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Background: The treatment of patients with multiple trauma including blunt chest/thoracic trauma (TxT) and hemorrhagic shock (H) is still challenging. Numerous studies show detrimental consequences of TxT and HS resulting in strong inflammatory changes, organ injury and mortality. Additionally, the reperfusion (R) phase plays a key role in triggering inflammation and worsening outcome. Ethyl pyruvate (EP), a stable lipophilic ester, has anti-inflammatory properties. Here, the influence of EP on the inflammatory reaction and liver injury in a double hit model of TxT and H/R in rats was explored.
Methods: Female Lewis rats were subjected to TxT followed by hemorrhage/H (60 min, 35±3 mm Hg) and resuscitation/R (TxT+H/R). Reperfusion was performed by either Ringer`s lactated solution (RL) alone or RL supplemented with EP (50 mg/kg). Sham animals underwent all surgical procedures without TxT+H/R. After 2h, blood and liver tissue were collected for analyses, and survival was assessed after 24h.
Results: Resuscitation with EP significantly improved haemoglobin levels and base excess recovery compared with controls after TxT+H/R, respectively (p<0.05). TxT+H/R-induced significant increase in alanine aminotransferase levels and liver injury were attenuated by EP compared with controls (p<0.05). Local inflammation as shown by increased gene expression of IL-6 and ICAM-1, enhanced ICAM-1 and HMGB1 protein expression and infiltration of the liver with neutrophils were also significantly attenuated by EP compared with controls after TxT+H/R (p<0.05). EP significantly reduced TxT+H/R-induced p65 activation in liver tissue. Survival rates improved by EP from 50% to 70% after TxT+H/R.
Conclusions: These data support the concept that the pronounced local pro-inflammatory response in the liver after blunt chest trauma and hemorrhagic shock is associated with NF-κB. In particular, the beneficial anti-inflammatory effects of ethyl pyruvate seem to be regulated by the HMGB1/NF-κB axis in the liver, thereby, restraining inflammatory responses and liver injury after double hit trauma in the rat.
The lncRNA GATA6-AS epigenetically regulates endothelial gene expression via interaction with LOXL2
(2018)
Impaired or excessive growth of endothelial cells contributes to several diseases. However, the functional involvement of regulatory long non-coding RNAs in these processes is not well defined. Here, we show that the long non-coding antisense transcript of GATA6 (GATA6-AS) interacts with the epigenetic regulator LOXL2 to regulate endothelial gene expression via changes in histone methylation. Using RNA deep sequencing, we find that GATA6-AS is upregulated in endothelial cells during hypoxia. Silencing of GATA6-AS diminishes TGF-β2-induced endothelial–mesenchymal transition in vitro and promotes formation of blood vessels in mice. We identify LOXL2, known to remove activating H3K4me3 chromatin marks, as a GATA6-AS-associated protein, and reveal a set of angiogenesis-related genes that are inversely regulated by LOXL2 and GATA6-AS silencing. As GATA6-AS silencing reduces H3K4me3 methylation of two of these genes, periostin and cyclooxygenase-2, we conclude that GATA6-AS acts as negative regulator of nuclear LOXL2 function.
Protein aggregation of the p63 transcription factor underlies severe skin fragility in AEC syndrome
(2018)
The p63 gene encodes a master regulator of epidermal commitment, development, and differentiation. Heterozygous mutations in the C-terminal domain of the p63 gene can cause ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome, a life-threatening disorder characterized by skin fragility and severe, long-lasting skin erosions. Despite deep knowledge of p63 functions, little is known about mechanisms underlying disease pathology and possible treatments. Here, we show that multiple AEC-associated p63 mutations, but not those causative of other diseases, lead to thermodynamic protein destabilization, misfolding, and aggregation, similar to the known p53 gain-of-function mutants found in cancer. AEC mutant proteins exhibit impaired DNA binding and transcriptional activity, leading to dominant negative effects due to coaggregation with wild-type p63 and p73. Importantly, p63 aggregation occurs also in a conditional knock-in mouse model for the disorder, in which the misfolded p63 mutant protein leads to severe epidermal defects. Variants of p63 that abolish aggregation of the mutant proteins are able to rescue p63’s transcriptional function in reporter assays as well as in a human fibroblast-to-keratinocyte conversion assay. Our studies reveal that AEC syndrome is a protein aggregation disorder and opens avenues for therapeutic intervention.
Background: Recurrent airway infections are common in patients with Down’s syndrome (DS). Hence, ruling out Cystic Fibrosis (CF) in these patients is often required. In the past, the value of sweat testing – the gold standard to diagnose CF – has been questioned in DS as false positive results have been reported. However, these reports are based on measurements of sweat osmolality or sodium concentrations, not chloride concentrations. This study analyses sweat secretion rate and chloride concentration in sweat samples of patients with DS in comparison to healthy controls.
Methods: We assessed sweat samples in 16 patients with DS and 16 healthy controls regarding sweat secretion rate (SSR) and sweat chloride concentration.
Results: All measured chloride concentrations were within the normal range. The chloride concentrations were slightly, but not significantly lower in patients with DS (15,54 mmol/l (±4,47)) compared to healthy controls (18,31 mmol/l (±10,12)). While no gender gap in chloride concentration could be found, chloride concentration increased with age in both groups.
Insufficient sweat was collected in 2 females with DS (12.5% of the study group) but not in an individual of the control group. A significant lower sweat secretion rate was found in the DS group (27,6 μl/30 min (± 12,18)) compared to the control group (42,7 μl/30 min (± 21,22)). In a sub-analysis, female patients produced significantly less sweat (20,8 ± 10,6 μl/30 min) than male patients with DS (36,4 ± 7,8 μl/30 min), which accounts for the difference between patients and controls. Furthermore, while the sweating secretion rate increased with age in the control group, it did not do so in the DS group. Once again this was due to female patients with DS, who did not show a significant increase of sweat secretion rate with age.
Conclusions: Sweat chloride concentrations were within the normal range in patients with DS and therefore seem to be a reliable tool for testing for CF in these patients. Interestingly, we found a reduced sweat secretion rate in the DS group. Whether the last one has a functional and clinical counterpart, possibly due to a disturbed thermoregulation in DS patients, requires further investigation.
Coordination of circuit breakers? Volume migration and volatility spillover in fragmented markets
(2018)
We study circuit breakers in a fragmented, multi-market environment and investigate whether a coordination of circuit breakers is necessary to ensure their effectiveness. In doing so, we analyze 2,337 volatility interruptions on Deutsche Boerse and research whether a volume migration and an accompanying volatility spillover to alternative venues that continue trading can be observed. Different to prevailing theoretical rationale, trading volume on alternative venues significantly decreases during circuit breakers on the main market and we do not find any evidence for volatility spillover. Moreover, we show that the market share of the main market increases sharply during a circuit breaker. Surprisingly, this is amplified with increasing levels of fragmentation. We identify high-frequency trading as a major reason for the vanishing trading activity on the alternative venues and give empirical evidence that a coordination of circuit breakers is not essential for their effectiveness as long as market participants shift to the dominant venue during market stress.
We investigate different designs of circuit breakers implemented on European trading venues and examine their effectiveness to manage excess volatility and to preserve liquidity. Specifically, we empirically analyze volatility and liquidity around volatility interruptions implemented on the German and Spanish stock market which differ regarding specific design parameters. We find that volatility interruptions in general significantly decrease volatility in the post interruption phase. Unfortunately, this decrease in volatility comes at the cost of decreased liquidity. Regarding design parameters, we find tighter price ranges and shorter durations to support volatility interruptions in achieving their goals.
A primordial state of matter consisting of free quarks and gluons that existed in the early universe a few microseconds after the Big Bang is also expected to form in high-energy heavy-ion collisions. Determining the equation of state (EoS) of such a primordial matter is the ultimate goal of high-energy heavy-ion experiments. Here we use supervised learning with a deep convolutional neural network to identify the EoS employed in the relativistic hydrodynamic simulations of heavy ion collisions. High-level correlations of particle spectra in transverse momentum and azimuthal angle learned by the network act as an effective EoS-meter in deciphering the nature of the phase transition in quantum chromodynamics. Such EoS-meter is model-independent and insensitive to other simulation inputs including the initial conditions for hydrodynamic simulations.
Background: Agrocybe aegerita is an agaricomycete fungus with typical mushroom features, which is commercially cultivated for its culinary use. In nature, it is a saprotrophic or facultative pathogenic fungus causing a white-rot of hardwood in forests of warm and mild climate. The ease of cultivation and fructification on solidified media as well as its archetypal mushroom fruit body morphology render A. aegerita a well-suited model for investigating mushroom developmental biology.
Results: Here, the genome of the species is reported and analysed with respect to carbohydrate active genes and genes known to play a role during fruit body formation. In terms of fruit body development, our analyses revealed a conserved repertoire of fruiting-related genes, which corresponds well to the archetypal fruit body morphology of this mushroom. For some genes involved in fruit body formation, paralogisation was observed, but not all fruit body maturation-associated genes known from other agaricomycetes seem to be conserved in the genome sequence of A. aegerita. In terms of lytic enzymes, our analyses suggest a versatile arsenal of biopolymer-degrading enzymes that likely account for the flexible life style of this species. Regarding the amount of genes encoding CAZymes relevant for lignin degradation, A. aegerita shows more similarity to white-rot fungi than to litter decomposers, including 18 genes coding for unspecific peroxygenases and three dye-decolourising peroxidase genes expanding its lignocellulolytic machinery.
Conclusions: The genome resource will be useful for developing strategies towards genetic manipulation of A. aegerita, which will subsequently allow functional genetics approaches to elucidate fundamentals of fruiting and vegetative growth including lignocellulolysis.
Ausgangspunkt der Dissertation bilden 2.700 keltische und römische Fundmünzen sowie zahlreiche Produktionsreste aus Bunt- und Edelmetall, die auf dem Castellberg, Kreis Bitburg-Prüm, geborgen wurden. Die Funde stammen zum überwiegenden Teil aus den großflächigen Ausgrabungen und Prospektionen, die im Rahmen des von der Deutschen Forschungsgemeinschaft geförderten Schwerpunktprogramms „Romanisierung“ durchgeführt wurden.
Nach bisherigem Forschungsstand befand sich auf dem ausgedehnten Bergplateau vom 2. bis 1. Jh. v. Chr. ein Oppidum der Treverer. Im Verlauf der römischen Okkupation entwickelten sich an diesem Platz ein gallo-römisches Heiligtum sowie eine Zivilsiedlung, welche eine Platzkontinuität bis zum Beginn des 5. Jh. n. Chr. aufweisen.
Aufgrund der komplexen Siedlungsabfolge sowie der gut dokumentierten archäologischen Kontexte nehmen die Funde vom Castellberg eine Schlüsselrolle für die Erforschung der latènezeitlichen Münzprägung Nordgalliens ein und bieten beste Voraussetzungen, Zirkulation und Funktion von Münzen in diesem Raum bis zur Spätantike zu untersuchen.
Wesentliches Ziel der Studie bilden die Erfassung und Dokumentation der genannten Funde sowie deren archäologische, archäometrische und numismatische Auswertung auf Grundlage der erschlossenen Fundkontexte.
Zu Beginn stehen methodische Überlegungen zur chronologischen Einordnung und zur histographischen Darstellung des Fundgutes.
Die anschließenden Betrachtungen widmen sich dem antiken Geldbegriff. Die Auseinandersetzung mit der Wertgrundlage des antiken Geldes stellt eine Voraussetzung dar, um das Vorkommen von Münzen aus archäologischen Kontexten historisch angemessen zu beschreiben und damit die Funktion von und den Umgang mit Geld in der Antike zu erfassen.
Einen Schwerpunkt der Arbeit stellen die nachfolgenden quellenkritischen Untersuchungen zu den Bedingungen des Zustandekommens und der Überlieferung der Münzfunde dar. Anhand des Fundmaterials vom Castellberg werden exemplarisch die Auswirkungen antiker und nachantiker selektiver Faktoren dargelegt. Durch den Abgleich mit strukturell vergleichbaren Fundplätzen wird anschließend eine Überprüfung und Erweiterung der Ergebnisse vorgenommen, wobei insbesondere Fragen nach den antiken Selektionsmechanismen im Vordergrund stehen.
Im Anschluss erfolgt die Auswertung der Fundmünzen aus den Ausgrabungen und Prospektionen. Mit Hilfe von Befundanalysen, Münzkartierungen und Münzreihenauswertungen werden die einzelnen Fundkomplexe detailliert auf ihre zeitlichen und räumlichen Verhältnisse hin untersucht. Auf diesem Weg gelingt es, weiterführende Erkenntnisse zur Genese, Entwicklung und zum Ende des spätlatènezeitlichen Oppidums sowie des gallo-römischen Vicus und Heiligtums auf dem Castellberg zu gewinnen.
Am Ende der Arbeit stehen Fragen zum treverischen Münzwesen im Vordergrund. Neben dem umfangreichen Material vom Castellberg wurden zahlreiche weitere keltische Münzen von Vergleichsfundplätzen als Materialbasis für die vorgenommenen Stempelstudien, Gewichtsuntersuchungen und Metallanalysen herangezogen.
Es wird zunächst aufgezeigt, dass die bisher gebräuchliche Typologie der treverischen Silberprägung weiter zu differenzieren und präzisieren ist. Die Ergebnisse führen ferner zu Konsequenzen für die relativchronologische Fixierung der betreffenden Münztypen.
Die nachfolgenden Stempelstudien konzentrieren sich auf die beiden frühesten Silbermünztypen der Treverer; es werden Art und Umfang dieser Prägungen aufgezeigt sowie Rückschlüsse für die Fertigungstechnik der Prägestempel gezogen.
Einen zentralen Aspekt der Dissertation bildet die abschließende Auswertung der Metallanalysen an ausgewählten Münztypen der Treverer, Remer und Leuker. Die Analysen geben Auskunft über die Spezifika der betreffenden Emissionen und liefern ein ergänzendes Bild zu den numismatischen Studien. Des Weiteren wird dargelegt, inwieweit die Herkunft der ausgemünzten Erze nachvollzogen werden kann.
Ausgehend von dem bedeutenden Neufund einer Patrize sowie zahlreichen Funden von Münzschrötlingen, Fehlgüssen und Metallschmelzresten vom Castellberg wird darüber hinaus die Frage geklärt, ob auf dem Plateau eine treverische Prägestätte zu lokalisieren ist und welche Münztypen dort geprägt wurden. Weitere Funde von Prägewerkzeugen aus dem Untersuchungsgebiet werfen grundlegende Fragen zu den Fertigungstechniken auf, denen in diesem Zusammenhang ebenso nachgegangen wird.
Die Untersuchungen liefern erstmals konkrete Erkenntnisse zu Ablauf und Organisation des Münzwesens der Treverer sowie zu strukturellen Veränderungen, die im Zusammenhang mit dem Gallischen Krieg und der nachfolgenden römischen Einflussnahme zu sehen sind.
Passt das deutsche Dreisäulensystem in eine zunehmend harmonisierte Bankenstruktur für Europa?
(2018)
Das deutsche Bankensystem ruht seit Jahrzehnten auf drei Säulen: den privaten Kreditbanken, einschließlich der großen Banken in Aktionärsbesitz, den öffentlichen Banken und den Genossenschaftsbanken. Fast nirgendwo anders in Europa hat ein solches Dreisäulensystem überlebt. Passt es also noch in ein Europa, in dem die Bankpolitik, die Regulierung und die Aufsicht inzwischen weitgehend in die Zuständigkeit der EU fallen? Für eine Bewahrung des Systems sprechen vor allem Gesichtspunkte der Stabilität. Angesichts ihrer Gruppenzugehörigkeit sind die deutschen "stakeholder-value-orientierten" Banken der Säulen 2 und 3 finanziell keineswegs weniger erfolgreich, sogar ein wenig erfolgreicher als die "shareholder-value-orientierten" Großbanken der Säule 1. Insbesondere schwanken ihre Geschäftszahlen deutlich weniger als jene der Großbanken, die in der Regel ein riskanteres Geschäftsmodell verfolgen. In vielen Privatbanken ist die Gewinnorientierung und damit auch die Bereitschaft, hohe Risiken einzugehen, aus ordnungspolitischer Sicht zu hoch, was die Systemstabilität tendenziell gefährdet. Zudem erfüllen die Genossenschaftsbanken und Sparkassen eine regionalpolitische Ausgleichsfunktion und haben eine gesamtwirtschaftlich stabilisierende Wirkung.
Background: Von Willebrand disease (VWD) is the most common inherent bleeding disorder. Gingival bleeding is a frequently reported symptom of VWD. However, gingival bleeding is also a leading symptom of plaque-induced gingivitis and untreated periodontal disease. In type 1 VWD gingival bleeding was not increased compared to controls. Thus, this study evaluated whether type 2 and 3 VWD determines an increased susceptibility to gingival bleeding in response to the oral biofilm.
Methods: Twenty-four cases and 24 controls matched for age, sex, periodontal diagnosis, number of teeth and smoking were examined hematologically (VWF antigen, VWF activity, factor VIII activity) and periodontally (Gingival Bleeding Index [GBI]), bleeding on probing [BOP], Plaque Control Record [PCR], periodontal inflamed surface area [PISA], vertical probing attachment level).
Results: BOP (VWD: 14.5±10.1%; controls: 12.3±5.3%; p = 0.542) and GBI (VWD: 10.5±9.9%; controls: 8.8±4.8%; p = 0.852) were similar for VWD and controls. Multiple regressions identified female sex, HbA1c, PCR and PISA to be associated with BOP. HbA1c and PCR were associated with GBI. Number of remaining teeth was negatively correlated with BOP and GBI.
Conclusion: Type 2 and 3 VWD are not associated with a more pronounced inflammatory response to the oral biofilm in terms of BOP and GBI.
Stimulation of renal collecting duct principal cells with antidiuretic hormone (arginine-vasopressin, AVP) results in inhibition of the small GTPase RhoA and the enrichment of the water channel aquaporin-2 (AQP2) in the plasma membrane. The membrane insertion facilitates water reabsorption from primary urine and fine-tuning of body water homeostasis. Rho guanine nucleotide exchange factors (GEFs) interact with RhoA, catalyze the exchange of GDP for GTP and thereby activate the GTPase. However, GEFs involved in the control of AQP2 in renal principal cells are unknown. The A-kinase anchoring protein, AKAP-Lbc, possesses GEF activity, specifically activates RhoA, and is expressed in primary renal inner medullary collecting duct principal (IMCD) cells. Through screening of 18,431 small molecules and synthesis of a focused library around one of the hits, we identified an inhibitor of the interaction of AKAP-Lbc and RhoA. This molecule, Scaff10-8, bound to RhoA, inhibited the AKAP-Lbc-mediated RhoA activation but did not interfere with RhoA activation through other GEFs or activities of other members of the Rho family of small GTPases, Rac1 and Cdc42. Scaff10-8 promoted the redistribution of AQP2 from intracellular vesicles to the periphery of IMCD cells. Thus, our data demonstrate an involvement of AKAP-Lbc-mediated RhoA activation in the control of AQP2 trafficking.
Background: Published estimates of mortality and progression to AIDS as children with HIV approach adulthood are limited. We describe rates and risk factors for death and AIDS-defining events in children and adolescents after initiation of combination antiretroviral therapy (cART) in 17 middle- and high-income countries, including some in Western and Central Europe (W&CE), Eastern Europe (Russia and Ukraine), and Thailand.
Methods and findings: Children with perinatal HIV aged <18 years initiating cART were followed until their 21st birthday, transfer to adult care, death, loss to follow-up, or last visit up until 31 December 2013. Rates of death and first AIDS-defining events were calculated. Baseline and time-updated risk factors for early/late (≤/>6 months of cART) death and progression to AIDS were assessed. Of 3,526 children included, 32% were from the United Kingdom or Ireland, 30% from elsewhere in W&CE, 18% from Russia or Ukraine, and 20% from Thailand. At cART initiation, median age was 5.2 (IQR 1.4–9.3) years; 35% of children aged <5 years had a CD4 lymphocyte percentage <15% in 1997–2003, which fell to 15% of children in 2011 onwards (p < 0.001). Similarly, 53% and 18% of children ≥5 years had a CD4 count <200 cells/mm3 in 1997–2003 and in 2011 onwards, respectively (p < 0.001). Median follow-up was 5.6 (2.9–8.7) years. Of 94 deaths and 237 first AIDS-defining events, 43 (46%) and 100 (42%) were within 6 months of initiating cART, respectively. Multivariable predictors of early death were: being in the first year of life; residence in Russia, Ukraine, or Thailand; AIDS at cART start; initiating cART on a nonnucleoside reverse transcriptase inhibitor (NNRTI)-based regimen; severe immune suppression; and low BMI-for-age z-score. Current severe immune suppression, low current BMI-for-age z-score, and current viral load >400 c/mL predicted late death. Predictors of early and late progression to AIDS were similar. Study limitations include incomplete recording of US Centers for Disease Control (CDC) disease stage B events and serious adverse events in some countries; events that were distributed over a long time period, and that we lacked power to analyse trends in patterns and causes of death over time.
Conclusions: In our study, 3,526 children and adolescents with perinatal HIV infection initiated antiretroviral therapy (ART) in countries in Europe and Thailand. We observed that over 40% of deaths occurred ≤6 months after cART initiation. Greater early mortality risk in infants, as compared to older children, and in Russia, Ukraine, or Thailand as compared to W&CE, raises concern. Current severe immune suppression, being underweight, and unsuppressed viral load were associated with a higher risk of death at >6 months after initiation of cART.
In optogenetics, rhodopsins were established as light-driven tools to manipulate neuronal activity. However, during long-term photostimulation using channelrhodopsin (ChR), desensitization can reduce effects. Furthermore, requirement for continuous presence of the chromophore all-trans retinal (ATR) in model systems lacking sufficient endogenous concentrations limits its applicability. We tested known, and engineered and characterized new variants of de- and hyperpolarizing rhodopsins in Caenorhabditis elegans. ChR2 variants combined previously described point mutations that may synergize to enable prolonged stimulation. Following brief light pulses ChR2(C128S;H134R) induced muscle activation for minutes or even for hours (‘Quint’: ChR2(C128S;L132C;H134R;D156A;T159C)), thus featuring longer open state lifetime than previously described variants. Furthermore, stability after ATR removal was increased compared to the step-function opsin ChR2(C128S). The double mutants C128S;H134R and H134R;D156C enabled increased effects during repetitive stimulation. We also tested new hyperpolarizers (ACR1, ACR2, ACR1(C102A), ZipACR). Particularly ACR1 and ACR2 showed strong effects in behavioral assays and very large currents with fast kinetics. In sum, we introduce highly light-sensitive optogenetic tools, bypassing previous shortcomings, and thus constituting new tools that feature high effectiveness and fast kinetics, allowing better repetitive stimulation or investigating prolonged neuronal activity states in C. elegans and, possibly, other systems.
The increased susceptibility to infections of neonates is caused by an immaturity of the immune system as a result of both qualitative and quantitative differences between neonatal and adult immune cells. With respect to B cells, neonatal antibody responses are known to be decreased. Accountable for this is an altered composition of the neonatal B cell compartment towards more immature B cells. However, it remains unclear whether the functionality of individual neonatal B cell subsets is altered as well. In the current study we therefore compared phenotypical and functional characteristics of corresponding neonatal and adult B cell subpopulations. No phenotypic differences could be identified with the exception of higher IgM expression in neonatal B cells. Functional analysis revealed differences in proliferation, survival, and B cell receptor signaling. Most importantly, neonatal B cells showed severely impaired class-switch recombination (CSR) to IgG and IgA. This was associated with increased expression of miR-181b in neonatal B cells. Deficiency of miR-181b resulted in increased CSR. With this, our results highlight intrinsic differences that contribute to weaker B cell antibody responses in newborns.
Deutschland und Europa
(2018)
Otmar Issing erörtert die Reaktionen in Deutschland auf die Pläne des französischen Präsidenten Macron aus dessen viel beachteter Rede zur Zukunft Europas an der Pariser Sorbonne. Issing wertet das Ergebnis der Sondierungsgespräche zwischen CDU/CSU und SPD als Abschied von der Vorstellung einer auf Stabilität gerichteten europäischen Gemeinschaft und mahnt an, den einheitlichen Markt und die damit verbundenen Freiheiten nicht durch überzogene Ambitionen zu gefährden und damit zunehmendes Misstrauen gegenüber Europa zu fördern.
Insbesondere in der geplanten Weiterentwicklung des ESM zu einem im Unionsrecht verankerten Europäischen Währungsfonds sieht Issing die Auslieferung der durch den Fonds zur Verfügung gestellten Mittel an eine politische Mehrheit. Zudem führe die Bestellung eines europäischen Finanzministers zur Schaffung einer die Währungsunion ergänzenden Fiskalunion und damit zur Verlagerung finanzpolitischer Kompetenz von der nationalen auf die europäische Ebene. In letzter Konsequenz bedeute dies eine Aufgabe des grundlegenden Prinzips der demokratischen Legitimierung und Kontrolle finanzpolitischer Entscheidungen.
Das Ergebnis der Sondierungsgespräche muss man als Abschied von der Vorstellung einer auf Stabilität gerichteten europäischen Gemeinschaft verstehen. Damit werden die Versprechen gebrochen, die man den Bürgern in Deutschland vor der Einführung des Euros gegeben hat.
Background: Leaf venation traits are important for many research fields such as systematics and evolutionary biology, plant physiology, climate change, and paleoecology. In spite of an increasing demand for vein trait data, studies are often still data-limited because the development of methods that allow rapid generation of large sets of vein data has lagged behind. Recently, non-destructive X-ray technology has proven useful as an alternative to traditional slow and destructive chemical-based methods. Non-destructive techniques more readily allow the use of herbarium specimens, which provide an invaluable but underexploited resource of vein data and related environmental information. The utility of 2D X-ray technology and microfocus X-ray computed tomography, however, has been compromised by insufficient image resolution. Here, we advanced X-ray technology by increasing image resolution and throughput without the application of contrast agents.
Results: For 2D contact microradiography, we developed a method which allowed us to achieve image resolutions of up to 7 µm, i.e. a 3.6-fold increase compared to the industrial standard (25 µm resolution). Vein tracing was further optimized with our image processing standards that were specifically adjusted for different types of leaf structure and the needs of higher imaging throughput. Based on a test dataset, in 91% of the samples the 7 µm approach led to a significant improvement in estimations of minor vein density compared to the industrial standard. Using microfocus X-ray computed tomography, very high-resolution images were obtained from a virtual 3D–2D transformation process, which was superior to that of 3D images.
Conclusions: Our 2D X-ray method with a significantly improved resolution advances rapid non-destructive bulk scanning at a quality that in many cases is sufficient to determine key venation traits. Together with our high-resolution microfocus X-ray computed tomography method, both non-destructive approaches will help in vein trait data mining from museum collections, which provide an underexploited resource of historical and recent data on environmental and evolutionary change. In spite of the significant increase in effective image resolution, a combination of high-throughput and full visibility of the vein network (including the smallest veins and their connectivity) remains challenging, however.
Die Wahrscheinlichkeit einer pathologischen Komplettremission (pCR) bei Brustkrebs nach neoadjuvanter Chemotherapie (NACT) nimmt zu; vor allem in den Subgruppen der tripel-negativen und HER-2-positiven Tumoren. Daher stellt sich die Frage, ob bei einer Komplettremission nach NACT eine operative Therapie der Brust notwendig ist, und ob es einen Vorteil für das onkologische Behandlungsergebnis hat, wenn kein Tumor mehr nachgewiesen werden kann. Ein Verzicht auf die Operation und gegebenenfalls auch auf die Radiotherapie ist jedoch nur auf der Basis einer verlässlichen pCR-Diagnose ohne Operation denkbar. Bildgebende Verfahren erreichen derzeit nicht die nötige Sensitivität und Spezifität, um die Diagnose einer pathologischen Komplettremission sicher zu stellen. Daher sind weitere Studien nötig, um herauszufinden, welche Methode die bestmögliche Evaluation des Tumoransprechens auf NACT erlaubt. Erste vielversprechende Ergebnisse zeigen sich in Studien zu bildgebungsgesteuerten, minimalinvasiven Biopsien nach NACT. Diese evaluieren die Möglichkeit einer pCR-Diagnose vor der Operation und könnten die Grundlage für weitere Studien zu einem möglichen Verzicht auf eine Operation in diesem ausgewählten Kollektiv sein.
The likelihood of pathological complete remission (pCR) of breast cancer following neoadjuvant chemotherapy (NACT) is increasing; most of all in the triple negative and HER2 positive tumour subgroups. The question thus arises whether or not breast surgery is necessary when there is complete remission after NACT, and whether it provides any improvement of the oncological treatment result when tumour is no longer detectable. Avoiding surgery and possibly even radiotherapy would only be conceivable on the basis of a reliable diagnosis of pCR without operating. Current imaging does not achieve the necessary sensitivity and specificity to assure the diagnosis of pathological complete remission. Further studies are therefore required to determine which methods are best able to evaluate tumour response to NACT. Studies on image-guided, minimally invasive biopsies after NACT have delivered first promising results towards diagnosing pCR before surgery and could provide the basis for further studies on the possibility of avoiding surgery in this specific patient collective.
I present a new business cycle model in which decision making follows a simple mental process motivated by neuroeconomics. Decision makers first compute the value of two different options and then choose the option that offers the highest value, but with errors. The resulting model is highly tractable and intuitive. A demand function in level replaces the traditional Euler equation. As a result, even liquid consumers can have a large marginal propensity to consume. The interest rate affects consumption through the cost of borrowing and not through intertemporal substitution. I discuss the implications for stimulus policies.
This paper analyses whether the post-crisis regulatory reforms developed by global-standard-setting bodies have created appropriate incentives for different types of market participants to centrally clear Over-The-Counter (OTC) derivative contracts. Beyond documenting the observed facts, we analyze four main drivers for the decision to clear: 1) the liquidity and riskiness of the reference entity; 2) the credit risk of the counterparty; 3) the clearing member’s portfolio net exposure with the Central Counterparty Clearing House (CCP) and 4) post trade transparency. We use confidential European trade repository data on single-name Sovereign Credit Derivative Swap (CDS) transactions, and show that for all the transactions reported in 2016 on Italian, German and French Sovereign CDS 48% were centrally cleared, 42% were not cleared despite being eligible for central clearing, while 9% of the contracts were not clearable because they did not satisfy certain CCP clearing criteria. However, there is a large difference between CCP clearing members that clear about 53% of their transactions and non-clearing members, even those that are subject to counterparty risk capital requirements, that almost never clear their trades. Moreover, we find that diverse factors explain clearing members’ decision to clear different CDS contracts: for Italian CDS, counterparty credit risk exposures matter most for the decision to clear, while for French and German CDS, margin costs are the most important factor for the decision. Clearing members use clearing to reduce their exposures to the CCP and largely clear contracts when at least one of the traders has a high counterparty credit risk.
The longevity of the population in the Okinawa Islands of Japan has been ascribed to genetic factors and the traditional Okinawa cuisine, which is low in calories and high in plant content. This diet includes shell ginger (Alpinia zerumbet (Pers.) B.L. Burtt & R.M. Sm) of the ginger family (Zingiberaceae). Due to its local popularity, Alpinia zerumbet has become the subject of a good deal of study at the University of the Ryukyus in Okinawa. Personal local experience and review of the literature now suggest that culinary shell ginger may contribute to longevity among the population in Okinawa. This is supported by its abundant phytochemical content, with antioxidant and anti-obesity properties. The major bioactive phytochemicals are dihydro-5,6-dehydrokawain (DDK; 80–410 mg g−1 fresh weight), 5,6-dehydrokawain (DK; ≤100 mg g−1), and essential oils, phenols, phenolic acids, and fatty acids (≤150 mg g−1 each). Further, Alpinia zerumbet extends the lifespan in animals by 22.6%. In conclusion, culinary shell ginger may significantly contribute to human longevity in Okinawa.
The blue light-dependent interaction between the proteins iLID and Nano allows recruiting and patterning proteins on GUV membranes, which thereby capture key features of patterns observed in nature. This photoswitchable protein interaction provides non-invasive, reversible and dynamic control over protein patterns of different sizes with high specificity and spatiotemporal resolution.
Compared to their protein-coding counterparts, almost nothing is known about the role of long noncoding RNAs (lncRNAs) in cardiac fibrosis. In the current report, Liang and Pan et al. characterized the pro-fibrotic lncRNA PFL in respect to cardiac fibrosis in mice. PFL was upregulated in the hearts of mice after myocardial infarction and in fibrotic cardiac fibroblasts. Moreover, PFL competitively sponged the cardio-protective miRNA let-7d in cardiac fibroblasts. Knockdown of platelet activating factor receptor (PTAFR) was shown to affect the pro-fibrotic collagen production mediated by PFL. PTAFR overexpression also led to collagen production and RNA abundance of PTAFR was also regulated by miRNA let-7d. Therefore, the PFL/PTAFR/let-7d-dependent gene regulatory mechanism proposed by the authors manifests the hypothesis of competing endogenous RNAs to cardiac fibrosis.
Digitalization expands the possibility for corporations to reduce taxes, mainly, but not exclusively, by allowing improved planning where profits can be shifted. Against this background, the European Commission and several countries emphatically demand and design new tax instruments. However, a selective turning away from internationally accepted principles of international taxation will bring up more questions than solutions. While there are good reasons to think about a fundamental regime switch in international corporate taxation, there are also good arguments for not turning to ad hoc measures that selectively target the relatively small market of Google and Facebook and raise only negligible tax revenues.
Monetary policy and prudential supervision – from functional separation to a holistic approach?
(2018)
When prudential supervision was put in the hands of the European Central Bank (ECB), it was the political understanding that the ECB should follow a policy of meticulous separation between monetary policy and financial supervision. However, the financial crisis showed that monetary policy and prudential supervision deeply affect each other and that an overly strict separation might generate systemic risk. As a consequence, the prevalent model of “functional separation” – central banking and financial supervision in separate entities – has been questioned and calls for a more holistic approach increased.
This policy letter states that from a legal perspective, such a holistic approach would be in conformity with the current legal framework of the Economic and Monetary Union. Although the realization of a holistic approach might intensify the doubts of democratic legitimation under the framework of the ESCB, the independence of the ECB should not be given up. As viable alternatives to protect monetary policy against the time inconsistency problem that would render central bank independence moot do not seem to be available and given the great importance of the independence of the European institutions for the European integration, the democratic control over the ECB should be strengthened instead of stripping the ECB of its independence.
Se registra por primera vez el ácaro rojo de las palmas, Raoiella indica Hirst (Acari: Tenuipalpidae), en Guatemala. Este ácaro invasivo se encontró en los departamentos de Petén e Izabal infestando palma de coco (Cocos nucifera), palma de Navidad (Adonidia merrillii) y palmera robeleni (Phoenix roebelenii).
En este estudio se describen dos nuevas especies de hemípteros del género Aleuropleurocelus (Hemiptera: Aleyrodidae): Aleuropleurocelus mexicanus Carapia y Sánchez sp. nov., encontrada en los estados de Coahuila, México, Puebla, Sonora, y Tlaxcala en hojas de Quercus agrifolia Née y Quercus sp., y Aleuropleurocelus anahuac Carapia y Sánchez sp. nov. encontrada en los estados de México, Morelos y Puebla en el envés de hojas de Quercus. Se proporcionan microfotografías de estructuras morfológicas de puparios y se discute la separación con otras especies ovales de Aleuropleurocelus.
An early, overlooked description of the genus Atelodesmis (Coleoptera, Cerambycidae, Lamiinae) is attributed to Chevrolat (in Duponchel and Chevrolat 1841), with A. mannerheimii Duponchel and Chevrolat, 1841 as its type species, and the genus redescribed. Atelodesmis Buquet, 1857, is a junior synonym and primary homonym of Atelodesmis Chevrolat. Atelodesmis hirticornis Buquet, 1857 and A. vestita Buquet, 1857 are synonymized with A. mannerheimii. Fallaxdesmis is described as a new genus with Atelodesmis unicolor Buquet, 1857 as type species. Atelodesmis piperita Bates, 1855 is transferred to Eupogonius and newly recorded for the state of Oaxaca, Mexico. A new species for Mexico and Guatemala, Eupogonius giesberti, is described. The following new combinations are established: Fallaxdesmis unicolor (Buquet, 1857) and Eupogonius piperita (Bates, 1855). Illustrations of A. mannerheimii, Fallaxdesmis unicolor, and the holotypes of A. hirticornis, A. vestita, A. unicolor, A. piperita and Eupogonius giesberti are included.
The Trichoptera of Panama V. Descriptions of new species, new country records, and a synonymy
(2018)
The Río Chiriqui basin is one of 52 major watershed areas, or cuencas, in the Republic of Panama. It occurs in western Panama, discharges into the Pacific Ocean, and includes portions of Volcán Barú on its northern extent. The Río Caldera occupies the northernmost subbasin of this basin. Two of its tributaries, Quebrada Grande and Quebrada Jaramillo, occur in close proximity and on opposite sides, and have different recent geologic histories and current land use patterns. During the course of investigating the caddisfly fauna of these two drainages, three new species of the microcaddisfly genus Neotrichia Morton (Trichoptera: Hydroptilidae) were identified: N. collierorum and N. anzuelo from Quebrada Jaramillo and N. tatianae from Quebrada Grande. These are described and figured herein. We also add one new genus (Rhyacopsyche Mueller) and five new country records (Hydroptila paschia Mosely, Metrichia ancora Bueno-Soria and Holzenthal, Ochrotrichia jolandae BuenoSoria and Holzenthal, Rhyacopsyche obliqua Flint, and Chimarra (Curgia) maritza Flint) for Panama. Finally, we designate Ochrotrichia abrelata Harris and Armitage, 2015 as a junior synonym of Ochrotrichia jolandae Bueno-Soria and Holzenthal, 2008. This synonymy and the newly recorded species and country records increase Panama’s known trichopteran fauna to 350 species, distributed among 15 families and 52 genera.
After publication of Blahnik and Holzenthal (2017), it was noticed that a large portion of the text had been accidentally removed from the "Phylogenetic and evolutionary comments" section during the proofing stage. The beginning of the deleted section completes the sentence on line 6 of page 129, which begins "The species included in the subgenus...". The Insecta Mundi editorial staff apologizes for this oversight. In order to provide context for the deleted excerpt, the entire "Phylogenetic and evolutionary comments" section is reproduced here, with the deleted text reincorporated. Insecta Mundi has also released a revised version of the Blahnik and Holzenthal (2017) manuscript, with this error corrected. However, the revised version is merely for convenience, and not an official peerreviewed article. Anyone wishing to reference the findings of Blahnik and Holzenthal (2017) should cite the original 2017 manuscript or this erratum. The references and figure plates cited in this section have also been reproduced here. ...
Automated deduction in higher-order program calculi, where properties of transformation rules are demanded, or confluence or other equational properties are requested, can often be done by syntactically computing overlaps (critical pairs) of reduction rules and transformation rules. Since higher-order calculi have alpha-equivalence as fundamental equivalence, the reasoning procedure must deal with it. We define ASD1-unification problems, which are higher-order equational unification problems employing variables for atoms, expressions and contexts, with additional distinct-variable constraints, and which have to be solved w.r.t. alpha-equivalence. Our proposal is to extend nominal unification to solve these unification problems. We succeeded in constructing the nominal unification algorithm NomUnifyASC. We show that NomUnifyASC is sound and complete for these problem class, and outputs a set of unifiers with constraints in nondeterministic polynomial time if the final constraints are satisfiable. We also show that solvability of the output constraints can be decided in NEXPTIME, and for a fixed number of context-variables in NP time. For terms without context-variables and atom-variables, NomUnifyASC runs in polynomial time, is unitary, and extends the classical problem by permitting distinct-variable constraints.
1998 ACM Subject Classification F.4.1 Mathematical Logic
Strong imprints of Indian culture in various forms or modes of expressions are significantly found in Java. Sanskrit-Old Javanese texts, amongst those texts and traditions, were produced in the island in the periods between 9th to 15th cen. A.D. It covers various genres and subjects enriching indigenous culture in the archipelago. Tutur or tattva texts were one genre of them recorded the dynamic of Javanese intellectuals or poet-sages in pursuing the truth; they reveal metaphysical or theological aspects of Brahmanism, Saivism, Buddhism, Tantrism, Samkhya, Yoga, etc. This paper attempts to study ideas behind the Hindi transliteration and translation of those texts. This is a library reserach, the data were collected from Hindi translation of those texts. This attempt is of high scientific and cultural values as Indian scholars paid attention to Indian culture spreading in foreign lands. With this attempt Indian intellectuals/scholars/students got acquainted with their own culture flourished outside India in different forms, since the works were written and produced in Devanagari script and Hindi language. It creates nuances of being Indian. It can widen their understanding on philosophical point of view, religious elements, and culture of Java, that unity in diversity does not only exist in native land but also abroad.
Dieser Artikel ist eine Einführung in die islamische Religionspädagogik im osmanischen Reiches von der Vormoderne bis zur Gründung der türkischen Republik. Der Frage nach dem Beginn einer islamischen Erziehung wird vor allem anhand primärer Quellen nachgegangen. Die Wissensvermittlung von einzelnen und bestimmten Wissenschaften geschieht hauptsächlich mit Hilfe arabischer Handbücher, die auf die Zeit der Vormoderne zurückgehen und sich mit islamischer Pädagogik befassen. Zudem werden anhand von konkreten Einzelfällen kulturelle Einflüsse beleuchtet und die Veränderungen eines erziehungsliterarischen Themas chronologisch und tabellarisch aufgezeigt. In diesem Artikel finden jeweils drei weitere Aspekte punktuell Berücksichtigung: Der Austausch von Erziehung, Religion und Sprache. Das Osmanische Reich hat, um die Bevölkerung nach seinen eigenen ideologischen Vorstellungen zu erziehen, dafür wie alle anderen Staaten Bildungseinrichtungen geschaffen. In der osmanischen Zeit lag der Schwerpunkt dieser Institutionen hauptsächlich auf Religionslehre. Bis zum 17. Jahrhundert wurden Religions- und Naturwissenschaften in derselben Institution gelehrt. Von der Gründung des Reiches bis zu seinem Niedergang blieben diese Bildungseinrichtungen bestehen; wurden aber mit der Zeit inhaltlich reformiert. Man kann diese Einrichtungen, welche vom Staat und von verschiedenen Stiftungen gegründet und weiterentwickelt wurden, in zwei Hauptgruppen unterteilen: in formale Bildungsinstitute und verbreitete Bildungsinstitute.
This study investigated associations between parenting stress in parents and self-reported stress in children with children's diurnal cortisol secretion and whether these associations are moderated by known stress-regulating capacities, namely child cognitive control. Salivary cortisol concentrations were assessed from awakening to evening on two weekend days from 53 6-to-7-year-old children. Children completed a cognitive control task and a self-report stress questionnaire with an experimenter, while parents completed a parenting stress inventory. Hierarchical, linear mixed effects models revealed that higher parenting stress was associated with overall reduced cortisol secretion in children, and this effect was moderated by cognitive control. Specifically, parenting stress was associated with reduced diurnal cortisol levels in children with lower cognitive control ability and not in children with higher cognitive control ability. There were no effects of self-reported stress in children on their cortisol secretion, presumably because 6-to-7-year-old children cannot yet self-report on stress experiences. Our results suggest that higher cognitive control skills may buffer the effects of parenting stress in parents on their children’s stress regulation in middle childhood. This could indicate that training cognitive control skills in early life could be a target to prevent stress-related disorders.
Background: We evaluated the sensitivity of the D-statistic, a parsimony-like method widely used to detect gene flow between closely related species. This method has been applied to a variety of taxa with a wide range of divergence times. However, its parameter space and thus its applicability to a wide taxonomic range has not been systematically studied. Divergence time, population size, time of gene flow, distance of outgroup and number of loci were examined in a sensitivity analysis.
Result: The sensitivity study shows that the primary determinant of the D-statistic is the relative population size, i.e. the population size scaled by the number of generations since divergence. This is consistent with the fact that the main confounding factor in gene flow detection is incomplete lineage sorting by diluting the signal. The sensitivity of the D-statistic is also affected by the direction of gene flow, size and number of loci. In addition, we examined the ability of the f-statistics, fˆGf^G and fˆhomf^hom, to estimate the fraction of a genome affected by gene flow; while these statistics are difficult to implement to practical questions in biology due to lack of knowledge of when the gene flow happened, they can be used to compare datasets with identical or similar demographic background.
Conclusions: The D-statistic, as a method to detect gene flow, is robust against a wide range of genetic distances (divergence times) but it is sensitive to population size. The D-statistic should only be applied with critical reservation to taxa where population sizes are large relative to branch lengths in generations.
The influenza vaccination is recommended for all German pregnant women and health care personnel (HCP). We are the first to publish vaccination rates of mothers of hospitalized newborns and HCP in neonatal units. Between September 2016 and March 2017, data were collected in our level-III neonatology department in this descriptive multidisciplinary study, using an anonymous questionnaire. As a result, 513 persons were asked to participate, including 330 parents and 183 HCP. We received an 80.3% (412/513) response rate, 87.3% (288/330), and 67.8% (124/183) from parents and HCP, respectively. Ten percent (16/160) of mothers and 4.7% (6/127) of fathers had been vaccinated in 2016–2017 and 54.4% (87/160) mothers and 52.2% (66/127) fathers ever in their lifetime. In 2016–2017, 51.2% (21/41) of physicians had been vaccinated, 25.5% (14/55) of nurses, and 50.0% (14/28) of other staff members. When comparing those who had more than five influenza vaccinations in their life time, physicians were at 43.9% (18/41) versus nurses at 10.9% (6/55) (p < 0.01), and other HCP at 7.4% (2/27) (p < 0.01). The influenza vaccine uptake rate of 10% in mothers of hospitalized neonates is disappointingly low, resulting in 90% of hospitalized neonates being potentially vulnerable to influenza infection at a time where the risk for influenza-related complication can be severe.
Background: Despite the numerous associations of vitamin D with health and disease, vitamin D deficiency is still common from a global perspective. While basic research, clinical and preventive activities grow constantly in vitamin D research, there is no in-depth analysis of the related global scientific productivity available so far.
Methods: Density equalizing mapping procedures (DEMP) were combined with socioeconomic benchmarks using the NewQIS platform.
Results: A total of 25,992 vitamin D-related research articles were identified between 1900 to 2014 with a significant increase (r2 = .6541) from 1900 to 2014. Authors located in Northern America – especially in the USA – distributed the majority of global vitamin D research, followed by their Western European counterparts. DEMP-analysis illustrates that Africa and South America exhibit only minor scientific productivity. Among high-income group countries, Scandinavian nations such as Denmark or Finland (2147.9 and 1607.7 vitamin D articles per GDP in 1000 billion USD) were highly active with regard to socioeconomic figures.
Conclusion: Networks dedicated to vitamin D research are present around the world. Overall, the Northern American and Western European nations occupy prominent positions. However, South American, African and Asian countries apart from Japan only play a minor role in the global research production related to vitamin D. Since vitamin D deficiency is currently increasing in the Americas, Europe and parts of the Middle East, research in these regions may need to be encouraged.
Background: In 2007, the European Association of Palliative Care (EAPC) provided a comprehensive set of recommendations and standards for the provision of adequate pediatric palliative care. A number of studies have shown deficits in pediatric palliative care compared to EAPC standards. In Germany, pediatric palliative care patients can be referred to specialized outpatient palliative care (SOPC) services, which are known to enhance quality of life, e.g. by avoiding hospitalization. However, current regulations for the provision of SOPC in Germany do not account for the different circumstances and needs of children and their families compared to adult palliative care patients. The "Evaluation of specialized outpatient palliative care (SOPC) in the German state of Hesse (ELSAH)" study aims to perform a needs assessment for pediatric patients (children, adolescents and young adults) receiving SOPC. This paper presents the study protocol for this assessment (work package II).
Methods/Design: The study uses a sequential mixed-methods study design with a focus on qualitative research. Data collection from professional and family caregivers and, as far as possible, pediatric patients, will involve both a written questionnaire based on European recommendations for pediatric palliative care, and semi-structured interviews. Additionally, professional caregivers will take part in focus group discussions and participatory observations. Interviews and focus groups will be tape- or video-recorded, transcribed verbatim and analyzed in accordance with the principles of grounded theory (interviews) and content analysis (focus groups). A structured field note template will be used to record notes taken during the participatory observations. Statistical Package for Social Sciences (SPSS, version 22 or higher) will be used for descriptive statistical analyses. The qualitative data analyses will be software-assisted by MAXQDA (version 12 or higher).
Discussion: This study will provide important information on what matters most to family caregivers and pediatric patients receiving SOPC. The results will add valuable knowledge to the criteria that distinguish SOPC for pediatric from SOPC for adult patients, and will provide an indication of how the German SOPC rule of procedure can be optimized to satisfy the special needs of pediatric patients.
Trial registration: Internet Portal of the German Clinical Trials Register (www.germanctr.de, DRKS-ID: DRKS00012431).
Background: Although polypharmacy can cause adverse health outcomes, patients often know little about their medication. A regularly conducted medication review (MR) can help provide an overview of a patient’s medication, and benefit patients by enhancing their knowledge of their drugs. As little is known about patient attitudes towards MRs in primary care, the objective of this study was to gain insight into patient-perceived barriers and facilitators to the implementation of an MR.
Methods: We conducted a qualitative study with a convenience sample of 31 patients (age ≥ 60 years, ≥3 chronic diseases, taking ≥5 drugs/d); in Hesse, Germany, in February 2016. We conducted two focus groups and, in order to ensure the participation of elderly patients with reduced mobility, 16 telephone interviews. Both relied on a semi-structured interview guide dealing with the following subjects: patients’ experience of polypharmacy, general design of MRs, potential barriers and facilitators to implementation etc. Interviews were audio-recorded, transcribed verbatim, and analysed by two researchers using thematic analysis.
Results: Patients’ average age was 74 years (range 62–88 years). We identified barriers and facilitators for four main topics regarding the implementation of MRs in primary care: patient participation, GP-led MRs, pharmacist-led MRs, and the involvement of healthcare assistants in MRs. Barriers to patient participation concerned patient autonomy, while facilitators involved patient awareness of medication-related problems. Barriers to GP-led MRs concerned GP’s lack of resources while facilitators related to the trusting relationship between patient and GP. Pharmacist-led MRs might be hindered by a lack of patients’ confidence in pharmacists’ expertise, but facilitated by pharmacies’ digital records of the patients’ medications. Regarding the involvement of healthcare assistants in MRs, a potential barrier was patients’ uncertainty regarding the extent of their training. Patients could, however, imagine GPs delegating some aspects of MRs to them.
Conclusions: Our study suggests that patients regard MRs as beneficial and expect indications for their medicines to be checked, and possible interactions to be identified. To foster the implementation of MRs in primary care, it is important to consider barriers and facilitators to the four identified topics.
Background: Methotrexate (MTX) remains the anchor drug in rheumatoid arthritis (RA) treatment, but is poorly tolerated or contraindicated in some patients. There is a wealth of data supporting the use of abatacept in combination with MTX, but data on alternative conventional synthetic disease-modifying antirheumatic drug (csDMARD) combinations with abatacept are scarce.
Methods: In this post-hoc exploratory analysis, efficacy and safety data were extracted from abatacept RA studies in which combination with csDMARDs other than MTX was permitted: three interventional trials (ATTAIN, ASSURE, and ARRIVE) and one real-world study (ACTION). Patients with moderate-to-severe RA received abatacept in combination with MTX, hydroxychloroquine, sulfasalazine, azathioprine, or leflunomide for 6 months to 2 years according to the study design. Change from baseline in physical function (Health Assessment Questionnaire—Disability Index (HAQ-DI); all studies) and 28-joint Disease Activity Score (C-reactive protein) (DAS28 (CRP); ATTAIN, ARRIVE, and ACTION), American College of Rheumatology response rates (ATTAIN), and safety were assessed for individual and pooled csDMARD combinations for each trial. A meta-analysis was also performed on pooled data for HAQ-DI and DAS28 (CRP) across interventional trials.
Results: Across all four studies, 731 patients received abatacept plus one non-MTX csDMARD (hydroxychloroquine n = 152; sulfasalazine n = 123; azathioprine n = 59; and leflunomide n = 397) and 2382 patients received abatacept plus MTX. Mean changes from baseline in HAQ-DI scores for abatacept plus MTX (all csDMARDs pooled) vs abatacept plus a non-MTX csDMARD were –0.54 vs –0.44 (ATTAIN), –0.43 vs –0.43 (ASSURE), and –0.39 vs –0.36 (ARRIVE). Mean changes from baseline in DAS28 (CRP) and ACR response rates were also similar with abatacept plus MTX or non-MTX csDMARDs. Data for individual non-MTX csDMARDs (pooled across studies) and real-world data were consistent with these findings. Rates of treatment-related adverse events and serious adverse events, respectively, for abatacept plus one non-MTX csDMARD vs abatacept plus MTX were 35.7% vs 41.7% and 2.4% vs 2.3% (ATTAIN), 58.0% vs 55.9% and 4.2% vs 1.7% (ASSURE), and 38.1% vs 44.3% and 0.6% vs 2.9% (ARRIVE).
Conclusions: Abatacept in combination with non-MTX csDMARDs is clinically effective and well tolerated in patients with moderate-to-severe RA, providing similar benefits to those seen with abatacept plus MTX.