Background: Adverse outcome pathway (AOP) networks are versatile tools in toxicology and risk assessment that capture and visualize mechanisms driving toxicity originating from various data sources. They share a common structure consisting of a set of molecular initiating events and key events, connected by key event relationships, leading to the actual adverse outcome. AOP networks are to be considered living documents that should be frequently updated by feeding in new data. Such iterative optimization exercises are typically done manually, which not only is a time-consuming effort, but also bears the risk of overlooking critical data. The present study introduces a novel approach for AOP network optimization of a previously published AOP network on chemical-induced cholestasis using artificial intelligence to facilitate automated data collection followed by subsequent quantitative confidence assessment of molecular initiating events, key events, and key event relationships. Methods: Artificial intelligence-assisted data collection was performed by means of the free web platform Sysrev. Confidence levels of the tailored Bradford-Hill criteria were quantified for the purpose of weight-of-evidence assessment of the optimized AOP network. Scores were calculated for biological plausibility, empirical evidence, and essentiality, and were integrated into a total key event relationship confidence value. The optimized AOP network was visualized using Cytoscape with the node size representing the incidence of the key event and the edge size indicating the total confidence in the key event relationship. Results: This resulted in the identification of 38 and 135 unique key events and key event relationships, respectively. Transporter changes was the key event with the highest incidence, and formed the most confident key event relationship with the adverse outcome, cholestasis. Other important key events present in the AOP network include: nuclear receptor changes, intracellular bile acid accumulation, bile acid synthesis changes, oxidative stress, inflammation and apoptosis. Conclusions: This process led to the creation of an extensively informative AOP network focused on chemical-induced cholestasis. This optimized AOP network may serve as a mechanistic compass for the development of a battery of in vitro assays to reliably predict chemical-induced cholestatic injury.
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Background: Acne vulgaris is a multifaceted skin disorder, affecting more than 85% of young individuals worldwide. Pharmacological therapy is not always desirable because of the development of antibiotic resistance or the potential risk of adverse effects. Non‐pharmacological therapies can be viable alternatives for conventional therapies. However, sufficient evidence‐based support in the efficacy and safety of non‐pharmacological therapies is lacking. Objective: To assess the efficacy and safety of several non‐pharmacological therapies in the treatment of acne vulgaris. Methods: A systematic literature review, including a best‐evidence synthesis, was performed to identify literature. Three electronic databases were accessed and searched for studies published between January 2000 and May 2017. Results: Thirty‐three eligible studies were included in our systematic review. Three main types of non‐pharmacological therapies were identified laser‐ and light‐based therapies, chemical peels and fractional microneedling radiofrequency. The majority of the included studies demonstrated a significant reduction in acne lesions. However, only seven studies had a high methodologic quality. Based on these seven trials, a best‐evidence synthesis was conducted. Strong evidence was found for glycolic acid (10–40%). Moderate evidence was found for amino fruit acid (20–60%), intense pulsed light (400–700 and 870–1200 nm) and the diode laser (1450 nm). Initially, conflicting evidence was found for pulsed dye laser (585–595 nm). The most frequently reported side‐effects for non‐pharmacological therapies included erythema, tolerable pain, purpura, oedema and a few cases of hyperpigmentation, which were in most cases mild and transient. Conclusion: Circumstantial evidence was found for non‐pharmacological therapies in the treatment of acne vulgaris. However, the lack of high methodological quality among included studies prevented us to draw clear conclusions, regarding a stepwise approach. Nevertheless, our systematic review including a best‐evidence synthesis did create order and structure in resulting outcomes in which a first step towards future research is generated.
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With a market demand for low cost, easy to produce, flexible and portable applications in healthcare, energy, biomedical or electronics markets, large research programs are initiated to develop new technologies to provide this demand with new innovative ideas. One of these fast developing technologies is organic printed electronics. As the term printed electronics implies, functional materials are printed via, e.g. inkjet, flexo or gravure printing techniques, on to a substrate material. Applications are, among others, organic light emitting diodes (OLED), sensors and Lab-on-a-chip devices. For all these applications, in some way, the interaction of fluids with the substrate is of great importance. The most used substrate materials for these low-cost devices are (coated) paper or plastic. Plastic substrates have a relatively low surface energy which frequently leads to poor wetting and/or poor adhesion of the fluids on the substrates during printing and/ or post-processing. Plasma technology has had a long history in treating materials in order to improve wetting or promote adhesion. The µPlasma patterning tool described in this thesis combines a digital inkjet printing platform with an atmospheric dielectric barrier discharge plasma tool. Thus enabling selective and local plasma treatment, at atmospheric pressure, of substrates without the use of any masking materials. In this thesis, we show that dependent on the gas composition the substrate surface can either be functionalized, thus increasing its surface energy, or material can be deposited on the surface, lowering its surface energy. Through XPS and ATR-FTIR analysis of the treated (polymer) substrate surfaces, chemical modification of the surface structure was confirmed. The chemical modification and wetting properties of the treated substrates remained present for at least one month after storage. Localized changes in wettability through µPlasma patterning were obtained with a resolution of 300µm. Next to the control of wettability of an ink on a substrate in printed electronics is the interaction of ink droplets with themselves of importance. In printing applications, coalescence of droplets is standard practice as consecutive droplets are printed onto, or close to each other. Understanding the behaviour of these droplets upon coalescence is therefore important, especially when the ink droplets are of different composition and/or volume. For droplets of equal volume, it was found that dye transport across the coalescence bridge could be fully described by diffusion only. This is as expected, as due to the droplet symmetry on either side of the bridge, the convective flows towards the bridge are of equal size but opposite in direction. For droplets of unequal volume, the symmetry across the bridge is no longer present. Experimental analysis of these merging droplets show that in the early stages of coalescence a convective flow from the small to large droplet is present. Also, a smaller convective flow of shorter duration from the large into the small droplet was identified. The origin of this flow might be due to the presence of vortices along the interface of the bridge, due to the strong transverse flow to open the bridge. To conclude, three potential applications were showcased. In the first application we used µPlasma patterning to create hydrophilic patterns on hydrophobic dodecyl-trichlorosilane (DTS) covered glass. Capillaries for a Lab-on-a-chip device were successfully created by placing two µPlasma patterned glass slides on top of each other separated by scotch tape. In the second application we showcased the production of a RFID tag via inkjet printing. Functional RFID-tags on paper were created via inkjet printing of silver nanoparticle ink connected to an integrated circuit. The optimal operating frequency of the produced tags is in the range of 860-865 MHz, making them usable for the European market, although the small working range of 1 m needs further improvement. Lastly, we showed the production of a chemresistor based gas sensor. In house synthesised polyemeraldine salt (PANi) was coated by hand on top of inkjet printed silver electrodes. The sensor proved to be equally sensitive to ethanol and water vapour, reducing its selectivity in detecting changes in gas composition.
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