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Institute
- Theodor-Boveri-Institut für Biowissenschaften (173)
- Graduate School of Life Sciences (124)
- Institut für Anorganische Chemie (73)
- Medizinische Klinik und Poliklinik I (67)
- Klinik und Poliklinik für Allgemein-, Viszeral-, Gefäß- und Kinderchirurgie (Chirurgische Klinik I) (59)
- Medizinische Klinik und Poliklinik II (59)
- Institut für Psychologie (55)
- Institut für Informatik (51)
- Neurologische Klinik und Poliklinik (51)
- Institut für Organische Chemie (48)
Schriftenreihe
Sonstige beteiligte Institutionen
- Cologne Game Lab (3)
- DFG Forschungsgruppe 2757 / Lokale Selbstregelungen im Kontext schwacher Staatlichkeit in Antike und Moderne (LoSAM) (2)
- Klinikum Fulda (2)
- Open University of the Netherlands (2)
- Ökologische Station Fabrikschleichach (2)
- Airbus Defence and Space GmbH (1)
- Akademie der Wissenschaften und der Literatur, Mainz (1)
- Apotheke, Universitätsklinikum Würzburg (1)
- Biomedical Center Munich, Department of Physiological Chemistry, Ludwig-Maximilians-Universität München (1)
- Birmingham City University (1)
Barlinn, J. ; Winzer, S. ; Worthmann, H. ; Urbanek, C. ; Häusler, K. G. ; Günther, A. ; Erdur, H. ; Görtler, M. ; Busetto, L. ; Wojciechowski, C. ; Schmitt, J. ; Shah, Y. ; Büchele, B. ; Sokolowski, P. ; Kraya, T. ; Merkelbach, S. ; Rosengarten, B. ; Stangenberg-Gliss, K. ; Weber, J. ; Schlachetzki, F. ; Abu-Mugheisib, M. ; Petersen, M. ; Schwartz, A. ; Palm, F. ; Jowaed, A. ; Volbers, B. ; Zickler, P. ; Remi, J. ; Bardutzky, J. ; Bösel, J. ; Audebert, H. J. ; Hubert, G. J. ; Gumbinger, C.
Hintergrund und Ziel
Telemedizinische Schlaganfall-Netzwerke tragen dazu bei, die Schlaganfallversorgung und insbesondere den Zugang zu zeitkritischen Schlaganfalltherapien in vorrangig strukturschwachen, ländlichen Regionen zu gewährleisten. Ziel ist eine Darstellung der Nutzungsfrequenz und regionalen Verteilung dieser Versorgungsstruktur.
Methoden
Die Kommission „Telemedizinische Schlaganfallversorgung“ der Deutschen Schlaganfall-Gesellschaft führte eine Umfragestudie in allen Schlaganfall-Netzwerken durch.
Ergebnisse
In Deutschland sind 22 telemedizinische Schlaganfall-Netzwerke aktiv, welche insgesamt 43 Zentren (pro Netzwerk: Median 1,5, Interquartilsabstand [IQA] 1–3) sowie 225 Kooperationskliniken (pro Netzwerk: Median 9, IQA 4–17) umfassen und an einem unmittelbaren Zugang zur Schlaganfallversorgung für 48 Mio. Menschen teilhaben. Im Jahr 2018 wurden 38.211 Telekonsile (pro Netzwerk: Median 1340, IQA 319–2758) durchgeführt. Die Thrombolyserate betrug 14,1 % (95 %-Konfidenzintervall 13,6–14,7 %), eine Verlegung zur Thrombektomie wurde bei 7,9 % (95 %-Konfidenzintervall 7,5–8,4 %) der ischämischen Schlaganfallpatienten initiiert. Das Finanzierungssystem ist uneinheitlich mit einem Vergütungssystem für die Zentrumsleistungen in nur drei Bundesländern.
Diskussion
Etwa jeder 10. Schlaganfallpatient wird telemedizinisch behandelt. Die telemedizinischen Schlaganfall-Netzwerke erreichen vergleichbar hohe Lyseraten und Verlegungen zur Thrombektomie wie neurologische Stroke-Units und tragen zur Sicherstellung einer flächendeckenden Schlaganfallversorgung bei. Eine netzwerkübergreifende Sicherstellung der Finanzierung und einheitliche Erhebung von Qualitätssicherungsdaten haben das Potenzial diese Versorgungsstruktur zukünftig weiter zu stärken.
Lawitschka, Anita ; Brunmair, Matthias ; Bauer, Dorothea ; Zubarovskaya, Natalia ; Felder-Puig, Rosemarie ; Strahm, Brigitte ; Bader, Peter ; Strauss, Gabriele ; Albert, Michael ; Luettichau, Irene von ; Greinix, Hildegard ; Wolff, Daniel ; Peters, Christina
Background
The psychometric properties of an instrument, the Activity Scale for Kids-performance (ASKp), were assessed which was proposed to capture physical functioning after allogeneic hematopoietic stem cell transplantation (HSCT). Additionally, this multicenter observational prospective study investigated the influence of clinical correlates focusing on chronic graft-versus-host disease (cGVHD).
Methods
Patient-reported ASKp, clinician-reported Karnofsky/Lansky status (KPS/PSS), patient characteristics and cGVHD details were assessed of 55 patients with a median age of 12 years at baseline after day +100 post-HSCT and every 3 months during the next 18 months. The psychometric properties were evaluated and ASKp and KPS/PSS status was compared using ANOVAS and multiple regression models.
Results
The German version of the ASKp showed good psychometric properties except for ceiling effects. Discrimination ability of the ASKp was good regarding the need for devices but failed to predict cGVHD patients. Both the ASKp and the KPS/PSS were associated with patients after adoptive cell therapy being in need for devices, suffering from overlap cGVHD and from steroid side effects but not with patients’ age and gender. In contrast to the KPS/PSS the ASKp only showed significant differences after merging moderate and severe cGHVD patients when comparing them to No-cGVHD (F = 4.050; p = 0.049), being outperformed by the KPS/PSS (F = 20.082; p < 0.001).
Conclusion
The ASKp showed no clear advantages compared to KPS/PSS even though economical and patients’ effort was higher. Further application range may be limited through ceiling effects. Both should be taken into consideration. Therefore, the results may not support the usage of ASKp after HSCT and rather suggest KPS/PSS, both patient and clinician reported.
Dorji, Yonten ; Schuldt, Bernhard ; Neudam, Liane ; Dorji, Rinzin ; Middleby, Kali ; Isasa, Emilie ; Körber, Klaus ; Ammer, Christian ; Annighöfer, Peter ; Seidel, Dominik
Key message
Mobile laser scanning and geometrical analysis revealed relationships between tree geometry and seed dispersal mechanism, latitude of origin, as well as growth.
Abstract
The structure and dynamics of a forest are defined by the architecture and growth patterns of its individual trees. In turn, tree architecture and growth result from the interplay between the genetic building plans and environmental factors. We set out to investigate whether (1) latitudinal adaptations of the crown shape occur due to characteristic solar elevation angles at a species’ origin, (2) architectural differences in trees are related to seed dispersal strategies, and (3) tree architecture relates to tree growth performance. We used mobile laser scanning (MLS) to scan 473 trees and generated three-dimensional data of each tree. Tree architectural complexity was then characterized by fractal analysis using the box-dimension approach along with a topological measure of the top heaviness of a tree. The tree species studied originated from various latitudinal ranges, but were grown in the same environmental settings in the arboretum. We found that trees originating from higher latitudes had significantly less top-heavy geometries than those from lower latitudes. Therefore, to a certain degree, the crown shape of tree species seems to be determined by their original habitat. We also found that tree species with wind-dispersed seeds had a higher structural complexity than those with animal-dispersed seeds (p < 0.001). Furthermore, tree architectural complexity was positively related to the growth performance of the trees (p < 0.001). We conclude that the use of 3D data from MLS in combination with geometrical analysis, including fractal analysis, is a promising tool to investigate tree architecture.
Ghirardo, Andrea ; Nosenko, Tetyana ; Kreuzwieser, Jürgen ; Winkler, J. Barbro ; Kruse, Jörg ; Albert, Andreas ; Merl-Pham, Juliane ; Lux, Thomas ; Ache, Peter ; Zimmer, Ina ; Alfarraj, Saleh ; Mayer, Klaus F. X. ; Hedrich, Rainer ; Rennenberg, Heinz ; Schnitzler, Jörg-Peter
Climate change is increasing the frequency and intensity of warming and drought periods around the globe, currently representing a threat to many plant species. Understanding the resistance and resilience of plants to climate change is, therefore, urgently needed. As date palm (Phoenix dactylifera) evolved adaptation mechanisms to a xeric environment and can tolerate large diurnal and seasonal temperature fluctuations, we studied the protein expression changes in leaves, volatile organic compound emissions, and photosynthesis in response to variable growth temperatures and soil water deprivation. Plants were grown under controlled environmental conditions of simulated Saudi Arabian summer and winter climates challenged with drought stress. We show that date palm is able to counteract the harsh conditions of the Arabian Peninsula by adjusting the abundances of proteins related to the photosynthetic machinery, abiotic stress and secondary metabolism. Under summer climate and water deprivation, these adjustments included efficient protein expression response mediated by heat shock proteins and the antioxidant system to counteract reactive oxygen species formation. Proteins related to secondary metabolism were downregulated, except for the P. dactylifera isoprene synthase (PdIspS), which was strongly upregulated in response to summer climate and drought. This study reports, for the first time, the identification and functional characterization of the gene encoding for PdIspS, allowing future analysis of isoprene functions in date palm under extreme environments. Overall, the current study shows that reprogramming of the leaf protein profiles confers the date palm heat- and drought tolerance. We conclude that the protein plasticity of date palm is an important mechanism of molecular adaptation to environmental fluctuations.
Purpose
Diaschisis of cerebrocerebellar loops contributes to cognitive and motor deficits in pediatric cerebellar brain tumor survivors. We used a cerebellar white matter atlas and hypothesized that lesion symptom mapping may reveal the critical lesions of cerebellar tracts.
Methods
We examined 31 long-term survivors of pediatric posterior fossa tumors (13 pilocytic astrocytoma, 18 medulloblastoma). Patients underwent neuronal imaging, examination for ataxia, fine motor and cognitive function, planning abilities, and executive function. Individual consolidated cerebellar lesions were drawn manually onto patients’ individual MRI and normalized into Montreal Neurologic Institute (MNI) space for further analysis with voxel-based lesion symptom mapping.
Results
Lesion symptom mapping linked deficits of motor function to the superior cerebellar peduncle (SCP), deep cerebellar nuclei (interposed nucleus (IN), fastigial nucleus (FN), ventromedial dentate nucleus (DN)), and inferior vermis (VIIIa, VIIIb, IX, X). Statistical maps of deficits of intelligence and executive function mapped with minor variations to the same cerebellar structures.
Conclusion
We identified lesions to the SCP next to deep cerebellar nuclei as critical for limiting both motor and cognitive function in pediatric cerebellar tumor survivors. Future strategies safeguarding motor and cognitive function will have to identify patients preoperatively at risk for damage to these critical structures and adapt multimodal therapeutic options accordingly.
Brenzinger, Kristof ; Costa, Ohana Y. A. ; Ho, Adrian ; Koorneef, Guusje ; Robroek, Bjorn ; Molenaar, Douwe ; Korthals, Gerard ; Bodelier, Paul L. E.
We steered the soil microbiome via applications of organic residues (mix of cover crop residues, sewage sludge + compost, and digestate + compost) to enhance multiple ecosystem services in line with climate-smart agriculture. Our result highlights the potential to reduce greenhouse gases (GHG) emissions from agricultural soils by the application of specific organic amendments (especially digestate + compost). Unexpectedly, also the addition of mineral fertilizer in our mesocosms led to similar combined GHG emissions than one of the specific organic amendments. However, the application of organic amendments has the potential to increase soil C, which is not the case when using mineral fertilizer. While GHG emissions from cover crop residues were significantly higher compared to mineral fertilizer and the other organic amendments, crop growth was promoted. Furthermore, all organic amendments induced a shift in the diversity and abundances of key microbial groups. We show that organic amendments have the potential to not only lower GHG emissions by modifying the microbial community abundance and composition, but also favour crop growth-promoting microorganisms. This modulation of the microbial community by organic amendments bears the potential to turn soils into more climate-smart soils in comparison to the more conventional use of mineral fertilizers.
D'Andrea, David ; Soria, Francesco ; Grotenhuis, Anne J. ; Cha, Eugene K. ; Malats, Nuria ; Di Stasi, Savino ; Joniau, Steven ; Cai, Tommaso ; Rhijn, Bas W. G. van ; Irani, Jaques ; Karnes, Jeffrey ; Varkarakis, John ; Baniel, Jack ; Palou, Joan ; Babjuk, Marek ; Spahn, Martin ; Ardelt, Peter ; Colombo, Renzo ; Serretta, Vincenzo ; Dalbagni, Guido ; Gontero, Paolo ; Bartoletti, Riccardo ; Larré, Stephane ; Malmstrom, Per-Uno ; Sylvester, Richard ; Shariat, Shahrokh F.
Purpose
To investigate the association of patients’ sex with recurrence and disease progression in patients treated with intravesical bacillus Calmette–Guérin (BCG) for T1G3/HG urinary bladder cancer (UBC).
Materials and methods
We analyzed the data of 2635 patients treated with adjuvant intravesical BCG for T1 UBC between 1984 and 2019. We accounted for missing data using multiple imputations and adjusted for covariate imbalance between males and females using inverse probability weighting (IPW). Crude and IPW-adjusted Cox regression analyses were used to estimate the hazard ratios (HR) with their 95% confidence intervals (CI) for the association of patients’ sex with HG-recurrence and disease progression.
Results
A total of 2170 (82%) males and 465 (18%) females were available for analysis. Overall, 1090 (50%) males and 244 (52%) females experienced recurrence, and 391 (18%) males and 104 (22%) females experienced disease progression. On IPW-adjusted Cox regression analyses, female sex was associated with disease progression (HR 1.25, 95%CI 1.01–1.56, p = 0.04) but not with recurrence (HR 1.06, 95%CI 0.92–1.22, p = 0.41). A total of 1056 patients were treated with adequate BCG. In these patients, on IPW-adjusted Cox regression analyses, patients’ sex was not associated with recurrence (HR 0.99, 95%CI 0.80–1.24, p = 0.96), HG-recurrence (HR 1.00, 95%CI 0.78–1.29, p = 0.99) or disease progression (HR 1.12, 95%CI 0.78–1.60, p = 0.55).
Conclusion
Our analysis generates the hypothesis of a differential response to BCG between males and females if not adequately treated. Further studies should focus on sex-based differences in innate and adaptive immune system and their association with BCG response.
Linz, Christian ; Brands, Roman C. ; Kertels, Olivia ; Dierks, Alexander ; Brumberg, Joachim ; Gerhard-Hartmann, Elena ; Hartmann, Stefan ; Schirbel, Andreas ; Serfling, Sebastian ; Zhi, Yingjun ; Buck, Andreas K. ; Kübler, Alexander ; Hohm, Julian ; Lapa, Constantin ; Kircher, Malte
Purpose
While [\(^{18}\)F]-fluorodeoxyglucose ([\(^{18}\)F]FDG) is the standard for positron emission tomography/computed tomography (PET/CT) imaging of oral squamous cell carcinoma (OSCC), diagnostic specificity is hampered by uptake in inflammatory cells such as neutrophils or macrophages. Recently, molecular imaging probes targeting fibroblast activation protein α (FAP), which is overexpressed in a variety of cancer-associated fibroblasts, have become available and might constitute a feasible alternative to FDG PET/CT.
Methods
Ten consecutive, treatment-naïve patients (8 males, 2 females; mean age, 62 ± 9 years) with biopsy-proven OSCC underwent both whole-body [\(^{18}\)F]FDG and [\(^{68}\)Ga]FAPI-04 (FAP-directed) PET/CT for primary staging prior to tumor resection and cervical lymph node dissection. Detection of the primary tumor, as well as the presence and number of lymph node and distant metastases was analysed. Intensity of tracer accumulation was assessed by means of maximum (SUV\(_{max}\)) and peak (SUV\(_{peak}\) standardized uptake values. Histological work-up including immunohistochemical staining for FAP served as standard of reference.
Results
[\(^{18}\)F]FDG and FAP-directed PET/CT detected all primary tumors with a SUVmax of 25.5 ± 13.2 (FDG) and 20.5 ± 6.4 (FAP-directed) and a SUVpeak of 16.1 ± 10.3 ([\(^{18}\)F]FDG) and 13.8 ± 3.9 (FAP-directed), respectively. Regarding cervical lymph node metastases, FAP-directed PET/CT demonstrated comparable sensitivity (81.3% vs. 87.5%; P = 0.32) and specificity (93.3% vs. 81.3%; P = 0.16) to [\(^{18}\)F]FDG PET/CT. FAP expression on the cell surface of cancer-associated fibroblasts in both primary lesions as well as lymph nodes metastases was confirmed in all samples.
Conclusion
FAP-directed PET/CT in OSCC seems feasible. Future research to investigate its potential to improve patient staging is highly warranted.
Giesel, Frederik L. ; Kratochwil, Clemens ; Schlittenhardt, Joel ; Dendl, Katharina ; Eiber, Matthias ; Staudinger, Fabian ; Kessler, Lukas ; Fendler, Wolfgang P. ; Lindner, Thomas ; Koerber, Stefan A. ; Cardinale, Jens ; Sennung, David ; Roehrich, Manuel ; Debus, Juergen ; Sathekge, Mike ; Haberkorn, Uwe ; Calais, Jeremie ; Serfling, Sebastian ; Buck, Andreas L.
Purpose
FAPI ligands (fibroblast activation protein inhibitor), a novel class of radiotracers for PET/CT imaging, demonstrated in previous studies rapid and high tumor uptake. The purpose of this study is the head-to-head intra-individual comparison of \(^{68}\)Ga-FAPI versus standard-of-care \(^{18}\)F-FDG in PET/CT in organ biodistribution and tumor uptake in patients with various cancers.
Material and Methods
This international retrospective multicenter analysis included PET/CT data from 71 patients from 6 centers who underwent both \(^{68}\)Ga-FAPI and \(^{18}\)F-FDG PET/CT within a median time interval of 10 days (range 1–89 days). Volumes of interest (VOIs) were manually drawn in normal organs and tumor lesions to quantify tracer uptake by SUVmax and SUVmean. Furthermore, tumor-to-background ratios (TBR) were generated (SUVmax tumor/ SUVmax organ).
Results
A total of 71 patients were studied of, which 28 were female and 43 male (median age 60). In 41 of 71 patients, the primary tumor was present. Forty-three of 71 patients exhibited 162 metastatic lesions. \(^{68}\)Ga-FAPI uptake in primary tumors and metastases was comparable to 18F-FDG in most cases. The SUVmax was significantly lower for \(^{68}\)Ga-FAPI than \(^{18}\)F-FDG in background tissues such as the brain, oral mucosa, myocardium, blood pool, liver, pancreas, and colon. Thus, \(^{68}\)Ga-FAPI TBRs were significantly higher than 18F-FDG TBRs in some sites, including liver and bone metastases.
Conclusion
Quantitative tumor uptake is comparable between \(^{68}\)Ga-FAPI and \(^{18}\)F-FDG, but lower background uptake in most normal organs results in equal or higher TBRs for \(^{68}\)Ga-FAPI. Thus, \(^{68}\)Ga-FAPI PET/CT may yield improved diagnostic information in various cancers and especially in tumor locations with high physiological \(^{18}\)F-FDG uptake.
Pennig, Lenhard ; Hoyer, Ulrike Cornelia Isabel ; Krauskopf, Alexandra ; Shahzad, Rahil ; Jünger, Stephanie T. ; Thiele, Frank ; Laukamp, Kai Roman ; Grunz, Jan-Peter ; Perkuhn, Michael ; Schlamann, Marc ; Kabbasch, Christoph ; Borggrefe, Jan ; Goertz, Lukas
Purpose
To evaluate whether a deep learning model (DLM) could increase the detection sensitivity of radiologists for intracranial aneurysms on CT angiography (CTA) in aneurysmal subarachnoid hemorrhage (aSAH).
Methods
Three different DLMs were trained on CTA datasets of 68 aSAH patients with 79 aneurysms with their outputs being combined applying ensemble learning (DLM-Ens). The DLM-Ens was evaluated on an independent test set of 104 aSAH patients with 126 aneuryms (mean volume 129.2 ± 185.4 mm3, 13.0% at the posterior circulation), which were determined by two radiologists and one neurosurgeon in consensus using CTA and digital subtraction angiography scans. CTA scans of the test set were then presented to three blinded radiologists (reader 1: 13, reader 2: 4, and reader 3: 3 years of experience in diagnostic neuroradiology), who assessed them individually for aneurysms. Detection sensitivities for aneurysms of the readers with and without the assistance of the DLM were compared.
Results
In the test set, the detection sensitivity of the DLM-Ens (85.7%) was comparable to the radiologists (reader 1: 91.2%, reader 2: 86.5%, and reader 3: 86.5%; Fleiss κ of 0.502). DLM-assistance significantly increased the detection sensitivity (reader 1: 97.6%, reader 2: 97.6%,and reader 3: 96.0%; overall P=.024; Fleiss κ of 0.878), especially for secondary aneurysms (88.2% of the additional aneurysms provided by the DLM).
Conclusion
Deep learning significantly improved the detection sensitivity of radiologists for aneurysms in aSAH, especially for secondary aneurysms. It therefore represents a valuable adjunct for physicians to establish an accurate diagnosis in order to optimize patient treatment.
Fekete, Stefanie ; Egberts, K. ; Preissler, T. ; Wewetzer, C. ; Mehler-Wex, C. ; Romanos, M. ; Gerlach, M.
Purpose
Tiapride is commonly used in Europe for the treatment of tics. The aim of this study was to examine the relationship between dose and serum concentrations of tiapride and potential influential pharmacokinetic factors in children and adolescents. In addition, a preliminary therapeutic reference range for children and adolescents with tics treated with tiapride was calculated.
Methods
Children and adolescents treated with tiapride at three university hospitals and two departments of child and adolescents psychiatry in Germany and Austria were included in the study. Patient characteristics, doses, serum concentrations, and therapeutic outcome were assessed during clinical routine care using standardised measures.
Results
In the 49 paediatric patients (83.7% male, mean age = 12.5 years), a positive correlation was found between tiapride dose (median 6.9 mg/kg, range 0.97–19.35) and serum concentration with marked inter-individual variability. The variation in dose explained 57% of the inter-patient variability in tiapride serum concentrations; age, gender, and concomitant medication did not contribute to the variability. The symptoms improved in 83.3% of the patients. 27.1% of the patients had mild or moderate ADRs. No patient suffered from severe ADRs.
Conclusions
This study shows that tiapride treatment was effective and safe in most patients with tics. Compared with the therapeutic concentration range established for adults with Chorea Huntington, our data hinted at a lower lower limit (560 ng/ml) and similar upper limit (2000 ng/ml).
Barile, Frank A. ; Berry, Colin ; Blaauboer, Bas ; Boobis, Alan ; Bolt, Herrmann M. ; Borgert, Christopher ; Dekant, Wolfgang ; Dietrich, Daniel ; Domingo, Jose L. ; Galli, Corrado L. ; Gori, Gio Batta ; Greim, Helmut ; Hengstler, Jan G. ; Heslop-Harrison, Pat ; Kacew, Sam ; Marquardt, Hans ; Mally, Angela ; Pelkonen, Olavi ; Savolainen, Kai ; Testai, Emanuela ; Tsatsakis, Aristides ; Vermeulen, Nico P.
The EU chemicals strategy for sustainability (CSS) asserts that both human health and the environment are presently threatened and that further regulation is necessary. In a recent Guest Editorial, members of the German competent authority for risk assessment, the BfR, raised concerns about the scientific justification for this strategy. The complexity and interdependence of the networks of regulation of chemical substances have ensured that public health and wellbeing in the EU have continuously improved. A continuous process of improvement in consumer protection is clearly desirable but any initiative directed towards this objective must be based on scientific knowledge. It must not confound risk with other factors in determining policy. This conclusion is fully supported in the present Commentary including the request to improve both, data collection and the time-consuming and bureaucratic procedures that delay the publication of regulations.
Guth, Sabine ; Hüser, Stephanie ; Roth, Angelika ; Degen, Gisela ; Diel, Patrick ; Edlund, Karolina ; Eisenbrand, Gerhard ; Engel, Karl-Heinz ; Epe, Bernd ; Grune, Tilman ; Heinz, Volker ; Henle, Thomas ; Humpf, Hans-Ulrich ; Jäger, Henry ; Joost, Hans-Georg ; Kulling, Sabine E. ; Lampen, Alfonso ; Mally, Angela ; Marchan, Rosemarie ; Marko, Doris ; Mühle, Eva ; Nitsche, Michael A. ; Röhrdanz, Elke ; Stadler, Richard ; van Thriel, Christoph ; Vieths, Stefan ; Vogel, Rudi F. ; Wascher, Edmund ; Watzl, Carsten ; Nöthlings, Ute ; Hengstler, Jan G.
Since the addition of fluoride to drinking water in the 1940s, there have been frequent and sometimes heated discussions regarding its benefits and risks. In a recently published review, we addressed the question if current exposure levels in Europe represent a risk to human health. This review was discussed in an editorial asking why we did not calculate benchmark doses (BMD) of fluoride neurotoxicity for humans. Here, we address the question, why it is problematic to calculate BMDs based on the currently available data. Briefly, the conclusions of the available studies are not homogeneous, reporting negative as well as positive results; moreover, the positive studies lack control of confounding factors such as the influence of well-known neurotoxicants. We also discuss the limitations of several further epidemiological studies that did not meet the inclusion criteria of our review. Finally, it is important to not only focus on epidemiological studies. Rather, risk analysis should consider all available data, including epidemiological, animal, as well as in vitro studies. Despite remaining uncertainties, the totality of evidence does not support the notion that fluoride should be considered a human developmental neurotoxicant at current exposure levels in European countries.
Healthy functioning of the female reproductive tract (FRT) depends on balanced and dynamic regulation by hormones during the menstrual cycle, pregnancy and childbirth. The mucosal epithelial lining of different regions of the FRT—ovaries, fallopian tubes, uterus, cervix and vagina—facilitates the selective transport of gametes and successful transfer of the zygote to the uterus where it implants and pregnancy takes place. It also prevents pathogen entry. Recent developments in three-dimensional (3D) organoid systems from the FRT now provide crucial experimental models that recapitulate the cellular heterogeneity and physiological, anatomical and functional properties of the organ in vitro. In this review, we summarise the state of the art on organoids generated from different regions of the FRT. We discuss the potential applications of these powerful in vitro models to study normal physiology, fertility, infections, diseases, drug discovery and personalised medicine.
Pinkawa, Michael ; Aebersold, Daniel M. ; Böhmer, Dirk ; Flentje, Michael ; Ghadjar, Pirus ; Schmidt-Hegemann, Nina-Sophie ; Höcht, Stefan ; Hölscher, Tobias ; Müller, Arndt-Christian ; Niehoff, Peter ; Sedlmayer, Felix ; Wolf, Frank ; Zamboglou, Constantinos ; Zips, Daniel ; Wiegel, Thomas
Objective
The current article encompasses a literature review and recommendations for radiotherapy in nodal oligorecurrent prostate cancer.
Materials and methods
A literature review focused on studies comparing metastasis-directed stereotactic ablative radiotherapy (SABR) vs. external elective nodal radiotherapy (ENRT) and studies analyzing recurrence patterns after local nodal treatment was performed. The DEGRO Prostate Cancer Expert Panel discussed the results and developed treatment recommendations.
Results
Metastasis-directed radiotherapy results in high local control (often > 90% within a follow-up of 1–2 years) and can be used to improve progression-free survival or defer androgen deprivation therapy (ADT) according to prospective randomized phase II data. Distant progression after involved-node SABR only occurs within a few months in the majority of patients. ENRT improves metastases-free survival rates with increased toxicity in comparison to SABR according to retrospective comparative studies. The majority of nodal recurrences after initial local treatment of pelvic nodal metastasis are detected within the true pelvis and common iliac vessels.
Conclusion
ENRT with or without a boost should be preferred to SABR in pelvic nodal recurrences. In oligometastatic prostate cancer with distant (extrapelvic) nodal recurrences, SABR alone can be performed in selected cases. Application of additional systemic treatments should be based on current guidelines, with ADT as first-line treatment for hormone-sensitive prostate cancer. Only in carefully selected patients can radiotherapy be initially used without additional ADT outside of the current standard recommendations. Results of (randomized) prospective studies are needed for definitive recommendations.
Moris, Victoria C. ; Christmann, Katharina ; Wirtgen, Aline ; Belokobylskij, Sergey A. ; Berg, Alexander ; Liebig, Wolf-Harald ; Soon, Villu ; Baur, Hannes ; Schmitt, Thomas ; Niehuis, Oliver
The mason wasp Odynerus spinipes shows an exceptional case of intrasexual cuticular hydrocarbon (CHC) profile dimorphism. Females of this species display one of two CHC profiles (chemotypes) that differ qualitatively and quantitatively from each other. The ratio of the two chemotypes was previously shown to be close to 1:1 at three sites in Southern Germany, which might not be representative given the Palearctic distribution of the species. To infer the frequency of the two chemotypes across the entire distributional range of the species, we analyzed with GC–MS the CHC profile of 1042 dry-mounted specimens stored in private and museum collections. We complemented our sampling by including 324 samples collected and preserved specifically for studying their CHCs. We were capable of reliably identifying the chemotypes in 91% of dry-mounted samples, some of which collected almost 200 years ago. We found both chemotypes to occur in the Far East, the presumed glacial refuge of the species, and their frequency to differ considerably between sites and geographic regions. The geographic structure in the chemotype frequencies could be the result of differential selection regimes and/or different dispersal routes during the colonization of the Western Palearctic. The presented data pave the route for disentangling these factors by providing information where to geographically sample O. spinipes for population genetic analyses. They also form the much-needed basis for future studies aiming to understand the evolutionary and geographic origin as well as the genetics of the astounding CHC profile dimorphism that O. spinipes females exhibit.
Baur, Johannes ; Ramser, Michaela ; Keller, Nicola ; Muysoms, Filip ; Dörfer, Jörg ; Wiegering, Armin ; Eisner, Lukas ; Dietz, Ulrich A.
Endoscopic management of umbilical and incisional hernias has adapted to the limitations of conventional laparoscopic instruments over the past 30 years. This includes the development of meshes for intraperitoneal placement (intraperitoneal onlay mesh, IPOM), with antiadhesive coatings; however, adhesions do occur in a significant proportion of these patients. Minimally invasive procedures result in fewer perioperative complications, but with a slightly higher recurrence rate. With the ergonomic resources of robotics, which offers angled instruments, it is now possible to implant meshes in a minimally invasively manner in different abdominal wall layers while achieving morphologic and functional reconstruction of the abdominal wall. This video article presents the treatment of ventral and incisional hernias with mesh implantation into the preperitoneal space (robot-assisted transabdominal preperitoneal ventral hernia repair, r‑ventral TAPP) as well as into the retrorectus space (r-Rives and robotic transabdominal retromuscular umbilical prosthetic repair, r‑TARUP, respectively). The results of a cohort study of 118 consecutive patients are presented and discussed with regard to the added value of the robotic technique in extraperitoneal mesh implantation and in the training of residents.
Ramser, Michaela ; Baur, Johannes ; Keller, Nicola ; Kukleta, Jan F. ; Dörfer, Jörg ; Wiegering, Armin ; Eisner, Lukas ; Dietz, Ulrich A.
The treatment of inguinal hernias with open and minimally invasive procedures has reached a high standard in terms of outcome over the past 30 years. However, there is still need for further improvement, mainly in terms of reduction of postoperative seroma, chronic pain, and recurrence. This video article presents the endoscopic anatomy of the groin with regard to robotic transabdominal preperitoneal patch plasty (r‑TAPP) and illustrates the surgical steps of r‑TAPP with respective video sequences. The results of a cohort study of 302 consecutive hernias operated by r‑TAPP are presented and discussed in light of the added value of the robotic technique, including advantages for surgical training. r‑TAPP is the natural evolution of conventional TAPP and has the potential to become a new standard as equipment availability increases and material costs decrease. Future studies will also have to refine the multifaceted added value of r‑TAPP with new parameters.
Dietz, Ulrich A. ; Kudsi, O. Yusef ; Garcia-Ureña, Miguel ; Baur, Johannes ; Ramser, Michaela ; Maksimovic, Sladjana ; Keller, Nicola ; Dörfer, Jörg ; Eisner, Lukas ; Wiegering, Armin
The principle of targeted separation or weakening of individual components of the abdominal wall to relieve tension in the median line during major abdominal reconstruction has been known for over 30 years as anterior component separation (aCS) and is an established procedure. In search of alternatives with lower complication rates, posterior component separation (pCS) was developed; transversus abdominis release (TAR) is a nerve-sparing modification of pCS. With the ergonomic resources of robotics (e.g., angled instruments), TAR can be performed in a minimally invasive manner (r-TAR): hernia gaps of up to 14 cm can be closed and a large extraperitoneal mesh implanted. In this video article, the treatment of large incisional hernias using the r‑TAR technique is presented. Exemplary results of a cohort study in 13 consecutive patients are presented. The procedure is challenging, but our own results—as well as reports from the literature—are encouraging. The r‑TAR is becoming the pinnacle procedure for abdominal wall reconstruction.
Wie kann pädagogische Integrationsförderung von Heranwachsenden mit Fluchterfahrung gelingen? Ziel des Buches ist es, auf Basis einer quantitativen und qualitativen Längsschnittstudie Gelingensbedingungen pädagogischer Integrationsförderung im Kontext außerschulischer Bildungsangebote zu identifizieren. Eine integrationsfördernde Wirkung wird für einzelne Gelingensbedingungen nachgewiesen und eine erste Typologie institutioneller Handlungslogiken aufgestellt.
Bislang sind nur wenige Studien zu verzeichnen, die sich mit dem integrationsfördernden Potenzial außerschulischer Bildungsangebote für Heranwachsende mit Fluchterfahrung auseinandersetzen. An diesem Punkt setzt die vorliegende Studie an und erörtert den Effekt von Gelingensbedingungen für eine pädagogische Integrationsförderung auf Grundlage einer quantitativen sowie qualitativen Längsschnittstudie. Eine Identifikation dieser integrationsfördernden Gelingensbedingungen erfolgt auf den Ebenen des Individuums, der Interaktion sowie der Institution.
Während für koloniale Straßennamen im heutigen deutschsprachigen Raum ein reges Interesse zu verzeichnen ist, das vorrangig an Diskussionen einer etwaigen Notwendigkeit ihrer Umbenennung in einzelnen Städten anknüpft, sind die sprachhistorischen Benennungen in ortsübergreifender Perspektive in Bezug auf Kolonialismus und koloniale Themen unerforscht.
Die Arbeit geht den linguistischen Praktiken solcher toponymischer Namenvergabeprozesse vom Beginn der faktischen Kolonialzeit bis zur Endphase der nationalsozialistischen Herrschaft nach. Sie erhebt und analysiert strukturbezogen-funktionale Muster sowie diskursive Argumentationszusammenhänge hinsichtlich der damit versprachlichten kolonisatorischen Gewissheiten.
Der umfangreiche Datenbestand (über 500 Straßennamen), deren koloniale Benennungsmotivik anhand zahlreicher Quellen und Quellengattungen bis 1945 nachgewiesen werden kann, zeigt, dass die Bedeutung kolonialtoponomastischer Raumaneignung bzw. -besetzung in erheblichem Ausmaß auch auf das Deutsche Reich zurückwirkte. In der Verbindung innovativer Onomastik und Diskurslinguistik werden die globalen Verflechtungsgeschichten erstmalig anhand der Benennung des öffentlichen Raumes in der deutschen Metropole umfassend erfasst und erläutert.
Heidenreich, Julius F. ; Gassenmaier, Tobias ; Ankenbrand, Markus J. ; Bley, Thorsten A. ; Wech, Tobias
Purpose
To fully automatically derive quantitative parameters from late gadolinium enhancement (LGE) cardiac MR (CMR) in patients with myocardial infarction and to investigate if phase sensitive or magnitude reconstructions or a combination of both results in best segmentation accuracy.
Methods
In this retrospective single center study, a convolutional neural network with a U-Net architecture with a self-configuring framework (“nnU-net”) was trained for segmentation of left ventricular myocardium and infarct zone in LGE-CMR. A database of 170 examinations from 78 patients with history of myocardial infarction was assembled. Separate fitting of the model was performed, using phase sensitive inversion recovery, the magnitude reconstruction or both contrasts as input channels.
Manual labelling served as ground truth. In a subset of 10 patients, the performance of the trained models was evaluated and quantitatively compared by determination of the Sørensen-Dice similarity coefficient (DSC) and volumes of the infarct zone compared with the manual ground truth using Pearson’s r correlation and Bland-Altman analysis.
Results
The model achieved high similarity coefficients for myocardium and scar tissue. No significant difference was observed between using PSIR, magnitude reconstruction or both contrasts as input (PSIR and MAG; mean DSC: 0.83 ± 0.03 for myocardium and 0.72 ± 0.08 for scars). A strong correlation for volumes of infarct zone was observed between manual and model-based approach (r = 0.96), with a significant underestimation of the volumes obtained from the neural network.
Conclusion
The self-configuring nnU-net achieves predictions with strong agreement compared to manual segmentation, proving the potential as a promising tool to provide fully automatic quantitative evaluation of LGE-CMR.
Introducción
(2021)
El presente volumen se caracteriza por dos pilares temáticos. En la primera parte, reúne contribuciones sobre cuestiones generales del derecho colombiano administrativo y de responsabilidad del Estado, en lo cual también se adopta una perspectiva de derecho comparado con el ordenamiento jurídico alemán. La segunda parte está dedicada a las diferentes facetas del debate sobre la sostenibilidad y su marco normativo en la legislación colombiana y ecuatoriana
Einführung
(2021)
Der vorliegende Band zeichnet sich durch zwei thematische Säulen aus. Im ersten Teil versammelt er Beiträge zu allgemeinen Fragen des kolumbianischen Verwaltungsund Staatshaftungsrechts, wobei auch die rechtsvergleichende Perspektive mit der deutschen Rechtsordnung eingenommen wird. Der zweite Teil widmet sich sodann unterschiedlichen Facetten der Nachhaltigkeitsdebatte und ihres normativen Rahmens im Recht Kolumbiens und Ecuadors.
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Navarro, Stefano ; Stegner, David ; Nieswandt, Bernhard ; Heemskerk, Johan W. M. ; Kuijpers, Marijke J. E.
In hemostasis and thrombosis, the complex process of thrombus formation involves different molecular pathways of platelet and coagulation activation. These pathways are considered as operating together at the same time, but this has not been investigated. The objective of our study was to elucidate the time-dependency of key pathways of thrombus and clot formation, initiated by collagen and tissue factor surfaces, where coagulation is triggered via the extrinsic route. Therefore, we adapted a microfluidics whole-blood assay with the Maastricht flow chamber to acutely block molecular pathways by pharmacological intervention at desired time points. Application of the technique revealed crucial roles of glycoprotein VI (GPVI)-induced platelet signaling via Syk kinase as well as factor VIIa-induced thrombin generation, which were confined to the first minutes of thrombus buildup. A novel anti-GPVI Fab EMF-1 was used for this purpose. In addition, platelet activation with the protease-activating receptors 1/4 (PAR1/4) and integrin αIIbβ3 appeared to be prolongedly active and extended to later stages of thrombus and clot formation. This work thereby revealed a more persistent contribution of thrombin receptor-induced platelet activation than of collagen receptor-induced platelet activation to the thrombotic process.
Prerequisite to any biological laboratory assay employing living animals is consideration about its necessity, feasibility, ethics and the potential harm caused during an experiment. The imperative of these thoughts has led to the formulation of the 3R-principle, which today is a pivotal scientific standard of animal experimentation worldwide. The rising amount of laboratory investigations utilizing living animals throughout the last decades, either for regulatory concerns or for basic science, demands the development of alternative methods in accordance with 3R to help reduce experiments in mammals. This demand has resulted in investigation of additional vertebrate species displaying favourable biological properties. One prominent species among these is the zebrafish (Danio rerio), as these small laboratory ray-finned fish are well established in science today and feature outstanding biological characteristics. In this review, we highlight the advantages and general prerequisites of zebrafish embryos and larvae before free-feeding stages for toxicological testing, with a particular focus on cardio-, neuro, hepato- and nephrotoxicity. Furthermore, we discuss toxicokinetics, current advances in utilizing zebrafish for organ toxicity testing and highlight how advanced laboratory methods (such as automation, advanced imaging and genetic techniques) can refine future toxicological studies in this species.
Ramírez-Rodríguez, Gloria Belén ; Pereira, Ana Rita ; Herrmann, Marietta ; Hansmann, Jan ; Delgado-López, José Manuel ; Sprio, Simone ; Tampieri, Anna ; Sandri, Monica
In bone tissue engineering, the design of 3D systems capable of recreating composition, architecture and micromechanical environment of the native extracellular matrix (ECM) is still a challenge. While perfusion bioreactors have been proposed as potential tool to apply biomechanical stimuli, its use has been limited to a low number of biomaterials. In this work, we propose the culture of human mesenchymal stem cells (hMSC) in biomimetic mineralized recombinant collagen scaffolds with a perfusion bioreactor to simultaneously provide biochemical and biophysical cues guiding stem cell fate. The scaffolds were fabricated by mineralization of recombinant collagen in the presence of magnesium (RCP.MgAp). The organic matrix was homogeneously mineralized with apatite nanocrystals, similar in composition to those found in bone. X-Ray microtomography images revealed isotropic porous structure with optimum porosity for cell ingrowth. In fact, an optimal cell repopulation through the entire scaffolds was obtained after 1 day of dynamic seeding in the bioreactor. Remarkably, RCP.MgAp scaffolds exhibited higher cell viability and a clear trend of up-regulation of osteogenic genes than control (non-mineralized) scaffolds. Results demonstrate the potential of the combination of biomimetic mineralization of recombinant collagen in presence of magnesium and dynamic culture of hMSC as a promising strategy to closely mimic bone ECM.
Schlecht, Anja ; Thien, Adrian ; Wolf, Julian ; Prinz, Gabriele ; Agostini, Hansjürgen ; Schlunck, Günther ; Wieghofer, Peter ; Boneva, Stefaniya ; Lange, Clemens
Immunosenescence is considered a possible factor in the development of age-related macular degeneration and choroidal neovascularization (CNV). However, age-related changes of myeloid cells (MCs), such as microglia and macrophages, in the healthy retina or during CNV formation are ill-defined. In this study, Cx3cr1-positive MCs were isolated by fluorescence-activated cell sorting from six-week (young) and two-year-old (old) Cx3cr1\(^{GFP/+}\) mice, both during physiological aging and laser-induced CNV development. High-throughput RNA-sequencing was performed to define the age-dependent transcriptional differences in MCs during physiological aging and CNV development, complemented by immunohistochemical characterization and the quantification of MCs, as well as CNV size measurements. These analyses revealed that myeloid cells change their transcriptional profile during both aging and CNV development. In the steady state, senescent MCs demonstrated an upregulation of factors contributing to cell proliferation and chemotaxis, such as Cxcl13 and Cxcl14, as well as the downregulation of microglial signature genes. During CNV formation, aged myeloid cells revealed a significant upregulation of angiogenic factors such as Arg1 and Lrg1 concomitant with significantly enlarged CNV and an increased accumulation of MCs in aged mice in comparison to young mice. Future studies need to clarify whether this observation is an epiphenomenon or a causal relationship to determine the role of immunosenescence in CNV formation.
Sedaghat-Hamedani, Farbod ; Rebs, Sabine ; El-Battrawy, Ibrahim ; Chasan, Safak ; Krause, Tobias ; Haas, Jan ; Zhong, Rujia ; Liao, Zhenxing ; Xu, Qiang ; Zhou, Xiaobo ; Akin, Ibrahim ; Zitron, Edgar ; Frey, Norbert ; Streckfuss-Bömeke, Katrin ; Kayvanpour, Elham
Introduction: Familial dilated cardiomyopathy (DCM) is clinically variable and has been associated with mutations in more than 50 genes. Rapid improvements in DNA sequencing have led to the identification of diverse rare variants with unknown significance (VUS), which underlines the importance of functional analyses. In this study, by investigating human-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs), we evaluated the pathogenicity of the p.C335R sodium voltage-gated channel alpha subunit 5 (SCN5a) variant in a large family with familial DCM and conduction disease. Methods: A four-generation family with autosomal dominant familial DCM was investigated. Next-generation sequencing (NGS) was performed in all 16 family members. Clinical deep phenotyping, including endomyocardial biopsy, was performed. Skin biopsies from two patients and one healthy family member were used to generate human-induced pluripotent stem cells (iPSCs), which were then differentiated into cardiomyocytes. Patch-clamp analysis with Xenopus oocytes and iPSC-CMs were performed. Results: A SCN5a variant (c.1003T>C; p.C335R) could be detected in all family members with DCM or conduction disease. A novel truncating TTN variant (p.Ser24998LysfsTer28) could also be identified in two family members with DCM. Family members with the SCN5a variant (p.C335R) showed significantly longer PQ and QRS intervals and lower left ventricular ejection fractions (LV-EF). All four patients who received CRT-D were non-responders. Electrophysiological analysis with Xenopus oocytes showed a loss of function in SCN5a p.C335R. Na\(^+\) channel currents were also reduced in iPSC-CMs from DCM patients. Furthermore, iPSC-CM with compound heterozygosity (SCN5a p.C335R and TTNtv) showed significant dysregulation of sarcomere structures, which may be contributed to the severity of the disease and earlier onset of DCM. Conclusion: The SCN5a p.C335R variant is causing a loss of function of peak INa in patients with DCM and cardiac conduction disease. The co-existence of genetic variants in channels and structural genes (e.g., SCN5a p.C335R and TTNtv) increases the severity of the DCM phenotype.
Gupta, Shishir K. ; Srivastava, Mugdha ; Minocha, Rashmi ; Akash, Aman ; Dangwal, Seema ; Dandekar, Thomas
A viral infection involves entry and replication of viral nucleic acid in a host organism, subsequently leading to biochemical and structural alterations in the host cell. In the case of SARS-CoV-2 viral infection, over-activation of the host immune system may lead to lung damage. Albeit the regeneration and fibrotic repair processes being the two protective host responses, prolonged injury may lead to excessive fibrosis, a pathological state that can result in lung collapse. In this review, we discuss regeneration and fibrosis processes in response to SARS-CoV-2 and provide our viewpoint on the triggering of alveolar regeneration in coronavirus disease 2019 (COVID-19) patients.
Advances in breast cancer management and extracellular vesicle research, a bibliometric analysis
(2021)
Teles, Ramon Handerson Gomes ; Yano, Rafael Sussumu ; Villarinho, Nicolas Jones ; Yamagata, Ana Sayuri ; Jaeger, Ruy Gastaldoni ; Meybohm, Patrick ; Burek, Malgorzata ; Freitas, Vanessa Morais
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.
Previous research on the melt electrowriting (MEW) of poly(vinylidene difluoride) (PVDF) resulted in electroactive fibers, however, printing more than five layers is challenging. Here, we investigate the influence of a heated collector to adjust the solidification rate of the PVDF jet so that it adheres sufficiently to each layer. A collector temperature of 110°C is required to improve fiber processing, resulting in a total of 20 fiber layers. For higher temperatures and higher layers, an interesting phenomenon occurred, where the intersection points of the fibers coalesced into periodic spheres of diameter 206 ± 52 μm (26G, 150°C collector temperature, 2000 mm/min, 10 layers in x- and y-direction).The heated collector is an important component of a MEW printer that allows polymers with a high melting point to be processable with increased layers.
Crowdsourced network measurements (CNMs) are becoming increasingly popular as they assess the performance of a mobile network from the end user's perspective on a large scale. Here, network measurements are performed directly on the end-users' devices, thus taking advantage of the real-world conditions end-users encounter. However, this type of uncontrolled measurement raises questions about its validity and reliability. The problem lies in the nature of this type of data collection. In CNMs, mobile network subscribers are involved to a large extent in the measurement process, and collect data themselves for the operator. The collection of data on user devices in arbitrary locations and at uncontrolled times requires means to ensure validity and reliability. To address this issue, our paper defines concepts and guidelines for analyzing the precision of CNMs; specifically, the number of measurements required to make valid statements. In addition to the formal definition of the aspect, we illustrate the problem and use an extensive sample data set to show possible assessment approaches. This data set consists of more than 20.4 million crowdsourced mobile measurements from across France, measured by a commercial data provider.
In this article, we explain and demonstrate how to model norm scores with the cNORM package in R. This package is designed specifically to determine norm scores when the latent ability to be measured covaries with age or other explanatory variables such as grade level. The mathematical method used in this package draws on polynomial regression to model a three-dimensional hyperplane that smoothly and continuously captures the relation between raw scores, norm scores and the explanatory variable. By doing so, it overcomes the typical problems of classical norming methods, such as overly large age intervals, missing norm scores, large amounts of sampling error in the subsamples or huge requirements with regard to the sample size. After a brief introduction to the mathematics of the model, we describe the individual methods of the package. We close the article with a practical example using data from a real reading comprehension test.
Gehrmann, Andrea ; Fiedler, Katrin ; Leutritz, Anna Linda ; Koreny, Carolin ; Kittel-Schneider, Sarah
Lithium salts are the first-line prophylaxis treatment for bipolar disorder in most guidelines. The majority of bipolar women are treated with mood stabilizers at the time they wish to get pregnant. One reason for this is the rising average age at first childbirth, at least in the high-income countries, which increases in general the likelihood of a medication with psychotropic drugs. Previously, lithium exposition during pregnancy was thought to strongly increase the risk of severe cardiac malformation. However, recent studies only point to a low teratogenic risk, so nowadays an increasing number of women are getting pregnant with ongoing lithium treatment. Regarding lithium medication during breastfeeding, there is evidence that lithium transfers to the breastmilk and can also be detected in the infants' serum. The influence on the infant is still a largely understudied topic. Regular monitoring of the infants' renal clearance, thyroid function, and lithium levels is warranted when breastfeeding under lithium exposure. In this case series, we present three case reports of bipolar mothers who were treated with lithium during pregnancy and breastfeeding to add to the scarce literature on this important topic. In short, we strengthen the importance of therapeutic drug monitoring due to fluctuating plasma levels during pregnancy and after birth, and we can report the birth and development of three healthy infants despite lithium medication during pregnancy and breastfeeding.
Inflammatory mechanisms in the pathophysiology of diabetic peripheral neuropathy (DN) — new aspects
(2021)
The pathogenesis of diabetic neuropathy is complex, and various pathogenic pathways have been proposed. A better understanding of the pathophysiology is warranted for developing novel therapeutic strategies. Here, we summarize recent evidence from experiments using animal models of type 1 and type 2 diabetes showing that low-grade intraneural inflammation is a facet of diabetic neuropathy. Our experimental data suggest that these mild inflammatory processes are a likely common terminal pathway in diabetic neuropathy associated with the degeneration of intraepidermal nerve fibers. In contrast to earlier reports claiming toxic effects of high-iron content, we found the opposite, i.e., nutritional iron deficiency caused low-grade inflammation and fiber degeneration while in normal or high non-heme iron nutrition no or only extremely mild inflammatory signs were identified in nerve tissue. Obesity and dyslipidemia also appear to trigger mild inflammation of peripheral nerves, associated with neuropathy even in the absence of overt diabetes mellitus. Our finding may be the experimental analog of recent observations identifying systemic proinflammatory activity in human sensorimotor diabetic neuropathy. In a rat model of type 1 diabetes, a mild neuropathy with inflammatory components could be induced by insulin treatment causing an abrupt reduction in HbA1c. This is in line with observations in patients with severe diabetes developing a small fiber neuropathy upon treatment-induced rapid HbA1c reduction. If the inflammatory pathogenesis could be further substantiated by data from human tissues and intervention studies, anti-inflammatory compounds with different modes of action may become candidates for the treatment or prevention of diabetic neuropathy.