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Background: Oral anticoagulation (OAC) with coumarins and new anticoagulants are highly effective in preventing thromboembolic complications. However, some studies indicate that over- and under-treatment with anticoagulants are fairly common. The aim of this paper is to assess the appropriateness of treatment in patients with a long-term indication for OAC, and to describe the corresponding characteristics of such patients on the basis of screening results from the cluster randomized PICANT trial.
Methods: Randomly selected family practices in the federal state of Hesse, Germany, were visited by study team members. Eligible patients were screened using an anonymous patient list that was generated by the general practitioners? software according to predefined instructions. A documentation sheet was filled in for all screened patients. Eligible patients were classified into 3 categories (1: patients with a long-term indication for OAC and taking anticoagulants, 2: patients with a long-term indication for OAC but not taking anticoagulants, 3: patients without a long-term indication for OAC but taking an anticoagulant on a permanent basis). IBM SPSS Statistics 20 was used for descriptive statistical analysis.
Results: We screened 2,036 randomly selected, potentially eligible patients from 52 family practices. 275 patients could not be assigned to one of the 3 categories and were therefore not considered for analysis. The final study sample comprised 1,761 screened patients, 1,641 of whom belonged to category 1, 78 to category 2, and 42 to category 3. INR values were available for 1,504 patients of whom 1,013 presented INR values within their therapeutic ranges. The majority of screened patients had very good compliance, as assessed by the general practitioner. New antithrombotic drugs were prescribed in 6.1% of cases.
Conclusions: The screening results showed that a high proportion of patients were receiving appropriate anticoagulation therapy. The numbers of patients with a long-term indication for OAC therapy that were not receiving oral anticoagulants, and without a long-term indication that were receiving OAC, were considerably lower than expected. Most patients take coumarins, and the quality of OAC control is reasonably high.
We study the equilibrium properties of strongly-interacting infinite parton-hadron matter, characterized by the transport coefficients such as shear and bulk viscosity and electric conductivity, and the non-equilibrium dynamics of heavy-ion collisions within the Parton-Hadron-String Dynamics (PHSD) transport approach, which incorporates explicit partonic degrees of freedom in terms of strongly interacting quasiparticles (quarks and gluons) in line with an equation of state from lattice QCD as well as the dynamical hadronization and hadronic collision dynamics in the final reaction phase. We discuss in particular the possible origin for the strong elliptic flow v2 of direct photons observed at RHIC energies.
Reaction times to previously ignored information are often delayed, a phenomenon referred to as negative priming (NP). Rothermund et al. (2005) proposed that NP is caused by the retrieval of incidental stimulus-response associations when consecutive displays share visual features but require different responses. In two experiments we examined whether the features (color, shape) that reappear in consecutive displays, or their level of processing (early-perceptual, late-semantic) moderate the likelihood that stimulus-response associations are retrieved. Using a perceptual matching task (Experiment 1), NP occurred independently of whether responses were repeated or switched. Only when implementing a semantic-matching task (Experiment 2), negative priming was determined by response-repetition as predicted by response-retrieval theory. The results can be explained in terms of a task-dependent temporal discrimination process (Milliken et al., 1998): Response-relevant features are encoded more strongly and/or are more likely to be retrieved than irrelevant features.
Reintroductions of plant species are increasingly popular in conservation practice. Steppe grasslands contain many rare and endangered plant species that are potential objects for such reintroductions. Most reintroduction projects, however, can only target a restricted number of species, which raises the question of how species should be prioritised. Here, we present a method to select priority species for reintroduction based on species' characteristics that are widely used in conservation practice. We first determined the local species pool containing those vascular plant species that occurred both in our target region (Thuringia, Germany) and target habitat (steppe grasslands), yielding 369 species. With the help of an a priori filter that selected currently endangered species with limited distribution, 136 potential target species were determined. These potential target species had experienced stronger decline, had a narrower phytosociological amplitude and were more likely to be species of the Festuco-Brometea class and the Festucetalia valesiacae order than non-target species. Potential target species were then ranked by a points system based on ten conservation-relevant characteristics of the species from the categories "threat and protection status", "distribution and decline", and "habitat affiliation". In the ranking, six steppe grassland plant species (Astragalus exscapus, Bothriochloa ischaemum, Prunella laciniata, Pulsatilla pratensis subsp. nigricans, Scorzonera purpurea, and Seseli hippomarathrum) achieved the highest scores. An additional seven species not specifically characteristic for steppe grasslands also scored highly. A post hoc evaluation of these 13 highest scoring species based on additional conservation criteria left five species (Astragalus exscapus, Linum leonii, Orchis morio, Pulsatilla pratensis subsp. nigricans and Scorzonera purpurea) as species with highest priority for reintroductions and another five species as highly suitable for reintroductions. Associations between the ranking order and different ranking criteria revealed that a species’ threat and rarity in Thuringia and its protection status had the highest representation in the ranking, followed by threat in Germany, regional decline and habitat affiliation. In contrast, international threat and responsibility of Thuringia for its conservation had only low representation in the ranking, probably because these characteristics applied to only a few species. The ranking list gives a selection of species for reintroductions, which combined with additional information based on comprehensive local and floristic knowledge, allows the identification of the species with the highest priority. Our method can be transferred to other regions or habitat types.
Central European dry grasslands are remarkably diverse plant communities that occur at the western edge of the Eurasian forest-steppe zone and harbour many species of continental distribution. Although their plant community types have been described in detail, the diversity patterns and their environmental determinants are still poorly known for these grasslands. Here, we study environmental drivers of species composition and richness in dry grasslands of northern Bohemia (České středohoří Mts) and central Bohemia (Křivoklát region), both in the Czech Republic. In vegetation plots of 100 m2 we recorded all vascular plant species, measured soil chemistry variables, above-ground biomass production and nutrient concentrations in biomass. Species richness in these plots ranged from 13 to 55. The relationships between species composition and the environment were explored using detrended correspondence analysis and canonical correspondence analysis, while the relationships between species richness and the environment were assessed using univariate and multiple regression models. In both regions, species composition and richness strongly responded to the soil pH (ranging from 4.0 to 7.8), which was positively correlated with calcium and magnesium concentrations and negatively with annual precipitation. The response of species richness to soil pH was unimodal with a peak at pH of about 6.5 in the České středohoří Mts, and positive in the Křivoklát region. Plots on soils with a pH higher than 5 consistently contained more than 35 species. In the České středohoří Mts, species richness was positively related to the aboveground biomass production, whereas in the Křivoklát region, this relationship was only significant for graminoid species. In both areas, plots with soils deeper than 20 cm and with aboveground biomass dry weight above 200 g/m2 harboured more than 40 species per 100 m2. Moreover, in the České středohoří Mts, nitrogen concentrations in the biomass had considerable effects on both species composition and richness: species numbers were lower at sites with higher nitrogen concentration. This indicates a threat to diversity of these dry grasslands under currently high atmospheric nitrogen deposition coupled with the absence of management at most of the studied sites.
Cryophytic steppes in the Minusinskaya intermountain basin containing plant species that are predominantly distributed in the alpine zone such as Androsace dasyphylla, Dryas oxyodonta, Festuca sphagnicola, Kobresia myosuroides, K. filifolia, Minuartia verna, Oxytropis bracteata, Sagina saginoides, Papaver nudicaule, Patrinia sibirica, Pedicularis lasiostachys, Pulsatilla ambigua, Saussurea schanginiana, which are considered remnants of the Pleistocene vegetation. Based on 89 relevés, we classified cryophytic steppes using the Braun-Blanquet method within two phytosociological classes: Central Asian steppes of the Cleistogenetea squarrosae and West Palearctic steppes of the Festuco-Brometea. Three associations (Androsaco dasyphyllae-Caricetum pediformis, Pulsatillo patentis-Caricetum pediformis and Bupleuro multinervi-Helictotrichetum desertori) with three subassociations and three variants were described with respect to their phytosociological affinities and ecology. DCA ordination showed floristic differences between syntaxa, while correlations of DCA axes and floristic and environmental variables detected substrate type and temperature regime as presumably main drivers for vegetation differentiation. Another driver for vegetation differentiation seems to be continentality of the climate. Small scale distribution of cryophytic steppes were mapped using satellite images with resolution of 1.8 m. Cryophytic steppes always occupy only small areas in landscapes, on convex parts of undulated microrelief of mountain slopes and summits characterised by drought in summer and deep soil freezing in winter. These special micro-ecological conditions play an essential role for the existence of alpine flora in the Minusinskaya intermountain basin.
We present the data of the 2nd research expedition of the European Dry Grassland Group (EDGG), which was conducted in 2010 in Central Podolia, Ukraine. The aim was to collect plot data to compare Ukrainian dry grasslands with those of other parts of Europe in terms of syntaxonomy and biodiversity. We sampled 21 nested-plot series (0.0001–100 m2) and 184 normal plots (10 m2) covering the full variety of dry grassland types occurring in the study region. For all plots, we recorded species composi-tion of terrestrial vascular plants, bryophytes and lichens, while for the 226 10-m2 plots we estimated and measured percentage cover of all species, structural, topographic, soil and landuse parameters. The 10-m² plots were used for phytosociological classification based on iteratively refined TWINSPAN classification as well as for DCA ordination. Differences between the derived vegetation types with respect to environmental conditions and species richness were assessed with ANOVAs. We assigned our plots to nine association-level units but refrained from placing them into formal associations with two exceptions. In the study area, dry grasslands of the Festuco-Brometea were far more common than those of the Koelerio-Corynephoretea. Among the Festuco-Brometea, xeric Festucetalia valesiacae grasslands were more frequent and represented by the Festucion valesiacae (2 associations, including the Allio taurici-Dichanthietum ischaemi ass. nova) and the Stipion lessingianae (1) compared to the Brachypodietalia pinnati with the Agrostio vinealis-Avenulion schellianae (3). The Koelerio-Corynephoretea were represented by three associations, each from a different order and alliance: basiphilous outcrops (Alysso alyssoidis-Sedetalia: Alysso alyssoidis-Sedion?), acidophilous outcrops (Sedo-Scleranthetalia: Veronico dillenii-Sedion albi?) and mesoxeric sandy grasslands (Trifolio arvensis-Festucetalia ovinae: Agrostion vinealis). We discuss the issue of the mesoxeric order Galietalia veri placed within the Molinio-Arrhenatheretea by Ukrainian authors and conclude that the content of that order would probably be better placed in the mesoxeric orders of the Koelerio-Corynephoretea and Festuco-Brometea. Other syntaxonomic questions could not be solved with our geographically limited dataset and await a supraregional analysis, e.g. whether the Ukrainian outcrop communities should be assigned to the same alliances as known from Central Europe or rather represent new vicariant units. The analysis of the biodiversity patterns showed that at a grain size of 10 m2, Podolian Koelerio-Corynephoretea communities were overall richer than Festuco-Brometea communities (46.4 vs. 40.6 species). This difference was due to the Koelerio-Corynephoretea containing twice as many bryophytes and nine times more lichens, while vascular plant species richness did not differ significantly between classes. The orders within the classes showed no real differences in species richness. The richness patterns observed in Podolia were almost the opposite of those usually found in dry grasslands, where Brachypodietalia pinnati are richer than Festucetalia valesiacae, and these richer than stands of the Koelerio-Corynpehoretea – and we do not have a good explanation for these idiosyncrasies. In conclusion, Podolian dry grasslands behave quite unexpectedly regarding biodiversity, and their syntaxonomy is still poorly understood. These knowledge gaps can only be addressed with supranational analyses based on comprehensive datasets.
An extensive survey of the relevant literature of dry grassland communities described for the territory of Serbia allowed us to check the validity and legitimacy of the nomenclature of this vegetation. Nomenclature rules of the International Code of Phytosociological Nomenclature were strictly followed. The syntaxonomic affiliation of communities to higher syntaxa was assessed according to existing syntaxonomic schemes for Serbia and the position determined by the original source. Higher syntaxa followed the synsystem of the socalled “EuroVegChecklist”. We have highlighted problems and some disagreement with the existing classification of dry grassland communities in Europe. A total of 134 dry grassland communities have so far been registered for Serbia. This list of syntaxa may serve for further research of grassland vegetation and its appropriate positioning within a syntaxonomical scheme of Europe.
Der diesjährige 9. Trockenrasen-Sonderteil von Tuexenia beginnt mit einem Bericht über die aktuellen Aktivitäten der European Dry Grassland Group (EDGG). Zunächst geben wir einen Überblick über die Entwicklung der Mitgliederzahl. Dann berichten wir vom letzten European Dry Grassland Meeting in Zamość (Polen, 2013) und vom letzten European Dry Grassland Field Workshop in Chakassien (Russland, 2013) und informieren über künftige Veranstaltungen der EDGG. Anschließend erläutern wir die Publikationsaktivitäten der EDGG. Im zweiten Teil des Editorials geben wir eine Einführung zu den fünf Artikeln des diesjährigen Trockenrasen-Sonderteils: Zwei davon beschäftigen sich mit der Syntaxonomie von Trockenrasen in Osteuropa: Der eine Artikel präsentiert erstmalig eine nach internationalen Nomenklaturregeln gültige Liste der Trockenrasengesellschaften Serbiens während der andere die Ergebnisse des zweiten EDGG-Field Workshop 2010 nach Podolien (Ukraine) vorstellt. Im dritten Artikel werden kryophytische Steppen in Südsibirien (Russland) analysiert. Der vierte Artikel analysiert in Böhmen (Tschechien) die bestimmenden Kräfte für Artenreichtum und Artenzusammensetzung der Trockenrasen. Der fünfte Artikel befasst sich mit der Auswahl von Wiederansiedlungsarten am Beispiel der Steppenrasen in Thüringen (Deutschland).
Flächenbezogene Artenzahlen sind besonders im Kontext von Monitoringprojekten grundlegend für die Beurteilung von Veränderungen der Biodiversität. Diese Studie vergleicht die von neun Bearbeitern (5 Einzelbearbeiter, 2 Zweierteams) erfasste Zahl an Gefäßpflanzenarten bei Vegetationserhebungen auf markierten Flächen von 4, 100 und 400 m2 Größe in einem artenreichen Kalkbuchenwald im Göttinger Stadtwald. Dabei wurden Bearbeiter- und Zeiteffekte untersucht, sowie artspezifische Übersehensraten, Fehlbestimmungsraten und Ungenauigkeiten bei der Zuordnung von Pflanzenindividuen zur jeweiligen Aufnahmefläche (Fehlzuordnungsraten) abgeschätzt.
Protokollierte Fragen ließen keine systematischen Unterschiede bei der Vertrautheit der Bearbeiter mit der Vegetation vor Ort erkennen, so dass Ausbildung und Erfahrung für gefundene Unterschiede ausschlaggebend sein dürften. Bei den 4 m2 großen Erhebungseinheiten ergaben sich bei der Artenzahl relative Abweichungen der Bearbeiter vom Erwartungswert von 8 bis 26 % (1 bis 4 Arten absolut). Diese waren bei den 100 m2 großen Erhebungseinheiten mit 9 bis 27 % (2 bis 6 Arten absolut) höher. Mit zunehmender Flächengröße nahm der Flächenidentitätseffekt tendenziell ab und der Bearbeitereffekt signifikant zu. Bei den 100 m2 großen Flächen hatte eine längere Bearbeitungszeit einen positiven Effekt auf die Artenzahl.
Mit Hilfe artbezogener Auswertungen wurden Übersehens-, Fehlbestimmungs- und Fehlzuordnungsraten ermittelt. Nicht eine Art wurde von allen Bearbeitern auf allen Flächen gefunden, auf denen sie jeweils auftrat. Schwer differenzierbare Arten sowie Arten in ungünstigen Entwicklungsstadien wiesen höhere Übersehens-, aber auch höhere Fehlbestimmungsraten auf. Bei morphologisch gut charakterisierten Arten wurde bei Einzelfunden von einer Fehlzuordnung zur Erhebungseinheit ausgegangen.
Die erzielten Ergebnisse sind auch für andere Projekte zur Erfassung der Biodiversität relevant und Bemühungen zur Reduzierung entsprechender Bearbeitereffekte sollten unternommen werden. Eine organisatorische Einbindung entsprechender Bemühungen wird vorgeschlagen.
The Feldbach district is situated near the town of Feldbach in the southeastern province of Styria, Austria. Since 2007, a climate observation network of 151 climate stations within an area of approximately 20 x 15 km (grid cell 1.4 × 1.4 km) has provided a unique collection of spatial and temporal meteorological data. Examining short-lived ruderal and arable weed communities, we search for correlations and spatial patterns between the community composition and climate data. Do such plant communities respond to temperature differences within an agricultural landscape and on a regional scale? Data of 277 relevés from short-lived weed communities were collected across the investigated area during the summer of 2011. Relevés were assigned to the corresponding climate stations and classified. Average Ellenberg indicator values for temperature were calculated for each relevé and community cluster. Measured temperature data were assigned and correlated with community data by applying linear regression and redundancy analyses (RDA). The classification resulted in six associations; the two most frequently observed associations were divided into subtypes resulting in 13 vegetation clusters that could be analyzed further. A significant relationship could be found only between the clusters of arable weed communities and the average winter temperatures. Site variables explain twice as much variance as measured climate variables; this ratio changes to 50 : 50 when we analyzed only arable field community data. No clear spatial patterns concerning mean annual temperature were visible. However, the Setaria faberi subtype of the Echinochloo-Setarietum and the Sorghum halepense subtype of the Convolvulo-Agropyretum show a tendency toward a temperature-induced spatial pattern, such that both were sensitive to winter temperature. On a regional scale, the occurrence and composition of short-lived ruderal plant communities correlated weakly with climate variables. However, the studied arable weed communities showed a certain tendency to follow small-scale temperature differences, especially those of average winter temperature. We conclude that short-lived weed communities have the potential to be indicators for global warming, but the spatial temperature gradients are not clear enough in our approach to allow the production of better regression models and elucidation of distinct spatial patterns.
Background: IL28B gene polymorphism is the best baseline predictor of response to interferon alfa-based antiviral therapies in chronic hepatitis C. Recently, a new IFN-L4 polymorphism was identified as first potential functional variant for induction of IL28B expression. Individualization of interferon alfa-based therapies based on a combination of IL28B/IFN-L4 polymorphisms may help to optimize virologic outcome and economic resources.
Methods: Optimization of treatment outcome prediction was assessed by combination of different IL28B and IFN-L4 polymorphisms in patients with chronic HCV genotype 1 (n = 385), 2/3 (n = 267), and 4 (n = 220) infection treated with pegylated interferon alfa (PEG-IFN) and ribavirin with (n = 79) or without telaprevir. Healthy people from Germany (n = 283) and Egypt (n = 96) served as controls.
Results: Frequencies of beneficial IL28B rs12979860 C/C genotypes were lower in HCV genotype 1/4 infected patients in comparison to controls (20–35% vs. 46–47%) this was also true for ss469415590 TT/TT (20–35% vs. 45–47%). Single interferon-lambda SNPs (rs12979860, rs8099917, ss469415590) correlated with sustained virologic response (SVR) in genotype 1, 3, and 4 infected patients while no association was observed for genotype 2. Interestingly, in genotype 3 infected patients, best SVR prediction was based on IFN-L4 genotype. Prediction of SVR with high accuracy (71–96%) was possible in genotype 1, 2, 3 and 4 infected patients who received PEG-IFN/ribavirin combination therapy by selection of beneficial IL28B rs12979860 C/C and/or ss469415590 TT/TT genotypes (p<0.001). For triple therapy with first generation protease inhibitors (PIs) (boceprevir, telaprevir) prediction of high SVR (90%) rates was based on the presence of at least one beneficial genotype of the 3 IFN-lambda SNPs.
Conclusion: IFN-L4 seems to be the best single predictor of SVR in genotype 3 infected patients. For optimized prediction of SVR by treatment with dual combination or first generation PI triple therapies, grouping of interferon-lambda haplotypes may be helpful with positive predictive values of 71–96%.
Background: In cystic fibrosis, highly variable glucose tolerance is suspected. However, no study provided within-patient coefficients of variation. The main objective of this short report was to evaluate within-patient variability of oral glucose tolerance.
Methods: In total, 4,643 standardized oral glucose tolerance tests of 1,128 cystic fibrosis patients (median age at first test: 15.5 [11.5; 21.5] years, 48.8% females) were studied. Patients included were clinically stable, non-pregnant, and had at least two oral glucose tolerance tests, with no prior lung transplantation or systemic steroid therapy. Transition frequency from any one test to the subsequent test was analyzed and within-patient coefficients of variation were calculated for fasting and two hour blood glucose values. All statistical analysis was implemented with SAS 9.4.
Results: A diabetic glucose tolerance was confirmed in 41.2% by the subsequent test. A regression to normal glucose tolerance at the subsequent test was observed in 21.7% and to impaired fasting glucose, impaired glucose tolerance or both in 15.2%, 12.0% or 9.9%. The average within-patient coefficient of variation for fasting blood glucose was 11.1% and for two hour blood glucose 25.3%.
Conclusion: In the cystic fibrosis patients studied, a highly variable glucose tolerance was observed. Compared to the general population, variability of two hour blood glucose was 1.5 to 1.8-fold higher.
The approximate number system (ANS) has been consistently found to be associated with math achievement. However, little is known about the interactions between the different instantiations of the ANS and in how many ways they are related to exact calculation. In a cross-sectional design, we investigated the relationship between three measures of ANS acuity (non-symbolic comparison, non-symbolic estimation and non-symbolic addition), their cross-sectional trajectories and specific contributions to exact calculation. Children with mathematical difficulties (MD) and typically achieving (TA) controls attending the first six years of formal schooling participated in the study. The MD group exhibited impairments in multiple instantiations of the ANS compared to their TA peers. The ANS acuity measured by all three tasks positively correlated with age in TA children, while no correlation was found between non-symbolic comparison and age in the MD group. The measures of ANS acuity significantly correlated with each other, reflecting at least in part a common numerosity code. Crucially, we found that non-symbolic estimation partially and non-symbolic addition fully mediated the effects of non-symbolic comparison in exact calculation.
Introduction: Curare is one of the best-examined neurotoxins of the world, which has empirically been used for centuries by American Indigenes. Research on curare has been performed much later, a global scientometric analysis on curare research or its derivates does not yet exist. This bibliometric analysis is part of the global NewQis-project and should illuminate both toxic and historic issues of research on curare.
Methods: The ISI Web of Science was searched for data covering 1900 to 2013 using a term which included as many original articles on curare as possible. 3,867 articles were found and analyzed for common bibliometric items such as the number of citations, language of the articles or the (modified) Hirsch-Index (h-index). Results are illustrated utilizing modern density equalizing map projections (DEMP) or beam diagrams.
Results: Most publications were located in North America and Europe. The USA has the highest number of publications as well as the highest h-index. The number of publications overall rose until the late 1990s and later decreased. Furthermore, sudden increases of research activity are ascribable to historic events, like the first use of curare as muscle relaxant during surgery.
Discussion: This scientometric analysis of curare research reflects several tendencies as previously seen in other bibliometric investigations, i.e. the scientific quality standard of North America and Europe. Research on curare decreased however, due to the declining attention towards this muscle relaxant. This work exemplifies also how scientometric methods can be used to illuminate historic circumstances immediately stimulating scientific research.
Introduction: To determine the esthetic outcome of implant-based reconstructions after autologous and allogeneic bone grafting.
Methods: From 2003 to 2009, 67 patients underwent alveolar ridge augmentation and were enrolled in the study, 41 meet the inclusion criteria and 31 agreed to take part in the study. Patients were 18-69 years old (mean: 49.3 ± 13.8 years), and predominantly female. Patients received bone block grafts either autologous (n = 48) (AUBB) or allografts (ABB) (n = 19). Implants were inserted 4-7 months (autografts) or 5-6 months (allografts) after bone grafting. The Pink Esthetic Score (PES) as well as radiographic and subjective assessments were employed for the outcome analysis. The PES was assessed twice within one month based on digital photographic images that were randomly rearranged between evaluations by three independent, experienced investigators.
Results: Across all observations and investigators, the average PES was 7.5 ± 2.6 without differences between implants inserted in auto- and allografted bone, respectively. Patients assessed the allograft procedures as less painful and would have repeated it more often. The intra-rater reliability was excellent (correlation coefficients 0.7-0.9). The inter-observer agreement was lower (correlation coefficients 0.6-0.8).
Conclusions: Bone grafting with ABB allografts yields equivalent results to autologous grafting, and patients appreciate the omission of bone harvesting. The PES is a reliable method but should be performed by the same individual.
In this study, we describe the synthesis of 1,4-disustituted-1,2,3-triazolo-quinazoline ribonucleosides or acyclonucleosides by means of 1,3-dipolar cycloaddition between various O or N-alkylated propargyl-quinazoline and 1'-azido-2',3',5'-tri-O-benzoylribose or activated alkylating agents under microwave conditions. None of the compounds selected showed significant anti-HCV activity in vitro.
Recent advances in understanding the mechanisms of nonsmall cell lung cancer (NSCLC) has led to the development of targeted treatments, including the reversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors gefitinib and erlotinib, and the irreversible ErbB family blocker afatinib. Several important activating EGFR mutations have now been identified, which correlate strongly with response to treatment with these agents. Multiple randomised controlled trials have confirmed the association between the presence of activating EGFR mutations and objective response to gefitinib, erlotinib and afatinib, thus demonstrating their superiority over platinum-based chemotherapy as first-line treatment for NSCLC patients with EGFR mutation-positive tumours, and resulting in approval of these agents for use in this setting. It can be tempting to compare outcome data across multiple clinical trials and agents; however, substantial differences in methodology between studies, including investigator versus independent assessment and differences in patient eligibility, makes such comparisons fraught with difficulty. This critical review provides an overview of the evolution of the methodology used in eight phase III trials investigating first-line targeted treatment of NSCLC, identifies key differences in methodology and reporting, and critically assesses how these differences should be taken into account when interpreting the findings from such trials.
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare haematopoietic malignancy characterized by dismal prognosis and overall poor therapeutic response. Since the biology of BPDCN is barely understood, our study aims to shed light on the genetic make-up of these highly malignant tumors. Using targeted high-coverage massive parallel sequencing, we investigated 50 common cancer genes in 33 BPDCN samples. We detected point mutations in NRAS (27.3% of cases), ATM (21.2%), MET, KRAS, IDH2, KIT (9.1% each), APC and RB1 (6.1% each), as well as in VHL, BRAF, MLH1, TP53 and RET (3% each). Moreover, NRAS, KRAS and ATM mutations were found to be mutually exclusive and we observed recurrent mutations in NRAS, IDH2, APC and ATM. CDKN2A deletions were detected in 27.3% of the cases followed by deletions of RB1 (9.1%), PTEN and TP53 (3% each). The mutual exclusive distribution of some mutations may point to different subgroups of BPDCN whose biological significance remains to be explored.
1D-3D hybrid modeling : from multi-compartment models to full resolution models in space and time
(2014)
Investigation of cellular and network dynamics in the brain by means of modeling and simulation has evolved into a highly interdisciplinary field, that uses sophisticated modeling and simulation approaches to understand distinct areas of brain function. Depending on the underlying complexity, these models vary in their level of detail, in order to cope with the attached computational cost. Hence for large network simulations, single neurons are typically reduced to time-dependent signal processors, dismissing the spatial aspect of each cell. For single cell or networks with relatively small numbers of neurons, general purpose simulators allow for space and time-dependent simulations of electrical signal processing, based on the cable equation theory. An emerging field in Computational Neuroscience encompasses a new level of detail by incorporating the full three-dimensional morphology of cells and organelles into three-dimensional, space and time-dependent, simulations. While every approach has its advantages and limitations, such as computational cost, integrated and methods-spanning simulation approaches, depending on the network size could establish new ways to investigate the brain. In this paper we present a hybrid simulation approach, that makes use of reduced 1D-models using e.g., the NEURON simulator—which couples to fully resolved models for simulating cellular and sub-cellular dynamics, including the detailed three-dimensional morphology of neurons and organelles. In order to couple 1D- and 3D-simulations, we present a geometry-, membrane potential- and intracellular concentration mapping framework, with which graph- based morphologies, e.g., in the swc- or hoc-format, are mapped to full surface and volume representations of the neuron and computational data from 1D-simulations can be used as boundary conditions for full 3D simulations and vice versa. Thus, established models and data, based on general purpose 1D-simulators, can be directly coupled to the emerging field of fully resolved, highly detailed 3D-modeling approaches. We present the developed general framework for 1D/3D hybrid modeling and apply it to investigate electrically active neurons and their intracellular spatio-temporal calcium dynamics.