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Background: Network science provides powerful access to essential organizational principles of the brain. The aim of this study was to investigate longitudinal evolution of gray matter networks in early relapsing–remitting MS (RRMS) compared with healthy controls (HCs) and contrast network dynamics with conventional atrophy measurements.
Methods: For our longitudinal study, we investigated structural cortical networks over 1 year derived from 3T MRI in 203 individuals (92 early RRMS patients with mean disease duration of 12.1 ± 14.5 months and 101 HCs). Brain networks were computed based on cortical thickness inter-regional correlations and fed into graph theoretical analysis. Network connectivity measures (modularity, clustering coefficient, local efficiency, and transitivity) were compared between patients and HCs, and between patients with and without disease activity. Moreover, we calculated longitudinal brain volume changes and cortical atrophy patterns.
Results: Our analyses revealed strengthening of local network properties shown by increased modularity, clustering coefficient, local efficiency, and transitivity over time. These network dynamics were not detectable in the cortex of HCs over the same period and occurred independently of patients’ disease activity. Most notably, the described network reorganization was evident beyond detectable atrophy as characterized by conventional morphometric methods.
Conclusion: In conclusion, our findings provide evidence for gray matter network reorganization subsequent to clinical disease manifestation in patients with early RRMS. An adaptive cortical response with increased local network characteristics favoring network segregation could play a primordial role for maintaining brain function in response to neuroinflammation.
Background: Available data on the incidence and outcome of invasive fungal diseases (IFD) in children with hematological malignancies or after allogeneic hematopoietic stem cell transplantation (HSCT) are mostly based on monocenter, retrospective studies or on studies performed prior to the availability of newer triazoles or echinocandins.
Procedure: We prospectively collected clinical data on incidence, diagnostic procedures, management and outcome of IFD in children treated for hematological malignancies or undergoing HSCT in three major European pediatric cancer centers.
Results: A total of 304 children (median age 6.0 years) who underwent 360 therapies (211 chemotherapy treatments, 138 allogeneic HSCTs and/or 11 investigational chemotherapeutic treatments) were included in the analysis. Nineteen children developed proven/probable IFD, mostly due to Aspergillus (n = 10) and Candida spp. (n = 5), respectively. In patients receiving chemotherapy, 11 IFDs occurred, all during induction or re-induction therapy. None of these patients died due to IFD, whereas IFD was lethal in 3 of the 8 HSCT recipients with IFD. Significant differences among centers were observed with regard to the use of imaging diagnostics and the choice, initiation and duration of antifungal prophylaxis.
Conclusion: This prospective multicenter study provides information on the current incidence and outcome of IFD in the real life setting. Practice variation between the centers may help to ultimately improve antifungal management in children at highest risk for IFDs.
Background: Germinal center-derived B cell lymphomas are tumors of the lymphoid tissues representing one of the most heterogeneous malignancies. Here we characterize the variety of transcriptomic phenotypes of this disease based on 873 biopsy specimens collected in the German Cancer Aid MMML (Molecular Mechanisms in Malignant Lymphoma) consortium. They include diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), Burkitt’s lymphoma, mixed FL/DLBCL lymphomas, primary mediastinal large B cell lymphoma, multiple myeloma, IRF4-rearranged large cell lymphoma, MYC-negative Burkitt-like lymphoma with chr. 11q aberration and mantle cell lymphoma.
Methods: We apply self-organizing map (SOM) machine learning to microarray-derived expression data to generate a holistic view on the transcriptome landscape of lymphomas, to describe the multidimensional nature of gene regulation and to pursue a modular view on co-expression. Expression data were complemented by pathological, genetic and clinical characteristics.
Results: We present a transcriptome map of B cell lymphomas that allows visual comparison between the SOM portraits of different lymphoma strata and individual cases. It decomposes into one dozen modules of co-expressed genes related to different functional categories, to genetic defects and to the pathogenesis of lymphomas. On a molecular level, this disease rather forms a continuum of expression states than clearly separated phenotypes. We introduced the concept of combinatorial pattern types (PATs) that stratifies the lymphomas into nine PAT groups and, on a coarser level, into five prominent cancer hallmark types with proliferation, inflammation and stroma signatures. Inflammation signatures in combination with healthy B cell and tonsil characteristics associate with better overall survival rates, while proliferation in combination with inflammation and plasma cell characteristics worsens it. A phenotypic similarity tree is presented that reveals possible progression paths along the transcriptional dimensions. Our analysis provided a novel look on the transition range between FL and DLBCL, on DLBCL with poor prognosis showing expression patterns resembling that of Burkitt’s lymphoma and particularly on "double-hit" MYC and BCL2 transformed lymphomas.
Conclusions: The transcriptome map provides a tool that aggregates, refines and visualizes the data collected in the MMML study and interprets them in the light of previous knowledge to provide orientation and support in current and future studies on lymphomas and on other cancer entities.
Background & Aims: We investigated the effect of albumin treatment (20% solution) on hypoalbuminemia, cardiocirculatory dysfunction, portal hypertension, and systemic inflammation in patients with decompensated cirrhosis with and without bacterial infections.
Methods: We performed a prospective study to assess the effects of long-term (12 weeks) treatment with low doses (1 g/kg body weight every 2 weeks) and high doses (1.5 g/kg every week) of albumin on serum albumin, plasma renin, cardiocirculatory function, portal pressure, and plasma levels of cytokines, collecting data from 18 patients without bacterial infections (the Pilot-PRECIOSA study). We also assessed the effect of short-term (1 week) treatment with antibiotics alone vs the combination of albumin plus antibiotics (1.5 g/kg on day 1 and 1 g/kg on day 3) on plasma levels of cytokines in biobanked samples from 78 patients with bacterial infections included in a randomized controlled trial (INFECIR-2 study).
Results: Circulatory dysfunction and systemic inflammation were extremely unstable in many patients included in the Pilot-PRECIOSA study; these patients had intense and reversible peaks in plasma levels of renin and interleukin 6. Long-term high-dose albumin, but not low-dose albumin, was associated with normalization of serum level of albumin, improved stability of the circulation and left ventricular function, and reduced plasma levels of cytokines (interleukin 6, granulocyte colony-stimulating factor, interleukin 1 receptor antagonist, and vascular endothelial growth factor) without significant changes in portal pressure. The immune-modulatory effects of albumin observed in the Pilot-PRECIOSA study were confirmed in the INFECIR-2 study. In this study, patients given albumin had significant reductions in plasma levels of cytokines.
Conclusions: In an analysis of data from 2 trials (Pilot-PRECIOSA study and INFECIR-2 study), we found that albumin treatment reduced systemic inflammation and cardiocirculatory dysfunction in patients with decompensated cirrhosis. These effects might be responsible for the beneficial effects of albumin therapy on outcomes of patients with decompensated cirrhosis. ClinicalTrials.gov, Numbers: NCT00968695 and NCT03451292.
Replacement therapy in severe hemophilia A leads to factor VIII (FVIII) inhibitors in 30% of patients. Factor VIII gene (F8) mutation type, a family history of inhibitors, ethnicity and intensity of treatment are established risk factors, and were included in two published prediction tools based on regression models. Recently investigated immune regulatory genes could also play a part in immunogenicity. Our objective is to identify bio-clinical and genetic markers for FVIII inhibitor development, taking into account potential genetic high order interactions. The study population consisted of 593 and 79 patients with hemophilia A from centers in Bonn and Frankfurt respectively. Data was collected in the European ABIRISK tranSMART database. A subset of 125 severely affected patients from Bonn with reliable information on first treatment was selected as eligible for risk stratification using a hybrid tree-based regression model (GPLTR). In the eligible subset, 58 (46%) patients developed FVIII inhibitors. Among them, 49 (84%) were “high risk” F8 mutation type. 19 (33%) had a family history of inhibitors. The GPLTR model, taking into account F8 mutation risk, family history of inhibitors and product type, distinguishes two groups of patients: a high-risk group for immunogenicity, including patients with positive HLA-DRB1*15 and genotype G/A and A/A for IL-10 rs1800896, and a low-risk group of patients with negative HLA-DRB1*15 / HLA-DQB1*02 and T/T or G/T for CD86 rs2681401. We show associations between genetic factors and the occurrence of FVIII inhibitor development in severe hemophilia A patients taking into account for high-order interactions using a generalized partially linear tree-based approach.
The volume under review is the result of a conference on historical graffiti held at the Ludwig-Maximilians-University of Munich in 2017. The aim of this book is to analyse — for the first time — graffiti from the ancient, medieval and modern periods in their historical and geographical contexts from an interdisciplinary point of view. Following this comparative approach the authors show the tremendous potential of this nascent area of research by investigating epigraphic material that has been neglected and underestimated by scholars for a long time. ...
While prediction errors (PE) have been established to drive learning through adaptation of internal models, the role of model-compliant events in predictive processing is less clear. Checkpoints (CP) were recently introduced as points in time where expected sensory input resolved ambiguity regarding the validity of the internal model. Conceivably, these events serve as on-line reference points for model evaluation, particularly in uncertain contexts. Evidence from fMRI has shown functional similarities of CP and PE to be independent of event-related surprise, raising the important question of how these event classes relate to one another. Consequently, the aim of the present study was to characterise the functional relationship of checkpoints and prediction errors in a serial pattern detection task using electroencephalography (EEG). Specifically, we first hypothesised a joint P3b component of both event classes to index recourse to the internal model (compared to non-informative standards, STD). Second, we assumed the mismatch signal of PE to be reflected in an N400 component when compared to CP. Event-related findings supported these hypotheses. We suggest that while model adaptation is instigated by prediction errors, checkpoints are similarly used for model evaluation. Intriguingly, behavioural subgroup analyses showed that the exploitation of potentially informative reference points may depend on initial cue learning: Strict reliance on cue-based predictions may result in less attentive processing of these reference points, thus impeding upregulation of response gain that would prompt flexible model adaptation. Overall, present results highlight the role of checkpoints as model-compliant, informative reference points and stimulate important research questions about their processing as function of learning und uncertainty.
The expression of thrombospondin-4 correlates with disease severity in osteoarthritic knee cartilage
(2019)
Osteoarthritis (OA) is a progressive joint disease characterized by a continuous degradation of the cartilage extracellular matrix (ECM). The expression of the extracellular glycoprotein thrombospondin-4 (TSP-4) is known to be increased in injured tissues and involved in matrix remodeling, but its role in articular cartilage and, in particular, in OA remains elusive. In the present study, we analyzed the expression and localization of TSP-4 in healthy and OA knee cartilage by reverse transcription polymerase chain reaction (RT-PCR), immunohistochemistry, and immunoblot. We found that TSP-4 protein expression is increased in OA and that expression levels correlate with OA severity. TSP-4 was not regulated at the transcriptional level but we detected changes in the anchorage of TSP-4 in the altered ECM using sequential protein extraction. We were also able to detect pentameric and fragmented TSP-4 in the serum of both healthy controls and OA patients. Here, the total protein amount was not significantly different but we identified specific degradation products that were more abundant in sera of OA patients. Future studies will reveal if these fragments have the potential to serve as OA-specific biomarkers.
Cardiovascular disease (CVD) remains the leading cause of cardiac morbidity and mortality in the entire world population. Heart failure (HF) is the fastest growing cardiac diagnosis, with an annual incidence of 10 cases per 1000 people in individuals older than 65 [1]. This is partly a reflection of an aging population and success of treatment of acute coronary syndromes with reduced premature mortality due to ischaemic heart disease (IHD), as well as increasing ability to recognise non-ischaemic - intrinsic myocardial processes- due to advances in genetics and imaging. The conventional imaging predictors of outcome in CVD patients primarily include left ventricular ejection fraction (LVEF) and late gadolinium enhancement (LGE) using cardiovascular magnetic resonance (CMR). LVEF represents the main universal, as well as the multimodality biomarker of risk stratification. ...
We study the information flow from the ECB on policy dates since its inception, using tick data. We show that three factors capture about all of the variation in the yield curve but that these are different factors with different variance shares in the window that contains the policy decision announcement and the window that contains the press conference. We also show that the QE-related policy factor has been dominant in the recent period and that Forward Guidance and QE effects have been very persistent on the longer-end of the yield curve. We further show that broad and banking stock indices' responses to monetary policy surprises depended on the perceived nature of the surprises. We find no evidence of asymmetric responses of financial markets to positive and negative surprises, in contrast to the literature on asymmetric real effects of monetary policy. Lastly, we show how to implement our methodology for any policy-related news release, such as policymaker speeches. To carry out the analysis, we construct the Euro Area Monetary Policy Event- Study Database (EA-MPD). This database, which contains intraday asset price changes around the policy decision announcement as well as around the press conference, is a contribution on its own right and we expect it to be the standard in monetary policy research for the euro area.
Decisions under ambiguity depend on both the belief regarding possible scenarios and the attitude towards ambiguity. This paper exclusively investigates the belief formation and belief updating process under ambiguity, using laboratory experiments. The results show that half of the subjects tend to adopt a simple heuristic strategy when updating beliefs, while the other half seems to partially adopt the Bayesian updates. We recover beliefs, represented by distributions of the priors/posteriors. The recoverable initial priors mostly follow a uniform distribution. We also find that subjects on average demonstrate slight pessimism in an ambiguous environment.
Background: Tularemia is caused by Francisella tularensis and can occasionally establish foodborne transmission.
Methods: Patients were identified by active case detection through contact with the treating physicians and consent for publication was obtained. Clinical data were accumulated through a review of the patient charts. Serology, culture, and PCR methods were performed for confirmation of the diagnosis.
Case cluster: A 46-year-old patient was hospitalised in the University Hospital Frankfurt (a tertiary care hospital) for pharyngitis and cervical lymphadenitis with abscess. A diagnosis of tularemia was made serologically, but treatment with ciprofloxacin initially failed. F. tularensis was detected in pus from the lymph node using a specific real-time PCR. The use of RD1 PCR led to the identification of the subspecies holarctica. Antibiotic therapy with high-dose ciprofloxacin and gentamicin was administered and was subsequently changed to ciprofloxacin and rifampicin. During a must-tasting, five other individuals became infected with tularemia by ingestion of contaminated must. All patients required treatment durations of more than 14 days.
Conclusions: Mechanically harvested agricultural products, such as wine must, can be a source of infection, probably due to contamination with animal carcasses. The clinical course of tularemia can be complicated and prolonged and requires differentiated antibiotic treatment.
Objectives: To investigate the prevalence of depressive symptoms in rheumatoid arthritis (RA) patients using two previously validated questionnaires in a large patient sample, and to evaluate depressive symptoms in the context of clinical characteristics (e.g. remission of disease) and patient-reported impact of disease.
Methods: In this cross-sectional study, the previously validated Patient Health Questionnaire (PHQ-9) and Beck-Depression Inventory II (BDI-II) were used to assess the extent of depressive symptoms in RA patients. Demographic background, RA disease activity score (DAS28), RA impact of disease (RAID) score, comorbidities, anti-rheumatic therapy and antidepressive treatment, were recorded. Cut-off values for depressive symptomatology were PHQ-9 ≥5 or BDI-II ≥14 for mild depressive symptoms or worse and PHQ-9 ≥ 10 or BDI-II ≥ 20 for moderate depressive symptoms or worse. Prevalence of depressive symptomatology was derived by frequency analysis while factors independently associated with depressive symptomatology were investigated by using multiple logistic regression analyses. Ethics committee approval was obtained, and all patients provided written informed consent before participation.
Results: In 1004 RA-patients (75.1% female, mean±SD age: 61.0±12.9 years, mean disease duration: 12.2±9.9 years, DAS28 (ESR): 2.5±1.2), the prevalence of depressive symptoms was 55.4% (mild or worse) and 22.8% (moderate or worse). Characteristics independently associated with depressive symptomatology were: age <60 years (OR = 1.78), RAID score >2 (OR = 10.54) and presence of chronic pain (OR = 3.25). Of patients classified as having depressive symptoms, only 11.7% were receiving anti-depressive therapy.
Conclusions: Mild and moderate depressive symptoms were common in RA patients according to validated tools. In routine clinical practice, screening for depression with corresponding follow-up procedures is as relevant as incorporating these results with patient-reported outcomes (e.g. symptom state), because the mere assessment of clinical disease activity does not sufficiently reflect the prevalence of depressive symptoms.
Clinical trial registration number: This study is registered in the Deutsches Register Klinischer Studien (DRKS00003231) and ClinicalTrials.gov (NCT02485483).
Der Terminus „Annotation“ gewinnt mit der fortschreitenden Verankerung der Digital Humanities innerhalb der akademischen Landschaft immer stärker an Bedeutung. Gleichzeitig steht er in den Geistes- und Informationswissenschaften für jeweils unterschiedliche Konzepte, welche zwar in Umfang, Einsatz und Zielausrichtung variieren, aber auch konzeptuelle Parallelen aufweisen. Vor dem Hintergrund der Zusammenarbeit der verschiedenen Wissenschaftsdisziplinen scheint es daher geboten, verschiedene Annotationspraxen und die mit ihnen verbundenen Konzepte von Annotationen zu reflektieren und diskutieren, ins Verhältnis zueinander zu setzen sowie Gemeinsamkeiten und Unterschiedlichkeiten zu systematisieren. Hierfür luden Julia Nantke und Frederik Schlupkothen (beide Bergische Universität Wuppertal) vom Graduiertenkolleg "Dokument – Text – Edition. Bedingungen und Formen ihrer Transformation und Modellierung in transdisziplinärer Perspektive" zur interdisziplinär angelegte Tagung "Annotationen in Edition und Forschung. Funktionsbestimmung, Differenzierung und Systematisierung" vom 20. bis zum 22. Februar 2019 an die Bergische Universität Wuppertal ein. Wissenschaftler*innen aus verschiedenen Ländern und Fachbereichen berichteten in fünf Sektionen über ihre Forschungsprojekte und –ergebnisse zu Annotationen, deren unterschiedlichen Erscheinungsformen und Funktionsweisen sowie zu verschiedenen terminologischen, methodischen und technischen Fragestellungen. Der Annotationsbegriff wurde hierbei bewusst weit gefasst und sowohl auf digitale und analoge sowie manuelle und automatisierte Annotationsprozesse in unterschiedlichen Medien bezogen.
updated version --
The Multilingual Assessment Instrument for Narratives (MAIN) was designed in order to assess narrative skills in children who acquire one or more languages from birth or from early age. MAIN is suitable for children from 3 to 10 years and evaluates both comprehension and production of narratives. Its design allows for the assessment of several languages in the same child, as well as for different elicitation modes: Model Story, Retelling, and Telling. MAIN contains four parallel stories, each with a carefully designed six-picture sequence. The stories are controlled for cognitive and linguistic complexity, parallelism in macrostructure and microstructure, as well as for cultural appropriateness and robustness. The instrument has been developed on the basis of extensive piloting with more than 550 monolingual and bilingual children aged 3 to 10, for 15 different languages and language combinations. Even though MAIN has not been norm-referenced yet, its standardized procedures can be used for evaluation, intervention and research purposes. MAIN is currently available in the following languages: English, Afrikaans, Albanian, Basque, Bulgarian, Croatian, Cypriot Greek, Danish, Dutch, Estonian, Finnish, French, German, Greek, Hebrew, Icelandic, Italian, Lithuanian, Norwegian, Polish, Russian, Spanish, Standard Arabic, Swedish, Turkish, Vietnamese, and Welsh.
The main objective of this PhD work is to assess the impact of fine-scale air-sea interaction on the performance of a regional climate prediction model in marginal sea regions. Focus is on the North and Baltic Seas, the largest marginal sea area in the mid-latitudes. Motivation for this work is to better understand the interaction between the different components of the climate system, namely atmosphere, ocean and sea-ice. In addition to that, the sea regions of interest, the North and Baltic Seas, are orographically complex and cannot be resolved by a global ocean model. The ice coverage on the Baltic Sea is underestimated in the stand-alone atmospheric model COSMO-CLM due to the low water freezing temperature value assumed, which is not applicable for such brackish water body. To fulfil the thesis goal, a new regional coupled atmosphere-ocean-ice system was developed for these two seas, named COSMO-CLM/NEMO. The two-way coupling system involves active feedback from both component models: the limited-area climate model COSMO-CLM and the regional ocean model NEMO-NORDIC.
The coupled system COSMO-CLM/NEMO for the North and Baltic Seas was used to study the impact of sea surface temperature and sea ice on the atmosphere on diffrent topics. The long term impact of the North and Baltic Seas was studied through 15- year long simulations driven by European Center for Medium-Range Weather Forecasts (ECMWF) Interim reanalysis (ERA-Interim) data. Furthermore, to see whether the marginal sea modelling can advance the simulation of extreme climate events, the coupled model was used to reproduce six extreme snowband phenomena over the Baltic Sea in simulations driven by ERA-interim data. Last but not least, the role of the North and Baltic Sea model in improving long-term regional climate prediction was examined. Two sets of experiments with coupled and uncoupled models, each set has five independent decadal hindcasts forced by global climate model, were carried out.
All results were compared with observations and the stand-alone atmospheric model COSMO-CLM results. In all experiments, COSMO-CLM/NEMO showed good agreement with observations. Improvements compared with the uncoupled COSMO-CLM were also found. Coupling was found to affect the air temperature not only around the coupled sea region but also inland. The convective snowbands over the Baltic Sea were successfully reproduced by the coupled model. The high contrast of temperature in the air column, as well as considerably high amounts of surface heat fluxes exchanged between air and sea could not be simulated by COSMO-CLM without the help of reanalysis data. The coupled model also provided better forecasts in decadal scales compared with the uncoupled model and the global model. The added predictability came from the initialized regional seas and better simulated sea surface temperatures by the ocean model.
The impact of the North and Baltic Seas on the climate of the surrounding regions is in certain phases dominated by the North Atlantic Oscillation (NAO) activity. In this thesis, the relation between the NAO and the marginal sea influences was studied. It is confirmed by this study that, in strong phases, the NAO can overpower the impact of the local seas. During dominant phases of NAO, the European climate is mainly governed by large-scale circulation. On the other hand, the local seas play an important role in determining the European climate when NAO is in weak phases.
The added value of the coupled model raises promising perspectives for research in this field. It points to a potential benefit of using the coupled atmosphere-ocean-ice system for climate prediction in the region surrounding the North and Baltic Seas. Along with that, it is still a challenge to complete the model representation of the climate system by adding more climate components (such as a hydrological model). Further improvement of the coupled system can be achieved by coupling for a larger sea region, or by trying to reduce remaining low performance of the coupled model in some areas with a better configuration of the current system.
This dissertation is an investigation of pitch accent, or lexical tone, in standard Croatian. The first chapter presents an in-depth overview of the history of the Croatian language, its relationship to Serbo-Croatian, its dialect groups and pronunciation variants, and general phonology. The second chapter explains the difference between various types of prosodic prominence and describes systems of pitch accent in various languages from different parts of the world: Yucatec Maya, Lithuanian and Limburgian. Following is a detailed account of the history of tone in Serbo-Croatian and Croatian, the specifics of its tonal system, intonational phonology and finally, a review of the most prominent phonetic investigations of tone in that language.
The focal point of this dissertation is a production experiment, in which ten native speakers of Croatian from the region of Slavonia were recorded. The material recorded included a diverse selection of monosyllabic, bisyllabic, trisyllabic and quadrisyllabic words, containing all four accents of standard Croatian: short falling, long falling, short rising and long rising. Each target word was spoken in initial, medial and final positions of natural Croatian sentences. This research fills several gaps in the existing literature. Namely, the production of tone was investigated in words with a syllabic /r̩/, in pretonal syllables and in non-initial context. Acoustic parameters measured included duration, F0 in every 10% of the nucleus duration, overall pitch, pitch range and pitch peak alignment.
Results showed that differences between falling and rising accents in Croatian are produced mainly with tonal parameters and that the most salient features were pitch peak alignment and overall pitch. The difference between long and short accents was primarily durational and optionally tonal. Words produced in initial and medial sentence positions had a rising contour in their accented syllable, while in the final, segments were usually falling.
SAFE Newsletter : 2019, Q2
(2019)
The differences between contemporary Monte Carlo generators of high energy hadronic interactions are discussed and their impact on the interpretation of experimental data on ultra-high energy cosmic rays (UHECRs) is studied. Key directions for further model improvements are outlined. The prospect for a coherent interpretation of the data in terms of the UHECR composition is investigated.
IFLS-Journal. Nr. 24, 2019
(2019)