Universitätsklinikum Erlangen
Recent publications
Out of the wide range of calcium phosphate (CaP) biomaterials, calcium phosphate bone cements (CPCs) have attracted increased attention since their discovery in the 1980s due to their valuable properties such as bioactivity, osteoconductivity, injectability, hardening ability through a low-temperature setting reaction and moldability. Thereafter numerous researches have been performed to enhance the properties of CPCs. Nonetheless, low mechanical performance of CPCs limits their clinical application in load bearing regions of bone. Also, the in vivo resorption and replacement of CPC with new bone tissue is still controversial, thus further improvements of high clinical importance are required. Bioactive glasses (BGs) are biocompatible and able to bond to bone, stimulating new bone growth while dissolving over time. In the last decades extensive research has been performed analyzing the role of BGs in combination with different CaPs. Thus, the focal point of this review paper is to summarize the available research data on how injectable CPC properties could be improved or affected by the addition of BG as a secondary powder phase. It was found that despite the variances of setting time and compressive strength results, desirable injectable properties of bone cements can be achieved by the inclusion of BGs into CPCs. The published data also revealed that the degradation rate of CPCs is significantly improved by BG addition. Moreover, the presence of BG in CPCs improves the in vitro osteogenic differentiation and cell response as well as the tissue-material interaction in vivo.
Background In severe cases, SARS-CoV-2 infection leads to acute respiratory distress syndrome (ARDS), often treated by extracorporeal membrane oxygenation (ECMO). During ECMO therapy, anticoagulation is crucial to prevent device-associated thrombosis and device failure, however, it is associated with bleeding complications. In COVID-19, additional pathologies, such as endotheliitis, may further increase the risk of bleeding complications. To assess the frequency of bleeding events, we analyzed data from the German COVID-19 autopsy registry (DeRegCOVID). Methods The electronic registry uses a web-based electronic case report form. In November 2021, the registry included N = 1129 confirmed COVID-19 autopsy cases, with data on 63 ECMO autopsy cases and 1066 non-ECMO autopsy cases, contributed from 29 German sites. Findings The registry data showed that ECMO was used in younger male patients and bleeding events occurred much more frequently in ECMO cases compared to non-ECMO cases (56% and 9%, respectively). Similarly, intracranial bleeding (ICB) was documented in 21% of ECMO cases and 3% of non-ECMO cases and was classified as the immediate or underlying cause of death in 78% of ECMO cases and 37% of non-ECMO cases. In ECMO cases, the three most common immediate causes of death were multi-organ failure, ARDS and ICB, and in non-ECMO cases ARDS, multi-organ failure and pulmonary bacterial ± fungal superinfection, ordered by descending frequency. Interpretation Our study suggests the potential value of autopsies and a joint interdisciplinary multicenter (national) approach in addressing fatal complications in COVID-19.
Background The aim of this study was to evaluate the long-term outcome and freedom from pulmonary valve replacement (PVR) after initial repair of tetralogy of Fallot (TOF). Patients and Methods The cohort of 306 patients treated between 1980 and 2017 was divided into anatomical subgroups according to the diagnosis of TOF-pulmonary stenosis, TOF-pulmonary atresia and TOF-double outlet right ventricle. Patients were treated with transannular patch (TAP), valve sparing repair (VSR), or conduits from the right ventricle to the pulmonary arteries (RVPA conduits). Results There were 21 deaths (6.9%), 14 being hospital deaths (4.6%) after primary correction and four deaths (1.3%) occurred after PVR. One patient died after a non-cardiac operation (0.3%). There were two late deaths (0.7%). During the past 12 years no early mortality has been observed. Ninety-one patients (30.4%) received PVR after a median of 12.1 ± 7.0 years with an early mortality of 4.4% (n = 4) and no late mortality. A significant difference in freedom from reoperation after TAP, VSR, and RVPA-conduits could be identified. Multivariate analysis displayed transannular repair (p = 0.016), primary palliation (p <0.001), the presence of major aortopulmonary collateral arteries (MAPCA; p = 0.023), and pulmonary valve Z-scores < − 4.0 (p = 0.040) as significant risk factors for PVR. Conclusion TOF repair has a beneficial long-term prognosis with low morbidity and mortality. Pulmonary valve Z-scores < − 4.0, transannular repair, and presence of MAPCAs are associated with earlier PVR. Non-VSRs and TOF-pulmonary atresia lead to earlier reoperation but have no negative impact on survival.
Background Cognitive Aids (checklists) are a common tool to improve patient safety. But the factors for their successful implementation and continuous use are not yet fully understood. Recent publications suggest safety culture to play a key role in this context. However, the effects on the outcome of implementation measures remain unclear. Hospitals and clinics that are involved in cognitive aid development and research might have significantly different safety cultures than their counterparts, resulting in skewed assessments of proper implementation. Therefore, the objective of this study was to assess the correlation between cognitive aid implementation and safety attitudes of staff members in early adopting and later adopting clinics. Methods An online survey of the Safety Attitudes Questionnaire (SAQ) was carried out in German anaesthesiology departments during the initial implementation of a new checklist for emergencies during anesthesia (“eGENA” app). Subsequently an analysis between subgroups (“eGENA” app usage and occupation), with Kruskal–Wallis- and Mann–Whitney-U-Tests was carried out for the general SAQ, as well as it six subscales. Results Departments that introduced “eGENA” app (Median 3,74, IQR 0,90) reported a significantly higher median SAQ (U (N eGENA = 6, N non eGENA = 14) = 70,0, z = 2,31, p = 0,02, r = 0,516) than their counterparts (Median 2,82, IQR 0,77) with significant differences in the dimensions teamwork climate, work satisfaction, perception of management and working conditions. Conclusion Early adopters of cognitive aids are likely to show a significantly higher perception of safety culture in the SAQ. Consequently, successful implementation steps from these settings might not be sufficient in different clinics. Therefore, further investigation of the effects of safety culture on cognitive aid implementation should be conducted.
Checkpoint control and immunomodulatory antibodies have become important tools for modulating tumor or self-reactive immune responses. A major issue preventing to make full use of the potential of these immunomodulatory antibodies are the severe side-effects, ranging from systemic cytokine release syndrome to organ-specific toxicities. The IgG Fc-portion has been demonstrated to contribute to both, the desired as well as the undesired antibody activities of checkpoint control and immunomodulatory antibodies via binding to cellular Fcγ-receptors (FcγR). Thus, choosing IgG subclasses, such as human IgG4, with a low ability to interact with FcγRs has been identified as a potential strategy to limit FcγR or complement pathway dependent side-effects. However, even immunomodulatory antibodies on the human IgG4 background may interact with cellular FcγRs and show dose limiting toxicities. By using a humanized mouse model allowing to study the immunomodulatory activity of human checkpoint control antibodies in vivo , we demonstrate that deglycosylation of the CD137-specific IgG4 antibody urelumab results in an amelioration of liver toxicity, while maintaining T cell stimulatory activity. In addition, our results emphasize that antibody dosing impacts the separation of side-effects of urelumab from its therapeutic activity via IgG deglycosylation. Thus, glycoengineering of human IgG4 antibodies may be a possible approach to limit collateral damage by immunomodulatory antibodies and allow for a greater therapeutic window of opportunity.
Introduction Due to the Corona-lockdowns the closure of sports facilities and schools has led to a decline in physical activity (PA) for months. PA is essential for maintaining cardiopulmonary function assessed by peak oxygen uptake. Since peak oxygen uptake represents the best predictor for mortality and morbidity in children with congenital heart disease the impact of lockdowns on this parameter is vital. Methods We evaluated retrospectively cardiopulmonary exercise data from our patient collective from before lockdown with twin-paired data from during lockdown. The twin-pairing was achieved by matching patients with similar heart disease, age, sex, and test method. Cardiopulmonary exercise testing was achieved on either the treadmill or the bicycle. Results We were able to twin-pair 90 cases (26 twins with heart disease and 19 healthy twins). There was a significant decrease of cardiopulmonary function (V̇O2peak: 35.7±9.8 vs.30.4±10.6) in the heart disease cohort along with a significant decrease in peak oxygen pulse (13.3±4.1 vs. 11.4±4.5), and peak minute ventilation (V ̇E: 83.05±29.08 vs.71,49±24.96). The healthy children improved over the timeframe, but this only reached significance for peak minute ventilation (81.72±25.79 vs.97.94±31.4). Conclusion We observed a significant decline of peak oxygen uptake during lockdown in the group of congenital heart disease (CHD) patients. This involved a loss of cardiac function as well as pulmonary function. This could be explained by limited access to sports facilities and restriction of regular daily movement due to school closure and overprotection. Healthy children improved their pulmonary function. This might be an indication of an improvement of exercise during confinement.
Purpose Higher doses of cytarabine appear to improve long-term outcome in acute myeloid leukemia (AML), in particular for younger patients. To this end, the optimal dosage of single-agent cytarabine in consolidation therapy remains elusive. Here, we assessed the impact of different dosages of cytarabine consolidation after 7 + 3 induction on outcome in a large real-world data set from the German Study Alliance Leukemia-Acute Myeloid Leukemia (SAL-AML) registry. Methods Patients between 18 and 64 years of age, registered between April 2005 and September 2020, who attained complete remission after intensive induction and received at least one consolidation cycle with intermediate (IDAC) or high-dose cytarabine (HiDAC) were selected. To account for differences in patient and disease characteristics between both groups, the average treatment effect was estimated by propensity score weighting. Results Six-hundred-forty-two patients received HiDAC consolidation with median dosage of 17.6 (IQR (interquartile range), 16.5–18.0) g/m ² for a median number of 3 cycles (IQR, 2–3), whereas 178 patients received IDAC consolidation with 5.9 (IQR, 5.7–8.6) g/m ² for a median of 2 cycles (IQR, 1–3). Both groups differed significantly in some important characteristics (age, sex, cytogenetic risk group, ECOG performance status, disease status, HCT-CI, number of induction cycles). After propensity score weighting for differences in patient and disease characteristics, relapse-free survival after 2 years was comparable between HiDAC-treated (55.3%) and IDAC-treated (55.6%) patients (HR = 0.935, p = 0.69). Moreover, no significant differences in overall survival were observed after 2 years (84.7 vs. 80.6%, HR = 1.101, p = 0.65). Notably, more patients treated with IDAC received allogeneic hematopoietic cell transplantation in first remission (37.6 vs. 19.8%, p < 0.001). Censoring for allogeneic hematopoietic cell transplantation in first remission revealed no significant survival difference with regard to cytarabine dosage. Considering only of European LeukemiaNet (ELN) favorable-risk AML patients, there was no significant difference in outcome. Of note, significantly more patients treated with HiDAC suffered from ≥ 3 CTCAE infectious complications (56.7 [95%-CI 52.8–60.6%] vs. 44.1% [95%-CI 36.6–51.7%]; p = 0,004). The rate of other ≥ 3 CTCAE non-hematological toxicities and secondary malignancies was comparable in both treatment groups. Conclusions This retrospective analysis suggests no significant benefit of high-dose cytarabine compared to intermediate dosages in consolidation for AML patients under 65 years of age, independent of ELN risk group. Trial registration NCT03188874.
Background Due to the corona pandemic and also to the new competence-oriented catalogue of learning objectives in medicine and the master plan for medical studies 2020, the development of digital and practical teaching concepts has experienced a great increase in importance.Aim of the workAs a result of this development, it was an important task to establish this combination and incorporate it into the curricular teaching process.Material and methodsThe “Toolkit dermatology” was established, which was sent to a total of more than 650 students at German university dermatology clinics. Using educational films, the students were able to practice their skills. In a further development, the toolkit was combined with classroom lectures and the students were asked to evaluate the toolkit online.ResultsThe vast majority of students (95–100%) clearly stated that the toolkit helped them to develop their practical skills. Some of them were in fact motivated to complete a clinical traineeship/practical tertial year in dermatology (21–88%). The combination of toolkit and subsequent classroom teaching was also rated very positively (82.2%), as this hybrid mode of teaching provided a better understanding.DiscussionDigital teaching formats as part of the concept of blended learning, i.e. the combination of virtual and analogue teaching formats, are becoming increasingly more important. Solutions for the disadvantages, such as the lack of real interaction and suitable examination formats, still remain to be found; however, the toolkit project demonstrates that hands-on and digital teaching can lead to high student motivation as well as a high educational standard.
Congenital lower urinary tract obstructions (LUTO) are most often caused by posterior urethral valves (PUV), a male limited anatomical obstruction of the urethra affecting 1 in 4,000 male live births. Little is known about the genetic background of PUV. Here, we report the largest genome-wide association study (GWAS) for PUV in 4 cohorts of patients and controls. The final meta-analysis included 756 patients and 4,823 ethnicity matched controls and comprised 5,754,208 variants that were genotyped or imputed and passed quality control in all 4 cohorts. No genome-wide significant locus was identified, but 33 variants showed suggestive significance ( P < 1 × 10 ⁻⁵ ). When considering only loci with multiple variants residing within < 10 kB of each other showing suggestive significance and with the same effect direction in all 4 cohorts, 3 loci comprising a total of 9 variants remained. These loci resided on chromosomes 13, 16, and 20. The present GWAS and meta-analysis is the largest genetic study on PUV performed to date. The fact that no genome-wide significant locus was identified, can be explained by lack of power or may indicate that common variants do not play a major role in the etiology of PUV. Nevertheless, future studies are warranted to replicate and validate the 3 loci that yielded suggestive associations.
Capturing complex dependence structures between outcome variables (e.g., study endpoints) is of high relevance in contemporary biomedical data problems and medical research. Distributional copula regression provides a flexible tool to model the joint distribution of multiple outcome variables by disentangling the marginal response distributions and their dependence structure. In a regression setup each parameter of the copula model, i.e. the marginal distribution parameters and the copula dependence parameters, can be related to covariates via structured additive predictors. We propose a framework to fit distributional copula regression via model‐based boosting, which is a modern estimation technique that incorporates useful features like an intrinsic variable selection mechanism, parameter shrinkage and the capability to fit regression models in high dimensional data setting, i.e. situations with more covariates than observations. Thus, model‐based boosting does not only complement existing Bayesian and maximum‐likelihood based estimation frameworks for this model class but rather enables unique intrinsic mechanisms that can be helpful in many applied problems. The performance of our boosting algorithm for copula regression models with continuous margins is evaluated in simulation studies that cover low‐ and high‐dimensional data settings and situations with and without dependence between the responses. Moreover, distributional copula boosting is used to jointly analyze and predict the length and the weight of newborns conditional on sonographic measurements of the fetus before delivery together with other clinical variables. This article is protected by copyright. All rights reserved
Zusammenfassung Die Mammasonografie hat sich seit vielen Jahren neben der Mammografie als wichtige Methode zur Abklärung von Brustbefunden etabliert. Problematisch bleiben jedoch Unterschiede in der Interpretation von Befunden 1 2. Dies vermindert die diagnostische Treffsicherheit der Sonografie nach Detektion eines Befundes, erschwert die interdisziplinäre Kommunikation und den Vergleich von wissenschaftlichen Arbeiten 3. Das American College of Radiology (ACR) hatte 1999 eine Arbeitsgruppe gebildet (International Expert Working Group), die auf der Basis der langjährig etablierten BI-RADS-Klassifizierung von mammografischen Befunden und unter Berücksichtigung von Literaturdaten eine ähnliche Einteilung für die Ultraschalluntersuchung erarbeitet hatte 4. Aufgrund inhaltlicher Unterschiede hatte die DEGUM bereits 2006 einen eigenen BI-RADS-analogen Kriterienkatalog publiziert 3. Die aktuelle 5. Edition des ACR-BI-RADS-Katalogs offenbart neben diesen weiterhin bestehenden inhaltlichen Unterschieden zudem das Problem der formalen Lizenzierung, wird aber inhaltlich von der DEGUM als weiteres Befundbeschreibungs- und Dokumentationssystem anerkannt. Der Arbeitskreis Mammasonografie der DEGUM beabsichtigt mit der „Best Practice Guideline“, den senologisch tätigen Kolleginnen und Kollegen einen aktuellen Dignitätskriterien- und Befundungskatalog sowie „Best Practice“-Empfehlungen zu den verschiedenen Modalitäten an die Hand zu geben.
Background: Endogenous retrovirus (ERV) elements are genomic footprints of ancestral retroviral infections within the human genome. Previous studies have demonstrated that dysregulated ERV transcription level is associated with immune cell infiltration in cancers, but the association between ERV expression and programmed cell death protein 1 (PD-1) blockade response is currently unraveled for solid cancers, such as advanced clear cell renal cell carcinoma (ccRCC). Methods: ERV mRNA profiles were obtained from three clinical trials of ccRCC where the patients were treated with anti-PD-1 (CM-009, CM-010, CM-025, and TCGA-KIRC data). Patients treated with nivolumab were divided into training and test cohort, while the TCGA-KIRC cohort was used as an external validation. Univariate Cox regression analysis and least absolute shrinkage and selection operator regression were used to establish the signature. Immune cell infiltration analysis and gene set enrichment analysis were performed to explore potential biological mechanisms. Results: An ERV signature was established based on nine ERV expression patterns. In the training cohort, the median overall survival in the low- and high-risk group was 45.2 and 19.6 months [hazard ratio (HR) = 0.49, 0.32–0.75, p
The ligand-activated transcription factor Aryl Hydrocarbon Receptor (AHR) regulates cellular detoxification, proliferation, and immune evasion in a range of cell types and tissues, including cancer cells. In this study, we used RNA-seq to identify the signature of AHR target genes regulated by the pollutant 2,3,7,8-tetrachlorodibenzodioxin (TCDD) and the endogenous ligand kynurenine (Kyn), a tryptophan-derived metabolite. This approach identified a signature of six genes (CYP1A1, ALDH1A3, ABCG2, ADGFR1, and SCIN) as commonly activated by endogenous or exogenous ligands of AHR in multiple colon cancer cell lines. Among these, the actin-severing protein Scinderin (SCIN) was necessary for cell proliferation; SCIN downregulation limited cell proliferation and its expression increased it. SCIN expression is elevated in a subset of colon cancer patient samples, which also contain elevated β-catenin levels. Remarkably, SCIN expression promotes nuclear translocation of β-catenin and activates the WNT pathway. Our study identified a new mechanism for adhesion-mediated signaling in which SCIN, likely via its ability to alter the actin cytoskeleton, facilitates the nuclear translocation of β-catenin.
Background Immunotherapies, like immune checkpoint inhibition and tumor infiltrating lymphocytes, have had remarkable success in treating melanoma. However, many patients do still not respond or relapse with therapy-resistant disease. To overcome said limitations, we propose a controlled adoptive cell therapy approach, where T cells are armed with EGFRvIII synthetic agonistic receptors (E3 SAR) that are selectively activated by a cross-linking bispecific antibody (BiAb) specific for both SAR T cell and melanoma-associated antigens. Materials and Methods Murine as well as human SAR constructs were generated and T cells were retrovirally transduced to stably express the SAR constructs. We validated our approach in murine, human and patient-derived cancer models expressing the melanoma-associated target antigens TYRP1 and MCSP. SAR T cells were functionally characterised by proving specific activation and proliferation of SAR T cells, as well as their tumor-directed cytotoxicity, in vitro and in vivo. Results Both on a mRNA and protein level, MCSP and TYRP1 were shown to be differentially expressed in treatment-naive as well as treatment-resistant melanoma patients compared to samples from healthy donors. Crosslinking anti-TYRP1 x anti-E3 and anti-MCSP x anti-E3 BiAb mediated conditional antigen-dependent activation, proliferation of SAR-T cells and lead to tumor cell lysis in all models tested. In vivo, anti-tumoral activity and tumor-free survival was mediated by the co-administration of SAR T cells and BiAb in a syngeneic tumor model and was further confirmed in several xenograft models. Conclusions Here, we apply the SAR x BiAb approach in an effortto deliver specific and conditional activation of SAR transduced T cells, and targeted tumor cell lysis in melanoma models. The modularity of our approach is key for targeting melanoma and is essential towards personalised immunotherapies addressing cancer heterogeneity. Due to variations of antigen expression in primary melanoma tissues, we propose that a dual-targeting approach, either simultaneous or sequential, could mitigate issues of heterogeneity and deliver therapeutic benefit to patients. Disclosure Information M. Benmebarek A. Employment (full or part-time); Significant; Klinikum der Universität München. F. Märkl A. Employment (full or part-time); Significant; Klinikum der Universität München. J. Keyl None. B. Cadilha A. Employment (full or part-time); Significant; Klinikum der Universität München. E. Ownership Interest (stock, stock options, patent or other intellectual property); Significant; Pantent in the immuno-oncology field. M. Geiger A. Employment (full or part-time); Significant; Roche. E. Ownership Interest (stock, stock options, patent or other intellectual property); Significant; Stocks and patents with Roche. C. Karches A. Employment (full or part-time); Significant; Klinikum der Universität München. H. Obeck None. M. Schwerdtfeger A. Employment (full or part-time); Significant; Klinikum der Universität München. D. Briukhovetska A. Employment (full or part-time); Significant; Klinikum der Universität München. J. Jobst None. P.J. Müller None. M. Seifert None. R. Grünmeier None. M. Thomas A. Employment (full or part-time); Significant; Helmholtz München. C. Marr A. Employment (full or part-time); Significant; Helmholtz München. B. Research Grant (principal investigator, collaborator or consultant and pending grants as well as grants already received); Significant; European Research Council. M. Levesque A. Employment (full or part-time); Significant; University Hospital Zurich. M. Heppt A. Employment (full or part-time); Significant; Universitätsklinikum Erlangen. S. Endres A. Employment (full or part-time); Significant; Klinikum der Universität München. B. Research Grant (principal investigator, collaborator or consultant and pending grants as well as grants already received); Significant; Elite Network of Bavaria, LMU Munich’s Institutional Strategy LMUexcellent. E. Ownership Interest (stock, stock options, patent or other intellectual property); Significant; Patents in the field of immuno-oncology. C. Klein A. Employment (full or part-time); Significant; Roche. E. Ownership Interest (stock, stock options, patent or other intellectual property); Significant; Stocks and patents with Roche. S. Kobold A. Employment (full or part-time); Significant; Klinikum der Universität München. B. Research Grant (principal investigator, collaborator or consultant and pending grants as well as grants already received); Significant; Volkswagen Foundation, European Research Council, Hector Foundation, Elite Network of Bavaria, Melanoma Research Alliance, Else Kröner-Fresenius-Stiftung, German Cancer Aid, Ernst-Jung-Sfiftung, LMU Munich’s Institutional Strategy LMUexcellent, Bundesministerium für Bildung und Forschung, European Research Council Grant, Fritz-Bender Foundation, José-Carreras Foundation. C. Other Research Support (supplies, equipment, receipt of drugs or other in-kind support); Significant; German Research Foundation. D. Speakers Bureau/Honoraria (speakers bureau, symposia, and expert witness); Significant; TTCR2 Inc, Novartis, BMS, GSK. E. Ownership Interest (stock, stock options, patent or other intellectual property); Significant; Patents in the field of immuno-oncology.
Background: The prognostic value of Claudin-6 (CLDN6) in non clear cell renal cell carcinoma (RCC) is still unclear. Aim: To evaluate the prognostic impact of CLDN6 expression in a large cohort of chromophobe RCC (chRCC). Material and methods: Patients who underwent renal surgery due to chRCC were recruited. Clinical data were retrospectively evaluated. Tumor specimens were analyzed for CLDN6 expression by immunohistochemistry. Results: 81 chRCC patients were eligible for analysis, thereof 10 (12.3%) patients were positive for CLDN6. No significant associations were found for CLDN6 expression and clinical attributes in patients with chRCC. Kaplan-Meier analysis revealed no differences in overall survival (OS) for patients with CLDN6⁻ compared to CLDN6⁺ tumors (87.0% versus 62.5%; p=0.174). Conclusion: In chRCC CLDN6 expression is not associated with parameters of aggressiveness or survival. Due to the rare incidence of chRCC further studies with larger cohorts are warranted.
Background Long COVID occurs in lower frequency in children and adolescents than in adults. Morphologic and free-breathing phase-resolved functional low-field MRI may identify persistent pulmonary manifestations after SARS-CoV-2 infection. Purpose To characterize both morphologic and functional changes of lung parenchyma on low-field MRI in children and adolescents with post COVID-19 compared with healthy controls. Materials and Methods Between August and December 2021, a cross-sectional, prospective clinical trial using low-field MRI was performed in children and adolescents from a single academic medical center. The primary outcome was the frequency of morphologic changes on MRI. Secondary outcomes included MRI-derived functional proton ventilation and perfusion parameters. Clinical symptoms, the duration from positive RT-PCR test and serological parameters were compared with imaging results. Nonparametric tests for pairwise and corrected tests for groupwise comparisons were applied to assess differences in healthy controls, recovered participants and with long COVID. Results A total of 54 participants post COVID-19 infection (mean age, 11 years ±3 [SD], 56 males) and 9 healthy controls (mean age, 10 years ±3 [SD], 70 males) were included: 29 (54%) in the COVID-19 group had recovered from infection and 25 (46%) were classified as having long COVID on the day of enrollment. Morphologic abnormality was identified in one recovered participant. Both ventilated and perfused lung parenchyma (V/Q match) was reduced from 81±6.1% in healthy controls to 62±19% (P =.006) in the recovered group and 60±20% (P=.003) in the long COVID group. V/Q match was lower in post COVID patients with infection less than 180 days (63±20%, P=.03), 180 to 360 days (63±18%, P=0.03) and 360 days ago (41±12%, P<.001) as compared with the never-infected healthy controls (81±6.1%). Conclusion Low-field MRI showed persistent pulmonary dysfunction in both children and adolescents recovered from COVID-19 and with long COVID. ClinicalTrials.gov: NCT04990531.
Nasal septum defects can currently only be reconstructed using autologous cartilage grafts. In this study, we examine the reconstruction of septal cartilage defects in a rabbit model using porcine decellularized nasal septal cartilage (DNSC) functionalized with recombinant platelet-derived growth factor-BB (PDFG-BB). The supportive function of the transplanted DNSC was estimated by the degree of septum deviation and shrinkage using magnetic resonance imaging (MRI). The biocompatibility of the transplanted scaffolds was evaluated by histology according to international standards. A study group with an autologous septal transplant was used as a reference. In situ regeneration of cartilage defects was assessed by histological evaluation 4 and 16 weeks following DNSC transplantation. A study group with non-functionalized DNSC was introduced for estimation of the effects of PDFG-BB functionalization. DNSC scaffolds provided sufficient structural support to the nasal septum, with no significant shrinkage or septal deviations as evaluated by the MRI. Biocompatibility analysis after 4 weeks revealed an increased inflammatory reaction of the surrounding tissue in response to DNSC as compared to the autologous transplants. The inflammatory reaction was, however, significantly attenuated after 16 weeks in the PDGF-BB group whereas only a slight improvement of the biocompatibility score was observed in the untreated group. In situ regeneration of septal cartilage, as evidenced by the degradation of the DNSC matrix and production of neocartilage, was observed in both experimental groups after 16 weeks but was more pronounced in the PDFG-BB group. Overall, DNSC provided structural support to the nasal septum and stimulated in situ regeneration of the cartilage tissue. Furthermore, PDFG-BB augmented the regenerative potential of DNSC and enhanced the healing process, as demonstrated by reduced inflammation after 16 weeks.
Irritable bowel syndrome (IBS) is a gut-brain disorder of multifactorial origin. Evidence of disturbed serotonergic function in IBS accumulated for the 5-HT3 receptor family. 5-HT3Rs are encoded by HTR3 genes and control GI function, and peristalsis and secretion, in particular. Moreover, 5-HT3R antagonists are beneficial in the treatment of diarrhea predominant IBS (IBS-D). We previously reported on functionally relevant SNPs in HTR3A c.-42C > T (rs1062613), HTR3C p.N163K (rs6766410), and HTR3E c.*76G > A (rs56109847 = rs62625044) being associated with IBS-D, and the HTR3B variant p.Y129S (rs1176744) was also described within the context of IBS. We performed a multi-center study to validate previous results and provide further evidence for the relevance of HTR3 genes in IBS pathogenesis. Therefore, genotype data of 2682 IBS patients and 9650 controls from 14 cohorts (Chile, Germany (2), Greece, Ireland, Spain, Sweden (2), the UK (3), and the USA (3)) were taken into account. Subsequent meta-analysis confirmed HTR3E c.*76G > A (rs56109847 = rs62625044) to be associated with female IBS-D (OR = 1.58; 95% CI (1.18, 2.12)). Complementary expression studies of four GI regions (jejunum, ileum, colon, sigmoid colon) of 66 IBS patients and 42 controls revealed only HTR3E to be robustly expressed. On top, HTR3E transcript levels were significantly reduced in the sigma of IBS patients (p = 0.0187); more specifically, in those diagnosed with IBS-D (p = 0.0145). In conclusion, meta-analysis confirmed rs56109847 = rs62625044 as a risk factor for female IBS-D. Expression analysis revealed reduced HTR3E levels in the sigmoid colon of IBS-D patients, which underlines the relevance of HTR3E in the pathogenesis of IBS-D.
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992 members
Stefan Uderhardt
  • Bereich für Rheumatologie
Burkhard Kasper
  • Bereich für Epilepsie
Xin Lai
  • Laboratory of Systems Tumor Immunology, Department of Dermatology
Paul David
  • Department of Surgery
Waldstr. 1, 91054, Erlangen, Germany
Head of institution
Heinrich Iro, M.D., Professor