Nasal and Plasma Severe Acute Respiratory Syndrome Coronavirus 2 RNA Levels Are Associated With Timing of Symptom Resolution in the ACTIV-2 Trial of Nonhospitalized Adults With Coronavirus Disease 2019.

Acute Coronavirus Disease 2019 symptoms limit daily activities, but little is known about its association with severe acute respiratory syndrome coronavirus 2 viral burden. In this exploratory analysis of placebo recipients in the ACTIV-2/A5401 platform trial, we showed that high anterior nasal RNA levels and detectable plasma RNA were associated with delayed symptom improvement. Clinical Trials Registration. https://clinicaltrials.gov/ct2/show/NCT04518410.

Sample size calculation for randomized trials via inverse probability of response weighting when outcome data are missing at random.

Randomized trials are an established method to evaluate the causal effects of interventions. Despite concerted efforts to retain all trial participants, some missing outcome data are often inevitable. It is unclear how best to account for missing outcome data in sample size calculations. A standard approach is to inflate the sample size by the inverse of one minus the anticipated dropout probability. However, the performance of this approach in the presence of informative outcome missingness has not been well-studied. We investigate sample size calculation when outcome data are missing at random given the randomized intervention group and fully observed baseline covariates under an inverse probability of response weighted (IPRW) estimating equations approach. Using M-estimation theory, we derive sample size formulas for both individually randomized and cluster randomized trials (CRTs). We illustrate the proposed method by calculating a sample size for a CRT designed to detect a difference in HIV testing strategies under an IPRW approach. We additionally develop an R shiny app to facilitate implementation of the sample size formulas.

Structures and systems influencing quality improvement in Australian early childhood education and care centres.

This study assessed the impact of structural characteristics on quality rating and improvement systems (QRIS) outcomes in an Australian national study. Data from the Australian Children's Education and Care Quality Authority (ACECQA) repository of National Quality Standard (NQS) ratings were used to identify long day care services that had improved from Working Towards NQS to Meeting or Exceeding NQS or had no change over two assessments. QRIS outcomes were examined for state/territory jurisdiction, urban-rural location, community socio-economic status, type and size of provider organisation, centre size and stability of centre owner/provider using multinomial logistic regression analyses. Controlling for jurisdiction, results showed that improvement to Meeting NQS was more likely for not-for-profit versus for-profit providers and for large multi-site provider organisations versus small, stand-alone providers. Improvement to Exceeding NQS was also associated with not-for-profit and larger provider organisations, as well as larger versus smaller centres, and centres that had stable ownership.

Power calculation for analyses of cross-sectional stepped-wedge cluster randomized trials with binary outcomes via generalized estimating equations.

Power calculation for stepped-wedge cluster randomized trials (SW-CRTs) presents unique challenges, beyond those of standard parallel cluster randomized trials, due to the need to consider temporal within cluster correlations and background period effects. To date, power calculation methods specific to SW-CRTs have primarily been developed under a linear model. When the outcome is binary, the use of a linear model corresponds to assessing a prevalence difference; yet trial analysis often employs a nonlinear link function. We propose power calculation methods for cross-sectional SW-CRTs under a logistic model fitted by generalized estimating equations. Firstly, under an exchangeable correlation structure, we show the power based on a logistic model is lower than that from assuming a linear model in the absence of period effects. We then evaluate the impact of background prevalence changes over time on power. To allow the correlation among outcomes in the same cluster to change over time and with treatment status, we generalize the methods to more complex correlation structures. Our simulation studies demonstrate that the proposed power calculation methods perform well with the model-based variance under the true correlation structure and reveal that a working independence structure can result in substantial efficiency loss, while a working exchangeable structure performs well even when the underlying correlation structure deviates from exchangeable. An extension to our methods accounts for variable cluster sizes and reveals that unequal cluster sizes have a modest impact on power. We illustrate the approaches by application to a quality of care improvement trial for acute coronary syndrome.

Poor quality of life and incomplete self-reported adherence predict second-line ART virological failure in resource-limited settings.

We evaluated health-related quality of life (QoL) and self-reported incomplete adherence as predictors of early second-line antiretroviral (ART) virological failure (VF). ACTG A5273 study participants completed the ACTG SF-21 measure which has 8 QoL domains. We used exact logistic regression to assess the association of QoL at baseline and week 4 with early VF adjusted for self-reported adherence. Of 500 individuals (51% women, median age 39 years) in this analysis, 79% and 75% self-reported complete adherence (no missing doses in the past month) at weeks 4 and 24, respectively. Early VF was experienced by 7% and more common among those who self-reported incomplete adherence. Participants with low week 4 QoL scores had higher rates of early VF than participants with high scores. After adjusting for self-reported adherence at week 4, VL and CD4 at baseline, cognitive functioning, pain and mental health domains were significantly associated with subsequent early VF. In this post-hoc analysis, poorer QoL adds to self-reported incomplete adherence after 4 weeks of second-line ART in predicting VF at week 24. Evaluation is needed to assess whether individuals with poorer QoL might be targeted for greater support to reduce risk of VF.Trial registration: ClinicalTrials.gov identifier: NCT01352715.

Power calculation for cross-sectional stepped wedge cluster randomized trials with variable cluster sizes.

Standard sample size calculation formulas for stepped wedge cluster randomized trials (SW-CRTs) assume that cluster sizes are equal. When cluster sizes vary substantially, ignoring this variation may lead to an under-powered study. We investigate the relative efficiency of a SW-CRT with varying cluster sizes to equal cluster sizes, and derive variance estimators for the intervention effect that account for this variation under a mixed effects model-a commonly used approach for analyzing data from cluster randomized trials. When cluster sizes vary, the power of a SW-CRT depends on the order in which clusters receive the intervention, which is determined through randomization. We first derive a variance formula that corresponds to any particular realization of the randomized sequence and propose efficient algorithms to identify upper and lower bounds of the power. We then obtain an "expected" power based on a first-order approximation to the variance formula, where the expectation is taken with respect to all possible randomization sequences. Finally, we provide a variance formula for more general settings where only the cluster size arithmetic mean and coefficient of variation, instead of exact cluster sizes, are known in the design stage. We evaluate our methods through simulations and illustrate that the average power of a SW-CRT decreases as the variation in cluster sizes increases, and the impact is largest when the number of clusters is small.

Effect of HIV Antibody VRC01 on Viral Rebound after Treatment Interruption.

BACKGROUND: The discovery of potent and broadly neutralizing antibodies (bNAbs) against human immunodeficiency virus (HIV) has made passive immunization a potential strategy for the prevention and treatment of HIV infection. We sought to determine whether passive administration of VRC01, a bNAb targeting the HIV CD4-binding site, can safely prevent or delay plasma viral rebound after the discontinuation of antiretroviral therapy (ART). METHODS: We conducted two open-label trials (AIDS Clinical Trials Group [ACTG] A5340 and National Institutes of Health [NIH] 15-I-0140) of the safety, side-effect profile, pharmacokinetic properties, and antiviral activity of VRC01 in persons with HIV infection who were undergoing interruption of ART. RESULTS: A total of 24 participants were enrolled, and one serious alcohol-related adverse event occurred. Viral rebound occurred despite plasma VRC01 concentrations greater than 50 µg per milliliter. The median time to rebound was 4 weeks in the A5340 trial and 5.6 weeks in the NIH trial. Study participants were more likely than historical controls to have viral suppression at week 4 (38% vs. 13%, P=0.04 by a two-sided Fisher's exact test in the A5340 trial; and 80% vs. 13%, P<0.001 by a two-sided Fisher's exact test in the NIH trial) but the difference was not significant at week 8. Analyses of virus populations before ART as well as before and after ART interruption showed that VRC01 exerted pressure on rebounding virus, resulting in restriction of recrudescent viruses and selection for preexisting and emerging antibody neutralization-resistant virus. CONCLUSIONS: VRC01 slightly delayed plasma viral rebound in the trial participants, as compared with historical controls, but it did not maintain viral suppression by week 8. In the small number of participants enrolled in these trials, no safety concerns were identified with passive immunization with a single bNAb (VRC01). (Funded by the National Institute of Allergy and Infectious Diseases and others; ACTG A5340 and NIH 15-I-0140 ClinicalTrials.gov numbers, NCT02463227 and NCT02471326 .).

Quality of life among HIV-infected individuals failing first-line antiretroviral therapy in resource-limited settings.

We evaluated health-related quality of life (QoL) in HIV infection participants with virologic failure (VF) on first-line antiretroviral therapy (ART) in 9 resource-limited settings (RLS). ACTG SF-21 was completed by 512 participants at A5273 study entry; 8 domains assessed: general health perceptions (GHP), physical functioning (PF), role functioning (RF), social functioning (SF), cognitive functioning (CF), pain (P), mental health (MH), and energy/fatigue (E/F); each was scored between 0 (worst) to 100 (best). Mean QoL scores ranged from 67 (GHP) to 91 (PF, SF, CF). QoL varied by country; high VL and low CD4 were associated with worse QoL in most domains, except RF (VL only), SF (CD4 only) and CF (neither). Number of comorbidities, BMI and history of AIDS were associated with some domains. Relationships between QoL and VL varied among countries for all domains. The association of worse disease status with worse QoL may reflect low QoL when ART was initiated and/or deterioration associated with VF.

Early Shared Reading, Socioeconomic Status, and Children's Cognitive and School Competencies: Six Years of Longitudinal Evidence.

This study explored the longitudinal association between early shared reading and children's later school achievement. We also examined the mediating role of children's academic school readiness and the moderating effect of family socioeconomic status. Data were drawn from the Longitudinal Study of Australian Children (n = 4,768). Frequency of shared reading and academic school readiness were assessed at the ages of 2-3 and 4-5. School achievement was assessed at age 8-9 via standardized national tests of school literacy and mathematics achievement. Results indicated that early shared reading was associated with children's school achievement directly and indirectly through receptive language and early academic skills. The results also showed that frequency of reading predicts the outcome measures, over and above other home activities such as telling child a story or practicing music. The associations were stronger among low and middle SES groups compared to the high SES group. We conclude that shared reading is uniquely associated to indicators of children's cognitive development such as language and early academic skills as well as children's school achievement. This effect is over and above families' socioeconomic status and other activities that parents do. This may be because books offer unique opportunities to teach children new words and concepts in a systematic way, and this is something that most parents would not be able to do otherwise.

Validation and norming of the Intelligibility in Context Scale in Northern Viet Nam.

Vietnamese is one of the 20 most commonly spoken languages in the world; however, there are no standardised tools to assess Vietnamese children's speech. This study aimed to validate and norm the Vietnamese version of the Intelligibility in Context Scale (ICS-VN). Data were collected from parents of 181 children (aged 2;0-5;11) living in Ha Noi, Northern Viet Nam. The mean ICS-VN score was 4.43 (out of a maximum of 5), indicating that children were 'usually' to 'always' intelligible; however, item-level scores demonstrated significant differences between communication partners. Children with parental concerns about speech and language had significantly lower mean scores than children without parental concerns. Scores also differed by children's age, parents' occupation and mothers' education level but not by sex of child or fathers' education level. The ICS-VN had good psychometric properties indicating it to be a valid tool for use with Vietnamese-speaking children in Northern Viet Nam.

CCR5-Δ32 Heterozygosity, HIV-1 Reservoir Size, and Lymphocyte Activation in Individuals Receiving Long-term Suppressive Antiretroviral Therapy.

We conducted a case-controlled study of the associations of CCR5-Δ32 heterozygosity with human immunodeficiency virus type 1 (HIV-1) reservoir size, lymphocyte activation, and CCR5 expression in 114 CCR5(Δ32/WT) and 177 wild-type CCR5 AIDS Clinical Trials Group participants receiving suppressive antiretroviral therapy. Overall, no significant differences were found between groups for any of these parameters. However, higher levels of CCR5 expression correlated with lower amounts of cell-associated HIV-1 RNA. The relationship between CCR5-Δ32 heterozygosity, CCR5 expression, and markers of HIV-1 persistence is likely to be complex and may be influenced by factors such as the duration of ART.

An evaluation of confidence intervals for a cumulative proportion to enable decisions at interim reviews of single-arm trials.

BACKGROUND: Clinical trials often include interim analyses of the proportion of participants experiencing an event by a fixed time-point. A pre-specified proportion excluded from a corresponding confidence interval (CI) may lead an independent monitoring committee to recommend stopping the trial. Frequently this cumulative proportion is estimated by the Kaplan-Meier estimator with a Wald approximate CI, which may have coverage issues with small samples. METHODS: We reviewed four alternative CI methods for cumulative proportions (Beta Product Confidence Procedure (BPCP), BPCP Mid P, Rothman-Wilson, Thomas-Grunkemeier) and two CI methods for simple proportions (Clopper-Pearson, Wilson). We conducted a simulation study comparing CI methods across true event proportions for 12 scenarios differentiated by sample sizes and censoring patterns. We re-analyzed interim data from A5340, a HIV cure trial considering the proportion of participants experiencing virologic failure. RESULTS: Our simulation study highlights the lower and upper tail error probabilities for each CI method. Across scenarios, we found differences in the performance of lower versus upper bounds. No single method is always preferred. The upper bound of a Wald approximate CI performed reasonably with some error inflation, whereas the lower bound of the BPCP Mid P method performed well. For a trial design similar to A5340, we recommend BPCP Mid P. CONCLUSIONS: The design of future single-arm interim analyses of event proportions should consider the most appropriate CI method based on the relevant bound, anticipated sample size and event proportion. Our paper summarizes available methods, demonstrates performance in a simulation study, and includes code for implementation.

Macro-structural predictors of Australian family day care quality.

Introduction: This study explores the predictive power of macro-structural characteristics on quality rating and improvement system (QRIS) outcomes of Family Day Care (FDC) services in Australia. Methods: The dataset consisted of 441 FDC National Quality Standard (NQS) ratings from all Australian states and territories, with overall ratings of Exceeding NQS, Meeting NQS, Working Towards NQS, or Significant Improvement Required. Results: Multinomial logistic regressions confirmed that management type, community socioeconomic status (SES), level of urbanization, and government jurisdiction explained 6.9 to 19.3% of the variation in QRIS outcomes. Results indicated that lower FDC NQS ratings were more likely for (1) private for-profit vs. not-for-profit; (2) low-SES vs. high-SES area; and (3) regional or remote area vs. metropolitan. State/territory jurisdiction also influenced NQS ratings. Discussion: These findings imply the need for policy attention to inequalities in FDC quality associated with systemic and organizational differences. Greater effort is needed to promote equality and equity in FDC services.

The role of digital technologies in supporting quality improvement in Australian early childhood education and care settings.

This national study explored the role of digital technologies in early childhood education and care settings and whether they could contribute to quality improvement as reported by educators and assessors of quality in Australia. In this paper, data from Stage 2 of the Quality Improvement Research Project were used, which comprised 60 Quality Improvement Plans from educators linked with 60 Assessment and Rating reports from the assessors who visited early childhood centres as part of the administration of the National Quality Standards by each of Australia's State and Territory jurisdictions. Bronfenbrenner's ecological systems theory ( Bronfenbrenner, U. (1995). Developmental ecology through space and time: A future perspective. In P. Moen, G. H. Elder, Jr., & K. Lüscher (Eds.), Examining lives in context: Perspectives on the ecology of human development (pp. 619-647). American Psychological Association. 10.1037/10176-018; Bronfenbrenner & Ceci, Bronfenbrenner and Ceci, Psychological Review 101:568-586, 1994) was adopted to facilitate a systemic and dynamic view on the use of digital technologies in these 60 ECEC settings. References (e.g. comments/ suggestions/ examples) made by the educators about the implementation of digital technologies were counted and thematically analysed. Results revealed the strong role new technologies (e.g. documentation and management platforms, tablets, apps, etc.) play in the majority of ECEC settings and especially in relation to three of the seven Quality Areas: Educational programme and practice (Quality Area 1); Collaborative partnerships with families and communities (Quality Area 6) and Governance and leadership (Quality Area 7). Future directions for research are suggested and implications for embracing a more holistic, integrated and broad view on the use of digital technologies are discussed.

Readability and beyond - Health literacy and numeracy and COVID-19 communications in early childhood education: Are we communicating effectively?

OBJECTIVE: Analyse the linguistic and numerical complexity of COVID-19-related health information communicated from Australian national and state governments and health agencies to national and local early childhood education (ECE) settings. METHODS: Publicly available health information (n = 630) was collected from Australian national and state governments and health agencies, and ECE agencies and service providers. A purposive sample of documents (n = 33) from 2020 to 2021 was analysed inductively and deductively combining readability, health numeracy and linguistic analyses and focusing on the most frequent actionable health advice topics. RESULTS: COVID-19 health advice most frequently related to hygiene, distancing and exclusion. Readability scores in 79% (n = 23) of documents were above the recommended grade 6 reading level for the public. Advice was delivered using direct linguistic strategies (n = 288), indirect strategies (n = 73), and frequent mitigating hedges (n = 142). Most numerical concepts were relatively simple, but lacked elaborative features (e.g., analogies) and/or required subjective interpretation. CONCLUSION: COVID-19 health advice available to the ECE sector included linguistic and numerical information open to mis/interpretation making it difficult to understand and implement. PRACTICE IMPLICATIONS: Combining readability scores with measures of linguistic and numerical complexity offers a more holistic approach to assessing accessibility of health advice and improving health literacy among its recipients.

Drawing Talking: Listening to Children With Speech Sound Disorders.

PURPOSE: Listening to children using age-appropriate techniques supports evidence-based clinical decision-making. In this article, we test the Sound Effects Study Drawing Protocol, an arts-based technique, to support children with speech sound disorder (SSD) to express their views about talking. METHOD: Participants were 124 Australian children aged 4-5 years in the Sound Effects Study. Their parents and teachers were concerned about their talking, and they were assessed as having SSD on the Diagnostic Evaluation of Articulation and Phonology. Drawings and children's interpretations were elicited then analyzed using the (a) Who Am I? Draw-a-Person Scale and (b) Sound Effects Study Focal Points. RESULTS: Drawings were developmentally typical for 4- to 5-year-olds. The six Sound Effects Study Focal Points were identified across the 124 drawings: body parts and facial expressions, talking and listening, relationships and connection, positivity, negativity, and no talking. Participants portrayed talking and listening as an action requiring mouths and ears represented by symbols (letters, speech bubbles) or as an activity with a variety of people. Children typically portrayed themselves as happy when talking; however, some portrayed negativity and some chose not to draw talking. CONCLUSIONS: In keeping with Articles 12 and 13 of the Convention on the Rights of the Child, this research demonstrated that 4- to 5-year-old children with SSD can express their views about talking via drawing. Professionals may use the Sound Effects Study Drawing Protocol as a child-friendly technique to support children to express views to guide holistic, evidence-based, child-centered speech-language pathology practice.

Epidemiology of speech and language impairment in a nationally representative sample of 4- to 5-year-old children.

PURPOSE: To draw on multiple sources of information to determine prevalence of speech and language impairment in young Australian children. METHOD: Information about 4,983 children (ages 4-5 years) from Growing Up in Australia: The Longitudinal Study of Australian Children (Australian Institute of Family Studies, 2007) was obtained via parent interviews and questionnaires, teacher questionnaires, and direct assessment. Data were statistically weighted to the Australian population of 253,202 children in the target age group. RESULTS: Parent-reported prevalence: 25.2% had concerns about how their child talked and made speech sounds (11.8% "concerned"; 13.4% "a little concerned"), and 9.5% had concerns about how their child understood language (4.4% "concerned"; 5.1% "a little concerned"). Parents who reported concerns identified "speech not clear to others" as the most frequent area of difficulty (12.0%). Teacher-reported prevalence: 22.3% of children were considered to be less competent than others in their expressive language ability (6.7% "much less competent"; 15.6% "less competent"); 16.9% were considered to be less competent than others in their receptive language ability (4.0% "much less competent"; 12.9% "less competent"). The match between parent and teacher identification was higher for expressive speech and language concern than for receptive language. Direct assessment: 13.0% of children were 1-2 SDs below the mean on the Adapted Peabody Picture Vocabulary Test-III (S. Rothman, 2003), and a further 1.7% were > 2 SDs below the mean. Parent and teacher reports were significantly correlated with scores obtained via direct assessment. Period prevalence: Parents and teachers reported that 14.5% of children had accessed speech-language pathologist (SLP) services. 2.2% indicated that they needed but could not access an SLP. CONCLUSION: Multiple indicators of speech and language impairment in diverse contexts confirmed the high prevalence of this condition in early childhood and a concomitant need for SLP services.

Early predictors of escalating internalizing problems across middle childhood.

The objective of this study is to examine the trajectory of internalizing problems across middle childhood among a population sample of Australian children, and to understand the timing of explanatory factors related to children's development of internalizing problems, by using multiple-indicator latent growth curve modeling. Participants were children, parents, and teachers in the Longitudinal Study of Australian Children (LSAC) Kindergarten (K) cohort (n = 3,153). Mothers reported on children's internalizing problems at 3 time points (6-7, 8-9, and 10-11 years). Explanatory factors included gender, emotional regulation skills, externalizing problems, peer relationships, parenting behaviors, socioeconomic status, and maternal mental health reported by mothers and teachers at 2 time points (4-5 years and 6-7 years). Growth modeling identified an increasing trajectory of internalizing problems over time. Initial levels were predicted by concurrent (6-7 years) emotional dysregulation, externalizing problems, angry parenting, and maternal mental health problems, as well as earlier (4-5 years) peer problems and maternal mental health. Escalation in internalizing problems was predicted by externalizing problems, peer problems, maternal mental health at 4-5 years, and emotional dysregulation and peer problems at 6-7 years. Girls had both higher initial levels and faster escalation of internalizing problems than boys. The findings provide ecological and developmental evidence and insights for effective intervention. Identifying and addressing early problems with peers may be particularly important to avoid the risk of escalating internalizing problems. Professional development sessions for educators to promote and support children's emotional regulation and peer interaction skills are likely to have a positive impact on children's well-being. (PsycINFO Database Record

Can teacher-child relationships support human rights to freedom of opinion and expression, education and participation?

PURPOSE: This study explored how teacher-child relationships change over the early school years, in terms of closeness and conflict, whether these trajectories differ in type and frequency for children with typical development and children with speech and language concern (SLC), and whether the trajectories are associated with school outcomes at 12-13 years. METHOD: Participants were children, parents and teachers in the Longitudinal Study of Australian Children. Parents identified 2890 children with typical communication and 1442 children with SLC. Teacher-rated teacher-child closeness and conflict were collected biennially over six years. Academic and social-emotional outcomes were reported by teachers and children. Growth mixture modelling was conducted to generate teacher-child relationship trajectories and Wald's chi-square analyses were used to test the association between trajectories and school outcomes at 12-13 years, after controlling for a range of covariates including child's sex, language background, Indigenous status, age and socio-economic position. RESULT: In both groups, the majority of children had teacher-child relationship trajectories with sustained high closeness and low conflict that predicted positive outcomes at age 12-13, but the SLC group was more at risk of less positive trajectories and poorer school outcomes. CONCLUSION: Close, less conflicted relationships with teachers may provide a supportive context for later language, literacy and social-emotional development. This study highlights the role of teachers in supporting children in their development of communication and academic skills that will optimise their capacity for freedom of opinions and expression, education and participation, as enshrined in Articles 19, 26 and 27 of the Universal Declaration of Human Rights.

Impact of Changes Over Time in the Stanford University Genotypic Resistance Interpretation Algorithm.

INTRODUCTION: The Stanford HIV-1 genotypic resistance interpretation algorithm has changed substantially over its lifetime. In many studies, the algorithm version used is not specified. It is easy to assume that results across versions are comparable, but the effects of version changes on resistance calls are unknown. We evaluate these effects for 20 antiretroviral drugs. METHODS: We calculated resistance interpretations for the same 5993 HIV-1 sequences, from participants in AIDS Clinical Trials Group studies, under 14 versions of the Stanford algorithm from 2002 to 2017. Trends over time were assessed using repeated-measures logistic regression. Changes in rule structure and scoring were examined. RESULTS: For most drugs, the proportion of high-level resistance calls on the same sequences was greater using more recent algorithm versions; 16/20 drugs showed significant upward trends. Some drugs, especially tenofovir, had a substantial increase. Only darunavir had a decrease. Algorithm changes impacted calls for subtype C more than B. For intermediate and high-level resistance combined, effects were weaker and more varied. Over time, rules in the Stanford algorithm have become more complex and contain more subrules. The types of rule changes responsible for trends varied widely by drug. DISCUSSION: Reporting the Stanford algorithm version used for resistance analysis is strongly recommended. Caution should be used when comparing results between studies, unless the same version of the algorithm was used. Comparisons using different Stanford versions may be valid for drugs with few changes over time, but for most comparisons, version matters, and for some drugs, the impact is large.