The Association Between Autism Symptomatology and Adaptive Functioning Over Six Months: Findings from the Pilot Phase of the PARC Study.

PURPOSE: In the context of developmental trajectories, the association between adaptive functioning and core autism symptomatology remains unclear. The current study examines the associations of adaptive behavior with autism symptom sub-domains and with different facets of symptom expression. METHODS: Participants include 36 children with a recent diagnosis of autism (33 males; mean age = 56.4 months; SD = 9 months). Families were recruited in the context of the Pediatric Autism Research Cohort (PARC) project. Parents filled out questionnaires at two time points, six months apart, regarding their child's autism symptoms and adaptive functioning. The longitudinal relationship between adaptive functioning and autism symptoms was investigated using Mixed Linear Model analyses: one assessing the relationship between general symptom levels and adaptive functioning, and another examining the associations between symptom frequency and impact with adaptive functioning. We conducted Pearson correlation tests at both time points to assess the associations between symptom sub-domains and adaptive functioning. RESULTS: Findings showed that higher autism symptoms associated with lower adaptive behavior skills, and that this association remained stable over time. Autism impact scores did not significantly relate to adaptive skills, as opposed to frequency scores. Associations between adaptive functioning and autism symptom sub-domains strengthened over time. CONCLUSION: These findings suggest that adaptive functioning is associated with parent-report autism symptomatology, and that this association changes and, on average, becomes stronger over time. Findings may indicate that frequency and impact of symptoms have differential roles in the development of adaptive skills and are worthy of further exploration.

The Pediatric Autism Research Cohort (PARC) Study: protocol for a patient-oriented prospective study examining trajectories of functioning in children with autism.

INTRODUCTION: The developmentally variable nature of autism poses challenges in providing timely services tailored to a child's needs. Despite a recent focus on longitudinal research, priority-setting initiatives with stakeholders highlighted the importance of studying a child's day-to-day functioning and social determinants of health to inform clinical care. To address this, we are conducting a pragmatic multi-site, patient-oriented longitudinal investigation: the Pediatric Autism Research Cohort (PARC) Study. In young children (<7 years of age) newly diagnosed with autism, we will: (1) examine variability in trajectories of adaptive functioning from the point of diagnosis into transition to school; and (2) identify factors associated with trajectories of adaptive functioning. METHODS AND ANALYSIS: We aim to recruit 1300 children under 7 years of age with a recent (within 12 months) diagnosis of autism from seven sites: six in Canada; one in Israel. Participants will be followed prospectively from diagnosis to age 8 years, with assessments at 6-month intervals. Parents/caregivers will complete questionnaires administered via a customized online research portal. Following each assessment timepoint, families will receive a research summary report describing their child's progress on adaptive functioning and related domains. Analysis of the longitudinal data will map trajectories and examine child, family and service characteristics associated with chronogeneity (interindividual and intraindividual heterogeneity over time) and possible trajectory turning points around sensitive periods like the transition to school. ETHICS AND DISSEMINATION: Ethics approvals have been received by all sites. All parents/respondents will provide informed consent when enrolling in the study. Using an integrated knowledge translation approach, where stakeholders are directly engaged in the research process, the PARC Study will identify factors associated with trajectories of functioning in children with autism. Resulting evidence will be shared with government policy makers to inform provincial and national programs. Findings will be disseminated at conferences and published in peer-reviewed journals.

CHAMPP4KIDS: Mixed methods study protocol to evaluate acceptability and feasibility of Parenting for Lifelong Health materials in a Canadian context.

BACKGROUND: Parents and caregivers play a key role in children's healthy development and well-being. Traditional parenting interventions promote positive parenting practices and are key to preventing child maltreatment. However, numerous barriers can limit access to programs, barriers which were further exacerbated by the COVID-19 pandemic. The Parenting for Lifelong Health group developed mass media and public health communication materials to promote positive caregiving behaviours on a population level. The Champions of Positive Parenting 4 Kids (CHAMPP4KIDS) study will examine the acceptability and feasibility of these materials for service providers and caregivers of children aged 2-6 years in Ontario, Canada. METHODS: This study will use a convergent mixed-methods design. Consenting service providers (n = 200) and caregivers (n = 100) will complete a quantitative survey to rate, rank and give feedback on Parenting for Lifelong Health tip sheets and social media ads. Caregivers will also complete self-report scales measuring depression and anxiety. We will hold focus group discussions with a sub-sample of surveyed providers (n = 40) and caregivers (n = 25). An adapted Trials of Improved Practices methodology will explore caregiver perspectives after implementing the tip sheets. Primary quantitative outcomes will be descriptive statistics of rankings, Likert Scale scores and descriptive analysis of caregiver depression and anxiety. Qualitative data will be analyzed using Rapid Qualitative Inquiry and triangulated through a convergent coding matrix. DISCUSSION: The Parenting for Lifelong Health COVID-19 parenting materials offer succinct, engaging parenting information in a mass media format that addresses some challenges associated with accessing in-person programming. The CHAMPP4KIDS study will provide mixed methods insights on the materials' acceptability and feasibility from different groups in a Canadian context, with a focus on marginalized families. The use of Trials of Improved Practices methodology could prove a useful tool for participant-led adaptation of existing parenting, early childhood development and other health intervention materials.

Protocol for the COVID-19 Wellbeing and Stress Study: a longitudinal study of parent distress, biological stress and child biopsychosocial development during the pandemic and beyond.

INTRODUCTION: The COVID-19 pandemic has had a unique impact on the mental health and well-being of pregnant individuals and parents of young children. However, the impact of COVID-19-related stress during pregnancy on early child biopsychosocial development, remains unclear. The COVID-19 Wellbeing and Stress Study will: (1) investigate the impact of different forms of prenatal stress experienced during the pandemic (including objective hardship, perceived psychological distress and biological stress) on child stress biology, (2) examine the association between child stress biology and child developmental outcomes, (3) determine whether child stress biology acts as a mechanism linking prenatal stress to adverse child developmental outcomes and (4) assess whether gestational age at the onset of the COVID-19 pandemic or child sex, moderate these associations. METHODS AND ANALYSES: The COVID-19 Wellbeing and Stress Study is a prospective longitudinal study, consisting of six time points, spanning from pregnancy to 3 years postpartum. The study began in June 2020, consisting of 304 pregnant people from Ontario, Canada. This multimethod study is composed of questionnaires, biological samples, behavioural observations and developmental assessments ETHICS AND DISSEMINATION: This study was approved by the Hamilton Integrated Research Ethics Board (#11034) and the Mount Saint Vincent University Research Ethics Board (#2020-187, #2021-075, #2022-008). Findings will be disseminated through peer-reviewed presentations and publications, community presentations, and electronic forums (social media, newsletters and website postings).

The membrane androgen receptor ZIP9 (SCL39A9) maintains ovarian homeostasis by mediating post-ovulatory follicle breakdown in zebrafish.

ZIP9 was recently characterized as a membrane androgen receptor in Atlantic croaker granulosa/theca (G/T) cells where it mediates androgen-induced apoptosis in vitro, but the physiological significance of this action has remained unclear. In the current study, we utilized ZIP9 knockout (zip9-/-) zebrafish to investigate the role of ZIP9-mediated androgen-induced G/T cell apoptosis in vivo. We first confirmed ZIP9 mediates apoptosis of zebrafish G/T cells in vitro. Testosterone increased apoptosis, intracellular free zinc, and expression of pro-apoptotic members bax and p53 in wildtype and zip9+/+ zebrafish G/T cells, but not in ZIP9 knockout and knockdown cell models. We hypothesized ZIP9-mediated G/T cell apoptosis may be involved in post-ovulatory follicle (POF) breakdown in vivo. Post ovulation, zip9, bax, and p53 were upregulated in zip9+/+ but not in zip9-/- ovaries. Immunoreactivity of cleaved caspase 3 was also higher in POFs from zip9+/+ ovaries compared to zip9-/-, and POF breakdown was significantly delayed in zip9-/- fish compared to zip9+/+ counterparts. To determine the detrimental consequences of delayed POF breakdown in the zip9-/- model, fish were challenged with repeated ovulation induction. After the challenge, zip9-/- fish exhibited abnormal ovarian lesions that contained debris consistent with atretic or necrotic cellular material. However, no abnormalities were observed in zip9+/+ fish ovaries, indicating that the abnormal phenotype is due to the loss of ZIP9. This study demonstrates an important role for ZIP9 in mediating POF breakdown and maintaining tissue remodeling and homeostasis in the teleost ovary and indicates a role for the ZIP9-mediated androgen-induced apoptotic response in vivo.

Variable patterns of daily activity participation across settings in autistic youth: A latent profile transition analysis.

LAY ABSTRACT: What people do or engage in in their daily lives, or daily life participation, is often linked to their state of being happy and healthy, as well as potential for living independently. To date, little research has been conducted on daily activity participation by autistic youth at home, at school or in the community. Learning more about individual differences in participation levels and what might influence them can help to create custom supports for autistic youth and their families. In this study, 158 caregivers of autistic youth were asked how often their children took part in 25 common activities at two assessments, about one year apart. The analysis showed three profiles for each of the home and school settings and two profiles for the community setting. These profiles reflected distinct patterns in how often autistic youth took part in various daily activities, particularly in doing homework, school club activities and community gatherings. Most autistic youth were in profiles marked by often taking part at home but less often at school and in the community, and about three-fourths of them tended to stay in the same profile over time. Autistic youth with limited participation profiles were more likely to have lower scores on measures of cognitive ability and daily life skills and more challenging behaviour, and faced more barriers in their environment. These findings show how important it is to think about each autistic person's strengths and weaknesses, and changing needs, to better support their daily life participation.

Positive Parenting and Early Childhood Cognition: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

This review examines the effectiveness of positive parenting interventions aimed at improving sensitivity, responsiveness, and/or non-harsh discipline on children's early cognitive skills, in four meta-analyses addressing general mental abilities, language, executive functioning, and pre-academics. The objectives are to assess the magnitude of intervention effectiveness and identify moderators of effectiveness. We include randomized controlled trials of interventions targeting positive parenting to improve cognition in children < 6 years. Studies that include children with neurodevelopmental and/or hearing disorders were excluded. MEDLINE, PsycINFO, ERIC, and ProQuest Dissertations & Theses (October 2021) and citation chaining identified relevant records. Five reviewers completed screening/assessments, extraction, and risk of bias. Pooled analysis in Comprehensive Meta-Analysis (Version 3) used random effects modeling, with moderation via Q-statistics and meta-regression. Positive parenting interventions led to significant improvements in mental abilities (g = 0.46, N = 5746; k = 33) and language (g = 0.25, N = 6428; k = 30). Effect sizes were smaller and nonsignificant for executive functioning (g = 0.07, N = 3628; k = 14) and pre-academics (g = 0.16, N = 2365; k = 7). Robust moderators emerged for language and cognition. For cognition, studies with higher risk of bias scores yielded larger intervention effects. For language, studies with younger children had larger effect sizes. Studies mitigated selection and detection bias, though greater transparency of reporting is needed. Interventions that promote parental sensitivity, responsiveness, and non-harsh discipline improve early mental abilities and language. Studies examining executive functioning and pre-academics are needed to examine moderators of intervention effectiveness. Trial registration Systematic review PROSPERO registration. CRD42020222143.

Longitudinal associations between early childhood irritability and adolescent depression symptoms in autistic children are mediated by peer relationships but not educational engagement.

In the general population, irritability is associated with later depression. Despite irritability being more prevalent in autistic children, the long-term sequelae are not well explored. We tested whether irritability in early childhood predicted depression symptoms in autistic adolescents, and whether associations could be explained by difficulties in peer relationships and lower educational engagement. Analyses tested the longitudinal associations between early childhood irritability (ages 3-5) and adolescent depression symptoms (age 14) in a prospective inception cohort of autistic children (N = 390), followed from early in development shortly after they received a clinical diagnosis. Mediators were measured in mid-childhood (age 10) by a combination of measures, from which latent factors for peer relationships and educational engagement were estimated. Results showed early childhood irritability was positively associated with adolescent depression symptoms, and this association remained when adjusting for baseline depression. A significant indirect pathway through peer relationships was found, which accounted for around 13% of the association between early childhood irritability and adolescent depression, suggesting peer problems may partially mediate the association between irritability and later depression. No mediation effects were found for education engagement. Results highlight the importance of early screening and intervention for co-occurring irritability and peer problems in young autistic children.

Population-Based Teacher-Rated Assessment of Anxiety Among Canadian Kindergarten Children.

Despite anxiety being a prevalent mental health problem in children, little data exist on the pervasiveness and levels of anxiety symptoms in kindergarteners. Data from the Early Development Instrument, a teacher-completed, population-level measure of child development, were collected across Canada from 2004 to 2015. The final analytic sample consisted of 974,319 children of whom 2.6% were classified as "highly anxious". Compared to children who exhibited "few to none" anxious behaviors, highly anxious children were more likely to be male, have English/French as a second language, and have a special needs designation. Furthermore, compared with their less anxious peers, highly anxious children had between 3.5 and 6.1 higher odds of scoring below the 10th percentile cut-off in physical, social, language/cognitive and communication domains. Our findings suggest that anxious behaviors are related to children's overall health and illustrate the consistency and extensiveness of anxiety at a very young age among Canadian children.

Examining clinical characteristics of autism and links with parent perceptions of sibling relationship quality.

LAY ABSTRACT: Sibling relationship quality is important for the well-being of children on the autism spectrum and their siblings. Little is known, however, about how varied behavior and abilities of children on the autism spectrum may be associated with parent perceptions of domains of sibling relationship quality. We drew data from a subsample of 119 children on the autism spectrum (ages 10-11 years), participating in an ongoing longitudinal study. We looked at how three clinical characteristics (autism symptoms, behavioral difficulties, and communication ability) related to four areas of parent-reported sibling relationship quality (warmth/closeness, conflict, relative status/power, and rivalry). We also examined whether the strength of the association between behavioral difficulties and parent-reported sibling relationship quality was influenced by communication ability. We found that more severe autism symptoms were associated with less conflict and rivalry, and higher communication ability was associated with more relative status/power. We also found that children on the autism spectrum with more behavioral difficulties and weaker communication ability had less warmth/closeness in their sibling relationships. Our findings highlight that it is important to consider autism symptoms, behavioral difficulties, and communication ability, as well as multiple domains of relationship quality, to better understand how parents view the relationships between autistic children and their siblings. Clinically, methods for improving sibling relationships may include teaching conflict resolution strategies to children on the autism spectrum with stronger communication abilities and their siblings, and fostering sibling connection for those with lower communication abilities.

Measuring the association between behavioural services and outcomes in young children with autism spectrum disorder.

BACKGROUND: Children with autism spectrum disorder (ASD) receive a wide range of services. AIMS: To examine the association between behavioural services received by children with ASD between ages 2 and 5 years and outcomes during primary school years. METHODS: A total of 414 preschool-aged children diagnosed with ASD were enrolled at five Canadian sites and were assessed within four months of diagnosis (T1), six months later (T2), 12 months later (T3), at school entry (T4), and then annually (T5-T8) to 11 years of age. The association between the receipt of behavioural services during T1 to T3 and T8 outcomes related to adaptive behaviour and behavioural problems was modelled using linear regressions adjusted for immigrant status, family income, child's age at diagnosis, site, sex assigned at birth, and baseline (T1) outcome. RESULTS: Children who received behavioural services during at least one time period from T1 to T3 did not have significantly different outcomes at T8 than children who did not receive any behavioural services. IMPLICATIONS: Pre-school use of behavioural services was not found to affect outcomes during later childhood. Numerous challenges accompany studies of the association between pre-school service use and later outcomes in a heterogeneous ASD sample. Recommendations for study design are provided.

Disentangling global and domain-level adaptive behavior trajectories among children with autism spectrum disorder.

BACKGROUND: Heterogeneity in adaptive behavior abilities among people with autism spectrum disorder (ASD) is expressed not only as uneven levels of impairment across domains, but also in the developmental trajectories of adaptive skills. We studied the question of whether, after accounting for global adaptive behavior development, we find evidence of heterogeneity in the trajectories of specific domains of adaptive behavior. METHODS: A sample of 504 children with ASD was obtained by combining data from two independent natural history studies conducted in North America. We used a factor of curves model to explain growth between 36 and 138 months in Vineland Adaptive Behavior Scales, Second Edition (VABS) age equivalents as a function of domain-specific and global growth processes. RESULTS: The domain-specific trajectories in all three domains (Communication, Daily Living Skills, and Socialization) reflected impairment relative to age expectations as well as slower-than-expected growth with age, and the parameters of these trajectories were moderately-to-strongly correlated across domains. The global adaptive behavior trajectory had an initial (36-41 months of age) developmental level of about 22 age-equivalent months, and eventually slowed after initially increasing by about 6 months each year. The global trajectory accounted for the majority of variance in the domain-level processes; however, additional variance remained (14%-38%) in the domain-level intercepts, slopes, and quadratic processes. CONCLUSIONS: These results extend existing theoretical and empirical support for the hierarchical structure of adaptive behavior to include its development over time in clinical samples of children with ASD. A latent global trajectory may be sufficient to describe the growth of adaptive behavior in children with ASD; however, the remaining domain-specific variability after accounting for global adaptive behavior development allows for the possibility that differential effects of intervention on specific domains may be possible and detectable.

Developmental cascades between insistence on sameness behaviour and anxiety symptoms in autism spectrum disorder.

Autistic children experience high rates of anxiety. Insistence on sameness behaviour (IS) is a core feature of autism that appears correlated with anxiety severity. The objective of this study was to examine the longitudinal relations between anxiety and IS in autistic children using a developmental cascade model. A longitudinal cohort of 421 autistic children was followed between 4 and 11 years of age. Anxiety was quantified using items from the Anxiety Problems subscale of the Child Behavior Checklist; sameness behaviours were measured using the Repetitive Behavior Scale-Revised, Ritualistic/sameness subscale (both parent-report measures). Structural equation modelling was used to examine the longitudinal and directional associations between anxiety and IS at four time-points, through cross-lagged panel models (CLPM) with and without a random-intercepts component (RI-CLPM). Both the CLPM and the RI-CLPM had good fit. Significant directional associations were detected whereby elevated or increasing IS preceded elevated or increasing anxiety symptoms 1-2 years later, respectively. Stable baseline tendencies towards anxiety and IS as between-person traits (intercepts) were strongly associated (standardized estimate = 0.69, p < 0.001). The magnitude of the cross-sectional associations between anxiety and IS appeared to lessen with age. IS and anxiety symptoms in autism are closely related. They appear to be shared traits that mirror each other particularly in younger children. Increasing IS may be a sign of emerging future anxiety. Interventions that target IS to reduce or prevent anxiety amongst school-aged autistic children merit further study.

The Family-Check-Up® Autism Implementation Research (FAIR) Study: protocol for a study evaluating the effectiveness and implementation of a family-centered intervention within a Canadian autism service setting.

Introduction: Prevalence rates of emotional and behavior problems (EBP) in autistic children and youth are high (40-70%), and often cause severe and chronic impairment. Furthermore, autistic children are also more likely to experience family "social-ecological" adversity compared to neurotypically developing peers, including social isolation, child maltreatment, caregiver mental illness, and socioeconomic risk. These family stressors increase the risk of co-occurring EBP among autistic children and can often impede access to evidence-based care, thus amplifying long-term health inequities for autistic children and their caregivers. In the current autism services landscape, there are few scalable, evidence-based programs that adequately address these needs. The Family Check-Up (FCU®) is a brief, strength-based, and tailored family-centered intervention that supports positive parenting and explicitly assesses the social determinants of child and family mental health within an ecological framework. Studies have demonstrated long-term positive child and caregiver outcomes in other populations, but the FCU® has not been evaluated in families of autistic children and youth. Therefore, we aimed to evaluate FCU® implementation within an established, publicly funded Autism Program in Ontario, Canada, with delivery by autism therapists, to demonstrate sustainable effectiveness within real-world settings. Methods: In this study, we outline the protocol for a hybrid implementation-effectiveness approach with two key components: (1) A parallel-arm randomized controlled trial of N = 80 autistic children/youth (ages 6-17 years) and high levels of EBP and their caregivers. Primary and secondary outcomes include child EBP, and caregiver well-being and parenting. (2) A mixed methods implementation study, to describe facilitators and barriers to implementation of the FCU® within an autism service setting. Discussion: Scalable, ecologically focused family-centered interventions offer promise as key components of a public health framework aimed at reducing mental health inequities among autistic children, youth, and their caregivers. Results of this study will inform further program refinement and scale-up.

Educators Describe the "Best Things" About Students with Autism at School.

This study examined educators' descriptions of the positive character traits of students with autism spectrum disorder at ages 7-8 and 10-11, using an adapted version of the Values in Action (VIA) Classification of Strengths. The most commonly endorsed strengths at both age intervals were kindness, specific skills, self-regulation, and perseverance. Higher scores for challenging behavior were associated with a lower likelihood of endorsement for Happiness and Courage traits. Higher autism symptom severity scores were associated with a lower likelihood of endorsement for Courage traits. Few significant differences were found for endorsement of trait categories by students' educational placement or the type of curriculum they received. Results may have implications for student-teacher relationships, educational assessments, and school-based interventions that emphasize strengths and resilience.

Exposure to family stressful life events in autistic children: Longitudinal associations with mental health and the moderating role of cognitive flexibility.

LAY ABSTRACT: Experiencing stressful life events, such as a parent having had serious illness, parental divorce, bullying and victimization, is known to increase risk for mental health difficulties in neurotypical children. However, few studies have looked at whether stressful life events have a similar impact in autistic youth and if any individual characteristics may moderate the impact of said life events. In this study, we tested whether in autistic children aged 7-11 years, exposure to family-level stressful life events predicted later mental health symptoms (and vice versa). We also tested whether associations between stressful life events and mental health symptoms differed depending on the child's level of cognitive flexibility. We found stressful life events only predicted internalizing symptoms (such as anxiety and depression) in children with clinically significant difficulties in cognitive flexibility (as rated by their parents). Mental health symptoms did not predict future exposure to stressful life events. Results suggest that information about exposure to stressful life events and cognitive inflexibility may be helpful in identifying autistic children who may be at risk of developing anxiety and depression symptoms.

Mental Health Help-Seeking in Parents and Trajectories of Depressive and Anxiety Symptoms: Lessons Learned From the Ontario Parent Survey During the COVID-19 Pandemic.

Tracking parents' mental health symptoms and understanding barriers to seeking professional help are critical for determining policies and services to support families' well-being. The COVID-19 pandemic has posed enormous challenges to parents' mental health and the access to professional help, and there are important public health lessons that must be learned from the past 2 years' experiences to inform future mental health responses to social- and family-level stressful events. This study examines the trajectories of parents' depressive and anxiety symptoms over a year during the pandemic as related to their mental health help-seeking. Data were collected from a sample of parents residing in Ontario, Canada at baseline (May-June, 2020; Wave 1) and again 1 year later (Wave 2; referred to as W1 and W2 below). Parents (n = 2,439; M age = 39.47, SD = 6.65; 95.0% females) reported their depressive and anxiety symptoms at both waves. Mental health help-seeking, including self-reported contact with professional help and perceived unmet mental health needs, was measured at W2. Parents were classified into four groups by mental health help-seeking. Inconsistent seekers and non-seeking needers, both reporting perceived unmet needs for professional help, showed greater increases in depressive and anxiety symptoms, whereas parents with no need or needs met showed smaller increases in depressive symptoms and decreases in anxiety symptoms. Belief in self-reliance and time constraints were the leading reasons for not seeking help. These findings suggest that over a year into the pandemic, parents with perceived unmet mental health needs were at greater risk for worsening depressive and anxiety symptoms. Recognizing the demands for mental health services when families experience chronic stressors and targeting the identified barriers may promote family well-being during and beyond this pandemic.

Prenatal distress, access to services, and birth outcomes during the COVID-19 pandemic: Findings from a longitudinal study.

BACKGROUND/AIMS: During the COVID-19 pandemic, pregnant people have experienced disruptions to prenatal care, as well elevated rates of mental health problems and distress. The current longitudinal study aims to understand how different forms of prenatal distress (mental health problems, COVID-19 stressful experiences, and access to prenatal services) impact infant birth outcomes during the pandemic. METHODS: Participants were 265 pregnant individuals from Ontario, Canada. Maternal depression, pregnancy-related anxiety, COVID-related stressors (i.e., financial difficulties, social isolation), and disruptions to prenatal and health services were assessed during pregnancy. Delivery experiences and birth outcomes were assessed in the early postpartum period. Associations between pregnancy stressors and birth outcomes were assessed using path analyses. RESULTS: Participants reported experiencing substantial changes to their prenatal care due to COVID-19; 23.0 % had prenatal appointments cancelled, 47.9 % had difficulty accessing prenatal classes, and 60.8 % reported changes to their birth plans. Results of path analyses showed a unique effect of pregnancy-related anxiety during the pandemic on lower birth weight, younger gestational age at birth, and more infant birth problems. Further, multi-group path analysis revealed these effects were more pronounced in male infants. CONCLUSIONS: Findings demonstrate that pregnant individuals in Ontario, Canada have experienced considerable disruptions to services during pregnancy. In addition, pregnancy-related anxiety was uniquely linked to elevated risk for adverse birth outcomes, which more heavily impacted male infants. These findings underscore the need for additional mental health support and access to services for pregnant people and their infants, to reduce long-term adverse maternal and fetal health outcomes.

Discovery of V-0219: A Small-Molecule Positive Allosteric Modulator of the Glucagon-Like Peptide-1 Receptor toward Oral Treatment for "Diabesity".

Peptidic agonists of the glucagon-like peptide-1 receptor (GLP-1R) have gained a prominent role in the therapy of type-2 diabetes and are being considered for reducing food intake in obesity. Potential advantages of small molecules acting as positive allosteric modulators (PAMs) of GLP-1R, including oral administration and reduced unwanted effects, could improve the utility of this class of drugs. Here, we describe the discovery of compound 9 (4-{[1-({3-[4-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5-yl}methyl)piperidin-3-yl]methyl}morpholine, V-0219) that exhibits enhanced efficacy of GLP-1R stimulation, subnanomolar potency in the potentiation of insulin secretion, and no significant off-target activities. The identified GLP-1R PAM shows a remarkable in vivo activity, reducing food intake and improving glucose handling in normal and diabetic rodents. Enantioselective synthesis revealed oral efficacy for (S)-9 in animal models. Compound 9 behavior bolsters the interest of a small-molecule PAM of GLP-1R as a promising therapeutic approach for the increasingly prevalent obesity-associated diabetes.

Predictors of language regression and its association with subsequent communication development in children with autism.

BACKGROUND: Language regression, broadly defined as the loss of acquired language skills in early childhood, is a distinctive feature of autism. Little is known about the factors underlying regression or the prognosis of children who exhibit regression. We examine potential predictors of language regression and test its association with language development in a prospective longitudinal sample of children with autism spectrum disorder (ASD) from diagnosis to age 10 years. METHODS: We analysed data from Pathways in ASD, a prospective longitudinal study of 421 children enrolled around the time of an autism diagnosis between 2 and 5 years. Autism Diagnostic Interview-Revised data were available for 408 children, of whom 90 (22%) were classified as having language regression. RESULTS: Demographic and other health factors including caregiver education, family income, child sex, reported seizures, and age of enrolment did not differ between children with and without language regression. Children with language regression walked earlier and attained first words sooner than those without regression. However, both groups attained phrase speech at comparable ages. Those with regression exhibited greater delays in expressive and receptive communication over the follow-up period, although this effect was attenuated when accounting for baseline differences in motor and cognitive ability. Overall, those with language regression continued to exhibit expressive but not receptive communication delay compared to those without regression. Communication trajectories were heterogeneous to age 10 years, irrespective of regression status. CONCLUSIONS: Although language regression can be alarming, our findings confirm that its occurrence does not necessarily foreshadow worse developmental outcomes relative to those without regression. Although a discrepancy in age-equivalent communication skills may persist, this can be expected to be of less practical importance with rising average levels of skills. Future studies need to account for the significant variability in language trajectories by considering factors beyond developmental regression.