BACKGROUNDChildren are often treated off-label and are at a disadvantage in pharmacotherapy. The aim of this study was to implement and evaluate a quality assurance measure (PaedPharm) for pediatric ...pharmacotherapy whose purpose is to reduce medication-related hospitalizations among children and adolescents.METHODSPaedPharm consisted of the digital pediatric drug information system PaedAMIS, pediatric pharmaceutical quality circles (PaedZirk), and an adverse drug event (ADE) reporting system (PaedReport). The intervention was implemented in a cluster-randomized trial (DRKS 00013924) in 12 regions, with a pediatric and adolescent medicine clinic in each and a total of 152 surrounding private practitioners, in 6 sequences over 8 quarters. In addition to the proportion of ADE-related hospital admissions (primary endpoint), comprehensive process evaluation included other endpoints such as coverage, user acceptance, and relevance to practice.RESULTS41 829 inpatient admissions were recorded, of which 5101 were patients of physicians who participated in our study. 4.1% of admissions were ADE-related under control conditions, and 3.1% under intervention conditions (95% CI: 2.3; 5.9 and 1.8; 4.5, respectively). A model-based comparison yielded an intervention effect of 0.73 (population-based odds ratio; 0.39; 1.37; p = 0.33). PaedAMIS achieved moderate user acceptance and PaedZirk achieved high user acceptance.CONCLUSIONThe introduction of PaedPharm was associated with a decrease in medication-related hospitalizations that did not reach statistical significance. The process evaluation revealed broad acceptance of the intervention in outpatient pediatrics and adolescent medicine.
In the past, molecular mechanisms that drive the initiation of an inflammatory response have been studied intensively. However, corresponding mechanisms that sustain the expression of inflammatory ...response genes and hence contribute to the establishment of chronic disorders remain poorly understood. Recently, we provided genetic evidence that signaling via the receptor for advanced glycation end products (Rage) drives the strength and maintenance of an inflammatory reaction. In order to decipher the mode of Rage function on gene transcription levels during inflammation, we applied global gene expression profiling on time-resolved samples of mouse back skin, which had been treated with the phorbol ester TPA, a potent inducer of skin inflammation.
Ranking of TPA-regulated genes according to their time average mean and peak expression and superimposition of data sets from wild-type (wt) and Rage-deficient mice revealed that Rage signaling is not essential for initial changes in TPA-induced transcription, but absolutely required for sustained alterations in transcript levels. Next, we used a data set of differentially expressed genes between TPA-treated wt and Rage-deficient skin and performed computational analysis of their proximal promoter regions. We found a highly significant enrichment for several transcription factor binding sites (TFBS) leading to the prediction that corresponding transcription factors, such as Sp1, Tcfap2, E2f, Myc and Egr, are regulated by Rage signaling. Accordingly, we could confirm aberrant expression and regulation of members of the E2f protein family in epidermal keratinocytes of Rage-deficient mice.
In summary, our data support the model that engagement of Rage converts a transient cellular stimulation into sustained cellular dysfunction and highlight a novel role of the Rb-E2f pathway in Rage-dependent inflammation during pathological conditions.
Objective
Autoreactive B cells are responsible for antineutrophil cytoplasmic antibody (ANCA) production in ANCA‐associated vasculitis (AAV). Rituximab (RTX) depletes circulating B cells, including ...autoreactive B cells. We aimed to evaluate changes and associations with relapse of the circulating autoreactive B cell pool following therapeutic B cell depletion in AAV.
Methods
Sequential flow cytometry was performed on 148 samples of peripheral blood mononuclear cells from 23 patients with proteinase 3 (PR3)–ANCA–positive AAV who were treated with RTX for remission induction and monitored after stopping therapy during long‐term follow‐up in a prospective clinical trial. PR3 was used as a ligand to target autoreactive PR3‐specific (PR3+) B cells. B cell recurrence was considered as the first blood sample with ≥10 B cells/μl after RTX treatment.
Results
At B cell recurrence, PR3+ B cell frequency among B cells was higher than baseline (P < 0.01). Within both PR3+ and total B cells, frequencies of transitional and naive subsets were higher at B cell recurrence than at baseline, while memory subsets were lower (P < 0.001 for all comparisons). At B cell recurrence, frequencies of B cells and subsets did not differ between patients who experienced relapse and patients who remained in remission. In contrast, the plasmablast frequency within the PR3+ B cell pool was higher in patients who experienced relapse and associated with a shorter time to relapse. Frequencies of PR3+ plasmablasts higher than baseline were more likely to be found in patients who experienced relapse within the following 12 months compared to those in sustained remission (P < 0.05).
Conclusion
The composition of the autoreactive B cell pool varies significantly following RTX treatment in AAV, and early plasmablast enrichment within the autoreactive pool is associated with future relapses.
In this paper, we focus on experience-based role play with virtual agents to provide young adults at the risk of exclusion with social skill training. We present a scenario-based serious game ...simulation platform. It comes with a social signal interpretation component, a scripted and autonomous agent dialog and social interaction behavior model, and an engine for 3-D rendering of lifelike virtual social agents in a virtual environment. We show how two training systems developed on the basis of this simulation platform can be used to educate people in showing appropriate socioemotive reactions in job interviews. Furthermore, we give an overview of four conducted studies investigating the effect of the agents' portrayed personality and the appearance of the environment on the players' perception of the characters and the learning experience.
Semantic amodal segmentation is a recently proposed extension to instance-aware segmentation that includes the prediction of the invisible region of each object instance. We present the first ...all-in-one end-to-end trainable model for semantic amodal segmentation that predicts the amodal instance masks as well as their visible and invisible part in a single forward pass. In a detailed analysis, we provide experiments to show which architecture choices are beneficial for an all-in-one amodal segmentation model. On the COCO amodal dataset, our model outperforms the current baseline for amodal segmentation by a large margin. To further evaluate our model, we provide two new datasets with ground truth for semantic amodal segmentation, D2S amodal and COCOA cls. For both datasets, our model provides a strong baseline performance. Using special data augmentation techniques, we show that amodal segmentation on D2S amodal is possible with reasonable performance, even without providing amodal training data.
G
proteins are universally important for signal transduction in mammalian cells. The underlying kinetics and transformation from extracellular stimuli into intracellular signaling, however could not ...be investigated in detail so far. Here we present the human Neuropsin (hOPN5) for specific and repetitive manipulation of G
signaling in vitro and in vivo with high spatio-temporal resolution. Properties and G protein specificity of hOPN5 are characterized by UV light induced IP
generation, Ca
transients and inhibition of G
channel activity in HEK cells. In adult hearts from a transgenic animal model, light increases the spontaneous beating rate. In addition, we demonstrate light induced contractions in the small intestine, which are not detectable after pharmacological G
protein block. All-optical high-throughput screening for TRPC6 inhibitors is more specific and sensitive than conventional pharmacological screening. Thus, we demonstrate specific G
signaling of hOPN5 and unveil its potential for optogenetic applications.
PDF
