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Sonstige beteiligte Institutionen
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- Klinikum Fulda (2)
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Background: Monitoring of motor function during surgery for supratentorial tumors under general anesthesia applies either transcranial electrical stimulation (TES) or direct cortical stimulation (DCS) to elicit motor-evoked potentials. To date, there is no guideline that favor one method over the other. Therefore, we designed this randomized study to compare between both methods regarding the prediction of postoperative motor deficits and extent of tumor resection. Methods: This is a multicenter (six centers in Germany and one in Switzerland), double blind, parallel group, exploratory, randomized controlled clinical trial. Patients without or with mild paresis, who are scheduled for surgical resection of motor-eloquent brain tumors under general anesthesia will be randomized to surgical resection under TES or surgical resection under DCS. The primary endpoint is sensitivity and specificity in prognosis of motor function 7 days after surgery. The main secondary endpoint is the extent of tumor resection. The study is planned to include 120 patients within 2 years. Discussion: The present exploratory study should compare TES and DCS regarding sensitivity and specificity in predicting postoperative motor deficit and extent of tumor resection to calculate the required number of patients in a confirmatory trial to test the superiority of one method over the other.
Electrospun carbon nanofibers (CNFs), which were modified with hydroxyapatite, were fabricated to be used as a substrate for bone cell proliferation. The CNFs were derived from electrospun polyacrylonitrile (PAN) nanofibers after two steps of heat treatment: stabilization and carbonization. Carbon nanofibrous (CNF)/hydroxyapatite (HA) nanocomposites were prepared by two different methods; one of them being modification during electrospinning (CNF-8HA) and the second method being hydrothermal modification after carbonization (CNF-8HA; hydrothermally) to be used as a platform for bone tissue engineering. The biological investigations were performed using in-vitro cell counting, WST cell viability and cell morphology after three and seven days. L929 mouse fibroblasts were found to be more viable on the hydrothermally-modified CNF scaffolds than on the unmodified CNF scaffolds. The biological characterizations of the synthesized CNF/HA nanofibrous composites indicated higher capability of bone regeneration.
Serotonin deficiency induced after brain maturation rescues consequences of early life adversity
(2021)
Brain serotonin (5-HT) system dysfunction is implicated in depressive disorders and acute depletion of 5-HT precursor tryptophan has frequently been used to model the influence of 5-HT deficiency on emotion regulation. Tamoxifen (TAM)-induced Cre/loxP-mediated inactivation of the tryptophan hydroxylase-2 gene (Tph2) was used to investigate the effects of provoked 5-HT deficiency in adult mice (Tph2 icKO) previously subjected to maternal separation (MS). The efficiency of Tph2 inactivation was validated by immunohistochemistry and HPLC. The impact of Tph2 icKO in interaction with MS stress (Tph2 icKOxMS) on physiological parameters, emotional behavior and expression of 5-HT system-related marker genes were assessed. Tph2 icKO mice displayed a significant reduction in 5-HT immunoreactive cells and 5-HT concentrations in the rostral raphe region within four weeks following TAM treatment. Tph2 icKO and MS differentially affected food and water intake, locomotor activity as well as panic-like escape behavior. Tph2 icKO prevented the adverse effects of MS stress and altered the expression of the genes previously linked to stress and emotionality. In conclusion, an experimental model was established to study the behavioral and neurobiological consequences of 5-HT deficiency in adulthood in interaction with early-life adversity potentially affecting brain development and the pathogenesis of depressive disorders.
Background
To identify injury patterns and mechanisms in professional men’s basketball by means of video match analysis.
Methods
In Germany, injuries are registered with the statutory accident insurance for professional athletes (VBG) by clubs or club physicians as part of occupational accident reporting. Moderate and severe injuries (absence of > 7 days) sustained during basketball competition in one of four seasons (2014–2017 and 2018–2019) in the first or second national men’s league in Germany were prospectively analyzed using a newly developed standardized observation form. Season 2017–2018 was excluded because of missing video material.
Results
Video analysis included 175 (53%) of 329 moderate and severe match injuries. Contact patterns categorized according to the different body sites yielded eight groups of typical injury patterns: one each for the head, shoulders, and ankles, two for the thighs, and three for the knees. Injuries to the head (92%), ankles (76%), shoulders (70%), knees (47%), and thighs (32%) were mainly caused by direct contact. The injury proportion of foul play was 19%. Most injuries (61%) occurred in the central zone below the basket. More injuries occurred during the second (OR 1.8, p = 0.018) and fourth quarter (OR 1.8, p = 0.022) than during the first and third quarter of the match.
Conclusion
The eight identified injury patterns differed substantially in their mechanisms. Moderate and severe match injuries to the head, shoulders, knees, and ankles were mainly caused by collision with opponents and teammates. Thus, stricter rule enforcement is unlikely to facilitate safer match play.
TERRAINS OF CONSCIOUSNESS emerges from an Indian-German-Swiss research collaboration. The book makes a case for a phenomenology of globalization that pays attention to locally situated socioeconomic terrains, everyday practices, and cultures of knowledge. This is exemplified in relation to three topics:
- the tension between ‘terrain’ and ‘territory’ in Defoe’s ‘Robinson Crusoe’ as a pioneering work of the globalist mentality (chapter 1)
- the relationship between established conceptions of feminism and the concrete struggles of women in India since the 19th century (chapter 2)
- the exploration of urban space and urban life in writings on India’s capital – from Ahmed Ali to Arundhati Roy (chapter 3).
Background
Treatment options for poorly differentiated (PDTC) and anaplastic (ATC) thyroid carcinoma are unsatisfactory and prognosis is generally poor. Lenvatinib (LEN), a multi-tyrosine kinase inhibitor targeting fibroblast growth factor receptors (FGFR) 1-4 is approved for advanced radioiodine refractory thyroid carcinoma, but response to single agent is poor in ATC. Recent reports of combining LEN with PD-1 inhibitor pembrolizumab (PEM) are promising.
Materials and Methods
Primary ATC (n=93) and PDTC (n=47) tissue samples diagnosed 1997-2019 at five German tertiary care centers were assessed for PD-L1 expression by immunohistochemistry using Tumor Proportion Score (TPS). FGFR 1-4 mRNA was quantified in 31 ATC and 14 PDTC with RNAscope in-situ hybridization. Normal thyroid tissue (NT) and papillary thyroid carcinoma (PTC) served as controls. Disease specific survival (DSS) was the primary outcome variable.
Results
PD-L1 TPS≥50% was observed in 42% of ATC and 26% of PDTC specimens. Mean PD-L1 expression was significantly higher in ATC (TPS 30%) than in PDTC (5%; p<0.01) and NT (0%, p<0.001). 53% of PDTC samples had PD-L1 expression ≤5%. FGFR mRNA expression was generally low in all samples but combined FGFR1-4 expression was significantly higher in PDTC and ATC compared to NT (each p<0.001). No impact of PD-L1 and FGFR 1-4 expression was observed on DSS.
Conclusion
High tumoral expression of PD-L1 in a large proportion of ATCs and a subgroup of PDTCs provides a rationale for immune checkpoint inhibition. FGFR expression is low thyroid tumor cells. The clinically observed synergism of PEM with LEN may be caused by immune modulation.
The putative attachment protein G of pneumonia virus of mice (PVM), a member of the Pneumoviruses, is an important virulence factor with so far ambiguous function in a virus-cell as well as in virus-host context. The sequence of the corresponding G gene is characterized by significant heterogeneity between and even within strains, affecting the gene and possibly the protein structure. This accounts in particular for the PVM strain J3666 for which two differing G gene organizations have been described: a polymorphism in nucleotide 65 of the G gene results in the presence of an upstream open reading frame (uORF) that precedes the main ORF in frame (GJ366665A) or extension of the major G ORF for 18 codons (GJ366665U). Therefore, this study was designed to analyse the impact of the sequence variations in the respective G genes of PVM strains J3666 and the reference strain 15 on protein expression, replication and virulence.
First, the controversy regarding the consensus sequence of PVM J3666 was resolved. The analysis of 45 distinct cloned fragments showed that the strain separated into two distinct virus populations defined by the sequence and structure of the G gene. This division was further supported by nucleotide polymorphisms in the neighbouring M and SH genes. Sequential passage of this mixed strain in the cell line standardly used for propagation of virus stocks resulted in selection for the GJ366665A-containing population in one of two experiments pointing towards a moderate replicative advantage. The replacement of the G gene of the recombinant PVM 15 with GJ366665A or GJ366665U, respectively, using a reverse genetic approach indicated that the presence of uORF within the GJ366665A significantly reduced the expression of the main G ORF on translational level while the potential extension of the ORF in GJ366665U increased G protein expression. In comparison, the effect of the G gene-structure on virus replication was inconsistent and dependent on cell line and type. While the presence of uORF correlated with a replication advantage in the standardly used BHK-21 cells and primary murine embryonic fibroblasts, replication in the murine macrophage cell line RAW 264.7 did not. In comparison, the GJ366665U variant was not associated with any effect on replication in cultured cells at all. Nonetheless, in-vivo analysis of the recombinant viruses associated the GJ366665U gene variant, and hence an increased G expression, with higher virulence whereas the GJ366665A gene, and therefore an impaired G expression, conferred an attenuated phenotype to the virus.
To extend the study to other G gene organizations, a recombinant PVM expressing a G protein without the cytoplasmic domain and for comparison a G-deletion mutant, both known to be attenuated in vivo, were studied. Not noticed before, this structure of the G gene was associated with a 75% reduction in G protein expression and a significant attenuation of replication in macrophage-like cells. This attenuation was even more prominent for the virus lacking G. Taking into consideration the higher reduction in G protein levels compared to the GJ366665A variant indicates that a threshold amount of G is required for efficient replication in these cells.
In conclusion, the results gathered indicated that the expression levels of the G protein were modulated by the sequence of the 5’ untranslated region of the gene. At the same time the G protein levels modulated the virulence of PVM.
Two-dimensional triangular lattices of group IV adatoms on semiconductor substrates provide a rich playground for the investigation of Mott-Hubbard physics. The possibility to combine various types of adatoms and substrates makes members of this material class versatile model systems to study the influence of correlation strength, band filling and spin-orbit coupling on the electronic structure - both experimentally and with dedicated many-body calculation techniques. The latter predict exotic ground states such as chiral superconductivity or spin liquid behavior for these frustrated lattices, however, experimental confirmation is still lacking. In this work, three different systems, namely the \(\alpha\)-phases of Sn/SiC(0001), Pb/Si(111), and potassium-doped Sn/Si(111) are investigated with scanning tunneling microscopy and photoemission spectroscopy in this regard. The results are potentially relevant for spintronic applications or quantum computing.
For the novel group IV triangular lattice Sn/SiC(0001), a combined experimental and theoretical study reveals that the system features surprisingly strong electronic correlations because they are boosted by the substrate through its partly ionic character and weak screening capabilities. Interestingly, the spectral function, measured for the first time via angle-resolved photoemission, does not show any additional superstructure beyond the intrinsic \(\sqrt{3} \times \sqrt{3} R30^{\circ}\) reconstruction, thereby raising curiosity regarding the ground-state spin pattern.
For Pb/Si(111), preceding studies have noted a phase transition of the surface reconstruction from \(\sqrt{3} \times \sqrt{3} R30^{\circ}\) to \(3 \times 3\) at 86 K. In this thesis, investigations of the low-temperature phase with high-resolution scanning tunneling microscopy and spectroscopy unveil the formation of a charge-ordered ground state. It is disentangled from a concomitant structural rearrangement which is found to be 2-up/1-down, in contrast to previous predictions. Applying an extended variational cluster approach, a phase diagram of local and nonlocal Coulomb interactions is mapped out. Based on a comparison of theoretical spectral functions with scattering vectors found via quasiparticle interference, Pb/Si(111) is placed in said phase diagram and electronic correlations are found to be the driving force of the charge-ordered state.
In order to realize a doped Mott insulator in a frustrated geometry, potassium was evaporated onto the well-known correlated Sn/Si(111) system. Instead of the expected insulator-to-metal transition, scanning tunneling spectroscopy data indicates that the electronic structure of Sn/Si(111) is only affected locally around potassium atoms while a metallization is suppressed. The potassium atoms were found to be adsorbed on empty \(T_4\) sites of the substrate which eventually leads to the formation of two types of K-Sn alloys with a relative potassium content of 1/3 and 1/2, respectively. Complementary measurements of the spectral function via angle-resolved photoemission reveal that the lower Hubbard band of Sn/Si(111) gradually changes its shape upon potassium deposition. Once the tin and potassium portion on the surface are equal, this evolution is complete and the system can be described as a band insulator without the need to include Coulomb interactions.
Arapaima gigas is one of the largest freshwater fish species of high ecological and economic importance. Overfishing and habitat destruction are severe threats to the remaining wild populations. By incorporating a chromosomal Hi-C contact map, we improved the arapaima genome assembly to chromosome-level, revealing an unexpected high degree of chromosome rearrangements during evolution of the bonytongues (Osteoglossiformes). Combining this new assembly with pool-sequencing of male and female genomes, we identified id2bbY, a duplicated copy of the inhibitor of DNA binding 2b (id2b) gene on the Y chromosome as candidate male sex-determining gene. A PCR-test for id2bbY was developed, demonstrating that this gene is a reliable male-specific marker for genotyping. Expression analyses showed that this gene is expressed in juvenile male gonads. Its paralog, id2ba, exhibits a male-biased expression in immature gonads. Transcriptome analyses and protein structure predictions confirm id2bbY as a prime candidate for the master sex-determiner. Acting through the TGF beta signaling pathway, id2bbY from arapaima would provide the first evidence for a link of this family of transcriptional regulators to sex determination. Our study broadens our current understanding about the evolution of sex determination genetic networks and provide a tool for improving arapaima aquaculture for commercial and conservation purposes.
Sex determination (SD) is a highly diverse and complex mechanism. In vertebrates, one of the first morphological differences between the sexes is the timing of initiation of the first meiosis, where its initiation occurs first in female and later in male. Thus, SD is intimately related to the responsiveness of the germ cells to undergo meiosis in a sex-specific manner. In some vertebrates, it has been reported that the timing for meiosis entry would be under control of retinoic acid (RA), through activation of Stra8. In this study, we used a fish model species for sex determination and lacking the stra8 gene, the Japanese medaka (Oryzias latipes), to investigate the connection between RA and the sex determination pathway. Exogenous RA treatments act as a stress factor inhibiting germ cell differentiation probably by activation of dmrt1a and amh. Disruption of the RA degrading enzyme gene cyp26a1 induced precocious meiosis and oogenesis in embryos/hatchlings of female and even some males. Transcriptome analyzes of cyp26a1–/–adult gonads revealed upregulation of genes related to germ cell differentiation and meiosis, in both ovaries and testes. Our findings show that germ cells respond to RA in a stra8 independent model species. The responsiveness to RA is conferred by sex-related genes, restricting its action to the sex differentiation period in both sexes.
Systemic chemotherapy of pediatric recurrent ependymomas: results from the German HIT-REZ studies
(2021)
Purpose
Survival in recurrent ependymoma (EPN) depends mainly on the extent of resection achieved. When complete resection is not feasible, chemotherapy is often used to extend progression-free and overall survival. However, no consistent effect of chemotherapy on survival has been found in patients with recurrent EPN.
Methods
Systemic chemotherapeutic treatment of 138 patients enrolled in the German HIT-REZ-studies was analyzed. Survival depending on the use of chemotherapy, disease-stabilization rates (RR), duration of response (DOR) and time to progression (TTP) were estimated.
Results
Median age at first recurrence was 7.6 years (IQR: 4.0–13.6). At first recurrence, median PFS and OS were 15.3 (CI 13.3–20.0) and 36.9 months (CI 29.7–53.4), respectively. The Hazard Ratio for the use of chemotherapy in local recurrences in a time-dependent Cox-regression analysis was 0.99 (CI 0.74–1.33). Evaluable responses for 140 applied chemotherapies were analyzed, of which sirolimus showed the best RR (50%) and longest median TTP [11.51 (CI 3.98; 14.0) months] in nine patients, with the strongest impact found when sirolimus was used as a monotherapy. Seven patients with progression-free survival > 12 months after subtotal/no-resection facilitated by chemotherapy were found. No definitive survival advantage for any drug in a specific molecularly defined EPN type was found.
Conclusion
No survival advantage for the general use of chemotherapy in recurrent EPN was found. In cases with incomplete resection, chemotherapy was able to extend survival in individual cases. Sirolimus showed the best RR, DOR and TTP out of all drugs analyzed and may warrant further investigation.
With an increasing variety of radiopharmaceuticals for diagnostic or therapeutic nuclear medicine as valuable diagnostic or treatment option, radiobiology plays an important role in supporting optimizations. This comprises particularly safety and efficacy of radionuclide therapies, specifically tailored to each patient. As absorbed dose rates and absorbed dose distributions in space and time are very different between external irradiation and systemic radionuclide exposure, distinct radiation-induced biological responses are expected in nuclear medicine, which need to be explored. This calls for a dedicated nuclear medicine radiobiology. Radiobiology findings and absorbed dose measurements will enable an improved estimation and prediction of efficacy and adverse effects. Moreover, a better understanding on the fundamental biological mechanisms underlying tumor and normal tissue responses will help to identify predictive and prognostic biomarkers as well as biomarkers for treatment follow-up. In addition, radiobiology can form the basis for the development of radiosensitizing strategies and radioprotectant agents. Thus, EANM believes that, beyond in vitro and preclinical evaluations, radiobiology will bring important added value to clinical studies and to clinical teams. Therefore, EANM strongly supports active collaboration between radiochemists, radiopharmacists, radiobiologists, medical physicists, and physicians to foster research toward precision nuclear medicine.
A liquid chromatography tandem mass spectrometry method for the analysis of ten kinase inhibitors (afatinib, axitinib, bosutinib,cabozantinib, dabrafenib, lenvatinib, nilotinib, osimertinib, ruxolitinib, and trametinib) in human serum and plasma for theapplication in daily clinical routine has been developed and validated according to the US Food and Drug Administration andEuropean Medicines Agency validation guidelines for bioanalytical methods. After protein precipitation of plasma samples withacetonitrile, chromatographic separation was performed at ambient temperature using a Waters XBridge® Phenyl 3.5μm(2.1×50 mm) column. The mobile phases consisted of water-methanol (9:1, v/v) with 10 mM ammonium bicarbonate as phase A andmethanol-water (9:1, v/v) with 10 mM ammonium bicarbonate as phase B. Gradient elution was applied at a flow rate of 400μL/min. Analytes were detected and quantified using multiple reaction monitoring in electrospray ionization positive mode. Stableisotopically labeled compounds of each kinase inhibitor were used as internal standards. The acquisition time was 7.0 min perrun. All analytes and internal standards eluted within 3.0 min. The calibration curves were linear over the range of 2–500 ng/mLfor afatinib, axitinib, bosutinib, lenvatinib, ruxolitinib, and trametinib, and 6–1500 ng/mL for cabozantinib, dabrafenib, nilotinib,and osimertinib (coefficients of correlation≥0.99). Validation assays for accuracy and precision, matrix effect, recovery,carryover, and stability were appropriate according to regulatory agencies. The rapid and sensitive assay ensures high throughputand was successfully applied to monitor concentrations of kinase inhibitors in patients.
Conventional bivalent IgG antibodies targeting a subgroup of receptors of the TNF superfamily (TNFSF) including fibroblast growth factor-inducible 14 (anti-Fn14) typically display no or only very limited agonistic activity on their own and can only trigger receptor signaling by crosslinking or when bound to Fcγ receptors (FcγR). Both result in proximity of multiple antibody-bound TNFRSF receptor (TNFR) molecules, which enables engagement of TNFR-associated signaling pathways. Here, we have linked anti-Fn14 antibodies to gold nanoparticles to mimic the “activating” effect of plasma membrane-presented FcγR-anchored anti-Fn14 antibodies. We functionalized gold nanoparticles with poly-ethylene glycol (PEG) linkers and then coupled antibodies to the PEG surface of the nanoparticles. We found that Fn14 binding of the anti-Fn14 antibodies PDL192 and 5B6 is preserved upon attachment to the nanoparticles. More importantly, the gold nanoparticle-presented anti-Fn14 antibody molecules displayed strong agonistic activity. Our results suggest that conjugation of monoclonal anti-TNFR antibodies to gold nanoparticles can be exploited to uncover their latent agonism, e.g., for immunotherapeutic applications.
Der Krankheitsverlauf der Herzinsuffizienz ist variabel. Typischerweise treten dabei wiederholte Episoden akuter kardialer Dekompensationen auf. Prospektive Untersuchungen zu longitudinalen Veränderungen der linksventrikulären Ejektionsfraktion (LVEF) nach akuter kardialer Dekompensation, sowie assoziierter echokardiographischer, laborchemischer und klinischer Parameter fehlten bisher.
Ziel der vorliegenden Arbeit war es deshalb, die Häufigkeit einer Verbesserung bzw.
Normalisierung der LVEF innerhalb von sechs Monaten nach einer Hospitalisierung aufgrund
akuter kardialer Dekompensation mit systolischer Herzinsuffizienz (LVEF vor Entlassung aus
dem Krankenhaus ≤40%), sowie begleitende Veränderungen in Biomarkerspiegeln und
echokardiographischen Parametern, zu beschreiben, deren prognostische Relevanz zu
untersuchen und mögliche Prädiktoren zu ermitteln.
Die Ergebnisse der Arbeit zeigen, dass in den folgenden 6 Monaten nach akuter kardialer Dekompensation variable LVEF-Verläufe zu erwarten sind. Mehr als 50% der Patienten erleben ein reverses Remodelling und wechseln dadurch die LVEF-basierte Herzinsuffizienz-Kategorie. LVEF-Verbesserungen sind mit komplexen kardialen, extrakardialen und klinischen Veränderungen - im Sinne eines systemischen reversen Remodellings – assoziiert und gehen mit einer verbesserten Langzeitprognose einher. Verschiedene Prädiktoren erlauben, nach akuter kardialer Dekompensation den Verlauf bereits bei Krankenhausentlassung abzuschätzen und damit personalisierte Behandlungsstrategien für den einzelnen Patienten zu etablieren.
Prospective longitudinal follow‐up of left ventricular ejection fraction (LVEF) trajectories after acute cardiac decompensation of heart failure is lacking. We investigated changes in LVEF and covariates at 6‐months' follow‐up in patients with a predischarge LVEF ≤40%, and determined predictors and prognostic implications of LVEF changes through 18‐months' follow‐up.
Methods and Results
Interdisciplinary Network Heart Failure program participants (n=633) were categorized into subgroups based on LVEF at 6‐months' follow‐up: normalized LVEF (>50%; heart failure with normalized ejection fraction, n=147); midrange LVEF (41%–50%; heart failure with midrange ejection fraction, n=195), or persistently reduced LVEF (≤40%; heart failure with persistently reduced LVEF , n=291). All received guideline‐directed medical therapies. At 6‐months' follow‐up, compared with patients with heart failure with persistently reduced LVEF, heart failure with normalized LVEF or heart failure with midrange LVEF subgroups showed greater reductions in LV end‐diastolic/end‐systolic diameters (both P<0.001), and left atrial systolic diameter (P=0.002), more increased septal/posterior end‐diastolic wall‐thickness (both P<0.001), and significantly greater improvement in diastolic function, biomarkers, symptoms, and health status. Heart failure duration <1 year, female sex, higher predischarge blood pressure, and baseline LVEF were independent predictors of LVEF improvement. Mortality and event‐free survival rates were lower in patients with heart failure with normalized LVEF (P=0.002). Overall, LVEF increased further at 18‐months' follow‐up (P<0.001), while LV end‐diastolic diameter decreased (P=0.048). However, LVEF worsened (P=0.002) and LV end‐diastolic diameter increased (P=0.047) in patients with heart failure with normalized LVEF hospitalized between 6‐months' follow‐up and 18‐months' follow‐up.
Conclusions
Six‐month survivors of acute cardiac decompensation for systolic heart failure showed variable LVEF trajectories, with >50% showing improvements by ≥1 LVEF category. LVEF changes correlated with various parameters, suggesting multilevel reverse remodeling, were predictable from several baseline characteristics, and were associated with clinical outcomes at 18‐months' follow‐up. Repeat hospitalizations were associated with attenuation of reverse remodeling."
Tinnitus is an auditory phantom perception in the absence of an external sound stimulation. People with tinnitus often report severe constraints in their daily life. Interestingly, indications exist on gender differences between women and men both in the symptom profile as well as in the response to specific tinnitus treatments. In this paper, data of the TrackYourTinnitus platform (TYT) were analyzed to investigate whether the gender of users can be predicted. In general, the TYT mobile Health crowdsensing platform was developed to demystify the daily and momentary variations of tinnitus symptoms over time. The goal of the presented investigation is a better understanding of gender-related differences in the symptom profiles of users from TYT. Based on two questionnaires of TYT, four machine learning based classifiers were trained and analyzed. With respect to the provided daily answers, the gender of TYT users can be predicted with an accuracy of 81.7%. In this context, worries, difficulties in concentration, and irritability towards the family are the three most important characteristics for predicting the gender. Note that in contrast to existing studies on TYT, daily answers to the worst symptom question were firstly investigated in more detail. It was found that results of this question significantly contribute to the prediction of the gender of TYT users. Overall, our findings indicate gender-related differences in tinnitus and tinnitus-related symptoms. Based on evidence that gender impacts the development of tinnitus, the gathered insights can be considered relevant and justify further investigations in this direction.
Ziel der prospektiven, klinischen und monozentrischen Beobachtungsstudie war es, die Eigenschaften der durch die DC/TMD (Diagnostic Criteria for Temporomandibular Disorders) eingeführten neuen Schemata der Schmerzzeichnung für Patienten mit Gesichtsschmerzen zu untersuchen. Der Fokus lag dabei zum einen auf der Reliabilität der Schmerzzeichnung sowie auf der Korrelation mit dem Grad der Schmerzchronifizierung und einer potentiellen psychischen Störung.
218 Patienten mit orofazialen Schmerzen wurden konsekutiv rekrutiert und bearbeiteten einen Fragebogen mit GCPS V.2, PHQ-9 und der Schmerzzeichnung. Eine Untergruppe füllte den Fragebogen nach einer fünfwöchigen Akupunkturtherapie zur Erhebung einer möglichen Veränderung der Schmerzintensität erneut aus. Eine weitere Untergruppe bearbeitete die Fragebögen erneut am selben Tag. Mit einem mehrschrittigen Auswertungsverfahren wurden alle Schmerzzeichnungen ausgewertet.
Die Studienpopulation bestand mit 77,1% aus weiblichen Patienten. Für 44,5% der Kohorte ergab sich eine durch orofaziale Schmerzen bedingte Beeinträchtigung. Die Auswertungsmethoden der Schmerzzeichnung ergaben starke geschlechtsspezifische Unterschiede. Das laterale Kopfschema wies sowohl für Frauen als auch für Männer mit Schmerzbeeinträchtigung signifikant mehr markierte Regionen auf im Vergleich zu Patienten ohne Schmerzbeeinträchtigung. Männer mit dysfunktionalen Schmerzen zeigten zudem eine signifikant höhere prozentual markierte Schmerzoberfläche. Für die männlichen Patienten zeigte sich außerdem für die Anzahl der Regionen und die prozentuale Markierung einen signifikanten Zusammenhang mit einer depressiven Störung. Für Frauen konnten diesbezüglich kein Zusammenhang festgestellt werden und auch der modifizierte Ransford-Score stellte für beide Geschlechter kein valides Screeninginstrument dar, um psychische Beeinträchtigungen zu identifizieren. Die Wiederholungszuverlässigkeit der Schmerzzeichnung war signifikant hoch für das Kopfschema und das intraorale Schema, nicht aber für das Ganzkörperschema.
Insgesamt erwiesen sich die neuen Schemata der Schmerzzeichnung im Rahmen einer CMD Diagnostik als vorteilhaft. Das Geschlecht des Patienten, schmerzbedingte Funktionsstörungen sowie psychische Beeinträchtigungen beeinflussen die durch die Schmerzzeichnung erzielten Ergebnisse unterschiedlich und bestätigen eine vielschichtige Ätiologie der Erkrankung. Die Ergebnisse verweisen zudem auf die Relevanz einer getrennten Betrachtung der Geschlechter in zukünftigen Studien mit orofazialen Schmerzpatienten. Die Summe aller Regionen des Kopfschemas von lateral könnte hinsichtlich der Einschätzung des Ausmaßes einer Schmerzchronifizierung künftig als Auswertungskriterium der Schmerzzeichnung Anwendung finden.
The bounded input bounded output (BIBO) stability for a nonlinear Caputo fractional system with time‐varying bounded delay and nonlinear output is studied. Utilizing the Razumikhin method, Lyapunov functions and appropriate fractional derivatives of Lyapunov functions some new bounded input bounded output stability criteria are derived. Also, explicit and independent on the initial time bounds of the output are provided. Uniform BIBO stability and uniform BIBO stability with input threshold are studied. A numerical simulation is carried out to show the system's dynamic response, and demonstrate the effectiveness of our theoretical results.
The olive tree is a venerable Mediterranean plant and often used in traditional medicine. The main aim of the present study was to evaluate the effect of Olea europaea L. cv. Arbosana leaf extract (OLE) and its encapsulation within a spanlastic dosage form on the improvement of its pro-oxidant and antiproliferative activity against HepG-2, MCF-7, and Caco-2 human cancer cell lines. The LC-HRESIMS-assisted metabolomic profile of OLE putatively annotated 20 major metabolites and showed considerable in vitro antiproliferative activity against HepG-2, MCF-7, and Caco-2 cell lines with IC\(_{50}\) values of 9.2 ± 0.8, 7.1 ± 0.9, and 6.5 ± 0.7 µg/mL, respectively. The encapsulation of OLE within a (spanlastic) nanocarrier system, using a spraying method and Span 40 and Tween 80 (4:1 molar ratio), was successfully carried out (size 41 ± 2.4 nm, zeta potential 13.6 ± 2.5, and EE 61.43 ± 2.03%). OLE showed enhanced thermal stability, and an improved in vitro antiproliferative effect against HepG-2, MCF-7, and Caco-2 (IC\(_{50}\) 3.6 ± 0.2, 2.3 ± 0.1, and 1.8 ± 0.1 µg/mL, respectively) in comparison to the unprocessed extract. Both preparations were found to exhibit pro-oxidant potential inside the cancer cells, through the potential inhibitory activity of OLE against glutathione reductase and superoxide dismutase (IC\(_{50}\) 1.18 ± 0.12 and 2.33 ± 0.19 µg/mL, respectively). These inhibitory activities were proposed via a comprehensive in silico study to be linked to the presence of certain compounds in OLE. Consequently, we assume that formulating such a herbal extract within a suitable nanocarrier would be a promising improvement of its therapeutic potential.