Towards a science-based testing strategy to identify maternal thyroid hormone imbalance and neurodevelopmental effects in the progeny - Part IV: the ECETOC and CLE Proposal for a Thyroid Function-Related Neurodevelopmental Toxicity Testing and Assessment Scheme (Thyroid-NDT-TAS).

Following the European Commission Endocrine Disruptor Criteria, substances shall be considered as having endocrine disrupting properties if they (a) elicit adverse effects, (b) have endocrine activity, and (c) the two are linked by an endocrine mode-of-action (MoA) unless the MoA is not relevant for humans. A comprehensive, structured approach to assess whether substances meet the Endocrine Disruptor Criteria for the thyroid modality (EDC-T) is currently unavailable. Here, the European Centre for Ecotoxicology and Toxicology of Chemicals Thyroxine Task Force and CropLife Europe propose a Thyroid Function-Related Neurodevelopmental Toxicity Testing and Assessment Scheme (Thyroid-NDT-TAS). In Tier 0, before entering the Thyroid-NDT-TAS, all available in vivo, in vitro and in silico data are submitted to weight-of-evidence (WoE) evaluations to determine whether the substance of interest poses a concern for thyroid disruption. If so, Tier 1 of the Thyroid-NDT-TAS includes an initial MoA and human relevance assessment (structured by the key events of possibly relevant adverse outcome pathways) and the generation of supportive in vitro/in silico data, if relevant. Only if Tier 1 is inconclusive, Tier 2 involves higher-tier testing to generate further thyroid- and/or neurodevelopment-related data. Tier 3 includes the final MoA and human relevance assessment and an overarching WoE evaluation to draw a conclusion on whether, or not, the substance meets the EDC-T. The Thyroid-NDT-TAS is based on the state-of-the-science, and it has been developed to minimise animal testing. To make human safety assessments more accurate, it is recommended to apply the Thyroid-NDT-TAS during future regulatory assessments.

Considering developmental neurotoxicity in vitro data for human health risk assessment using physiologically-based kinetic modeling: deltamethrin case study.

Developmental neurotoxicity (DNT) is a potential hazard of chemicals. Recently, an in vitro testing battery (DNT IVB) was established to complement existing rodent in vivo approaches. Deltamethrin (DLT), a pyrethroid with a well-characterized neurotoxic mode of action, has been selected as a reference chemical to evaluate the performance of the DNT IVB. The present study provides context for evaluating the relevance of these DNT IVB results for the human health risk assessment of DLT by estimating potential human fetal brain concentrations after maternal exposure to DLT. We developed a physiologically based kinetic (PBK) model for rats which was then translated to humans considering realistic in vivo exposure conditions (acceptable daily intake [ADI] for DLT). To address existing uncertainties, we designed case studies considering the most relevant drivers of DLT uptake and distribution. Calculated human fetal brain concentrations were then compared with the lowest benchmark concentration achieved in the DNT IVB. The developed rat PBK model was validated on in vivo rat toxicokinetic data of DLT over a broad range of doses. The uncertainty based case study evaluation confirmed that repeated exposure to DLT at an ADI level would likely result in human fetal brain concentrations far below the in vitro benchmark. The presented results indicate that DLT concentrations in the human fetal brain are highly unlikely to reach concentrations associated with in vitro findings under realistic exposure conditions. Therefore, the new in vitro DNT results are considered to have no impact on the current risk assessment approach.

Self-reported changes in sleep patterns and behavior in children and adolescents during COVID-19.

The COVID-19 pandemic and lockdowns worldwide forced children and adolescents to change and adapt their lives to an unprecedented situation. Using an online survey, we investigated whether they showed changes in sleep quality and other related factors due to this event. Between February 21st, 2021 and April 19th, 2021, a total of 2,290 Austrian children and adolescents (6-18 years) reported their sleep habits and quality of sleep as well as physical activity, daylight exposure and usage of media devices during and, retrospectively, before the pandemic. Results showed an overall delay of sleep and wake times. Almost twice as many respondents reported having sleeping problems during the pandemic as compared to before, with insomnia, nightmares and daytime sleepiness being the most prevalent problems. Furthermore, sleeping problems and poor quality of sleep correlated positively with COVID-19 related anxiety. Lastly, results showed a change from regular to irregular bedtimes during COVID-19, higher napping rates, a strong to very strong decrease in physical activity and daylight exposure, as well as a high to very high increase in media consumption. We conclude that the increase in sleeping problems in children and adolescent during COVID-19 is concerning. Thus, health promoting measures and programs should be implemented and enforced.

Slow oscillation-spindle coupling strength predicts real-life gross-motor learning in adolescents and adults.

Previously, we demonstrated that precise temporal coordination between slow oscillations (SOs) and sleep spindles indexes declarative memory network development (Hahn et al., 2020). However, it is unclear whether these findings in the declarative memory domain also apply in the motor memory domain. Here, we compared adolescents and adults learning juggling, a real-life gross-motor task. Juggling performance was impacted by sleep and time of day effects. Critically, we found that improved task proficiency after sleep lead to an attenuation of the learning curve, suggesting a dynamic juggling learning process. We employed individualized cross-frequency coupling analyses to reduce inter- and intragroup variability of oscillatory features. Advancing our previous findings, we identified a more precise SO-spindle coupling in adults compared to adolescents. Importantly, coupling precision over motor areas predicted overnight changes in task proficiency and learning curve, indicating that SO-spindle coupling relates to the dynamic motor learning process. Our results provide first evidence that regionally specific, precisely coupled sleep oscillations support gross-motor learning.

How Smart Is It to Go to Bed with the Phone? The Impact of Short-Wavelength Light and Affective States on Sleep and Circadian Rhythms.

Previously, we presented our preliminary results (N = 14) investigating the effects of short-wavelength light from a smartphone during the evening on sleep and circadian rhythms (Höhn et al., 2021). Here, we now demonstrate our full sample (N = 33 men), where polysomnography and body temperature were recorded during three experimental nights and subjects read for 90 min on a smartphone with or without a filter or from a book. Cortisol, melatonin and affectivity were assessed before and after sleep. These results confirm our earlier findings, indicating reduced slow-wave-sleep and -activity in the first night quarter after reading on the smartphone without a filter. The same was true for the cortisol-awakening-response. Although subjective sleepiness was not affected, the evening melatonin increase was attenuated in both smartphone conditions. Accordingly, the distal-proximal skin temperature gradient increased less after short-wavelength light exposure than after reading a book. Interestingly, we could unravel within this full dataset that higher positive affectivity in the evening predicted better subjective but not objective sleep quality. Our results show disruptive consequences of short-wavelength light for sleep and circadian rhythmicity with a partially attenuating effect of blue-light filters. Furthermore, affective states influence subjective sleep quality and should be considered, whenever investigating sleep and circadian rhythms.

Preliminary Results: The Impact of Smartphone Use and Short-Wavelength Light during the Evening on Circadian Rhythm, Sleep and Alertness.

Smartphone usage strongly increased in the last decade, especially before bedtime. There is growing evidence that short-wavelength light affects hormonal secretion, thermoregulation, sleep and alertness. Whether blue light filters can attenuate these negative effects is still not clear. Therefore, here, we present preliminary data of 14 male participants (21.93 ± 2.17 years), who spent three nights in the sleep laboratory, reading 90 min either on a smartphone (1) with or (2) without a blue light filter, or (3) on printed material before bedtime. Subjective sleepiness was decreased during reading on a smartphone, but no effects were present on evening objective alertness in a GO/NOGO task. Cortisol was elevated in the morning after reading on the smartphone without a filter, which resulted in a reduced cortisol awakening response. Evening melatonin and nightly vasodilation (i.e., distal-proximal skin temperature gradient) were increased after reading on printed material. Early slow wave sleep/activity and objective alertness in the morning were only reduced after reading without a filter. These results indicate that short-wavelength light affects not only circadian rhythm and evening sleepiness but causes further effects on sleep physiology and alertness in the morning. Using a blue light filter in the evening partially reduces these negative effects.

Gross motor adaptation benefits from sleep after training.

Sleep has been shown to facilitate the consolidation of newly acquired motor memories. However, the role of sleep in gross motor learning, especially in motor adaptation, is less clear. Thus, we investigated the effects of nocturnal sleep on the performance of a gross motor adaptation task, i.e. riding an inverse steering bicycle. Twenty-six male participants (M = 24.19, SD = 3.70 years) were randomly assigned to a PM-AM-PM (n = 13) or an AM-PM-AM (n = 13) group, i.e. they trained in the evening/morning and were re-tested the next morning/evening and the following evening/morning (PM-AM-PM/AM-PM-AM group) so that every participant spent one sleep as well as one wake interval between the three test sessions. Inverse cycling performance was assessed by speed (riding time) and accuracy (standard deviation of steering angle) measures. Behavioural results showed that in the PM-AM-PM group a night of sleep right after training stabilized performance (accuracy and speed) and was further improved over the subsequent wake interval. In the AM-PM-AM group, a significant performance deterioration after the initial wake interval was followed by the restoration of subjects' performance levels from right after training when a full night of sleep was granted. Regarding sleep, right hemispheric fast N2 sleep spindle activity was related to better stabilization of inverse cycling skills, thus possibly reflecting the ongoing process of updating the participants' mental model from "how to ride a bicycle" to "how to ride an inverse steering bicycle". Our results demonstrate that sleep facilitates the consolidation of gross motor adaptation, thus adding further insights to the role of sleep for tasks with real-life relevance.

The impact of sleep on complex gross-motor adaptation in adolescents.

Sleep has been shown to facilitate the consolidation of newly acquired motor memories in adults. However, the role of sleep in motor memory consolidation is less clear in children and adolescents, especially concerning real-life gross-motor skills. Therefore, we investigated the effects of sleep and wakefulness on a complex gross-motor adaptation task by using a bicycle with an inverse steering device. A total of 29 healthy adolescents aged between 11 and 14 years (five female) were either trained to ride an inverse steering bicycle (learning condition) or a stationary bicycle (control condition). Training took place in the morning (wake, n = 14) or in the evening (sleep, n = 15) followed by a 9-hr retention interval and a subsequent re-test session. Slalom cycling performance was assessed by speed (riding time) and accuracy (standard deviation of steering angle) measures. Behavioural results showed no evidence for sleep-dependent memory consolidation. However, overnight gains in accuracy were associated with an increase in left hemispheric N2 slow sleep spindle activity from control to learning night. Furthermore, decreases in REM and tonic REM duration were related to higher overnight improvements in accuracy. Regarding speed, an increase in REM and tonic REM duration was favourable for higher overnight gains in riding time. Thus, although not yet detectable on a behavioural level, sleep seemed to play a role in the acquisition of gross-motor skills. A promising direction for future research is to focus on the possibility of delayed performance gains in adolescent populations.

Treatment algorithm for metastatic renal cell carcinoma--recommendations based on evidence and clinical practice.

Until a few years ago, the treatment options for metastatic renal cell cancer (mRCC) were very limited. The growing understanding of the molecular pathomechanisms underlying RCC allowed the development of new treatment approaches. Meanwhile, several approved target-oriented substances from different drug classes are available for mRCC. The mechanism of action of vascular endothelial growth factor (VEGF) and VEGF receptor or mTOR inhibition is well documented by phase III trials and reflected in the current guidelines. However, no predictive biomarkers have been identified in mRCC so far to demonstrate a benefit by a specific compound in an individual patient. Meanwhile, the sequential use of 'targeted therapies' in mRCC has been established as standard treatment. The optimal sequence of available agents is still unclear. A German RCC expert panel discussed and developed an algorithm for the choices of first- and second-line treatment in mRCC based on established clinical criteria.

CRS-R score in disorders of consciousness is strongly related to spectral EEG at rest.

Patients suffering from disorders of consciousness still present a diagnostic challenge due to the fact that their assessment is mainly based on behavioral scales with their motor responses often being strongly impaired. We therefore focused on resting electroencephalography (EEG) in order to reveal potential alternative measures of the patient's current state independent of rather complex abilities (e.g., language comprehension). Resting EEG was recorded in nine minimally conscious state (MCS) and eight vegetative state/unresponsive wakefulness syndrome (VS/UWS) patients. Behavioral assessments were conducted using the Coma-Recovery Scale-Revised (CRS-R). The signal was analyzed in the frequency domain and association between resting EEG and CRS-R score as well as clinical diagnosis were calculated using Pearson correlation and repeated-measures ANOVAs. The analyses revealed robust positive correlations between CRS-R score and ratios between frequencies above 8 Hz and frequencies below 8 Hz. Furthermore, the frequency of the spectral peak was also highly indicative of the patient's CRS-R score. Concerning differences between clinical diagnosis and healthy controls, it could be revealed that while VS/UWS patients showed higher delta and theta activity than controls, MCS did not differ from controls in this frequency range. Alpha activity, on the other hand, was strongly decreased in both patient groups as compared to controls. The strong relationship between various resting EEG parameters and CRS-R score provides significant clinical relevance. Not only is resting activity easily acquired at bedside, but furthermore, it does not depend on explicit cooperation of the patient. Especially in cases where behavioral assessment is difficult or ambiguous, spectral analysis of resting EEG can therefore complement clinical diagnosis.