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Peer collaboration is a foundational skill that emerges in early childhood. Children spend significant time in early educational settings, making it an important setting where young children can learn how to collaborate with peers. However, research on how to support children's collaboration effectively is limited and findings in this area have been inconsistent. This systematic review synthesises the effectiveness of interventions designed to enhance peer collaboration among children aged zero to six in early educational settings. The searches were conducted in Education Resource Information Centre (ERIC), PsycINFO, Education Resource, and Child Development and Adolescent Studies. A total of 18 studies met our inclusion criteria and were included in the systematic review. Included interventions targeted five components of peer collobaration: (1) communication skills; (2) ability to share goals; (3) collaborative products; (4) knowledge exchange; and (5) collaborative prosocial skills. The structure and implementation of the interventions were examined. Diverse strategies such as grouping children based on criteria, evaluations of collaborative products, role assignments, and adult observation and guidance were used to enhance young children's peer collaboration. The interventions primarily focused on children's direct engagement in tasks, with limited attention given to educators. The systematic review found mixed results regarding the impact of interventions on children's peer collaboration. Our findings provide researchers, policy makers and educators with empirical guidance on how to support this skill in young children.

Instability in early childhood education and care (ECEC) arrangements may have detrimental consequences on children's mental health. This study examined ECEC trajectories in the first 30 months of life for 373 children from low-income families in Toronto. We provide information about patterns of instability and reasons for instability. We also tested whether instability in ECEC was related to children's mental health using the Strengths and Difficulties Questionnaire. Five main profiles of ECEC stability were identified: (1) 8% in Home-Only, (2) 56.3% in Home-Center, (3) 8.0% in Home-Center-Home, (4) 5.9% in In-and-Out, and (5) 20.9% in Home-Multiple-Centers. Frequently mentioned reasons for change were a new baby in the family, availability of grandparents, quality of ECEC and family relocation. Families in these different profiles had similar demographic characteristics. Of the five profiles, children in the Home-Center-Home profile had a significantly higher likelihood of experiencing mental health problems compared to the Home-Center and Home-Multiple-Centers groups. These findings have important implications for future research, policy and practice related to ECEC availability.

INTRODUCTION: Traditional methods for assessing movement quality rely on subjective standardized scales and clinical expertise. This limitation creates challenges for assessing patients with spinocerebellar ataxia (SCA), in whom changes in mobility can be subtle and varied. We hypothesized that a machine learning analytic system might complement traditional clinician-rated measures of gait. Our objective was to use a video-based assessment of gait dispersion to compare the effects of troriluzole with placebo on gait quality in adults with SCA. METHODS: Participants with SCA underwent gait assessment in a phase 3, double-blind, placebo-controlled trial of troriluzole (NCT03701399). Videos were processed through a deep learning pose extraction algorithm, followed by the estimation of a novel gait stability measure, the Pose Dispersion Index, quantifying the frame-by-frame symmetry, balance, and stability during natural and tandem walk tasks. The effects of troriluzole treatment were assessed in mixed linear models, participant-level grouping, and treatment group-by-visit week interaction adjusted for age, sex, baseline modified Functional Scale for the Assessment and Rating of Ataxia (f-SARA), and time since diagnosis. RESULTS: From 218 randomized participants, 67 and 56 participants had interpretable videos of a tandem and natural walk attempt, respectively. At Week 48, individuals assigned to troriluzole exhibited significant (p = 0.010) improvement in tandem walk Pose Dispersion Index versus placebo {adjusted interaction coefficient: 0.584 [95% confidence interval (CI) 0.137 to 1.031]}. A similar, nonsignificant trend was observed in the natural walk assessment [coefficient: 1.198 (95% CI - 1.067 to 3.462)]. Further, lower baseline Pose Dispersion Index during the natural walk was significantly (p = 0.041) associated with a higher risk of subsequent falls [adjusted Poisson coefficient: - 0.356 [95% CI - 0.697 to - 0.014)]. CONCLUSION: Using this novel approach, troriluzole-treated subjects demonstrated improvement in gait as compared to placebo for the tandem walk. Machine learning applied to video-captured gait parameters can complement clinician-reported motor assessment in adults with SCA. The Pose Dispersion Index may enhance assessment in future research. TRIAL REGISTRATION-CLINICALTRIALS. GOV IDENTIFIER: NCT03701399.

The Cerebellar Cognitive Affective/Schmahmann Syndrome (CCAS) manifests as impaired executive control, linguistic processing, visual spatial function, and affect regulation. The CCAS has been described in the spinocerebellar ataxias (SCAs), but its prevalence is unknown. We analyzed results of the CCAS/Schmahmann Scale (CCAS-S), developed to detect and quantify CCAS, in two natural history studies of 309 individuals Symptomatic for SCA1, SCA2, SCA3, SCA6, SCA7, or SCA8, 26 individuals Pre-symptomatic for SCA1 or SCA3, and 37 Controls. We compared total raw scores, domain scores, and total fail scores between Symptomatic, Pre-symptomatic, and Control cohorts, and between SCA types. We calculated scale sensitivity and selectivity based on CCAS category designation among Symptomatic individuals and Controls, and correlated CCAS-S performance against age and education, and in Symptomatic patients, against genetic repeat length, onset age, disease duration, motor ataxia, depression, and fatigue. Definite CCAS was identified in 46% of the Symptomatic group. False positive rate among Controls was 5.4%. Symptomatic individuals had poorer global CCAS-S performance than Controls, accounting for age and education. The domains of semantic fluency, phonemic fluency, and category switching that tap executive function and linguistic processing consistently separated Symptomatic individuals from Controls. CCAS-S scores correlated most closely with motor ataxia. Controls were similar to Pre-symptomatic individuals whose nearness to symptom onset was unknown. The use of the CCAS-S identifies a high CCAS prevalence in a large cohort of SCA patients, underscoring the utility of the scale and the notion that the CCAS is the third cornerstone of clinical ataxiology.

Oculomotor deficits are common in hereditary ataxia, but disproportionally neglected in clinical ataxia scales and as outcome measures for interventional trials. Quantitative assessment of oculomotor function has become increasingly available and thus applicable in multicenter trials and offers the opportunity to capture severity and progression of oculomotor impairment in a sensitive and reliable manner. In this consensus paper of the Ataxia Global Initiative Working Group On Digital Oculomotor Biomarkers, based on a systematic literature review, we propose harmonized methodology and measurement parameters for the quantitative assessment of oculomotor function in natural-history studies and clinical trials in hereditary ataxia. MEDLINE was searched for articles reporting on oculomotor/vestibular properties in ataxia patients and a study-tailored quality-assessment was performed. One-hundred-and-seventeen articles reporting on subjects with genetically confirmed (n=1134) or suspected hereditary ataxia (n=198), and degenerative ataxias with sporadic presentation (n=480) were included and subject to data extraction. Based on robust discrimination from controls, correlation with disease-severity, sensitivity to change, and feasibility in international multicenter settings as prerequisite for clinical trials, we prioritize a core-set of five eye-movement types: (i) pursuit eye movements, (ii) saccadic eye movements, (iii) fixation, (iv) eccentric gaze holding, and (v) rotational vestibulo-ocular reflex. We provide detailed guidelines for their acquisition, and recommendations on the quantitative parameters to extract. Limitations include low study quality, heterogeneity in patient populations, and lack of longitudinal studies. Standardization of quantitative oculomotor assessments will facilitate their implementation, interpretation, and validation in clinical trials, and ultimately advance our understanding of the evolution of oculomotor network dysfunction in hereditary ataxias.

Smartphone sensors are used increasingly in the assessment of ataxias. To date, there is no specific consensus guidance regarding a priority set of smartphone sensor measurements, or standard assessment criteria that are appropriate for clinical trials. As part of the Ataxia Global Initiative Digital-Motor Biomarkers Working Group (AGI WG4), aimed at evaluating key ataxia clinical domains (gait/posture, upper limb, speech and oculomotor assessments), we provide consensus guidance for use of internal smartphone sensors to assess key domains. Guidance was developed by means of a literature review and a two stage Delphi study conducted by an Expert panel, which surveyed members of AGI WG4, representing clinical, research, industry and patient-led experts, and consensus meetings by the Expert panel to agree on standard criteria and map current literature to these criteria. Seven publications were identified that investigated ataxias using internal smartphone sensors. The Delphi 1 survey ascertained current practice, and systems in use or under development. Wide variations in smartphones sensor use for assessing ataxia were identified. The Delphi 2 survey identified seven measures that were strongly endorsed as priorities in assessing 3/4 domains, namely gait/posture, upper limb, and speech performance. The Expert panel recommended 15 standard criteria to be fulfilled in studies. Evaluation of current literature revealed that none of the studies met all criteria, with most being early-phase validation studies. Our guidance highlights the importance of consensus, identifies priority measures and standard criteria, and will encourage further research into the use of internal smartphone sensors to measure ataxia digital-motor biomarkers.

OBJECTIVES: Friedreich ataxia (FRDA) is a rare genetic disorder caused by mutations in the FXN gene, leading to progressive coordination loss and other symptoms. The recently approved omaveloxolone targets this condition but is limited to patients over 16 years of age, highlighting the need for pediatric treatments due to the disorders early onset and more rapid progression in children. This population also experiences increased non-neurological complications; the FACHILD study aimed to augment and expand the knowledge about the natural history of the disease and clinical outcome assessments for trials in children in FRDA. METHODS: The study enrolled 108 individuals aged 7-18 years with a confirmed FRDA diagnosis, with visits occurring from October 2017 to November 2022 across three institutions. Several measures were introduced to minimize the impact of the COVID-19 pandemic, including virtual visits. Outcome measures centered on the mFARS score and its subscores, and data were analyzed using mixed models for repeated measures. For context and to avoid misinterpretation, the analysis was augmented with data from patients enrolled in the Friedreichs Ataxia Clinical Outcome Measures Study. RESULTS: Results confirmed the general usefulness of the mFARS score in children, but also highlighted issues, particularly with the upper limb subscore (FARS B). Increased variability, limited homogeneity across study subgroups, and potential training effects might limit mFARS application in clinical trials in pediatric populations. INTERPRETATION: The FARS E (Upright Stability) score might be a preferred outcome measure in this patient population.

BackgroundPatient-facing digital health tools have been promoted to help patients manage concerns related to COVID-19 and to enable remote care and self-care during the COVID-19 pandemic. It has also been suggested that these tools can help further our understanding of the clinical characteristics of this new disease. However, there is limited information on the characteristics and use patterns of these tools in practice. ObjectiveThe aims of this study are to describe the characteristics of people who use digital health tools to address COVID-19–related concerns; explore their self-reported symptoms and characterize the association of these symptoms with COVID-19; and characterize the recommendations provided by digital health tools. MethodsThis study used data from three digital health tools on the K Health app: a protocol-based COVID-19 self-assessment, an artificial intelligence (AI)–driven symptom checker, and communication with remote physicians. Deidentified data were extracted on the demographic and clinical characteristics of adults seeking COVID-19–related health information between April 8 and June 20, 2020. Analyses included exploring features associated with COVID-19 positivity and features associated with the choice to communicate with a remote physician. ResultsDuring the period assessed, 71,619 individuals completed the COVID-19 self-assessment, 41,425 also used the AI-driven symptom checker, and 2523 consulted with remote physicians. Individuals who used the COVID-19 self-assessment were predominantly female (51,845/71,619, 72.4%), with a mean age of 34.5 years (SD 13.9). Testing for COVID-19 was reported by 2901 users, of whom 433 (14.9%) reported testing positive. Users who tested positive for COVID-19 were more likely to have reported loss of smell or taste (relative rate [RR] 6.66, 95% CI 5.53-7.94) and other established COVID-19 symptoms as well as ocular symptoms. Users communicating with a remote physician were more likely to have been recommended by the self-assessment to undergo immediate medical evaluation due to the presence of severe symptoms (RR 1.19, 95% CI 1.02-1.32). Most consultations with remote physicians (1940/2523, 76.9%) were resolved without need for referral to an in-person visit or to the emergency department. ConclusionsOur results suggest that digital health tools can help support remote care and self-management of COVID-19 and that self-reported symptoms from digital interactions can extend our understanding of the symptoms associated with COVID-19.

BACKGROUND AND OBJECTIVES: Vamorolone is a dissociative agonist of the glucocorticoid receptor that has shown similar efficacy and reduced safety concerns in comparison with prednisone in Duchenne muscular dystrophy (DMD). This study was conducted to determine the efficacy and safety of vamorolone over 48 weeks and to study crossover participants (prednisone to vamorolone; placebo to vamorolone). METHODS: A randomized, double-blind, placebo-controlled and prednisone-controlled clinical trial of 2 doses of vamorolone was conducted in participants with DMD, in the ages from 4 years to younger than 7 years at baseline. The interventions were 2 mg/kg/d of vamorolone and 6 mg/kg/d of vamorolone for 48 weeks (period 1: 24 weeks + period 2: 24 weeks) and 0.75 mg/kg/d of prednisone and placebo for the first 24 weeks (before crossover). Efficacy was evaluated through gross motor outcomes and safety through adverse events, growth velocity, body mass index (BMI), and bone turnover biomarkers. This analysis focused on period 2. RESULTS: A total of 121 participants with DMD were randomized. Vamorolone at a dose of 6 mg/kg/d showed maintenance of improvement for all motor outcomes to week 48 (e.g., for primary outcome, time to stand from supine [TTSTAND] velocity, week 24 least squares mean [LSM] [SE] 0.052 [0.0130] rises/s vs week 48 LSM [SE] 0.0446 [0.0138]). After 48 weeks, vamorolone at a dose of 2 mg/kg/d showed similar improvements as 6 mg/kg/d for North Star Ambulatory Assessment (NSAA) (vamorolone 6 mg/kg/d-vamorolone 2 mg/kg/d LSM [SE] 0.49 [1.14]; 95% CI -1.80 to 2.78, p = 0.67), but less improvement for other motor outcomes. The placebo to vamorolone 6 mg/kg/d group showed rapid improvements after 20 weeks of treatment approaching benefit seen with 48-week 6 mg/kg/d of vamorolone treatment for TTSTAND, time to run/walk 10 m, and NSAA. There was significant improvement in linear growth after crossover in the prednisone to vamorolone 6 mg/kg/d group, and rapid reversal of prednisone-induced decline in bone turnover biomarkers in both crossover groups. There was an increase in BMI after 24 weeks of treatment that then stabilized for both vamorolone groups. DISCUSSION: Improvements of motor outcomes seen with 6 mg/kg/d of vamorolone at 24 weeks of treatment were maintained to 48 weeks of treatment. Vamorolone at a dose of 6 mg/kg/d showed better maintenance of effect compared with vamorolone at a dose of 2 mg/kg/d for most (3/5) motor outcomes. Bone morbidities of prednisone (stunting of growth and declines in serum bone biomarkers) were reversed when treatment transitioned to vamorolone. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier: NCT03439670. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for boys with DMD, the efficacy of vamorolone at a dose of 6 mg/kg/d was maintained over 48 weeks.

Characterizing bedside oculomotor deficits is a critical factor in defining the clinical presentation of hereditary ataxias. Quantitative assessments are increasingly available and have significant advantages, including comparability over time, reduced examiner dependency, and sensitivity to subtle changes. To delineate the potential of quantitative oculomotor assessments as digital-motor outcome measures for clinical trials in ataxia, we searched MEDLINE for articles reporting on quantitative eye movement recordings in genetically confirmed or suspected hereditary ataxias, asking which paradigms are most promising for capturing disease progression and treatment response. Eighty-nine manuscripts identified reported on 1541 patients, including spinocerebellar ataxias (SCA2, n = 421), SCA3 (n = 268), SCA6 (n = 117), other SCAs (n = 97), Friedreich ataxia (FRDA, n = 178), Niemann-Pick disease type C (NPC, n = 57), and ataxia-telangiectasia (n = 85) as largest cohorts. Whereas most studies reported discriminatory power of oculomotor assessments in diagnostics, few explored their value for monitoring genotype-specific disease progression (n = 2; SCA2) or treatment response (n = 8; SCA2, FRDA, NPC, ataxia-telangiectasia, episodic-ataxia 4). Oculomotor parameters correlated with disease severity measures including clinical scores (n = 18 studies (SARA: n = 9)), chronological measures (e.g., age, disease duration, time-to-symptom onset; n = 17), genetic stratification (n = 9), and imaging measures of atrophy (n = 5). Recurrent correlations across many ataxias (SCA2/3/17, FRDA, NPC) suggest saccadic eye movements as potentially generic quantitative oculomotor outcome. Recommendation of other paradigms was limited by the scarcity of cross-validating correlations, except saccadic intrusions (FRDA), pursuit eye movements (SCA17), and quantitative head-impulse testing (SCA3/6). This work aids in understanding the current knowledge of quantitative oculomotor parameters in hereditary ataxias, and identifies gaps for validation as potential trial outcome measures in specific ataxia genotypes.

Abstract: Health and safety standards offer a convenient means by which governments can claim to be protecting the population, even while pursuing more parochial goals. In the realm of international trade, such standards have most often been studied as a means of veiled protectionism. Yet precisely because health and safety standards create ambiguity about their intent, nations may seek to use them for goals that extend well beyond protecting domestic industry. We theorize that governments will, at times, enforce regulations in ways intended to exact political retribution. To show this, we collect original data on import refusals by Chinese border inspectors between 2011 and 2019. Though ostensibly intended to keep dangerous products out of the hands of Chinese consumers, we demonstrate that import refusals have systematically been used by the Chinese government as a way to punish states that act against China's interest.

Friedreichs ataxia is a neurodegenerative disorder caused by reduced frataxin levels. It leads to motor and sensory impairments and has a median life expectancy of around 35 years. As the most common inherited form of ataxia, Friedreichs ataxia lacks reliable, non-invasive biomarkers, prolonging and inflating the cost of clinical trials. This study proposes TUG1, a long non-coding RNA, as a promising blood-based biomarker for Friedreichs ataxia, which is known to regulate various cellular processes. In a previous study using a frataxin knockdown mouse model, we observed several hallmark Friedreichs ataxia symptoms. Building on this, we hypothesized that a dual-source approach-comparing the data from peripheral blood samples from Friedreichs ataxia patients with tissue samples from affected areas in Friedreichs ataxia knockdown mice, tissues usually unattainable from patients-would effectively identify robust biomarkers. A comprehensive reanalysis was conducted on gene expression data from 183 age- and sex-matched peripheral blood samples of Friedreichs ataxia patients, carriers and controls and 192 tissue data sets from Friedreichs ataxia knockdown mice. Blood and tissue samples underwent RNA isolation and quantitative reverse transcription polymerase chain reaction, and frataxin knockdown was confirmed through enzyme-linked immunosorbent assays. Tug1 RNA interaction was explored via RNA pull-down assays. Validation was performed in serum samples on an independent set of 45 controls and 45 Friedreichs ataxia patients and in blood samples from 66 heterozygous carriers and 72 Friedreichs ataxia patients. Tug1 and Slc40a1 emerged as potential blood-based biomarkers, confirmed in the Friedreichs ataxia knockdown mouse model (one-way ANOVA, P ≤ 0.05). Tug1 was consistently downregulated after Fxn knockdown and correlated strongly with Fxn levels (R 2 = 0.71 during depletion, R 2 = 0.74 during rescue). Slc40a1 showed a similar but tissue-specific pattern. Further validation of Tug1s downstream targets strengthened its biomarker candidacy. In additional human samples, TUG1 levels were significantly downregulated in both whole blood and serum of Friedreichs ataxia patients compared with controls (Wilcoxon signed-rank test, P < 0.05). Regression analyses revealed a negative correlation between TUG1 fold-change and disease onset (P < 0.0037) and positive correlations with disease duration and functional disability stage score (P < 0.04). This suggests that elevated TUG1 levels correlate with earlier onset and more severe cases. This study identifies TUG1 as a potential blood-based biomarker for Friedreichs ataxia, showing consistent expression variance in human and mouse tissues related to disease severity and key Friedreichs ataxia pathways. It correlates with frataxin levels, indicating its promise as an early, non-invasive marker. TUG1 holds potential for Friedreichs ataxia monitoring and therapeutic development, meriting additional research.

The genetic ataxias have no cures and no proven ways to delay progression (no disease-modifying therapies). The acquired ataxias may have treatments that address the underlying cause and may slow or stop progression, but will not reverse damage already sustained. The idiopathic ataxias (of unknown genetic or acquired cause) also have no proven disease-modifying therapies. However, for all patients with ataxia of any cause, there is always something that can be done to improve quality of life-treat associated symptoms, provide information and resources, counsel patient and family, help with insurance and disability concerns, be available to listen and answer the many questions they will have.

OBJECTIVE: The natural history of Friedreich ataxia is being investigated in a multi-center longitudinal study designated the Friedreich ataxia Clinical Outcome Measures Study (FACOMS). To understand the utility of this study in analysis of clinical trials, we performed a propensity-matched comparison of data from the open-label MOXIe extension (omaveloxolone) to that from FACOMS. METHODS: MOXIe extension patients were matched to FACOMS patients using logistic regression to estimate propensity scores based on multiple covariates: sex, baseline age, age of onset, baseline modified Friedreich Ataxia Rating scale (mFARS) score, and baseline gait score. The change from baseline in mFARS at Year 3 for the MOXIe extension patients compared to the matched FACOMS patients was analyzed as the primary efficacy endpoint using mixed model repeated measures analysis. RESULTS: Data from the MOXIe extension show that omaveloxolone provided persistent benefit over 3 years when compared to an untreated, matched cohort from FACOMS. At each year, in all analysis populations, patients in the MOXIe extension experienced a smaller change from baseline in mFARS score than matched FACOMS patients. In the primary pooled population (136 patients in each group) by Year 3, patients in the FACOMS matched set progressed 6.6 points whereas patients treated with omaveloxolone in MOXIe extension progressed 3 points (difference = -3.6; nominal p value = 0.0001). INTERPRETATION: These results suggest a meaningful slowing of Friedreich ataxia progression with omaveloxolone, and consequently detail how propensity-matched analysis may contribute to understanding of effects of therapeutic agents. This demonstrates the direct value of natural history studies in clinical trial evaluations.

There has been a continuous focus on developing quality physical education (PE) experiences that empower students to understand movement and engage in physical activity. This article describes a pedagogical approach that was developed to assist the PE student in understanding more about their own and others' physical activity capacities. This new instructional approach, which is grounded in scientific methods, is called the Informed Learner in Physical Education (ILPE). The ILPE was developed to provide teachers with a pedagogical approach to facilitate meaningful learning and empower students within PE with the overarching goal of students becoming "informed learners of and about movement and physical activity." Within the ILPE there are four features: (1) Activity Context and Educational Focus, (2) Inquiry Question, (3) Investigation, and (4) Evaluation and Articulation of Findings. These features and teacher considerations are discussed to assist PE teachers in the design and implementation of an ILPE experience.

Suboptimal parenting characterized by low self-efficacy and perceived impact is associated with poor child mental health and academic outcomes, especially for at-risk families. This study capitalized on a longitudinal study conducted prior to and after the onset of the COVID-19 pandemic to test how prior parenting cognitions and environmental risk factors predict mental health and educational challenges faced by children during the pandemic. Pre-pandemic parenting and environmental risk data are available for a sample of 252 low-income mother-child dyads in Toronto, Canada. Research Findings: Mothers who had lower parental self-efficacy, but higher perceived parental impact prior to COVID-19 reported that their children faced educational challenges during the pandemic. In addition, mothers who reported lower levels of pre-pandemic parental self-efficacy reported that their children were more likely to have emotional and conduct problems greater than the sample average during COVID-19. Practice or Policy: Parents with specific profiles of parenting cognitions may need additional support to help their children cope during the pandemic.

High-quality early childhood education and care (ECEC) - particularly care defined by highly responsive interactions between educators and children - has the potential to have lasting positive impacts on children's development. While there is variability in the level of quality among early education and care settings, professional development for early childhood educators has been shown to be an effective means to improve both ECEC quality and child outcomes. As many professional development programs are time and resource intensive, we sought out to test the efficacy of a brief (5 hr) professional development program that included a workshop, individual coaching, video feedback and text messaging. "Research Findings:" Results of a cluster randomized controlled trial with 93 educators indicated that the program improved educators' responsivity three-months after intervention (d = 0.60, p = 0.035), but not classroom-wide levels of emotional support or instructional quality. Trend analysis revealed the greatest improvements occurred after the workshop and first coaching session and leveled off over time. "Practice or Policy:" Preliminary evidence suggests brief professional development programs may improve interaction quality with effect sizes comparable to those of longer programs. Well-powered studies using multiple arms or sequential randomization will help optimize the efficiency and effectiveness of professional development.