Practical guidance to evaluate in vitro dermal absorption studies for pesticide registration: An industry perspective.

While there are some regulatory assessment criteria available on how to generally evaluate dermal absorption (DA) studies for risk assessment purposes, practical guidance and examples are lacking. The current manuscript highlights the challenges in interpretating data from in vitro assays and proposes holistic data-based assessment strategies from an industry perspective. Inflexible decision criteria may be inadequate for real data and may lead to irrelevant DA estimates. We recommend the use of mean values for reasonably conservative DA estimates from in vitro studies. In cases where additional conservatism is needed, e.g., due to non-robust data and acute exposure scenarios, the upper 95% confidence interval of the mean may be appropriate. It is critical to review the data for potential outliers and we provide some example cases and strategies to identify aberrant responses. Some regional regulatory authorities require the evaluation of stratum corneum (SC) residue, but here, as a very simple pro-rata approach, we propose to review whether the predicted post 24-h absorption flux exceeds the predicted elimination flux by desquamation because otherwise it is not possible for the SC residue to contribute to systemic dose. Overall, the adjustment of DA estimates due to mass balance (normalization) is not recommended.

Improving Children's Expressive Language and Auditory Comprehension Through Responsive Caregiving: Evidence from a Randomized Controlled Trial of a Strength-Based Video-Coaching Intervention.

Young children from low-SES backgrounds are at higher risk for delayed language development, likely due to differences in their home language environment and decreased opportunities for back and forth communicative exchange. Intervention strategies that encourage reciprocal caregiver-child interactions may effectively promote young children's language development and enhance optimal language outcomes. The Filming Interactions to Nurture Development (FIND) program is a brief strength-based video-coaching intervention designed to promote increased back and forth ("serve and return") interactions between caregivers and their children. The current study used data from a randomized controlled trial (RCT) to examine the effectiveness of the FIND program in improving auditory comprehension and expressive communication skills among children from low-SES backgrounds. The current study used a pretest-posttest design to evaluate intervention effects from an RCT with 91 low-SES families. Families with children aged 4 to 36 months old (41.8% female) were randomly assigned to an active control or FIND intervention group. Children's auditory comprehension and expressive communication were assessed using the Preschool Language Scales, Fifth Edition (PLS-5) during both pre- and post-intervention sessions. Children in the FIND intervention group showed significantly increased expressive communication skills and a non-significant increase in auditory comprehension skills across the intervention period. In contrast, children in the active control group showed non-significant changes in expressive communication and a statistically significant decline in auditory comprehension abilities between pre- and post-intervention assessments. All analyses controlled for sex, age, and home language. This study provides preliminary evidence that the FIND intervention promotes the development of expressive and receptive language skills among young children in high-stress, low-SES environments.

The COVID-19 Pandemic Impact on Households of Young Children With Special Healthcare Needs.

OBJECTIVE: This study examined how the COVID-19 pandemic differently affected households of children with versus without special healthcare needs. We compared caregivers' and children's emotional well-being (Aim 1), the utilization of preventive healthcare services for young children (Aim 2), and the promotive effects of social support on well-being outcomes (Aim 3) during the pandemic between the two groups. METHODS: Data were drawn from an ongoing, large, longitudinal, and national survey that assessed the pandemic impact on households of young children (0-5). Analyses for Aims 1 and 2 were based on 10,572 households, among which 10.96% had children with special healthcare needs. Analyses for Aim 3 were based on a subsample of 821 families, among which 12.54% had children with special healthcare needs. RESULTS: Caregivers of children with special healthcare needs exhibited more emotional distress and reported higher levels of household children's behavioral problems during the pandemic. The percentages of missed preventive healthcare visits and vaccinations were also higher in families of children with special healthcare needs due to structural barriers. Lastly, emotional social support was indirectly related to children's decreased behavioral problems through caregivers' reduced emotional distress, only among households of children without special healthcare needs. In other words, social support alone was not sufficient in promoting caregivers' and children's better well-being outcomes among households of children with special healthcare needs. CONCLUSIONS: The pandemic has caused extensive burdens on families of children with special healthcare needs. Actions from policymakers and early intervention service providers are urgently needed to mitigate these impacts.

A new conceptional model for deriving average dermal absorption estimates from studies with multiple tested concentrations for non-dietary risk assessment of pesticides.

Dermal absorption values are used to translate external dermal exposure into potential systemic exposure for non-dietary risk assessment of pesticides. While the Environmental Protection Agency of the United States of America (US EPA) derives a common dermal absorption factor for active substances covering all related products, the European Food Safety Authority (EFSA) requests specific product-based estimates for individual concentrations covering the intended use rates. The latter poses challenges, because it disconnects exposure dose from applied dose in absorption studies, which may not be suitable in scenarios where concentration is not relevant. We analyzed the EFSA dermal absorption database, collected 33 human in vitro studies from CropLife Europe (CLE) companies, where ≥3 in-use dilution concentrations were tested, and 15 dermal absorption triple pack datasets. This shows that absolute dermal absorption correlates with absolute applied dose on a decadic logarithm-scale, which is concordant with the toxicological axiom that risk is driven by exposure dose. This method is radically different from the current European approach focused on concentrations and offers new insights into the relationship of internal and external exposure doses when utilizing data from in vitro studies. A single average dermal absorption value can be simply derived from studies with multiple tested concentrations, by calculating the y-intercept of a linear model on a decadic logarithm scale while assuming a slope of 1. This simplifies risk assessment and frees resources to explore exposure refinements. It also serves as a basis to harmonize dermal absorption estimation globally for use in exposure-driven risk assessments.

An OECD TG 428 study ring trial with 14C-Caffeine demonstrating repeatability and robustness of the dermal absorption in vitro method.

The dermal absorption potential of 14C-Caffeine applied as a 4 mg/mL concentration (10 µL/cm2 finite dose) was investigated in six laboratories under Good Laboratory Practice conditions using an OECD TG 428-compliant in vitro assay with flow-through cells and split-thickness human skin. Potential sources of variation were reduced by a standardized protocol, test item and skin source. Particularly, skin samples from same donors were distributed over two repeats and between labs in a non-random, stratified design. Very similar recovery was achieved in the various assay compartments between laboratories, repeats and donors, demonstrating that the assay can be robustly and reliably performed. The absorption in one laboratory was 5-fold higher than in the others. This did not clearly correlate with skin integrity parameters but might be associated with an accidental COVID-19 pandemic-related interruption in sample shipment. It is possible that other factors may affect dermal absorption variation not routinely assessed or considered in the current method. The mean receptor fluid recovery, potential absorption (recovery in receptor fluid and skin except tape strips 1 and 2) and mass balance of caffeine was 6.99%, 7.14% and 99.13%, respectively, across all and 3.87%, 3.96% and 99.00% in the subset of five laboratories.

The Effectiveness of KEEP for Families of Children with Developmental Delays: Integrating FIND Video Coaching into Parent Management Training-Oregon Model: a Randomized Trial.

Children with developmental delays or disabilities (DD) are at risk for self-regulation difficulties and behaviour problems compared to typically developing children. Intervening early is crucial to prevent long-term adjustment challenges across home and school contexts. Parenting has been identified as a malleable target of intervention for improving children's adaptive functioning across behavioural, emotional and cognitive domains. Although parent management training (PMT) is an identified best-practice, key questions remain about the critical components of interventions and how novel approaches like video feedback may offer additional benefits. Using a pre-test-post-test one group and superiority design, we evaluated the efficacy of two models of the Keeping Parents Trained and Supported (KEEP) preschool program with parent-only components among 175 families with children diagnosed or at-risk for DD. KEEP-P included core PMT (Oregon Model) methods and KEEP-V integrated KEEP with Filming Interactions to Nurture Development video coaching methods for enhancing developmentally supportive interactions. Intervention outcomes on children's behaviour problems and executive functioning, parenting stress and parent-child relationship quality were compared between groups. Both groups demonstrated significant reductions over time in child behavioural problems, developmental problems and parenting stress. Significant improvements were observed in children's executive functioning, parents' sense of competence and mindfulness in parenting. Group differences were observed in parent's sense of competence, with individuals receiving KEEP-P displaying greater increases over time. Higher intervention dosage predicted a greater reduction in stressful child behaviours and greater improvements in children's inhibitory control.

Effects of a school readiness intervention on electrophysiological indices of external response monitoring in children in foster care.

This study examined the impact of a school readiness intervention on external response monitoring in children in foster care. Behavioral and event-related potential (ERP) data were collected during a flanker task from children who received the Kids In Transition to School (KITS) Program (n = 26) and children who received services as usual (n = 19) before and after the intervention. While there were no significant group differences on the behavioral data, the ERP data for the two groups of children significantly differed. Specifically, in contrast to the children who received services as usual, the children who received the KITS Program displayed greater amplitude differences between positive and negative performance feedback over time for the N1, which reflects early attention processes, and feedback-related negativity, which reflects evaluation processes. In addition, although the two groups did not differ on amplitude differences between positive and negative performance feedback for these ERP components before the intervention, the children who received the KITS Program displayed greater amplitude differences than the children who received services as usual after the intervention. These results suggest that the KITS Program had an effect on responsivity to external performance feedback, which may be beneficial during the transition into kindergarten.

Improving Caregiver Self-Efficacy and Children's Behavioral Outcomes via a Brief Strength-Based Video Coaching Intervention: Results from a Randomized Controlled Trial.

Many existing preventive intervention programs focus on promoting responsive parenting practices. However, these parenting programs are often long in duration and expensive, and meta-analytic evidence indicates that families facing high levels of adversity typically benefit less. Moreover, due to a lack of specification and evaluation of conceptual models, the mechanisms underlying program-related changes in caregivers and their children often remain unclear. The current study aimed to test the effectiveness of a video feedback parenting intervention program, Filming Interactions to Nurture Development (FIND), in improving caregivers' self-efficacy and reducing children's behavioral problems. Data derived from a randomized controlled trial using pretest-posttest design with low-income families reporting high levels of stress (N = 91, children aged 4 to 36 months old, 41.8% female). Families were randomly assigned to an active control or FIND intervention group. Results indicated that caregivers in the FIND group exhibited significant improvement in self-report sense of parenting competence and self-efficacy in teaching tasks. These program impacts were particularly pronounced among caregivers who experience high levels of childhood adversity. Findings provide preliminary support for the FIND conceptual model. Specifically, caregivers' improved self-efficacy in teaching tasks was linked to children's reduced internalizing and externalizing problems (notably, direct FIND intervention effects on children's behavioral outcomes were not observed). Overall, results support the effectiveness of FIND in enhancing caregivers' sense of parenting competence and potentially promoting optimal child development.

Feeling left out or just surprised? Neural correlates of social exclusion and overinclusion in adolescence.

Social belonging is an important human drive that influences mood and behavior. Neural responses to social exclusion are well-characterized, but the specificity of these responses to processing rejection-related affective distress is unknown. The present study compares neural responses to exclusion and overinclusion, a condition that similarly violates fairness expectations but does not involve rejection, with a focus on implications for models of dorsal anterior cingulate cortex (dACC) and anterior insula (AI) function. In an fMRI adaptation of the Cyberball paradigm with adolescents aged 11.1-17.7 years (N = 69), we employed parametric modulators to examine scaling of neural signal with cumulative exclusion and inclusion events, an approach that overcomes arbitrary definitions of condition onsets/offsets imposed on fluid, continuous gameplay. We identified positive scaling of dACC and posterior insula response with cumulative exclusion events, but these same regions exhibited trending signal decreases with cumulative inclusion events. Furthermore, areas within the dACC and insula also responded to context incongruency (throws to the participant in the exclusion run; throws between computer players in the overinclusion run). These findings caution against interpretations that responses in these regions uniquely reflect the affective distress of exclusion within social interaction paradigms. We further identified that the left ventrolateral PFC, rostromedial PFC, and left intraparietal sulcus responded similarly to cumulative exclusion and inclusion. These findings shed light on which neural regions exhibit patterns of differential sensitivity to exclusion or overinclusion, as well as those that are more broadly engaged by both types of social interaction.

Alpha electroencephalogram (EEG) asymmetry among toddlers in foster care.

The majority of children living in foster care in the United States have a history of maltreatment and/or disrupted caregiving. Maltreatment in early childhood adversely affects development at many levels, including neurobiology and behavior. One neurobiological measure associated with maltreatment is alpha electroencephalogram (EEG) asymmetry. Prior research has found greater right frontal asymmetry among children with a history of maltreatment. However, little research has been extended developmentally downward to examine alpha asymmetry and its behavioral correlates among toddlers in foster care; this was the purpose of the present study. Differences in EEG asymmetry were examined between a sample of foster toddlers (mean age = 3.21 years, n = 38) and a community comparison, low-income sample without a history of foster care (mean age = 3.04 years, n = 16). The toddlers in the foster care group exhibited greater right alpha asymmetry, primarily driven by differences in parietal asymmetry. Neither frontal nor parietal asymmetry were clearly related to internalizing or externalizing behaviors, measured concurrently or at previous time points. These findings reveal differences in alpha EEG asymmetry among toddlers in foster care, and highlight the need to better understand associations between neurobiological and behavioral functioning following early adversity.

Acute stress impairs children's sustained attention with increased vulnerability for children of mothers reporting higher parenting stress.

Despite evidence that acute stress impairs attention in adults, there has been minimal research in children. Here, the effects of acute stress on Go/No-go performance were examined in young children (M age = 5.41 years). Given the critical role of the parent-child relationship to children's self-regulatory development, the extent to which parenting stress predicts children's cognitive vulnerability to acute stress and autonomic reactivity was also investigated. A between-groups design (n = 58 stress, n = 26 control) was used with oversampling of the stressor-exposed children to examine individual differences. The Parenting Stress Index and subscales were employed as a measure of parenting stress. Acute stress impaired children's sustained attention, but not inhibitory control. Higher parenting stress was associated with vulnerability to attentional impairment. Parenting distress was also positively associated with sympathetic reactivity to acute stress, but neither sympathetic nor parasympathetic reactivity was associated with attentional impairment. A conceptual model of pathways through which repetitive acute stress may contribute to self-regulatory difficulties is presented, including the potential buffering role of caregivers.

Expectations of Social Consequences Impact Anticipated Involvement in Health-Risk Behavior During Adolescence.

This study examined how individual differences in expectations of social consequences relate to individuals' expected involvement in health-risk behaviors (HRBs). A total of 122 adolescents (aged 11-17) reported their expected involvement in a number of risk behaviors and whether or not they expect to be liked more or less by engaging in the behavior: the expected social benefit. Higher perceived social benefit was associated with higher anticipated involvement in said behavior. This relationship was stronger for adolescents who reported a higher degree of peer victimization, supporting the hypothesis that experiencing victimization increases the social value of peer interactions. Findings suggest that adolescents incorporate expectations of social consequences when making decisions regarding their involvement in HRBs.

Measurement of parental executive function in early childhood settings: Instrument reliability and validity in community-led research projects.

A growing number of early childhood (EC) parenting programs target adult executive function (EF) to build responsive parenting behaviors and to promote positive child development. Although measurement of EF is well understood in academic research, little work has examined EF measurement in community settings. The present study examined psychometric properties of the Behavior Rating Inventory of Executive Function-Adult Version among 203 parents whose children were enrolled in EC programs serving under-resourced communities. We calculated Cronbach's α and mean-item correlations to test internal consistency reliability. To test factor structure, we conducted exploratory factor analysis and confirmatory factor analyses. Results suggest adequate internal consistency and that factor structures, beyond the original proposed, are appropriate for our community sample. Together, findings indicate that self-report measures of adult EF may perform differently for families experiencing adversity, raising questions about the acceptability of clinical EF tools in in underserved communities.

Dermal absorption study OECD TG 428 mass balance recommendations based on the EFSA database.

The European Food Safety Authority (EFSA) guidance (EFSA, 2017) for dermal absorption (DA) studies recommends stringent mass balance (MB) limits of 95-105%. EFSA suggested that test material can be lost after penetration and requires that for chemicals with <5% absorption the non-recovered material must be added to the absorbed dose if MB is <95%. This has huge consequences for low absorption pesticides. Indeed, one third of the MBs in the EFSA DA database are outside the refined criteria. This is also true for DA data generated by Cosmetics Europe (Gregoire et al., 2019), indicating that this criterion is often not achieved even when using highly standardized protocols. While EFSA hypothesizes that modern analytical and pipetting techniques would enable to achieve this criterion, no scientific basis was provided. We describe how protocol procedures impact MB and evaluate the EFSA DA database to demonstrate that MB is subject to random variation. Generic application of "the addition rule" skews the measured data and increases the DA estimate, which results in unnecessary risk assessment failure. In conclusion, "missing material" is just a random negative deviation to the nominal dose. We propose a data-driven MB criterion of 90-110%, fully in line with OECD recommendations.

Is adolescence the missing developmental link in Microbiome-Gut-Brain axis communication?

Gut microbial research has recently opened new frontiers in neuroscience and potentiated novel therapies for mental health problems (Mayer, et al., 2014). Much of our understanding of the gut microbiome's role in brain function and behavior, however, has been largely derived from research on nonhuman animals. Even less is known about how the development of the gut microbiome influences critical periods of neural and behavioral development, particularly adolescence. In this review, we first discuss why the gut microbiome has become increasingly relevant to developmental cognitive neuroscience and provide a synopsis of the known connections of the gut microbiome with social-affective brain function and behavior, specifically highlighting human developmental work when possible. We then focus on adolescence, a key period of neurobiological and social-affective development. Specifically, we review the links between the gut microbiome and six overarching domains of change during adolescence: (a) social processes, (b) motivation and behavior, (c) neural development, (d) cognition, (e) neuroendocrine function, and (f) physical health and wellness. Using a developmental science perspective, we summarize key changes across these six domains to underscore the promise for the gut microbiome to bidirectionally influence and transform adolescent development.

Novel insights from the Yellow Light Game: Safe and risky decisions differentially impact adolescent outcome-related brain function.

Changes across the span of adolescence in the adolescent reward system are thought to increase the tendency to take risks. While developmental differences in decision and outcome-related reward processes have been studied extensively, existing paradigms have largely neglected to measure how different types of decisions modulate reward-related outcome processes. We modified an existing decision-making paradigm (the Stoplight Task; Chein et al., 2011) to create a flexible laboratory measure of decision-making and outcome processing, including the ability to assess modulatory effects of safe versus risky decisions on reward-related outcome processes: the Yellow Light Game (YLG). We administered the YLG in the MRI scanner to 81 adolescents, ages 11-17 years, recruited from the community. Results showed that nucleus accumbens activation was enhanced for (1) risky > safe decisions, (2) positive > negative outcomes, and (3) outcomes following safe decisions compared to outcomes following risky decisions, regardless of whether these outcomes were positive or negative. Outcomes following risky decisions (compared to outcomes following safe decisions) were associated with enhanced activity in cortical midline structures. Furthermore, while there were no developmental differences in risk-taking behavior, more pubertally mature adolescents showed enhanced nucleus accumbens activation during positive > negative outcomes. These findings suggest that outcome processing is modulated by the types of decisions made by adolescents and highlight the importance of investigating processes involved in safe as well as risky decisions to better understand the adolescent tendency to take risks.

Replication and reproducibility issues in the relationship between C-reactive protein and depression: A systematic review and focused meta-analysis.

One of the most common inflammatory markers examined in depression is C-reactive protein (CRP). However, the magnitude of the association between CRP and depression when controlling for potentially confounding factors such as age, sex, socio-economic status, body mass index, medication and other substance use, and medical illness, is unclear. Inconsistencies in other methodological practices, such as sample collection, assaying, and data cleaning and transformation, may contribute to variations in results. We aggregate studies that examined the association between CRP and depression in two ways. First, a systematic review summarizes how studies of CRP and depression have reported on methodological issues. Second, a tiered meta-analysis aggregates studies that have adhered to various levels of methodological rigor. Findings from the systematic review indicate a lack of protocol detail provided. The effect between depression and CRP was small, but highly significant across all stages of the meta-analysis (p < 0.01). The effect size in the most methodologically rigorous stage of the meta-analysis, which included studies controlling for age, sex, obesity, medical conditions and substance, medication, or psychosocial factors, was small (r = 0.05). There were also only 26 articles in this stage (13% of studies from the systematic review), suggesting that more studies that consistently account for these confounding factors are needed. Additionally, an a priori quality score of methodological rigor was a significant moderator in this stage of the meta-analysis. The effect size was strikingly attenuated (r = 0.005) and non-significant in studies with higher quality scores. We describe a set of recommended guidelines for future research to consider, including sample collection and assaying procedures, data cleaning and statistical methods, and control variables to assess.

Children's biological responsivity to acute stress predicts concurrent cognitive performance.

Although prior research has characterized stress system reactivity (i.e. hypothalamic-pituitary-adrenal axis, HPAA; autonomic nervous system, ANS) in children, it has yet to examine the extent to which biological reactivity predicts concurrent goal-directed behavior. Here, we employed a stressor paradigm that allowed concurrent assessment of both stress system reactivity and performance on a speeded-response task to investigate the links between biological reactivity and cognitive function under stress. We further investigated gender as a moderator given previous research suggesting that the ANS may be particularly predictive of behavior in males due to gender differences in socialization. In a sociodemographically diverse sample of young children (N = 58, M age = 5.38 yrs; 44% male), individual differences in sociodemographic covariates (age, household income), HPAA (i.e. cortisol), and ANS (i.e. respiratory sinus arrhythmia, RSA, indexing the parasympathetic branch; pre-ejection period, PEP, indexing the sympathetic branch) function were assessed as predictors of cognitive performance under stress. We hypothesized that higher income, older age, and greater cortisol reactivity would be associated with better performance overall, and flexible ANS responsivity (i.e. RSA withdrawal, PEP shortening) would be predictive of performance for males. Overall, females performed better than males. Two-group SEM analyses suggest that, for males, greater RSA withdrawal to the stressor was associated with better performance, while for females, older age, higher income, and greater cortisol reactivity were associated with better performance. Results highlight the relevance of stress system reactivity to cognitive performance under stress. Future research is needed to further elucidate for whom and in what situations biological reactivity predicts goal-directed behavior.

Effects of a school readiness intervention on hypothalamus-pituitary-adrenal axis functioning and school adjustment for children in foster care.

Maltreated children in foster care are at high risk for dysregulated hypothalamus-pituitary-adrenal (HPA) axis functioning and educational difficulties. The present study examined the effects of a short-term school readiness intervention on HPA axis functioning in response to the start of kindergarten, a critical transition marking entry to formal schooling, and whether altered HPA axis functioning influenced children's school adjustment. Compared to a foster care comparison group, children in the intervention group showed a steeper diurnal cortisol slope on the first day of school, a pattern previously observed among nonmaltreated children. A steeper first day of school diurnal cortisol slope predicted teacher ratings of better school adjustment (i.e., academic performance, appropriate classroom behaviors, and engagement in learning) in the fall of kindergarten. Furthermore, the children's HPA axis response to the start of school mediated the effect of the intervention on school adjustment. These findings support the potential for ameliorative effects of interventions targeting critical transitional periods, such as the transition of formal schooling. This school readiness intervention appears to influence stress neurobiology, which in turn facilitates positive engagement with the school environment and better school adjustment in children who have experienced significant early adversity.

Polyvictimization and externalizing symptoms in foster care children: The moderating role of executive function.

Prior research has identified the role of childhood maltreatment in externalizing problems and executive function (EF) deficits, but minimal work has been done to characterize the effects of co-occurring maltreatment types, defined as polyvictimization. Here, we sought to characterize the association between polyvictimization and externalizing problems in a sample of foster care children aged 3-4 years (N = 84) and examine how EF may mediate or moderate that relationship. A moderation model was supported in that only polyvictimized children with EF scores 1.62 or more standard deviations below the mean were at heightened risk for clinically severe externalizing problems, while no association between polyvictimization and externalizing problems were observed for children who scored at the mean or above on the EF measure. Findings highlight that EF may serve as a resilience factor indicating that individual differences in polyvictimized children's EF skills help to predict variability in externalizing problems. Future research on designing and optimizing intervention programs that target EF skills may mitigate the development of maladaptive outcomes for polyvictimized children.