unit (ICU) and ICU patients. This is a single-center study at the University Hospital of Wuerzburg, Germany. Patients eligible were hospitalized with COVID-19 between March 2020 and December 2020. Patients were interviewed 3 and 12 months after hospital discharge. Questionnaires included the European Quality of Life 5 Dimensions 5 Level (EQ-5D-5L), patient health questionnaire-9 (PHQ-9), the generalized anxiety disorder 7 scale (GAD-7), FACIT fatigue scale, perceived stress scale (PSS-10) and posttraumatic symptom scale 10 (PTSS-10). 85 patients were included in the study. The EQ5D-5L-Index significantly differed between non-ICU (0.78 ± 0.33 and 0.84 ± 0.23) and ICU (0.71 ± 0.27; 0.74 ± 0.2) patients after 3- and 12-months. Of non-ICU 87% and 80% of ICU survivors lived at home without support after 12 months. One-third of ICU and half of the non-ICU patients returned to work. A higher percentage of ICU patients was limited in their activities of daily living compared to non-ICU patients. Depression and fatigue were present in one fifth of the ICU patients. Stress levels remained high with only 24% of non-ICU and 3% of ICU patients (p = 0.0186) having low perceived stress. Posttraumatic symptoms were present in 5% of non-ICU and 10% of ICU patients. HRQoL is limited in COVID-19 ICU patients 3- and 12-months post COVID-19 hospitalization, with significantly less improvement at 12-months compared to non-ICU patients. Mental disorders were common highlighting the complexity of post-COVID-19 symptoms as well as the necessity to educate patients and primary care providers about monitoring mental well-being post COVID-19. KW - health care KW - public health KW - quality of life Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-357174 VL - 13 ER - TY - JOUR A1 - Sarukhanyan, Edita A1 - Shityakov, Sergey A1 - Dandekar, Thomas T1 - Rational drug design of Axl tyrosine kinase type I inhibitors as promising candidates against cancer JF - Frontiers in Chemistry N2 - The high level of Axl tyrosine kinase expression in various cancer cell lines makes it an attractive target for the development of anti-cancer drugs. In this study, we carried out several sets of in silico screening for the ATP-competitive Axl kinase inhibitors based on different molecular docking protocols. The best drug-like candidates were identified, after parental structure modifications, by their highest affinity to the target protein. We found that our newly designed compound R5, a derivative of the R428 patented analog, is the most promising inhibitor of the Axl kinase according to the three molecular docking algorithms applied in the study. The molecular docking results are in agreement with the molecular dynamics simulations using the MM-PBSA/GBSA implicit solvation models, which confirm the high affinity of R5 toward the protein receptor. Additionally, the selectivity test against other kinases also reveals a high affinity of R5 toward ABL1 and Tyro3 kinases, emphasizing its promising potential for the treatment of malignant tumors. KW - Axl tyrosine kinase KW - anti-cancer drug-like molecules KW - rational drug design KW - molecular docking KW - molecular dynamics Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-199505 SN - 2296-2646 VL - 7 IS - 920 ER - TY - JOUR A1 - Wurmb, Thomas A1 - Franke, Axel A1 - Schorscher, Nora A1 - Kowalzik, Barbara A1 - Helm, Matthias A1 - Bohnen, Renate A1 - Helmerichs, Jutta A1 - Grueneisen, Ulrich A1 - Cwojdzinski, Detlef A1 - Jung, Georg A1 - Lücking, Gesa A1 - Weber, Martin T1 - Emergency response to terrorist attacks: results of the federal-conducted evaluation process in Germany JF - European Journal of Trauma and Emergency Surgery N2 - Purpose Rescue missions during terrorist attacks are extremely challenging for all rescue forces (police as well as non-police forces) involved. To improve the quality and safety of the rescue missions during an active killing event, it is obligatory to adapt common rescue mission goals and strategies. Methods After the recent attacks in Europe, the Federal Office of Civil Protection and Disaster Assistance started an evaluation process on behalf of the Federal Ministry of the Interior and the Federal Ministry of Health. This was done to identify weaknesses, lessons learned and to formulate new adapted guidelines. Results The presented bullet point recommendations summarise the basic and most important results of the ongoing evaluation process for the Federal Republic of Germany. The safety of all the rescue forces and survival of the greatest possible number of casualties are the priority goals. Furthermore, the preservation and re-establishment of the socio-political integrity are the overarching goals of the management of active killing events. Strategic incident priorities are to stop the killing and to save as much lives as possible. The early identification and prioritised transportation of casualties with life-threatening non-controllable bleeding are major tasks and the shortest possible on-scene time is an important requirement with respect to safety issues. Conclusion With respect to hazard prevention tactics within Germany, we attributed the highest priority impact to the bullet points. The focus of the process has now shifted to intense work about possible solutions for the identified deficits and implementation strategies of such solutions during mass killing incidents. KW - terror attack KW - mission strategies KW - lessons learned KW - first responders KW - safety Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-231777 SN - 1863-9933 VL - 46 ER - TY - JOUR A1 - Rösing, Nils A1 - Salvador, Ellaine A1 - Güntzel, Paul A1 - Kempe, Christoph A1 - Burek, Malgorzata A1 - Holzgrabe, Ulrike A1 - Soukhoroukov, Vladimir A1 - Wunder, Christian A1 - Förster, Carola T1 - Neuroprotective Effects of Isosteviol Sodium in Murine Brain Capillary Cerebellar Endothelial Cells (cerebEND) After Hypoxia JF - Frontiers in Cellular Neuroscience N2 - Ischemic stroke is one of the leading causes of death worldwide. It damages neurons and other supporting cellular elements in the brain. However, the impairment is not only confined to the region of assault but the surrounding area as well. Besides, it also brings about damage to the blood-brain barrier (BBB) which in turn leads to microvascular failure and edema. Hence, this necessitates an on-going, continuous search for intervention strategies and effective treatment. Of late, the natural sweetener stevioside proved to exhibit neuroprotective effects and therapeutic benefits against cerebral ischemia-induced injury. Its injectable formulation, isosteviol sodium (STVNA) also demonstrated favorable results. Nonetheless, its effects on the BBB have not yet been investigated to date. As such, this present study was designed to assess the effects of STVNA in our in vitro stroke model of the BBB.The integrity and permeability of the BBB are governed and maintained by tight junction proteins (TJPs) such as claudin-5 and occludin. Our data show increased claudin-5 and occludin expression in oxygen and glucose (OGD)-deprived murine brain capillary cerebellar endothelial cells (cerebEND) after STVNa treatment. Likewise, the upregulation of the transmembrane protein integrin-αv was also observed. Finally, cell volume was reduced with the simultaneous administration of STVNA and OGD in cerebEND cells. In neuropathologies such as stroke, the failure of cell volume control is a major feature leading to loss of cells in the penumbra as well as adverse outcomes. Our initial findings, therefore, point to the neuroprotective effects of STVNA at the BBB in vitro, which warrant further investigation for a possible future clinical intervention. KW - isosteviol sodium KW - hypoxia KW - cerebEND cells KW - blood brain barrier KW - neuroprotection Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-215013 SN - 1662-5102 VL - 14 ER - TY - JOUR A1 - Jung‐König, Mona A1 - Füllenbach, Christoph A1 - Murphy, Michael F. A1 - Manzini, Paola A1 - Laspina, Stefan A1 - Pendry, Kate A1 - Mühling, Jörg A1 - Wikman, Agneta A1 - Humbrecht, Catherine A1 - Rigal, Jean‐Christophe A1 - Lasocki, Sigismond A1 - Folléa, Gilles A1 - Seifried, Erhard A1 - Müller, Markus M. A1 - Geisen, Christof A1 - Aranko, Kari A1 - Zacharowski, Kai A1 - Meybohm, Patrick T1 - Programmes for the management of preoperative anaemia: audit in ten European hospitals within the PaBloE (Patient Blood Management in Europe) working group JF - Vox Sanguinis N2 - Background and objectives Preoperative anaemia is an independent risk factor for a higher morbidity and mortality, a longer hospitalization and increased perioperative transfusion rates. Managing preoperative anaemia is the first of three pillars of Patient Blood Management (PBM), a multidisciplinary concept to improve patient safety. While various studies provide medical information on (successful) anaemia treatment pathways, knowledge of organizational details of diagnosis and management of preoperative anaemia across Europe is scarce. Materials and methods To gain information on various aspects of preoperative anaemia management including organization, financing, diagnostics and treatment, we conducted a survey (74 questions) in ten hospitals from seven European nations within the PaBloE (Patient Blood Management in Europe) working group covering the year 2016. Results Organization and activity in the field of preoperative anaemia management were heterogeneous in the participating hospitals. Almost all hospitals had pathways for managing preoperative anaemia in place, however, only two nations had national guidelines. In six of the ten participating hospitals, preoperative anaemia management was organized by anaesthetists. Diagnostics and treatment focused on iron deficiency anaemia which, in most hospitals, was corrected with intravenous iron. Conclusion Implementation and approaches of preoperative anaemia management vary across Europe with a primary focus on treating iron deficiency anaemia. Findings of this survey motivated the hospitals involved to critically evaluate their practice and may also help other hospitals interested in PBM to develop action plans for diagnosis and management of preoperative anaemia. KW - iron deficiency KW - patient blood management KW - preoperative anaemia management Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-214049 VL - 115 IS - 3 SP - 182 EP - 191 ER - TY - JOUR A1 - Meybohm, Patrick A1 - Straub, Niels A1 - Füllenbach, Christoph A1 - Judd, Leonie A1 - Kleinerüschkamp, Adina A1 - Taeuber, Isabel A1 - Zacharowski, Kai A1 - Choorapoikayil, Suma T1 - Health economics of Patient Blood Management: a cost‐benefit analysis based on a meta‐analysis JF - Vox Sanguinis N2 - Background and Objectives Patient Blood Management (PBM) is the timely application of evidence‐based medical and surgical concepts designed to improve haemoglobin concentration, optimize haemostasis and minimize blood loss in an effort to improve patient outcomes. The focus of this cost‐benefit analysis is to analyse the economic benefit of widespread implementation of a multimodal PBM programme. Materials and Methods Based on a recent meta‐analysis including 17 studies (>235 000 patients) comparing PBM with control care and data from the University Hospital Frankfurt, a cost‐benefit analysis was performed. Outcome data were red blood cell (RBC) transfusion rate, number of transfused RBC units, and length of hospital stay (LOS). Costs were considered for the following three PBM interventions as examples: anaemia management including therapy of iron deficiency, use of cell salvage and tranexamic acid. For sensitivity analysis, a Monte Carlo simulation was performed. Results Iron supplementation was applied in 3·1%, cell salvage in 65% and tranexamic acid in 89% of the PBM patients. In total, applying these three PBM interventions costs €129·04 per patient. However, PBM was associated with a reduction in transfusion rate, transfused RBC units per patient, and LOS which yielded to mean savings of €150·64 per patient. Thus, the overall benefit of PBM implementation was €21·60 per patient. In the Monte Carlo simulation, the cost savings on the outcome side exceeded the PBM costs in approximately 2/3 of all repetitions and the total benefit was €1 878 000 in 100·000 simulated patients. Conclusion Resources to implement a multimodal PBM concept optimizing patient care and safety can be cost‐effectively. KW - Patient Blood Management (PBM) KW - haemoglobin concentration KW - haemostasis KW - blood loss Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-214084 VL - 115 IS - 2 SP - 182 EP - 188 ER - TY - JOUR A1 - Zullo, Alberto A1 - Fleckenstein, Johannes A1 - Schleip, Robert A1 - Hoppe, Kerstin A1 - Wearing, Scott A1 - Klingler, Werner T1 - Structural and Functional Changes in the Coupling of Fascial Tissue, Skeletal Muscle, and Nerves During Aging JF - Frontiers in Physiology N2 - Aging is a one-way process associated with profound structural and functional changes in the organism. Indeed, the neuromuscular system undergoes a wide remodeling, which involves muscles, fascia, and the central and peripheral nervous systems. As a result, intrinsic features of tissues, as well as their functional and structural coupling, are affected and a decline in overall physical performance occurs. Evidence from the scientific literature demonstrates that senescence is associated with increased stiffness and reduced elasticity of fascia, as well as loss of skeletal muscle mass, strength, and regenerative potential. The interaction between muscular and fascial structures is also weakened. As for the nervous system, aging leads to motor cortex atrophy, reduced motor cortical excitability, and plasticity, thus leading to accumulation of denervated muscle fibers. As a result, the magnitude of force generated by the neuromuscular apparatus, its transmission along the myofascial chain, joint mobility, and movement coordination are impaired. In this review, we summarize the evidence about the deleterious effect of aging on skeletal muscle, fascial tissue, and the nervous system. In particular, we address the structural and functional changes occurring within and between these tissues and discuss the effect of inflammation in aging. From the clinical perspective, this article outlines promising approaches for analyzing the composition and the viscoelastic properties of skeletal muscle, such as ultrasonography and elastography, which could be applied for a better understanding of musculoskeletal modifications occurring with aging. Moreover, we describe the use of tissue manipulation techniques, such as massage, traction, mobilization as well as acupuncture, dry needling, and nerve block, to enhance fascial repair. KW - aging KW - connective tissue KW - fascia KW - skeletal muscle KW - nerve Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-206890 SN - 1664-042X VL - 11 IS - 592 ER - TY - JOUR A1 - Lock, J. F. A1 - Ungeheuer, L. A1 - Borst, P. A1 - Swol, J. A1 - Löb, S. A1 - Brede, E. M. A1 - Röder, D. A1 - Lengenfelder, B. A1 - Sauer, K. A1 - Gremer, C. - T. T1 - Markedly increased risk of postoperative bleeding complications during perioperative bridging anticoagulation in general and visceral surgery JF - Perioperative Medicine N2 - Background Increasing numbers of patients receiving oral anticoagulants are undergoing elective surgery. Low molecular weight heparin (LMWH) is frequently applied as bridging therapy during perioperative interruption of anticoagulation. The aim of this study was to explore the postoperative bleeding risk of patients receiving surgery under bridging anticoagulation. Methods We performed a monocentric retrospective two-arm matched cohort study. Patients that received perioperative bridging anticoagulation were compared to a matched control group with identical surgical procedure, age, and sex. Emergency and vascular operations were excluded. The primary endpoint was the incidence of major postoperative bleeding. Secondary endpoints were minor postoperative bleeding, thromboembolic events, length of stay, and in-hospital mortality. Multivariate analysis explored risk factors of major postoperative bleeding. Results A total of 263 patients in each study arm were analyzed. The patient cohort included the entire field of general and visceral surgery including a large proportion of major oncological resections. Bridging anticoagulation increased the postoperative incidence of major bleeding events (8% vs. 1%; p < 0.001) as well as minor bleeding events (14% vs. 5%; p < 0.001). Thromboembolic events were equally rare in both groups (1% vs. 2%; p = 0.45). No effect on mortality was observed (1.5% vs. 1.9%). Independent risk factors of major postoperative bleeding were full-therapeutic dose of LMWH, renal insufficiency, and the procedure-specific bleeding risk. Conclusion Perioperative bridging anticoagulation, especially full-therapeutic dose LMWH, markedly increases the risk of postoperative bleeding complications in general and visceral surgery. Surgeons should carefully consider the practice of routine bridging. KW - low molecular heparin KW - atrial fibrillation KW - postoperative bleeding KW - thromboembolism KW - anticoagulation KW - bridging KW - antithrombotic therapy KW - warfarin interruption KW - oral anticoagulants KW - management Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-230690 VL - 9 ER - TY - JOUR A1 - Herrmann, Anna A1 - Herrmann, Matthias A1 - Passlick, Bernward A1 - Herth, Felix A1 - Herrmann, Johannes T1 - Cycling‐induced recurrent spontaneous pneumomediastinum and pneumopericardium in a young female patient JF - Clinical Case Reports N2 - We present an exceptional case of recurrent cycling‐induced spontaneous pneumomediastinum and pneumopericardium in a female patient without any trauma. Radiological and endoscopic examinations were carried out to exclude other differential diagnoses. Decision for in‐hospital observation and conservative treatment was made. No symptoms were reported 12 months after return to sports activity. KW - Hamman's syndrome KW - spontaneous pneumomediastinum KW - spontaneous pneumopericardium KW - sport medicine Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-276465 VL - 10 IS - 3 ER - TY - JOUR A1 - Asch, Silke A1 - Kaufmann, Tobias Peter A1 - Walter, Michaela A1 - Leistner, Marcus A1 - Danner, Bernd C. A1 - Perl, Thorsten A1 - Kutschka, Ingo A1 - Niehaus, Heidi T1 - The effect of perioperative hemadsorption in patients operated for acute infective endocarditis—A randomized controlled study JF - Artificial Organs N2 - Patients operated for infective endocarditis (IE) are at high risk of developing an excessive systemic hyperinflammatory state, resulting in systemic inflammatory response syndrome and septic shock. Hemoadsorption (HA) by cytokine adsorbers has been successfully applied to remove inflammatory mediators. This randomized controlled trial investigates the effect of perioperative HA therapy on inflammatory parameters and hemodynamic status in patients operated for IE. A total of 20 patients were randomly assigned to either HA therapy or the control group. HA therapy was initiated intraoperatively and continued for 24 hours postoperatively. Cytokine levels (IL‐6, IL‐1b, TNF‐α), leukocytes, C‐reactive protein (CRP), and Procalcitonin (PCT) as well as catecholamine support, and volume requirement were compared between both groups. Operative procedures included aortic (n = 7), mitral (n = 6), and multiple valve surgery (n = 7). All patients survived to discharge. No significant differences concerning median cytokine levels (IL‐6 and TNF‐α) were observed between both groups. CRP and PCT baseline levels were significantly higher in the HA group (59.5 vs. 26.3 mg/dL, P = .029 and 0.17 vs. 0.05 µg/L, P = .015) equalizing after surgery. Patients in the HA group required significantly higher doses of vasopressors (0.093 vs. 0.025 µg/kg/min norepinephrine, P = .029) at 12 hours postoperatively as well as significantly more overall volume replacement (7217 vs. 4185 mL at 12 hours, P = .015; 12 021 vs. 4850 mL at 48 hours, P = .015). HA therapy did neither result in a reduction of inflammatory parameters nor result in an improvement of hemodynamic parameters in patients operated for IE. For a more targeted use of HA therapy, appropriate selection criteria are required. KW - cytokines KW - endocarditis KW - hemadsorption KW - sepsis KW - SIRS Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-262681 VL - 45 IS - 11 SP - 1328 EP - 1337 ER - TY - JOUR A1 - Oehler, Beatrice A1 - Mohammadi, Milad A1 - Perpina Viciano, Cristina A1 - Hackel, Dagmar A1 - Hoffmann, Carsten A1 - Brack, Alexander A1 - Rittner, Heike L. T1 - Peripheral interaction of Resolvin D1 and E1 with opioid receptor antagonists for antinociception in inflammatory pain in rats JF - Frontiers in Molecular Neuroscience N2 - Antinociceptive pathways are activated in the periphery in inflammatory pain, for instance resolvins and opioid peptides. Resolvins are biosynthesized from omega-3 polyunsaturated fatty acids such as eicosapentaenoic acid and docosahexaenoic acid. Resolvin D1 (RvD1) and resolvin E1 (RvE1) initiate the resolution of inflammation and control of hypersensitivity via induction of anti-inflammatory signaling cascades. RvD1 binds to lipoxin A4/annexin-A1 receptor/formyl-peptide receptor 2 (ALX/FPR2), RvE1 to chemerin receptor 23 (ChemR23). Antinociception of RvD1 is mediated by interaction with transient receptor potential channels ankyrin 1 (TRPA1). Endogenous opioid peptides are synthesized and released from leukocytes in the tissue and bind to opioid receptors on nociceptor terminals. Here, we further explored peripheral mechanisms of RvD1 and chemerin (Chem), the ligand of ChemR23, in complete Freund’s adjuvant (CFA)-induced hindpaw inflammation in male Wistar rats. RvD1 and Chem ameliorated CFA-induced hypersensitivity in early and late inflammatory phases. This was prevented by peripheral blockade of the μ-opioid peptide receptor (MOR) using low dose local naloxone or by local injection of anti-β-endorphin and anti-met-enkephalin (anti-ENK) antibodies. Naloxone also hindered antinociception by the TRPA1 inhibitor HC-030031. RvD1 did not stimulate the release of β-endorphin from macrophages and neutrophils, nor did RvD1 itself activate G-proteins coupled MOR or initiate β-arrestin recruitment to the membrane. TRPA1 blockade by HC-030031 in inflammation in vivo as well as inhibition of the TRPA1-mediated calcium influx in dorsal root ganglia neurons in vitro was hampered by naloxone. Peripheral application of naloxone alone in vivo already lowered mechanical nociceptive thresholds. Therefore, either a perturbation of the balance of endogenous pro- and antinociceptive mechanisms in early and late inflammation, or an interaction of TRPA1 and opioid receptors weaken the antinociceptive potency of RvD1 and TRPA1 blockers. KW - transient receptor potential channels KW - pain behavior KW - resolvin KW - opioid receptors KW - opioid peptides KW - inflammation KW - animals Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-158642 VL - 10 IS - 242 ER - TY - JOUR A1 - Shityakov, Sergey A1 - Skorb, Ekaterina V. A1 - Förster, Carola Y. A1 - Dandekar, Thomas T1 - Scaffold Searching of FDA and EMA-Approved Drugs Identifies Lead Candidates for Drug Repurposing in Alzheimer’s Disease JF - Frontiers in Chemistry N2 - Clinical trials of novel therapeutics for Alzheimer’s Disease (AD) have consumed a significant amount of time and resources with largely negative results. Repurposing drugs already approved by the Food and Drug Administration (FDA), European Medicines Agency (EMA), or Worldwide for another indication is a more rapid and less expensive option. Therefore, we apply the scaffold searching approach based on known amyloid-beta (Aβ) inhibitor tramiprosate to screen the DrugCentral database (n = 4,642) of clinically tested drugs. As a result, menadione bisulfite and camphotamide substances with protrombogenic and neurostimulation/cardioprotection effects were identified as promising Aβ inhibitors with an improved binding affinity (ΔGbind) and blood-brain barrier permeation (logBB). Finally, the data was also confirmed by molecular dynamics simulations using implicit solvation, in particular as Molecular Mechanics Generalized Born Surface Area (MM-GBSA) model. Overall, the proposed in silico pipeline can be implemented through the early stage rational drug design to nominate some lead candidates for AD, which will be further validated in vitro and in vivo, and, finally, in a clinical trial. KW - scaffold search KW - approved drugs KW - drug repurposing KW - alzheimer's disease KW - chemical similarity KW - molecular modeling Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-248703 SN - 2296-2646 VL - 9 ER - TY - JOUR A1 - Chen, Jeremy Tsung-Chieh A1 - Schmidt, Lea A1 - Schürger, Christina A1 - Hankir, Mohammed K. A1 - Krug, Susanne M. A1 - Rittner, Heike L. T1 - Netrin-1 as a multitarget barrier stabilizer in the peripheral nerve after injury JF - International Journal of Molecular Sciences N2 - The blood–nerve barrier and myelin barrier normally shield peripheral nerves from potentially harmful insults. They are broken down during nerve injury, which contributes to neuronal damage. Netrin-1 is a neuronal guidance protein with various established functions in the peripheral and central nervous systems; however, its role in regulating barrier integrity and pain processing after nerve injury is poorly understood. Here, we show that chronic constriction injury (CCI) in Wistar rats reduced netrin-1 protein and the netrin-1 receptor neogenin-1 (Neo1) in the sciatic nerve. Replacement of netrin-1 via systemic or local administration of the recombinant protein rescued injury-induced nociceptive hypersensitivity. This was prevented by siRNA-mediated knockdown of Neo1 in the sciatic nerve. Mechanistically, netrin-1 restored endothelial and myelin, but not perineural, barrier function as measured by fluorescent dye or fibrinogen penetration. Netrin-1 also reversed the decline in the tight junction proteins claudin-5 and claudin-19 in the sciatic nerve caused by CCI. Our findings emphasize the role of the endothelial and myelin barriers in pain processing after nerve damage and reveal that exogenous netrin-1 restores their function to mitigate CCI-induced hypersensitivity via Neo1. The netrin-1-neogenin-1 signaling pathway may thus represent a multi-target barrier protector for the treatment of neuropathic pain. KW - neuropathic pain KW - netrin-1 KW - blood-nerve barrier KW - tight junction proteins Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-261695 SN - 1422-0067 VL - 22 IS - 18 ER - TY - JOUR A1 - Oehler, Beatrice A1 - Kistner, Katrin A1 - Martin, Corinna A1 - Schiller, Jürgen A1 - Mayer, Rafaela A1 - Mohammadi, Milad A1 - Sauer, Reine-Solange A1 - Filipovic, Milos R. A1 - Nieto, Francisco R. A1 - Kloka, Jan A1 - Pflücke, Diana A1 - Hill, Kerstin A1 - Schaefer, Michael A1 - Malcangio, Marzia A1 - Reeh, Peter W. A1 - Brack, Alexander A1 - Blum, Robert A1 - Rittner, Heike L. T1 - Inflammatory pain control by blocking oxidized phospholipid-mediated TRP channel activation JF - Scientific Reports N2 - Phospholipids occurring in cell membranes and lipoproteins are converted into oxidized phospholipids (OxPL) by oxidative stress promoting atherosclerotic plaque formation. Here, OxPL were characterized as novel targets in acute and chronic inflammatory pain. Oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (OxPAPC) and its derivatives were identified in inflamed tissue by mass spectrometry and binding assays. They elicited calcium influx, hyperalgesia and induced pro-nociceptive peptide release. Genetic, pharmacological and mass spectrometric evidence in vivo as well as in vitro confirmed the role of transient receptor potential channels (TRPA1 and TRPV1) as OxPAPC targets. Treatment with the monoclonal antibody E06 or with apolipoprotein A-I mimetic peptide D-4F, capturing OxPAPC in atherosclerosis, prevented inflammatory hyperalgesia, and in vitro TRPA1 activation. Administration of D-4F or E06 to rats profoundly ameliorated mechanical hyperalgesia and inflammation in collagen-induced arthritis. These data reveal a clinically relevant role for OxPAPC in inflammation offering therapy for acute and chronic inflammatory pain treatment by scavenging OxPAPC. KW - chronic pain KW - ion channels in the nervous system KW - molecular medicine KW - pain Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-158536 VL - 7 IS - 5447 ER - TY - JOUR A1 - Kindl, Gudrun A1 - Teichmüller, Karolin A1 - Escolano-Lozano, Fabiola A1 - Birklein, Frank A1 - Rittner, Heike L. T1 - Pain, disability, and lifestyle: Patients with complex regional pain syndrome compared to chronic musculoskeletal pain-A retrospective analysis JF - European Journal of Pain N2 - Background Complex regional pain syndrome (CRPS) is an orphan disease occurring as a complication after trauma. Due to its acute onset and the typical clinical presentation of the inflammatory and autonomous signs, it is an eye-catching chronic pain disease affecting also young and working people. In social media and the internet, high pain severity and the unfavourable prognosis are often empathized. Methods Here, we compared epidemiological, pain and lifestyle factors of 223 CPRS patients from the “ncRNAPain” cohort with 255 patients with chronic musculoskeletal pain (MSK). MSK patients were recruited at the beginning of a multimodal pain therapy programme. We searched for factors predicting pain intensity. Results Both chronic pain diseases affected women in middle age. Patients with MSK were more obese, drank more alcohol, and were less educated (Pearson chi-square Test or Mann–Whitney/U-Test). Both groups smoked more than healthy people in the OECD (Organization for Economic Cooperation and Development). Mann–Whitney/U-Test confirmed that CRPS patients did not have more severe pain and did not suffer more from pain-related disability than patients with MSK. CRPS patients also had less psychiatric comorbidities. Multiple linear regression analysis revealed that group assignment, depressive characteristics, body mass index, average alcohol consumption and smoking predicted higher pain ratings, while disease duration, anxiety symptoms or gender had no influence on pain intensity. Conclusion In summary, our study supports a more optimistic view on pain in CRPS patients in comparison to MSK and identifies lifestyle factors that might contribute to the pathophysiology like smoking and drinking. Important next steps are the identification of CRPS patients at risk for chronification or—vice versa—with protective factors for pain resolution. Significance This study compares complex regional pain syndrome (CRPS) and chronic musculoskeletal pain and questions previously reported pain, disability and lifestyle factors associated with CRPS. KW - complex regional pain syndrome KW - chronic musculoskeletal pain KW - comparison Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-318200 VL - 26 IS - 3 SP - 719 EP - 728 ER - TY - JOUR A1 - Hill, Aileen A1 - Heyland, Daren K. A1 - Rossaint, Rolf A1 - Arora, Rakesh C. A1 - Engelman, Daniel T. A1 - Day, Andrew G. A1 - Stoppe, Christian T1 - Longitudinal outcomes in octogenarian critically ill patients with a focus on frailty and cardiac surgery JF - Journal of Clinical Medicine N2 - Cardiac surgery (CSX) can be lifesaving in elderly patients (age ≥ 80 years) but may still be associated with complications and functional decline. Frailty represents a determinant to outcomes in critically ill patients, but little is known about its influence on elderly CSX-patients. This is a secondary exploratory analysis of a multi-center, prospective observational cohort study of 610 elderly patients admitted to the ICU and followed for one year to document long-term outcomes. CSX-ICU-patients (n = 49) were compared to surgical ICU patients (n = 184) with regard to demographics, frailty, and outcomes. Of all surgical patients, 102 (43%) were considered vulnerable or frail. The subdistribution hazard ratio (SHR) of time to discharge home (TTDH) for vulnerable/frail vs. fit/well patients was 0.54 (95% confidence interval (CI), 0.34, 0.86, p = 0.007). The p-value for effect modification between surgery group (CSX vs. surgical ICU patients) and Clinical Frailty Scale (CFS) group was not significant (p = 0.37) suggesting that the observed difference in the CFS effect between the CSX and surgical ICU patients is consistent with random error. A further subgroup analysis shows that among surgical ICU patients, the SHR of time to discharge home (TTDH) for vulnerable/frail vs. fit/well patients was 0.49 (95% CI, 0.29, 0.83) while the corresponding SHR for CSX patients was 0.77 (0.32–1.88). In conclusion, preoperative frailty reduced the rate of discharge to home in both surgical and CSX patients, but a larger sample of CSX patients is needed to adequately address this question in this patient group. KW - population characteristics KW - demography KW - aged 80 and over KW - critical illness KW - cardiac surgery KW - critical care KW - frailty KW - prospective studies KW - nutrition therapy Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-220064 SN - 2077-0383 VL - 10 IS - 1 ER - TY - JOUR A1 - Lehmann, Martin A1 - Oehler, Beatrice A1 - Zuber, Jonas A1 - Malzahn, Uwe A1 - Walles, Thorsten A1 - Muellenbach, Ralf M. A1 - Roewer, Norbert A1 - Kredel, Markus T1 - Redistribution of pulmonary ventilation after lung surgery detected with electrical impedance tomography JF - Acta Anaesthesiologica Scandinavica N2 - Background: Regional ventilation of the lung can be visualized by pulmonary electrical impedance tomography (EIT). The aim of this study was to examine the post‐operative redistribution of regional ventilation after lung surgery dependent on the side of surgery and its association with forced vital capacity. Methods: In this prospective, observational cohort study 13 patients undergoing right and 13 patients undergoing left‐sided open or video‐thoracoscopic procedures have been investigated. Pre‐operative measurements with EIT and spirometry were compared with data obtained 3 days post‐operation. The center of ventilation (COV) within a 32 × 32 pixel matrix was calculated from EIT data. The transverse axis coordinate of COV, COVx (left/right), was modified to COVx′ (ipsilateral/contralateral). Thus, COVx′ shows a negative change if ventilation shifts contralateral independent of the side of surgery. This enabled testing with two‐way ANOVA for repeated measurements (side, time). Results: The perioperative shift of COVx′ was dependent on the side of surgery (P = .007). Ventilation shifted away from the side of surgery after the right‐sided surgery (COVx′‐1.97 pixel matrix points, P < .001), but not after the left‐sided surgery (COVx′‐0.61, P = .425). The forced vital capacity (%predicted) decreased from 94 (83‐109)% (median [quartiles]; [left‐sided]) and 89 (80‐97)% (right‐sided surgery) to 61 (59‐66)% and 62 (40‐72)% (P < .05), respectively. The perioperative changes in forced vital capacity (%predicted) were weakly associated with the shift of COVx′. Conclusion: Only after right‐sided lung surgery, EIT showed reduced ventilation on the side of surgery while vital capacity was markedly reduced in both groups. KW - electrical impedance tomography KW - general anaesthesia KW - one‐lung ventilation KW - postoperative complications KW - pulmonary function tests KW - pulmonary surgical procedures Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-213575 VL - 64 IS - 4 ER - TY - JOUR A1 - Esmaeilpour, Donya A1 - Broscheit, Jens Albert A1 - Shityakov, Sergey T1 - Cyclodextrin-based polymeric materials bound to corona protein for theranostic applications JF - International Journal of Molecular Sciences N2 - Cyclodextrins (CDs) are cyclic oligosaccharide structures that could be used for theranostic applications in personalized medicine. These compounds have been widely utilized not only for enhancing drug solubility, stability, and bioavailability but also for controlled and targeted delivery of small molecules. These compounds can be complexed with various biomolecules, such as peptides or proteins, via host-guest interactions. CDs are amphiphilic compounds with water-hating holes and water-absorbing surfaces. Architectures of CDs allow the drawing and preparation of CD-based polymers (CDbPs) with optimal pharmacokinetic and pharmacodynamic properties. These polymers can be cloaked with protein corona consisting of adsorbed plasma or extracellular proteins to improve nanoparticle biodistribution and half-life. Besides, CDs have become famous in applications ranging from biomedicine to environmental sciences. In this review, we emphasize ongoing research in biomedical fields using CD-based centered, pendant, and terminated polymers and their interactions with protein corona for theranostic applications. Overall, a perusal of information concerning this novel approach in biomedicine will help to implement this methodology based on host-guest interaction to improve therapeutic and diagnostic strategies. KW - cyclodextrin KW - theranostics KW - protein corona KW - nanomedicine KW - therapy KW - polymers Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-297399 SN - 1422-0067 VL - 23 IS - 21 ER - TY - JOUR A1 - Reschke, Moritz A1 - Salvador, Ellaine A1 - Schlegel, Nicolas A1 - Burek, Malgorzata A1 - Karnati, Srikanth A1 - Wunder, Christian A1 - Förster, Carola Y. T1 - Isosteviol sodium (STVNA) reduces pro-inflammatory cytokine IL-6 and GM-CSF in an in vitro murine stroke model of the blood–brain barrier (BBB) JF - Pharmaceutics N2 - Early treatment with glucocorticoids could help reduce both cytotoxic and vasogenic edema, leading to improved clinical outcome after stroke. In our previous study, isosteviol sodium (STVNA) demonstrated neuroprotective effects in an in vitro stroke model, which utilizes oxygen-glucose deprivation (OGD). Herein, we tested the hypothesis that STVNA can activate glucocorticoid receptor (GR) transcriptional activity in brain microvascular endothelial cells (BMECs) as previously published for T cells. STVNA exhibited no effects on transcriptional activation of the glucocorticoid receptor, contrary to previous reports in Jurkat cells. However, similar to dexamethasone, STVNA inhibited inflammatory marker IL-6 as well as granulocyte-macrophage colony-stimulating factor (GM-CSF) secretion. Based on these results, STVNA proves to be beneficial as a possible prevention and treatment modality for brain ischemia-reperfusion injury-induced blood–brain barrier (BBB) dysfunction. KW - IL-6 KW - ischemia KW - isosteviol sodium (STVNA) KW - dexamethasone KW - glucocorticoid receptor KW - cerebEND Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-286275 SN - 1999-4923 VL - 14 IS - 9 ER - TY - JOUR A1 - Fareed, Muhammad Mazhar A1 - Qasmi, Maryam A1 - Aziz, Shaan A1 - Völker, Elisabeth A1 - Förster, Carola Yvette A1 - Shityakov, Sergey T1 - The role of clusterin transporter in the pathogenesis of Alzheimer’s disease at the blood–brain barrier interface: a systematic review JF - Biomolecules N2 - Alzheimer’s disease (AD) is considered a chronic and debilitating neurological illness that is increasingly impacting older-age populations. Some proteins, including clusterin (CLU or apolipoprotein J) transporter, can be linked to AD, causing oxidative stress. Therefore, its activity can affect various functions involving complement system inactivation, lipid transport, chaperone activity, neuronal transmission, and cellular survival pathways. This transporter is known to bind to the amyloid beta (Aβ) peptide, which is the major pathogenic factor of AD. On the other hand, this transporter is also active at the blood–brain barrier (BBB), a barrier that prevents harmful substances from entering and exiting the brain. Therefore, in this review, we discuss and emphasize the role of the CLU transporter and CLU-linked molecular mechanisms at the BBB interface in the pathogenesis of AD. KW - clusterin transporter KW - Wnt signaling KW - Alzheimer’s disease KW - AD pathogenesis KW - blood–brain barrier KW - apolipoprotein J Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-290279 SN - 2218-273X VL - 12 IS - 10 ER - TY - JOUR A1 - Förster, Carola Y. A1 - Shityakov, Sergey A1 - Scheper, Verena A1 - Lenarz, Thomas T1 - Linking cerebrovascular dysfunction to age-related hearing loss and Alzheimer’s disease — are systemic approaches for diagnosis and therapy required? JF - Biomolecules N2 - Alzheimer’s disease (AD), the most common cause of dementia in the elderly, is a neurodegenerative disorder associated with neurovascular dysfunction, cognitive decline, and the accumulation of amyloid β peptide (Aβ) in the brain and tau-related lesions in neurons termed neurofibrillary tangles (NFTs). Aβ deposits and NFT formation are the central pathological hallmarks in AD brains, and the majority of AD cases have been shown to exhibit a complex combination of systemic comorbidities. While AD is the foremost common cause of dementia in the elderly, age-related hearing loss (ARHL) is the most predominant sensory deficit in the elderly. During aging, chronic inflammation and resulting endothelial dysfunction have been described and might be key contributors to AD; we discuss an intriguing possible link between inner ear strial microvascular pathology and blood–brain barrier pathology and present ARHL as a potentially modifiable and treatable risk factor for AD development. We present compelling evidence that ARHL might well be seen as an important risk factor in AD development: progressive hearing impairment, leading to social isolation, and its comorbidities, such as frailty, falls, and late-onset depression, link ARHL with cognitive decline and increased risk of dementia, rendering it tempting to speculate that ARHL might be a potential common molecular and pathological trigger for AD. Additionally, one could speculate that amyloid-beta might damage the blood–labyrinth barrier as it does to the blood–brain barrier, leading to ARHL pathology. Finally, there are options for the treatment of ARHL by targeted neurotrophic factor supplementation to the cochlea to improve cognitive outcomes; they can also prevent AD development and AD-related comorbidity in the future. KW - Alzheimer’s disease KW - age-related hearing loss KW - neurovasculature KW - blood–brain barrier KW - blood–labyrinth barrier KW - spiral ganglion neuron KW - pharmacotherapy KW - neurotrophic factor KW - inner ear Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-297552 SN - 2218-273X VL - 12 IS - 11 ER - TY - JOUR A1 - Bauer, Maria A1 - Opitz, Anne A1 - Filser, Jörg A1 - Jansen, Hendrik A1 - Meffert, Rainer H. A1 - Germer, Christoph T. A1 - Roewer, Norbert A1 - Muellenbach, Ralf M. A1 - Kredel, Markus T1 - Perioperative redistribution of regional ventilation and pulmonary function: a prospective observational study in two cohorts of patients at risk for postoperative pulmonary complications JF - BMC Anesthesiology N2 - Background Postoperative pulmonary complications (PPCs) increase morbidity and mortality of surgical patients, duration of hospital stay and costs. Postoperative atelectasis of dorsal lung regions as a common PPC has been described before, but its clinical relevance is insufficiently examined. Pulmonary electrical impedance tomography (EIT) enables the bedside visualization of regional ventilation in real-time within a transversal section of the lung. Dorsal atelectasis or effusions might cause a ventral redistribution of ventilation. We hypothesized the existence of ventral redistribution in spontaneously breathing patients during their recovery from abdominal and peripheral surgery and that vital capacity is reduced if regional ventilation shifts to ventral lung regions. Methods This prospective observational study included 69 adult patients undergoing elective surgery with an expected intermediate or high risk for PPCs. Patients undergoing abdominal and peripheral surgery were recruited to obtain groups of equal size. Patients received general anesthesia with and without additional regional anesthesia. On the preoperative, the first and the third postoperative day, EIT was performed at rest and during spirometry (forced breathing). The center of ventilation in dorso-ventral direction (COVy) was calculated. Results Both groups received intraoperative low tidal volume ventilation. Postoperative ventral redistribution of ventilation (forced breathing COVy; preoperative: 16.5 (16.0–17.3); first day: 17.8 (16.9–18.2), p < 0.004; third day: 17.4 (16.2–18.2), p = 0.020) and decreased forced vital capacity in percentage of predicted values (FVC%predicted) (median: 93, 58, 64%, respectively) persisted after abdominal surgery. In addition, dorsal to ventral shift was associated with a decrease of the FVC%predicted on the third postoperative day (r = − 0.66; p < 0.001). A redistribution of pulmonary ventilation was not observed after peripheral surgery. FVC%predicted was only decreased on the first postoperative day (median FVC%predicted on the preoperative, first and third day: 85, 81 and 88%, respectively). In ten patients occurred pulmonary complications after abdominal surgery also in two patients after peripheral surgery. Conclusions After abdominal surgery ventral redistribution of ventilation persisted up to the third postoperative day and was associated with decreased vital capacity. The peripheral surgery group showed only minor changes in vital capacity, suggesting a role of the location of surgery for postoperative redistribution of pulmonary ventilation. KW - Electrical impedance tomography KW - General anaesthesia KW - Postoperative complications KW - Pulmonary function tests Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-200730 VL - 19 ER - TY - JOUR A1 - Holzmann-Littig, Christopher A1 - Braunisch, Matthias Christoph A1 - Kranke, Peter A1 - Popp, Maria A1 - Seeber, Christian A1 - Fichtner, Falk A1 - Littig, Bianca A1 - Carbajo-Lozoya, Javier A1 - Allwang, Christine A1 - Frank, Tamara A1 - Meerpohl, Joerg Johannes A1 - Haller, Bernhard A1 - Schmaderer, Christoph T1 - COVID-19 vaccination acceptance and hesitancy among healthcare workers in germany JF - Vaccines N2 - Vaccination hesitancy is a threat to herd immunity. Healthcare workers (HCWs) play a key role in promoting Coronavirus disease 2019 (COVID-19) vaccination in the general population. We therefore aimed to provide data on COVID-19 vaccination acceptance/hesitancy among German HCWs. For this exploratory, cross-sectional study, an online survey was conducted in February 2021. The survey included 54 items on demographics; previous vaccination behavior; trust in vaccines, physicians, the pharmaceutical industry and health politics; fear of adverse effects; assumptions regarding the consequences of COVID-19; knowledge about vaccines; and information seeking behavior. Odds ratios with 95% confidence intervals were calculated and chi-square tests were performed. Four thousand five hundred surveys were analyzed. The overall vaccination acceptance was 91.7%. The age group ≤20 years showed the lowest vaccination acceptance. Factors associated with vaccination hesitancy were lack of trust in authorities and pharmaceutical companies. Attitudes among acquaintances were associated with vaccination hesitancy too. Participants with vaccination hesitancy more often obtained information about COVID-19 vaccines via messenger services or online video platforms and underperformed in the knowledge test. We found high acceptance amongst German HCWs. Several factors associated with vaccination hesitancy were identified which could be targeted in HCW vaccination campaigns. KW - COVID-19 KW - vaccine KW - vaccination KW - vaccination hesitancy KW - vaccine refusal KW - vaccination campaign Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-242627 SN - 2076-393X VL - 9 IS - 7 ER - TY - JOUR A1 - Konrad, Franziska M. A1 - Bury, Annette A1 - Schick, Martin A. A1 - Ngamsri, Kristian-Christos A1 - Reutershan, Jörg T1 - The Unrecognized Effects of Phosphodiesterase 4 on Epithelial Cells in Pulmonary Inflammation JF - PLoS ONE N2 - Acute pulmonary inflammation is characterized by migration of polymorphonuclear neutrophils (PMNs) into the different compartments of the lung, passing an endothelial and epithelial barrier. Recent studies showed evidence that phosphodiesterase (PDE) 4-inhibitors stabilized endothelial cells. PDE4B and PDE4D subtypes play a pivotal role in inflammation, whereas blocking PDE4D is suspected to cause gastrointestinal side effects. We thought to investigate the particular role of the PDE4-inhibitors roflumilast and rolipram on lung epithelium. Acute pulmonary inflammation was induced by inhalation of LPS. PDE4-inhibitors were administered i.p. or nebulized after inflammation. The impact of PDE4-inhibitors on PMN migration was evaluated in vivo and in vitro. Microvascular permeability, cytokine levels, and PDE4B and PDE4D expression were analyzed. In vivo, both PDE4-inhibitors decreased transendothelial and transepithelial migration even when administered after inflammation, whereas roflumilast showed a superior effect compared to rolipram on the epithelium. Both inhibitors decreased TNF\(\alpha\), IL6, and CXCL2/3. CXCL1, the strong PMN chemoattractant secreted by the epithelium, was significantly more reduced by roflumilast. In vitro assays with human epithelium also emphasized the pivotal role of roflumilast on the epithelium. Additionally, LPS-induced stress fibers, an essential requirement for a direct migration of PMNs into the alveolar space, were predominantly reduced by roflumilast. Expression of PDE4B and PDE4D were both increased in the lungs by LPS, PDE4-inhibitors decreased mainly PDE4B. The topical administration of PDE4-inhibitors was also effective in curbing down PMN migration, further highlighting the clinical potential of these compounds. In pulmonary epithelial cells, both subtypes were found coexistent around the nucleus and the cytoplasm. In these epithelial cells, LPS increased PDE4B and, to a lesser extend, PDE4D, whereas the effect of the inhibitors was prominent on the PDE4B subtype. In conclusion, we determined the pivotal role of the PDE4-inhibitor roflumilast on lung epithelium and emphasized its main effect on PDE4B in hyperinflammation. KW - acute lung injury KW - PDE4-inhibitor roflumilast KW - GRO alpha KW - expression KW - 4D KW - respiratory distress syndrome KW - mice KW - infiltration KW - rolipram KW - disease Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-143203 VL - 10 IS - 4 ER - TY - THES A1 - Lux, Thomas Joachim T1 - Characterization of Junctional Proteins in the Dorsal Root Ganglion of Rats with Traumatic Nerve Injury T1 - Charakterisierung von Junktionsproteinen im Spinalganglion von Ratten mit traumatischer Nervenverletzung N2 - In my thesis, I characterized aGPCRs Adgrl1 and Adgrl3, tight junction proteins and the blood-DRG-barrier in rats’ lumbar dorsal root ganglions after traumatic neuropathy. In contrast to the otherwise tightly sealed barriers shielding neural tissues, the dorsal root ganglion’s neuron rich region is highly permeable in its healthy state. Furthermore, the DRG is a source of ectopic signal generation during neuropathy; the exact origin of which is still unclear. I documented expression of Adgrl1 and Adgrl3 in NF200 + , CGRP + and IB4 + neurons. One week after CCI, I observed transient downregulation of Adgrl1 in non-peptidergic nociceptors (IB4+). In the context of previous data, dCirl deletion causing an allodynia-like state in Drosophila, our research hints to a possible role of Adgrl1 nociceptive signal processing and pain resolution in neuropathy. Furthermore, I demonstrated similar claudin-1, claudin-12, claudin-19, and ZO-1 expression of the dorsal root ganglion’s neuron rich and fibre rich region. Claudin-5 expression in vessels of the neuron rich region was lower compared to the fibre rich region. Claudin-5 expression was decreased one week after nerve injury in vessels of the neuron rich region while permeability for small and large injected molecules remained unchanged. Nevertheless, we detected more CD68+ cells in the neuron rich region one week after CCI. As clinically relevant conclusion, we verified the high permeability of the neuron rich regions barrier as well as a vessel specific claudin-5 downregulation after CCI. We observed increased macrophage invasion into the neuron rich region after CCI. Furthermore, we identified aGPCR as potential target for further research and possible treatments for neuropathy, which should be easily accessible due to the blood-DRG-barriers leaky nature. Its precise function in peripheral tissues, its mechanisms of activation, and its role in pain resolution should be evaluated further. N2 - Die vorliegende Arbeit charakterisiert die aGPCR Adgrl1 und Adgrl3, repräsentative Tight Junction Proteine, sowie die Blut-Spinalganglion-Schranke in lumbalen Spinalganglien von Ratten mit und ohne traumatische Neuropathie. Die hohe Permeabilität der zellulären, neuronenreichen Region von Spinalganglien in naiven Tieren ist eine der wenigen Ausnahmen der sonst sehr dichten Barrieren des Nervensystems. Ich konnte die Expression von Adgrl1 und Adgrl3 in NF200+ , CGRP+ und IB4+ Neuronen nachweisen. Eine Woche nach CCI war die Adgrl1 Expression in nicht-peptidergen Nozizeptoren (IB4+ ) vorübergehend herabreguliert. Zusätzlich konnten wir eine ähnliche Expression von Claudin-1, Claudin-12, Claudin-19 und ZO-1 in der neuronenreichen sowie der faserreichen Region zeigen. Claudin-5 ist in Gefäßen der neuronenreichen Region niedriger exprimiert als in Gefäßen der faserreichen Region. Nach Nervenläsion war die Claudin-5 Immunoreaktivität in Gefäßen der neuronenreichen Region reduziert, die Permeabilität für große und kleine Moleküle jedoch unverändert. Allerdings konnten wir nach traumatischer Nervenverletzung vermehrt Makrophagen in der neuronenreichen Region nachweisen. Weiterhin haben wir einen neuen endogenen antinozizeptiven Rezeptor, Adrlg1, ähnlich den Opioidrezeptoren, als potenzielles, und aufgrund der permeablen Blut-Spinalganglion-Schranke therapeutisch gut erreichbares, Target für die antineuropathische Therapie identifiziert. KW - Neuropathy KW - Neuropathic Pain KW - Claudin KW - Latrophilin KW - Tight Junction Proteins KW - Dorsal Root Ganglion Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-251926 ER - TY - JOUR A1 - Bleilevens, Christian A1 - Soppert, Josefin A1 - Hoffmann, Adrian A1 - Breuer, Thomas A1 - Bernhagen, Jürgen A1 - Martin, Lukas A1 - Stiehler, Lara A1 - Marx, Gernot A1 - Dreher, Michael A1 - Stoppe, Christian A1 - Simon, Tim-Philipp T1 - Macrophage migration inhibitory factor (MIF) plasma concentration in critically ill COVID-19 patients: a prospective observational study JF - Diagnostics N2 - Mortality in critically ill coronavirus disease 2019 (COVID-19) patients is high and pharmacological treatment strategies remain limited. Early-stage predictive biomarkers are needed to identify patients with a high risk of severe clinical courses and to stratify treatment strategies. Macrophage migration inhibitory factor (MIF) was previously described as a potential predictor for the outcome of critically ill patients and for acute respiratory distress syndrome (ARDS), a hallmark of severe COVID-19 disease. This prospective observational study evaluates the predictive potential of MIF for the clinical outcome after severe COVID-19 infection. Plasma MIF concentrations were measured in 36 mechanically ventilated COVID-19 patients over three days after intensive care unit (ICU) admission. Increased compared to decreased MIF was significantly associated with aggravated organ function and a significantly lower 28-day survival (sequential organ failure assessment (SOFA) score; 8.2 ± 4.5 to 14.3 ± 3, p = 0.009 vs. 8.9 ± 1.9 to 12 ± 2, p = 0.296; survival: 56% vs. 93%; p = 0.003). Arterial hypertension was the predominant comorbidity in 85% of patients with increasing MIF concentrations (vs. decreasing MIF: 39%; p = 0.015). Without reaching significance, more patients with decreasing MIF were able to improve their ARDS status (p = 0.142). The identified association between an early MIF response, aggravation of organ function and 28-day survival may open future perspectives for biomarker-based diagnostic approaches for ICU management of COVID-19 patients. KW - Macrophage Migration Inhibitory Factor (MIF) KW - COVID-19 KW - ICU treatment KW - acute respiratory distress syndrome (ARDS) KW - SOFA Score KW - Horowitz Quotient Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-228967 SN - 2075-4418 VL - 11 IS - 2 ER - TY - JOUR A1 - Shityakov, Sergey A1 - Roewer, Norbert A1 - Förster, Carola A1 - Broscheit, Jens-Albert T1 - In silico modeling of indigo and Tyrian purple single-electron nano-transistors using density functional theory approach JF - Nanoscale Research Letters N2 - The purpose of this study was to develop and implement an in silico model of indigoid-based single-electron transistor (SET) nanodevices, which consist of indigoid molecules from natural dye weakly coupled to gold electrodes that function in a Coulomb blockade regime. The electronic properties of the indigoid molecules were investigated using the optimized density-functional theory (DFT) with a continuum model. Higher electron transport characteristics were determined for Tyrian purple, consistent with experimentally derived data. Overall, these results can be used to correctly predict and emphasize the electron transport functions of organic SETs, demonstrating their potential for sustainable nanoelectronics comprising the biodegradable and biocompatible materials. KW - density functional theory KW - indigo KW - Tyrian purple KW - single-electron transistor Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-158332 VL - 12 IS - 439 ER - TY - JOUR A1 - Hoppe, Kerstin A1 - Sartorius, Tina A1 - Chaiklieng, Sunisa A1 - Wietzorrek, Georg A1 - Ruth, Peter A1 - Jurkat-Rott, Karin A1 - Wearing, Scott A1 - Lehmann-Horn, Frank A1 - Klingler, Werner T1 - Paxilline Prevents the Onset of Myotonic Stiffness in Pharmacologically Induced Myotonia: A Preclinical Investigation JF - Frontiers in Physiology N2 - Reduced Cl\(^{-}\) conductance causes inhibited muscle relaxation after forceful voluntary contraction due to muscle membrane hyperexcitability. This represents the pathomechanism of myotonia congenita. Due to the prevailing data suggesting that an increased potassium level is a main contributor, we studied the effect of a modulator of a big conductance Ca\(^{2+}\)- and voltage-activated K\(^{+}\) channels (BK) modulator on contraction and relaxation of slow- and high-twitch muscle specimen before and after the pharmacological induction of myotonia. Human and murine muscle specimens (wild-type and BK\(^{-/-}\)) were exposed to anthracene-9-carboxylic acid (9-AC) to inhibit CLC-1 chloride channels and to induce myotonia in-vitro. Functional effects of BK-channel activation and blockade were investigated by exposing slow-twitch (soleus) and fast-twitch (extensor digitorum longus) murine muscle specimens or human musculus vastus lateralis to an activator (NS1608) and a blocker (Paxilline), respectively. Muscle-twitch force and relaxation times (T\(_{90/10}\)) were monitored. Compared to wild type, fast-twitch muscle specimen of BK\(^{-/-}\) mice resulted in a significantly decreased T\(_{90/10}\) in presence of 9-AC. Paxilline significantly shortened T\(_{90/10}\) of murine slow- and fast-twitch muscles as well as human vastus lateralis muscle. Moreover, twitch force was significantly reduced after application of Paxilline in myotonic muscle. NS1608 had opposite effects to Paxilline and aggravated the onset of myotonic activity by prolongation of T\(_{90/10}\). The currently used standard therapy for myotonia is, in some individuals, not very effective. This in vitro study demonstrated that a BK channel blocker lowers myotonic stiffness and thus highlights its potential therapeutic option in myotonia congenital (MC). KW - paxilline KW - NS1608 KW - repetitive firing KW - myotonia congenita KW - muscle disease KW - BK channel Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-218152 VL - 11 ER - TY - JOUR A1 - Reinhold, Ann Kristin A1 - Krug, Susanne M. A1 - Salvador, Ellaine A1 - Sauer, Reine S. A1 - Karl-Schöller, Franziska A1 - Malcangio, Marzia A1 - Sommer, Claudia A1 - Rittner, Heike L. T1 - MicroRNA-21-5p functions via RECK/MMP9 as a proalgesic regulator of the blood nerve barrier in nerve injury JF - Annals of the New York Academy of Sciences N2 - Both nerve injury and complex regional pain syndrome (CRPS) can result in chronic pain. In traumatic neuropathy, the blood nerve barrier (BNB) shielding the nerve is impaired—partly due to dysregulated microRNAs (miRNAs). Upregulation of microRNA-21-5p (miR-21) has previously been documented in neuropathic pain, predominantly due to its proinflammatory features. However, little is known about other functions. Here, we characterized miR-21 in neuropathic pain and its impact on the BNB in a human-murine back translational approach. MiR-21 expression was elevated in plasma of patients with CRPS as well as in nerves of mice after transient and persistent nerve injury. Mice presented with BNB leakage, as well as loss of claudin-1 in both injured and spared nerves. Moreover, the putative miR-21 target RECK was decreased and downstream Mmp9 upregulated, as was Tgfb. In vitro experiments in human epithelial cells confirmed a downregulation of CLDN1 by miR-21 mimics via inhibition of the RECK/MMP9 pathway but not TGFB. Perineurial miR-21 mimic application in mice elicited mechanical hypersensitivity, while local inhibition of miR-21 after nerve injury reversed it. In summary, the data support a novel role for miR-21, independent of prior inflammation, in elicitation of pain and impairment of the BNB via RECK/MMP9. KW - claudin-1 KW - RECK KW - MMP9 KW - CRPS KW - microRNA KW - neuropathic pain KW - blood nerve barrier Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-318226 VL - 1515 IS - 1 SP - 184 EP - 195 ER - TY - JOUR A1 - Kaiser, Mathias A1 - Burek, Malgorzata A1 - Britz, Stefan A1 - Lankamp, Frauke A1 - Ketelhut, Steffi A1 - Kemper, Björn A1 - Förster, Carola A1 - Gorzelanny, Christian A1 - Goycoolea, Francisco M. T1 - The influence of capsaicin on the integrity of microvascular endothelial cell monolayers JF - International Journal of Molecular Sciences N2 - Microvascular endothelial cells are an essential part of many biological barriers, such as the blood–brain barrier (BBB) and the endothelium of the arteries and veins. A reversible opening strategy to increase the permeability of drugs across the BBB could lead to improved therapies due to enhanced drug bioavailability. Vanilloids, such as capsaicin, are known to reversibly open tight junctions of epithelial and endothelial cells. In this study, we used several in vitro assays with the murine endothelial capillary brain cells (line cEND) as a BBB model to characterize the interaction between capsaicin and endothelial tight junctions. KW - tight junctions KW - capsaicin KW - endothelial cells Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-284865 SN - 1422-0067 VL - 20 IS - 1 ER - TY - JOUR A1 - Schmid, Benedikt A1 - Griesel, Mirko A1 - Fischer, Anna-Lena A1 - Romero, Carolina S. A1 - Metzendorf, Maria-Inti A1 - Weibel, Stephanie A1 - Fichtner, Falk T1 - Awake prone positioning, high-flow nasal oxygen and non-invasive ventilation as non-invasive respiratory strategies in COVID-19 acute respiratory failure: a systematic review and meta-analysis JF - Journal of Clinical Medicine N2 - Background: Acute respiratory failure is the most important organ dysfunction of COVID-19 patients. While non-invasive ventilation (NIV) and high-flow nasal cannula (HFNC) oxygen are frequently used, efficacy and safety remain uncertain. Benefits and harms of awake prone positioning (APP) in COVID-19 patients are unknown. Methods: We searched for randomized controlled trials (RCTs) comparing HFNC vs. NIV and APP vs. standard care. We meta-analyzed data for mortality, intubation rate, and safety. Results: Five RCTs (2182 patients) were identified. While it remains uncertain whether HFNC compared to NIV alters mortality (RR: 0.92, 95% CI 0.65–1.33), HFNC may increase rate of intubation or death (composite endpoint; RR 1.22, 1.03–1.45). We do not know if HFNC alters risk for harm. APP compared to standard care probably decreases intubation rate (RR 0.83, 0.71–0.96) but may have little or no effect on mortality (RR: 1.08, 0.51–2.31). Conclusions: Certainty of evidence is moderate to very low. There is no compelling evidence for either HFNC or NIV, but both carry substantial risk for harm. The use of APP probably has benefits although mortality appears unaffected. KW - respiratory failure KW - non-invasive ventilation KW - high-flow nasal cannula KW - awake prone positioning KW - COVID-19 KW - systematic review Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-255225 SN - 2077-0383 VL - 11 IS - 2 ER - TY - JOUR A1 - Oehler, Beatrice A1 - Brack, Alexander A1 - Blum, Robert A1 - Rittner, Heike L. T1 - Pain Control by Targeting Oxidized Phospholipids: Functions, Mechanisms, Perspectives JF - Frontiers in Endocrinology N2 - Within the lipidome oxidized phospholipids (OxPL) form a class of chemically highly reactive metabolites. OxPL are acutely produced in inflamed tissue and act as endogenous, proalgesic (pain-inducing) metabolites. They excite sensory, nociceptive neurons by activating transient receptor potential ion channels, specifically TRPA1 and TRPV1. Under inflammatory conditions, OxPL-mediated receptor potentials even potentiate the action potential firing rate of nociceptors. Targeting OxPL with D-4F, an apolipoprotein A-I mimetic peptide or antibodies like E06, specifically binding oxidized headgroups of phospholipids, can be used to control acute, inflammatory pain syndromes, at least in rodents. With a focus on proalgesic specificities of OxPL, this article discusses, how targeting defined substances of the epilipidome can contribute to mechanism-based therapies against primary and secondary chronic inflammatory or possibly also neuropathic pain. KW - oxidized phospholipids KW - TRP channel KW - ion channel KW - analgesia KW - pain therapy KW - nociception KW - therapeutic antibody KW - mimetic peptide Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-223432 SN - 1664-2392 VL - 11 ER - TY - JOUR A1 - Lux, Thomas J. A1 - Hu, Xiawei A1 - Ben-Kraiem, Adel A1 - Blum, Robert A1 - Chen, Jeremy Tsung-Chieh A1 - Rittner, Heike L. T1 - Regional differences in tight junction protein expression in the blood−DRG barrier and their alterations after nerve traumatic injury in rats JF - International Journal of Molecular Sciences N2 - The nervous system is shielded by special barriers. Nerve injury results in blood–nerve barrier breakdown with downregulation of certain tight junction proteins accompanying the painful neuropathic phenotype. The dorsal root ganglion (DRG) consists of a neuron-rich region (NRR, somata of somatosensory and nociceptive neurons) and a fibre-rich region (FRR), and their putative epi-/perineurium (EPN). Here, we analysed blood–DRG barrier (BDB) properties in these physiologically distinct regions in Wistar rats after chronic constriction injury (CCI). Cldn5, Cldn12, and Tjp1 (rats) mRNA were downregulated 1 week after traumatic nerve injury. Claudin-1 immunoreactivity (IR) found in the EPN, claudin-19-IR in the FRR, and ZO-1-IR in FRR-EPN were unaltered after CCI. However, laser-assisted, vessel specific qPCR, and IR studies confirmed a significant loss of claudin-5 in the NRR. The NRR was three-times more permeable compared to the FRR for high and low molecular weight markers. NRR permeability was not further increased 1-week after CCI, but significantly more CD68\(^+\) macrophages had migrated into the NRR. In summary, NRR and FRR are different in naïve rats. Short-term traumatic nerve injury leaves the already highly permeable BDB in the NRR unaltered for small and large molecules. Claudin-5 is downregulated in the NRR. This could facilitate macrophage invasion, and thereby neuronal sensitisation and hyperalgesia. Targeting the stabilisation of claudin-5 in microvessels and the BDB barrier could be a future approach for neuropathic pain therapy. KW - tight junction KW - claudin-5 KW - neuropathic pain KW - nerve injury KW - dorsal root ganglion Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-285029 SN - 1422-0067 VL - 21 IS - 1 ER - TY - JOUR A1 - Salvador, Ellaine A1 - Burek, Malgorzata A1 - Löhr, Mario A1 - Nagai, Michiaki A1 - Hagemann, Carsten A1 - Förster, Carola Y. T1 - Senescence and associated blood-brain barrier alterations in vitro JF - Histochemistry and Cell Biology N2 - Progressive deterioration of the central nervous system (CNS) is commonly associated with aging. An important component of the neurovasculature is the blood-brain barrier (BBB), majorly made up of endothelial cells joined together by intercellular junctions. The relationship between senescence and changes in the BBB has not yet been thoroughly explored. Moreover, the lack of in vitro models for the study of the mechanisms involved in those changes impede further and more in-depth investigations in the field. For this reason, we herein present an in vitro model of the senescent BBB and an initial attempt to identify senescence-associated alterations within. KW - senescence KW - in vitro model KW - aging KW - CNS diseases KW - blood–brain barrier Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-267435 SN - 1432-119X VL - 156 IS - 3 ER - TY - JOUR A1 - Kippnich, Maximilian A1 - Schorscher, Nora A1 - Kredel, Markus A1 - Markus, Christian A1 - Eden, Lars A1 - Gassenmaier, Tobias A1 - Lock, Johann A1 - Wurmb, Thomas T1 - Dual‑room twin‑CT scanner in multiple trauma care: first results after implementation in a level one trauma centre JF - European Journal of Trauma and Emergency Surgery N2 - Purpose The trauma centre of the Wuerzburg University Hospital has integrated a pioneering dual-room twin-CT scanner in a multiple trauma pathway. For concurrent treatment of two trauma patients, two carbon CT examination and intervention tables are positioned head to head with one sliding CT-Gantry in the middle. The focus of this study is the process of trauma care with the time to CT (tCT) and the time to operation (tOR) as quality indicator. Methods All patients with suspected multiple trauma, who required emergency surgery and who were initially diagnosed by the CT trauma protocol between 05/2018 and 12/2018 were included. Data relating to time spans (tCT and tOR), severity of injury and outcome was obtained. Results 110 of the 589 screened trauma patients had surgery immediately after finishing primary assessment in the ER. The ISS was 17 (9–34) (median and interquartile range, IQR). tCT was 15 (11–19) minutes (median and IQR) and tOR was 96.5 (75–119) minutes (median and IQR). In the first 30 days, seven patients died (6.4%) including two within the first 24 h (2%). There were two ICU days (1–6) (median and IQR) and one (0–1) (median and IQR) ventilator day. Conclusion The twin-CT technology is a fascinating tool to organize high-quality trauma care for two multiple trauma patients simultaneously KW - trauma centre KW - trauma management KW - resuscitation time KW - dual-room whole-body CT Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-232390 SN - 1863-9933 ER - TY - THES A1 - Hu, Xiawei T1 - Role of claudin-12 in neuronal barriers in painful murine and human neuropathy T1 - Rolle von Claudin-12 im neuronalen Barrieren bei schmerzhaften Neuropathien in Mäusen und Patienten N2 - In peripheral nervous system (PNS), the blood-nerve barrier (BNB) and myelin barrier (MB) are important physiological fences for maintaining the environment for axons, Schwann cells and other associated cells within peripheral nerves. The perineurium surrounding the nerves and endoneurial vessels nourishing the nerves compose the BNB. Schwann cells wrapping around neurons form the MB. Destruction or malfunction of the barriers has been postulated as an initial step in the development of pathologic conditions concerning human peripheral nerves, such as traumatic neuropathy and the disease of chronic inflammatory demyelination polyneuropathy (CIDP). Tight junction proteins (TJPs) are intercellular junctions building the microstructure of barriers. They play a key role in tightly connecting adjacent cells, controlling the passage of ions, water and other molecules via the paracellular pathway, and maintaining the cell polarity. Among the family of TJPs, claudins are the major structural components which form the backbone of TJs. Certain key TJPs [e.g. claudins (claudin-1, -5, -19, occludin, zona occludens (ZO-1)] have been identified in neural barriers and explored for therapeutic targets. The expression of Cldn12 gene has been documented in human/rodent tibial nerves, spinal cord and DRG. However, the role of claudin-12 in PNS is unknown. In the present study, we firstly found a loss of claudin-12 immunoreactivity (IR) in male or postmenopausal female patients with painful CIDP or non-inflammatory polyneuropathy (PNP). Then, we utilized male and female Cldn12-KO mice and the chronic constriction injury (CCI) model. Cldn12 mRNA and IR were reduced in WT mice after nerve injury. Deletion of Cldn12 via general knockout (KO) induced mechanical allodynia at baseline level and after CCI in time-dependent manner in male mice. KO of Cldn12 in males resulted in loss of small axons, perineurial barrier and MB breakdown, as well as TJP complex disruption with claudin-1, -19 and Pmp22 reduction. Moreover, local Cldn12 siRNA application mimicked mechanical allodynia and MB breakdown. In conclusion, claudin-12 deficiency is associated with painful CIDP/non-inflammatory PNP. Claudin-12 is a regulatory TJP crucial for mechanical nociception, perineurial barrier and MB integrity, and proper TJP composition in mice. Therefore, further investigating the functions of claudin-12 and its mechanism is important to prompt the development of new therapeutic approaches for painful neuropathies. N2 - Im peripheren Nervensystem (PNS) sind die Blut-Nerven-Schranke (BNB) und die Myelin-Schranke (MB) wichtige physiologische Barrieren zur Aufrechterhaltung des Milieus für Axone, Schwann-Zellen und andere assoziierte Zellen innerhalb der peripheren Nerven. Das die Nerven umgebende Perineurium und die die Nerven ernährenden endoneurialen Gefäße bilden die BNB. Schwannsche Zellen, die sich um Neuronen wickeln, bilden die MB. Die Funktionsstörung der Barrieren wird als Schlüsselelement für die Entwicklung verschiedener neurologischer Erkrankungen wie der chronisch entzündlichen Demyelinisierungs-Polyneuropathie (CIDP) und der traumatischen Neuropathie angesehen. Tight Junction-Proteine (TJPs) sind interzelluläre Verbindungen und bilden die Mikrostruktur der Barrieren. Sie spielen eine Schlüsselrolle bei der engen Verbindung benachbarter Zellen, der Kontrolle des parazellulären Flusses von Ionen, Wasser und anderen Molekülen und der Aufrechterhaltung der Zellpolarität. In der Superfamilie der TJPs sind Claudine die Hauptstrukturkomponenten, die das Rückgrat der TJs bilden. Bestimmte TJPs [z.B. Claudin-1, -5, -19, Occludin, Zona occludens (ZO-1)] wurden in neuronalen Barrieren identifiziert und als therapeutische Targets untersucht. In neueren Untersuchungen wurde die Expression des Cldn12-Gens im N. tibialis, Rückenmark und DRG bei Nagern und Menschen dokumentiert. Die Rolle von Claudin-12 im PNS ist jedoch nicht bekannt. In der vorliegenden Studie wurde zunächst ein Verminderung der Immunreaktivität (IR) von Claudin-12 bei männlichen oder postmenopausalen weiblichen Patienten mit schmerzhafter CIDP oder nichtentzündlicher Polyneuropathie (PNP) belegt. Im Folgenden untersuchten wir männliche und weibliche Cldn12-KO-Mäuse bei traumatischer Neuopathie, der „chronic constriction injury“ (CCI), die ebefalls eine deutliche Entzündungsreaktion zeigt. Cldn12-mRNA und -IR waren in WT-Mäusen nach einer Nervenverletzung erniedrigt . Die vollständige Deletion von Cldn12 (KO) induzierte bei naiven männlichen Mäusen bereits eine mechanische Allodynie, die sich nach CCI weiter verstärkte. Cldn12- KO in männlichen Mäusen führte zum Verlust kleinkalibriger Axone, einer Öffnung der perineurialen Barriere und der MB sowie zu einer Störung der TJP-Komplexe mit Claudin-1, -19 und Pmp22. Darüberhinaus replizierte die lokale Anwendung von Cldn12 siRNA die mechanische Allodynie und den MB- Abbau nach. Zusammenfassend lässt sich sagen, dass gerade die schmerzhafte CIDP/nicht entzündlichen PNP mit einem Claudin-12-Mangel verbunden sind. Claudin-12 ist ein regulatorisches TJP, welches für die Nozizeption mechanischer Reize, die perineuriale Barriere und die MB-Integrität sowie die richtige TJP- Zusammensetzung bei Mäusen entscheidend ist. Die weitere Erforschung der Funktionen von Claudin- 12 könnte die Entwicklung neuer therapeutischer Ansätze für schmerzhafte Neuropathien anstoßen. KW - claudin-12 KW - neuropathy KW - blood nerve barrier KW - myelin barrier Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-208065 ER - TY - JOUR A1 - Nagai, Michiaki A1 - Förster, Carola Yvette A1 - Dote, Keigo T1 - Sex hormone-specific neuroanatomy of Takotsubo syndrome: is the insular cortex a moderator? JF - Biomolecules N2 - Takotsubo syndrome (TTS), a transient form of dysfunction in the heart's left ventricle, occurs predominantly in postmenopausal women who have emotional stress. Earlier studies support the concept that the human circulatory system is modulated by a cortical network (consisting of the anterior cingulate gyrus, amygdala, and insular cortex (Ic)) that plays a pivotal role in the central autonomic nervous system in relation to emotional stressors. The Ic plays a crucial role in the sympathovagal balance, and decreased levels of female sex hormones have been speculated to change functional cerebral asymmetry, with a possible link to autonomic instability. In this review, we focus on the Ic as an important moderator of the human brain–heart axis in association with sex hormones. We also summarize the current knowledge regarding the sex-specific neuroanatomy in TTS. KW - insular cortex KW - autonomic nervous system KW - laterality KW - sex hormone KW - central autonomic network KW - Takotsubo cardiomyopathy Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-254776 SN - 2218-273X VL - 12 IS - 1 ER - TY - JOUR A1 - Wurmb, Thomas A1 - Scholtes, Katja A1 - Kolibay, Felix A1 - Schorscher, Nora A1 - Ertl, Georg A1 - Ernestus, Ralf-Ingo A1 - Vogel, Ulrich A1 - Franke, Axel A1 - Kowalzik, Barbara T1 - Hospital preparedness for mass critical care during SARS-CoV-2 pandemic JF - Critical Care N2 - Mass critical care caused by the severe acute respiratory syndrome corona virus 2 pandemic poses an extreme challenge to hospitals. The primary goal of hospital disaster preparedness and response is to maintain conventional or contingency care for as long as possible. Crisis care must be delayed as long as possible by appropriate measures. Increasing the intensive care unit (ICU) capacities is essential. In order to adjust surge capacity, the reduction of planned, elective patient care is an adequate response. However, this involves numerous problems that must be solved with a sense of proportion. This paper summarises preparedness and response measures recommended to acute care hospitals. KW - Mass critical care KW - Disaster response KW - SARS-CoV-2 KW - Hospital emergency plan Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-230201 VL - 24 ER - TY - JOUR A1 - Schuster, Frank A1 - Johannsen, Stephan A1 - Isbary, Susanne A1 - Türkmeneli, Ismail A1 - Roewer, Norbert T1 - In vitro effects of levosimendan on muscle of malignant hyperthermia susceptible and non-susceptible swine JF - BMC Anesthesiology N2 - Background: The calcium sensitizer levosimendan is increasingly used to improve hemodynamics in patients with acutely decompensated heart failure. By binding to cardiac troponin C the conformation of the calcium-troponin C complex is stabilized, which leads to acceleration of actin-myosin crossbrigde formation and increased force generating capacity of muscle fibers. Besides indications in cardiac failure, beneficial effects of levosimendan in skeletal muscle disorders are currently evaluated. The aim of this study was to investigate differential effects of levosimendan on skeletal muscle of pigs with and without susceptibility to malignant hyperthermia (MH) in order to identify possible risks of this emerging drug for patients with predisposition to MH. Methods: Muscle bundles of 17 pigs (9 MH susceptible (MHS); 8 MH non-susceptible (MHN)) were excised under general anesthesia and examined in the tissue bath with increasing concentrations of levosimendan (0.065; 0.125; 0.5; 1.0; 10 and 50 μg/ml). Baseline tension and twitch force were monitored continuously. Data are presented as median and interquartile range. Statistical evaluation was performed using D’Agostino & Pearson test for normal distribution and student’s t test and 2-way ANOVA for differences between the groups. P < 0.05 was considered significant. Results: There were no differences between the groups concerning length, weight, initial twitch force and pre-drug resting tension of the investigated muscle strips. After an initial decrease in both groups, twitch amplitude was significantly higher in MHN (− 3.0 [− 5.2–0.2] mN) compared to MHS (− 7.5 [− 10.8- -4.5] mN) (p = 0.0034) muscle at an applied levosimendan concentration of 50 μg/ml. A marked increase in resting tension was detected following levosimendan incubation with 50 μg/ml in MHS muscle bundles (3.3 [0.9–6.1] mN) compared to MHN (− 0.7 [− 1.3–0.0] mN) (p < 0.0001). Conclusions: This in vitro investigation revealed the development of significant contractures in muscle bundles of MHS pigs after incubation with levosimendan. However, the effect appeared only at supra-therapeutic concentrations and further research is needed to determine the impact of levosimendan on MHS individuals in vivo. KW - malignant hyperthermia KW - levosimendan KW - muscle KW - pigs KW - in vitro contracture test Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-176991 VL - 18 IS - 182 ER - TY - JOUR A1 - Chen, Shasha A1 - Lotz, Christopher A1 - Roewer, Norbert A1 - Broscheit, Jens-Albert T1 - Comparison of volatile anesthetic-induced preconditioning in cardiac and cerebral system: molecular mechanisms and clinical aspects JF - European Journal of Medical Research N2 - Volatile anesthetic-induced preconditioning ( APC) has shown to have cardiac and cerebral protective properties in both pre-clinical models and clinical trials. Interestingly, accumulating evidences demonstrate that, except from some specific characters, the underlying molecular mechanisms of APC-induced protective effects in myocytes and neurons are very similar; they share several major intracellular signaling pathways, including mediating mitochondrial function, release of inflammatory cytokines and cell apoptosis. Among all the experimental results, cortical spreading depolarization is a relative newly discovered cellular mechanism of APC, which, however, just exists in central nervous system. Applying volatile anesthetic preconditioning to clinical practice seems to be a promising cardio- and neuroprotective strategy. In this review, we also summarized and discussed the results of recent clinical research of APC. Despite all the positive experimental evidences, large-scale, long-term, more precisely controlled clinical trials focusing on the perioperative use of volatile anesthetics for organ protection are still needed. KW - APC KW - ischemia-reperfusion injury KW - mitochondria KW - apoptosis Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-175509 VL - 23 IS - 10 ER - TY - JOUR A1 - Holzmann-Littig, Christopher A1 - Frank, Tamara A1 - Schmaderer, Christoph A1 - Braunisch, Matthias C. A1 - Renders, Lutz A1 - Kranke, Peter A1 - Popp, Maria A1 - Seeber, Christian A1 - Fichtner, Falk A1 - Littig, Bianca A1 - Carbajo-Lozoya, Javier A1 - Meerpohl, Joerg J. A1 - Haller, Bernhard A1 - Allwang, Christine T1 - COVID-19 Vaccines: Fear of side effects among German health care workers JF - Vaccines N2 - (1) Background: Health care workers (HCWs) play a key role in increasing anti-COVID vaccination rates. Fear of potential side effects is one of the main reasons for vaccine hesitancy. We investigated which side effects are of concern to HCWs and how these are associated with vaccine hesitancy. (2) Methods: Data were collected in an online survey in February 2021 among HCWs from across Germany with 4500 included participants. Free-text comments on previously experienced vaccination side effects, and fear of short- and long-term side effects of the COVID-19 vaccination were categorized and analyzed. (3) Results: Most feared short-term side effects were vaccination reactions, allergic reactions, and limitations in daily life. Most feared long-term side effects were (auto-) immune reactions, neurological side effects, and currently unknown long-term consequences. Concerns about serious vaccination side effects were associated with vaccination refusal. There was a clear association between refusal of COVID-19 vaccination in one's personal environment and fear of side effects. (4) Conclusions: Transparent information about vaccine side effects is needed, especially for HCW. Especially when the participants' acquaintances advised against vaccination, they were significantly more likely to fear side effects. Thus, further education of HCW is necessary to achieve good information transfer in clusters as well. KW - COVID-19 KW - vaccine hesitancy KW - health care workers KW - side-effects KW - fears Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-270561 SN - 2076-393X VL - 10 IS - 5 ER - TY - JOUR A1 - Shityakov, Sergey A1 - Bencurova, Elena A1 - Förster, Carola A1 - Dandekar, Thomas T1 - Modeling of shotgun sequencing of DNA plasmids using experimental and theoretical approaches JF - BMC Bioinformatics N2 - Background Processing and analysis of DNA sequences obtained from next-generation sequencing (NGS) face some difficulties in terms of the correct prediction of DNA sequencing outcomes without the implementation of bioinformatics approaches. However, algorithms based on NGS perform inefficiently due to the generation of long DNA fragments, the difficulty of assembling them and the complexity of the used genomes. On the other hand, the Sanger DNA sequencing method is still considered to be the most reliable; it is a reliable choice for virtual modeling to build all possible consensus sequences from smaller DNA fragments. Results In silico and in vitro experiments were conducted: (1) to implement and test our novel sequencing algorithm, using the standard cloning vectors of different length and (2) to validate experimentally virtual shotgun sequencing using the PCR technique with the number of cycles from 1 to 9 for each reaction. Conclusions We applied a novel algorithm based on Sanger methodology to correctly predict and emphasize the performance of DNA sequencing techniques as well as in de novo DNA sequencing and its further application in synthetic biology. We demonstrate the statistical significance of our results. KW - Shotgun method KW - Sanger sequencing KW - Virtual sequencing KW - Polymerase chain reaction KW - Gene expression vectors KW - Synthetic biology Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-229169 VL - 2020 ER - TY - JOUR A1 - Weibel, Stephanie A1 - Popp, Maria A1 - Reis, Stefanie A1 - Skoetz, Nicole A1 - Garner, Paul A1 - Sydenham, Emma T1 - Identifying and managing problematic trials: A research integrity assessment tool for randomized controlled trials in evidence synthesis JF - Research Synthesis Methods N2 - Evidence synthesis findings depend on the assumption that the included studies follow good clinical practice and results are not fabricated or false. Studies which are problematic due to scientific misconduct, poor research practice, or honest error may distort evidence synthesis findings. Authors of evidence synthesis need transparent mechanisms to identify and manage problematic studies to avoid misleading findings. As evidence synthesis authors of the Cochrane COVID-19 review on ivermectin, we identified many problematic studies in terms of research integrity and regulatory compliance. Through iterative discussion, we developed a research integrity assessment (RIA) tool for randomized controlled trials for the update of this Cochrane review. In this paper, we explain the rationale and application of the RIA tool in this case study. RIA assesses six study criteria: study retraction, prospective trial registration, adequate ethics approval, author group, plausibility of methods (e.g., randomization), and plausibility of study results. RIA was used in the Cochrane review as part of the eligibility check during screening of potentially eligible studies. Problematic studies were excluded and studies with open questions were held in awaiting classification until clarified. RIA decisions were made independently by two authors and reported transparently. Using the RIA tool resulted in the exclusion of >40% of studies in the first update of the review. RIA is a complementary tool prior to assessing “Risk of Bias” aiming to establish the integrity and authenticity of studies. RIA provides a platform for urgent development of a standard approach to identifying and managing problematic studies. KW - COVID-19 pandemic KW - systematic review KW - research integrity KW - randomized controlled trial KW - good clinical practice KW - evidence synthesis Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-318236 VL - 14 IS - 3 SP - 357 EP - 369 ER -