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BackgroundLittle is known about fetal acetaminophen (paracetamol) pharmacokinetics and its potential for toxicity, despite the frequent use of acetaminophen during pregnancy. The aim of this study was to develop a feto-maternal physiologically based pharmacokinetic model (f-m PBPK) to predict placental transfer and PK of acetaminophen and its metabolites in fetus at term pregnancy.MethodsPreviously, a pregnancy PBPK model was developed for prediction of maternal PK of acetaminophen and its metabolites. This model was structurally extended with the fetal liver, and quantitative information on the maturation of relevant enzymes was integrated. Three different approaches (ex vivo placenta perfusion experiments, scaling of passive diffusion transfer rates, and the Mobi® default method) to describe placental drug transfer were tested. Predicted maternal and fetal acetaminophen concentrations were compared with those observed in the literature. umbilical cord data at birth.ResultsThe 3 different approaches to predicted acetaminophen PK in the umiblical vein were found to yield broadly similar results. Acetaminophen exposure was similar in maternal blood compared to venous umbilical cord blood. Prediction of the median dose fraction of acetaminophen converted to its metabolites (fm) revealed higher maternal acetaminophen-glucuronide formation clearance and sulphate formation compared to that in the fetal liver (fm_glucuronide52.2 vs 0% and fm_sulphate30.4 vs 0.8%, respectively) and higher fraction of acetaminophen converted to the reactive metabolite N-acetyl-p-benzoquinone-imine (fm_NAPQI, 6.5 vs 0.06%) in pregnant women compared to their fetus.ConclusionNo differences were observed in the 3 approaches for integration of placental drug transfer. Differences in acetaminophen biotransformation to its metabolites between pregnant women and their fetuses were quantitatively predicted.Disclosure(s)Paola Mian received a Short term Minor (STM-2017) grant from the Stichting Sophia Kinderziekenhuis fonds to conduct this research.

In the last few years, the advent of metal halide perovskite solar cells has revolutionized the prospects of next-generation photovoltaics. As this technology is maturing at an exceptional rate, research on its environmental impact is becoming increasingly relevant.

Intensive development of organometal halide perovskite solar cells has lead to a dramatic surge in power conversion efficiency up to 20%. Unfortunately, the most efficient perovskite solar cells all contain lead (Pb), which is an unsettling flaw that leads to severe environmental concerns and is therefore a stumbling block envisioning their large-scale application. Aiming for the retention of favorable electro-optical properties, tin (Sn) has been considered the most likely substitute. Preliminary studies have however shown that Sn-based perovskites are highly unstable and, moreover, Sn is also enlisted as a harmful chemical, with similar concerns regarding environment and health. To bring more clarity into the appropriateness of both metals in perovskite solar cells, we provide a case study with systematic comparison regarding the environmental impact of Pb- and Sn-based perovskites, using zebrafish ( Danio Rerio ) as model organism. Uncovering an unexpected route of intoxication in the form of acidification, it is shown that Sn based perovskite may not be the ideal Pb surrogate.

Analyzing the repetitive pattern of historical lead poisoning that to present-day has shaped our legislatorial systems regarding lead consumption, this work focuses on creating awareness and caution toward lead halide perovskite commercialization while concurrently pointing out considerations and ambiguity in policies and regulations. Lead halide perovskites have caused a paradigm shift in state-of-the-art photovoltaic technology half a decade ago and have gained tremendous momentum ever since. Given their seemingly imminent commercialization, rigorous scrutiny regarding their potential environmental impact is becoming increasingly relevant. In light of the current need for sustainable energy resources, several start-up and spin-off companies have been established, initially promising modules on the market by the end of 2017. On the downside, lead representing approximately one third by weight of the absorber layer in such photovoltaic devices is enough reason to become wary about the potential environmental impact of their large-scale implementation. Whilst many have wondered where the acceptable boundaries lie regarding lead consumption, it remains a focal point in many discussions, as it seems almost unattainable to ban lead usage from our society. Currently listed as one of the ten chemicals of major health concern by the World Health Organization, the magnitude of misgivings expands even more as recent studies also demonstrate promising applications of lead halide perovskites in light emitting diodes, lasers, batteries, and photodetectors. Hence, there is no doubt that a discussion should be commenced on how to assess and handle the impact of lead in a new technology of such high potential. By reflecting on the historical experience gained from anthropogenic lead poisoning that is still shaping our legislatorial systems at present-day, this work investigates and carefully scrutinizes current legislation that governs the exploitation of lead halide perovskites in optoelectronic applications. Analyzing the repetitive pattern of historical lead consumption, focus is extended on creating awareness and caution toward lead halide perovskite commercialization while concurrently pointing out considerations and ambiguity in policies and regulations. Ultimately, this work aims to initialize a discussion on “if” and “how” this burgeoning class of materials can enter the consumer market.

Focused-ion beam lift-out and annular milling is the most common method used for obtaining site specific specimens for atom probe tomography (APT) experiments and transmission electron microscopy. However, one of the main limitations of this technique comes from the structural damage as well as chemical degradation caused by the beam of high-energy ions. These aspects are especially critical in highly-sensitive specimens. In this regard, ion beam milling under cryogenic conditions has been an established technique for damage mitigation. Here, we implement a cryo-focused ion beam approach to prepare specimens for APT measurements from a quadruple cation perovskite-based solar cell device with 19.7% efficiency. As opposed to room temperature FIB milling we found that cryo-milling considerably improved APT results in terms of yield and composition measurement, i.e. halide loss, both related to less defects within the APT specimen. Based on our approach we discuss the prospects of reliable atom probe measurements of perovskite based solar cell materials. An insight into the field evaporation behavior of the organic-inorganic molecules that compose the perovskite material is also given with the aim of expanding the applicability of APT experiments towards nano-characterization of complex organo-metal materials.

To explore posttranslational modifications (PTMs), including proteolytic activation, multimerization, complex formation and citrullination of gelatinases, in particular of gelatinase B/MMP-9, and to detect in gelatin-Sepharose affinity-purified synovial fluids, the presence of specific MMP proteoforms in relation to arthritis. Latent, activated, complexed and truncated gelatinase-A/MMP-2 and gelatinase B/MMP-9 proteoforms were detected with the use of zymography analysis to compare specific levels, with substrate conversion assays, to test net proteolytic activities and by Western blot analysis to decipher truncation variants. Citrullination was detected with enhanced sensitivity, by the use of a new monoclonal antibody against modified citrullines. All MMP-9 and MMP-2 proteoforms were identified in archival synovial fluids with the use of zymography analysis and the levels of MMP-9 MMP-2 were studied in various arthritic diseases, including rheumatoid arthritis (RA). Secondly, we resolved misinterpretations of MMP-9 levels proteolytic activities. Thirdly, a citrullinated, truncated proteoform of MMP-9 was discovered in archival RA synovial fluid samples and its presence was corroborated as citrullinated hemopexin-less MMP-9 in a small prospective RA sample cohort. Synovial fluids from rheumatoid arthritis contain high levels of MMP-9, including its truncated and citrullinated proteoform. The combination of MMP-9 as analyte and its PTM by citrullination could be of clinical interest, especially in the field of arthritic diseases.

We demonstrate four- and two-terminal perovskite-perovskite tandem solar cells with ideally matched band gaps. We develop an infrared-absorbing 1.2-electron volt band-gap perovskite, FA0.75Cs0.25Sn0.5Pb0.5I₃, that can deliver 14.8% efficiency. By combining this material with a wider-band gap FA0.83Cs0.17Pb(I0.5Br0.5)₃ material, we achieve monolithic two-terminal tandem efficiencies of 17.0% with >1.65-volt open-circuit voltage. We also make mechanically stacked four-terminal tandem cells and obtain 20.3% efficiency. Notably, we find that our infrared-absorbing perovskite cells exhibit excellent thermal and atmospheric stability, not previously achieved for Sn-based perovskites. This device architecture and materials set will enable \"all-perovskite\" thin-film solar cells to reach the highest efficiencies in the long term at the lowest costs.

Background and Objective Although acetaminophen is frequently used during pregnancy, little is known about fetal acetaminophen pharmacokinetics. Acetaminophen safety evaluation has typically focused on hepatotoxicity, while other events (fetal ductal closure/constriction) are also relevant. We aimed to develop a fetal–maternal physiologically based pharmacokinetic (PBPK) model (f-m PBPK) to quantitatively predict placental acetaminophen transfer, characterize fetal acetaminophen exposure, and quantify the contributions of specific clearance pathways in the term fetus. Methods An acetaminophen pregnancy PBPK model was extended with a compartment representing the fetal liver, which included maturation of relevant enzymes. Different approaches to describe placental transfer were evaluated (ex vivo cotyledon perfusion experiments, placental transfer prediction based on Caco-2 cell permeability or physicochemical properties [MoBi ® ]). Predicted maternal and fetal acetaminophen profiles were compared with in vivo observations. Results Tested approaches to predict placental transfer showed comparable performance, although the ex vivo approach showed highest prediction accuracy. Acetaminophen exposure in maternal venous blood was similar to fetal venous umbilical cord blood. Prediction of fetal acetaminophen clearance indicated that the median molar dose fraction converted to acetaminophen-sulphate and N -acetyl- p- benzoquinone imine was 0.8% and 0.06%, respectively. The predicted mean acetaminophen concentration in the arterial umbilical cord blood was 3.6 mg/L. Conclusion The median dose fraction of acetaminophen converted to its metabolites in the term fetus was predicted. The various placental transfer approaches supported the development of a generic f-m PBPK model incorporating in vivo placental drug transfer. The predicted arterial umbilical cord acetaminophen concentration was far below the suggested postnatal threshold (24.47 mg/L) for ductal closure.

BackgroundPregnant women and their fetuses are or-phan populations with respect to knowledge on safety and efficacy of drugs. It is estimated that over 90% of pregnant women uses over-the-counter or prescription medication.1 Albeit, data on transplacental transfer or fetal effects are still lacking for most of the medicines and food supplements. The ex vivo human placenta perfusion model is an effective and non-invasive method to study transplacental passage of drugs and environmental com-pounds in humans.2 It is the only method that retains the full structure of a full term human placenta, making it possible to study transplacental passage without harm-ing the foetus or the mother.3 Due to many challenges and its high complexity it remains difficult to incorporate it routinely into laboratories.MethodsA step-by-step protocol for the implementa-tion and validation of a closed-closed ex vivo perfusion model was developed. Different quality controls were implemented to ensure the integrity, viability and func-tionality of the method: (i). Antipyrine is a small drug molecule that does not bind to proteins and that passes the placental barrier by passive diffusion; It was used here to determine ‘overlap’ (solute exchange) between foetal and maternal circulation; (ii) the pressure and the flow rate in the foetal circulation as a marker for leakage; (iii) pH and glucose consumption were implemented as a marker for tissueviability.ResultsIn total 89 placentas were collected of which 34 placentas were successfully perfused with antipyrine and fulfilled all quality control measurements. A foe-tal/maternal antipyrine concentration ratio of 0.75 was reached within 89±21 min, while 210 min were required to achieve equilibrium. The foetal pressure remained un-der 70 mmHg during the entire experiment. The end foe-tal flow was 98% of the foetal starting flow. The average glucose consumption was 0.30±0.15 µmol/min/g. Every 30 min the maternal pH declined to 7.29±0.06 and was adjusted to 7.4. The foetal pH stayed stable at 7.30±0.05.ConclusionBased on the multiple quality control mea-surements, the described method of a closed human ex-vivo placenta perfusion model was validated. The success rate (38%) was more than twice the success rate reported in literature (15%).