Risk of Neurotoxicity with Multiple General Anaesthetics for Examination Under Anaesthesia in Paediatric Ophthalmology - A Cause for Concern?

Purpose: To evaluate the impact of clinical protocol change via active minimisation on the number of general anaesthetic (GA)/sedation episodes for diagnostic ophthalmic purposes at Children's Health Ireland at Temple Street (CHI-TS), Dublin, Ireland, from 2016 to 2019, inclusive. Change was implemented following published cautionary principles in 2016 by the FDA regarding the potential neurotoxic risk from multiple GA exposure in children. Methods: Retrospective analysis of electronic operating theatre records was completed using procedure codes "Ophthalmological examination" and "Examination of fundi". Available records for patients undergoing multiple examination under anaesthesia (EUA) procedures were assessed for demographics, indication. Comparison was made regarding overall EUA numbers and breakdown for each year, before and after the new departmental approach. From 2018 onward, a patient-centred, departmental strategy of active minimisation of EUA was adopted, using strategies of "training, technology and patience". A literature review was conducted using online databases. Results: A total of 450 EUAs were performed over the 4 years investigated. In the former 2 years of the study period, prior to departmental policy change, EUAs represented 32% (304 of 948 total theatre episodes) of the ophthalmic theatre caseload. In the latter 2 years of this study period, this proportion fell to 19% (146 EUAs of 783 theatre episodes). Total theatre case numbers were comparable in both time periods. Eighteen children had multiple EUAs (ie, ≥2 EUAs, mean 6.5, SD 2.9) for life/sight threatening indications, totalling 116 EUAs (25.7%). Conclusion: A significant reduction in diagnostic EUA volume was accomplished resulting in reduced individual patient risk and increased capacity for surgical interventions. A detailed description of this methodology is included for the purposes of replication at comparable units. EUA will continue to play a crucial role in the management of life/sight threatening conditions but the application of a cautionary principle to reduce EUA, where possible, is appropriate to reduce potential for neurotoxicity.

MFRP-Associated Retinopathy and Nanophthalmos in Two Irish Probands: A Case Report.

The conjunction of nanophthalmos (NO) and retinitis pigmentosa (RP) provides challenges to effective clinical management while narrowing the genetic spectrum for targeted molecular diagnostics. This case study describes two not knowingly related adult cases of MFRP-associated retinopathy and nanophthalmos (MARN). Structural features including short axial lengths (mean 16.4 mm), steep keratometry (mean 49.98 D), adult-onset signs, and symptoms of retinal dystrophy and acquired disease (i.e., cataract, angle-closure glaucoma) were evident in both cases. Pathogenic variants in the MFRP gene impair both prenatal eye growth and childhood emmetropization while also leading to RPE/outer retinal degeneration in 75% of cases. We discuss the "small-eye" phenotype spectrum and associated defining characteristics, molecular mechanisms with particular focus on MFRP-associated NO with RP features (MARN), the spectrum of visual morbidities (e.g., extreme refractive error, amblyopia, cystoid macular lesions, early cataract) and the challenges of their treatment/surgical management.

Can quality management drive evidence generation?

Recent guidance documents from international regulators emphasize the importance of thoughtful trial design and risk-based oversight in delivering reliable results. In practice, these recommendations are often implemented in a fragmented manner, reducing their effectiveness. We argue that collaborative, cross-stakeholder engagement that prioritizes both optimal trial design and tailored oversight are a necessary and effective approach to modernize quality management. This practice is at the core of Quality by Design, an approach that involves identifying important errors that could undermine trial credibility or participant safety and addressing them proactively. While Quality by Design is well suited for clinical trials supporting regulatory approval of a new medicinal product, we describe how the approach is equally relevant for pragmatic trials, including those conducted in the context of a pandemic.

A Validation Study of the Alcohol Related Neurodevelopmental Disorders Behavioral Checklist.

BACKGROUND: The initial confirmatory factor analysis of the Alcohol Related Neurodevelopmental Disorder Behavioral Checklist (ABC) utilized a population of 203 children. The analysis identified 10 independent measures (executive functioning, attention and concentration, cognition, memory, confabulation, gullibility, communication skills, academic skills, living/social skills, and juvenile justice). The 10 measures differentiated children with FASD from non-FASD controls. In this study, we present a validity study of the ABC using a different population of children with FASD and non-FASD controls. METHODS: A chart review identified 224 children with ABC checklist scores who had been evaluated for FASD. From this sample, we implemented a case-control study of 76 children diagnosed with FASD and 76 non-FASD controls who were matched by gender and closest age in years (mean age was 8.5 years). RESULTS: The averages of the total score and individual domain scores were compared between the 2 data sets and then between children with FASD and non-FASD controls. Children with FASD had significantly higher scores on all 10 measures than the non-FASD controls. There were very high sensitivity and specificity scores for the total score cutoff and for all 10 of the individual measures. CONCLUSIONS: In an independent sample, we found minimal differences between the previous data and the current validation study on measures of average total score cutoffs, scores for the 10 measures and correlations. Combining the 2 samples yielded robust differences in scores between children with FASD and non-FASD controls. The sensitivity, specificity and accuracy estimates were also very high. The ABC Screen appears to have acceptable epidemiologic performance data to support its use as a screening tool and as an initial step in differentiating children with FASD from those who do not have FASD.

Early childhood educators' knowledge about language and literacy: Associations with practice and children's learning.

Educators' language and literacy knowledge is considered important for informing classroom practices and thereby supporting children's early language and literacy development. This includes both disciplinary content knowledge (knowledge concerning how oral and written language are structured and map to one another) and knowledge for practice (knowledge of effective strategies and practices for supporting early language and literacy). In this study, we examined the associations among 485 early childhood educators' content knowledge and knowledge for practice, their observed language and literacy practices, and the emergent literacy learning of 2004 children enrolled in their classrooms. We found significant, positive correlations between measures of educators' content knowledge and knowledge for practice and classroom practice, indicating that early childhood educators with greater levels of knowledge tended to exhibit more desirable classroom language and literacy practices. We also found significant, positive associations between educators' knowledge and children's print concept, letter naming, and phonological awareness learning, but not children's oral language learning. The associations between educators' knowledge and children's print concept learning were mediated by classroom practice. Together, these results reiterate the importance of educators' language and literacy knowledge and also provide some support for practice as the mechanism through which knowledge relates to children's learning.

Psychometric Properties and Convergent Validity of the Chinese Version of the Rosenberg Self-Esteem Scale.

The present study used the Rasch rating scale model (RSM) to reassess the psychometric properties of the Chinese version of Rosenberg self-esteem scale (RSES) among 501 Grade 10 students in Taiwan. The reliability, dimensionality, and differential item functioning were examined. The dimensionality assumption was met after excluding item 8 ("I wish I could have more respect for myself."). The successive response categories for item 7 ("I feel that I am a person of worth, at least on an equal plane with others.") were not located in an expected order. After eliminating items 7 and 8 from analysis, the remaining 8-item RSES had acceptable fit statistics, good content coverage and high categorical omega, Rasch person and item reliability. The five response categories performed well; evidence for convergent validity was established through the high correlation between RSES and psychological being scores. Implications and recommendations for instrument users are discussed.

Clinical trial quality: From supervision to collaboration and beyond.

Over the past decade, clinical trial quality has evolved from an after-the-fact, reactive activity to one focused on the important work of evidence generation from well-designed trials. This article explores the role the Clinical Trials Transformation Initiative has played in advancing quality as a core element of clinical trial design, through project work that initially focused on monitoring but evolved into a holistic, prospective, and comprehensive quality by design approach to clinical trial design and conduct.

Relationship between serostatus disclosure and categories of HIV transmission risk in men who have sex with men living with HIV.

In prior studies, the relationship between serostatus disclosure and reduced HIV transmission risk has been mixed. The demonstration of a clear connection may be restricted by three main methodological limitations. This study evaluates the relationship between (1) more refined measures of serostatus disclosure and (2) eight categories of HIV transmission risk (lowest to highest risk) among men who have sex with men (MSM) living with HIV, while (3) considering a number of control variables. Results demonstrate that disclosure is more likely in sexual encounters involving no intercourse or involving protected and unprotected anal intercourse with HIV-positive partners than unprotected insertive anal intercourse with HIV-negative/unknown status partners. Additionally, substance use prior to sexual encounters is less likely in lower risk categories than the highest risk category. Results of this study are important to the design of future studies, prevention, and intervention programs for MSM and to the methods used to evaluate their effectiveness.

Teacher-child relationships and classroom-learning behaviours of children with developmental language disorders.

BACKGROUND: Children with developmental language disorders (DLDs) often struggle with classroom behaviour. No study has examined whether positive teacher-child relationships may act as a protective factor for children with DLDs in that these serve to enhance children's important classroom-learning behaviours. AIMS: To examine the association between the quality of teacher-child relationships and teacher-rated classroom-learning behaviours of children with DLDs in both preschool and kindergarten. METHODS & PROCEDURES: Longitudinal data were collected on 191 preschoolers (mean = 42.4 months of age, SD = 11.6 months) with DLDs in special education classrooms during preschool and in kindergarten. Teacher-child relationship quality was assessed in preschool, and children's classroom-learning behaviours were measured in preschool and kindergarten. Regression models were used to examine the relationship between teacher-child relationship quality and children's concurrent and future classroom-learning behaviours. OUTCOMES & RESULTS: Positive teacher-child relationship quality in preschool was associated with better classroom-learning behaviours in preschool and kindergarten for children with DLDs. Preschool teacher-child relationship quality characterized by low levels of conflict and high levels of closeness was associated with positive classroom-learning behaviours during preschool. Teacher-child conflict but not closeness was predictive of children's classroom-learning behaviours in kindergarten. CONCLUSIONS & IMPLICATIONS: These results suggest that the quality of the teacher-child relationship for children with DLDs during preschool is associated within their learning-related behaviours in the classroom both concurrently and in the subsequent year. Findings suggest that teacher-child relationships should be explored as a mechanism for improving the learning-related behaviours of children with DLDs.

Improving public health by improving clinical trial guidelines and their application.

Evidence generated from randomized controlled trials forms the foundation of cardiovascular therapeutics and has led to the adoption of numerous drugs and devices that prolong survival and reduce morbidity, as well as the avoidance of interventions that have been shown to be ineffective or even unsafe. Many aspects of cardiovascular research have evolved considerably since the first randomized trials in cardiology were conducted. In order to be large enough to provide reliable evidence about effects on major outcomes, cardiovascular trials may now involve thousands of patients recruited from hundreds of clinical sites in many different countries. Costly infrastructure has developed to meet the increasingly complex organizational and operational requirements of these clinical trials. Concerns have been raised that this approach is unsustainable, inhibiting the reliable evaluation of new and existing treatments, to the detriment of patient care. These issues were considered by patients, regulators, funders, and trialists at a meeting of the European Society of Cardiology Cardiovascular Roundtable in October 2015. This paper summarizes the key insights and discussions from the workshop, highlights subsequent progress, and identifies next steps to produce meaningful change in the conduct of cardiovascular clinical research.

Step-Count Accuracy of 3 Motion Sensors for Older and Frail Medical Inpatients.

OBJECTIVE: To measure the step-count accuracy of an ankle-worn accelerometer, a thigh-worn accelerometer, and a pedometer in older and frail inpatients. DESIGN: Cross-sectional design study. SETTING: Research room within a hospital. PARTICIPANTS: Convenience sample of inpatients (N=32; age, ≥65 years) who were able to walk 20m independently with or without a walking aid. INTERVENTIONS: Patients completed a 40-minute program of predetermined tasks while wearing the 3 motion sensors simultaneously. Video recording of the procedure provided the criterion measurement of step count. MAIN OUTCOME MEASURES: Mean percentage errors were calculated for all tasks, for slow versus fast walkers, for independent walkers versus walking-aid users, and over shorter versus longer distances. The intraclass correlation was calculated, and accuracy was graphically displayed by Bland-Altman plots. RESULTS: Thirty-two patients (mean age, 78.1±7.8y) completed the study. Fifteen (47%) were women, and 17 (51%) used walking aids. Their median speed was .46m/s (interquartile range [IQR], .36-.66m/s). The ankle-worn accelerometer overestimated steps (median error, 1% [IQR, -3% to 13%]). The other motion sensors underestimated steps (median error, 40% [IQR, -51% to -35%] and 38% [IQR -93% to -27%], respectively). The ankle-worn accelerometer proved to be more accurate over longer distances (median error, 3% [IQR, 0%-9%]) than over shorter distances (median error, 10% [IQR, -23% to 9%]). CONCLUSIONS: The ankle-worn accelerometer gave the most accurate step-count measurement and was most accurate over longer distances. Neither of the other motion sensors had acceptable margins of error.

Understanding Risk for Reading Difficulties in Children With Language Impairment.

Purpose: The purpose of this study was to retrospectively examine the preschool language and early literacy skills of kindergarten good and poor readers, and to determine the extent to which these skills predict reading status. Method: Participants were 136 children with language impairment enrolled in early childhood special education classrooms. On the basis of performance on a word recognition task given in kindergarten, children were classified as either good or poor readers. Comparisons were made across these 2 groups on a number of language and early literacy measures administered in preschool, and logistic regression was used to determine the best predictors of kindergarten reading status. Results: Twenty-seven percent of the sample met criterion for poor reading in kindergarten. These children differed from good readers on most of the skills measured in preschool. The best predictors of kindergarten reading status were oral language, alphabet knowledge, and print concept knowledge. Presence of comorbid disabilities was not a significant predictor. Classification accuracy was good overall. Conclusion: Results suggest that risk of reading difficulty for children with language impairment can be reliably estimated in preschool, prior to the onset of formal reading instruction. Measures of both language and early literacy skills are important for identifying which children are likely to develop later reading difficulties.

Enhancing clinical evidence by proactively building quality into clinical trials.

BACKGROUND: Stakeholders across the clinical trial enterprise have expressed concern that the current clinical trial enterprise is unsustainable. The cost and complexity of trials have continued to increase, threatening our ability to generate reliable evidence essential for making appropriate decisions concerning the benefits and harms associated with clinical interventions. Overcoming this inefficiency rests on improving protocol design, trial planning, and quality oversight. METHODS: The Clinical Trials Transformation Initiative convened a project to evaluate methods to prospectively build quality into the scientific and operational design of clinical trials ("quality-by-design"), such that trials are feasible to conduct and important errors are prevented rather than remediated. A working group evaluated aspects of trial design and oversight and developed the Clinical Trials Transformation Initiative quality-by-design principles document, outlining a series of factors generally relevant to the reliability of trial conclusions and to patient safety. These principles were then applied and further refined during a series of hands-on workshops to evaluate their utility in facilitating proactive, cross-functional dialogue, and decision-making about trial design and planning. Following these workshops, independent qualitative interviews were conducted with 19 workshop attendees to explore the potential challenges for implementing a quality-by-design approach to clinical trials. The Clinical Trials Transformation Initiative project team subsequently developed recommendations and an online resource guide to support implementation of this approach. CONCLUSION: The Clinical Trials Transformation Initiative quality-by-design principles provide a framework for assuring that clinical trials adequately safeguard participants and provide reliable information on which to make decisions on the effects of treatments. The quality-by-design workshops highlighted the value of active discussions incorporating the different perspectives within and external to an organization (e.g. clinical investigators, research site staff, and trial participants) in improving trial design. Workshop participants also recognized the value of focusing oversight on those aspects of the trial where errors would have a major impact on participant safety and reliability of results. Applying the Clinical Trials Transformation Initiative quality-by-design recommendations and principles should enable organizations to prioritize the most critical determinants of a trial's quality, identify non-essential activities that can be eliminated to streamline trial conduct and oversight, and formulate appropriate plans to define, avoid, mitigate, monitor, and address important errors.

TransCelerate's Clinical Quality Management System: From a Vision to a Conceptual Framework.

The Quality Management System (QMS) initiative of TransCelerate BioPharma Inc has identified potential benefits that could be captured from the development of a flexible, proactive clinical QMS conceptual framework for clinical research. Such a framework would aid organizations in seamlessly managing the complex clinical trial environment and, ultimately, in expediting delivery of needed treatments to patients. This article chronicles the evolution of a TransCelerate concept paper describing a proposed clinical QMS framework and reviews feedback from varied global clinical trial stakeholders during socialization of the concept paper. Many stakeholders recognized the potential for the concept paper to inform development of a harmonized International Council for Harmonisation (ICH) guideline, providing needed clarity from regulators on their expectations for QMS in the clinical realm. Accordingly, the article also describes TransCelerate's efforts to work with regulators to facilitate harmonization on this important topic and reviews ongoing work to develop additional tools and resources that may support organizations in evaluating whether and how they might translate the conceptual framework principles into practice.

Mapping protein binding sites on the biomolecular corona of nanoparticles.

Nanoparticles in a biological milieu are known to form a sufficiently long-lived and well-organized 'corona' of biomolecules to confer a biological identity to the particle. Because this nanoparticle-biomolecule complex interacts with cells and biological barriers, potentially engaging with different biological pathways, it is important to clarify the presentation of functional biomolecular motifs at its interface. Here, we demonstrate that by using antibody-labelled gold nanoparticles, differential centrifugal sedimentation and various imaging techniques it is possible to identify the spatial location of proteins, their functional motifs and their binding sites. We show that for transferrin-coated polystyrene nanoparticles only a minority of adsorbed proteins exhibit functional motifs and the spatial organization appears random, which is consistent, overall, with a stochastic and irreversible adsorption process. Our methods are applicable to a wide array of nanoparticles and can offer a microscopic molecular description of the biological identity of nanoparticles.

Enhancing Quality and Efficiency in Clinical Development Through a Clinical QMS Conceptual Framework: Concept Paper Vision and Outline.

A quality management system (QMS) is an integrated framework through which organizations can systematically plan and achieve their quality objectives. While the International Conference on Harmonisation (ICH) Q10 provides clear guidance for QMS in the pharmaceutical manufacturing sector, there is no harmonized regulatory guidance describing a framework that provides an enterprise-wide view of achievement of clinical quality objectives, that is capable of being customized to fit an organization's unique circumstances, and that accommodates the variability inherent in clinical development. In the absence of such guidance, clinical QMS varies dramatically across industry, sometimes resulting in over-engineered, cumbersome systems that are not adaptable or fit-for-purpose. This paper will describe the ongoing activities of a TransCelerate initiative developing a conceptual framework for a Clinical QMS designed to provide a consistent, streamlined, and proactive quality approach across all stages of clinical research.

The efficacy of serostatus disclosure for HIV Transmission risk reduction.

Interventions to assist HIV+ persons in disclosing their serostatus to sexual partners can play an important role in curbing rates of HIV transmission among men who have sex with men (MSM). Based on the methods of Pinkerton and Galletly (AIDS Behav 11:698-705, 2007), we develop a mathematical probability model for evaluating effectiveness of serostatus disclosure in reducing the risk of HIV transmission and extend the model to examine the impact of serosorting. In baseline data from 164 HIV+ MSM participating in a randomized controlled trial of a disclosure intervention, disclosure is associated with a 45.0 % reduction in the risk of HIV transmission. Accounting for serosorting, a 61.2 % reduction in risk due to disclosure was observed in serodisconcordant couples. The reduction in risk for seroconcordant couples was 38.4 %. Evidence provided supports the value of serostatus disclosure as a risk reduction strategy in HIV+ MSM. Interventions to increase serostatus disclosure and that address serosorting behaviors are needed.

Approaches to academic growth assessment.

BACKGROUND: There is much interest in assessing growth in student learning. Assessments of growth have important implications and affect many policy decisions at many levels. AIMS: In the present article, we review some of the different approaches to measuring growth and examine the implications of their usage. SAMPLE: Samples used in research on growth models typically include students enrolled in public schools that primarily serve kindergarten through the 12th grade. METHOD: Definitions of growth and gain are reviewed, and five types of growth models are examined: (1) Student Gain Score Model, (2) The Covariate Adjustment Model, (3) The Student Percentile Gain Model - referred to as single-wave value-added models, (4) Univariate Value-Added Response Models, and (5) Multivariate Value-Added Response Models. RESULTS: Modelling approaches are vastly different, whereas Student Gain Models are mathematically and conceptually simple, Multivariate Models are highly complex. CONCLUSION: Educators assessing growth must make critical decisions about measurement. The type of instrument that is selected and the type of analytic techniques selected are of great importance. Growth must be considered from technical, pedagogical, and policy perspectives.

Vocabulary gain among children with language disorders: contributions of children's behavior regulation and emotionally supportive environments.

PURPOSE: Behavior regulation is a positive predictor of language outcomes for children with typically developing language skills, and children with language disorders are at greater risk for difficulties with behavior regulation. This study investigated the unique role of behavior regulation on vocabulary gain for children receiving language therapy in the public schools as well as the unique and moderating influence of emotional support within therapy sessions on outcomes. METHOD: A total of 121 kindergarten and 1st-grade students with language disorders, nested within 42 speech-language pathologists (SLPs), participated in the study. Direct child measures, indirect child measures, and therapy session videotapes were used for all analyses. RESULTS: Hierarchical linear modeling indicated a positive association between children's behavior regulation and vocabulary gain. The emotional support of therapy sessions was not a significant predictor of vocabulary gain. CONCLUSIONS: Results from this study suggest that children's behavior regulation is a significant predictor of vocabulary gain for children with language disorders; children with higher behavior regulation gain more over the academic year than do peers with lower behavior regulation. Findings highlight the importance of SLPs considering children's behavior regulation when planning and implementing therapy.