Refine
Year of publication
- 2020 (3438) (remove)
Document Type
- Article (1914)
- Part of Periodical (478)
- Doctoral Thesis (235)
- Preprint (169)
- Contribution to a Periodical (160)
- Book (128)
- Working Paper (123)
- Review (104)
- Part of a Book (86)
- Bachelor Thesis (11)
Language
- English (2168)
- German (1132)
- Portuguese (43)
- French (31)
- Turkish (28)
- Multiple languages (17)
- Spanish (13)
- Italian (3)
- slo (3)
Keywords
- taxonomy (88)
- Deutsch (53)
- new species (50)
- Spracherwerb (34)
- Sprachtest (33)
- Capital Markets Union (25)
- Financial Markets (25)
- Literatur (25)
- Übersetzung (25)
- Coronavirus (24)
Institute
- Medizin (744)
- Präsidium (278)
- Physik (267)
- Wirtschaftswissenschaften (220)
- Sustainable Architecture for Finance in Europe (SAFE) (167)
- Biowissenschaften (161)
- Frankfurt Institute for Advanced Studies (FIAS) (150)
- Informatik (116)
- Biochemie, Chemie und Pharmazie (104)
- Neuere Philologien (95)
Complete reosseointegration after treatment of periimplantitis was never published yet. This short scientific communication reports about results of a randomized controlled preclinical study. An electrolytic approach was compared to a classical modality (ablative, cotton pellets soaked with sodium chloride solution and H2O2. For electrolytic cleaning a complete reosseointegration was achieved in several cases serving as a proof of concept.
Objective: Pancreatic ductal adenocarcinoma (PDAC) still carries a dismal prognosis with an overall 5-year survival rate of 9%. Conventional combination chemotherapies are a clear advance in the treatment of PDAC; however, subtypes of the disease exist, which exhibit extensive resistance to such therapies. Genomic MYC amplifications represent a distinct subset of PDAC with an aggressive tumour biology. It is clear that hyperactivation of MYC generates dependencies that can be exploited therapeutically. The aim of the study was to find and to target MYC-associated dependencies.
Design: We analysed human PDAC gene expression datasets. Results were corroborated by the analysis of the small ubiquitin-like modifier (SUMO) pathway in a large PDAC cohort using immunohistochemistry. A SUMO inhibitor was used and characterised using human and murine two-dimensional, organoid and in vivo models of PDAC.
Results: We observed that MYC is connected to the SUMOylation machinery in PDAC. Components of the SUMO pathway characterise a PDAC subtype with a dismal prognosis and we provide evidence that hyperactivation of MYC is connected to an increased sensitivity to pharmacological SUMO inhibition.
Conclusion: SUMO inhibitor-based therapies should be further developed for an aggressive PDAC subtype.
Introduction: There is still an ongoing debate whether a transrectal ultrasound (TRUS) approach for prostate biopsies is associated with higher (infectious) complications rates compared to transperineal biopsies. This is especially of great interests in settings with elevated frequencies of multidrug resistant organisms (MDRO).
Materials and Methods: Between 01/2018 and 05/2019 230 patients underwent a TRUS-guided prostate biopsy at the department of Urology at University Hospital Frankfurt. Patients were followed up within the clinical routine that was not conducted earlier than 6 weeks after the biopsy. Among 230 biopsies, 180 patients took part in the follow-up. No patients were excluded. Patients were analyzed retrospectively regarding complications, infections and underlying infectious agents or needed interventions.
Results: Of all patients with follow up, 84 patients underwent a systematic biopsy (SB) and 96 a targeted biopsy (TB) after MRI of the prostate with additional SB. 74.8% of the patients were biopsy-naïve. The most frequent objective complications (classified by Clavien-Dindo) lasting longer than one day after biopsy were hematuria (17.9%, n = 32), hematospermia (13.9%, n = 25), rectal bleeding (2.8%, n = 5), and pain (2.2%, n = 4). Besides a known high MDRO prevalence in the Rhine-Main region, only one patient (0.6%) developed fever after biopsy. One patient each (0.6%) consulted a physician due to urinary retention, rectal bleeding or gross hematuria. There were no significant differences in complications seen between SB and SB + TB patients. The rate of patients who consulted a physician was significantly higher for patients with one or more prior biopsies compared to biopsy-naïve patients.
Conclusion: Complications after transrectal prostate biopsies are rare and often self-limiting. Infections were seen in <1% of all patients, regardless of an elevated local prevalence of MDROs. Severe complications (Clavien-Dindo ≥ IIIa) were only seen in 3 (1.7%) of the patients. Repeated biopsy is associated with higher complication rates in general.
Using an original dataset on professional networks of directors sitting on the boards of large US corporations, we examine how personal relationships are used by firms to improve job match quality in the high-skill segment of the labor market. Analyzing explicit social connection data between new hires and recruiters, we are able to test predictions of well established job referral models. We find that referred executive directors have a fifteen percent longer tenure than their non-referred counterparts. Referred executive directors also tend to be similar to their referrers on multiple dimensions, giving support to network homophily hypotheses.
Background: Prolonged grief disorder (PGD) will be newly included in the ICD-11, while a clinically similar diagnosis, persistent complex bereavement disorder (PCBD), has already been added to the DSM-5. Only few studies have evaluated these criteria-sets for prolonged grief.
Objective: The aim of this study was to evaluate the ICD-11 accessory symptom threshold and compare the diagnostic performance of the two criteria-sets in treatment-seeking bereaved persons.
Method: 113 grief treatment-seeking bereaved persons completed the Interview for Prolonged Grief-13. We used receiver operator characteristic analysis to determine an optimum ICD-11 accessory symptom threshold. We calculated diagnostic rates for PGD and PCBD and examined associations of PGD and PCBD caseness with concurrently assessed psychopathology and prolonged grief symptoms assessed one month later.
Results: An ICD-11 threshold of six accessory symptoms distinguished optimally between interview-diagnosed participants with and without prolonged grief. The prevalence of PGD (69%) was significantly higher than that of PCBD (48%) and of PGD with a 6-symptom threshold (47%). PGD caseness was associated with the relation to the deceased, 6-symptom threshold PGD and PCBD caseness with the time since loss. All criteria-sets were linked to concurrent prolonged grief, depression, and general mental distress. PCBD and 6-symptom threshold PGD but not PGD were associated with prolonged grief severity one month later.
Conclusions: The results support the validity of PGD and PCBD but, at the same time, they provide further support for differing prevalence rates. Using an empirically determined ICD-11 accessory symptom threshold could prevent the pathologisation of grief reactions.
CD8+ T cells are key players in immunity against intracellular infections and tumors. The main cytokine associated with these protective responses is interferon-γ (IFN-γ), whose production is known to be regulated at the transcriptional level during CD8+ T cell differentiation. Here we found that microRNAs constitute a posttranscriptional brake to IFN-γ expression by CD8+ T cells, since the genetic interference with the Dicer processing machinery resulted in the overproduction of IFN-γ by both thymic and peripheral CD8+ T cells. Using a gene reporter mouse for IFN-γ locus activity, we compared the microRNA repertoires associated with the presence or absence of IFN-γ expression. This allowed us to identify a set of candidates, including miR-181a and miR-451, which were functionally tested in overexpression experiments using synthetic mimics in peripheral CD8+ T cell cultures. We found that miR-181a limits IFN-γ production by suppressing the expression of the transcription factor Id2, which in turn promotes the Ifng expression program. Importantly, upon MuHV-4 challenge, miR-181a-deficient mice showed a more vigorous IFN-γ+ CD8+ T cell response and were able to control viral infection significantly more efficiently than control mice. These data collectively establish a novel role for miR-181a in regulating IFN-γ–mediated effector CD8+ T cell responses in vitro and in vivo.
Biologics have transformed the treatment of immune-mediated inflammatory diseases such as rheumatoid arthritis (RA) and inflammatory bowel disease (IBD). Biosimilars—biologic medicines with no clinically meaningful differences in safety or efficacy from licensed originators—can stimulate market competition and have the potential to expand patient access to biologics within the parameters of treatment recommendations. However, maximizing the benefits of biosimilars requires cooperation between multiple stakeholders. Regulators and developers should collaborate to ensure biosimilars reach patients rapidly without compromising stringent quality, safety, or efficacy standards. Pharmacoeconomic evaluations and payer policies should be updated following biosimilar market entry, minimizing the risk of imposing nonmedical barriers to biologic treatment. In RA, disparities between treatment guidelines and national reimbursement criteria could be addressed to ensure more uniform patient access to biologics and enable rheumatologists to effectively implement treat-to-target strategies. In IBD, the cost-effectiveness of biologic treatment earlier in the disease course is likely to improve when biosimilars are incorporated into pharmacoeconomic analyses. Patient understanding of biosimilars is crucial for treatment success and avoiding nocebo effects. Full understanding of biosimilars by physicians and carefully considered communication strategies can help support patients initiating or switching to biosimilars. Developers must operate efficiently to be sustainable, without undermining product quality, the reliability of the supply chain, or pharmacovigilance. Developers should also facilitate information sharing to meet the needs of other stakeholders. Such collaboration will help to ensure a sustainable future for both the biosimilar market and healthcare systems, supporting the availability of effective treatments for patients.
Broadly neutralizing antibodies (bNAbs) represent a promising approach to prevent and treat HIV-1 infection. However, viral escape through mutation of the HIV-1 envelope glycoprotein (Env) limits clinical applications. Here we describe 1-18, a new VH1-46-encoded CD4 binding site (CD4bs) bNAb with outstanding breadth (97%) and potency (GeoMean IC50 = 0.048 μg/mL). Notably, 1-18 is not susceptible to typical CD4bs escape mutations and effectively overcomes HIV-1 resistance to other CD4bs bNAbs. Moreover, mutational antigenic profiling uncovered restricted pathways of HIV-1 escape. Of most promise for therapeutic use, even 1-18 alone fully suppressed viremia in HIV-1-infected humanized mice without selecting for resistant viral variants. A 2.5-Å cryo-EM structure of a 1-18-BG505SOSIP.664 Env complex revealed that these characteristics are likely facilitated by a heavy-chain insertion and increased inter-protomer contacts. The ability of 1-18 to effectively restrict HIV-1 escape pathways provides a new option to successfully prevent and treat HIV-1 infection.
Introduction: In the development of bio-enabling formulations, innovative in vivo predictive tools to understand and predict the in vivo performance of such formulations are needed. Etravirine, a non-nucleoside reverse transcriptase inhibitor, is currently marketed as an amorphous solid dispersion (Intelence® tablets). The aims of this study were 1) to investigate and discuss the advantages of using biorelevant in vitro setups in simulating the in vivo performance of Intelence® 100 mg and 200 mg tablets, in the fed state, 2) to build a Physiologically Based Pharmacokinetic (PBPK) model by combining experimental data and literature information with the commercially available in silico software Simcyp® Simulator V17.1 (Certara UK Ltd.), and 3) to discuss the challenges when predicting the in vivo performance of an amorphous solid dispersion and identify the parameters which influence the pharmacokinetics of etravirine most.
Methods: Solubility, dissolution and transfer experiments were performed in various biorelevant media simulating the fasted and fed state environment in the gastrointestinal tract. An in silico PBPK model for healthy volunteers was developed in the Simcyp® Simulator, using in vitro results and data available from the literature as input. The impact of pre- and post-absorptive parameters on the pharmacokinetics of etravirine was investigated using simulations of various scenarios.
Results: In vitro experiments indicated a large effect of naturally occurring solubilizing agents on the solubility of etravirine. Interestingly, supersaturated concentrations of etravirine were observed over the entire duration of dissolution experiments on Intelence® tablets. Coupling the in vitro results with the PBPK model provided the opportunity to investigate two possible absorption scenarios, i.e. with or without implementation of precipitation. The results from the simulations suggested that a scenario in which etravirine does not precipitate is more representative of the in vivo data. On the post-absorptive side, it appears that the concentration dependency of the unbound fraction of etravirine in plasma has a significant effect on etravirine pharmacokinetics.
Conclusions: The present study underlines the importance of combining in vitro and in silico biopharmaceutical tools to advance our knowledge in the field of bio-enabling formulations. Future studies on other bio-enabling formulations can be used to further explore this approach to support rational formulation design as well as robust prediction of clinical outcomes.
The Mad Man and the Old God : an essay on Friedrich Nietzsche's apocalypse of human existence
(2020)
The role of attentional focusing in motor tasks has been highlighted frequently. The “internal–external” dimension has emerged, but also the spatial distance between body and attended location. In two experiments, an extended attentional focus paradigm was introduced to investigate distality effects of attentional foci on balance performance. First, the distality of the coordinates of the point of focus was varied between a proximal and distal position on an artificial tool attached to the body. Second, the distance of the displayed effect on the wall was varied between a 2.5 and 5 m condition. Subjects were instructed to focus on controlling either a proximal or distal spot on a tool attached to their head, represented by two laser pointers. Subsequently, they needed to visually track their own body-movement effect of one of the laser pointers at a wall while completing various single leg stance tasks. Center of pressure (COP) sway was analyzed using a linear method (classic sway variables) as well as a nonlinear method (multiscale entropy). In addition, laser trajectories were videotaped and served as additional performance outcome measure. Experiment 1 revealed differences in balance performance under proximal compared to distal attentional focus conditions. Moreover, experiment 2 yielded differences in balance-related sway measures and laser data between the 2.5 and 5 m condition of the visually observable movement effect. In conclusion, varying the distality of the point of focus between proximal and distal impacted balance performance. However, this effect was not consistent across all balance tasks. Relevantly, the distality of the movement effect shows a significant effect on balance plus laser performance with advantages in more distal conditions. This research emphasizes the importance of the spatial distality of movement effects for human behavior.
Groundwater is the largest source of accessible freshwater with its dynamics having significantly changed due to human withdrawals, and being projected to continue to as a result of climate change. The pumping of groundwater has led to lowered water tables, decreased base flow, and depletion.
Global hydrological models (GHMs) are used to simulate the global freshwater cycle, assessing impacts of changes in climate and human freshwater use. Currently, groundwater is commonly represented by a bucket-like linear storage component in these models. Bucket models, however, cannot provide information on the location of the groundwater table. Due to this limitation, they can only simulate groundwater discharge to surface water bodies but not recharge from surface water to groundwater and calculate no lateral and vertical groundwater flow whatsoever among grid cells. For instance this may lead to an underestimation of groundwater resources in semiarid areas, where groundwater is often replenished by surface water. In order to overcome these limitations it is necessary to replace the linear groundwater model in GHMs with a hydraulic head gradient-based groundwater flow model
This thesis presents the newly developed global groundwater model G3M and its coupling to the GHM WaterGAP spanning over 70,000 lines of newly developed code. Development and validation of the modeling software are discussed along with numerical challenges. Based on the newly developed software, a global natural equilibrium groundwater model is presented showing better agreements with observations than previous models. Groundwater discharge to rivers is found to be the most dominant flow component globally, compared to flows to other surface water bodies and lateral flows. Furthermore, first global maps of the distribution of gaining and losing surface water bodies are displayed.
For the purpose of determining the uncertainty in model outcomes a sensitivity study is conducted with an innovative approach through applying a global sensitivity analysis for a computationally complex model. First global maps of spatially distributed parameter sensitivities are presented. The results at hand indicate that globally simulated hydraulic heads are equally sensitive to hydraulic conductivity, groundwater recharge and surface water body elevation, even though parameter sensitivities do vary regionally.
A high resolution model of New Zealand is developed to further understand the involved uncertainties connected to the spatial resolution of the global model. This thesis finds that a new understanding is necessary how these models can be evaluated and that a simple increase in spatial resolution is not improving the model performance when compared to observations.
Alongside the assessment of the natural equilibrium, the concept of a fully coupled transient model as integrated storage component replacing the former model in the hydrological model WaterGAP is discussed. First results reveal that the model shows reasonable response to seasonal variability although it contains persistent head trends leading to global overestimates of water table depth due to an incomplete coupling. Nonetheless, WaterGAP-G3M is already able to show plausible long term storage trends for areas that are known to be affected by groundwater depletion. In comparison with two established regional models in the Central Valley the coupled model shows a highly promising simulation of storage declines.
Background: Lipodystrophy syndromes comprise a group of extremely rare and heterogeneous diseases characterized by a selective loss of adipose tissue in the absence of nutritional deprivation or catabolic state. Because of the rarity of each lipodystrophy subform, research in this area is difficult and international co-operation mandatory. Therefore, in 2016, the European Consortium of Lipodystrophies (ECLip) decided to create a registry for patients with lipodystrophy.
Results: The registry was build using the information technology Open Source Registry System for Rare Diseases in the EU (OSSE), an open-source software and toolbox. Lipodystrophy specific data forms were developed based on current knowledge of typical signs and symptoms of lipodystrophy. The platform complies with the new General Data Protection Regulation (EU) 2016/679 by ensuring patient pseudonymization, informational separation of powers, secure data storage and security of communication, user authentication, person specific access to data, and recording of access granted to any data. Inclusion criteria are all patients with any form of lipodystrophy (with the exception of HIV-associated lipodystrophy). So far 246 patients from nine centres (Amsterdam, Bologna, Izmir, Leipzig, Münster, Moscow, Pisa, Santiago de Compostela, Ulm) have been recruited. With the help from the six centres on the brink of recruitment (Cambridge, Lille, Nicosia, Paris, Porto, Rome) this number is expected to double within the next one or 2 years.
Conclusions: A European registry for all patients with lipodystrophy will provide a platform for improved research in the area of lipodystrophy. All physicians from Europe and neighbouring countries caring for patients with lipodystrophy are invited to participate in the ECLip Registry.
Study registration: ClinicalTrials.gov (NCT03553420). Registered 14 March 2018, retrospectively registered.
Cholinesterase alterations in delirium after cardiosurgery: a German monocentric prospective study
(2020)
Objectives: Postoperative delirium (POD) is a common complication after elective cardiac surgery. Recent evidence indicates that a disruption in the normal activity of the cholinergic system may be associated with delirium.
Design: Prospective observational study.
Setting: Single-centre at a European academic hospital.
Primary: and secondary outcome measures In our study the enzyme activities of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) were determined preoperatively as well as on the first and second postoperative day. The confusion assessment method for the intensive care unit was used to screen patients for the presence of POD.
Results: A total of 114 patients were included in the study. POD was associated with a decrease in BChE activity on postoperative day 1 (p=0.03). In addition, patients who developed POD, had significantly lower preoperative AChE activity than patients without POD (p<0.01). Multivariate analysis identified a preoperatively decreased AChE activity (OR 3.1; 95% CI 1.14 to 8.46), anticholinergic treatment (OR 5.09; 95% CI 1.51 to 17.23), elevated European System for Cardiac Operative Risk Evaluation (OR 3.68; 95% CI 1.04 to 12.99) and age (OR 3.02; 95% CI 1.06 to 8.62) to be independently associated with the development of POD.
Conclusions: We conclude that a reduction in the acetylcholine hydrolysing enzyme activity in patients undergoing cardiac surgery may correlate with the development of POD.
We study whether and how time preferences change over the life cycle, exploiting representative long-term panel data. We estimate the age patterns of discount rates from age 25 to 80. In order to identify age effects, we have to disentangle them from cohort and period factors. We address this identification problem by estimating individual fixed effects models, where we substitute period effects with determinants of time preferences that depend on calendar years. We find that discount rates decrease with age and the decline is remarkably linear over the life cycle.