A Longitudinal Analysis of Mothers' Parenting Stress and Internalizing and Externalizing Behavior of Young Children on the Autism Spectrum.

We investigated longitudinal relations between internalizing, externalizing, and total behaviors that challenge in young children on the autism spectrum and mothers' parenting stress. Participants included 93 mothers of children on the autism spectrum aged 27.89-65.84 months, who completed questionnaires on maternal parenting stress, and children's internalizing (anxiety), externalizing (disruptive), and total behaviors that challenge. Data were collected on early intervention program intake and approximately one year later. Cross-sectional findings indicated small to medium effect size associations between internalizing and externalizing behavior and parenting stress. However, cross-lagged structural equation models found that neither internalizing nor externalizing behavior predicted later parenting stress, nor the reverse. Significant stability effects were found for measures of child internalizing (anxiety), externalizing (disruptive), and total behaviors, and parenting stress. Relations between behaviors that challenge and parenting stress over time were non-significant in our models that controlled for stability of behaviors and parenting stress over time. Implications for research and clinical practice, in understanding and targeting the persistence of behaviors that challenge and parenting stress, are discussed.

The relationshipbetween anxiety and social outcomes in autistic children and adolescents: A meta-analysis.

Anxiety is one of the most frequently reported co-occurring conditions for autistic children and adolescents. The relationship between anxiety and social outcomes in autistic youth has been the focus of a range of studies, with mixed results. This meta-analysis aimed to identify the strength of the association between anxiety and a frequently researched social outcome (social competence) in autistic young people and whether that association is influenced by individual or research design factors. A previous preregistered systematic review was updated with a search of the same three databases (CINAHL, ERIC, and PsycINFO) as the original review. Through this, 20 studies with sufficient data on a neurotypically-defined measure of social competence and anxiety were identified. Results were synthesised using a mixed effects model. The meta-analysis on 2,321 participants (from 22 samples) highlighted wide heterogeneity in results. The findings show that anxiety has a significant, small negative impact on social competence (d = - 0.48; 95% CI = - 0.71, - 0.26), meaning that as scores on measures of anxiety increase, scores on measures of social competence decrease. This relationship between anxiety and social competence was moderated by age, becoming weaker as age increased. Whilst this is an important finding for supporting mental health and well-being of autistic young people, the large amount of variance left unexplained suggests that multiple factors, including the use of measures designed for neurotypical people and the potential impact of camouflaging on such measures, need to be considered in future designs.

A Parent-Mediated Anxiety Intervention Specifically Tailored for Autistic Preschoolers: A Pilot Study.

IMPORTANCE: Autistic children experience reduced participation in life activities. One factor that may contribute to their reduced levels of participation is anxiety, which is identified at higher rates among young autistic children than among their neurotypical peers. Anxiety is also strongly associated with sensory overresponsivity and has a considerable impact on daily functioning. OBJECTIVE: To determine the feasibility, acceptability, and usefulness of a small-group, parent-mediated intervention to prevent and reduce anxiety. DESIGN: Pre-post. SETTING: University research center. PARTICIPANTS: Three parents of autistic children (ages 4-7 yr). OUTCOMES AND MEASURES: Parents completed a six-session group training program. Parents completed an anxiety scale for their child before and after parent training. At the end of training, parents participated in a focus group and were interviewed 4 mo after training. RESULTS: Positively received aspects of the intervention were the benefits of a small group, composed of parents of autistic children, run by a facilitator with expertise in autism and anxiety. Parents gained knowledge, resulting in "taking a different approach" with their child and "seeing an interplay between anxiety and autism." After the intervention, parents reported a reduction in children's reported anxiety levels. CONCLUSIONS AND RELEVANCE: Knowledge of autism and anxiety acquired during a parent-mediated group increased parents' understanding of their child's behaviors and assisted them in supporting their child's participation. Further research, including larger studies, is required to determine the effectiveness of this intervention. What This Article Adds: The findings from this research provide preliminary support for the adaptation of an existing parent intervention (Cool Little Kids) to reduce anxiety among autistic children. Parents reported an increased awareness and understanding of anxiety and of the interplay between anxiety and autistic traits. Positionality Statement: This article uses the identity-first language autistic people. This nonableist language describes their strengths and abilities and is a conscious decision. This language is favored by autistic communities and self-advocates and has been adopted by health care professionals and researchers (Bottema-Beutel et al., 2021; Kenny et al., 2016).

Protocol for a longitudinal study investigating the role of anxiety on academic outcomes in children on the autism spectrum.

BACKGROUND: Children on the autism spectrum are consistently reported to underachieve compared to ability. In typically developing children, anxiety is a strong predictor of poor school performance. Despite the high prevalence of anxiety disorders among children on the spectrum, the impact of their anxiety on academic achievement is under-researched. The main aim of this project is to determine the moderating role anxiety may have in the development of academic learning behaviours (academic enablers) in children on the spectrum. This project addresses a gap in knowledge about the possible associations between anxiety and academic achievement in children on the spectrum. Understanding these associations opens up the possibility of new intervention pathways to enhance academic outcomes through anxiety reduction/prevention. METHODS: This longitudinal study will aim to recruit 64 children on the spectrum aged 4-5 years and their parents. Information will be gathered from children, parents and teachers. Children will be randomly assigned to one of two conditions in order to experimentally manipulate anxiety levels in the sample: experimental (to receive an anxiety reduction/prevention program, N = 32) or control (no intervention/treatment as usual, N = 32). The primary outcome measures are child academic skills and enabling behaviours assessed using the Academic Competence Evaluation Scales and the WIAT-II. Anxiety will be assessed through parent and teacher report. Assessments will be conducted at baseline, post-experimental manipulation of anxiety, and within the first year of formal schooling. It is hypothesised that anxiety will moderate the relationship between autism characteristics and academic enablers. DISSEMINATION: Results will be disseminated through peer-reviewed manuscripts and conference presentations. Lay summaries will be provided to all participants and available on the research centre website.

Bioanalytical strategies in drug discovery and development.

A reliable, rapid, and effective bioanalytical method is essential for the determination of the pharmacokinetic, pharmacodynamic, and toxicokinetic parameters that inform the safety and efficacy profile of investigational drugs. The overall goal of bioanalytical method development is to elucidate the procedure and operating conditions under which a method can sufficiently extract, qualify, and/or quantify the analyte(s) of interest and/or their metabolites for the intended purpose. Given the difference in the physicochemical properties of small and large molecule drugs, different strategies need to be adopted for the development of an effective and efficient bioanalytical method. Herein, we provide an overview of different sample preparation strategies, analytical platforms, as well as procedures for achieving high throughput for bioanalysis of small and large molecule drugs.

Separable effects of the approximate number system, symbolic number knowledge, and number ordering ability on early arithmetic development.

There is evidence that early variations in the development of an approximate number system (ANS) and symbolic number understanding are both influences on the later development of formal arithmetic skills. We report a large-scale (N = 552) longitudinal study of the predictors of arithmetic spanning a critical developmental period (the first 3 years of formal education). Variations in early knowledge of symbolic representations of number and the ordinal associations between them are direct predictors of later arithmetic skills. The development of number ordering ability is in turn predicted by earlier variations in arithmetic, the ANS (numerosity judgments), and rapid automatized naming (RAN). These findings have important implications for theories of numerical and arithmetical development and potentially for the teaching of these skills.

The Production Effect Improves Memory in 7- to 10-Year-Old Children.

The production effect-whereby reading words aloud improves memory for those words relative to reading them silently-was investigated in two experiments with 7- to 10-year-old children residing in Brisbane, Australia. Experiment 1 (n = 41) involved familiar printed words, with words read aloud or silently appearing either in mixed- or blocked-list formats in a within-subject design. Recognition for words read aloud was better than for those read silently, an effect consistent across both list formats. These results were confirmed in Experiment 2 (n = 40) using longer lists of printed novel nonwords. Final analyses indicated that the production effect was comparable for words and nonwords. Findings are discussed in relation to the distinctiveness account and the use of production as a mnemonic in children.

Data on numerosity discrimination, inhibition and arithmetic during the early school years.

Participants consisted of 496 children (mean age = 6 years; 9 months) recruited from 11 schools in Brisbane, Australia. Children were assessed on the addition and subtraction subtests of the Test of Basic Arithmetic and Number Skills (TOBANS), an adapted version of the Head-Toes-Knees-Shoulders task to measure inhibition, numerosity discrimination using eight subtests varying ratio (2:3 or 5:6) and congruency, and non-verbal cognitive ability using an adapted version of Raven's Coloured Progressive Matrices. Information on children's demographics (gender, English as an additional language, and learning difficulty status) is also provided. All assessments were administered during the second year of formal schooling (i.e. Grade 1). Findings regarding the impact of inhibition on the relation between numerosity discrimination and arithmetic are reported elsewhere [1].

Stage 2 Registered Report: There is no appreciable relationship between strength of hand preference and language ability in 6- to 7-year-old children.

Background: Weak or inconsistent hand preference has been postulated to be a risk factor for developmental language delay. Following on from our Registered Stage 1 report this study assessed the extent to which variations in language skills are associated with the strength of hand preference. Methods: Data are drawn from a large sample ( N = 569) of 6- to 7-year-old children unselected for ability, assessed at two time points, 6 months apart. Hand preference was assessed using the Quantitative Hand Preference (QHP) task and five uni-manual motor tasks. Language skills (expressive and receptive vocabulary, receptive grammar, and morphological awareness) were assessed with standardized measures. Results: We found QHP scores did not distinguish children with weaker language skills from those with stronger language skills and the correlation between QHP scores and language ability was negligible in this study. Hand preference on the QHP task was significantly stronger among right-handed than left-handed children and left-handed children were typically inconsistent in the hand used across different tasks.  Conclusions: The findings presented here fail to provide any support for the theory that weak cerebral lateralisation (as assessed here by the QHP task) places children at risk of language difficulties . Stage 1 report:  https://doi.org/10.12688/wellcomeopenres.15077.1.

The relationship between numerosity discrimination and arithmetic skill reflects the approximate number system and cannot be explained by inhibitory control.

Numerosity discrimination tasks (judging which of two random dotarrays contains the larger number) have been widely used as a measure of the efficiency of an approximate number system (ANS) and are a correlate of early arithmetic skills. Recently, it has been suggested that the relationship between numerosity discrimination and arithmeticis explained by inhibition rather than the ANS. We assessed this hypothesis in astudy of 496 children (mean age = 81.23 months) using numerosity discrimination tasks that manipulated the congruency between surface area and numerosity. Numerosity discrimination for incongruent arrays (which are postulated to require inhibition due to a conflict between judgments based on surface area rather than numerosity) was more difficult than that for congruent arrays. However, all numerosity discrimination tasks showed substantial correlations with each other and correlated with arithmetic. A latent variable path model showed that a general numerosity judgment factorcorrelated witharithmetic even after controlling for a measure of response inhibition. In contrast, numerosity discrimination for incongruent arrays showed no unique relationship with arithmetic ability. Our results do not support the view that the relationship between numerosity discrimination and arithmetic is largely attributable to inhibition; rather, theyare consistent withthe view that numerosity discrimination tasks tap the operation of an ANS.

Targeting ferroptosis: A novel therapeutic strategy for the treatment of mitochondrial disease-related epilepsy.

BACKGROUND: Mitochondrial disease is a family of genetic disorders characterized by defects in the generation and regulation of energy. Epilepsy is a common symptom of mitochondrial disease, and in the vast majority of cases, refractory to commonly used antiepileptic drugs. Ferroptosis is a recently-described form of iron- and lipid-dependent regulated cell death associated with glutathione depletion and production of lipid peroxides by lipoxygenase enzymes. Activation of the ferroptosis pathway has been implicated in a growing number of disorders, including epilepsy. Given that ferroptosis is regulated by balancing the activities of glutathione peroxidase-4 (GPX4) and 15-lipoxygenase (15-LO), targeting these enzymes may provide a rational therapeutic strategy to modulate seizure. The clinical-stage therapeutic vatiquinone (EPI-743, α-tocotrienol quinone) was reported to reduce seizure frequency and associated morbidity in children with the mitochondrial disorder pontocerebellar hypoplasia type 6. We sought to elucidate the molecular mechanism of EPI-743 and explore the potential of targeting 15-LO to treat additional mitochondrial disease-associated epilepsies. METHODS: Primary fibroblasts and B-lymphocytes derived from patients with mitochondrial disease-associated epilepsy were cultured under standardized conditions. Ferroptosis was induced by treatment with the irreversible GPX4 inhibitor RSL3 or a combination of pharmacological glutathione depletion and excess iron. EPI-743 was co-administered and endpoints, including cell viability and 15-LO-dependent lipid oxidation, were measured. RESULTS: EPI-743 potently prevented ferroptosis in patient cells representing five distinct pediatric disease syndromes with associated epilepsy. Cytoprotection was preceded by a dose-dependent decrease in general lipid oxidation and the specific 15-LO product 15-hydroxyeicosatetraenoic acid (15-HETE). CONCLUSIONS: These findings support the continued clinical evaluation of EPI-743 as a therapeutic agent for PCH6 and other mitochondrial diseases with associated epilepsy.

Stage 1 Registered Report: The relationship between handedness and language ability in children.

Weak or inconsistent hand preference may be a risk factor for developmental language delay.  This study will test the extent to which variations in language skills are associated with the strength of hand preference. Data are drawn from a large sample (n = 569) of 6- to 7-year-old children unselected for ability, assessed at two time points, 6 months apart. Hand preference is assessed using the Quantitative Hand Preference task (QHP) and five uni-manual motor tasks. Language skills (expressive and receptive vocabulary, receptive grammar, and morphological awareness) are assessed with standardized measures. If weak cerebral lateralisation (as assessed by the QHP task) is a risk factor for language difficulties, it should be possible to detect such effects in the large representative sample of children examined here.

Learning correspondences between magnitudes, symbols and words: Evidence for a triple code model of arithmetic development.

According to the Triple Code Model, early arithmetic development depends on learning the mappings between non-verbal representations of magnitude (quantity) and symbolic verbal (number words) and visual (Arabic numerals) representations of number. We examined this hypothesis in a sample of 166 4- to 7-year old children. Children completed 4 paired-associate learning tasks and a broad range of measures assessing early numerical (symbolic and non-symbolic magnitude comparison, digit writing, arithmetic) and reading skills (letter-sound knowledge, phoneme awareness, rapid automatized naming, word reading). A path model showed that paired-associate learning tasks involving mapping magnitudes onto verbal or visual stimuli predicted arithmetic performance over and above other well-established predictors. This relationship was specific to arithmetic and, consistent with the Triple Code Model, highlights that mapping between non-symbolic magnitude representations and the corresponding symbolic forms (verbal and visual) is important to the development of arithmetic skills.

Diffusiophoresis of charged colloidal particles in the limit of very high salinity.

Diffusiophoresis is the migration of a colloidal particle through a viscous fluid, caused by a gradient in concentration of some molecular solute; a long-range physical interaction between the particle and solute molecules is required. In the case of a charged particle and an ionic solute (e.g., table salt, NaCl), previous studies have predicted and experimentally verified the speed for very low salt concentrations at which the salt solution behaves ideally. The current study presents a study of diffusiophoresis at much higher salt concentrations (approaching the solubility limit). At such large salt concentrations, electrostatic interactions are almost completely screened, thus eliminating the long-range interaction required for diffusiophoresis; moreover, the high volume fraction occupied by ions makes the solution highly nonideal. Diffusiophoretic speeds were found to be measurable, albeit much smaller than for the same gradient at low salt concentrations.

Vitamin E hydroquinone is an endogenous regulator of ferroptosis via redox control of 15-lipoxygenase.

Ferroptosis is a form of programmed cell death associated with inflammation, neurodegeneration, and ischemia. Vitamin E (alpha-tocopherol) has been reported to prevent ferroptosis, but the mechanism by which this occurs is controversial. To elucidate the biochemical mechanism of vitamin E activity, we systematically investigated the effects of its major vitamers and metabolites on lipid oxidation and ferroptosis in a striatal cell model. We found that a specific endogenous metabolite of vitamin E, alpha-tocopherol hydroquinone, was a dramatically more potent inhibitor of ferroptosis than its parent compound, and inhibits 15-lipoxygenase via reduction of the enzyme's non-heme iron from its active Fe3+ state to an inactive Fe2+ state. Furthermore, a non-metabolizable isosteric analog of vitamin E which retains antioxidant activity neither inhibited 15-lipoxygenase nor prevented ferroptosis. These results call into question the prevailing model that vitamin E acts predominantly as a non-specific lipophilic antioxidant. We propose that, similar to the other lipophilic vitamins A, D and K, vitamin E is instead a pro-vitamin, with its quinone/hydroquinone metabolites responsible for its anti-ferroptotic cytoprotective activity.

Emojis: Insights, Affordances, and Possibilities for Psychological Science.

We live in a digital society that provides a range of opportunities for virtual interaction. Consequently, emojis have become popular for clarifying online communication. This presents an exciting opportunity for psychologists, as these prolific online behaviours can be used to help reveal something unique about contemporary human behaviour.

Concentrations of Pro-Inflammatory Cytokines Are Not Associated with Senescence Marker p16INK4a or Predictive of Intracellular Emtricitabine/Tenofovir Metabolite and Endogenous Nucleotide Exposures in Adults with HIV Infection.

OBJECTIVES: As the HIV-infected population ages, the role of cellular senescence and inflammation on co-morbid conditions and pharmacotherapy is increasingly of interest. p16INK4a expression, a marker for aging and senescence in T-cells, is associated with lower intracellular concentrations of endogenous nucleotides (EN) and nucleos(t)ide reverse transcriptase inhibitors (NRTIs). This study expands on these findings by determining whether inflammation is contributing to the association of p16INK4a expression with intracellular metabolite (IM) exposure and endogenous nucleotide concentrations. METHODS: Samples from 73 HIV-infected adults receiving daily tenofovir/emtricitabine (TFV/FTC) with either efavirenz (EFV) or atazanavir/ritonavir (ATV/r) were tested for p16INK4a expression, and plasma cytokine and intracellular drug concentrations. Associations between p16INK4a expression and cytokine concentrations were assessed using maximum likelihood methods, and elastic net regression was applied to assess whether cytokines were predictive of intracellular metabolite/endogenous nucleotide exposures. RESULTS: Enrolled participants had a median age of 48 years (range 23-73). There were no significant associations between p16INK4a expression and cytokines. Results of the elastic net regression showed weak relationships between IL-1Ra and FTC-triphosphate and deoxyadenosine triphosphate exposures, and MIP-1ß, age and TFV-diphosphate exposures. CONCLUSIONS: In this clinical evaluation, we found no relationships between p16INK4a expression and cytokines, or cytokines and intracellular nucleotide concentrations. While inflammation is known to play a role in this population, it is not a major contributor to the p16INK4a association with decreased IM/EN exposures in these HIV-infected participants.

The cognitive foundations of early arithmetic skills: It is counting and number judgment, but not finger gnosis, that count.

Following on from ideas developed by Gerstmann, a body of work has suggested that impairments in finger gnosis may be causally related to children's difficulties in learning arithmetic. We report a study with a large sample of typically developing children (N=197) in which we assessed finger gnosis and arithmetic along with a range of other relevant cognitive predictors of arithmetic skills (vocabulary, counting, and symbolic and nonsymbolic magnitude judgments). Contrary to some earlier claims, we found no meaningful association between finger gnosis and arithmetic skills. Counting and symbolic magnitude comparison were, however, powerful predictors of arithmetic skills, replicating a number of earlier findings. Our findings seriously question theories that posit either a simple association or a causal connection between finger gnosis and the development of arithmetic skills.

Cervicovaginal and Rectal Fluid as a Surrogate Marker of Antiretroviral Tissue Concentration: Implications for Clinical Trial Design.

BACKGROUND: Quantifying tissue drug concentrations can yield important information during drug development, but complicates pharmacokinetic study design. Mucosal fluids collected by direct aspiration (cervicovaginal fluid; CVF) or swab (rectal fluid; RF) might be used as tissue concentration surrogates, but these relationships are not well characterized. METHODS: Forty-nine healthy women, given a single oral dose of tenofovir, maraviroc, emtricitabine, or raltegravir at 50%-200% of the treatment dose, provided 13 plasma, 12 CVF, 12 RF and one cervical, vaginal and rectal tissue biopsy over 48 hours. Relationships between these paired samples were characterized by linear and multiple linear regression. Adjusted r values were used to select the final predictive models. RESULTS: CVF exposure increased linearly with dose for all antiretrovirals (r(2) ≥ 0.23, P ≤ 0.02) except raltegravir (r(2) = 0.08, P = 0.19). In RF, only emtricitabine increased linearly with dose (r(2) = 0.27, P = 0.01). For all antiretrovirals, CVF and RF concentrations significantly correlated with mucosal tissue concentrations (female genital tract r(2) ≥ 0.37, rectal tissue (2)r ≥ 0.50, P ≤ 0.001). In the final multivariate models, plasma and fluid concentrations were both associated with FGT concentrations for all antiretrovirals (r(2) ≥ 0.81, P < 0.001). The same was noted for rectal tissue (r(2) ≥ 0.58, P < 0.001) except for tenofovir, for which RF alone was predictive of tissue concentration (r(2) = 0.91, P < 0.001). CONCLUSIONS: Mucosal fluids were positively correlated with tissue concentrations and including plasma concentrations improved the regression models in most cases. Dose linearity in CVF, but not RF, suggests a saturation process in lower gastrointestinal tract tissue. These findings suggest that mucosal fluid and plasma concentrations may be used for qualitative inference of tissue concentrations for these antiretrovirals.

A Translational Pharmacology Approach to Predicting Outcomes of Preexposure Prophylaxis Against HIV in Men and Women Using Tenofovir Disoproxil Fumarate With or Without Emtricitabine.

BACKGROUND: A novel translational pharmacology investigation was conducted by combining an in vitro efficacy target with mucosal tissue pharmacokinetic (PK) data and mathematical modeling to determine the number of doses required for effective human immunodeficiency virus (HIV) preexposure prophylaxis (PrEP). METHODS: A PK/pharmacodynamic (PD) model was developed by measuring mucosal tissue concentrations of tenofovir, emtricitabine, their active metabolites (tenofovir diphosphate [TFVdp] and emtricitabine triphosphate [FTCtp], respectively), and competing endogenous nucleotides (dATP and dCTP) in 47 healthy women. TZM-bl and CD4(+) T cells were used to identify 90% effective concentration (EC90) ratios of TFVdp to dATP and FTCtp to dCTP (alone and in combination) for protection against HIV. Monte-Carlo simulations were then performed to identify minimally effective dosing strategies to protect lower female genital tract and colorectal tissues. RESULTS: The colorectal TFVdp concentration was 10 times higher than that in the lower female genital tract, whereas concentrations of endogenous nucleotides were 7-11 times lower. Our model predicted that ≥98% of the population achieved protective mucosal tissue exposure by the third daily dose of tenofovir disoproxil fumarate plus emtricitabine. However, a minimum adherence to 6 of 7 doses/week (85%) was required to protect lower female genital tract tissue from HIV, while adherence to 2 of 7 doses/week (28%) was required to protect colorectal tissue. CONCLUSIONS: This model is predictive of recent PrEP trial results in which 2-3 doses/week was 75%-90% effective in men but ineffective in women. These data provide a novel approach for future PrEP investigations that can optimize clinical trial dosing strategies.