Pharmacokinetic studies in children: recommendations for practice and research.

Optimising the dosing of medicines for neonates and children remains a challenge. The importance of pharmacokinetic (PK) and pharmacodynamic (PD) research is recognised both in medicines regulation and paediatric clinical pharmacology, yet there remain barriers to undertaking high-quality PK and PD studies. While these studies are essential in understanding the dose-concentration-effect relationship and should underpin dosing recommendations, this review examines how challenges affecting the design and conduct of paediatric pharmacological studies can be overcome using targeted pharmacometric strategies. Model-based approaches confer benefits at all stages of the drug life-cycle, from identifying the first dose to be used in children, to clinical trial design, and optimising the dosing regimens of older, off-patent medications. To benefit patients, strategies to ensure that new PK, PD and trial data are incorporated into evidence-based dosing recommendations are needed. This review summarises practical strategies to address current challenges, particularly the use of model-based (pharmacometric) approaches in study design and analysis. Recommendations for practice and directions for future paediatric pharmacological research are given, based on current literature and our joint international experience. Success of PK research in children requires a robust infrastructure, with sustainable funding mechanisms at its core, supported by political and regulatory initiatives, and international collaborations. There is a unique opportunity to advance paediatric medicines research at an unprecedented pace, bringing the age of evidence-based paediatric pharmacotherapy into sight

A prominence eruption from the Sun to the Parker Solar Probe with multi-spacecraft observations

In the early hours of 2021 April 25, the Solar Probe Cup on board Parker Solar Probe registered the passage of a solar wind structure characterized by a clear and constant He2+/H+ density ratio above 6% during three hours. The He2+ contribution remained present but fainting and intermittent within a twelve-hour window. Solar Orbiter and Parker Solar Probe were in nearly perfect quadrature, allowing for optimal observing configuration in which the material impacting the Parker Solar Probe was in the Solar Orbiter plane of the sky and visible off the limb. In this work, we report the journey of the helium-enriched plasma structure from the Sun to the Parker Solar Probe by combining multi-spacecraft remote-sensing and in situ measurements. We identify an erupting prominence as the likely source, behind the Sun relative to the Earth, but visible to multiple instruments on both the Solar-Terrestrial Relations Observatory-A and Solar Orbiter. The associated CME was also observed by coronagraphs and heliospheric imagers from both spacecrafts before reaching the Parker Solar Probe at 46 R⊙, 8 h after the spacecraft registered a crossing of the heliospheric current sheet. Except for extraordinary helium enhancement, the CME showed ordinary plasma signatures and a complex magnetic field with an overall strength enhancement. The images from the Wide-field Imager for Solar Probe (WISPR) aboard Parker Solar Probe show a structure entering the field of view a few hours before the in situ crossing, followed by repetitive transient structures that may be the result of flying through the CME body. We believe this to be the first example of a CME being imaged by WISPR directly before and during being detected in situ. This study highlights the potential of combining the Parker Solar Probe in situ measurements in the inner heliosphere with simultaneous remote-sensing observations in (near) quadrature from other spacecrafts

Trends in drinking habits among adolescents in the Baltic countries over the period of transition: HBSC survey results, 1993–2002

BACKGROUND: The Baltic countries – Estonia, Latvia, and Lithuania – are considered to be an example of regional homogeneity over the period of transition. The World Health Organization cross-national study on Health Behavior in School-aged Children (HBSC) allows a comparison and time trends analysis of behavioral patterns among adolescents in this region. The aim of this study was to estimate the prevalence and trends of alcohol consumption and drunkenness among adolescents of Estonia, Latvia, and Lithuania in 1993/94, 1997/98, and 2001/02. METHODS: Representative samples of 5286 boys and 6485 girls aged 15 from Estonia, Latvia, and Lithuania were surveyed in 1993/94, 1997/98, and 2001/02 school-year within the framework of HBSC study. The standardized survey methods were applied. The research focused on the following outcome variables: i) frequency of drinking beer, wine, and spirits; and ii) frequency of drunkenness. The same wording of questions on the consumption of alcohol was retained in each survey. RESULTS: Beer was the most frequently used alcoholic beverage across the Baltic countries among adolescents. The rate of weekly drinking of any alcoholic beverage increased considerably during the eight years of observation, especially among Estonian and Lithuanian students. In 2001/02, 25% of boys and 12.5% of girls have reported drinking alcohol at least weekly. The rate of regular alcohol drinking was two times higher in boys, while irregular drinking was more prevalent in girls. Two or more episodes of drunkenness in the lifespan were reported by 30% of boys and 15% of girls in 1993/94 and by 52% of boys and 36% of girls in 2001/02. The use of alcoholic beverages was related to the perceived family wealth: the students from the families perceived by them as wealthy were more likely to drink weekly as compared to the students from the families perceived by them as not wealthy. CONCLUSION: Over the period between 1993 and 2002 the prevalence of alcohol consumption among adolescents increased considerably across the Baltic countries. The efforts of dealing with this problem should employ a combination of measures, including the strategies relevant for the period of transition

Pharmacokinetic-Pharmacodynamic Modeling in Pediatric Drug Development, and the Importance of Standardized Scaling of Clearance.

Pharmacokinetic/pharmacodynamic (PKPD) modeling is important in the design and conduct of clinical pharmacology research in children. During drug development, PKPD modeling and simulation should underpin rational trial design and facilitate extrapolation to investigate efficacy and safety. The application of PKPD modeling to optimize dosing recommendations and therapeutic drug monitoring is also increasing, and PKPD model-based dose individualization will become a core feature of personalized medicine. Following extensive progress on pediatric PK modeling, a greater emphasis now needs to be placed on PD modeling to understand age-related changes in drug effects. This paper discusses the principles of PKPD modeling in the context of pediatric drug development, summarizing how important PK parameters, such as clearance (CL), are scaled with size and age, and highlights a standardized method for CL scaling in children. One standard scaling method would facilitate comparison of PK parameters across multiple studies, thus increasing the utility of existing PK models and facilitating optimal design of new studies

Slow Solar Wind Connection Science during Solar Orbiter’s First Close Perihelion Passage

The Slow Solar Wind Connection Solar Orbiter Observing Plan (Slow Wind SOOP) was developed to utilize the extensive suite of remote-sensing and in situ instruments on board the ESA/NASA Solar Orbiter mission to answer significant outstanding questions regarding the origin and formation of the slow solar wind. The Slow Wind SOOP was designed to link remote-sensing and in situ measurements of slow wind originating at open–closed magnetic field boundaries. The SOOP ran just prior to Solar Orbiter’s first close perihelion passage during two remote-sensing windows (RSW1 and RSW2) between 2022 March 3–6 and 2022 March 17–22, while Solar Orbiter was at respective heliocentric distances of 0.55–0.51 and 0.38–0.34 au from the Sun. Coordinated observation campaigns were also conducted by Hinode and IRIS. The magnetic connectivity tool was used, along with low-latency in situ data and full-disk remote-sensing observations, to guide the target pointing of Solar Orbiter. Solar Orbiter targeted an active region complex during RSW1, the boundary of a coronal hole, and the periphery of a decayed active region during RSW2. Postobservation analysis using the magnetic connectivity tool, along with in situ measurements from MAG and SWA/PAS, showed that slow solar wind originating from two out of three of the target regions arrived at the spacecraft with velocities between ∼210 and 600 km s−1. The Slow Wind SOOP, despite presenting many challenges, was very successful, providing a blueprint for planning future observation campaigns that rely on the magnetic connectivity of Solar Orbiter

Future water quality monitoring - Adapting tools to deal with mixtures of pollutants in water resource management

Environmental quality monitoring of water resources is challenged with providing the basis for safeguarding the environment against adverse biological effects of anthropogenic chemical contamination from diffuse and point sources. While current regulatory efforts focus on monitoring and assessing a few legacy chemicals, many more anthropogenic chemicals can be detected simultaneously in our aquatic resources. However, exposure to chemical mixtures does not necessarily translate into adverse biological effects nor clearly shows whether mitigation measures are needed. Thus, the question which mixtures are present and which have associated combined effects becomes central for defining adequate monitoring and assessment strategies. Here we describe the vision of the international, EU-funded project SOLUTIONS, where three routes are explored to link the occurrence of chemical mixtures at specific sites to the assessment of adverse biological combination effects. First of all, multi-residue target and non-target screening techniques covering a broader range of anticipated chemicals co-occurring in the environment are being developed. By improving sensitivity and detection limits for known bioactive compounds of concern, new analytical chemistry data for multiple components can be obtained and used to characterise priority mixtures. This information on chemical occurrence will be used to predict mixture toxicity and to derive combined effect estimates suitable for advancing environmental quality standards. Secondly, bioanalytical tools will be explored to provide aggregate bioactivity measures integrating all components that produce common (adverse) outcomes even for mixtures of varying compositions. The ambition is to provide comprehensive arrays of effect-based tools and trait-based field observations that link multiple chemical exposures to various environmental protection goals more directly and to provide improved in situ observations for impact assessment of mixtures. Thirdly, effect-directed analysis (EDA) will be applied to identify major drivers of mixture toxicity. Refinements of EDA include the use of statistical approaches with monitoring information for guidance of experimental EDA studies. These three approaches will be explored using case studies at the Danube and Rhine river basins as well as rivers of the Iberian Peninsula. The synthesis of findings will be organised to provide guidance for future solution-oriented environmental monitoring and explore more systematic ways to assess mixture exposures and combination effects in future water quality monitoring.Seventh Framework Programme (E.U