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Background: By performing case management, general practitioners and health care assistants can provide additional benefits to their chronically ill patients. However, the economic effects of such case management interventions often remain unclear although how to manage the burden of chronic disease is a key question for policy-makers. This analysis aimed to compare the cost-effectiveness of 24 months of primary care case management for patients with a long-term indication for oral anticoagulation therapy with usual care.
Methods: This analysis is part of the cluster-randomized controlled Primary Care Management for Optimized Antithrombotic Treatment (PICANT) trial. A sample of 680 patients with German statutory health insurance was initially considered for the cost analysis (92% of all participants at baseline). Costs included all disease-related direct health care costs from the payer’s perspective (German statutory health insurers) plus case management costs for the intervention group. A-Quality Adjusted Life Year (QALY) measurement (EQ-5D-3 L instrument) was used to evaluate utility, and incremental cost-effectiveness ratio (ICER) to assess cost-effectiveness. Mean differences were calculated and displayed with 95%-confidence intervals (CI) from non-parametric bootstrapping (1000 replicates).
Results: N = 505 patients (505/680, 74%) were included in the cost analysis (complete case analysis with a follow-up after 12 and 24 months as well as information on cost and QALY). After two years, the mean difference of direct health care costs per patient (€115, 95% CI [− 201; 406]) and QALYs (0.03, 95% CI [− 0.04; 0.11]) in the two groups was small and not significant. The costs of case management in the intervention group caused mean total costs per patient in this group to rise significantly (mean difference €503, 95% CI [188; 794]). The ICER was €16,767 per QALY. Regardless of the willingness of insurers to pay per QALY, the probability of the intervention being cost-effective never rose above 70%.
Conclusions: A primary care case management for patients with a long-term indication for oral anticoagulation therapy improved QALYs compared to usual care, but was more costly. However, the results may help professionals and policy-makers allocate scarce health care resources in such a way that the overall quality of care is improved at moderate costs, particularly for chronically ill patients.
Trial registration: Current Controlled Trials ISRCTN41847489.
We investigate the transmission of central bank liquidity to bank deposits and loan spreads in Europe over the January 2006 to June 2010 period. We find evidence consistent with an impaired transmission channel due to bank risk. Central bank liquidity does not translate into lower loan spreads for high-risk banks, even as it lowers deposit rates for both high-risk and low-risk banks. This adversely affects the balance sheets of high-risk bank borrowers, leading to lower payouts, lower capital expenditures, and lower employment. Overall, our results suggest that banks’ capital constraints at the time of an easing of monetary policy pose a challenge to the effectiveness of the bank lending channel and the effectiveness of the central bank as a lender of last resort.
Change ahead—emerging life-course transitions as practical accomplishments of growing old(er)
(2019)
With the aging of the "Baby Boomer" cohort, more and more adults are transiting from work into retirement. In public discourse, this development is framed as one of the major challenges of today's welfare societies. To develop social innovations that consider the everyday lives of older people requires a deeper theoretical understanding of the retiring process. In age studies, retiring has been approached from various theoretical perspectives, most prominently disengagement perspectives (retirement as the withdrawal from social roles and responsibilities) and rational choice perspectives (retiring as a rational decision based on incentives and penalties). Whereas, the former have been accused of promoting a deficient image of aging, the latter are criticized for concealing the socially stratified constraints older people experience. This paper proposes a practice-theoretical perspective on retiring, understanding it as a processual, practical accomplishment that involves various social practices, sites, and human, as well as non-human, actors. To exemplify this approach, I draw upon data from the project "Doing Retiring" that follows 30 older adults in Germany from 1 year before to 3 years after retirement. Results depict retiring as a complex process of change, assembled by social practices that are scattered across time, space, and carriers. Practice sequences and constellations differ significantly between older adults who retire expectedly and unexpectedly, for example through sudden job loss or illness. However, even among those who envisaged retiring "on their own terms," the agency to retire was distributed across the network of employers, retirement schemes, colleagues, laws, families, workplaces, bodies and health, and the future retiree themselves. Results identified a distinct set of sequentially organized practices that were temporally and spatially configured. Many study participants expressed an idea about a "right time to retire" embedded in the imagination of a chrononormative life-course, and they often experienced spatio-temporal withdrawal from the workplace (e.g., reduction of working hours) which entailed affective disengagement from work as well. In conclusion, a practice-theoretical perspective supports social innovations that target more than just the retiring individual.
In this paper, we investigate whether timing in monolingual acquisition interacts with age of onset and input effects in child bilingualism. Six different morpho-syntactic and semantic phenomena acquired early, late or very late are considered, with their timing in L1 acquisition varying between age 3 (subject-verb agreement) and after age 6 (case marking). Data from simultaneous bilingual children (2L1) whose mean age of onset to German was 3 months are compared with data from early second language learners of German (eL2) whose mean age of onset to German was 35 months as well as with data from monolingual children. To explore change over time, children were tested twice at the ages of 4;4 and 5;8 years. The main findings were that 2L1 children had an advantage over their eL2 peers in early acquired phenomena, which disappeared with time, whereas in late acquired phenomena 2L1 and eL2 children did not differ. Moreover, 2L1 children performed like monolingual children in early acquired phenomena but had a disadvantage in the late acquired phenomena with the amount of delay decreasing with time. We conclude that age of onset effects are modulated by effects of timing in monolingual acquisition. Contrary to expectation, input in terms of language dominance, measured as the dominant language used at home, did not affect simultaneous bilingual children’s performance in any of the phenomena. We discuss the implications of our findings for the hypothesis that acquisition of late phenomena is determined by input alone and suggest an alternative concept: the learner’s internal need for time to master a phenomenon, which is determined by its complexity and cross-linguistic robustness.
Orthologs document the evolution of genes and metabolic capacities encoded in extant and ancient genomes. However, the similarity between orthologs decays with time, and ultimately it becomes insufficient to infer common ancestry. This leaves ancient gene set reconstructions incomplete and distorted to an unknown extent. Here we introduce the "evolutionary traceability" as a measure that quantifies, for each protein, the evolutionary distance beyond which the sensitivity of the ortholog search becomes limiting. Using yeast, we show that genes that were thought to date back to the last universal common ancestor are of high traceability. Their functions mostly involve catalysis, ion transport, and ribonucleoprotein complex assembly. In turn, the fraction of yeast genes whose traceability is not sufficient to infer their presence in last universal common ancestor is enriched for regulatory functions. Computing the traceabilities of genes that have been experimentally characterized as being essential for a self-replicating cell reveals that many of the genes that lack orthologs outside bacteria have low traceability. This leaves open whether their orthologs in the eukaryotic and archaeal domains have been overlooked. Looking at the example of REC8, a protein essential for chromosome cohesion, we demonstrate how a traceability-informed adjustment of the search sensitivity identifies hitherto missed orthologs in the fast-evolving microsporidia. Taken together, the evolutionary traceability helps to differentiate between true absence and nondetection of orthologs, and thus improves our understanding about the evolutionary conservation of functional protein networks. "protTrace," a software tool for computing evolutionary traceability, is freely available at https://github.com/BIONF/protTrace.git; last accessed February 10, 2019.
Job loss expectations, durable consumption and household finances : evidence from linked survey data
(2019)
Job security is important for durable consumption and household savings. Using surveys, workers express a probability that they will lose their job in the next 12 months. In order to assess the empirical content of these probabilities, we link survey data to administrative data with labor market outcomes. Workers predict job loss quite well, in particular those whose job loss is followed by unemployment. Workers with higher job loss expectations acquire cheaper cars, and are less likely to buy new cars. In line with models of precautionary saving, higher job loss expectations are associated with more savings and less exposure to risky assets.
Introduction: Chronic heart failure (CHF) is a heterogeneous condition requiring complex treatment from diverse healthcare services. An increasingly holistic understanding of healthcare has resulted in contextual factors such as perceived quality of care, as well as patients’ acceptance, preferences and subjective expectations of health services, all gaining in importance. How patients with CHF experience the use of healthcare services has not been studied within the scope of a systematic review in a German healthcare context. The aim of this scoping review is therefore to review systematically the experiences of patients affected by CHF with healthcare services in Germany in the literature and to map the research foci. Further objectives are to identify gaps in evidence, develop further research questions and to inform decision makers concerned with improving healthcare of patients living with CHF.
Methods and analysis: This scoping review will be based on a broad search strategy involving systematic and comprehensive electronic database searches in MEDLINE, EMBASE, PsycINFO, PSYNDEX, CINAHL and Cochrane’s Database of Systematic Reviews, grey literature searches, as well as hand searches through reference lists and non-indexed key journals. The methodological procedure will be based on an established six-stage framework for conducting scoping reviews that includes two independent reviewers. Data will be systematically extracted, qualitatively and quantitatively analysed and summarised both narratively and visually. To ensure the research questions and extracted information are meaningful, a patient representative will be involved.
Ethics and dissemination: Ethical approval will not be required to conduct this review. Results will be disseminated through a clearly illustrated report that will be part of a wider research project. Furthermore, it is intended that the review’s findings should be made available to relevant stakeholders through conference presentations and publication in peer-reviewed journals (knowledge transfer). Protocol registration in PROSPERO is not applicable for scoping reviews.
Glioblastoma (GBM), WHO grade IV, is the most aggressive primary brain tumor in adults. The median survival time using standard therapy is only 12–15 months with a 5-year survival rate of around 5%. Thus, new and effective treatment modalities are of significant importance. Signal transducer and activator of transcription 3 (Stat3) is a key signaling protein driving major hallmarks of cancer and represents a promising target for the development of targeted glioblastoma therapies. Here we present data showing that the therapeutic application of siRNAs, formulated in nanoscale lipopolyplexes (LPP) based on polyethylenimine (PEI) and the phospholipid 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), represents a promising new approach to target Stat3 in glioma. We demonstrate that the LPP-mediated delivery of siRNA mediates efficient knockdown of Stat3, suppresses Stat3 activity and limits cell growth in murine (Tu2449) and human (U87, Mz18) glioma cells in vitro. In a therapeutic setting, intracranial application of the siRNA-containing LPP leads to knockdown of STAT3 target gene expression, decreased tumor growth and significantly prolonged survival in Tu2449 glioma-bearing mice compared to negative control-treated animals. This is a proof-of-concept study introducing PEI-based lipopolyplexes as an efficient strategy for therapeutically targeting oncoproteins with otherwise limited druggability.
A case of Lymphangioleiomyomatosis (LAM) of the lung in a patient with a history of breast cancer
(2019)
Background: Lymphangioleiomyomatosis (LAM) is a rare progressive cystic and nodular disease of the lung characterized by smooth muscle cell proliferation. LAM predominantly affects young premenopausal women. This report is of a case of LAM presenting in a 47-year-old woman with a past history of breast cancer and discusses the possibility of an association between the two conditions.
Case report: A 47-year-old woman presented as an emergency with an exacerbation of a four-month history of shortness of breath and dry cough. Her symptoms began following the start of anti-hormonal treatment with letrozole and goserelin acetate for a moderately differentiated (grade 2) invasive ductal carcinoma of the breast (pT2, pN0, M0) which was positive for expression of estrogen receptor (ER+), progesterone receptor (PR+), and human epidermal growth factor receptor 2 (HER2+). Until the previous four months, she had breast-conserving treatment with radiotherapy and tamoxifen therapy. Following hospital admission, she was found to be in type I respiratory failure. Chest X-ray, lung computed tomography (CT), and positron-emission tomography (PET) showed diffuse cystic and nodular lung lesions, consistent with a diagnosis of LAM, and antihormonal therapy was discontinued. She developed pericarditis that was treated with the anti-inflammatory agent, colchicine. Treatment with letrozole and sirolimus improved her respiratory symptoms.
Conclusions: A rare case of LAM is presented in a woman with a recent history of breast cancer. Because both tumors were hormone-dependent, this may support common underlying gene associations and signaling pathways between the two types of tumor.
This study aims to elaborate the relevance of trauma severity and traumatic injury pattern in different multiple and/or polytrauma models by comparing five singular trauma to two different polytrauma (PT) models with high and one multiple trauma (MT) model with low injury-severity score (ISS). The aim is to provide a baseline for reducing animal harm according to 3Rs by providing less injury as possible in polytrauma modeling. Mice were randomly assigned to 10 groups: controls (Ctrl; n = 15), Sham (n = 15); monotrauma groups: hemorrhagic shock (HS; n = 15), thoracic trauma (TxT; n = 18), osteotomy with external fixation (Fx; n = 16), bilateral soft tissue trauma (bSTT; n = 16) or laparotomy (Lap; n = 16); two PT groups: PT I (TxT + HS + Fx; ISS = 18; n = 18), PT II (TxT + HS + Fx + Lap; ISS = 22; n = 18), and a MT group (TxT + HS + bSTT + Lap, ISS = 13; n = 18). Activity and mortality were assessed. Blood gas analyses and organ damage markers were determined after 6 h. Significant mortality occurred in TxT, PT and MT (11.7%). Activity decreased significantly in TxT, HS, both polytrauma and MT vs. Ctrl/Sham. PT-groups and MT had significantly decreased activity vs. bsTT, Lap or Fx. MT had significantly lower pCO2 vs. Ctrl/Sham, Lap or bsTT. Transaminases increased significantly in PT-groups and MT vs. Ctrl, Sham or monotrauma. Traumatic injury pattern is of comparable relevance as injury severity for experimental multiple or (poly)trauma modeling.
Up to 50% of patients initially treated for prostate cancer in a curative intent experience biochemical recurrence, possibly requiring adjuvant treatment. However, salvage treatment decisions, such as lymph node dissection or radiation therapy, are typically based on prostate specific antigen (PSA) recurrence. Importantly, common imaging modalities (e.g., computed tomography [CT], magnetic resonance imaging, and bone scan) are limited and the detection of recurrent disease is particularly challenging if PSA is low. Prostate specific membrane antigen (PSMA) positron-emission tomography/computed tomography (PET/CT) is a novel and promising imaging modality which aims to overcome the incapability of early identification of distant and regional metastases. Within this review, we summarize the current evidence related to PSMA-PET/CT in prostate cancer men diagnosed with biochemical recurrence after local treatment with curative intent. We discuss detection rates of PSMA-PET/CT stratified by PSA-levels and its impact on clinical decision making. Furthermore, we compare different imagefusion techniques such as PSMA-PET vs. F-/C-Choline-PET scans vs. PSMA-single photon emission computed tomography/CT. Finally, we touch upon the contemporary role of radio-guided-PSMA salvage lymphadenectomy.
After removal of a dental implant or extraction of a tooth in the upper jaw, the closure of an oroantral fistula (OAF) or oroantral communication (OAC) can be a difficult problem confronting the dentist and surgeon working in the oral and maxillofacial region. Oroantral communication (OAC) acts as a pathological pathway for bacteria and can cause infection of the antrum, which further obstructs the healing process as it is an unnatural communication between the oral cavity and the maxillary sinus. There are different ways to perform the surgical closure of the OAC. The decision-making in closure of oroantral communication and fistula is influenced by many factors. Consequently, it requires a combination of knowledge, experience, and information gathering. Previous narrative research has focused on assessments and comparisons of various surgical techniques for the closure of OAC/OAF. Thus, the decision-making process has not yet been described comprehensively.
The present study aims to illustrate all the factors that have to be considered in the management of OACs and OAFs that determine optimal treatment.
Die Steuerung biochemischer Prozesse oder die Verbesserung von Materialien erfordert zunächst ein tiefgründiges Verständnis über die zugrundeliegenden Systeme. Zur Untersuchung eignet sich Licht als ideales Werkzeug, da hiermit nützliche Informationen über die chemische Struktur, ihre Eigenschaften sowie den zusammenhängenden, schnellen Reaktionsabläufen erhalten werden können. Um die Aufklärung zu erleichtern können kleine, chemische Verbindungen eingeführt werden, welche beispielsweise ein Fluoreszenzmarker, eine photolabile Schutzgruppe oder eine photoschaltbare Verbindung sein können. Von jeweils einem Vertreter dieser Moleküle wurden unterschiedliche Studien durchgeführt, dessen Ergebnisse in dieser Arbeit in insgesamt drei Projekten zusammengefasst werden.
Zunächst wurde die Funktionalität der Helikase RhlB untersucht, die der Familie der DEAD-Box Proteine zugeordnet wird, und RNA-Duplexe in ihre Einzelstränge entwindet. Als RNA-Modellduplex diente JM2h, an dem ein RNA-Einzelstrang fluoreszenzmarkiert war (M2AP6). Die Einführung dieses Markers ermöglichte die Durchführung von statischen Fluoreszenzmessungen sowie von Mischexperimenten, die mit Hilfe der stopped-flow-Technik durchgeführt wurden. In den einleitenden Studien wurde die Helikase weggelassen, wodurch der Fokus auf den Fluoreszenzeigenschaften der RNA gelegt wurde. Die Ergebnisse hierzu zeigten, dass die Fluoreszenzintensität des Einzelstrangs durch Zugabe des komplementären Strangs deutlich abnimmt, wobei das Minimum bei einem äquimolaren Verhältnis erreicht wird. Die dazugehörigen stopped-flow-Messungen zeigten eine Beschleunigung der Hybridisierungsreaktion, wenn höhere Konzentrationen des Gegenstrangs in der Lösung vorhanden waren. Nach anschließender Zugabe der Helikase zur Lösung wurde ein Anstieg der Fluoreszenzintensität erwartet, der vom separierten Einzelstrang M2AP6 herrühren sollte. Dieser Anstieg wurde jedoch erst nach weiterer Zugabe von ATP beobachtet, der auf eine ATP-Abhängigkeit der Entwindungsreaktion von RhlB hindeutet. Diese Abhängigkeit wurde auch bereits für andere Helikasen der DEAD-Box Familie entdeckt. Die korrekte Funktionalität sowie die ATP-Abhängigkeit wurden in stopped-flow-Messungen verfiziert, bei denen der Fluoreszenzanstieg auch zeitaufgelöst betrachtet werden konnte. Für die spektralen Korrekturen der Fluoreszenzspektren wurde ein selbstgeschriebenes MATLAB-Programm namens FluCY verwendet (engl.: Fluorescence Correction & Quantum yield), welches eine schnelle und fehlerfreie Verarbeitung des Datensatzes ermöglichte.
Die zwei im folgenden beschriebenen Projekte handeln von photoaktivierbaren Molekülen. Zum einen photolabile Verbindungen, welche die Funktion z.B. eines Biomoleküls durch eine chemische Modifikation deaktivieren können. Durch eine lichtinduzierte Reaktion kommt es zur Abspaltung der Modifikation und die Funktion ist wiederhergestellt. In dieser Arbeit wurden verschiedene photolabile Schutzgruppen untersucht, die denselben Chromophor BIST (BIsStyryl-Thiophen) tragen. Durch die Einführung dieses Chromophors absorbierten sämtliche untersuchte Verbindungen sehr effizient sichtbares Licht (epsilon(445)=55.700 M^(-1) cm^(-1)), wodurch der photoinduzierte Bindungsbruch mit Wellenlängen durchgeführt werden, die bei einer biologischen Anwendungen keinen Schaden an der Zelle anrichten würden. Hieraufhin wurden in statischen und zeitaufgelösten Absorptionsmessungen Teilschritte der Freisetzungsreaktion untersucht, indem nach Photoanregung die Absorptionsänderungen auf verschiedenen Zeitskalen analysiert wurden. Die ultraschnelle Dynamik im Piko- bis Nanosekundenbereich (10^(-12)-10^(-9) s) wird durch eine spektral breite, positive Absorptionsänderng dominiert. Diese impliziert, dass die Deaktivierung über den Triplettpfad abläuft, der die vergleichsweise niedrigen Freisetzungsausbeuten erklärt (phi(u) < 5). Aufgrund des hohen Extinktionskoeffizienten reichen dennoch bereits niedrige Strahlungsdosen aus, um eine Freisetzung zu initiieren. Der geschwindigkeitsbestimmende Schritt dieser Reaktion ist dem Zerfall des aci-nitro Intermediats zugeordnet. Für ein sekundäres Amin, welches mit BIST geschützt wurde, ist eine Lebensdauer des Intermediats von 71 µs gefunden worden.
In einigen Fällen ist es erwünscht, eine vorliegende Aktivität nicht nur ein-, sondern auch ausschalten zu können, wofür photochrome Verbindungen (oder Photoschalter) verwendet werden. Die in dieser Arbeit untersuchte Verbindung ceCAM ist ein Alken-Photoschalter und vollführt bei Bestrahlung mit Licht eine cis/trans-Isomerisierung. ceCAM ist das Cyanoester-Derivat (ce) von Cumarin-substituierten Allylidenmalonat, von denen beide Konformere sehr effizient sichtbares Licht absorbieren trans: epsilon(489)=50.300 M^(-1) cm^(-1); cis: epsilon(437)=18.600 M^(-1) cm^(-1)). Andere photophysikalische Eigenschaften umfassen u.a. hohe thermische und photochemische Stabilität. Letztere wurde über ein Experiment nachgewiesen, bei dem die lichtinduzierte Isomerisierung alternierend durchgeführt wurde und selbst bei über 250 Zyklen keine signifikate Abnahme der Absorption beobachtet werden konnte. Des Weiteren konnte die Reaktion mit Quantenausbeuten von 39% (trans) und 42% (cis) induziert werden, wobei im photostationären Gleichgewicht auch hohe Isomerenverhältnisse mit bis zu 80% (trans) und 96% (cis) akkumuliert werden konnten. Die Geschwindigkeit der Reaktion wurde mit Hilfe der Ultakurzzeit-Spektroskopie untersucht. Die Dynamik im Zeitbereich von ps-ns zeigte, dass die trans/cis-Isomerisierung unterhalb von 0,5 ns und die umgekehrte Reaktion noch viel schneller (wenige ps) abgeschlossen ist. Durch die Untersuchungen in dieser Arbeit an den BIST-Verbindungen und ceCAM sind viele vorteilhafte, photophysikalische Eigenschaften charakterisiert worden, wodurch sie als verbesserte Alternative zu den bisher bekannten photolabilen Schutzgruppen oder Photoschaltern anzusehen sind.
5-lipoxygenase (5-LO) is the key enzyme in the biosynthesis of leukotrienes and specialized proresolving lipid mediators (SPM). It is mainly expressed in leukocytes and is part of the innate immune system. 5-LO can shuttle between the cytosol and the nucleus. Upon cell activation the protein translocates from soluble cellular compartments to the nuclear membrane. Besides FLAP which is required for cellular leukotriene and SPM formation, 5-LO interacts with other proteins like coactosin-like protein (CLP), Dicer, β-catenin and p53. In this review, the factors involved in the regulation of 5-LO expression, the role of 5-LO in the regulation of stem cell proliferation and differentiation and its biological functions apart from leukotriene and SPM formation are summarized.
Chirality is omnipresent in living nature. On the single molecule level, the response of a chiral species to a chiral probe depends on their respective handedness. A prominent example is the difference in the interaction of a chiral molecule with left or right circularly polarized light. In the present study, we show by Coulomb explosion imaging that circularly polarized light can also induce a chiral fragmentation of a planar and thus achiral molecule. The observed enantiomer strongly depends on the orientation of the molecule with respect to the light propagation direction and the helicity of the ionizing light. This finding might trigger new approaches to improve laser-driven enantioselective chemical synthesis.
CRFVoter : gene and protein related object recognition using a conglomerate of CRF-based tools
(2019)
Background: Gene and protein related objects are an important class of entities in biomedical research, whose identification and extraction from scientific articles is attracting increasing interest. In this work, we describe an approach to the BioCreative V.5 challenge regarding the recognition and classification of gene and protein related objects. For this purpose, we transform the task as posed by BioCreative V.5 into a sequence labeling problem. We present a series of sequence labeling systems that we used and adapted in our experiments for solving this task. Our experiments show how to optimize the hyperparameters of the classifiers involved. To this end, we utilize various algorithms for hyperparameter optimization. Finally, we present CRFVoter, a two-stage application of Conditional Random Field (CRF) that integrates the optimized sequence labelers from our study into one ensemble classifier.
Results: We analyze the impact of hyperparameter optimization regarding named entity recognition in biomedical research and show that this optimization results in a performance increase of up to 60%. In our evaluation, our ensemble classifier based on multiple sequence labelers, called CRFVoter, outperforms each individual extractor’s performance. For the blinded test set provided by the BioCreative organizers, CRFVoter achieves an F-score of 75%, a recall of 71% and a precision of 80%. For the GPRO type 1 evaluation, CRFVoter achieves an F-Score of 73%, a recall of 70% and achieved the best precision (77%) among all task participants.
Conclusion: CRFVoter is effective when multiple sequence labeling systems are to be used and performs better then the individual systems collected by it.
Congenitally blind individuals have been shown to activate the visual cortex during non-visual tasks. The neuronal mechanisms of such cross-modal activation are not fully understood. Here, we used an auditory working memory training paradigm in congenitally blind and in sighted adults. We hypothesized that the visual cortex gets integrated into auditory working memory networks, after these networks have been challenged by training. The spectral profile of functional networks was investigated which mediate cross-modal reorganization following visual deprivation. A training induced integration of visual cortex into task-related networks in congenitally blind individuals was expected to result in changes in long-range functional connectivity in the theta-, beta- and gamma band (imaginary coherency) between visual cortex and working memory networks. Magnetoencephalographic data were recorded in congenitally blind and sighted individuals during resting state as well as during a voice-based working memory task; the task was performed before and after working memory training with either auditory or tactile stimuli, or a control condition. Auditory working memory training strengthened theta-band (2.5-5 Hz) connectivity in the sighted and beta-band (17.5-22.5 Hz) connectivity in the blind. In sighted participants, theta-band connectivity increased between brain areas typically involved in auditory working memory (inferior frontal, superior temporal, insular cortex). In blind participants, beta-band networks largely emerged during the training, and connectivity increased between brain areas involved in auditory working memory and as predicted, the visual cortex. Our findings highlight long-range connectivity as a key mechanism of functional reorganization following congenital blindness, and provide new insights into the spectral characteristics of functional network connectivity.
We study how the informativeness of stock prices changes with the presence of high-frequency trading (HFT). Our estimate is based on the staggered start of HFT participation in a panel of international exchanges. With HFT presence, market prices are a less reliable predictor of future cash flows and investment, even more so for longer horizons. Further, firm-level idiosyncratic volatility decreases, and the holdings and trades by institutional investors deviate less from the market-capitalization weighted portfolio as a benchmark. Our results document that the informativeness of prices decreases subsequent to the start of HFT. These findings are consistent with theoretical models of HFTs' ability to anticipate informed order flow, resulting in decreased incentives to acquire fundamental information.
Purpose: Prisoners have a higher risk of suicide compared to non-incarcerated individuals. One aim of suicide prevention for prisoners is to identify risk factors in order to put stronger support mechanisms in place for the more vulnerable detainees. This study investigates the suicide risk (SR) in offence-related sub-populations in a representative German sample and differentiates between SR for adolescent and adult prisoners.
Methods: Conducting a national study with data from public German records on the entire prison population from 2000 to 2016 and suicide numbers in German prisons in the same period, SR was calculated for the total male prison population as well as for both subgroups, adolescent and adult male prisoners.
Results: In the study period, male prisoners spent 959.584 life years (LY) in German criminal detention. Among those, 524 prisoners died of suicide. SR was higher for detainees imprisoned for an offence resulting in extensive physical harm for another person, e.g. homicide (suicide rate = 134,8 suicides per 100.000 LY; OR = 2,47; CI95%: 1,98–3,08), bodily injury (suicide rate = 87,3; OR = 1,60; CI95%: 1,29–1,99), and sexual offences (suicide rate = 84,2; OR = 1,54; CI95%: 1,18–2,01) compared with the SR of the total prison population (suicide rate = 54.6). Age differences between offence-related SR were found for theft, with adolescents (suicide rate = 69,3; OR = 1,25; CI95%: 0,85–1,84) showing higher SR than adults (suicide rate = 38,2; OR = 0,7; CI95%: 0,54–0,92).
Conclusion: The index offence of detainees is associated with SR and age-related differences exist. Suicide prevention in prisons should take both into account to determine populations at risk.
We study the well-known resonance ψ(4040), corresponding to a 33S1 charm–anticharm vector state ψ(3S), within a QFT approach, in which the decay channels into DD, D∗D, D∗D∗, DsDs and D∗s Ds are considered. The spectral function shows sizable deviations from a Breit–Wigner shape (an enhancement, mostly generated by DD∗loops, occurs); moreover, besides the c ¯ c pole of ψ(4040), a second dynamically generated broad pole at 4 GeV emerges. Naively, it is tempting to identify this new pole with the unconfirmed state Y (4008). Yet, this state was not seen inthe reaction e+e− → ψ(4040) → DD∗, but in processes with π+π−J/ψ in the final state. A detailed study shows a related but different mechanism: a broad peak at 4GeV in the process e+e− → ψ(4040) → DD∗ → π+π−J/ψ appears when DD∗ loops are considered. Its existence in this reaction is not necessarily connected to the existence of a dynamically generated pole, but the underlying mechanism – the strong coupling of c ¯ c to DD∗ loops – can generate both of them. Thus, the controversial state Y (4008) may not be a genuine resonance, but a peak generated by the ψ(4040) and D∗D loops with π+π−J/ψ in the final state.
We investigate the well-known vector state ψ(4040) in the frame-work of a quantum field theoretical model. In particular, we study its spectral function and search for the pole(s) in the complex plane. Quite interestingly, the spectral function has a non-standard shape and two poles are present. The role of the meson-meson quantum loops (in particular DD* ones) is crucial and could also explain the not yet conformed “state” Y(4008).
As a first step, a simple and pedagogical recall of the η-η′ system is presented, in which the role of the axial anomaly, related to the heterochiral nature of the multiplet of (pseudo)scalar states, is underlined. As a consequence, η is close to the octet and η′ to the singlet configuration. On the contrary, for vector and tensor states, which belong to homochiral multiplets, no anomalous contribution to masses and mixing is present. Then, the isoscalar physical states are to a very good approximation nonstrange and strange, respectively. Finally, for pseudotensor states, which are part of an heterochiral multiplet (just as pseudoscalar ones), a sizable anomalous term is expected: η2(1645) roughly corresponds to the octet and η2(1870) to the singlet.
Charmonia with different transverse momentum pT usually comes from different mechanisms in the relativistic heavy ion collisions. This work tries to review the theoretical studies on quarkonium evolutions in the deconfined medium produced in p-Pb and Pb-Pb collisions. The charmonia with high pT are mainly from the initial hadronic collisions, and therefore sensitive to the initial energy density of the bulk medium. For those charmonia within 0.1 < pT < 5 GeV/c at the energies of Large Hadron Collisions (LHC), They are mainly produced by the recombination of charm and anti-charm quarks in the medium. In the extremely low pT ∼ 1/RA (RA is the nuclear radius), additional contribution from the coherent interactions between electromagnetic fields generated by one nucleus and the target nucleus plays a non-negligible role in the J/ψ production even in semi-central Pb-Pb collisions.
Background: Posttraumatic stress disorder (PTSD) after childhood abuse (CA) is often related to severe co-occurring psychopathology, such as symptoms of borderline personality disorder (BPD). The ICD-11 has included Complex PTSD as a new diagnosis, which is defined by PTSD symptoms plus disturbances in emotion regulation, self-concept, and interpersonal relationships. Unfortunately, the empirical database on psychosocial treatments for survivors of CA is quite limited. Furthermore, the few existing studies often have either excluded subjects with self-harm behaviour and suicidal ideation — which is common behaviour in subjects suffering from Complex PTSD. Thus, researchers are still trying to identify efficacious treatment programmes for this group of patients.
We have designed DBT-PTSD to meet the specific needs of patients with Complex PTSD. The treatment programme is based on the rules and principles of dialectical behavioural therapy (DBT), and adds interventions derived from cognitive behavioural therapy, acceptance and commitment therapy and compassion-focused therapy. DBT-PTSD can be provided as a comprehensive residential programme or as an outpatient programme. The effects of the residential programme were evaluated in a randomised controlled trial. Data revealed significant reduction of posttraumatic symptoms, with large between-group effect sizes when compared to a treatment-as-usual wait list condition (Cohen’s d = 1.5).
The first aim of this project on hand is to evaluate the efficacy of the outpatient DBT-PTSD programme. The second aim is to identify the major therapeutic variables mediating treatment efficacy. The third aim is to study neural mechanisms and treatment sensitivity of two frequent sequelae of PTSD after CA: intrusions and dissociation.
Methods: To address these questions, we include female patients who experienced CA and who fulfil DSM-5 criteria for PTSD plus borderline features, including criteria for severe emotion dysregulation. The study is funded by the German Federal Ministry of Education and Research, and started in 2014. Participants are randomised to outpatient psychotherapy with either DBT-PTSD or Cognitive Processing Therapy. Formal power analysis revealed a minimum of 180 patients to be recruited. The primary outcome is the change on the Clinician-Administered PTSD Scale for DSM-5.
Discussion: The expected results will be a major step forward in establishing empirically supported psychological treatments for survivors of CA suffering from Complex PTSD.
Trial registration: German Clinical Trials Register: registration number DRKS00005578, date of registration 19 December 2013.
Synthesis and SAR of the antistaphylococcal natural product nematophin from Xenorhabdus nematophila
(2019)
The repeated and improper use of antibiotics had led to an increased number of multiresistant bacteria. Therefore, new lead structures are needed. Here, the synthesis and an expanded structure–activity relationship of the simple and antistaphylococcal amide nematophin from Xenorhabdus nematophila and synthetic derivatives are described. Moreover, the synthesis of intrinsic fluorescent derivatives, incorporating azaindole moieties was achieved for the first time.
Background: While the incidence and aspects of pneumonia in ICU patients has been extensively discussed in the literature, studies on the occurrence of pneumonia in severely injured patients are rare. The aim of the present study is to elucidate factors associated with the occurrence of pneumonia in severely injured patients with thoracic trauma.
Setting: Level-I University Trauma Centres associated with the TraumaRegister DGU®.
Methods: A total of 1162 severely injured adult patients with thoracic trauma documented in the TraumaRegister DGU® (TR-DGU) were included in this study. Demographic data, injury severity, duration of mechanical ventilation (MV), duration of ICU stay, occurrence of pneumonia, bronchoalveolar lavage, aspiration, pathogen details, and incidences of mortality were evaluated. Statistical evaluation was performed using SPSS (Version 25.0, SPSS, Inc.) software.
Results: The overall incidence of pneumonia was 27.5%. Compared to patients without pneumonia, patients with pneumonia had sustained more severe injuries (mean ISS: 32.6 vs. 25.4), were older (mean age: 51.3 vs. 47.5) and spent longer periods under MV (mean: 368.9 h vs. 114.9 h). Age, sex (male), aspiration, and duration of MV were all independent predictors for pneumonia occurrence in a multivariate analysis. The cut-off point for duration of MV that best discriminated between patients who would and would not develop pneumonia during their hospital stay was 102 h. The extent of thoracic trauma (AISthorax), ISS, and presence of pulmonary comorbidities did not show significant associations to pneumonia incidence in our multivariate analysis. No significant difference in mortality between patients with and without pneumonia was observed.
Conclusions: Likelihood of pneumonia increases with age, aspiration, and duration of MV. These parameters were not found to be associated with differences in outcomes between patients with and without pneumonia. Future studies should focus on independent parameters to more clearly identify severely injured subgroups with a high risk of developing pneumonia.
Level of evidence: Level II - Retrospective medical record review.
Glioblastoma is one of the deadliest malignancies and is virtually incurable. Accumulating evidence indicates that a small population of cells with a stem-like phenotype is the major culprit of tumor recurrence. Enhanced DNA repair capacity and expression of stemness marker genes are the main characteristics of these cells. Elimination of this population might delay or prevent tumor recurrence following radiochemotherapy. The aim of this study was to analyze whether interference with the Hedgehog signaling (Hh) pathway or combined Hh/Notch blockade using small-molecule inhibitors can efficiently target these cancer stem cells and sensitize them to therapy. Using tumor sphere lines and primary patient-derived glioma cultures we demonstrate that the Hh pathway inhibitor GANT61 (GANT) and the arsenic trioxide (ATO)-mediated Hh/Notch inhibition are capable to synergistically induce cell death in combination with the natural anticancer agent (−)-Gossypol (Gos). Only ATO in combination with Gos also strongly decreased stemness marker expression and prevented sphere formation and recovery. These synergistic effects were associated with distinct proteomic changes indicating diminished DNA repair and markedly reduced stemness. Finally, using an organotypic brain slice transplantation model, we show that combined ATO/Gos treatment elicits strong growth inhibition or even complete elimination of tumors. Collectively, our data show for the first time that ATO and Gos, two drugs that can be used in the clinic, represent a promising targeted therapy approach for the synergistic elimination of glioma stem-like cells.
Current technologies used to generate CRISPR/Cas gene perturbation reagents are labor intense and require multiple ligation and cloning steps. Furthermore, increasing gRNA sequence diversity negatively affects gRNA distribution, leading to libraries of heterogeneous quality. Here, we present a rapid and cloning-free mutagenesis technology that can efficiently generate covalently-closed-circular-synthesized (3Cs) CRISPR/Cas gRNA reagents and that uncouples sequence diversity from sequence distribution. We demonstrate the fidelity and performance of 3Cs reagents by tailored targeting of all human deubiquitinating enzymes (DUBs) and identify their essentiality for cell fitness. To explore high-content screening, we aimed to generate the largest up-to-date gRNA library that can be used to interrogate the coding and noncoding human genome and simultaneously to identify genes, predicted promoter flanking regions, transcription factors and CTCF binding sites that are linked to doxorubicin resistance. Our 3Cs technology enables fast and robust generation of bias-free gene perturbation libraries with yet unmatched diversities and should be considered an alternative to established technologies.
The paper outlines a method for investigating the speed effect due to a time limit in testing. It is assumed that the time limit enables latent processing speed to influence responses by causing omissions in the case of insufficient speed. Because of processing speed as additional latent source, the customary confirmatory factor model is enlarged by a second latent variable representing latent processing speed. For distinguishing this effect from other method effects, the factor loadings are fixed according to the cumulative normal distribution. With the second latent variable added, confirmatory factor analysis of reasoning data (N=518) including omissions because of a time limit yielded good model fit and discriminated the speed effect from other possible effects due to the item difficulty, the homogeneity of an item subset and the item positions. Because of the crucial role of the cumulative normal distribution for fixing the factor loadings a check of the normality assumption is also reported.
Discovery of key whole-brain transitions and dynamics during human wakefulness and non-REM sleep
(2019)
The modern understanding of sleep is based on the classification of sleep into stages defined by their electroencephalography (EEG) signatures, but the underlying brain dynamics remain unclear. Here we aimed to move significantly beyond the current state-of-the-art description of sleep, and in particular to characterise the spatiotemporal complexity of whole-brain networks and state transitions during sleep. In order to obtain the most unbiased estimate of how whole-brain network states evolve through the human sleep cycle, we used a Markovian data-driven analysis of continuous neuroimaging data from 57 healthy participants falling asleep during simultaneous functional magnetic resonance imaging (fMRI) and EEG. This Hidden Markov Model (HMM) facilitated discovery of the dynamic choreography between different whole-brain networks across the wake-non-REM sleep cycle. Notably, our results reveal key trajectories to switch within and between EEG-based sleep stages, while highlighting the heterogeneities of stage N1 sleep and wakefulness before and after sleep.
Background: Peritonitis is responsible for thousands of deaths annually in Germany alone. Even source control (SC) and antibiotic treatment often fail to prevent severe sepsis or septic shock, and this situation has hardly improved in the past two decades. Most experimental immunomodulatory therapeutics for sepsis have been aimed at blocking or dampening a specific pro-inflammatory immunological mediator. However, the patient collective is large and heterogeneous. There are therefore grounds for investigating the possibility of developing personalized therapies by classifying patients into groups according to biomarkers. This study aims to combine an assessment of the efficacy of treatment with a preparation of human immunoglobulins G, A, and M (IgGAM) with individual status of various biomarkers (immunoglobulin level, procalcitonin, interleukin 6, antigen D-related human leucocyte antigen (HLA-DR), transcription factor NF-κB1, adrenomedullin, and pathogen spectrum).
Methods/design: A total of 200 patients with sepsis or septic shock will receive standard-of-care treatment (SoC). Of these, 133 patients (selected by 1:2 randomization) will in addition receive infusions of IgGAM for 5 days. All patients will be followed for approximately 90 days and assessed by the multiple-organ failure (MOF) score, by the EQ QLQ 5D quality-of-life scale, and by measurement of vital signs, biomarkers (as above), and survival.
Discussion: This study is intended to provide further information on the efficacy and safety of treatment with IgGAM and to offer the possibility of correlating these with the biomarkers to be studied. Specifically, it will test (at a descriptive level) the hypothesis that patients receiving IgGAM who have higher inflammation status (IL-6) and poorer immune status (low HLA-DR, low immunoglobulin levels) have a better outcome than patients who do not receive IgGAM. It is expected to provide information that will help to close the knowledge gap concerning the association between the effect of IgGAM and the presence of various biomarkers, thus possibly opening the way to a personalized medicine.
Trial registration: EudraCT, 2016–001788-34; ClinicalTrials.gov, NCT03334006. Registered on 17 Nov 2017.
Trial sponsor: RWTH Aachen University, represented by the Center for Translational & Clinical Research Aachen (contact Dr. S. Isfort).
Glaubt man Hermann Parzinger, entsteht in Berlin das würdige Zentrum einer Art Welthauptstadt: "Das Humboldt Forum: 'So viel Welt mit sich verbinden als möglich'"– das ist der Titel des 2011 herausgegebenen Folianten der Stiftung Preußischer Kulturbesitz, deren Präsident Parzinger ist. Die markigen Worte umreißen das Ziel des "wichtigsten Kulturprojekts in Deutschland zu Beginn des 21. Jahrhunderts", wie es im Untertitel heißt. "So viel Welt mit sich verbinden als möglich". Von wem stammt dieses werbewirksame Schlagwort? Und: Wie ist dieses Verbinden zu denken? [...] Mich interessiert hier und im Folgenden der erste Kontakt, der sich im Verb "ergreifen" ausdrückt. Offensichtlich setzt die Etablierung einer möglichst engen Verbindung von 'Mensch' und 'Welt' ein initiales Moment voraus, ein aktives Zupacken durch das Subjekt, das in der Folge die Fusion beider allererst ermöglicht. Das Ergreifen von "so viel Welt, als möglich" bildet das Fundament für humanistische Allgemeinbildung im Humboldt’schen Sinne: "[D]iese Aufgabe löst sich allein durch die Verknüpfung unsres Ich mit der Welt zu der allgemeinsten, regesten und freiesten Wechselwirkung." Angesichts der kontrovers geführten Kolonialismus-Debatte um das Humboldt-Forum ist es bemerkenswert, dass Parzingers Werbetext das Ergreifen tilgt, negiert er doch damit auch ein mögliches Gewaltmoment. Schließlich wurden Kolonien zuerst ergriffen, gewaltsam ein-genommen, bevor es zu einem zumindest einseitig produktiven Austausch von Waren, Kunst und dergleichen, zu einer "Verknüpfung" kommen konnte. Indem der Text die Kontaktanbahnung, das Ausgreifen verschweigt, kaschiert er damit auch das preußisch-imperiale Erbe. Wie sehr aber wirkt in jener Humboldt’schen Verbindung von Bildungssubjekt und Welt die initiale Gewalt fort, die an ihrem Anfang steht? Wie ist das Verhältnis von der "freiesten Wechselwirkung", also einer reziproken Interaktion, zum aggressiven, aktiven Ergreifen? Diese Fragen und der imperiale Wunsch, Berlin möge mit dem Humboldt-Forum nun zur "Angelegenheit der gesamten Welt werden", führen zu 'dem' Modell und Phantasma einer Welthauptstadt – zu Rom, genauer zum Rom Johann Wolfgang von Goethes.
In der Erinnerungskultur der Goethezeit spielt das haptische Erleben von Souvenirs eine entscheidende Rolle – im taktilen Umgang mit Andenken werden über Form, Materialität und Funktion Abwesende vergegenwärtigt, Erinnerungen und Gefühle evoziert. Nachvollziehbar wird die Kultivierung und Reflexion dieser Praktik der Erinnerungskultur in dem sehr gut überlieferten Nachlass von Johann Wolfgang von Goethe, der von der Klassik Stiftung Weimar bewahrt wird. Obwohl Goethe dem Tastsinn jegliche Erkenntnisfähigkeit abspricht und ihn als den niedersten der Sinne diskreditiert, werden das Berühren und Berührtwerden von Körpern und Dingen in seinen literarischen Werken sowie insbesondere in seinen privaten Korrespondenzen variantenreich verhandelt. Eingebettet in empfindsame Liebessemantik, assoziiert mit religiösen Praktiken und medizinischen Diskursen oder verknüpft mit erotischen Momenten ist die Berührung ein wiederkehrender Gegenstand expliziter und impliziter Auseinandersetzungen.
Für Aristoteles gleicht das Drama einem 'zóon', einem Lebewesen mit Anfang, Mitte und Ende. Gemeint sind Entstehung, Ausgestaltung und Abschluss der Handlungsstruktur, und zwar als 'psyché', als Seele, des Dramas. Aus einem Blickwinkel, der weniger am 'dráma' und mehr an den körperlichen Dimensionen des Theaters orientiert ist, ließe sich Aristoteles’ Vergleich auch zur Frage nach einer Organologie des Theaters und ihrer politischen und sinnesphysiologischen Implikationen wenden. Darum geht es mir im Folgenden – für ein unterschätztes Organ: für die Füße.
Air-sea feedbacks between the Mediterranean Sea and the atmosphere on various temporal and spatial scales play a major role in the Mediterranean regional climate system and beyond. The Mediterranean Sea is a source of moisture due to excess evaporation and, on a long-term average, is associated with a warming of the lower atmosphere in contact with the sea surface due to heat loss at the air-sea interface. The complex air-sea interactions and feedbacks in the Mediterranean basin strongly modulate the sea surface fluxes and favor several cyclogenetic activities under certain meteorological conditions. Examples of such cyclonic activities are medicanes (Mediterranean hurricanes) and Vb-cyclones. Medicanes are mesoscale, marine, and warm-core Mediterranean cyclones that exhibit some similarities to tropical cyclones, while Vb-cyclones are extra-tropical cyclones, that propagate from the Western Mediterranean Sea and travel across the Eastern European Alps into the Central European region. Extremely strong winds and heavy precipitation associated with these cyclones can lead to severe destruction and flooding. Changes in the intensity and frequency of these cyclones are also projected under changing future climate conditions, where the Mediterranean region has been identified as a hotspot in terms of rising temperatures.
The development of high-resolution regional climate models (RCMs) has progressed our understanding of the processes characterizing the Mediterranean climate. However, large uncertainties still exist regarding the estimates of air-sea fluxes, which, in turn, affect the simulation of the Mediterranean climate. Several factors can be attributed to such discrepancies, such as data quality, temporal and spatial resolution, and the misrepresentation of physical processes. To overcome some of these inconsistencies and deficiencies of the existing climate simulations, a new high-resolution atmosphere-ocean regional coupled model (AORCM) has been developed to simulate the air-sea feedback mechanisms. This coupled model incorporates the coupling of RCM COSMO-CLM (CCLM) and the regional ocean model NEMO-MED12 for the Mediterranean Sea (MED) as well as NEMO-NORDIC for the North- and Baltic Sea (NORDIC). Several experiments were performed using both the coupled and uncoupled models to investigate the impact of air-sea interactions and feedbacks on sea surface heat fluxes, wind speed, and on the formation of Mediterranean cyclones (i.e., medicanes and Vb-cyclones). These experiments were performed using different horizontal atmospheric grid resolutions to analyze the effect of resolution on sea surface heat fluxes, wind speed, and the development of medicanes.
The results of the present study indicate that a finer atmospheric grid resolution ([is as appreciated as]9 vs. [is as appreciated as]50 km) improved the wind speed simulations (particularly near coastal areas) and subsequently improved the simulations of the turbulent heat fluxes. Both parameters were better simulated in the coupled simulations than in the uncoupled simulations, but coupling introduced a warm SST bias in winter. Radiation fluxes were slightly better represented in coarse-grid simulations than in fine-grid simulations. However, the higher-resolution coupled model could reproduce the observed net outgoing total surface heat flux over the Mediterranean Sea. In addition to that sub diurnal SST variations have a strong effect on sub-daily heat fluxes and wind speed but minor effects at longer timescales. Regarding the impact of atmospheric grid resolution ([is as appreciated as]50, 25, and [is as appreciated as]9 km) and ocean coupling on medicanes, it was detected that the coupled model with a finer atmospheric grid ([is as appreciated as]9 km) was able to not only reproduce most medicane events, but also improved the track length, warm core, and wind speed compared to the uncoupled model. The coupled model with the coarse-grid ([is as appreciated as]50 and [is as appreciated as]25 km) did not show any improvement in simulating medicanes compared to the uncoupled model. The spectral nudging technique, applied on the wind components above 850 hPa in the interior domain to keep large-scale circulation close to the driving data (i.e., ERAInterim reanalysis), improved the accuracy of the times and locations of generated medicanes, but no improvement was found in the track length and intensity.
Concerning the role of the Mediterranean Sea coupling on Vb cyclones, the investigation showed that atmosphere-ocean coupling had an overall positive impact, although with a strong case-by-case variation, on the trajectories and intensity of Vb-cyclones as a result of the variation in moisture source for each event. In general, all model configurations could replicate Vbcyclones, their trajectories, and associated precipitation fields. The average structure of the precipitation field was best represented in the coupled simulations. Coupling of the North- and Baltic Seas also showed an improvement in some of the simulated Vb-cyclones.
The atmosphere-ocean coupling showed an overall positive impact on the simulation of sea surface heat fluxes and Mediterranean cyclones (medicanes and Vb-cyclones). Moreover, the representation of sea surface heat fluxes, wind speed, and medicane features was more realistic when using a finer atmospheric grid resolution (less than 10 km). The present study suggests that the combination of a finer atmospheric grid resolution together with atmosphere-ocean coupling is advantageous in simulating the Mediterranean climate system.
During the past 15 years there have been dramatic changes in the medical landscape, particularly in oncology and regenerative medicine. Cell therapies have played a substantial part in this progress. Cellular immunotherapies can use immune cells, such as T cells or natural killer cells that, after functional modification ex vivo, exert powerful anti-cancer effects when given to the patient. Innovative technologies, such as re-programming terminally differentiated cells into pluripotent stem cells or into other cell types and applying specific enzymes to more precisely edit the human genome, are paving the way towards more potent cell and gene therapies.
Mesenchymal stromal cells are promising cellular immunotherapeutics, which also have potential for use in tissue engineering strategies and other regenerative medicine applications. However, substantial gaps in our knowledge of their biology and therapeutic efficacy present major challenges to their sustainable implementation in the clinical routine.
In this article, progress in the field of cell therapeutics during the past 15 years will be briefly discussed, with a focus on mesenchymal stromal cells, highlighting the impact of this field on patient care.
Memory impairments are a major characteristic of schizophrenia (SZ). In the current study, we used an associative memory task to test the hypothesis that SZ patients and first-degree relatives have altered functional patterns in comparison to healthy controls. We analyzed the fMRI activation pattern during the presentation of a face-name task in 27 SZ patients, 23 first-degree relatives, and 27 healthy controls. In addition, we performed correlation analyses between individual psychopathology, accuracy and reaction time of the task and the beta scores of the functional brain activations. We observed a lower response accuracy and increased reaction time during the retrieval of face-name pairs in SZ patients compared with controls. Deficient performance was accompanied by abnormal functional activation patterns predominantly in DMN regions during encoding and retrieval. No significant correlation between individual psychopathology and neuronal activation during encoding or retrieval of face-name pairs was observed. Findings of first-degree relatives indicated slightly different functional pattern within brain networks in contrast to controls without significant differences in the behavioral task. Both the accuracy of memory performance as well as the functional activation pattern during retrieval revealed alterations in SZ patients, and, to a lesser degree, in relatives. The results are of potential relevance for integration within a comprehensive model of memory function in SZ. The development of a neurophysiological model of cognition in psychosis may help to clarify and improve therapeutic options to improve memory and functioning in the illness.
Numerous cell–cell and cell–matrix interactions within the bone marrow microenvironment enable the controlled lifelong self-renewal and progeny of hematopoietic stem and progenitor cells (HSPCs). On the cellular level, this highly mutual interaction is granted by cell adhesion molecules (CAMs) integrating differentiation, proliferation, and pro-survival signals from the surrounding microenvironment to the inner cell. However, cell–cell and cell–matrix interactions are also critically involved during malignant transformation of hematopoietic stem/progenitor cells. It has become increasingly apparent that leukemia-associated gene products, such as activated tyrosine kinases and fusion proteins resulting from chromosomal translocations, directly regulate the activation status of adhesion molecules, thereby directing the leukemic phenotype. These observations imply that interference with adhesion molecule function represents a promising treatment strategy to target pre-leukemic and leukemic lesions within the bone marrow niche. Focusing on myeloid leukemia, we provide a current overview of the mechanisms by which leukemogenic gene products hijack control of cellular adhesion to subsequently disturb normal hematopoiesis and promote leukemia development.
IKZF1 deletion (ΔIKZF1) is an important predictor of relapse in both childhood and adult B-cell precursor acute lymphoblastic leukemia (B-ALL). Previously, we revealed that COBL is a hotspot for breakpoints in leukemia and could promote IKZF1 deletions. Through an international collaboration, we provide a detailed genetic and clinical picture of B-ALL with COBL rearrangements (COBL-r). Patients with B-ALL and IKZF1 deletion (n = 133) were included. IKZF1 ∆1-8 were associated with large alterations within chromosome 7: monosomy 7 (18%), isochromosome 7q (10%), 7p loss (19%), and interstitial deletions (53%). The latter included COBL-r, which were found in 12% of the IKZF1 ∆1-8 cohort. Patients with COBL-r are mostly classified as intermediate cytogenetic risk and frequently harbor ETV6, PAX5, CDKN2A/B deletions. Overall, 56% of breakpoints were located within COBL intron 5. Cryptic recombination signal sequence motifs were broadly distributed within the sequence of COBL, and no enrichment for the breakpoint cluster region was found. In summary, a diverse spectrum of alterations characterizes ΔIKZF1 and they also include deletion breakpoints within COBL. We confirmed that COBL is a hotspot associated with ΔIKZF1, but these rearrangements are not driven by RAG-mediated recombination.
Background: Posaconazole (POS) is a potent triazole antifungal agent approved in adults for treatment and prophylaxis of invasive fungal infections (IFIs). The objectives of this study were to evaluate the pharmacokinetics (PK), safety, and tolerability of POS oral suspension in pediatric subjects with neutropenia.
Methods: This was a prospective, multicenter, sequential dose-escalation study. Enrolled subjects were divided into 3 age groups: AG1, 7 to <18 years; AG2, 2 to <7 years; and AG3, 3 months to <2 years. AG1 and AG2 were divided into 3 dosage cohorts: DC1, 12 mg/kg/day divided twice daily (BID); DC2, 18 mg/kg/day BID; and DC3, 18 mg/kg/day divided thrice daily (TID). AG3 was also divided into DC1 and DC2; however, no subjects were enrolled in DC2. Subjects received 7–28 days of POS oral suspension. PK samples were collected at predefined time points. The POS PK target was predefined as ~90% of subjects with Cavg (AUC /dosing interval) between 500 and 2500 ng/mL, with an anticipated mean steady state Cavg exposure of ~1200 ng/mL.
Results: The percentage of subjects meeting the PK target was <90% across all age groups and dosage cohorts (range: 31% to 80%). The percentage of subjects that achieved the Cavg target of 500 to 2500 ng/mL on Day 7 ranged from 31% to 80%, with the lowest proportion in subjects 2 to <7 years receiving 12 mg/kg/day BID (AG2/DC1) and the highest proportion in subjects 7 to <18 years receiving 18 mg/kg/day TID (AG1/DC3). At all three dose levels (12 mg/kg/day BID, 18 mg/kg/day BID and 18 mg/kg/day TID), subjects in AG1 (7 to <18 years old) had higher mean PK exposures at steady state than those in AG2. High variability in exposures was observed in all groups. POS oral suspension was generally well tolerated and most of the reported adverse events were related to the subjects’ underlying diseases.
Conclusion: The POS PK target of 90% of subjects with Cavg between 500 and 2500 ng/mL was not achieved in any of the age groups across the different dosage cohorts. New formulations of the molecule with a greater potential to achieve the established PK target are currently under investigation.
Trial registration: ClinicalTrials.gov identifier: NCT01716234
In this note, we first highlight different developments for banks under direct ECB supervision within the SSM that may prompt further investigation by supervisors. We find that banks that were weakly capitalized at the start of direct ECB supervision (1) still face elevated levels of non-performing loans, (2) are less cost-efficient and (3) reduced their share of subordinated debt financing over the last years. We then stress the importance of continuous and ongoing cost-benefit analysis regarding banking supervision in Europe. We also encourage processes to question existing supervisory practices to ensure a lean and efficient banking supervision. Finally, we underline the need of continuous and intensified coordination among regulatory bodies in the Banking Union since the efficacy of European bank supervision rests on its interplay with many different institutions.
This document was requested by the European Parliament's Committee on Economic and Monetary Affairs. It was originally published on the European Parliament’s webpage.
Nach der 2008 startenden Finanzmarktkrise sind Maßnahmen zur Regulierung und Stabilisierung der Finanzmärkte in das Zentrum der politischen und der gesellschaftlichen Aufmerksamkeit gerückt. Insbesondere die hohen fiskalischen Kosten der Staaten zur Stützung ihrer Bankensysteme sowie die volkswirtschaftlichen Kosten infolge des Einbruchs des Wirtschaftswachstums in den Jahren nach der Insolvenz der US Investmentbank Lehman Brothers hatten einen globalen Konsens über die Notwendigkeit neuer Regulierungsmaßnahmen zur Folge. Im Ergebnis wurden das internationale Regulierungswerk Basel III sowie weitere nationale Maßnahmen zur Stabilisierung des Finanzsektors neu konzipiert und in Europa im Wege einer in nationales Recht umzusetzenden Richtlinie (die Capital Require-ments Directive IV - CRD IV) sowie einer Verordnung (die Capital Requirements Regulation CRR, welche unmittelbar geltendes Recht darstellt) eingeführt.
Vor diesem Hintergrund analysiert das vorliegende interdisziplinäre Gutachten die Auswirkungen der Regulierungsmaßnahmen, die zwischen 2008 bis zu Beginn des Jahres 2018 umgesetzt wurden auf dem deutschen Finanzsektor.
In diesem explorativen Beitrag machen wir uns Gedanken über die Zukunft von Deutscher Bank und Commerzbank und entwickeln einen neuen Zugang zu dem Thema: Statt einer Fusion von DB und CB schlagen wir eine Teilfusion nur der Datenzentren vor – es entsteht auf diese Weise die Grundlage für eine Open Banking Plattform als „utility“, also als Betrieb im Eigentum der Nutzer, an der perspektivisch weitere Finanzinstitute teilnehmen können. Die über die Daten kooperierenden Institute bleiben mit Blick auf Produkte und Dienstleistungen unverändert Konkurrenten – „national champions“ entstehen auf diese Weise nicht. Aber es wird damit in Europa die Basis für einen erfolgversprechenden Wettbewerb mit den großen Datenplattformen aus USA und China (Facebook, Amazon, Alipay) gelegt, die früher oder später in den Finanzmarkt eindringen werden. Das von uns vorgeschlagene Modell einer offenen Datenplattform für Banken verhindert das Entstehen von „national champions“ und schützt damit auch das Kernanliegen der Bankenunion: Die Schaffung eines Finanzsystems, dessen Banken jede für sich ausscheiden können ohne eine systemische Krise auszulösen, und ohne den Steuerzahler zu einer Rettungsaktion zu zwingen
Purpose: To review the role of radiotherapy (RT) in the treatment of renal cell cancer (RCC) in the curative and palliative setting.
Content: Details related to the clinical outcomes of primary, preoperative, postoperative and palliative RT are discussed, along with a presentation of the established role of surgery and systemic therapy. An overview of data derived from mono- and multi-institutional trials is provided.
Conclusion: Radiotherapy has been shown to provide good symptom palliation and local control in RCC depending on the dose that can be delivered. There is emerging data suggesting that with the use of high-precision RT methods the indication spectrum of RT can be exploited covering different clinical situations particularly for unresectable local recurrences and oligometastatic disease.
The interdependence of selective cues during development of regulatory T cells (Treg cells) in the thymus and their suppressive function remains incompletely understood. Here, we analyzed this interdependence by taking advantage of highly dynamic changes in expression of microRNA 181 family members miR-181a-1 and miR-181b-1 (miR-181a/b-1) during late T-cell development with very high levels of expression during thymocyte selection, followed by massive down-regulation in the periphery. Loss of miR-181a/b-1 resulted in inefficient de novo generation of Treg cells in the thymus but simultaneously permitted homeostatic expansion in the periphery in the absence of competition. Modulation of T-cell receptor (TCR) signal strength in vivo indicated that miR-181a/b-1 controlled Treg-cell formation via establishing adequate signaling thresholds. Unexpectedly, miR-181a/b-1–deficient Treg cells displayed elevated suppressive capacity in vivo, in line with elevated levels of cytotoxic T-lymphocyte–associated 4 (CTLA-4) protein, but not mRNA, in thymic and peripheral Treg cells. Therefore, we propose that intrathymic miR-181a/b-1 controls development of Treg cells and imposes a developmental legacy on their peripheral function.
Das Phänomen Straßenmusik: Teil einer städtischen Identität? : eine Analyse am Fallbeispiel Dublin
(2019)
The objective of this work is to understand the significance of street music for the city of Dublin and to what extent street music is part of the collective identity of its inhabitants. The idea behind this topic is this: A modern city stands for concentrated diversity. Despite this enormous diversity of people, ideas and beliefs, there are certain factors that every identity in a city shares: in this case, it is the street music. The work first introduces the research „Das Dublin Projekt. Die Rolle der Straßenmusik in der Hauptstadtkultur" (The Dublin Project. The role of street music in the capital city culture) of 2018 and uses selected points of analysis to illustrate the observed high value of street music as well as the process of the research and an overview of the applied scientific methods. In the second part of this work, the actual research-thesis will be explained and various theories on „identity" will be illustrated. For this purpose, selected theories are used to interpret the own findings with regard to the research-thesis. The focus here is on urban and collective identity theories. Finally, the answers to the questions posed will be given as well as an outlook on possible, supplementary and further research. Medial support of this work comes from attached photos of the described scenes as well as from map sections showing the distances covered and the hotspots of the research.
SAFE Newsletter : 2019, Q1
(2019)
In the current study we compared the molecular signature of expanded mesenchymal stromal cells (MSCs) derived from selected CD271+ bone marrow mononuclear cells (CD271-MSCs) and MSCs derived from non-selected bone marrow mononuclear cells by plastic adherence (PA-MSCs). Transcriptome analysis demonstrated for the first time the upregulation of 115 and downregulation of 131 genes in CD271-MSCs. Functional enrichment analysis showed that the upregulated genes in CD271-MSCs are significantly enriched for extracellular matrix (tenascin XB, elastin, ABI family, member 3 (NESH) binding protein, carboxypeptidase Z, laminin alpha 2 and nephroblastoma overexpressed) and cell adhesion (CXCR7, GPNMB, MYBPH, SVEP1, ARHGAP6, TSPEAR, PIK3CG, ABL2 and NCAM1). CD271-MSCs expressed higher gene transcript levels that are involved in early osteogenesis/chondrogenesis/adipogenesis (ZNF145, FKBP5). In addition, increased transcript levels for early and late osteogenesis (DPT, OMD, ID4, CRYAB, SORT1), adipogenesis (CTNNB1, ZEB, LPL, FABP4, PDK4, ACDC), and chondrogenesis (CCN3/NOV, CCN4/WISP1, CCN5/WISP2 and ADAMTS-5) were detected. Interestingly, CD271-MSCs expressed increased levels of hematopoiesis associated genes (CXCL12, FLT3L, IL-3, TPO, KITL). Down-regulated genes in CD271-MSCs were associated with WNT and TGF-beta signaling, and cytokine/chemokine signaling pathways. In addition to their capacity to support hematopoiesis, these results suggest that CD271-MSCs may contain more osteo/chondro progenitors and/or feature a greater differentiation potential.
Application of blood flow restriction to optimize exercise countermeasures for human space flight
(2019)
In recent years there has been a strong increase in publications on blood flow restriction (BFR) training. In particular, the fact that this type of training requires only low resistance to induce muscle strength and mass gains, makes BFR training interesting for athletes and scientists alike. For the same reason this type of training is particularly interesting for astronauts working out in space. Lower resistance during training would have the advantage of reducing the risk of strain-induced injuries. Furthermore, strength training with lower resistances would have implications for the equipment required for training under microgravity conditions, as significantly lower resistances have to be provided by the training machines. Even though we are only about to understand the effects of blood flow restriction on exercise types other than low-intensity strength training, the available data indicate that BFR of leg muscles is also able to improve the training effects of walking or running at slow speeds. The underlying mechanisms of BFR-induced functional and structural adaptations are still unclear. An essential aspect seems to be the premature fatigue of Type-I muscle fibers, which requires premature recruitment of Type-II muscle fibers to maintain a given force output. Other theories assume that cell swelling, anabolic hormones, myokines and reactive oxygen species are involved in the mediation of BFR training-related effects. This review article is intended to summarize the main advantages and disadvantages, but also the potential risks of such training for astronauts.
We present a study of the elliptic flow and RAA of D and D¯ mesons in Au+Au collisions at FAIR energies. We propagate the charm quarks and the D mesons following a previously applied Langevin dynamics. The evolution of the background medium is modeled in two different ways: (I) we use the UrQMD hydrodynamics + Boltzmann transport hybrid approach including a phase transition to QGP and (II) with the coarse-graining approach employing also an equation of state with QGP. The latter approach has previously been used to describe di-lepton data at various energies very successfully. This comparison allows us to explore the effects of partial thermalization and viscous effects on the charm propagation. We explore the centrality dependencies of the collisions, the variation of the decoupling temperature and various hadronization parameters. We find that the initial partonic phase is responsible for the creation of most of the D/D¯ mesons elliptic flow and that the subsequent hadronic interactions seem to play only a minor role. This indicates that D/D¯ mesons elliptic flow is a smoking gun for a partonic phase at FAIR energies. However, the results suggest that the magnitude and the details of the elliptic flow strongly depend on the dynamics of the medium and on the hadronization procedure, which is related to the medium properties as well. Therefore, even at FAIR energies the charm quark might constitute a very useful tool to probe the quark–gluon plasma and investigate its physics.
Background: Electrochemical signals play an important role in cell communication and behavior. Electrically charged ions transported across cell membranes maintain an electrochemical imbalance that gives rise to bioelectric signaling, called membrane potential or Vmem. Vmem plays a key role in numerous inter- and intracellular functions that regulate cell behaviors like proliferation, differentiation and migration, all playing a critical role in embryonic development, healing, and regeneration.
Methods: With the goal of analyzing the changes in Vmem during cell proliferation and differentiation, here we used direct current electrical stimulation (EStim) to promote cell proliferation and differentiation and simultaneously tracked the corresponding changes in Vmem in adipose derived mesenchymal stem cells (AT-MSC).
Results: We found that EStim caused increased AT-MSC proliferation that corresponded to Vmem depolarization and increased osteogenic differentiation that corresponded to Vmem hyperpolarization. Taken together, this shows that Vmem changes associated with EStim induced cell proliferation and differentiation can be accurately tracked during these important cell functions. Using this tool to monitor Vmem changes associated with these important cell behaviors we hope to learn more about how these electrochemical cues regulate cell function with the ultimate goal of developing new EStim based treatments capable of controlling healing and regeneration.
Do competition and incentives offered to designated market makers (DMMs) improve market liquidity? Using data from NYSE Euronext Paris, we show that an exogenous increase in competition among DMMs leads to a significant decrease in quoted and effective spreads, mainly through a reduction in adverse selection costs. In contrast, changes in incentives, through small changes in rebates and requirements for DMMs, do not have any tangible effect on market liquidity. Our results are of relevance for designing optimal contracts between exchanges and DMMs and for regulatory market oversight.
Hypoxia poses a stress to cells and decreases mitochondrial respiration, in part by electron transport chain (ETC) complex reorganization. While metabolism under acute hypoxia is well characterized, alterations under chronic hypoxia largely remain unexplored. We followed oxygen consumption rates in THP-1 monocytes during acute (16 h) and chronic (72 h) hypoxia, compared to normoxia, to analyze the electron flows associated with glycolysis, glutamine, and fatty acid oxidation. Oxygen consumption under acute hypoxia predominantly demanded pyruvate, while under chronic hypoxia, fatty acid- and glutamine-oxidation dominated. Chronic hypoxia also elevated electron-transferring flavoproteins (ETF), and the knockdown of ETF–ubiquinone oxidoreductase lowered mitochondrial respiration under chronic hypoxia. Metabolomics revealed an increase in citrate under chronic hypoxia, which implied glutamine processing to α-ketoglutarate and citrate. Expression regulation of enzymes involved in this metabolic shunting corroborated this assumption. Moreover, the expression of acetyl-CoA carboxylase 1 increased, thus pointing to fatty acid synthesis under chronic hypoxia. Cells lacking complex I, which experienced a markedly impaired respiration under normoxia, also shifted their metabolism to fatty acid-dependent synthesis and usage. Taken together, we provide evidence that chronic hypoxia fuels the ETC via ETFs, increasing fatty acid production and consumption via the glutamine-citrate-fatty acid axis.
Application of the Luttinger theorem to the Kondo lattice YbRh2Si2 suggests that its large 4f-derived Fermi surface (FS) in the paramagnetic (PM) regime should be similar in shape and volume to that of the divalent local-moment antiferromagnet (AFM) EuRh2Si2 in its PM regime. Here we show by angle-resolved photoemission spectroscopy that paramagnetic EuRh2Si2 has a large FS essentially similar to the one seen in YbRh2Si2 down to 1 K. In EuRh2Si2 the onset of AFM order below 24.5 K induces an extensive fragmentation of the FS due to Brillouin zone folding, intersection and resulting hybridization of the Fermi-surface sheets. Our results on EuRh2Si2 indicate that the formation of the AFM state in YbRh2Si2 is very likely also connected with similar changes in the FS, which have to be taken into account in the controversial analysis and discussion of anomalies observed at the quantum critical point in this system.
Since Inhibitor of Apoptosis (IAP) proteins have been implicated in cellular adaptation to endoplasmic reticulum (ER) stress, we investigated the regulation of ER stress-induced apoptosis by small-molecule second mitochondria-derived activator of caspase (Smac) mimetics that antagonize IAP proteins. Here, we discover that Smac mimetic suppresses tunicamycin (TM)-induced apoptosis via resolution of the unfolded protein response (UPR) and ER stress. Smac mimetics such as BV6 selectively inhibit apoptosis triggered by pharmacological or genetic inhibition of protein N-glycosylation using TM or knockdown of DPAGT1, the enzyme that catalyzes the first step of protein N-glycosylation. In contrast, BV6 does not rescue cell death induced by other typical ER stressors (i.e., thapsigargin (TG), dithiothreitol, brefeldin A, bortezomib, or 2-deoxyglucose). The protection from TM-triggered apoptosis is found for structurally different Smac mimetics and for genetic knockdown of cellular IAP (cIAP) proteins in several cancer types, underlining the broader relevance. Interestingly, lectin microarray profiling reveals that BV6 counteracts TM-imposed inhibition of protein glycosylation. BV6 consistently abolishes TM-stimulated accumulation of ER stress markers such as glucose-regulated protein 78 (GRP78) and C/EBP homologous protein (CHOP) and reduces protein kinase RNA-like ER kinase (PERK) phosphorylation and X box-binding protein 1 (XBP1) splicing upon TM treatment. BV6-stimulated activation of nuclear factor-κB (NF-κB) contributes to the resolution of ER stress, since NF-κB inhibition by overexpression of dominant-negative IκBα superrepressor counteracts the suppression of TM-stimulated transcriptional activation of CHOP and GRP78 by BV6. Thus, our study is the first to show that Smac mimetic protects from TM-triggered apoptosis by resolving the UPR and ER stress. This provides new insights into the regulation of cellular stress responses by Smac mimetics.
Purpose: To analyze leg pain severity data from a randomized controlled trial (RCT) of lumbar disc surgery using integrated approaches that adjust pain scores collected at scheduled follow-up visits for confounding clinical events occurring between visits. Methods. Data were derived from an RCT of a bone-anchored annular closure device (ACD) following lumbar discectomy versus lumbar discectomy alone (Control) in patients with large postsurgical annular defects. Leg pain was recorded on a 0 to 100 scale at 6 weeks, 3 months, 6 months, 1 year, and 2 years of follow-up. Patients with pain reduction ≥20 points relative to baseline were considered responders. Unadjusted analyses utilized pain scores reported at follow-up visits. Since symptomatic reherniation signifies clinical failure of lumbar discectomy, integrated analyses adjusted pain scores following a symptomatic reherniation by baseline observation carried forward for continuous data or classification as nonresponders for categorical data.
Results: Among 550 patients (272 ACD, 278 Control), symptomatic reherniation occurred in 10.3% of ACD patients and in 21.9% of controls (p < 0.001) through 2 years. There was no difference in leg pain scores at the 2-year visit between ACD and controls (12 versus 14; p = 0.33) in unadjusted analyses, but statistically significant differences favoring ACD (19 versus 29; p < 0.001) in integrated analyses. Unadjusted nonresponder rates were 6.0% with ACD and 6.7% with controls (p = 0.89), but 15.7% and 27.8% (p = 0.001) in integrated analyses. The probability of nonresponse was 16.4% with ACD and 18.3% with controls (p = 0.51) in unadjusted analysis, and 23.7% and 31.2% (p = 0.04) in integrated analyses.
Conclusion: In an RCT of lumbar disc surgery, an integrated analysis of pain severity that adjusted for the confounding effects of clinical failures occurring between follow-up visits resulted in different conclusions compared to an unadjusted analysis of pain scores reported at follow-up visits only.
Music is an effective means of stress-reduction. However, to date there has been no systematic comparison between musical and language-based means of stress reduction in an ambulatory setting. Furthermore, although the aim for listening to music appears to play a role in its effect, this has not yet been investigated thoroughly. We compared musical means, language-based means like guided relaxation or self-enhancement exercises, and a combination of both with respect to their potential to reduce perceived stress. Furthermore, we investigated whether the aim one wants to achieve by listening to these means had an impact on their effect. We tested 64 participants (age: M = 40.09 years; 18 female) for 3–10 days during their everyday life using an app containing three means: musical means, language-based means, and a combination of both. For the music and the combination conditions participants were asked to select an aim: relaxation or activation. We measured perceived stress, relaxation, activation, and electrical skin resistance (ESR) as a marker of sympathetic nervous system (SNS) activity before and after using the app. Participants were instructed to use the app as often as desired. Overall, perceived stress was reduced after using the app, while perceived relaxation and activation were increased. There were no differences between the three means regarding their effect on perceived stress and relaxation, but music led to a greater increase in ESR and perceived activation compared to the other means. There was a decrease in ESR only for music. Moreover, perceived stress was reduced and perceived relaxation was increased to greater extent if the aim “relaxation” had been selected. Perceived activation, however, showed a larger increase if the aim had been “activation,” which was even more marked in the case of music listening. Our results indicate that all three means reduced perceived stress and promoted feelings of relaxation and activation. For enhancing feelings of activation music seems to be more effective than the other means, which was reflected in increased SNS activity as well. Furthermore, the choice of an aim plays an important role for the reduction of stress, and promotion of relaxation and activation.
Background: Transcatheter aortic valve replacement (TAVR) is a therapeutic option for patients with aortic valve stenosis at increased surgical risk. Telomeres are an established marker for cellular senescence and have served to evaluate cardiovascular diseases including severe aortic valve stenosis. In our study, we hypothesized that telomere length may be a predictor for outcome and associated with comorbidities in patients with TAVR.
Methods and results: We analyzed leucocyte telomere length from 155 patients who underwent TAVR and correlated the results with 1-year mortality and severe comorbidities. The cohort was subdivided into 3 groups according to telomere length. Although a trend for a positive correlation of telomere length with a lower EuroSCORE could be found, telomere length was not associated with survival, aortic valve opening area or cardiovascular comorbidities (peripheral, coronary or cerebrovascular disease). Interestingly, long telomeres were significantly correlated to a reduced left ventricular ejection fraction (LVEF).
Conclusion: In elderly patients with severe aortic valve stenosis, leucocyte telomere length did not predict post-procedural survival. The correlation between long telomere length and reduced LVEF in these patients deserves further attention.
kurz und kn@pp news : Nr. 45
(2019)
Der Beitrag liest Hebbels Judith (1840) vor dem Hintergrund der politischen Ereignisse im postrevolutionären und postrestaurativen Europa, wobei das Interesse der imaginären Dimension der Politik gilt. Ausgehend von einer gespenstischen Hand im Theatertext und der jungfräulichen Titelfigur als Guillotine wiederholt das Drama die brutale Enthauptung, die Europa im ausgehenden 18. Jahrhundert erschütterte und eine kopflose Gemeinschaft hinterließ. Eine unheimliche Hand, die sich "aus der schwarzen Erde" ausstreckt, lässt den Theatertext zunächst nicht nur zwischen einer restaurativen und revolutionären Politik, sondern auch zwischen einer idealistisch-romantischen und realistischen Kunst oszillieren. Die dramatische Aufführungspraxis rechnet dabei zum einen mit der Romantik ab. Zum anderen lässt sich anhand von Modi des realistischen Darstellens auf der Theaterbühne beobachten, wie die restaurative Politik mit den Anfängen des realistischen Erzählens zusammenfällt.
Der Artikel schlägt vor, die Frage nach dem Berühren indirekt, d.h. ausgehend von einer Unhaltbarkeit der Unbetroffenheit aufzugreifen. In 'Schiffbruch mit Zuschauer' diskutiert Hans Blumenberg den Verlust der Zuschauerposition als einen rezeptionsgeschichtlichen Umschlagpunkt. Entscheidend hierfür sind die von Jacob Burckhardt beschriebenen Aporien der Geschichtsschreibung im "Revolutionszeitalter". Ein Blick auf Burckhardts Metaphernkonstellationen kann zeigen, dass die beschriebene "Krisis" die Logik der großen historischen Instanzen gerade unberührt lässt. Demgegenüber lässt sich mit Blumenbergs bereits 1979 angekündigter 'Theorie der Unbegrifflichkeit' eine Variante möglichen Distanzverlusts erschließen, die sich keinem hintergründigen Spiel historisch wirksamer Kräfte, sondern der immanenten – und darin keineswegs ahistorischen – Destruktion der Leistung des Begriffs verdankt. Unter dem Titel der Berührbarkeit wird die Wiederkehr des Sinnlichen zunächst als eine Krise methodischer Sicherungen reformulierbar.