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Results of Endometrial Biopsy and Its Impact on Survival Data in Patients with High-Risk Uterine Sarcoma
Get PDFBackground: There are conflicting data regarding the detection rate of high-risk uterine sarcoma (HRUS) by endometrial biopsy. In addition, there are no studies in the literature on its impact on the chosen surgical approach and survival. Methods: This study includes 415 patients with HRUS. Of these, 178 (42.9%) patients had undergone endometrial biopsy. We analyzed the detection rate of endometrial biopsy and its impact on surgical approach and survival data. Results: Correct specific histologic diagnosis was achieved in only 30.0% of LMS and 33.3% of HGESS/UUS. Other uterine sarcoma, unspecified malignant mesenchymal tumor, carcinosarcoma or carcinoma were found in 45% of LMS and 78.2% of HGESS/UUS. As a result of the histologic findings, the rate of inadequate surgery was reduced by up to 19.9%. As tumor morcellation was performed significantly less often with biopsy (32.5% with vs. 55.4% without biopsy, p < 0.001), the locoregional recurrence-free interval remained unaffected between the two groups (p = 0.81). This is obviously an advantage of biopsy, although it does not affect the local recurrence rate in morcellated patients. Conclusions: Indicated endometrial biopsy is an important step in the diagnosis of HRUS, despite its low detection rate. It helps to avoid inappropriate surgical procedures but does not affect OS
Less is more! Low amount of Fusobacterium nucleatum supports macrophage-mediated trophoblast functions in vitro
Get PDFF. nucleatum, involved in carcinogenesis of colon carcinomas, has been described as part of the commensal flora of the female upper reproductive tract. Although its contribution to destructive inflammatory processes is well described, its role as commensal uterine bacteria has not been thoroughly investigated. Since carcinogenesis shares similar mechanisms with early pregnancy development (including proliferation, invasion, blood supply and the induction of tolerance), these mechanisms induced by F. nucleatum could play a role in early pregnancy. Additionally, implantation and placentation require a well-balanced immune activation, which might be suitably managed by the presence of a limited amount of bacteria or bacterial residues. We assessed the effect of inactivated F. nucleatum on macrophage-trophoblast interactions. Monocytic cells (THP-1) were polarized into M1, M2a or M2c macrophages by IFN-γ, IL-4 or TGF-β, respectively, and subsequently treated with inactivated fusobacteria (bacteria:macrophage ratio of 0.1 and 1). Direct effects on macrophages were assessed by viability assay, flow cytometry (antigen presentation molecules and cytokines), qPCR (cytokine expression), in-cell Western (HIF and P-NF-κB) and ELISA (VEGF secretion). The function of first trimester extravillous trophoblast cells (HTR-8/SVneo) in response to macrophage-conditioned medium was microscopically assessed by migration (scratch assay), invasion (sprouting assay) and tube formation. Underlying molecular changes were investigated by ELISA (VEGF secretion) and qPCR (matrix-degrading factors and regulators). Inflammation-primed macrophages (M1) as well as high bacterial amounts increased pro-inflammatory NF-κB expression and inflammatory responses. Subsequently, trophoblast functions were impaired. In contrast, low bacterial stimulation caused an increased HIF activation and subsequent VEGF-A secretion in M2c macrophages. Accordingly, there was an increase of trophoblast tube formation. Our results suggest that a low-mass endometrial/decidual microbiome can be tolerated and while it supports implantation and further pregnancy processes
Influence of School Type and Class Level on Mean Caries Experience in 12-Year-Olds in Serial Cross-Sectional National Oral Health Survey in Germany—Proposal to Adjust for Selection Bias
Get PDFThe objective of this study is to analyse the effects of attended school type and class level on the reported caries experience (DMFT) obtained in the serial cross-sectional National Oral Health Study in Children in Germany (NOHSC) for the WHO reference group of 12-year-olds. Methods: Caries data from the 2016 NOHSC were adjusted for each federal state on the basis of two additional large-scale datasets for school type and class level. Results: Twelve-year-olds in all grades in Saxony-Anhalt (n = 96,842) exhibited significantly higher DMFT values than 12-year-olds in 6th grade (n = 76,456; +0.10 DMFT; ~14.2%, p < 0.001). Adjustments for school type had effects on DMFT on the level of federal states but almost balanced out on the national level (−0.01 DMFT; ~2%). Due to putatively similar structures of the federal states, the national mean DMFT for 12-year-olds in the latest NOHSC (2016; n = 55,002) was adjusted from 0.44 to 0.50 DMFT, correcting for selection bias. Conclusion: Selection bias in this NOHSC leads to an underestimation of caries levels by about 15%. Due to very low caries experience in children in Germany, these precise adjustments (+0.06 DMFT) have only a minor effect on interpretations of the national epidemiologic situation. Consequently, other national caries studies worldwide using the robust marker of DMFT should also adjust for systematic selection bias related to socio-economic background rather than increasing efforts in examination strategy
The extracellular serine protease from Staphylococcus epidermidis elicits a type 2-biased immune response in atopic dermatitis patients
Get PDFBackground
Atopic dermatitis (AD) is a chronic, relapsing inflammatory skin disease with skin barrier defects and a misdirected type 2 immune response against harmless antigens. The skin microbiome in AD is characterized by a reduction in microbial diversity with a dominance of staphylococci, including Staphylococcus epidermidis ( S. epidermidis ).
Objective
To assess whether S. epidermidis antigens play a role in AD, we screened for candidate allergens and studied the T cell and humoral immune response against the extracellular serine protease (Esp).
Methods
To identify candidate allergens, we analyzed the binding of human serum IgG4, as a surrogate of IgE, to S. epidermidis extracellular proteins using 2-dimensional immunoblotting and mass spectrometry. We then measured serum IgE and IgG1 binding to recombinant Esp by ELISA in healthy and AD individuals. We also stimulated T cells from AD patients and control subjects with Esp and measured the secreted cytokines. Finally, we analyzed the proteolytic activity of Esp against IL-33 and determined the cleavage sites by mass spectrometry.
Results
We identified Esp as the dominant candidate allergen of S. epidermidis . Esp-specific IgE was present in human serum; AD patients had higher concentrations than controls. T cells reacting to Esp were detectable in both AD patients and healthy controls. The T cell response in healthy adults was characterized by IL-17, IL-22, IFN-γ, and IL-10, whereas the AD patients’ T cells lacked IL-17 production and released only low amounts of IL-22, IFN-γ, and IL-10. In contrast, Th2 cytokine release was higher in T cells from AD patients than from healthy controls. Mature Esp cleaved and activated the alarmin IL-33.
Conclusion
The extracellular serine protease Esp of S. epidermidis can activate IL-33. As an antigen, Esp elicits a type 2-biased antibody and T cell response in AD patients. This suggests that S. epidermidis can aggravate AD through the allergenic properties of Esp
Climatic conditions at provenance origin influence growth stability to changes in climate in two major tree species
Get PDFClimate change is expected to outpace the rate at which populations of forest trees can migrate. Hence, in forestry there is growing interest in intervention strategies such as assisted migration to mitigate climate change impacts. However, until now the primary focus when evaluating candidates for assisted migration has been mean or maximum performance. We explore phenotypic plasticity as a potentially new avenue to help maintain the viability of species and populations in the face of climate change. Capitalizing on large, multi-site international provenance trials of four economically and ecologically important forest tree species ( Fagus sylvatica , Picea abies , Picea engelmannii , Pinus contorta ), we quantify growth stability as the width of the response function relating provenance growth performance and trial site climate. We found significant differences in growth stability among species, with P. engelmannii being considerably more stable than the other three species. Additionally, we found no relationship between growth performance and growth stability of provenances, indicating that there are fast-growing provenances with a broad climate optimum. In two of the four species, provenances’ growth stability showed a significant relationship with the climate of the seed source, the direction of which depends on the species. When taken together with data on growth performance in different climate conditions, a measure of growth stability can improve the choice of species and provenances to minimize future risks in forest restoration and reforestation
Magnetron Sputtering as a Versatile Tool for Precise Synthesis of Hybrid Iron Oxide–Graphite Nanomaterial for Electrochemical Applications
Get PDFIron oxide nanomaterials are promising candidates for various electrochemical applications. However, under operating conditions high electric resistance is still limiting performance and lifetime. By incorporating the electronically conductive carbon into a nanohybrid, performance may be increased and degeneration due to delamination may be prevented, eliminating major drawbacks. For future applications, performance is an important key, but also cost-effective manufacturing suitable for scale-up must be developed. A possible approach that shows good potential for up-scale is magnetron sputtering. In this study, a systematic investigation of iron oxides produced by RF magnetron sputtering was carried out, with a focus on establishing correlations between process parameters and resulting structural properties. It was observed that increasing the process pressure was favourable with regard to porosity. Over the entire pressure range investigated, the product consisted of low-crystalline Fe3O4, as well as Fe2O3 as a minor phase. During sputtering, a high degree of graphitisation of carbon was achieved, allowing for sufficient electronic conductivity. By means of a new alternating magnetron sputtering process, highly homogeneous salt-and-pepper-type arrangements of both nanodomains, iron oxide and carbon were achieved. This nano-containment of the redox-active species in a highly conductive carbon domain improves the material’s overall conductivity, while simultaneously increasing the electrochemical stability by 44%, as confirmed by cyclic voltammetry
The microbiome of the lichen Lobaria pulmonaria varies according to climate on a subcontinental scale
Get PDFThe Lobaria pulmonaria holobiont comprises algal, fungal, cyanobacterial and bacterial components. We investigated L. pulmonaria's bacterial microbiome in the adaptation of this ecologically sensitive lichen species to diverse climatic conditions. Our central hypothesis posited that microbiome composition and functionality aligns with subcontinental‐scale (a stretch of ~1100 km) climatic parameters related to temperature and precipitation. We also tested the impact of short‐term weather dynamics, sampling season and algal/fungal genotypes on microbiome variation. Metaproteomics provided insights into compositional and functional changes within the microbiome. Climatic variables explained 41.64% of microbiome variation, surpassing the combined influence of local weather and sampling season at 31.63%. Notably, annual mean temperature and temperature seasonality emerged as significant climatic drivers. Microbiome composition correlated with algal, not fungal genotype, suggesting similar environmental recruitment for the algal partner and microbiome. Differential abundance analyses revealed distinct protein compositions in Sub‐Atlantic Lowland and Alpine regions, indicating differential microbiome responses to contrasting environmental/climatic conditions. Proteins involved in oxidative and cellular stress were notably different. Our findings highlight microbiome plasticity in adapting to stable climates, with limited responsiveness to short‐term fluctuations, offering new insights into climate adaptation in lichen symbiosis
Hopf Algebras Related to Image and Time Series Data
Get PDFSignatures have proven beneficial as features in time series analysis. This work contributes in three major directions to the theory of signatures and its underlying Hopf algebras. In data science, recent works have successfully applied iterated integrals to images. The algebraic picture of two-parameter signatures becomes considerably more involved, and we introduce two-parameter analogues of shuffle and quasi-shuffle Hopf algebras. We furthermore introduce a two-parameter sums signature, together its corresponding quasisymmetric functions. We then show that this novel signature characterizes invariance under dynamic time warping, when applied in both directions independently. We establish the well-definedness of the barycenter, in the sense of Buser and Karcher, for the free nilpotent Lie group of step L. We provide an algorithm for computing it, using methods from Lie theory (namely, the Baker-Campbell-Hausdorff formula) and from the theory of Gröbner bases of modules. Our main motivation are L-truncated iterated-integrals signatures, which are elements in such a Lie group. Finally, we suggest a linear-time attention layer based on signature-type features.Signaturen haben sich als nützliche Merkmale in der Zeitreihenanalyse erwiesen. Diese Arbeit leistet in drei wesentlichen Bereichen einen Beitrag zur Theorie der Signaturen und ihrer zugrunde liegenden Hopf-Algebren. In der Datenwissenschaft wurden iterierte Integrale erfolgreich auf Bilder angewendet. Das algebraische Bild von Zweiparameter-Signaturen wird erheblich komplexer, und wir führen Zweiparameter-Analogien der Shuffle- und Quasi-Shuffle-Hopf-Algebren ein. Darüber hinaus führen wir eine Zweiparameter-Summen-Signatur ein, zusammen mit den entsprechenden quasysymmetrischen Funktionen. Wir zeigen dann, dass diese neuartige Signatur die Invarianz unter dynamischer Zeitverzerrung charakterisiert, wenn sie in beide Richtungen unabhängig angewendet wird. Wir stellen die Wohldefiniertheit des Baryzentrums im Sinne von Buser und Karcher für die freie nilpotente Lie-Gruppe vom Schritt L fest. Wir bieten einen Algorithmus zu dessen Berechnung an, der Methoden aus der Lientheorie (nämlich die Baker-Campbell-Hausdorff-Formel) und der Theorie der Gröbner-Basen von Moduln verwendet. Unsere Hauptmotivation sind L-trunkierte Signaturen iterierter Integrale, die Elemente einer solchen Lie-Gruppe sind. Schließlich schlagen wir eine Attention-Methode mit linearer Laufzeit basierend auf Signatur-ähnlichen Merkmalen vor
Fecal calprotectin and platelet count predict histologic disease activity in pediatric ulcerative colitis: results from a projection-predictive feature selection
Get PDFEspecially for pediatric patients, proxies of mucosal inflammation are needed. The Pediatric Ulcerative Colitis Activity Index (PUCAI) has been established to predict clinical and endoscopic disease activity. However, histologic inflammation might persist. We applied a special variable selection technique to predict histologic healing in pediatric ulcerative colitis (UC) as parsimoniously (but still as precisely) as possible. The retrospective analysis included data from two study cohorts, comprising 91 visits from 59 pediatric patients with UC. A Bayesian ordinal regression model was used in combination with a projection-predictive feature selection (PPFS) to identify a minimal subset of clinical and laboratory parameters sufficient for the prediction of histologic disease activity. Following the PPFS, CEDATA-GPGE patient registry data were analyzed to investigate the relevance of the selected predictors in relation to PUCAI and Physician Global Assessment (PGA) in up to 6697 patient visits. Fecal calprotectin (FC) and platelet count were identified as the minimal subset of predictors sufficient for prediction of histologic disease activity in pediatric UC. FC and platelet count also appeared to be associated with increasing disease activity as measured by PUCAI and PGA in the CEDATA-GPGE registry. Based on the selected model, predictions can be performed with a Shiny web app.
Conclusion: Our statistical approach constitutes a reproducible and objective tool to select a minimal subset of the most informative parameters to predict histologic inflammation in pediatric UC. A Shiny app shows how physicians may predict the histologic activity in a user-friendly way using FC and platelet count. To generalize the findings, further prospective studies will be needed.
What is Known:
• Histologic healing is a major endpoint in the therapy of ulcerative colitis (UC).
• The PUCAI score has been established to predict disease activity in pediatric UC but is not suitable for the prediction of histologic healing.
What is New:
• Our Bayesian ordinal regression model in combination with a projection-predictive feature selection is a reproducible and objective tool to select the minimal subset of clinical and laboratory parameters to predict histologic inflammation in pediatric UC.
• Histologic inflammation in pediatric UC can be non-invasively predicted based on the combination of fecal calprotectin levels and platelet count
Prednisolone Versus Colchicine for Acute Gout in Primary Care: statistical analysis plan for the pragmatic, multicenter, randomized, and double-blinded COPAGO non-inferiority trial
Get PDFBackground
To date, colchicine and prednisolone are two effective therapies for the treatment of acute gout but have never been compared directly in a randomized clinical trial. In addition, in previous trials of treating acute gout patients with concomitant comorbidities were often excluded due to contraindications to naproxen.
Study design
This pragmatic, prospective, double-blind, double-dummy, parallel-group, randomized, non-inferiority trial compares prednisolone with colchicine in terms of non-inferiority in patients with acute gout. Patients presenting to their general practitioner with acute gout can be included if the gout attack has occurred within the last 2 days. A total of 60 practices in the vicinity of three university medical centers (Greifswald, Göttingen, and Würzburg) participate in the study. The intervention group receives 30 mg prednisolone for 5 days, while the group of standard care receives low-dose colchicine (day 1: 1.5 mg; days 2–5: 1 mg). The first dose of treatment is provided at day 0 when patients present to the general practitioner due to an acute gout attack. From day 0 to day 6, patients will be asked to complete a study diary on daily basis regarding pain quantification. For safety reasons, potential side effects and the course of systolic blood pressure are also assessed.
Statistical analysis plan
N = 314 patients have to be recruited to compensate for 10% of dropout and to allow for showing non-inferiority of prednisolone compared to colchicine with a power of 90%. We use permuted block randomization with block sizes of 2, 4, and 6 to avoid imbalanced treatment arms in this multi-center study; patients are randomized in a 1:1 ratio. The absolute level of pain on day 3 (in the last 24 h) is the primary outcome and measured on a numerical rating scale (NRS: 0–10). Using a multiple linear regression model adjusted for age, sex, and pain at baseline, prednisolone is considered non-inferior if the effect estimate including the confidence intervals is lower than a margin of 1 unit on the NRS. Average response to treatment, joint swelling and tenderness, physical function of the joint, and patients’ global assessment of treatment success are secondary outcomes.
Discussion
The trial will provide evidence from a direct comparison of colchicine and prednisolone regarding their efficacy of pain reduction in acute gout patients of primary care and to indicate possible safety signals.
Trial registration
ClinicalTrials.gov Identifier: NCT05698680 first posted on January 26, 2023 (retrospectively registered)