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.

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.

Timing of Delayed Retinal Pathology in Patients Presenting with Acute Posterior Vitreous Detachment in the IRIS® Registry (Intelligent Research in Sight).

OBJECTIVE: To determine the timing of delayed retinal pathology in eyes presenting with acute posterior vitreous detachment (PVD). DESIGN: Retrospective database study. SUBJECTS: Patients in the Intelligent Research in Sight (IRIS) registry found to have acute PVD based on the International Classification of Diseases, Ninth and Tenth Revision, codes were followed. METHODS: Patients coded to have a PVD from 2013 to 2018 along with common procedural technology coding of extended ophthalmoscopy were included. Ocular baseline characteristics included visual acuity, lens status, presence or absence of vitreous hemorrhage, myopia, lattice degeneration, and subspecialty training of the treating physician. MAIN OUTCOME MEASURES: Timing (days) to delayed retinal break or detachment RESULTS: A total of 434 046 eyes met inclusion/exclusion criteria, and 10 518 eyes (2.42%) presented with a delayed retinal break or detachment after initial PVD. The median time to retinal break and detachment after initial PVD was 42 (range, 1-365) days and 51 (range, 1-365) days, respectively. Eyes with vitreous hemorrhage (hazard ratio [HR], 9.30; 95% confidence interval [CI], 8.50-10.2), history of retinal break/retinal detachment in the fellow eye (HR, 3.91; 95% CI, 3.64-4.20), lattice degeneration (HR, 2.61; 95% CI, 2.35-2.90), and myopia (HR, 1.42; 95% CI, 1.33-1.53) were found to be at a higher risk of developing delayed break or detachment. CONCLUSIONS: Follow-up examination after initial PVD is necessary to diagnose delayed or missed retinal pathology. In eyes with no initial pathology, providers should consider repeat examination at least once within 6 weeks, and sooner for eyes with higher-risk features. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

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.

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.

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.

Parent Perspectives of Ear Health and the Relationship with Children's Speech and Language in the Longitudinal Study of Indigenous Children.

Health and well-being are holistic concepts that are perceived to be inseparable for Aboriginal and Torres Strait Islander peoples. We examined relationships between parent-reported ear symptoms for 787 Indigenous children at two time points (age 2-3 years, age 4-5 years) and two parent-reported speech and language outcomes one year later (age 5-6 years). Most parents (80.2%) reported no concern about their child's expressive language and (93.8%) receptive language. Binary logistic regression models examined ear health as a predictor of children's expressive and receptive speech and language adjusting for sociodemographic and health covariates. For children without parent-reported ear symptoms, there were lower odds of parental concern about expressive speech and language (aOR = 0.45; 95% CI 0.21-0.99) and receptive language (aOR = 0.24; 95% CI 0.09-0.62). Parents were less likely to have concerns about the child's expressive speech and language if their child was female, lived in urban or regional areas, had excellent or very good global health, or had no disability when aged 2-5 years. Since parent-reported ear health and speech and language concerns were related, Aboriginal and Torres Strait Islander children could benefit from culturally safe, strength-based, and family-centered integrated speech, language, and ear health services.

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.

Concentrations of dexmedetomidine and effect on biomarkers of cartilage toxicity following intra-articular administration in horses.

OBJECTIVE: The goal of this study was to determine plasma, urine, and synovial fluid concentrations and describe the effects on biomarkers of cartilage toxicity following intra-articular dexmedetomidine administration to horses. ANIMALS: 12 research horses. PROCEDURES: Horses received a single intra-articular administration of 1 µg/kg or 5 µg/kg dexmedetomidine or saline. Plasma, urine, and synovial fluid were collected prior to and up to 48 hours postadministration, and concentrations were determined. The effects on CS846 and C2C were determined in synovial fluid at 0, 12, and 24 hours postadministration using immunoassays. RESULTS: Plasma concentrations of dexmedetomidine fell below the limit of quantification (LOQ) (0.005 ng/mL) by 2.5 and 8 hours postadministration of 1 and 5 µg/kg, respectively. Synovial fluid concentrations were above the LOQ (0.1 ng/mL) of the assay at 24 hours in both dose groups. Drug was not detected in urine samples at any time postdrug administration. CS846 concentrations were significantly decreased relative to baseline at 12 hours postadministration in the saline group and significantly increased in the 5-µg/kg-dose group at 24 hours. Concentrations of C2C were significantly decreased at 12 and 24 hours postadministration in the saline treatment group. There were no significant differences in CS846 or C2C concentrations between dose groups at any time. CLINICAL RELEVANCE: Systemic concentrations of dexmedetomidine remained low, compared to synovial fluid concentrations. CS846, a marker of articular cartilage synthesis, increased in a dose-dependent fashion. Based on these findings, further dose titration and investigation of analgesic and adverse effects are warranted.

Pharmacokinetics and pharmacodynamics of intra-articular isoflupredone following administration to horses with lipopolysaccharide-induced synovitis.

BACKGROUND: Intra-articular corticosteroids, such as isoflupredone acetate, are commonly used in the treatment of joint inflammation, especially in performance horses. Following administration in a non-inflamed joints blood concentrations of isoflupredone were low and detectable for only a short period of time post-administration compared to synovial fluid concentrations. For some drugs, inflammation can affect pharmacokinetics, therefore, the goal of the current study was to describe the pharmacokinetics of isoflupredone acetate following intra-articular administration using a model of acute synovitis. Secondarily, pharmacodynamic effects, including effects on joint circumference, joint flexion, and lameness following intra-articular administration of isoflupredone acetate in the experimental model were described. METHODS: Sixteen horses received a single intra-articular dose of 8 mg of isoflupredone acetate or saline 12 h post-administration of lipopolysaccharide. Blood and urine samples were collected up to 72 h and synovial fluid for 28 days post-administration, drug concentrations determined by liquid chromatography- mass spectrometry and pharmacokinetic analysis performed. Joint circumference, maximum angle of pain free joint flexion and lameness were evaluated prior to and post-treatment. RESULTS: The maximum isoflupredone plasma concentration was 2.45 ± 0.61 ng/mL at 2.5 ± 0.75 h and concentrations were less than the limit of quantitation by 72 h. Isoflupredone was below detectable concentrations in urine by 72 h post-administration in all horses and no longer detectable in synovial fluid by 96 h post-administration. Joint circumference was significantly decreased in the isoflupredone treatment group compared to the saline group at 24 and 48 h post drug administration. Pain free joint flexion was significantly different between the saline and isoflupredone treatment groups on day 4 post-treatment. CONCLUSIONS: Synovial fluid concentrations and maximum plasma concentrations of isoflupredone differed slightly between the current study and a previous one describing administration into a non-inflamed joint, however, the detection time of isoflupredone in blood was comparable. Effects of isoflupredone on joint circumference and degree of pain free joint flexion suggest a short duration of effect with respect to alleviation of lipopolysaccharide induced synovitis, however, results of this study support future studies of the anti-inflammatory effects of intra-articular isoflupredone acetate.

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.

Metabolic and cardiovascular effects of body weight supported treadmill walking in healthy older adults.

BACKGROUND: The purpose of this study was to determine if body weight supported treadmill training (BWSTT) decreased metabolic and cardiovascular demand in older (50-74 years) healthy adults while walking a self-selected speed. The results of this study could impact clinician application to exercise therapy. METHODS: Twenty subjects (50% female, 58.3±7.3 years) completed 3, 5-minute treadmill walking trials at a self-selected pace, with 0%, 15%, and 30% body weight support (BWS). Blood pressure (BP), heart rate (HR), and oxygen uptake (V̇O2) were measured at rest, and during walking trials. Mean data from minutes 3-5 were analyzed for difference by repeated measures ANOVA and Bonferroni post-hoc test. RESULTS: At rest, HR was 70.8±8.2 bpm and BP was 126.8±12.2/84.3±8.6 mmHg. Mean walking speed was 67.1 m/min. Tested parameters during exercise trials were significantly (P<0.05) different from rest, but no significant differences were detected among the 3 exercise trials. CONCLUSIONS: In older adults walking at self-selected speeds, up to 30% BWS had no significant impact on metabolic or cardiovascular demand.

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.

Cardiomyocyte Oga haploinsufficiency increases O-GlcNAcylation but hastens ventricular dysfunction following myocardial infarction.

RATIONALE: The beta-O-linkage of N-acetylglucosamine (i.e., O-GlcNAc) to proteins is a pro-adaptive response to cellular insults. To this end, increased protein O-GlcNAcylation improves short-term survival of cardiomyocytes subjected to acute injury. This observation has been repeated by multiple groups and in multiple models; however, whether increased protein O-GlcNAcylation plays a beneficial role in more chronic settings remains an open question. OBJECTIVE: Here, we queried whether increasing levels of cardiac protein O-GlcNAcylation would be beneficial during infarct-induced heart failure. METHODS AND RESULTS: To achieve increased protein O-GlcNAcylation, we targeted Oga, the gene responsible for removing O-GlcNAc from proteins. Here, we generated mice with cardiomyocyte-restricted, tamoxifen-inducible haploinsufficient Oga gene. In the absence of infarction, we observed a slight reduction in ejection fraction in Oga deficient mice. Overall, Oga reduction had no major impact on ventricular function. In additional cohorts, mice of both sexes and both genotypes were subjected to infarct-induced heart failure and followed for up to four weeks, during which time cardiac function was assessed via echocardiography. Contrary to our prediction, the Oga deficient mice exhibited exacerbated-not improved-cardiac function at one week following infarction. When the observation was extended to 4 wk post-MI, this acute exacerbation was lost. CONCLUSIONS: The present findings, coupled with our previous work, suggest that altering the ability of cardiomyocytes to either add or remove O-GlcNAc modifications to proteins exacerbates early infarct-induced heart failure. We speculate that more nuanced approaches to regulating O-GlcNAcylation are needed to understand its role-and, in particular, the possibility of cycling, in the pathophysiology of the failing heart.

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.

Long term renal function in Asian HIV-1 infected adults receiving tenofovir disoproxil fumarate without protease inhibitors.

OBJECTIVES: The risk of kidney dysfunction on the WHO recommended first line regimens containing tenofovir disoproxil fumarate (TDF) without protease inhibitors (PI) remains unclear in Asian patients, especially those with low body weight. METHODS: Using data collected in a multicenter clinical trial in Thailand and proportional hazard regression models, we compared the risk of a >25% estimated glomerular filtration rate (eGFR) reduction in HIV naïve patients initiating TDF or zidovudine (AZT) containing non-PI regimen. RESULTS: Of 640 patients included in the analysis, 461 (72%) received a TDF-containing regimen for a median 6.7 years and 179 (28%) an AZT-containing regimen for 6.5 years. The risk of a >25% eGFR reduction was not associated with treatment (HR 1.11, 95% CI 0.84-1.47, P = 0.46). In multivariate analysis, the risk of >25% eGFR reduction form baseline was associated with body weight at baseline (HR 2.12, 95% CI 1.48-3.02 for <48 kg patients and HR 1.64, 95% CI 1.20-2.25 for 48-59.9 kg patients, compared to those with >60 kg, P < 0.001) and hypertension (HR 4.03, 95% CI 2.0-8.0, P < 0.001). The effect of baseline weight on >25% eGFR reduction did not significantly vary with treatment (P = 0.27). CONCLUSIONS: The risk of eGFR reduction was not higher on TDF- versus AZT-based non-PI regimens. Although the risk of eGFR reduction was greater for patients of lower body weight, this risk was not significantly increased by TDF.