Publications by authors named "René Tolba"

170 Publications

Acute myocardial injury secondary to severe acute liver failure: A retrospective analysis supported by animal data.

PLoS One 2021 30;16(8):e0256790. Epub 2021 Aug 30.

Department of Anesthesiology, Faculty of Medicine, RWTH Aachen University, Aachen, Germany.

To investigate whether acute liver failure (ALF) leads to secondary acute myocardial injury, 100 ALF patients that were retrospectively identified in a single center based on ICD 10 codes and 8 rats from an experimental study that died early after bile duct ligation (BDL) were examined. Creatine kinase (CK), creatine kinase-MB isoenzyme (CKMB) and cardiac troponin-I (cTnI) were analyzed as markers of myocardial injury. For histological analysis, hematoxylin-eosin (HE), elastic Van Gieson (EVG), CD41 and myeloperoxidase were used to stain rat hearts. Major adverse cardiac events (MACEs) were a critical factor for mortality (p = 0.037) in human ALF. Deceased patients exhibited higher levels of CKMB than survivors (p = 0.023). CKMB was a predictor of mortality in ALF (p = 0.013). Animals that died early after BDL exhibited increased cTnI, CKMB, tumor necrosis factor α (TNFα) and interleukin-6 (IL-6) levels compared to controls (cTnI: p = 0.011, CKMB: p = 0.008, TNFα: p = 0.003, IL-6: p = 0.006). These animals showed perivascular lesions and wavy fibers, microthrombi and neutrophilic infiltration in the heart. MACEs are decisive for mortality in human ALF, and elevated CKMB values indicate that this might be due to structural myocardial damage. Accordingly, CKMB was found to have predictive value for mortality in ALF. The results are substantiated by data from a rat BDL model demonstrating diffuse myocardial injury.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0256790PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8405020PMC
August 2021

Assessing the severity of laparotomy and partial hepatectomy in male rats-A multimodal approach.

PLoS One 2021 2;16(8):e0255175. Epub 2021 Aug 2.

Institute for Laboratory Animal Science & Experimental Surgery, Faculty of Medicine, RWTH Aachen University, Aachen, Germany.

This study assessed the postoperative severity after three different visceral surgical interventions in rats by using objective parameters pertaining to various disciplines. The objective was to evaluate whether the degree of severity increases with the invasiveness of the intervention and whether this is in accordance with the EU Directive 2010/63. 136 adult male WistarHan rats were assigned to three groups: Sham-laparotomy (Sham) [7 days post-surgical survival time]; 50% partial hepatectomy (PH); 70% PH [PH groups with 1, 3, or 7 days post-surgical survival times]. Post-surgical severity assessment was performed via several multimodal assessment tools: I) model-specific score sheet focusing on body weight, general condition, spontaneous behavior, and the animals' willingness to move as well as on wound healing; II) Open Field tests evaluating the total distance and velocity an animal moved within 10 minutes and its rearing behavior during the test; III) telemetric data analyzing heart rate and blood pressure; and IV) analysis of blood (AST, ALT, and hemogram) and fecal samples (fecal corticosterone metabolites). Significant differences among the experimental groups and models were observed. We demonstrated that the Open Field test can detect significant changes in severity levels. Sham-laparotomy and removal of 50% of the liver mass were associated with comparable severity (mild-moderate); the severity parameters returned to baseline levels within seven days. Removal of 70% of the liver tissue seemed to be associated with a moderate severity grade and entailed a longer recovery period (>7 days) for complete regeneration. We recommend the use of Open Field tests as part of multimodal objective severity assessment.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0255175PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8328343PMC
August 2021

Hypothermic Oxygenated Machine Perfusion (HOPE) Reduces Early Allograft Injury and Improves Post-Transplant Outcomes in Extended Criteria Donation (ECD) Liver Transplantation from Donation After Brain Death (DBD): Results from a Multicenter Randomized Controlled Trial (HOPE ECD-DBD).

Ann Surg 2021 Jul 29. Epub 2021 Jul 29.

Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen, Germany Department of Surgery, Campus Charité Mitte | Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Germany Department of Transplantation Surgery, Institute for Clinical and Experimental Medicine, Prague, Czech Republic Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany Department of HPB Surgery and Liver Transplantation, Royal Free Hospital, London, UK University College London, London, UK Department of Hepatology, Maastricht University Medical Center (MUMC), Maastricht, The Netherlands Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen, Germany Institute for Laboratory Animal Science and Experimental Surgery, University Hospital RWTH Aachen, Aachen, Germany Institute for Biometry and Clinical Epidemiology, Charité-Universitätsmedizin Berlin, Campus Charité Mitte, Berlin, Germany Department of Hepatology and Gastroenterology, Campus Charité Mitte | Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Germany Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Germany Department of General Surgery and Liver transplantation, Fundeni Clinical Institute, Bucharest, Romania Department for General, Visceral and Transplant Surgery, Hannover Medical School, Hannover, Germany Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA.

Objective: To evaluate peak serum alanine aminotransferase (ALT) and postoperative clinical outcomes after hypothermic oxygenated machine perfusion (HOPE) versus static cold storage (SCS) in extended criteria donation (ECD) liver transplantation (LT) from donation after brain death (DBD).

Background: HOPE might improve outcomes in LT, particularly in high-risk settings such as ECD organs after DBD, but this hypothesis has not yet been tested in a randomized controlled clinical trial (RCT).

Methods: Between 09/2017-09/2020 46 patients undergoing ECD-DBD LT from four centers were randomly assigned to HOPE (n=23) or SCS (n=23). Peak-ALT levels within seven days following LT constituted the primary endpoint. Secondary endpoints included incidence of postoperative complications (Clavien-Dindo classification (CD), Comprehensive Complication Index (CCI)), length of intensive care- (ICU) and hospital-stay, and incidence of early allograft dysfunction (EAD).

Results: Demographics were equally distributed between both groups (donor age: 72 [IQR:59-78] years, recipient age: 62 [IQR:55-65] years, labMELD: 15 [IQR:9-25], 38 male and 8 female recipients). HOPE resulted in a 47% decrease in serum peak ALT (418 [IQR: 221-828] vs. 796 [IQR:477-1195] IU/L, p=0.030), a significant reduction in 90-day complications (44% vs. 74% CD grade ≥3, p=0.036; 32 [IQR:12-56] vs. 52 [IQR:35-98] CCI, p=0.021), and shorter ICU- and hospital-stays (5 [IQR:4-8] vs. 8 [IQR:5-18] days, p=0.045; 20 [IQR:16-27] vs. 36 [IQR:23-62] days, p=0.002) compared to SCS. A trend towards reduced EAD was observed for HOPE (17% vs. 35%; p=0.314).

Conclusion: This multicenter RCT demonstrates that HOPE, in comparison to SCS, significantly reduces early allograft injury and improves post-transplant outcomes in ECD-DBD liver transplantation.
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http://dx.doi.org/10.1097/SLA.0000000000005110DOI Listing
July 2021

Efficacy of a Novel Medical Adhesive for Sealing Lung Parenchyma: An in vitro Study in Rabbit Lungs.

Eur Surg Res 2021 Jul 21:1-7. Epub 2021 Jul 21.

Department of Thoracic and Cardiovascular Surgery, University Hospital RWTH Aachen, Aachen, Germany.

Introduction: During thoracic resection procedures, complete hemostasis and aerostasis are priorities. A persistent alveolar air leak is associated with increased morbidity and mortality rates. This study aimed to evaluate whether the novel medical adhesive VIVO (Adhesys Medical GmbH Aachen, Germany) is a reliable alternative sealing technique to routine surgical procedures.

Methods: We conducted an in vitro animal study by analyzing 21 lungs of New Zealand (n = 19) and Chinchilla Bastard (n = 2) rabbits (age, 11-18 weeks; weight, 2,400-3,600 g). Three groups, each comprising 7 animals, were evaluated. VIVO (VIVO-group) was compared with standard surgical lung parenchymal lesion closure with a polypropylene suture (Suture-group) and TachoSil® (TachoSil-group). We adopted a stable, pressure-controlled ventilation protocol. After explantation, a surgical incision 0.5-cm deep and 1.5-cm wide was made in the lungs using a customized template. Air leak was measured quantitatively (mL/min) using a respirator and visualized qualitatively by 2 observers who made independent judgments. Next, the leak was closed using VIVO, suture, or TachoSil® as specified by the manufacturer. Subsequently, positive end-expiratory pressure (PEEP) and inspiratory pressure were gradually increased until a maximum of 15 and 30 mbar were attained, respectively.

Results: At PEEPs of 8, 10, and 15 mbar, VIVO achieved complete sealing of the profound parenchymal defect in all (n = 7) lungs. After closure of the incision, we observed an air leak variation of 127 ± 114 mL/min (Suture-group), 31 ± 49 mL/min (VIVO-group), and 114 ± 134 mL/min (TachoSil-group). VIVO showed a significantly lower air leak than surgical sutures (p = 0.031) and TachoSil® (p = 0.046).

Conclusion: VIVO offers sufficient closure of the lung parenchymal lesions. The novel adhesive enabled significantly better sealing with lower persistent air leakage than TachoSil® or surgical sutures. Further investigation using in vivo models is strongly encouraged to confirm our findings.
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http://dx.doi.org/10.1159/000517173DOI Listing
July 2021

Microvascular anastomosis techniques using the medical adhesive VIVO and expandable micro-stents in a rat carotid artery model.

Ann Anat 2021 Nov 16;238:151782. Epub 2021 Jun 16.

Department of Oral and Maxillofacial Surgery, University Hospital of Aachen, Pauwelsstraße 30, 52074 Aachen, Germany.

Background: Sutured anastomosis remains the gold standard in microvascular surgery. The procedure is not free of complications and is a time-consuming operation requiring a high level of experience. The aim of this study was to develop new methods for a stable, faster, and safer anastomosis using a novel biodegradable adhesive, VIVO, and a custom-made microvascular stent.

Methods: The VIVO medical adhesive was used for a total of 30 anastomoses in rats in the right carotid artery: 15 anastomoses were performed with a temporary intraluminal catheter, VIVO, and reduced sutures (VIVO + TC). A further 15 anastomoses were performed with nitinol stents, VIVO, and reduced sutures (VIVO + SM). Sutured anastomoses served as controls (C) and were performed on the left carotid arteries of the 30 rats. Operation and bleeding times were assessed, and patency was evaluated by Doppler flowmetry and indocyanine green (ICG) angiography. Subsequently, the anastomoses were evaluated histopathological.

Results: The overall patency was recorded as 100% in all groups. No thrombosis or circulatory disturbance was found. Compared to C and VIVO + SM, VIVO + TC proved to be significantly less traumatic, less demanding, and time-saving. The sealing properties of VIVO lead to shorter bleeding times and less oozing. In contrast, VIVO + SM proved to be the most technically demanding and time-consuming procedure.

Conclusion: The success of a microvascular sutured anastomosis is determined by a short ischemic interval. Compared to sutured anastomosis, VIVO + TC showed ease of use as well as shorter time taken for anastomosis, less trauma, and lower blood loss. More long-term studies on the functions, biological interactions, and survival rates of glue-based anastomoses need to be initiated.
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http://dx.doi.org/10.1016/j.aanat.2021.151782DOI Listing
November 2021

Re-Sterilisation of Single-Use Telemetric Devices.

Eur Surg Res 2021 Jun 3:1-5. Epub 2021 Jun 3.

Institute for Laboratory Animal Science and Experimental Surgery, RWTH Aachen University, Faculty of Medicine, Aachen, Germany.

Implantable telemetric transponders for contactless measurement of physiological parameters are often used in animal-based research. After explantation, single-use devices cannot be re-implanted because of non-validated functionality and necessary re-sterilisation. This is disadvantageous because the battery life would enable a second implantation cycle in another animal. To save costs and time taken for the manufacturer's refurbishing process, we validated and implemented a re-sterilisation protocol for single-use transponders using hydrogen peroxide gas. The described protocol was established with models, i.e., for large (n = 7) and small (n = 3) animals, of telemetric device from 2 different manufacturers (Data Science International and EMKA). All transponders, prepared according to the protocol, were previously implanted subcutaneously in the flank of pigs or rats for a duration of 21 days. Our investigations demonstrate that disinfection only is not sufficient against bacterial contamination and that sterility can only be achieved by additional gas sterilisation with hydrogen peroxide. Furthermore, re-implantation of the re-sterilised transponders into pigs caused neither undesired tissue reactions along the transponder nor impairment of the measured values when compared to the first implantation and after necropsy in 4 cases. We were able to demonstrate that, using our protocol, re-implantation of reprocessed single-use telemetric devices can be performed without compromising transponder quality.
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http://dx.doi.org/10.1159/000516829DOI Listing
June 2021

Web-based survey among animal researchers on publication practices and incentives for increasing publication rates.

PLoS One 2021 6;16(5):e0250362. Epub 2021 May 6.

Institute for Ethics, History, and Philosophy of Medicine, Hannover Medical School, Hannover, Germany.

Objectives: Publication bias, non-publication, and selective reporting of animal studies limit progress toward the 3Rs (Replacement, Reduction, and Refinement) that guide ethical animal testing, waste public resources, and result in redundant research, which collectively undermine the public's trust in scientific reliability. In this study, we aimed to 1) validate findings from a previous follow-up study by our team that examined the publication rates of animal studies from protocol to publication and 2) identify incentives for improving publication rates in animal research.

Methods: The researchers responsible for the animal proposals (n = 210) from our previous study were contacted as participants for a Web-based survey between October 2019 and April 2020. Question types varied between free text questions, answer options based on a 5-point Likert scale and closed yes/no questions.

Results: In total, 78 researchers responsible for 101 of 210 animal study proposals participated, yielding a response rate of 48.1%. Results showed that the publication rate increased from 67% in our follow-up study to 70%. According to a 5-point Likert scale (from 1 = "not relevant" to 5 = "extremely relevant"), the most widely accepted suggestions for increasing publication rates were "Publication costs for open access journals are fully covered by funders or universities" (mean 4.02, SD 1.01), "Performance-based allocation of intramural funds for results reporting of animal research not supporting the initial hypothesis (including preprints and repositories)" (mean 3.37, SD 1.05), and "Researchers receive more information from scientific journals that also publish non-significant results" (mean 3.30, SD 1.02).

Conclusion: While the extent of publication and publication practices have been thoroughly investigated for clinical trials, less data is available for animal research to date. Therefore, the study contributes in complementing the picture of publication practice in animal research. Suggestions from our survey may help improve the publication rates of animal studies.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0250362PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8101964PMC
May 2021

Hemorheological and Microcirculatory Factors in Liver Ischemia-Reperfusion Injury-An Update on Pathophysiology, Molecular Mechanisms and Protective Strategies.

Int J Mol Sci 2021 Feb 13;22(4). Epub 2021 Feb 13.

Institute for Laboratory Animal Science and Experimental Surgery, Faculty of Medicine, University Hospital RWTH-Aachen, 52047 Aachen, Germany.

Hepatic ischemia-reperfusion injury (IRI) is a multifactorial phenomenon which has been associated with adverse clinical outcomes. IRI related tissue damage is characterized by various chronological events depending on the experimental model or clinical setting. Despite the fact that IRI research has been in the spotlight of scientific interest for over three decades with a significant and continuous increase in publication activity over the years and the large number of pharmacological and surgical therapeutic attempts introduced, not many of these strategies have made their way into everyday clinical practice. Furthermore, the pathomechanism of hepatic IRI has not been fully elucidated yet. In the complex process of the IRI, flow properties of blood are not neglectable. Hemorheological factors play an important role in determining tissue perfusion and orchestrating mechanical shear stress-dependent endothelial functions. Antioxidant and anti-inflammatory agents, ischemic conditioning protocols, dynamic organ preservation techniques may improve rheological properties of the post-reperfusion hepatic blood flow and target endothelial cells, exerting a potent protection against hepatic IRI. In this review paper we give a comprehensive overview of microcirculatory, rheological and molecular-pathophysiological aspects of hepatic circulation in the context of IRI and hepatoprotective approaches.
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http://dx.doi.org/10.3390/ijms22041864DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7918617PMC
February 2021

Two Polyurethane Adhesives for PVDF Fixation Show Superior Biocompatibility in a Rat Model.

J Invest Surg 2020 Oct 14:1-7. Epub 2020 Oct 14.

Institute for Laboratory Animal Science & Experimental Surgery, RWTH Aachen University Hospital, Aachen, Germany.

Background: The current standard for open and laparoscopic repair of incisional hernia consist of an abdominal wall augmentation by mesh implantation. However, the ideal fixation method of the prothesis material remains under discussion, due to potential complications of conventional fixation methods such as chronic abdominal pain or intestinal obstruction. As the use of adhesive based mesh fixation is an option of growing interest, the aim of this experimental study was to investigate the strength and biocompatibility of two newly developed polyurethane-based adhesives in comparison to a cyanoacrylatic adhesive, which is currently in clinical use.

Methods: Two experimental polyurethane/urea-based adhesives (Adhesive-A and Adhesive-B) were compared to a conventional cyanoacrylatic adhesive and an untreated control group. Biomechanical testing was carried out using a pull-out test in uniaxial tensile mode, while biocompatibility assessment was performed in a rat model with 40 Sprague-Dawley rats receiving a subcutaneous implanted PVDF mesh fixed by the corresponding adhesive. Histological and immunohistochemical analysis by a Tissue FAXS system examined the tissue integration of the mesh/adhesive combination and characterized the foreign body reaction.

Results: Biomechanical testing of the mesh/adhesive combinations showed a minimal strength of 15.08 N without a significant difference between the groups. Cellular penetration into the mesh/adhesive interface was significantly improved after application of polyurethane adhesives and Adhesive-A showed a significantly lower migration of CD68 positive cells to the adhesive sites compared to cyanoacrylate after 7 days.

Conclusion: The developed polyurethane-based adhesives are a promising alternative with sufficient adhesive strength and superior short-term biocompatibility to cyanoacrylate.
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http://dx.doi.org/10.1080/08941939.2020.1833261DOI Listing
October 2020

The gut bacterium produces secondary bile acids and influences liver physiology in gnotobiotic mice.

Gut Microbes 2021 Jan-Dec;13(1):1-21

Functional Microbiome Research Group, Institute of Medical Microbiology, University Hospital of RWTH , Aachen, Germany.

is a newly described mouse gut bacterium which metabolizes cholic acid (CA) to deoxycholic acid (DCA) via 7α-dehydroxylation. Although bile acids influence metabolic and inflammatory responses, few models exist for studying their metabolism and impact on the host. Mice were colonized from birth with the simplified community Oligo-MM with or without . As the metabolism of bile acids is known to affect lipid homeostasis, mice were fed either a low- or high-fat diet for eight weeks before sampling and analyses targeting the gut and liver. Multiple Oligo-MM strains were capable of deconjugating primary bile acids produced DCA from CA either as pure compound or in mouse bile. This production was inducible by CA . Ursodeoxycholic, chenodeoxycholic, and β-muricholic acid were not metabolized under the conditions tested. All gnotobiotic mice were stably colonized with , which showed higher relative abundances after HF diet feeding. The presence of had minor, diet-dependent effects on Oligo-MM communities. The secondary bile acids DCA and surprisingly LCA and their taurine conjugates were detected exclusively in -colonized mice. colonization did not influence body weight, white adipose tissue mass, liver histopathology, hepatic aspartate aminotransferase, or blood levels of cholesterol, insulin, and paralytic peptide (PP). However, proteomics revealed shifts in hepatic pathways involved in amino acid, glucose, lipid, energy, and drug metabolism in -colonized mice. Liver fatty acid composition was substantially altered by dietary fat but not by In summary, stably colonized the gut of mice harboring a simplified community and produced secondary bile acids, which affected proteomes in the liver. This new gnotobiotic mouse model can now be used to study the pathophysiological role of secondary bile acids .
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http://dx.doi.org/10.1080/19490976.2020.1854008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7781625PMC
December 2020

A peritoneal defect covered by intraperitoneal mesh prosthesis effects an increased and distinctive foreign body reaction in a minipig model.

J Biomater Appl 2021 01 8;35(6):732-739. Epub 2020 Oct 8.

Department of General, Visceral and Transplant Surgery, RWTH Aachen University Hospital, Aachen, Germany.

Background: The incidence of incisional hernia is with up to 30% one of the frequent long-term complication after laparotomy. After establishing minimal invasive operations, the laparoscopic intraperitoneal onlay mesh technique (lap. IPOM) was first described in 1993. Little is known about the foreign body reaction of IPOM-meshes, which covered a defect of the parietal peritoneum. This is becoming more important, since IPOM procedure with peritoneal-sac resection and hernia port closing (IPOM plus) is more frequently used.

Methods: In 18 female minipigs, two out of three Polyvinylidene-fluoride (PVDF) -meshes (I: standard IPOM; II: IPOM with modified structure [bigger pores]; III: IPOM with the same structure as IPOM II + degradable hydrogel-coating) were placed in a laparoscopic IPOM procedure. Before mesh placement, a 2x2cm peritoneal defect was created. After 30 days, animals were euthanized, adhesions were evaluated by re-laparoscopy and mesh samples were explanted for histological and immunohistochemichal investigations.

Results: All animals recovered after implantation and had no complications during the follow-up period. Analysing foreign body reaction, the IPOM II mesh had a significant smaller inner granuloma, compared to the other meshes (IPOM II: 8.4 µm ± 1.3 vs. IPOM I 9.1 µm ± 1.3, p < 0.001). The degradable hydrogel coating does not prevent adhesions measured by Diamond score (p = 0.46). A peritoneal defect covered by a standard or modified IPOM mesh was a significant factor for increasing foreign body granuloma, the amount of CD3+ lymphocytes, CD68+ macrophages and decrease of pore size.

Conclusion: A peritoneal defect covered by IPOM prostheses leads to an increased foreign body reaction compared to intact peritoneum. Whenever feasible, a peritoneal defect should be closed accurately before placing an IPOM-mesh to avoid an excessive foreign body reaction and therefore inferior biomaterial properties of the prosthesis.
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http://dx.doi.org/10.1177/0885328220963918DOI Listing
January 2021

Publication rates of research projects of an internal funding program of a university medical center in Germany: A retrospective study (2004-2013).

PLoS One 2020 30;15(11):e0243092. Epub 2020 Nov 30.

Faculty of Medicine, Institute for Laboratory Animal Science & Experimental Surgery, RWTH Aachen University, Aachen, Germany.

Objectives: Non-publication and publication bias are topics of considerable importance to the scientific community. These issues may limit progress toward the 3R principle for animal research, promote waste of public resources, and generate biased interpretations of clinical outcomes. To investigate current publishing practices and to gain some understanding of the extent to which research results are reported, we examined publication rates of research projects that were approved within an internal funding program of the Faculty of Medicine at a university medical center in Germany, which is exemplary for comparable research funding programs for the promotion of young researchers in Germany and Europe.

Methods: We analyzed the complete set (n = 363) of research projects that were supported by an internal funding program between 2004 and 2013. We divided the projects into four different proposal types that included those that required an ethics vote, those that included an animal proposal, those that included both requirements, and those that included neither requirement.

Results: We found that 65% of the internally funded research projects resulted in at least one peer-reviewed publication; this increased to 73% if other research contributions were considered, including abstracts, book and congress contributions, scientific posters, and presentations. There were no significant differences with respect to publication rates based on (a) the clinic/institute of the applicant, (b) project duration, (c) scope of funding or (d) proposal type.

Conclusion: To the best of our knowledge, this is the first study to explore publication rates associated with early-career medical research funding. As >70% of the projects ultimately generated some form of publication, the program was overall effective toward this goal; however, non-publication of research results is still prevalent. Further research will explore the reasons underlying non-publication. We hope to use these findings to develop strategies that encourage publication of research results.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0243092PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7703943PMC
January 2021

Best variable identification by means of data-mining and cooperative game theory.

J Biomed Inform 2021 01 19;113:103625. Epub 2020 Nov 19.

Institute for Laboratory Animal Science & Experimental Surgery, RWTH Aachen University, Faculty of Medicine, Pauwelsstraße 30, 52074 Aachen, Germany. Electronic address:

Objective: To develop and evaluate methods to assess single and grouped variables impact on measuring intervention severities and support a search for most expressive variables.

Methods: Datasets of cohort studies are analyzed automatically based on algorithms. For this, a metric is developed to compare measured variables in different cohorts in a data-mining process. Variables are measured in all possible combinations to detect possible synergies of certain variable constellations and allow for a ranking of the combinations' expressiveness. Such ranking serves as a basis for a wide range of algorithmic data analysis. In an exemplary application, every group member's impact on the total result is determined based on the principle of the cooperative game theory besides to the total expressiveness of the variable groups.

Results: For different types of interventions, the method is applied to experimental data containing multiple recorded medical lab values. The expressiveness of variable combinations to indicate severity is ranked by means of a metric. Within each combination, any variable's contribution to the total effect is determined and accumulated over whole datasets to yield local and global variable importance measures. The computed results have been successfully matched with clinical expectations to prove their plausibility.

Conclusion: Algorithmic evaluation shows to be a promising approach in automatized quantification of variable expressiveness. It can assess descriptive power of measurements, help to improve future study designs and expose worthwhile research issues.
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http://dx.doi.org/10.1016/j.jbi.2020.103625DOI Listing
January 2021

Measuring endogenous corticosterone in laboratory mice - a mapping review, meta-analysis, and open source database.

ALTEX 2021 6;38(1):111-122. Epub 2020 Oct 6.

Institute for Laboratory Animal Science, Hannover Medical School, Hannover, Germany.

Evaluating stress in laboratory animals is a key principle in animal welfare. Measuring corticosterone is a common method to assess stress in laboratory mice. There are, however, numerous methods to measure glucocorticoids with differences in sample matrix (e.g., plasma, urine) and quantification techniques (e.g., enzyme immunoassay or radioimmunoassay). Here, the authors present a mapping review and a searchable database, giving a complete overview of all studies mea­suring endogenous corticosterone in mice up to February 2018. For each study, information was recorded regarding mouse strain and sex; corticosterone sample matrix and quantification technique; and whether the study covered the research theme animal welfare, neuroscience, stress, inflammation, or pain (the themes of specific interest in our con­sortium). Using all database entries for the year 2012, an exploratory meta-regression was performed to determine the effect of predictors on basal corticosterone concentrations. Seventy-five studies were included using the predictors sex, time-since-lights-on, sample matrix, quantification technique, age of the mice, and type of control. Sex, time-since-lights-on, and type of control significantly affected basal corticosterone concentrations. The resulting database can be used, inter alia, for preventing unnecessary duplication of experiments, identifying knowledge gaps, and standardizing or heterogenizing methodologies. These results will help plan more efficient and valid experiments in the future and can answer new questions in silico using meta-analyses.
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http://dx.doi.org/10.14573/altex.2004221DOI Listing
October 2020

Decrease of renal resistance during hypothermic oxygenated machine perfusion is associated with early allograft function in extended criteria donation kidney transplantation.

Sci Rep 2020 10 20;10(1):17726. Epub 2020 Oct 20.

Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen, Germany.

Hypothermic oxygenated machine perfusion (HOPE) was recently tested in preclinical trials in kidney transplantation (KT). Here we investigate the effects of HOPE on extended-criteria-donation (ECD) kidney allografts (KA). Fifteen ECD-KA were submitted to 152 ± 92 min of end-ischemic HOPE and were compared to a matched group undergoing conventional-cold-storage (CCS) KT (n = 30). Primary (delayed graft function-DGF) and secondary (e.g. postoperative complications, perfusion parameters) endpoints were analyzed within 6-months follow-up. There was no difference in the development of DGF between the HOPE and CCS groups (53% vs. 33%, respectively; p = 0.197). Serum urea was lower following HOPE compared to CCS (p = 0.003), whereas the CCS group displayed lower serum creatinine and higher eGFR rates on postoperative days (POD) 7 and 14. The relative decrease of renal vascular resistance (RR) following HOPE showed a significant inverse association with serum creatinine on POD1 (r = - 0.682; p = 0.006) as well as with serum urea and eGFR. Besides, the relative RR decrease was more prominent in KA with primary function when compared to KA with DGF (p = 0.013). Here we provide clinical evidence on HOPE in ECD-KT after brain death donation. Relative RR may be a useful predictive marker for KA function. Further validation in randomized controlled trials is warranted.Trial registration: clinicaltrials.gov (NCT03378817, Date of first registration: 20/12/2017).
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http://dx.doi.org/10.1038/s41598-020-74839-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7575556PMC
October 2020

Hematological and Chemical Profiles in a Porcine Model of Severe Multiple Trauma.

Eur Surg Res 2020 6;61(2-3):83-94. Epub 2020 Oct 6.

Department of Trauma and Reconstructive Surgery, Faculty of Medicine, RWTH Aachen University Hospital, Aachen, Germany.

Background: Clinical chemistry and hematological tests are widely used to monitor the clinical course of several diseases. However, these parameters are sparse in large-animal models of multiple trauma (MT). Thus, we aimed to provide these missing data to improve future experimental setups in trauma research.

Methods: Male pigs (German Landrace pigs) were randomized into either an MT group (n = 8) including blunt thoracic trauma, tibial fracture, and controlled hemorrhage or a sham group (n = 8) without any trauma. After trauma induction, all animals received intensive care treatment for 72 h under anesthesia, including mechanical ventilation and volume resuscitation. Blood and urine samples were obtained to measure common hematological and chemical parameters before trauma (0 h), after trauma (1.5 h), during resuscitation (2.5 h), after fracture stabilization (3.5 h), and at 12, 24, 48, and 72 h. Statistical analyses were performed using a linear mixed model (group × time) and Welch's ANOVA.

Results: MT led to a perceptible immunological reaction. Between groups, significantly different time courses of leukocyte counts (p = 0.034) and lymphocyte proportions (p = 0.001) were observed. Moreover, MT changed the time course of total protein (p = 0.006). Significantly lower concentrations compared to sham were found in MT at each single time point starting at 1.5 h to the end of the observation period (all p < 0.05).

Conclusions: Our results indicate that a traumatic insult leads to significant alterations in the immune system already shortly after trauma. Together with the additional catabolic reactions observed, these alterations might contribute to the occurrence of later complications. The presented data provide valid references for further experimental setups with prolonged observation times, especially in similar porcine models of MT.
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http://dx.doi.org/10.1159/000510267DOI Listing
July 2021

Severity assessment in mice subjected to carbon tetrachloride.

Sci Rep 2020 09 25;10(1):15790. Epub 2020 Sep 25.

Institute for Laboratory Animal Science and Experimental Surgery, Faculty of Medicine, RWTH, Aachen International University, Aachen, Germany.

The Directive 2010/63 EU requires classifying burden and severity in all procedures using laboratory animals. This study evaluated the severity of liver fibrosis induction by intraperitoneal carbon tetrachloride (CCl) injections in mice. 29 male C57BL/6N mice were treated three times per week for 4 weeks with an intraperitoneal injection (50 µl) of either 0.6 ml/kg body weight CCl-vehicle solution, germ oil (vehicle-control) or handling only. Severity assessment was performed using serum analysis, behavioral tests (open field test, rotarod, burrowing and nesting behavior), fecal corticosterone metabolite (FCM) measurement, and survival. The most significant group differences were noticed in the second week of treatment when the highest AST (1463 ± 1404 vs. 123.8 ± 93 U/L, p < 0.0001) and nesting values were measured. In addition, respective animals showed lower moving distances (4622 ± 1577 vs. 6157 ± 2060 cm, p < 0.01) and velocity in the Open field, identified as main factors in principal component analysis (PCA). Overall, a 50% survival rate was observed within the treatment group, in which the open field performance was a good tracer parameter for survival. In summary, this study demonstrates the feasibility of assessing severity in mice using behavioral tests and highlight the open field test as a possible threshold parameter for risk assessment of mortality.
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http://dx.doi.org/10.1038/s41598-020-72801-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7519684PMC
September 2020

Adenosine A2a Receptor Stimulation Attenuates Ischemia-Reperfusion Injury and Improves Survival in A Porcine Model of DCD Liver Transplantation.

Int J Mol Sci 2020 Sep 14;21(18). Epub 2020 Sep 14.

Institute for Laboratory Animal Science and Experimental Surgery, Faculty of Medicine, RWTH-Aachen University, 52074 Aachen, Germany.

Orthotopic liver transplantation (OLT) using allografts from donation after circulatory death (DCD) is potentially associated with compromised clinical outcomes due to ischemia-reperfusion injury (IRI)-induced organ damage and graft-related complications. The aim of this study was to provide in vivo data on the effects of adenosine A receptor stimulation in a clinically relevant large animal model of DCD liver transplantation. Cardiac arrest was induced in German Landrace pigs ( = 10; 20-25 kg). After 30 min of warm ischemia, the donor liver was retrieved following a cold flush with 3 L of histidine-tryptophan-ketoglutarate-HTK solution. Animals of the treatment group ( = 5/group) received a standard dose of the selective adenosine receptor agonist CGS 21680 added to the cold flush. All grafts were stored for 4.5 h at 4 °C in HTK-solution before OLT. Hepatocellular injury, apoptosis, protein kinase A-PKA activity, graft microcirculation, liver function, and animal survival were assessed. Compared to untreated livers, adenosine A receptor stimulation resulted in improved tissue microcirculation (103% ± 5% vs. 38% ± 4% compared to baseline; < 0.05), accelerated functional recovery of the graft (indocyanine green-plasma disappearance rate (ICG-PDR) of 75% ± 18% vs. 40% ± 30% after 3 h), increased PKA activity ratio (56% ± 3% vs. 32% ± 3%; < 0.001 after 1 h), and consequently reduced tissue necrosis and apoptosis. The potent protective effects were clinically manifested in significantly improved survival in the treatment group after 72 h (100% vs. 40%; 0.04). The ex vivo administration of adenosine A receptor agonist during the back-table flush mitigates IRI-mediated tissue damage and improves functional graft recovery and survival in a large animal model of DCD liver transplantation.
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http://dx.doi.org/10.3390/ijms21186747DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7555737PMC
September 2020

Orthotopic Kidney Auto-Transplantation in a Porcine Model Using 24 Hours Organ Preservation And Continuous Telemetry.

J Vis Exp 2020 08 21(162). Epub 2020 Aug 21.

Department of Surgery and Transplantation, Faculty of Medicine, University Hospital RWTH Aachen; Institute for Laboratory Animal Science, Faculty of Medicine, University Hospital RWTH Aachen;

In the present era of organ transplantation with critical organ shortage, various strategies are employed to expand the pool of available allografts for kidney transplantation (KT). Even though, the use of allografts from extended criteria donors (ECD) could partially ease the shortage of organ donors, ECD organs carry a potentially higher risk for inferior outcomes and postoperative complications. Dynamic organ preservation techniques, modulation of ischemia-reperfusion and preservation injury, and allograft therapies are in the spotlight of scientific interest in an effort to improve allograft utilization and patient outcomes in KT. Preclinical animal experiments are playing an essential role in translational research, especially in the medical device and drug development. The major advantage of the porcine orthotopic auto-transplantation model over ex vivo or small animal studies lies within the surgical-anatomical and physiological similarities to the clinical setting. This allows the investigation of new therapeutic methods and techniques and ensures a facilitated clinical translation of the findings. This protocol provides a comprehensive and problem-oriented description of the porcine orthotopic kidney auto-transplantation model, using a preservation time of 24 hours and telemetry monitoring. The combination of sophisticated surgical techniques with highly standardized and state-of-the-art methods of anesthesia, animal housing, perioperative follow up, and monitoring ensure the reproducibility and success of this model.
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http://dx.doi.org/10.3791/61591DOI Listing
August 2020

CD68+ macrophages as crucial components of the foreign body reaction demonstrate an unconventional pattern of functional markers quantified by analysis with double fluorescence staining.

J Biomed Mater Res B Appl Biomater 2020 11 30;108(8):3134-3146. Epub 2020 May 30.

Division of Infection and Immunity, Cardiff University, Cardiff, UK.

Implants like meshes for the reinforcement of tissues implement the formation of a persistent inflammation with an ambient fibrotic reaction. In the inflammatory infiltrate several distinct cell types have been identified, but CD68+ macrophages are supposed to be most important. To investigate the collaboration among the various cell types within the infiltrate we performed at explanted meshes from humans double fluorescence staining with CD68 as a constant marker and a variety of other antibodies as the second marker. The list of second markers includes lymphocytes (CD3, CD4, CD8, CD16, CD56, FoxP3, and CD11b) stem cells (CD34), leucocytes (CD45, CD15), macrophages (CD86, CD105, CD163, and CD206); deposition of EC matrix (collagen-I, collagen-III, MMP2, and MMP8); Ki67 as a marker for proliferation; and the tyrosine-protein kinase receptor AXL. The present study demonstrates within the inflammatory infiltrate the abundant capability of CD68+ cells to co-express a huge variety of other markers, including those of lymphocytes, varying between 5 and 83% of investigated cells. The observation of co-staining was not restricted to a specific polymer but was seen with polypropylene fibers as well as with fibers made of polyvinylidene fluoride, although with differences in co-expression rates. The persisting variability of these cells without the functional reduction toward differentiated mature cell types may favor the lack of healing at the interface of meshes.
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http://dx.doi.org/10.1002/jbm.b.34639DOI Listing
November 2020

Design of composite measure schemes for comparative severity assessment in animal-based neuroscience research: A case study focussed on rat epilepsy models.

PLoS One 2020 15;15(5):e0230141. Epub 2020 May 15.

Institute of Pharmacology, Toxicology and Pharmacy, Ludwig-Maximilians-University, Munich, Germany.

Comparative severity assessment of animal models and experimental interventions is of utmost relevance for harm-benefit analysis during ethical evaluation, an animal welfare-based model prioritization as well as the validation of refinement measures. Unfortunately, there is a lack of evidence-based approaches to grade an animal's burden in a sensitive, robust, precise, and objective manner. Particular challenges need to be considered in the context of animal-based neuroscientific research because models of neurological disorders can be characterized by relevant changes in the affective state of an animal. Here, we report about an approach for parameter selection and development of a composite measure scheme designed for precise analysis of the distress of animals in a specific model category. Data sets from the analysis of several behavioral and biochemical parameters in three different epilepsy models were subjected to a principal component analysis to select the most informative parameters. The top-ranking parameters included burrowing, open field locomotion, social interaction, and saccharin preference. These were combined to create a composite measure scheme (CMS). CMS data were subjected to cluster analysis enabling the allocation of severity levels to individual animals. The results provided information for a direct comparison between models indicating a comparable severity of the electrical and chemical post-status epilepticus models, and a lower severity of the kindling model. The new CMS can be directly applied for comparison of other rat models with seizure activity or for assessment of novel refinement approaches in the respective research field. The respective online tool for direct application of the CMS or for creating a new CMS based on other parameters from different models is available at https://github.com/mytalbot/cms. However, the robustness and generalizability needs to be further assessed in future studies. More importantly, our concept of parameter selection can serve as a practice example providing the basis for comparable approaches applicable to the development and validation of CMS for all kinds of disease models or interventions.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0230141PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7228039PMC
July 2020

Severity assessment using three common behavioral or locomotor tests after laparotomy in rats: a pilot study.

Lab Anim 2020 Dec 30;54(6):525-535. Epub 2020 Mar 30.

Institute for Laboratory Animal Science and Experimental Surgery, RWTH Aachen University, Faculty of Medicine, Germany.

The aim of this pilot study was to evaluate whether behavioral or locomotor tests (Open Field (OF), rotarod (RR), and CatWalk (CW)) can help assess the severity of laparotomy in rats.The new EU Directive (2010/63/EU) mandates severity assessment in experiments involving animals. However, validated and objective methods are needed to relate trial-specific monitoring results to the degree of distress caused to individual animals. Therefore, we focused on non-invasive or minimally invasive, simple, and convenient severity assessment methods in a surgical model.To evaluate surgical severity in this model, we compared moving velocity among three commonly used behavioral test methods (OF, RR, and CW) after midline laparotomy within postoperative 7 days.In this study, 30 adult male Wistar Han rats ( = 10 per test) were trained in their assigned test method and subsequently subjected to surgery. Severity scoring was performed daily using a modified score sheet developed previously. In addition, blood and fecal samples were collected to analyze surgical and postoperative corticosterone metabolite levels. We found significant differences among the experimental groups in terms of the analyzed parameters. In this context, the OF test was found to be the most suitable method for severity assessment after laparotomy in rats.
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http://dx.doi.org/10.1177/0023677220911680DOI Listing
December 2020

Influence of MRI Examinations on Animal Welfare and Study Results.

Invest Radiol 2020 08;55(8):507-514

From the Institute for Experimental Molecular Imaging.

Objectives: Magnetic resonance imaging (MRI) is considered to be well tolerated by laboratory animals. However, no systematic study has been performed yet, proving this assumption. Therefore, the aim of this study was to investigate the possible effects of longitudinal native and contrast-enhanced (CE) 1-T and 7-T MRI examinations on mouse welfare as well as 4T1 breast cancers progression and therapy response.

Material And Methods: Forty-seven healthy and 72 breast cancer-bearing mice (4T1) were investigated. One-Tesla (ICON) and 7-T (Biospec) MRI measurements were performed thrice per week under isoflurane anesthesia in healthy BALB/c mice for 4 weeks and 3 times within 2 weeks in tumor-bearing animals. Animal welfare was examined by an observational score sheet, rotarod performance, heart rate measurements, and assessment of fecal corticosterone metabolites. Furthermore, we investigated whether CE-MRI influences the study outcome. Therefore, hemograms and organ weights were obtained, and 4T1 tumor growth, perfusion, immune cell infiltration, as well as response to the multikinase inhibitor regorafenib were investigated. Statistical comparisons between groups were performed using analysis of variance and Tukey or Bonferroni post hoc tests.

Results: Mice showed no alterations in the observational score sheet rating, rotarod performance, heart rate, and fecal corticosterone metabolites (P > 0.05) after repeated MRI at both field strengths. However, spleen weights were reduced in all healthy mouse groups that received isoflurane anesthesia (P < 0.001) including the groups investigated by 1-T and 7-T MRI (P = 0.02). Neither tumor progression nor response to the regorafenib treatment was affected by isoflurane anesthesia or CE-MRI monitoring. Furthermore, immunohistological tumor analysis did not indicate an effect of isoflurane and MRI on macrophage infiltration of tumors, perfusion of tumor vessels, and apoptotic cell rate (P > 0.05).

Conclusions: Repeated MRI did not influence the welfare of mice and did not affect tumor growth and therapy response of 4T1 tumors. However, systemic immunological effects of isoflurane anesthesia need to be considered to prevent potential bias.
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http://dx.doi.org/10.1097/RLI.0000000000000669DOI Listing
August 2020

Gait analysis and muscle weight analysis after lower extremity fractures in a small animal model.

Gait Posture 2020 03 6;77:207-213. Epub 2020 Feb 6.

Department of Surgery, Division of Traumasurgery, Maastricht University Medical Center, P. Debyelaan 25, 6229 HX, Maastricht, Netherlands. Electronic address:

Background: Besides adequate healing of bone and soft tissues, mobility represents a significant factor in functional outcome after lower extremity fractures. Although gait analysis is gaining clinical interest and importance in the rehabilitation of patients with fractures, it is rarely used in experimental fracture healing research. The aim of this study is to establish an accurate gait analysis method for fracture healing research in small animal models and to evaluate the influence of a lower extremity fracture on gait pattern and muscle atrophy in rats.

Research Question: How does an intramedullary stabilized femur fracture influence the gait pattern and muscle atrophy during fracture healing in rats?

Methods: An isolated femur fracture with intramedullary stabilization was induced in 26 Sprague Dawley rats. Different gait parameters (e.g. intensity, print area, stand duration, duty cycle, and swing speed) were evaluated with the CatWalk gait analysis system during the fracture healing process. Furthermore, muscle weight analysis was performed at different time points.

Results: The gait analyses with the CatWalk system showed a high correlation with the osteogenesis of fracture healing in this model. Muscle atrophy increased during the early fracture healing stages and then decreased in the later stages.

Significance: We are the first to show that the CatWalk system is a useful tool to perform gait analyses after lower extremity fractures in a murine model. These results could form a basis for future gait analyses research in fracture healing studies to improve knowledge about bone regeneration and rehabilitation after lower extremity fractures.
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http://dx.doi.org/10.1016/j.gaitpost.2020.01.022DOI Listing
March 2020

Severity Assessment in animal based research.

Lab Anim 2020 Feb;54(1):16

Institute for Laboratory Animal Science and Experimental Surgery, RWTH Aachen University, Germany.

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http://dx.doi.org/10.1177/0023677219898105DOI Listing
February 2020

Contactless Anesthesia Monitoring in Spontanously Breathing Rodents.

Annu Int Conf IEEE Eng Med Biol Soc 2019 Jul;2019:6077-6080

Laboratory animal science plays a crucial role in medical and biological research. In the last decades, stricter regulations were enforced to safeguard laboratory animals. Following the "3Rs" guiding principles, animal trials should be replaced, reduced and refined, whenever possible.A contactless modality capable of assessing the respiratory rate (RR) and additional breath related characteristics can potentially refine anesthetic interventions in rodents by continuously monitoring their anesthetic depth. This can reduce complications and thus the number of needed animals.We were able to extract the instantaneous RR in rodents with a sum squared error (SSE) of 0.26 breaths/min from color video. A correlation of 0.9781 compared to an Electrocardiography (ECG) based reference was achieved. Furthermore, additional temporal and morphological characteristics were extracted, which are sensitive for changes in the anesthetic depth.
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http://dx.doi.org/10.1109/EMBC.2019.8856869DOI Listing
July 2019

Assessment of Laboratory Mouse Activity in Video Recordings Using Deep Learning Methods.

Annu Int Conf IEEE Eng Med Biol Soc 2019 Jul;2019:3673-3676

Analysis of laboratory animal behavior allows assessment of animal wellbeing. We present a method for the classification of different activities of laboratory mice by analyzing video clips using three deep learning methods. Animals placed in observation cages are filmed and short video clips are labelled as belonging to one of five defined behaviors. Subsequently, three different methods based on convolutional neural networks (CNNS) are applied to classify the clips. The best performing method - a two-stream network that analyzes individual frames as well as the video's optical flow - achieves an accuracy of 86.4%, including detection of important behavioral patterns such as self-grooming. These results show that the presented analysis protocol allows automated assessment of animal behavior by algorithmic analysis of videos of mice on observation boxes.
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http://dx.doi.org/10.1109/EMBC.2019.8857807DOI Listing
July 2019

All You Can Feed: Some Comments on Production of Mouse Diets Used in Biomedical Research with Special Emphasis on Non-Alcoholic Fatty Liver Disease Research.

Nutrients 2020 Jan 7;12(1). Epub 2020 Jan 7.

Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), RWTH University Hospital Aachen, D-52074 Aachen, Germany.

The laboratory mouse is the most common used mammalian research model in biomedical research. Usually these animals are maintained in germ-free, gnotobiotic, or specific-pathogen-free facilities. In these facilities, skilled staff takes care of the animals and scientists usually don't pay much attention about the formulation and quality of diets the animals receive during normal breeding and keeping. However, mice have specific nutritional requirements that must be met to guarantee their potential to grow, reproduce and to respond to pathogens or diverse environmental stress situations evoked by handling and experimental interventions. Nowadays, mouse diets for research purposes are commercially manufactured in an industrial process, in which the safety of food products is addressed through the analysis and control of all biological and chemical materials used for the different diet formulations. Similar to human food, mouse diets must be prepared under good sanitary conditions and truthfully labeled to provide information of all ingredients. This is mandatory to guarantee reproducibility of animal studies. In this review, we summarize some information on mice research diets and general aspects of mouse nutrition including nutrient requirements of mice, leading manufacturers of diets, origin of nutrient compounds, and processing of feedstuffs for mice including dietary coloring, autoclaving and irradiation. Furthermore, we provide some critical views on the potential pitfalls that might result from faulty comparisons of grain-based diets with purified diets in the research data production resulting from confounding nutritional factors.
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http://dx.doi.org/10.3390/nu12010163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7019265PMC
January 2020

Attitudes towards animal study registries and their characteristics: An online survey of three cohorts of animal researchers.

PLoS One 2020 6;15(1):e0226443. Epub 2020 Jan 6.

Institute for Ethics, History, and Philosophy of Medicine, Hannover Medical School, Hannover, Germany.

Objectives: Prospective registration of animal studies has been suggested as a new measure to increase value and reduce waste in biomedical research. We sought to further explore and quantify animal researchers' attitudes and preferences regarding animal study registries (ASRs).

Design: Cross-sectional online survey.

Setting And Participants: We conducted a survey with three different samples representing animal researchers: i) corresponding authors from journals with high Eigenfactor, ii) a random Pubmed sample and iii) members of the CAMARADES network.

Main Outcome Measures: Perceived level of importance of different aspects of publication bias, the effect of ASRs on different aspects of research as well as the importance of different research types for being registered.

Results: The survey yielded responses from 413 animal researchers (response rate 7%). The respondents indicated, that some aspects of ASRs can increase administrative burden but could be outweighed by other aspects decreasing this burden. Animal researchers found it more important to register studies that involved animal species with higher levels of cognitive capabilities. The time frame for making registry entries publicly available revealed a strong heterogeneity among respondents, with the largest proportion voting for "access only after consent by the principal investigator" and the second largest proportion voting for "access immediately after registration".

Conclusions: The fact that the more senior and experienced animal researchers participating in this survey clearly indicated the practical importance of publication bias and the importance of ASRs underscores the problem awareness across animal researchers and the willingness to actively engage in study registration if effective safeguards for the potential weaknesses of ASRs are put into place. To overcome the first-mover dilemma international consensus statements on how to deal with prospective registration of animal studies might be necessary for all relevant stakeholder groups including animal researchers, academic institutions, private companies, funders, regulatory agencies, and journals.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0226443PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6944338PMC
April 2020

Oxygen inhalation improves postoperative survival in ketamine-xylazine anaesthetised rats: An observational study.

PLoS One 2019 13;14(12):e0226430. Epub 2019 Dec 13.

Department of Anaesthesiology, Uniklinik RWTH Aachen, Aachen, Germany.

Objective: A simple but reliable and safe anaesthetic procedure is required for surgical interventions in small rodents. Combined ketamine and xylazine injections are often used in rats for less invasive surgery, possibly with spontaneous breathing and without airway management. However, there are important pitfalls to be avoided by special precautions and monitoring, as shown subsequently.

Study Design: Observational study.

Animals: Twenty-four anaesthetic procedures for bile duct ligation, sham operation or carotid artery dilatation in 20 male Sprague-Dawley rats, preoperatively weighing between 440 and 550 g.

Methods: Intolerable high mortality rates occurred in the first 7 postoperative days while establishing a new experimental model in rats using ketamine-xylazine anaesthesia. Rats were spontaneously breathing ambient air during the first 12 surgeries without airway management. An observed high mortality rate in these animals led to a change in the trial protocol: the insufflation of 2 litres of oxygen per minute via nose cone during the following 12 rat surgeries. Retrospective comparison of the outcome (without oxygen vs. with oxygen insufflation) was conducted.

Results: The perioperative mortality rate could be significantly reduced from 58% (7/12) to 17% (2/12) (p = 0.036) by oxygen insufflation via nose cone. Significantly different levels of intraoperative oxygen saturation (SpO2; 89 ± 4% [without oxygen] vs. 97 ± 0.5% [with oxygen], p < 0.0001), but no significant differences in heart rate (HR; 267 ± 7 beats minute-1 [bpm] [without oxygen] vs. 266 ± 6 bpm [with oxygen], p = 0.955) were observed.

Conclusions And Clinical Relevance: In summary, rats under ketamine-xylazine anaesthesia are susceptible to hypoxia. This may lead to increased delayed mortality related to hypoxia induced lung failure. Apparently, this is an underestimated problem. We highly recommend using additional oxygen insufflation in spontaneously breathing rats under ketamine-xylazine anaesthesia with basic monitoring such as measurement of oxygen saturation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0226430PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6910690PMC
April 2020
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