Intellectual Disability

BACKGROUND. The increasing prevalence of autism spectrum disorder (ASD), now at 1 in 36 children, highlights an urgent need for early interventions that are both effective and efficient, given the social and economic impact of the challenges experienced by individuals on the autism spectrum and their families. Several clinical trials have documented the benefits of parent-mediated interventions starting early in life, even before a formal autism diagnosis is established. Symptoms of autism manifest across the lifespan and can be diagnosed as early as 12 months of age. Although parents often identify concerns about their child's development during the first two years of life, the median age of diagnosis in the United States continues to be 49 months. Even following formal diagnosis, services often do not begin for another 9 months. These cumulative waiting times often result in children receiving minimal early intervention prior to school entry. Additionally, health disparities disproportionally affect access to services for families from minoritized and socioeconomically disadvantaged backgrounds. Families who are low-income, have low parental educational attainment, or are from minoritized racial and ethnic backgrounds not only experience delays in receiving diagnoses, but are also less likely to receive high-quality services following diagnosis. These inequities have been exacerbated by the COVID-19 pandemic. Barriers to accessing diagnostic services limit the opportunity to receive autism-specific interventions at the age for which they are shown to be maximally beneficial. Children on the autism spectrum whose needs are not addressed in a timely fashion are at an increased risk of impairments in cognitive, adaptive, and social dimensions of well-being, as well as physical and mental health issues. Further, the 'passive waiting' time in the waitlist is harmful for parental wellbeing and mental health, with research reporting feelings of frustration, worry, and stress in parents experiencing the yearlong 'odyssey' from initial concerns to diagnosis and intervention referral. Importantly, such harmful delays in accessing autism-specific early interventions are potentially avoidable, as many caregivers of children later diagnosed with autism identify concerns about their child's development before her or his second birthday, often as early as 13 months of age. Many difficulties identified by parents during infancy and toddlerhood can be successfully addressed through evidence-based intervention practices. For example, early emerging differences in verbal and nonverbal communication are amenable to improvements through targeted parent-mediated interventions, with benefits documented across multiple dimensions of wellbeing (i.e., adaptive and social-communicative functioning). Despite advances in this area, the potential benefits of early interventions remain largely untapped, as wait times to receive a formal diagnosis of autism are such a significant barrier that they have been referred to as a "crisis" in the field, with parents reporting an average wait time of 1.2 years in the US. The American Academy of Pediatrics recommends simultaneous referrals for clinical diagnostic evaluation and early intervention for young children with suspected autism - however, most children without an autism diagnosis receive low-intensity, generic early interventions rather than autism-specific early intervention programs that rely on evidence-based practices. Accordingly, key stakeholders, including caregivers and providers, have voiced the need for facilitating earlier access to intervention options to counteract the harmful impact of the waitlist crisis. Accordingly, the current project focuses on circumventing the roadblock of delayed access to diagnosis and intervention by empowering caregivers to address their children's needs while they are waiting to be seen for a formal diagnosis. One viable option to accomplish this goal is the delivery of parent-mediated intervention programs that do not require a previous diagnosis or enrollment in formal early intervention services. In particular, recent research has shown the promise of self-directed online intervention programs for caregivers of autistic children. These programs involve independent access to online resources that caregivers can utilize at their own pace and individualize to their own children by selecting content relevant to the specific difficulties experienced by their children. Implementation of the intervention strategies might be exclusively self-directed (i.e., parents deliver the intervention strategy without any assistance from a provider) or based on a hybrid format, whereby a clinician is available to provide guidance and clarification related to the program's content, although without explicit coaching and feedback. Across formats, self-directed programs do not rely on diagnostic and intervention services for eligibility, insurance and billing purposes, providing a potential avenue for circumventing the roadblock of delayed access to diagnosis and intervention. Research has documented that despite not being coached by experienced clinicians, caregivers have expressed a high degree of acceptability and satisfaction with the self-directed format, demonstrated fidelity of implementation, experienced gains in knowledge and their use of the intervention strategies was associated with child improvements following parent completion of programs. However, substantial variation in outcomes in response to different self-directed programs was documented, and existing research only focuses on children who were already diagnosed. Therefore, the potential impact of a self-directed intervention program during families' enrolment in waitlists for a diagnostic evaluation remains unexplored. Against this background, our project focuses the implementation and evaluation of the "Online Parent Training in Early Behavioral Intervention" (OPT-In-Early), a self-directed online resource for caregivers of children with autism or high likelihood of autism which will be made available during their enrolment in waitlists for a diagnostic evaluation. Key features of Opt-In-Early include: (a) a comprehensive scope (i.e., multiple domains are addressed), (b) the use of a Naturalistic Developmental Behavioral Intervention approach, i.e., evidence-supported strategies that blend behavioral and developmental components to address the needs of autistic children and their families, (c) a combination of required and optional modules, so that caregivers can learn autism-specific strategies and focus on areas most relevant to their specific child's needs, and (d) a hybrid format including access to web-based materials designed for self-directed implementation, as well as optional access to remote consultation with a clinician for advice, clarification and support (e.g., selection of appropriate modules). APPROACH. The overarching goal of our project is to evaluate the utility of the OPT-In-Early program for caregivers of toddlers who are on a waitlist for receiving diagnostic services. The OPT-In-Early program centers on the use of naturalistic, developmental, and behavioral principles to increase motivation and engagement, teach skills, and generalize skills across settings. The program emphasizes the importance of utilizing the parent-child relationship, the child's interests, and daily routines to facilitate skill acquisition, and to create developmentally appropriate learning experiences, to value small gains, and to use evidence-based applied behavior analytic principles including task analysis, prompting and prompt fading, and contingent reinforcement. Optional modules focus on specific needs, such as toilet training and picky eating. To evaluate whether the OPT-In-Early program is an acceptable and effective tool for caregivers who are on a waitlist for receiving diagnostic services, the following specific aims will be addressed: 1. Comparing outcomes for 120 toddlers aged 16-48 months whose caregivers are on a waitlist to receive a formal autism diagnosis, randomly assigned to receive either OPT-In-Early or no intervention for six months period. The investigators hypothesize that children randomized to the OPT-In-Early condition will have superior gains. 2. Examining feasibility and acceptability of the intervention (both hypothesized to be high). 3. As an exploratory aim, the investigators will examine theoretically- and empirically- motivated factors associated with intervention engagement and child outcomes. Participants and Setting. Participants will be 120 toddler-caregiver dyads (with each dyad including one toddler and one caregiver) who are on a waitlist to receive a formal diagnostic evaluation due to autism concerns identified by either parents or professionals. As the study does not involve in-person contact between investigators and participants, participants will be recruited across any geographical area. Inclusion criteria include (a) age between 16-48 months, (b) parental consent, (c) being on a waitlist to receive a formal diagnostic evaluation at the time of parent consent due to autism concerns, (d) parents speak English, (e) an initial score of 8 or greater or Follow-Up score of 2 or greater on the Modified Checklist for Autism in Toddlers, Revised, with Follow-Up (M-CHAT-R/F) as an indication of autism likelihood. Exclusion criteria include (a) having already received a formal diagnosis of autism, (b) enrolment in early intervention programs delivering more than 5 h per week of evidence-based autism-specific interventions at the time of consent, (c) child has a gestational age less than 36 weeks associated with a birth weight less than 2500 g, (d) the child is not yet walking, or has severe hearing and/or vision impairment that is uncorrected with aids, or known neurological disorder or genetic syndrome (e.g., Down syndrome). Research Design. Our aims will be addressed using an intent-to-treat randomized controlled trial, with participants randomized to either the OPT-In-Early intervention or a waitlist control condition, stratified by age, language level and parental education. Data will be collected from each family prior to random assignment (baseline) and following completion of the 6-month trial period (or earlier for families electing to discontinuing their participation from the trial). The investigators will use REDCap, a HIPAA-compliant data management software to store data. To ensure data accuracy, data will be doubled entered by independent research team members, when not collected directly via REDCap. Study flow. The study flow is articulated in the 5 steps. In step 1 participants will be recruited through our extensive network of hospitals and clinical centers who provide diagnostic evaluations for autism, who will show study flyers in their waiting rooms and websites and inform families enrolled in their waitlist about the opportunity to participate. Interested caregivers will complete a phone screen to learn more about the study and to confirm eligibility. In step 2 caregivers who are invited and consented to the RCT will complete baseline assessments prior to randomization through an online procedure that includes completing online forms and phone interviews conducted by a clinician blind to group allocation and study hypotheses. Assessment measures will include standardized measures indexing broad adaptive functioning and severity of autism symptoms, as well as an idiographic measure capturing goals specific for each dyad. During the baseline assessment, a detailed description of the specific goals that each participant family wants to achieve with their child (e.g., addressing difficulties with verbal communication, toilet training, food refusal) will be obtained using Goal Attainment Scaling procedures. As part of the process, parents will be also asked to provide 3 to 5 "baseline goal" videos of 5- to 20-min in length illustrating the current level of performance in the skill that they are planning to address (one video for each goal) - such as, for example, a video illustrating lack of responsiveness to the child's name being called, a second video illustrating food refusal during lunch, and a third video illustrating the child having a tantrum when asked to brush her teeth. The study coordinator will provide guidance on the videos (e.g., duration, camera angle) to ensure consistency across participants. These videos will be used for later coding of change occurring from baseline to post-intervention. In step 3 each child-parent dyad will be randomly assigned to either the OPT-In-Early condition or the waitlist condition using the online randomization program randomize.net. Randomization will be concealed from clinicians assessing outcomes and stratified by child age (older than vs. equal to or younger than 24 months) language level (expressive language age equivalence score on the Vineland older than vs. equal to or younger than 18 months, reflecting benchmarks of pre-verbal vs. verbal functioning) and parental education (dichotomized as "some college or less" vs "bachelor's degree or more"), based on the literature suggesting that these factors are associated with response to early intervention. In step 4, child-parent dyads randomly assigned to the OPT-In-Early condition will be granted access to the online password-protected OPT-In-Early website for up to 6 months, and provided guidance on the selection of modules within OPT-In-Early that are relevant to the goals caregivers indicated as their priorities during the baseline assessment. The OPT-In-Early program includes 14 modules (6 mandatory, 8 optional) comprising text and video demonstrations to teach caregivers effective methods for improving their children's language, social, and adaptive skills (e.g., using utensils, toilet training), and reducing their children's disruptive behavior. Parents are taught how to facilitate joint attention, imitation, pretend play, language, sharing, emotional engagement, social play, and self-help skills such as feeding and dressing in their child using behavioral principles (e.g. prompting, shaping and fading) during play and naturalistic daily routines. The optional modules cover such topics as picky eating and toilet training. Parents in the OPT-In-Early condition will be also offered the option to schedule brief (i.e.,15-30 min) support calls with a clinician with a BCBA credential and expertise in each module's content (e.g., PECS, behavior assessment) for the duration of the 6-month trial, with a limit of three calls per week. These optional support calls are designed to provide parents with clarification and guidance on how to navigate the website materials, including selection of the appropriate modules. However, no instruction or feedback on how the parents are implementing the strategies (i.e., fidelity monitoring) will be provided, consistent with the self-directed nature of the intervention. Child-parent dyads randomly assigned to the waitlist group will receive access to the OPT-In-Early website immediately after their second (i.e., "post-intervention") assessment. Therefore, all participants will be given access to the intervention, with the only difference being that access will be given after a 6-month wait time for dyads assigned to the waitlist group (although intervention outcomes will not be assessed for those assigned to the waitlist group after receiving OPT-In). In step 5, post-intervention outcomes will be assessed by clinicians who will be blind to group assignment after 6 months from the baseline assessments. A group comparison approach was favored over a cross-over design due to the risk of carry-over effects. The post- intervention evaluation will include the same measures administered at baseline. MEASURES The Modified Checklist for Autism in Toddlers, Revised with Follow-Up (M-CHAT-R/F) is a 20-item (yes/no) parent-report, autism-specific screener; although initially validated for ages 16-30m, evidence supports use to 48 m. The M-CHAT-R/F provides scores that are indicative of "low likelihood" (\< 3), "high likelihood" (≥8), or "moderate likelihood" (3-7) for autism. Moderate likelihood scores trigger the structured Follow-Up questions, with two at-risk items on the follow-up signaling the need for evaluation referral. Initial M-CHAT-R items requires 5 min to complete and follow-up questions require an additional 10 min. The M-CHAT-R/F will be used to determine eligibility, based on the presence of clinical concerns operationalized as an initial score of 8 or greater or follow-up score of 2 or greater, and to quantify the degree of clinical concerns at baseline. The M-CHAT-R/F will be also used to characterize participants at baseline and will not be repeated at post-intervention as it is not used as an outcome measure. The Goal Attainment Scaling (GAS) will be used as a proximal measure of intervention response, i.e., a measure that captures changes in the specific goals selected for each participant. The GAS is designed to assess an individual's progress on a goal in relation to their baseline performance, and has been successfully utilized to capture proximal response to interventions for individuals on the autism spectrum, particularly for interventions that include different targets for different participants. Stakeholders have increasingly endorsed measurement of goals relevant to the needs of specific individuals within the autism population. Additionally, the GAS was selected to account for the heterogeneity of intervention targets within the OPT-In-Early intervention, whereby selection of modules and targets differ across participants. The GAS includes standardized procedures to generate a common metric of intervention change across participants who have different intervention goals, as articulated below. GAS Baseline assessment and goal setting. For each participant, goals will be developed based on detailed information obtained in a parent interview at the baseline assessment. Each goal is designed to identify an area in which the child is experiencing difficulties (e.g., picky eating, toilet training, self-injurious behavior) that caregivers want to address by teaching specific skills. Caregivers will be encouraged to identify three to five goals that are priorities for their family. The number of goals will vary across participants but is not expected to differ across groups, as goals will be established prior to randomization - however the number of goals targeted for each participant will be considered in the statistical analyses. The stringent standardization criteria detailed in Ruble et al., 2012 will be used to ensure that the goals are unambiguously operationalized and measurable based on: (1) the description of the skill planned to be targeted, (2) the prompt level required by the child for engaging in the targeted skill, and (3) the criterion for success. Caregivers will be asked to provide a set of 5- to 20-min videos (one for each to-be-targeted skill) illustrating their child's current level of performance in the skills that they are planning to target. GAS post-intervention outcome assessment. At the post intervention evaluation, caregivers will be asked to provide a second set of videos, one for each targeted goal, capturing their child's behavior in relation to the same situations/behaviors videotaped at baseline, so that change in relation to the specific goals identified by caregivers can be examined. GAS video collection procedures. For both phases of video collection, caregivers will be provided guidance by study personnel and asked to provide videos that capture the average or typical performance/ behavior currently displayed by their child with reference to the target goal, rather than the child's 'best' behavior. Previous research has shown that intervention participants typically do not use unrepresentative behavior samples in their selections of videos to be submitted for coding of goal attainment. Given the heterogeneity of needs in this population, the investigators expect different caregivers to identify different goals important to them, and to select different OPT-In-Early modules accordingly (e.g., the 'picky eating' module for a child displaying severe food refusal, or the 'toilet training' module for a child experiencing challenges in that domain). Consistent with the idiographic nature of the Goal Attainment Scaling, this will result in specific content and different quantity of videos from each participant. GAS rating. Following previous research, videos will be rated according to the GAS standard procedures whereby goals at baseline are assigned a score of -2 and are then scored on a 5-point scale at post-treatment with positive changes in score from baseline indicating increasingly positive benchmarks of improvement from the baseline to post-intervention. Consistent with previous trials that have used the GAS as an outcome measure, a trained clinician blind to study group and hypotheses will complete the ratings. A coding manual will be developed following Ruble et al., and 20% of videos will be coded by a senior rater (co-I de Marchena) to establish interrater reliability. Participant GAS scores will be averaged across modules to derive an overall score of goal attainment. The following measures will be used as secondary distal outcome measures . The Vineland Scales of Adaptive Behavior-3 (VABS-3), a standardized measure of adaptive functioning, will be administered to all participants at pre- and post-treatment to evaluate change occurring in adaptive behavior across groups. Previous research has documented that this measure has robust psychometric properties, is sensitive to change in response to early intervention, and captures dimensions that are highly valued by stakeholders. Participants' caregivers will also complete the Parenting Stress Index-4, Short-Form (PSI), a standardized measure of parental wellbeing with robust psychometric properties, which has been used in previous research with a similar population. The PSI will be completed at baseline and post-intervention to quantify intervention-related changes in stress. A focus on parenting stress has been endorsed as a top priority by autistic advocates as well as caregivers. The Autism Impact Measure (AIM) is a caregiver-report questionnaire that focuses on the frequency and impact of autism-associated challenges in social interaction, communication, peer interaction as well as repetitive and unusual behaviors. It will be administered at baseline and post-intervention to assess changes in social and communication functioning across groups. The AIM has been shown to have robust psychometric properties. The following measures will be administered to measure intervention feasibility and acceptability. Caregivers of participants randomized to the OPT-In condition will be administered the Acceptability of Intervention Measure and the Feasibility of Intervention Measure. These two standardized measures assess the extent to which end-users believe the intervention was acceptable and could be successfully carried out. To gain insight on feasibility and acceptability issues related to specific modules, participants will be asked to rate the program overall as well as each specific module they utilized. Both scales demonstrated robust discriminant validity and reliability. From onset of intervention until completion of post-intervention evaluation, caregivers will complete a monthly update either electronically or by phone (based on their preferences). Caregivers across conditions will report details about all interventions, services and supports the child is receiving outside the OPT-In-Early program. In addition, caregivers will be asked about any new medical conditions, medical updates, and updates on diagnostic evaluations. These factors will be accounted for in our analyses of the OPT-In-Early program. Finally, Opt-In-Early website usage analytics, including the frequency of access and the specific modules being accessed will be used to provide a measure of the caregivers' engagement with the website content. This information, together with a detailed log on the frequency of optional support calls by participants, will be used to examine the link between usage of the available resources and outcomes. ANALYTIC APPROACH Power analysis. The primary aim is to compare changes in the GAS rating in the OPT-In-Early intervention group to changes in the waitlist group from baseline to after 6 months. Although no research to our knowledge has used the GAS for this population, previous studies that have used the GAS to measure intervention-related change in children on the autism spectrum documented an improvement of 2.1 GAS units with a standard deviation of 0.79. Given our study population and goals, the investigators calculated the sample sizes required to detect change in GAS rating ranging from 0.5 to 2. The power table calculations are based on a mixed-model analysis with 2 observations per participant (e.g., baseline and 6 months). For example, to detect a difference in change in GAS rating in the OPT-In group compared to the waitlist group of 1.0, 76 participants (38 per group) are needed to achieve 80% power with a standard deviation of 1.0, within-subject correlation of 0.01, and significance level (alpha) of 0.025. Given the possibility of 30% dropout, a conservative enrollment plan of 120 participants (60 per group) will be implemented to ensure detection of a minimum difference of 1.0 in GAS rating. Statistical Plan. The investigators will employ best practices for collecting, verifying, managing, and analyzing data. Data will be examined to identify outliers, batch effects, and significant departures from normality for continuous outcomes. Accuracy and explanation for any identified outliers will be explored and dealt with accordingly. Analyses will be performed with and without extreme scores to evaluate their influence on the results. As some attrition is inevitable, baseline data also will be used to assess for non-equivalent attrition between groups and to subsequently support statistically controlling for any bias in attrition. This is consistent with our goal of conducting intent-to-treat analyses for all specific and exploratory aims discussed below. Aim 1 - Primary outcome. The investigators will employ a linear mixed effects modeling approach to compare change (baseline to 6 months) in GAS rating in the OPT-In-Early group to change in the waitlist group. The model will include participant-level random intercepts. Fixed effects in the model will include time (baseline, 6 months), treatment group, and the interaction between time and treatment group. Our model will include age, language level (as measured via the Vineland), M-CHAT-R/F score (as an indicator of clinical severity at baseline), and parental education as fixed effects. Given the RCT study design, the investigators expect balance at baseline on most covariates. However, the investigators will examine balance on other relevant variables - including family size, and other interventions received during the trial - and consider their inclusion in the model accordingly. Using this model, the investigators will estimate mean and 95% confidence intervals for GAS rating at baseline and 6 months. From these means, the investigators will estimate the change in GAS rating in the OPT-In-Early group and the waitlist group. Next, the investigators will contrast those changes with one another to quantify the intervention effect. Secondary distal outcomes. To investigate differences in VABS-3, PSI-4 and AIM score, the investigators will use a similar statistical approach to the one outlined for the primary proximal outcome. Mixed effects models will be used to estimate and contrast outcome changes in the OPT-In-Early group to changes in the waitlist group. Aim 2 - Feasibility and acceptability of the OPT-In-Early content and format will be investigated using the Acceptability of Intervention Measure and Feasibility of Intervention Measure, which use a 5-point Likert scale ranging from 1 (completely disagree) to 5 (completely agree). The investigators will classify participant agreement on feasibility and acceptability using as "in agreement" (average response score of ≥ 4) or "not in agreement" (average response score \< 4). Responses will be summarized using counts and percentages. The investigators will test whether at least 80% of participants are in agreement on each metric using one-sample tests of proportion. Aim 3 - In an exploratory analysis, the investigators will investigate theoretically and empirically motivated factors that may affect intervention engagement and child outcomes. Exploratory outcomes: engagement. Engagement outcomes will include engagement with program content (frequency of module access) and use of support calls (frequency of calls), evaluated separately. Explanatory variables of interest (i.e. putative predictors) will include diagnosis during participation in the trial, chronological age, baseline adaptive behavior and social communication functioning, and demographic factors (including parental education, employment status and family size). The investigators will model the relationship between these explanatory variables and rate of each of the outcomes using Poisson regression models. These models will be used to estimate and contrast the average rate of module access or rate of support calls by predictor group. Exploratory outcomes: child change. The investigators will examine whether putative predictors including program engagement (frequency of module access and frequency of calls), baseline adaptive behavior and social communication, chronological age, M-CHAT-R/F score, presence/absence of a diagnosis of autism during the trial, other interventions received during the trial, and demographic factors will affect change in GAS rating, assessed using a mixed effects modeling approach based on the approach described for Aim 1 (substituting the predictor variables for treatment group). Examining whether accessing and using OPT-In-Early during waitlist time is a viable alternative to the current "first diagnosis then intervention" format (for all children, or for children with specific profiles and needs) can be a critical step toward promoting a more efficient delivery model intervention, bridging the gap between timing of parental concerns and availability of intervention practices designed to target such concerns.

Purpose: Over the last 10 years, recommendations regarding the ideal level of oxygen for resuscitation in preterm infants have changed from 100 percent, down to low levels of oxygen (\<30 percent), up to moderate concentration (30-65 percent). In addition, in 2010, oxygen saturation targeting was recommended as standard of care and this contributed to a change in clinical practice as clinicians were more likely and comfortable to start resuscitation at either 21percent (room air) or titrated levels of oxygen such as 30-40 percent. When the guidelines were again revised in 2015, the International Liaison Committee on Resuscitation (ILCOR) acknowledged that a critical knowledge gap continued to exist for the resuscitation of the preterm infants \<37 weeks, highlighting the need to provide more concrete guidelines. This leaves clinicians in a challenging position. Despite the advances that have been achieved in perinatal and neonatal care, neonates are still vulnerable to the consequences of the oxidative effects from hyperoxia as well as the deleterious effects from hypoxia. A large, multi-centre international trial of sufficient sample size that is powered to look at safety outcomes such as mortality and adverse neurodevelopmental outcomes is required to provide the necessary evidenced to guide clinical practice with confidence. Hypothesis: the null hypothesis for this study is that the incidence of mortality or abnormal neurodevelopmental outcomes at 24+/- 6 months corrected age will be no different by using either higher initial oxygen concentration of 60 percent compared to using lower initial oxygen concentration of 30 percent for resuscitation of preterm infants of 23 0/7- 28 6/7 weeks gestation. Justification: The use of supplementary oxygen may be crucial, but also potentially detrimental to premature infants at birth. High oxygen levels may lead to organ damage through oxidative stress, while low oxygen levels may lead to increased mortality. Excess oxygen exposure during the early post-birth period is associated with many complications and morbidities of preterm birth. Preterm infants have lower levels of anti-oxidant pathways consistent with their expected fetal environment of low oxygen exposure. Excess of oxygen free-radicals in infants intrinsically deficient in enzymatic antioxidants and non-enzymatic antioxidants may contribute to these morbidities. Pulmonary oxygen toxicity, through the generation of reactive oxygen and nitrogen species in excess of antioxidant defenses, is believed to be a major contributor to the development of bronchopulmonary dysplasia (BPD). Using lower oxygen concentrations at birth results in decreased oxidative stress markers and a decrease risk of developing BPD compared to higher oxygen concentrations. Other organs that may be damaged by such oxidative stress include kidneys, myocardium and the retina. There is equally growing evidence that using lower oxygen concentrations will lead to lower oxygen saturation levels and bradycardia, which may lead to increased rates of mortality in this vulnerable group of infants. An individual patient analysis of clinical trials reported that 46% of preterm infants resuscitated with initial low oxygen concentration did not reach SpO2 of 80% at 5 min. This was associated with increased risk of major intraventricular hemorrhage (IVH), and an almost five times higher risk of death in this vulnerable group of infants. These data provide a warning note for the use of higher vs. lower initial oxygen concentration during delivery room resuscitation. As the investigator proceed in determining a safe range for resuscitation of ELBW/ELGA infants, it is highly likely that the optimum level of oxygen concentration is between the two extremes of 21 percent and 100 percent. Objectives: To determine whether initial resuscitation of preterm neonates with 60 percent versus 30 percent oxygen results in better neurodevelopmental outcomes at 24+/- 6 months. Research Method/Procedures: This will be a cluster crossover design, unmasked randomized controlled trial (RCT) comparing two oxygen concentrations at initiation of resuscitation. Infants will be placed on the resuscitation table with the initial steps of resuscitation carried out as per standard of care at each centre which usually follows current resuscitation guidelines. All centres will make every effort to establish adequate lung expansion using CPAP or positive pressure ventilation as needed. Enrolled infants will have a pulse oximeter sensor placed on the right arm in the first minute of life. Their resuscitation will be initiated with an oxygen concentration of 30 or 60 percent depending on the randomization sequence at the centre at the given time. Infants in the 30 percent group will remain in 30 percent oxygen until 5 min of age unless the infant's heart rate (HR) remains 100/min or less and does not show a tendency towards progressive increase before reaching 5 min of age or infant needs chest compression and/or epinephrine. No alteration in oxygen concentration will be made for an infant who is responding to resuscitation efforts with HR progressively increasing as minutes go by. At 5 min of age, the clinical team will assess oxygen saturation. If the saturation is less than 85 percent, oxygen should be increased by 10-20 percent every 60 sec to achieve saturations of 85 percent or greater or a saturation of 90-95 percent at 10 min of age. If saturations are greater than 95 percent at or before 5 min of age, oxygen should be decreased stepwise (every 60 sec) with an aim to maintain saturations of 85 percent or greater during 5-10 min of age or 90-95 percent at and beyond 10 min of age. The procedure for infants in the 60 percent group will be identical. The intervention duration for the trial will be the first 5 min after birth followed by initial monitoring/action for the next 5 min where titration in oxygen concentration will be made to achieve stability making a total of 10 min for study intervention. Titration of oxygen before 5 min after birth will only be made if the infant remains bradycardic (HR less than 100) and does not show a tendency towards a sustained increase in HR or if the oxygen saturation exceeds 95 percent. If the infant does not respond to ventilation with increasing HR in the first 5 min after birth, steps to ensure effective ventilation should be done before oxygen is titrated. Plan for Data Analysis: Generalized linear mixed model with binary outcome and maximum likelihood estimate will be used to evaluate the effect of an oxygen concentration on the primary outcome (as a composite at 24+/- 6 months corrected age of all-cause mortality or the presence of a major neurodevelopmental outcome). To account for cluster crossover design of the study, effects of centers (clusters) and a period (oxygen concentration) within center will be considered random, and effects of a period (oxygen concentration) will be entered as a fixed effect. This hierarchical model allows for the correlation of patients within periods and within clusters. The model will be adjusted for gestational age and whether or not infant required mask ventilation as potential confounding variables. Similar generalized linear mixed models will be performed to evaluate the effect of group on secondary outcomes. In addition, three subgroup analysis will be performed: i) Gestational age will be categorized into 2 categories: 23+0- 25+6 vs. 26+0-28+6 weeks; ii) Breathing support will be categorized by infants supported only with CPAP vs. received mask ventilation; iii) Sex/Gender will be categorized into 2 categories: female vs. male. For subgroup analysis baseline characteristics will be compared using linear and generalized linear mixed models. Sensitivity analysis will be performed to analyze the missing data; however, a very low number of missing values are expected due to the design of the study.

The purpose of this study is to examine the effectiveness of a 12-week early intervention program that will include 12 weekly hours in an intensive center-based preschool environment or in the home to treat social communication deficits in children with developmental disorders. The study will include children with developmental disorders, such as Autism Spectrum Disorder, neurogenetic disorders, or intellectual disability.

Design A cluster-randomized controlled trial will be conducted randomizing approximately 28 schools (clusters) with a total of 84 teachers/classrooms into either receiving training and supervision in PAX GBG or receiving equally much training and supervision for implementing one of the control interventions. Teachers in both arms will be implementing and using the intervention they were randomized to during the first year and then start implementing also the other intervention, while continuing using the first. When the baseline measure occurs at the end of grade 2 and the initial intervention is implemented for pupils during grade 3, the pupils in these classes will only receive one intervention since they move up to middle school where none of the methods are used. The teacher will instead start over with new pupils in grade 1 and use both methods with them. The sub-group of pupils that receives only one intervention will thus preserve the randomized controlled design also for long-term follow-ups. Procedure Ideally, half of the classrooms will be enrolled to start the intervention/control intervention during the spring semester and half during the autumn semester. The purpose of this is to control for the occasional effect of the point in time during the school year, and calendar year, when the intervention is introduced. Credible control interventions requiring the same amount of training and supervision will be used, to control for unspecific effects of implementing a new method. It also makes it possible to promote the study to schools and teachers as a way to implement and compare several useful methods, although for different purposes, which helps to avoid too high expectation or placebo effects for PAX and to minimize possible disappointment and nocebo effects related to having to wait one year before starting with PAX. The school will have the possibility to choose one of the two control interventions - a math application, 'Count On Me!', or Collegial learning community. This serves two purposes; (1) the possibility to choose will further reduce the risk of nocebo or being dissatisfied if not randomized to PAX and (2) it will enable more schools to participate if one of the control interventions would be seen as impractical to implement. Since neither fo the control interventions are deemed to have the same specific effects as PAX, at least not to the same extent, they will both act as controls for unspecific effects. A total of seven measures will be administered in relation to pupils, teachers and the classroom during the two years, with the baseline (Measurement 0) at the end of the semester before the implementation starts (Semester 0) and the primary endpoint (Measurement 4) one year afterwards. To reduce the burden for teachers and pupils, the full range of outcome measures will be conducted only on two occasions (Measurement 0 and Measurement 4) and otherwise a reduced set of measures will be used for pupils and teachers (For measures on classroom level, the full set of measures will always be applied). The reduced set of self-rating measures for teachers will include work related stress (primary outcome), classroom management, general stress, sleep problems, work ability and observed negative/positive effects of the method being implemented. For pupils, the reduced set will contain questions on well-being (primary measure). Teachers will also measure the well-being for each pupil at each measurement point. Following time frames will apply to the measurement points: Measurement 0 (M0) - semester before the first implementation semester, a 4-weeks administration window ending two weeks before the end of the semester. Measurement 1 (M1) - the first implementation semester, a 6-weeks administration window starting two weeks after the start of the semester (and preferably two weeks after the completion of the intervention training). Measurement 2 (M2) - the first implementation semester, a 4-weeks administration window ending two weeks before the end of the semester). Measurement 3 (M3) - the second implementation semester, a 4-weeks administration window starting two weeks after the start of the semester). Measurement 4 (M4) - primary endpoint, the second implementation semester, a 4-weeks administration window ending two weeks before the end of the semester. Measurement 5 (M5) - the third implementation semester, a 4-weeks administration window ending two weeks before the end of the semester. Measurement 6 (M6) - the fourth implementation semester, a 4-weeks administration window ending two weeks before the end of the semester. Participants and recruitment Schools, teachers, classrooms and other school staff The cluster-randomization will be performed on the school-level, and will in turn decide which teachers and pupils that are included. The schools will be recruited via an established network of PAX GBG trainers in Sweden and the research groups other connections with school-related networks and the recruitment will be country wide. The schools will be recruited from at least two different Regions and at least four different municipalities (kommuner) to increase the generalizability of the results. In total, around 28 schools will be included, depending on the number of classrooms participating from each school. A total of 84 classes, with an expected total of up to 100 teachers (as some classes have more than one teacher) will be included in the project. Other school staff is recruited only to participate in the qualitative evaluation of expectations and experiences of the interventions. The selection of these will be pragmatic and theoretically lead to reaching a saturation of qualitative data, with a maximum of four extra staff from each school. Pupils and their participation in interventions and data collection In total, 2200 pupils will be included, with approximately 26 pupils included from each classroom. All the pupils in a class related to the included teachers/classrooms will participate in the intervention since those are all implemented in the regular operation/teaching at the school and focused on the teachers' way of teaching and managing the class and the classroom and is not possible to exclude specific pupils from. Pupils can however be included in the data collection in three different ways: * Data from pupils to parents/custodians having signed the informed consent will have the data from their self-ratings, from the teachers ratings of them, and from registries connected to an ID-number, which in turn can be connected to their social security number (personnummer). * Data on pupils whose parents have not filled out the consent will still be collected, but without any ID-number or other identifier, which makes it impossible to connect it to the specific pupil and hence make the data anonymous. Only the interventions the pupil has been randomized to, and at which time-point the data was collected, is connected to this data. * Parents/custodians and the pupil himself/herself will be informed that the pupils do not need to fill out the self-ratings if they inform the teacher or researchers about their wish. Pupils will be informed of this before each self-rating. Randomization To ensure that the socioeconomic status (SES) of the schools do not differ too much, each school will be classified as being low, middle, or high SES and then, when there are enough schools in a cohort, randomized consecutively according to one of three corresponding block-randomized lists with block sizes varying randomly between 2, 4 and 6. The randomization will be handled by an independent third party, the Karolinska Trial Alliance, to ensure the researchers are not able to assess the lists or otherwise predict randomization results. Interventions The implementation procedure will be similar for each intervention, with smaller adjustments to fit specific needs of each method. Each starts with brief initial written information about the interventions, followed by one to two days of training/education for teachers. This is then followed by regular supervision face-to-face or via video/telephone depending on practical aspects and possible restrictions due to the Covid-19 pandemic. Supervision always includes some form of observation and monitoring of the use of the method by the supervisor, as a source to further inform the supervision. A total of six supervision sessions are planned: 4 sessions during the first implementation semester (held during the 1st to 4rth quarter of the semester respectively, starting with 2 individual sessions, followed by 1 group session and then by 1 individual session) and 2 sessions during the second implementation semester (held during the 1st and 2nd half of the semester respectively, 1 group session followed by 1 individual session). Teachers in all groups will also be able to receive briefer supervision on demand or additional supervision sessions initiated by the supervisor if deemed necessary. PAX Good Behavior Game PAX Good Behavior Game (GBG) is based on its precursor programme Good Behavior Game (GBG) that trains teachers to use principles of social learning in order to maximize the childrens' task-oriented and prosocial behaviors and minimize the occurrence of disruptive and off-task behaviors. PAX GBG is packaged into ten specific tools that the teachers are trained to introduce in their classroom management practice. The program introduces verbal and visual cues that facilitate prosocial and attentive behaviors One of the core elements of the program is the PAX-game, meaning that the children - while focusing on ordinary school tasks like math - get to play a game in teams where each team tries to make as few classroom rules infractions as possible during a certain period of time. The teams that succeed in achieving predetermined goals get a reward (often a fun and desirable activity) that serves as a reinforcer of prosocial and task-oriented behaviors. Supervision is performed individually with each teacher (4 sessions) and in group (2 sessions) and includes that the PAX-trainer observes a lecture given by the teacher before each supervision session. Count On Me! (Control condition) Count On Me! is an adaptive application teaching fluency in addition and subtraction facts (i.e., math facts), equality, compose and decompose numbers and a few more basic mathematical skills taught in the first grades of schooling. Count on me! is set in adventure game where the child has an avatar that travels thru different worlds/platforms by using their mathematical skills. The child starts of in the home of the avatar, in a house like environment, where the child discovers a magical map that brings the child into a different world called Numberia. During the adventures in Numberia the child learns that it has certain skills, called the mathemagical powers, that will be used to liberate Numberia from the evil Prince Claw that has captured all the beautiful things (e.g., the birds that used to sing in the forest). Count on me! was developed within a behavior analytic framework using a nonlinear programming process originally developed by Tiemann and Markle and later slightly revised by other researchers while creating Headsprout Early Reading and Headsprout Reading Comprehension. Instructional design elements from Tiemann and Markle, explicit instruction and the Morningside model of generative instruction were used to build the exercises. The math exercises contain at least one of three recurrent phases used in all training: the modeling, guide, and fluency phase. Modeling of new skills involves animations and hand-drawn examples along with audial instructions and requires frequent untimed student responding. Guided practice of newly modeled skills helps students achieve high levels of accuracy without timing. Finally, fluency building is aimed at developing proficiency with the skill at hand using timing. The guide and fluency phases comprise gamified elements. The application has been scientifically evaluated among Swedish low-performing elementary school pupils having shown significant improvements in math skills among the children having used the application with the largest improvement among the children with lower cognitive skills. Prior to the implementation start, the teachers' session focus on the functionality and content of the application and the way it corresponds to the math study plan for the class they're teaching. The training session will include the methods to introduce the application in the classroom, move forward and overcome common challenges. The teachers will be encouraged to start using the application in the classroom directly after the training session. The teachers will be recommended to use the application at least 4 times each week, approximately 15 minutes each time. Supervision will be held individually and in groups and will partly be based on the supervisors monitoring reports on how much and how the application is used. Collegial learning community (Control condition) Muijs and colleagues has defined five cyclical steps for professional learning for teachers. The first step is to assess the skill or knowledge gaps for students, using various data sources (for example testing, grades, surveys, student interviews). The second step is to reflect upon what skills the teacher needs to acquire in order to help the students to meet the goals. The third step is to deepen the professional knowledge and skills. The fourth step is engaging the students in the new practice, and in the fifth step to evaluate the impact the new practice has had on student outcomes. According to Timperley and other researchers, a feasible format for this kind of learning is a Collegial learning community, where teachers take help from their peers in each of these steps in a structured way. For example, way of deepening tacit or procedural knowledge (in step two) is to visit a colleague during class and make observations on their classroom practice. Timperley points out the importance of having a professional supervisor for maintaining the structure of the learning process. One common pitfall that the supervisor helps the teacher avoid is shifting focus from professional learning and instead ending up in entrenching current teacher practices, instead of learning new skills. Collegial learning communities can focus on practically any kind of teacher skills. The current intervention provide material to focus on any of the following: 1) formative assessment, 2) how to formulate and follow up on homework in order to engage students 3) How to teach fact knowledge in order to facilitate higher reasoning with students. These themes are chosen to mimimize the overlap with the content of PAX GBG but still be highly relevant for teachers. The intervention will be based on a web resource, and 6 supervision sessions with assignments in between. Supervision and observation will be combined in that the supervisor initially observes when the teachers perform a group supervision with their colleagues, and then gives immediate feedback to the whole group. This is followed by a further discussion of the method and brief, 10 to 15 minutes long individual sessions with each teacher. Measures Background data and the effectiveness and implementation outcomes of the intervention will be assessed with a range of different measures described below. The timing of the measures is described in table 1 above, and in some cases commented more on below. Extra background measures at baseline (M0) for schools, classrooms and teachers The measures described here are not the only one used as background data, but those specifically measured only at baseline. The SES for each school district measured in average income for parents and average level of education for parents (based on the data from Statistics Sweden) Number of pupils, teachers and extra resource persons in each class The pupil's need for additional help and extra resources, as well as presence of a neurodevelopmental diagnosis. Extra COPSOQ-III questionnaire subscales Quantitative Demands, Work Pace, Influence at Work, Predictability, Social Support from Supervisor, Social Support from Colleagues, Sense of Community at Work. Extra items from TALIS, the questions about employment and about other teachers at school. Effectiveness measures The effects of implementing PAX will be assessed on school level, teacher level, classroom level and student level. Classroom-focused measures Classroom-observations by a trained observer will be conducted during two or three lessons during the same or conceding days, for a minimum time of 20 minutes for each class. To increase standardization of the measure, only lessons where the focus is on theoretical subjects will be included. The observations will be based on an observational schedule that has already been tested in the PAX pilot trial and will be slightly adapted in a separate project prior to being implemented in the current trial. The schedule will focus on direct observation of the following aspects: 1) pupils being on-task/off-task (primary outcome), 2) number of pupils disruptive behaviors, 3) time for transition between different tasks and 4) number of positive/negative teacher-pupil interactions. The observations will be conducted by trained observers and will never identify single pupils, and hence produce anonymous data. However, the gender of the pupil will be recorded for assessment (1) - (4) to provide opportunity to conduct gender analyses. After each observed lesson, both observers and teachers will rate the observed lecture using a questionnaire that is being developed together with the observational schedule focusing on overall ratings of aspects like severity of disruptive behaviors in the classroom, level of noise in the classroom, how focused the class was during the lecture etc. Again, this data will be rated at classroom-level, with no possibility to identify individual students. During one week connected to the fixed measurement occasions, data on noise levels will be collected in each classroom. The noise levels will be assessed by a measuring device that will be placed in the classroom without disturbing classroom environment. The device will measure and store very short snippets of sound with random intervals of on average three seconds, making it impossible to identify source and content of the sound activity (e. g. hear a conversation) but being enough to calculate the decibel level at different ranges of frequency. Thus, this data is also anonymous. School attendance and the need of additional personnel in the class will be measured at the class level. The topic of the intervention's effect on the classroom, both positive and negative, will be covered by the qualitative interviews with the teachers and other school staff (described in the section for Implementation measures). Also, four free-text questions to the teacher at M3, M4 and M6 will cover this, prompting them to describe positive and negative effects of the intervention in relation to (a) themselves and (b) to the pupils, since the last measurement point. The pupils will also be asked about their attitude to PAX/control intervention. Measures of teachers' health and work A number of self-rated measures will be collected from teachers using a secure platform used for conducting online psychological treatments and requiring two-step authentication. The measures will include self-rated health-related measures, self-rated work-related data and registry-based data on health-care and prescription drugs consumption. Pupil-focused measures Self-rated questionnaires be answered by the pupils, with the aid of trained research assistants who will make sure that the students have understood the questions and the response alternatives and minimize the risk of them disturbing or influencing each other. Different ways of administering the questionnaire battery are available (administration via paper-and-pen or tablet in the whole class, in smaller groups, or individually, with the administrator giving instructions, sometimes also using a pre-recorded instruction) to be able to adapt to what would be most feasible for a specific classroom. The pupils will rate their health and wellbeing. The teachers will fill out the dysregulations scale (5 items) of the Strengths and Difficulties Questionnaire. Registry-based data will be used to analyse the pupils' health-care and prescription drugs consumption as well as the parents' need to take stay home from work to take care of a sick child. The children's academic attainment in mathematics and the Swedish language will be measured using standardized tests. Implementation measures The pre-conditions for the implementation process will be assessed using both quantitative and qualitative data collection. Semi-structured qualitative interviews will be conducted with randomly selected 25-50% of all the participating teachers. The goal of the interviews is to shed light on aspects that will not be captured by the standardized instruments, both in terms of the intervention's effectiveness and quality of implementation. The interview guide is being created as a part of a smaller pilot project. The interviews will be conducted by phone or video and will take approximately 20 minutes on average. The interviews will be conducted three times with each selected teacher: immediately after the PAX-training, at M2 and M4 (see the specification of the measurement points above). The interviews will be recorded, transcribed and analyzed using qualitative content analysis. Expectations and experience of the implemented intervention In order to study expectations, experiences and outcomes of the implemented intervention, the teachers and other school staff on several occasions will fill out the Normalisation Measure Development Questionnaire (NoMAD). The same dimensions will also be studied by by conducting interviews and collecting objective data, such as those on long-term use of the intervention according to the classroom observations, the proportion of the eligible teachers using the intervention in each school etc. Intervention Fidelity The teachers' fidelity to the method will be measured by direct observation conducted by the supervisor and by using a self-rated fidelity instrument for teachers to fill out. Adverse events Information on adverse events will be collected starting at M3 and onwards as open-ended questions that the teachers fill out in the platform. Questions on negative effects will also be included in the qualitative interviews. Statistical Analyses Statistical power of 80% for the pupils' psychological symptoms (the between-group effect size estimated from the pilot study equalling d=0.6) can be reached with a cluster-randomized design including 28 schools, 3 classes per school and 25 pupils in each class (a total of 2100 pupils), the expected data loss of 20% and the clustering effects known from similar studier in school environments of rho2=.1 (school level) and rho3=.25 (teacher level). Since the number of pupils can exceed 25, we expect the total number of included pupils to be 2200. Primary endpoint for outcomes will be at the one-year follow up (M4), before the teachers starts to use also the method they were not randomised to initially. The measures focusing on the teachers' and students' health, well-being and work/study environment, as well as classroom-based measures that are collected repeatedly will be analyzed with a hierarchal general linear model with a maximum of three nested levels (school, classroom/teacher, and pupil). The difference in the slopes of change over time between the PAX group and the control interventions will be tested for each outcome variable. A set of mixed effect models will be performed to detect factors (background factors and implementation-related factors) that influence the outcomes of the implementation (fidelity, acceptability, appropriateness etc.). Mixed effect models will also be used to detect whether implementation-related variables (e g readiness for change, fidelity, acceptability etc) affect the main outcomes of the trial (e g teachers' and students' health, well-being and work/study environment). The anonymous data from pupils will be used in two ways: (1) for missing data analyses by comparing the levels and changes in the anonymous data to the identifiable data and (2) to perform sensitivity analyses where all data are analysed on time and intervention group level only, i.e. ignoring information on school, classroom and pupil, even when those exists. The statistical methods will thus have less power, but on the other hand data from more pupils can be utilized and since the amount of missing data will be lower than in the main analyses, the risk for biases due to non-random attrition will be lower. For the anonymous data, if data from fewer than 10 pupils at one time-point and intervention are collected, the data will be discarded and deleted completely, in order to keep a safe margin from the possibility of in some way indirectly connect the data to a pupil. Cost effectiveness The teachers' mental health measured with GHQ-12 will be recalculated to quality adjusted life-years (QALY:s). The students health-related quality of life, measured with CHU9D, will be used to calculate QALY:s. The costs for the implementation (e g time for training and supervision), will be calculated together with the possible savings related to reduced sick leave absence for the teachers, as well as the need for additional personnel in the schools and reduced need of student health resources. The total QALY:s during the follow-up period will be studied using area under the curve method. The difference health outcome between the intervention group and the control condition will be analyzed using regression models. The costs and savings will be compared to the gains expressed in QALY:s, both for the teachers and the students. The results will be presented as a cost-effectiveness quota and illustrated as a cost-effectiveness plan, that will show the uncertainty in the results when it comes to the costs and health-effects for the intervention and the control group.

Réhabilitus is a remediation program focused on attentional functions and visuospatial, to limit the presence of behavioral disorders among adults with intellectual disabilities. The main objective is to validate the effectiveness of Réhabilitus program on behavioral disorders in adults with intellectual disabilities without autism spectrum disorder associated.

The aim of this study is to evaluate a novel tablet game-based neurodevelopmental assessment tool for young children aged 3 to 8 years old. The study's main aims are: (1) to determine whether the novel tablet-game based assessment tool can accurately differentiate children's neurodevelopmental status based on their performance on the game and (2) assess the validity of the game-based neurodevelopment assessment tool. The study aims to recruit 590 children who are 'typically' developing and/or have a diagnosed neurodevelopmental disorder including Attention Deficit Hyperactivity Disorder (ADHD), Autism Spectrum Disorder (ASD), Specific Learning Disorder, or a Communication Disorder. All participants will complete the tablet game-based assessment which aims to assess a range of neuropsychological functions including attention, memory, language, motor, executive functions and social-emotional skills. Parents/carers of participants will also complete a demographic questionnaire and the Adaptive Behaviour System - Third Edition (ABAS-3), which is a questionnaire that assesses a child's development. Some participants will be re-tested on the tablet game-based assessment approximately 2 weeks after the first tablet game-based assessment to ensure the game's validity.

Lev is a brief, transdiagnostic, interprofessional intervention targeting health-related habits that is intended for several care settings. The main population intended is individuals with neurodevelopmental disorders or parents or close relations to children with disabilities. This study will therefore be open for participants recruited from several types of healthcare services in Sweden. Study 1: The feasibility trial investigates the following questions: Completion: How many participants that started Lev completed the intervention? What were the reasons for not not completing Lev? How many sessions did the participants complete? Lev includes screening (Lev-s), three sessions + one booster session. Level of acceptability: Was Lev perceived as creditable and satisfactory by healthcare workers and participants? Treatment credibility will be measured before Lev and after the last session for both participants and healthcare workers. Treatment satisfaction will be evaluated after each session and after the intervention is completed. Session evaluations will be done by both participants and healthcare workers. Do the intervention lead to adverse events? To what extent were individual goals met?

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by disturbances in communication, poor social skills, and aberrant behaviors. Particularly detrimental are the presence of restricted and repetitive stereotyped behaviors and uncontrollable temper outbursts over trivial changes in the environment, which often cause emotional stress for the children, their families, schools and neighborhood communities. Fundamental to these cognitive and behavioral problems is the disordered cortical connectivity and resultant executive dysfunction that underpin the use of effective strategies to integrate information across contexts. Brain connectivity problems affect the rate at which information travels across the brain. Slow processing speed relates to a reduced capacity of executive function to recall and formulate thoughts and actions automatically, with the result that autistic children with poor processing speed have great difficulty learning or perceiving relationships across multiple experiences. In consequence, these children compensate for the impaired ability to integrate information from the environment by memorizing visual details or individual rules from each situation. This explains why children with autism tend to follow routines in precise detail and show great distress over seemingly trivial changes in the environment. To date, there is no known cure for ASD, and the disorder remains a highly disabling condition. Recently, a non-invasive brain stimulation technique, transcranial direct current Stimulation (tDCS) has shown great promise as a potentially effective and costeffective tool for reducing core symptoms such as anxiety, aggression, impulsivity, and inattention in patients with autism. This technique has been shown to modify behavior by inducing changes in cortical excitability and enhancing connectivity between the targeted brain areas. However, not all ASD patients respond to this intervention the same way and predicting the behavioral impact of tDCS in patients with ASD remains a clinical challenge. This proposed study thus aims to address these challenges by determining whether resting-state EEG and clinical data at baseline can be used to differentiate responders from non-responders to tDCS treatment. Findings from the study will provide new guidance for designing intervention programs for individuals with ASD.

Context Congenital heart disease (CHD) is the most common structural birth defect, affecting up to 1% of newborns. Half of children with CHD present neurodevelopmental impairments, including significant attention deficits. Compared to the general population, they are at 2.5 to 4 times greater risk for attention deficit hyperactivity disorder (ADHD). Despite the high prevalence of these disabilities, very little interest has been given to the design and implementation of CHD-specific interventions for improving attention. In fact, only one randomised controlled trial (RCT) aimed at improving cognition in adolescents with CHD and revealed promising results for attention and inhibitory control. To date, no RCT aiming to improve attention has been conducted in young children with CHD, although attention has been strongly associated with school readiness and can predict academic skills. Yet, a rich literature supports the notion that early intervention is key to ensure success in the crucial first years of education. There is emerging evidence from RCTs indicating that parent-child yoga interventions improve attention and reduce ADHD symptoms in both typically developing and clinical populations. However, no studies have tested this promising approach in children with CHD although these children have their own challenges. Our ultimate goal is to test the efficacy of a parent-child yoga intervention to reduce attention deficits in children with CHD at school entry. Before launching a full RCT involving multiple sites across Canada, we propose to conduct the 2-site Yoga for Little Hearts feasibility study, which is a necessary and critical step to ensure future assessment and implementation of our parent-child yoga intervention program. Results from this feasibility study will allow us to optimize the subsequent large-scale RCT by preventing procedural and methodological issues. Aims and hypotheses The principal objectives of the proposed feasibility study are to evaluate: 1) recruitment rates and capacity; 2) retention, dropout and withdrawal rates during the 8-week parent-child yoga program and at 6-month follow-up; 3) adherence to the intervention; 4) acceptability of the randomisation process by families; 5) heterogeneity in the delivery of the intervention between yoga instructors, and use of home-based exercise between participants; 6) proportion of missing data in the standardized neurodevelopmental assessment instruments and parental questionnaires, and 7) standard deviation of primary outcomes of the full RCT in order to determine an appropriate sample size for the future full trial. Following this feasibility study, we plan to conduct a full RCT including multiple centers aiming to test the efficacy of our 8-week parent-child yoga intervention in addition to the standard clinical care vs. standard clinical care alone in reducing attention deficits in 4-to-6-year-olds with CHD immediately and 6 months post-intervention. Population Children aged 4 to 6 years old with a diagnosis of CHD requiring heart surgery and their parents. Procedure The Yoga for Little Hearts feasibility methodology follows the Standard Protocol Items for Randomized Trials recommendations and the Consolidated Standards of Reporting Trials (CONSORT) statement - extension to randomized pilot and feasibility trials. Our proposed study is a single blind, two-center, two-arm randomized waitlist feasibility study. A total of 24 parent-child dyads, including children aged 4 to 6 years old with CHD, will be recruited in two centers and randomly assigned (2:1 allocation; 2 yoga intervention:1 standard of care) to receive either parent-child yoga intervention and standard clinical care (yoga intervention group) or standard clinical care alone with the opportunity to receive the yoga intervention after their participation in the study if desired (waitlist control group). Two waves of recruitment of 6 parent-child dyads will be held in each of the two participating sites, for a total of 24 dyads recruited over an 18-month period. The two participating sites are the CHU Ste-Justine and the Montreal Children's Hospital (MCH), covering more than half of the pediatric population with CHD in the Québec province. For each recruitment wave and site, 4 of the 6 recruited dyads will receive an 8-week parent-child yoga intervention. Meanwhile, dyads allocated to the waitlist control group (2 of the 6 recruited dyads) will receive the standard of care only, with the opportunity to receive the yoga intervention when their participation in the study will be completed. All participants from the yoga intervention group (n = 16) and the waitlist control group (n = 8) will undergo 3 standardized interdisciplinary neurodevelopmental assessments: 1) at baseline, before randomization (T0); 2) immediately post-intervention (T1); 3) 6-month post-intervention (T2).

In this study, a birth cohort was established, and infants were divided into two groups according to inclusion and exclusion criteria ( see study design ). One group was allergic group, and the other group was control group. The two groups will be followed up for up to 6 years, and specimens ( blood, urine, feces ) and test data ( height, weight, GESELL, etc. ) will be retained during the follow-up period. The outcome indicators were ASD, ADHD or LD, and DSM-5 was used as the diagnostic criteria.