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Two bar-press experiments with rats tested the rule that reducing expectation of reward increases the variation from which reward selects. Experiment 1 used a discrete-trial random-interval schedule, with trials signaled by light or sound. One signal always ended with reward; the other signal ended with reward less often. The 2 signals were randomly mixed. Bar-press duration (how long the bar was held down) varied more during the signal with the lower probability of reward. Experiment 2 closely resembled Experiment 1 but used a random-ratio schedule rather than a random-interval schedule. Again, bar-press duration varied more during the signal with the lower probability of reward. The results support the rule-the first well-controlled comparisons to do so.

Under regulations such as REACH, testing of novel and established compounds for their (neuro)toxic potential is a legal requirement in many countries. These are largely based on animal-, cost-, and time-intensive in vivo models, not in line with the 3 Rs' principle of animal experimentation. Thus, the development of alternative test methods has also received increasing attention in neurotoxicology. Such methods focus either on physiological alterations in brain development and neuronal pathways or on behavioral changes. An example of a behavioral developmental neurotoxicity (DNT) assay is the zebrafish (Danio rerio) embryo coiling assay, which quantifies effects of compounds on the development of spontaneous movement of zebrafish embryos. While the importance of embryo-to-embryo contact prior to hatching in response to environmental contaminants or natural threats has been documented for many other clutch-laying fish species, little is known about the relevance of intra-clutch contacts for zebrafish. Here, the model neurotoxin rotenone was used to assess the effect of grouped versus separate rearing of the embryos on the expression of the coiling behavior. Some group-reared embryos reacted with hyperactivity to the exposure, to an extent that could not be recorded effectively with the utilized software. Separately reared embryos showed reduced activity, compared with group-reared individuals when assessing. However, even the control group embryos of the separately reared cohort showed reduced activity, compared with group-reared controls. Rotenone could thus be confirmed to induce neurotoxic effects in zebrafish embryos, yet modifying one parameter in an otherwise well-established neurotoxicity assay such as the coiling assay may lead to changes in behavior influenced by the proximity between individual embryos. This indicates a complex dependence of the outcome of behavior assays on a multitude of environmental parameters., (© 2024. The Author(s).)

Quantifying impacts on marine ecosystems remains pivotal in estimating risks associated with offshore industry practices. Cuttings piles, formed during drilling operations, are commonly abandoned in situ, and left to attenuate on the seabed. In the present work, the presence and lability of mercury in samples obtained from drill cuttings piles of two decommissioned North Sea oil platforms (bp Miller and bp North West Hutton) and the surrounding sediment were investigated. Maximum concentrations of total mercury were measured at 0.23 and 0.37 μg/g dry weight (dw) for bp Miller and bp North West Hutton, respectively. Background concentrations of 3.6 and 8.3 ng/g dw were measured at reference sites at 3200 metre distance. Thermofractionation and DGT-analysis of the samples to assess the effective environmental impact of the measured mercury suggests that although total mercury concentrations are increased in the proximity of the cuttings pile, the effective environmental impact may be limited., Competing Interests: Declaration of competing interest NO affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers' bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The Sea of Azov, an inland shelf sea bounding Ukraine and Russia, experiences the effects of ongoing and legacy pollution. One of the main contaminants of concern is the heavy metal mercury (Hg), which is emitted from the regional coal industry, former Hg refineries, and the historic use of mercury-containing pesticides. The aquatic biome acts both as a major sink and source in this cycle, thus meriting an examination of its environmental fate. This study collated existing Hg data for the SoA and the adjacent region to estimate current Hg influxes and cycling in the ecosystem. The mercury-specific model "Hg Environmental Ratios Multimedia Ecosystem Sources" (HERMES), originally developed for Canadian freshwater lakes, was used to estimate anthropogenic emissions to the sea and regional atmospheric Hg concentrations. The computed water and sediment concentrations (6.8 ng/L and 55.7 ng/g dw, respectively) approximate the reported literature values. The ongoing military conflict will increase environmental pollution in the region, thus further intensifying the existing (legacy) anthropogenic pressures. The results of this study provide a first insight into the environmental Hg cycle of the Sea of Azov ecosystem and underline the need for further emission control and remediation efforts to safeguard environmental quality.

Introduction: Drug trials in neonates are scarce, and the neonates may consequently be at risk of adverse drug reactions (ADRs). Spontaneous ADR reporting is an important tool for expanding the knowledge on drug safety in neonates. This study explores the quality of current neonatal ADR reports and the ADR reports of the most common drugs used in neonatal departments., Methods: An observational cross-sectional study focused on neonates was conducted using data on spontaneous reports extracted from the U.S. Food and Drug Administration Adverse Events Reporting System (FAERS) from the third quarter of 2014 up to December 2022. Only the primary suspect drugs given to neonates or subjects aged <30 days were included in the analysis., Results: Spontaneous reports from 13 million patients of all ages, totaling 50 million ADRs, were evaluated. Information regarding the age was missing in 40% of the reports, and data on 43,737 neonates with 948 different suspected drugs were identified and included in the analysis. We report the frequency of spontaneous ADR reports in the FAERS database for the ten most frequently administered drugs in neonatal intensive care units in the USA., Conclusion: Overall, neonatal ADRs are still underreported. The FAERS database in its current form discriminates insufficiently between prenatal and postnatal drug exposures. Hence, improved neonatal pharmacovigilance systems are urgently needed., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declare that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Byskov, Baden, Andersen, Jimenez-Solem, Olsen, Gade and Lausten-Thomsen.)

The North Sea is an ecologically rich habitat for marine wildlife which has also been impacted by industrial developments and anthropogenic emissions of contaminants such as mercury. Marine mammals are particularly susceptible to mercury exposure, due to their trophic position, long lifespan, and dependence on (increasingly contaminated) aquatic prey species. To mitigate impact, marine mammals can detoxify methylmercury by binding it to selenium-containing biomolecules, creating insoluble mercury selenide granules. Here, liver, kidney, muscle, and brain samples from an adult male bottlenose dolphin (Tursiops truncatus) with known elevated mercury concentrations were analysed through scanning electron microscopy (SEM). Tiemannite (HgSe) deposits were identified in all organs, ranging from 400 nm to 5 μm in diameter, with particle size being organ-dependent. Although reported in other studies, this is the first time that the three-dimensional nature of tiemannite is captured in marine mammal tissue., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The prevalence of undocumented medical treatments among children is a significant issue, as well as many EU countries lack access to newly developed children-friendly medicines. Consequently, there is a pressing need for supplementary resources that can facilitate informed decision-making regarding children's medication. We therefore aim to describe the process of establishing a children's Drug and Therapeutics Committee (cDTC), as well as the preparing and implementation of recommendations for children in the capital region of Denmark. Following the guidelines outlined by the World Health Organization, we established a cDTC, and recommendations for paediatric medication practice were constructed from assessments of medication use patterns among children in the capital region between 2019 and 2021. The recommendations were meticulously crafted based on evaluation of the current marketing authorization landscape and existing best available evidence. In 2019, the capital region established the first cDTC supported by expert councils and an editorial board. A total of 2429 purchase item numbers covering 1 222 846 defined daily doses and 592 088 purchased packages covering 10 200 000 defined daily doses were identified in the secondary and primary sectors, respectively. Three comprehensive lists covering recommendations for newborns and children were published between 2021 and 2020 totaling 331 recommended pharmaceutical products. The recommendations primarily intended for use in the secondary healthcare sector were implemented through the revision of 38 paediatric- and six neonatal product ranges throughout capital region. In conclusion, recommendation lists for children governed by a cDTC provide a rational auxiliary tool that can be immediately implemented in the clinic., (© 2023 British Pharmacological Society.)

With increasing annual chemical development and production, safety testing demands and requirements have also increased. In addition to traditional animal testing, quantitative structure-activity relationship (QSAR) modelling can be used to predict the biological effect of a chemical structure, based on the analysis of quantitative characteristics of structure features. Whilst suitable for e.g., pharmaceuticals, other compounds can be more challenging to model. The naturally occurring heavy metal mercury speciates in the environment, with some toxic species accumulating in aquatic organisms. Although this is well known, only little data is available from (eco)toxicological studies, none of which account for this speciation behaviour. The present work highlights the current toxicity data for mercury in aquatic animals and gaps in our understanding and data for future QSAR modelling. All publicly available ecotoxicology data was obtained from databases and literature. Only few studies could be determined that assessed mercury toxicity in aquatic species. Of these, likely speciation products were determined using PHREEQc. This highlighted that the mercury exposure species was not always the predominant species in the medium. Finally, the descriptors for the modelled species were obtained from ChemDes, highlighting the limited availability of such details. Additional testing is required, accounting for speciation and biological interactions, to successfully determine the toxicity profile of different mercury species in aquatic environments. In the present work, insufficient mercury-species specific data was obtained, to conduct QSAR modelling successfully. This highlights a significant lack of data, for a heavy metal with potentially fatal repercussions., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Astley Hastings reports financial support was provided by The UK Energy Research Centre., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Knowledge within the field of multiple sclerosis treatment during pregnancy is vital to ensure the most optimal clinical practice. Immunomodulatory treatment in pregnancy could in theory affect the normal development and maturation of the immune system of the fetus with a potential increased risk of infections, consequently. We therefore set out to investigate whether exposure to interferon-beta in utero affected the risk of acquiring infections in early childhood., Methods: This retrospective matched cohort study utilized data from the Danish Multiple Sclerosis Registry linked with national Danish registries to identify all children born of mothers with MS in Denmark from 1998 to 2018. The study included 510 children exposed to interferon-beta in utero. The children were matched 1:1 on various of demographic characteristics with children born to mothers with untreated MS and 1:3 with children born to mothers without MS. Each child was followed for up to five years. Using individual-level data, we investigated all-cause mortality, rate of hospital admissions due to infections, and redeemed prescriptions of antibiotics. The primary statistical model applied was a negative binomial regression analysis., Results: We found no differences in childhood mortality, for hospital admissions the rate ratio compared to healthy controls was 0.79 (0.62-1.00). Regarding antibiotic prescriptions, the results were similar (RR 1.00 (0.90-1.11). Furthermore, we found no certain dose-response relationship between interferon-beta exposure duration and hospital admission rate (P = 0.47) or redeemed antibiotic prescription (P = 0.71)., Conclusion: Exposure to interferon-beta during gestation has little to no impact on the risk of acquiring significant infections during the first five years of childhood., Competing Interests: Declaration of Competing Interest Melinda Magyari has served on scientific advisory board, as consultant for, received support for congress participation or speaker honoraria from Biogen, Sanofi, Roche, Novartis, Merck, Alexion, Bristol Myers Squibb. The Danish MS Registry received research support from Biogen, Genzyme, Roche, Merck, Novartis. The rest of the authors declare that they have no conflict of interest., (Copyright © 2023. Published by Elsevier B.V.)

Background: Melatonin has become a widely used sleeping aid for young individuals currently not included in existing guidelines. The aim was to develop a recommendation on the use of melatonin in children and adolescents aged 2-20 years, with chronic insomnia due to disorders beyond indication., Methods: We performed a systematic search for guidelines, systematic reviews, and randomised trials (RCTs) in Medline, Embase, Cochrane Library, PsycInfo, Cinahl, Guidelines International Network, Trip Database, Canadian Agency for Drugs and Technologies in Health, American Academy of Sleep Medicine, European Sleep Research Society and Scandinavian Health Authorities databases. A separate search for adverse events was also performed. The latest search for guidelines, systematic reviews, and adverse events was performed on March 17, 2023. The latest search for RCTs was performed on to February 6, 2023. The language was restricted to English, Danish, Norwegian, and Swedish. Eligible participants were children and adolescents (2-20 years of age) with chronic insomnia due to underlying disorders, in whom sleep hygiene practices have been inadequate and melatonin was tested. Studies exclusively on autism spectrum disorders or attention deficit hyperactive disorder were excluded. There were no restrictions on dosage, duration of treatment, time of consumption or release formula. Primary outcomes were quality of sleep, daytime functioning and serious adverse events, assessed at 2-4 weeks post-treatment. Secondary outcomes included total sleep time, sleep latency, awakenings, drowsiness, quality of life, non-serious adverse events, and all-cause dropouts (assessed at 2-4 weeks post-treatment), plus quality of sleep and daytime functioning (assessed at 3-6 months post-treatment). Pooled estimates were calculated using inverse variance random effects model. Statistical heterogeneity was calculated using I 2 statistics. Risk of bias was assessed using Cochrane risk of bias tool. Publication bias was assessed using funnel plots. A multidisciplinary guideline panel constructed the recommendation using Grades of Recommendation, Assessment, Development and Evaluation (GRADE). The certainty of evidence was considered either high, moderate, low or very low depending on the extent of risk of bias, inconsistency, imprecision, indirectness, or publication bias. The evidence-to-decision framework was used to discuss the feasibility and acceptance of the constructed recommendation and its impact on resources and equity. The protocol is registered with the Danish Health Authority., Findings: We identified 13 RCTs, including 403 patients with a wide range of conditions. Melatonin reduced sleep latency by 14.88 min (95% CI 23.42-6.34, 9 studies, I 2  = 60%) and increased total sleep time by 18.97 min (95% CI 0.37-37.57, 10 studies, I 2  = 57%). The funnel plot for total sleep time showed no apparent indication of publication bias. No other clinical benefits were found. The number of patients experiencing adverse events was not statistically increased however, safety data was scarce. Certainty of evidence was low., Interpretation: Low certainty evidence supports a moderate effect of melatonin in treating sleep continuity parameters in children and adolescents with chronic insomnia due to primarily medical disorders beyond indication. The off-label use of melatonin for these patients should never be the first choice of treatment, but may be considered by medical specialists with knowledge of the underlying disorder and if non-pharmacological interventions are inadequate. If treatment with melatonin is initiated, adequate follow-up to evaluate treatment effect and adverse events is essential., Funding: The Danish Health Authority. The Parker Institute, Bispebjerg and Frederiksberg Hospital, supported by the Oak Foundation., Competing Interests: LB is a member of the Danish medication Reimbursement Committee. AV has previously received honoraria for lectures at AGB pharma, Takeda & Medice and holds stocks at Novo Nordisk. All other authors declare no competing interests. Statements of conflicts of interests can be found for all members of the guideline panel, the external reviewer of the national clinical guideline, the reference–and project group at the Danish Health Authority website (www.sst.dk)., (© 2023 The Authors.)

Background: Currently, melatonin is used to treat children and adolescents with insomnia without knowing the full extent of the short-term and long-term consequences. Our aim was to provide clinicians and guideline panels with a systematic assessment of serious-and non-serious adverse events seen in continuation of melatonin treatment and the impact on pubertal development and bone health following long-term administration in children and adolescents with chronic insomnia., Methods: We searched PubMed, Embase, Cinahl and PsycINFO via Ovid, up to March 17, 2023, for studies on melatonin treatment among children and adolescents (aged 5-20 years) with chronic insomnia. The language was restricted to English, Danish, Norwegian, and Swedish. Outcomes were non-serious adverse events and serious adverse events assessed 2-4 weeks after initiating treatment and pubertal development and bone health, with no restriction on definition or time of measurement. Observational studies were included for the assessment of long-term outcomes, and serious and non-serious adverse events were assessed via randomised studies. The certainty of the evidence was assessed using Grades of Recommendation, Assessment, Development and Evaluation (GRADE). The protocol is registered with the Danish Health Authority., Findings: We identified 22 randomised studies with 1350 patients reporting on serious-and non-serious adverse events and four observational studies with a total of 105 patients reporting on pubertal development. Melatonin was not associated with serious adverse events, yet the number of patients experiencing non-serious adverse events was increased (Relative risk 1.56, 95% CI 1.01-2.43, 17 studies, I 2  = 47%). Three studies reported little or no influence on pubertal development following 2-4 years of treatment, whereas one study registered a potential delay following longer treatment durations (>7 years). These findings need further evaluation due to several methodological limitations., Interpretation: Children who use melatonin are likely to experience non-serious adverse events, yet the actual extent to which melatonin leads to non-serious adverse events and the long-term consequences remain uncertain. This major gap of knowledge on safety calls for caution against complacent use of melatonin in children and adolescents with chronic insomnia and for more research to inform clinicians and guideline panels on this key issue., Funding: The Danish Health Authority. The Parker Institute, Bispebjerg and Frederiksberg Hospital, supported by the Oak Foundation., Competing Interests: LB is a member of the Danish medication reimbursement committee. AV has previously received honoraria for lectures at AGB pharma, Takeda & Medice, and holds stocks at Novo Nordisk. All other authors declare no competing interests. Statements of conflicts of interests can be found for all members of the guideline panel, the external reviewer of the national clinical guideline, the reference–and project group at the Danish Health Authority website (www.sst.dk)., (© 2023 The Authors.)

Background: Melatonin prescriptions for children and adolescents have increased substantially during the last decade. Existing clinical recommendations focus on melatonin as a treatment for insomnia related to neurodevelopmental disorders. To help guide clinical decision-making, we aimed to construct a recommendation on the use of melatonin in children and adolescents aged 5-20 years with idiopathic chronic insomnia., Methods: A systematic search for guidelines, systematic reviews and randomised controlled trials (RCT) were performed in Medline, Embase, Cochrane Library, PsycInfo, Cinahl, Guidelines International Network, Trip Database, Canadian Agency for Drugs and Technologies in Health, American Academy of Sleep Medicine, European Sleep Research Society and Scandinavian Health Authorities databases. A search for adverse events in otherwise healthy children and adolescents was also performed. The latest search for guidelines, systematic reviews, and adverse events was performed on March 18, 2023. The latest search for RCTs was performed on to February 6, 2023. The language was restricted to English, Danish, Norwegian, and Swedish. Eligible participants were children and adolescents (5-20 years of age) with idiopathic chronic insomnia, in whom sleep hygiene practices have been inadequate and melatonin was tested. There were no restrictions on dosage, duration of treatment, time of consumption, or release formula. Primary outcomes were quality of sleep, daytime functioning and serious adverse events. Secondary outcomes included total sleep time, sleep latency, awakenings, drowsiness, quality of life, all-cause dropouts, and non-serious adverse events. Outcomes were assessed at different time points to assess short-term and long-term effects. Meta-analysis was performed using inverse variance random-effects model and risk of bias was assessed using Cochrane risk of bias tool. If possible, funnel plots would be constructed to investigate publication bias. Heterogeneity was calculated via I 2 statistics. A multidisciplinary guideline panel formulated the recommendation according to Grading of Recommendations Assessment, Development and Evaluation (GRADE). The certainty of evidence was considered either high, moderate, low or very low depending on the extent of risk of bias, inconsistency, imprecision, indirectness, or publication bias. The evidence-to-decision framework was subsequently used to discuss the feasibility and acceptance of the constructed recommendation alongside the impact on resources and equity. The protocol is registered with the Danish Health Authority., Findings: We included eight RCTs with 419 children and adolescents with idiopathic chronic insomnia. Melatonin led to a moderate increase in total sleep time by 30.33 min (95% confidence interval (CI) 18.96-41.70, 4 studies, I 2  = 0%) and a moderate reduction in sleep latency by 18.03 min (95% CI -26.61 to -9.44, 3 studies, I 2  = 0%), both as assessed by sleep diary. No other beneficial effects were found. None of the studies provided information on serious adverse events, yet the number of participants experiencing non-serious adverse events was increased (Relative risk 3.44, 95% CI 1.25-9.42, 4 studies, I 2  = 0%). Funnel plots were not constructed due to the low number of studies. The certainty of evidence was very low on the quality of sleep and low for daytime functioning., Interpretation: Evidence of very low certainty shows that benefits are limited and unwanted events are likely when melatonin is used to treat otherwise healthy children and adolescents with chronic insomnia. Melatonin should never be the first choice of treatment for this particular population, yet carefully monitored short-term use may be considered if sleep hygiene practices and non-pharmacological interventions have proven inadequate, and only if daytime function is compromised., Funding: The Danish Health Authority and the Parker Institute, Bispebjerg and Frederiksberg Hospital supported by the Oak Foundation., Competing Interests: LB is a member of the Danish medication reimbursement committee. AV has previously received honoraria for lectures at AGB pharma, Takeda & Medice and holds stocks at Novo Nordisk. All other authors declare no competing interests. Statements of conflicts of interests can be found for all members of the guideline panel, the external reviewer of the national clinical guideline, the reference–and project group at the Danish Health Authority website (www.sst.dk)., (© 2023 The Authors.)

Subsea pipelines carrying well fluids from hydrocarbon fields accumulate mercury. If the pipelines (after cleaning and flushing) are abandoned in situ, their degradation may release residual mercury into the environment. To justify pipeline abandonment, decommissioning plans include environmental risk assessments to determine the potential risk of environmental mercury. These risks are informed by environmental quality guideline values (EQGVs) governing concentrations in sediment or water above which mercury toxicity may occur. However, these guidelines may not consider e.g., the bioaccumulation potential of methylated mercury. Therefore, EQGVs may not protect humans from exposure if applied as the sole basis for risk assessments. This paper outlines a process to assess the EQGVs' protectiveness from mercury bioaccumulation, providing preliminary insights to questions including how to (1) determine pipeline threshold concentrations, (2) model marine mercury bioaccumulation, and (3) determine exceedance of the methylmercury tolerable weekly intake (TWI) for humans. The approach is demonstrated with a generic example using simplifications to describe mercury behaviour and a model food web. In this example, release scenarios equivalent to the EQGVs resulted in increased marine organism mercury tissue concentrations by 0-33 %, with human dietary methylmercury intake increasing 0-21 %. This suggests that existing guidelines may not be protective of biomagnification in all circumstances. The outlined approach could inform environmental risk assessments for asset-specific release scenarios but must be parameterised to reflect local environmental conditions when tailored to local factors., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Some authors have undertaken research funded by the oil and gas industry. These funding sources have not influenced the approach or conclusions of this study. The authors have no further potential conflicts of interest to disclose., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

In the aim to determine neurotoxicity, new methods are being validated, including tests and test batteries comprising in vitro and in vivo approaches. Alternative test models such as the zebrafish (Danio rerio) embryo have received increasing attention, with minor modifications of the fish embryo toxicity test (FET; OECD TG 236) as a tool to assess behavioral endpoints related to neurotoxicity during early developmental stages. The spontaneous tail movement assay, also known as coiling assay, assesses the development of random movement into complex behavioral patterns and has proven sensitive to acetylcholine esterase inhibitors at sublethal concentrations. The present study explored the sensitivity of the assay to neurotoxicants with other modes of action (MoAs). Here, five compounds with diverse MoAs were tested at sublethal concentrations: acrylamide, carbaryl, hexachlorophene, ibuprofen, and rotenone. While carbaryl, hexachlorophene, and rotenone consistently induced severe behavioral alterations by ~ 30 h post fertilization (hpf), acrylamide and ibuprofen expressed time- and/or concentration-dependent effects. At 37-38 hpf, additional observations revealed behavioral changes during dark phases with a strict concentration-dependency. The study documented the applicability of the coiling assay to MoA-dependent behavioral alterations at sublethal concentrations, underlining its potential as a component of a neurotoxicity test battery., (© 2023. The Author(s).)

There is currently insufficient knowledge of gestational age dependent medicine disposition in neonates. Accordingly, the use of off-label medication, i.e., use of medicines outside its approved marketing authorization, is high in the neonatal departments. By using data from the Danish National Pharmaceutical Hospital Purchase Database, we identified the most commonly occurring medications and calculated the on/off-label ratios for premature and term neonates. Data was extracted on ATC level 5 and based on defined daily doses as per WHO. Data covered the 4 high-level NICUs and 10 of 13 of the intermediate/standard level Danish neonatal departments. Of the identified medication, 87% and 70% did not have approved marketing authorization for use in premature and full-term neonates, respectively. Furthermore, one-fifth of the top 100 medicines did not have a (Danish) marketing license. Overall, off-label medication was widespread covering virtually all ATC groups and no ATC group had an off-label level lower than 50% (range 50%-100%). Finally, in 21% of medications, additives from 8 different chemical groups with potential deleterious effects for neonates were identified. In conclusion, off-label medication in the Danish neonatal departments is widespread. The pharmaceutical industry is unlikely to solve this problem, and we may for a very long time be occasionally forced to use off-label medication. Practical solution must therefore come from multidisciplinary clinical and academic collaboration. Use of formulation list as guidance for prescriptions and NICU-friendly galenic formulations may mitigate the problem temporarily while waiting for definitive studies., (© 2022 The Authors. Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd.)

Aim: To evaluate the prevalence of potentially hepatoxic paracetamol ingestion and associated N-acetylcysteine treatment in young children suspected of paracetamol poisoning., Methods: A retrospective cohort study of children aged 0-6 years suspected of paracetamol poisoning with a related plasma-paracetamol measurement in the Capital Region of Denmark in the period 2010-2017. Data from the clinical laboratory system were linked to data from electronic patient records via the unique identification number given to all Danish residents., Results: Of 297 children included, suspected single paracetamol overdoses were present in 281 (95%). Sixty-nine per cent were treated with N-acetylcysteine, and the mean treatment period was 20.3 h (SD 20.8). A maximum of 6 (2%) of the children suspected of single overdose had plasma-paracetamol concentrations that exceeded the recommended treatment thresholds. No cases of severe hepatotoxicity were registered. Adverse events to N-acetylcysteine-treatment were registered in 3 (2%) children including one anaphylactoid reaction (0.5%)., Conclusion: This study shows that initiating N-acetylcysteine as a 'one size fit all' treatment regimen in all children aged 0-6 years with a suspected single paracetamol overdose leads to substantial overtreatment. The data support that it is feasible to initiate N-acetylcysteine within 10 h based on an early plasma-paracetamol test., (© 2021 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

The limit for possible survival after extremely preterm birth has steadily improved and consequently, more premature neonates with increasingly lower gestational age at birth now require care. This specialized care often include intensive pharmacological treatment, yet there is currently insufficient knowledge of gestational age dependent differences in drug metabolism. This potentially puts the preterm neonates at risk of receiving sub-optimal drug doses with a subsequent increased risk of adverse or insufficient drug effects, and often pediatricians are forced to prescribe medication as off-label or even off-science. In this review, we present some of the particularities of drug disposition and metabolism in preterm neonates. We highlight the challenges in pharmacometrics studies on hepatic drug metabolism in preterm and particularly extremely (less than 28 weeks of gestation) preterm neonates by conducting a scoping review of published literature. We find that >40% of included studies failed to report a clear distinction between term and preterm children in the presentation of results making direct interpretation for preterm neonates difficult. We present summarized findings of pharmacokinetic studies done on the major CYP sub-systems, but formal meta analyses were not possible due the overall heterogeneous approaches to measuring the phase I and II pathways metabolism in preterm neonates, often with use of opportunistic sampling. We find this to be a testament to the practical and ethical challenges in measuring pharmacokinetic activity in preterm neonates. The future calls for optimized designs in pharmacometrics studies, including PK/PD modeling-methods and other sample reducing techniques. Future studies should also preferably be a collaboration between neonatologists and clinical pharmacologists., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Mørk, Andersen, Lausten-Thomsen and Gade.)

Background: Midazolam is a first-line drug for the treatment of status epilepticus, both by buccal and intravenous administration. In children and adolescents with obesity, midazolam pharmacokinetics may be altered, and the current dosing guidelines may therefore be insufficient., Objective: The objective of this study was to investigate the pharmacokinetics of midazolam, after intravenous administration, in obese and non-obese adolescents aged 11-18 years., Methods: All trial participants received a 1-µg midazolam microdose as an intravenous bolus. 13 blood samples were collected per participant at pre-specified timepoints. Plasma concentration-time data were fitted to pharmacokinetic models using non-linear mixed-effects modeling. Covariates such as weight, age, and body mass index standard deviation score were tested to explain the inter-individual variability associated with the pharmacokinetic parameters., Results: Sixty-seven adolescents were included in the analysis. The pharmacokinetics of midazolam was best described with a two-compartment model. The rate of distribution was faster, and the peripheral volume of distribution was larger in adolescents with a high body mass index standard deviation score compared with adolescents with a lower standard deviation score. Simulations revealed that long-term infusions based on total body weight could lead to high plasma concentrations in adolescents with obesity. Furthermore, simulated plasma concentrations after a fixed buccal dose indicated that adolescents with obesity may be at risk of sub-therapeutic midazolam plasma concentrations., Conclusions: The body mass index standard deviation score was shown to have a significant influence on the peripheral volume of distribution and the inter-compartmental clearance of midazolam. The current dosing guidelines for status epilepticus, where the midazolam dose is adjusted to total body weight or age, may lead to supra- and sub-therapeutic plasma concentrations, respectively, in adolescents with obesity., Trial Registration: EudraCT: 2014-004554-34.

Introduction: Antimicrobial stewardship programmes recommend use of narrow-spectrum antibiotics as first-line treatment of childhood pneumonia in secondary care. The primary aim of the present study was to assess whether current guidelines are followed. A secondary aim was to assess if tracheal aspiration is a useful tool in the diagnostic process of suspected childhood pneumonia., Methods: This was a retrospective descriptive single-centre cohort study. Children between three months and 17 years with a pneumonia diagnosis were included. The children were divided into two groups based on whether or not they had been treated with antibiotics (TWA) by their general practitioner. We obtained information on blood samples, treatment and microbial findings. Finally, we compared the use of antibiotics and the microbiological diagnosis of children TWA prior to admittance with those of drug-naïve children (DN)., Results: Guidelines were followed in 55% (n = 78) of the cases, which is comparable to results reported by other studies. Tracheal aspiration culture identified a bacterial pathogen in 54% (n = 77) of the cases; Haemophilus influenzae was the most prevalent. A larger percentage of tracheal aspirations was positive in the TWA group than in the DN group (66%; n = 31 versus 48%; n = 46)., Conclusions: Compliance with local guidelines was comparable to findings reported in similar single-centre studies. Airway aspiration may be a useful supplement to other investigations., Funding: none., Trial Registration: not relevant., (Articles published in the DMJ are “open access”. This means that the articles are distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits any non-commercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.)

CYP2E1 activity is measured in vitro and in vivo via hydroxylation of the Chlorzoxazone (CHZ) producing the 6-hydroxychlorzoxazone (OH-CHZ) further metabolized as a glucuronide excreted in urine. Thus, the quantification of the OH-CHZ following enzymatic hydrolysis of CHZ-derived glucuronide appears to be a reliable assay to measure the CYP2E1 activity without direct detection of this glucuronide. However, OH-CHZ hydrolyzed from urinary glucuronide accounts for less than 80% of the CHZ administrated dose in humans leading to postulate the production of other unidentified metabolites. Moreover, the Uridine 5'-diphospho-glucuronosyltransferase (UGT) involved in the hepatic glucuronidation of OH-CHZ has not yet been identified. In this study, we used recombinant HepG2 cells expressing CYP2E1, metabolically competent HepaRG cells, primary hepatocytes and precision-cut human liver slices to identify metabolites of CHZ (300 μM) by high pressure liquid chromatography-UV and liquid-chromatography-mass spectrometry analyses. Herein, we report the detection of the CHZ-O-glucuronide (CHZ-O-Glc) derived from OH-CHZ in culture media but also in mouse and human urine and we identified a novel CHZ metabolite, the CHZ-N-glucuronide (CHZ-N-Glc), which is resistant to enzymatic hydrolysis and produced independently of CHZ hydroxylation by CYP2E1. Moreover, we demonstrate that UGT1A1, 1A6 and 1A9 proteins catalyze the synthesis of CHZ-O-Glc while CHZ-N-Glc is produced by UGT1A9 specifically. Together, we demonstrated that hydrolysis of CHZ-O-Glc is required to reliably quantify CYP2E1 activity because of the rapid transformation of OH-CHZ into CHZ-O-Glc and identified the CHZ-N-Glc produced independently of the CYP2E1 activity. Our results also raise the questions of the contribution of CHZ-N-Glc in the overall CHZ metabolism and of the quantification of CHZ glucuronides in vitro and in vivo for measuring UGT1A activities.