Applying computer-based language test to young children.

INTRODUCTION: This study aims at exploring the feasibility of applying a computer-based language test to young children aged 2-4 years. METHODS: Thirty-two Cantonese-speaking children, aged 2-4 years, were recruited from local kindergartens. All participants underwent assessment using both the computer-based and paper-pencil versions of the Macau Cantonese Language Screening Scale for Preschool Children, following a crossover study design. A short break of 15-30 minutes was provided between the two assessments. The data were analysed at three levels: the overall test, subcategory, and individual item levels. At the overall test and subcategory levels, data were analysed using the paired samples t-test and ICC. At the item level, the percentage of agreement and Cohen's kappa value were selected to assess the agreement of the two test formats. RESULTS: Excellent agreement was found for the overall test level, and good agreement was observed for four of the five subcategories. At the individual item level, 28 of the 35 items showed more than 80% agreement, and 16 items showed substantial to almost perfect agreement. CONCLUSION: These results suggest that the two test formats give similar total scores and subcategory scores for children aged 2-4. For children older than 2 years, 6 months, the agreement for matching items is as high as 83.68% (1318/1575). The computer-based test is thus highly recommended for this group of children. For children younger than 2 years, 6 months, a modified computer-based test is suggested to accommodate their needs.

CARD 2020: antibiotic resistome surveillance with the comprehensive antibiotic resistance database.

The Comprehensive Antibiotic Resistance Database (CARD; https://card.mcmaster.ca) is a curated resource providing reference DNA and protein sequences, detection models and bioinformatics tools on the molecular basis of bacterial antimicrobial resistance (AMR). CARD focuses on providing high-quality reference data and molecular sequences within a controlled vocabulary, the Antibiotic Resistance Ontology (ARO), designed by the CARD biocuration team to integrate with software development efforts for resistome analysis and prediction, such as CARD's Resistance Gene Identifier (RGI) software. Since 2017, CARD has expanded through extensive curation of reference sequences, revision of the ontological structure, curation of over 500 new AMR detection models, development of a new classification paradigm and expansion of analytical tools. Most notably, a new Resistomes & Variants module provides analysis and statistical summary of in silico predicted resistance variants from 82 pathogens and over 100 000 genomes. By adding these resistance variants to CARD, we are able to summarize predicted resistance using the information included in CARD, identify trends in AMR mobility and determine previously undescribed and novel resistance variants. Here, we describe updates and recent expansions to CARD and its biocuration process, including new resources for community biocuration of AMR molecular reference data.

Geographic inequalities in paediatric emergency department visits in Ontario and Alberta: a multilevel analysis of 2.5 million visits.

BACKGROUND: Research on intra- and inter-regional variations in emergency department (ED) visits among children can provide a better understanding of the patterns of ED utilization and further insight into how contextual features of the urban environment may be associated with these health events. Our objectives were to assess intra-urban and inter-urban variation in paediatric emergency department (PED) visits in census metropolitan areas (CMAs) in Ontario and Alberta, Canada and explore if contextual factors related to material and social deprivation, proximity to healthcare facilities, and supply of family physicians explain this variation. METHODS: A retrospective, population-based analysis of data on PED visits recorded between April 1, 2015 and March 31, 2017 was conducted. Random intercept multilevel regression models were constructed to quantify the intra- (between forward sortation areas [FSAs]) and inter- (between CMAs) variations in the rates of PED visits. RESULTS: In total, 2,537,442 PED visits were included in the study. The overall crude FSA-level rate of PED visits was 415.4 per 1,000 children population. Across CMAs, the crude rate of PED visits was highest in Thunder Bay, Ontario (771.6) and lowest in Windsor, Ontario (237.2). There was evidence of substantial intra- and inter-urban variation in the rates of PED visits. More socially deprived FSAs, FSAs with decreased proximity to healthcare facilities, and CMAs with a higher rate of family physicians per 1,000 children population had higher rates of PED visits. CONCLUSIONS: The variation in rates of PED visits across CMAs and FSAs cannot be fully accounted for by age and sex distributions, material and social deprivation, proximity to healthcare facilities, or supply of family physicians. There is a need to explore additional contextual factors to better understand why some metropolitan areas have higher rates of PED visits.

Oral Language Performance of Deaf and Hard-of-Hearing Students in Mainstream Schools.

In Hong Kong, students are expected to speak fluent Cantonese, Putonghua, and English. However, the curriculum does not include Cantonese studies, as children are expected to have already acquired Cantonese by the age of school entry. This study examined the language outcomes of Cantonese-speaking deaf or hard-of-hearing children who attend primary schools within the Hong Kong educational system and considered whether the system currently meets the needs of these children. The Hong Kong Cantonese Oral Language Assessment Scale, which comprises six subtests, was used to assess 98 children with mild to profound hearing loss. A regression analysis was used to examine the influences of various variables on oral language performance in these children. Notably, 41% of the participants had achieved age-appropriate oral language skills, while 18% and 41% exhibited mild-to-moderate or severe oral language impairment, respectively. The degree of hearing loss and the use of speech therapy were identified as significant negative predictors of oral language performance. The issues of a relatively late diagnosis and device fitting, as well as the very poor oral language outcomes, strongly emphasize the need for policy makers to reconsider the existing educational approaches and support for deaf or hard-of-hearing children.

The development of discourse referencing in Cantonese of deaf/hard-of-hearing children.

This paper investigates the development of discourse referencing in spoken Cantonese of fifteen deaf/hard-of-hearing children studying in a sign bilingual and co-enrollment education programme in a mainstream setting in Hong Kong. A comparison of their elicited narratives with those of the hearing children and adults shows that, despite a delay in acquiring the grammatical markings for (in)definiteness in Cantonese, these d/hh children show sensitivity towards the referential properties of different types of nominal expressions and their corresponding mappings with discourse functions. Specifically, they produced more bare nouns across all discourse contexts but fewer existential constructions, pronouns, demonstratives, and classifier-related constructions. Their choice of nominal expressions and the observed errors show striking similarities to the productions by the younger hearing children in this study, suggesting that the d/hh children's route of development of discourse referencing is likely to be similar to that of hearing children despite a slower rate of development.

A curated census of pathogenic and likely pathogenic UTR variants and evaluation of deep learning models for variant effect prediction.

Introduction: Variants in 5' and 3' untranslated regions (UTR) contribute to rare disease. While predictive algorithms to assist in classifying pathogenicity can potentially be highly valuable, the utility of these tools is often unclear, as it depends on carefully selected training and validation conditions. To address this, we developed a high confidence set of pathogenic (P) and likely pathogenic (LP) variants and assessed deep learning (DL) models for predicting their molecular effects. Methods: 3' and 5' UTR variants documented as P or LP (P/LP) were obtained from ClinVar and refined by reviewing the annotated variant effect and reassessing evidence of pathogenicity following published guidelines. Prediction scores from sequence-based DL models were compared between three groups: P/LP variants acting though the mechanism for which the model was designed (model-matched), those operating through other mechanisms (model-mismatched), and putative benign variants. PhyloP was used to compare conservation scores between P/LP and putative benign variants. Results: 295 3' and 188 5' UTR variants were obtained from ClinVar, of which 26 3' and 68 5' UTR variants were classified as P/LP. Predictions by DL models achieved statistically significant differences when comparing modelmatched P/LP variants to both putative benign variants and modelmismatched P/LP variants, as well as when comparing all P/LP variants to putative benign variants. PhyloP conservation scores were significantly higher among P/LP compared to putative benign variants for both the 3' and 5' UTR. Discussion: In conclusion, we present a high-confidence set of P/LP 3' and 5' UTR variants spanning a range of mechanisms and supported by detailed pathogenicity and molecular mechanism evidence curation. Predictions from DL models further substantiate these classifications. These datasets will support further development and validation of DL algorithms designed to predict the functional impact of variants that may be implicated in rare disease.

Correlates of child mental health and substance use related emergency department visits in Ontario: A linked population survey and administrative health data study.

Introduction: Knowledge of the sociodemographic, behavioural, and clinical characteristics of children visiting emergency departments (EDs) for mental health or substance use concerns in Ontario, Canada is lacking. Objectives: Using data from a population-based survey linked at the individual level to administrative health data, this study leverages a provincially representative sample and quasi-experimental design to strengthen inferences regarding the extent to which children's sociodemographic, behavioural, and clinical characteristics are associated with the risk of a mental health or substance use related ED visit. Methods: 9,301 children aged 4-17 years participating in the 2014 Ontario Child Health Study were linked retrospectively (6 months) and prospectively (12 months) with administrative health data on ED visits from the National Ambulatory Care Reporting System. Modified Poisson regression was used to examine correlates of mental health and substance use related ED visits among children aged 4-17 years over a 12-month period following their survey completion date, adjusting for ED visits in the 6 months prior to their survey completion date. Subgroup analyses of youths aged 14-17 years who independently completed survey content related to peer victimisation, substance use, and suicidality were also conducted. Results: Among children aged 4-17 years, older age, parental immigrant status, internalising problems, and perceived need for professional help were statistically significant correlates that increased the risk of a mental health or substance use related ED visit; low-income and suicidal ideation with attempt were statistically significant only among youths aged 14-17 years. Conclusions: Knowledge of the sociodemographic, behavioural, and clinical characteristics of children visiting EDs for mental health and substance use related concerns is required to better understand patient needs to coordinate effective emergency mental health care that optimises child outcomes, and to inform the development and targeting of upstream interventions that have the potential to prevent avoidable ED visits. Highlights: Growing rates of child mental health and substance use related ED visits have been observed internationally.A population-based survey linked at the individual level to administrative health data was used to examine the extent to which children's sociodemographic, behavioural, and clinical characteristics are associated with the risk of a mental health or substance use related ED visit in Ontario, Canada.Older age, low-income, parental immigrant status, perceived need for professional help, internalising problems, and suicidality increase the risk of an ED visit.Knowledge of the characteristics of children visiting EDs can be used to coordinate effective emergency mental health care that optimises child outcomes, and to inform the development and targeting of upstream interventions that have the potential to prevent avoidable ED visits.

Does the definition of preventable emergency department visit matter? An empirical analysis using 20 million visits in Ontario and Alberta.

OBJECTIVES: This study had two objectives: (1) to estimate the prevalence of preventable emergency department (ED) visits during the 2016-2020 time period among those living in 19 large urban centers in Alberta and Ontario, Canada, and (2) to assess if the definition of preventable ED visits matters in estimating the prevalence. METHODS: A retrospective, population-based study of ED visits that were reported to the National Ambulatory Care Reporting System from April 1, 2016, to March 31, 2020, was conducted. Preventable ED visits were operationalized based on the following approaches: (1) Canadian Triage and Acuity Scale (CTAS), (2) ambulatory care-sensitive conditions (ACSC), (3) family practice-sensitive conditions (FPSC), and (4) sentinel nonurgent conditions (SNC). The overall proportion of ED visits that were preventable was estimated. We also estimated the adjusted relative risks of preventable ED visits by patients' sex and age, fiscal year, province of residence, and census metropolitan area (CMA) of residence. RESULTS: There were 20,171,319 ED visits made by 8,919,618 patients ages 1 to 74 who resided in one of the 19 CMAs in Alberta or Ontario. On average, there were 2.26 visits per patient over the period of 4 fiscal years; most patients made one (44.22%) or two ED visits (20.72%). The overall unadjusted prevalence of preventable ED visits varied by definition; 35.33% of ED visits were defined as preventable based on CTAS, 12.88% based on FPSC, 3.41% based on SNC, and 2.33% based on ACSC. CONCLUSIONS: There is a substantial level of variation in prevalence estimates across definitions of preventable ED visits, and care should be taken when interpreting these estimates as each has a different meaning and may lead to different conclusions. The conceptualization and measurement of preventable ED visits is complex and multifaceted and may not be adequately captured by a single definition.

The Neoantigen Landscape of the Coding and Noncoding Cancer Genome Space.

Tumor mutation burden (TMB) is a measure to predict patient responsiveness to immune checkpoint immunotherapy because with increased mutation frequency, the likelihood of a greater neoantigen burden is increased. Although neoantigen prediction tools exist, tumor neoantigen burden has not been adopted as a measure to predict immunotherapy response. With both measures, current guidelines are limited to the coding regions, but ectopic expression of sequences in the noncoding space may potentially be a source of neoantigens. A pan-cancer cohort of 574 advanced disease stage patients with whole genome and transcriptome sequencing was analyzed to report mutation burden and neoantigen counts within the coding and noncoding regions. The efficacy of tumor neoantigen burden, reported as tumor neoantigen count (TNC), including neoantigens derived from the expression of noncoding regions, compared with TMB as a predictor of response to immunotherapy for 80 patients who had received treatment, was evaluated. TMB was found to be the best predictor of response to immunotherapy, whereas expression-derived TNC from the noncoding regions did not improve prediction of response. Therefore, there is minimal benefit in extending the calculation of TNC to the noncoding space for the purposes of predicting response. However, it is likely that there is a wealth of neoantigens derived from the noncoding space that may impact patient outcomes and treatments.

Interventions for people at ultra-high risk for psychosis: A systematic review of economic evaluations.

AIM: Psychotic disorders have long-term negative consequences for functioning and quality of life. Ultra-high risk (UHR) programs aim to identify and treat people during the prodromal period before their first psychotic episode. Though studies on the clinical effectiveness of treating prodromal symptoms in people at UHR for psychosis exist, no review has exclusively and comprehensively evaluated the economic impact of UHR programs. Our objective was to systematically review the literature on economic evaluations of UHR programs. METHODS: We searched the Cochrane, EMBASE, MEDLINE, and PsycInfo electronic databases, in addition to grey literature, from inception to March 2020 to identify economic evaluations of UHR programs. We included all cost and cost-effectiveness studies of interventions for people at UHR. The data were synthesized qualitatively, and a risk of bias assessment was performed. RESULTS: Of the 1916 articles retrieved, six studies met our inclusion criteria. These included three cost analysis studies and three cost-effectiveness studies. Five studies were conducted from the health system perspective and the time horizon varied between six months and ten years. Only two reported quality-adjusted life-years (QALYs) as their outcome. Overall, all cost-effectiveness studies and one cost analysis suggested that UHR programs were cost-effective and cost saving, respectively. The risk of bias assessment suggested moderate levels of bias across all studies. CONCLUSION: Economic evaluations of UHR programs varied in terms of outcomes and length of follow-up; however, most studies found them to be cost-effective. Future studies would benefit from long-term evaluations of UHR programs and consistent valuation of outcomes.

Use of Treatment-Focused Tumor Sequencing to Screen for Germline Cancer Predisposition.

Next-generation sequencing assays are capable of identifying cancer patients eligible for targeted therapies and can also detect germline variants associated with increased cancer susceptibility. However, these capabilities have yet to be routinely harmonized in a single assay because of challenges with accurately identifying germline variants from tumor-only data. We have developed the Oncology and Hereditary Cancer Program targeted capture panel, which uses tumor tissue to simultaneously screen for both clinically actionable solid tumor variants and germline variants across 45 genes. Validation using 14 tumor specimens, composed of patient samples and cell lines analyzed in triplicate, demonstrated high coverage with sensitive and specific identification of single-nucleotide variants and small insertions and deletions. Average coverage across all targets remained >2000× in 198 additional patient tumor samples. Analysis of 55 formalin-fixed, paraffin-embedded tumor samples for the detection of known germline variants within a subset of cancer-predisposition genes, including one multiexon deletion, yielded a 100% detection rate, demonstrating that germline variants can be reliably detected in tumor samples using a single panel. Combining targetable somatic and actionable germline variants into a single tumor tissue assay represents a streamlined approach that can inform treatment for patients with advanced cancers as well as identify those with potential germline variants who are eligible for confirmatory testing, but would not otherwise have been identified.

The origins and genomic diversity of American Civil War Era smallpox vaccine strains.

Vaccination has transformed public health, most notably including the eradication of smallpox. Despite its profound historical importance, little is known of the origins and diversity of the viruses used in smallpox vaccination. Prior to the twentieth century, the method, source and origin of smallpox vaccinations remained unstandardised and opaque. We reconstruct and analyse viral vaccine genomes associated with smallpox vaccination from historical artefacts. Significantly, we recover viral molecules through non-destructive sampling of historical materials lacking signs of biological residues. We use the authenticated ancient genomes to reveal the evolutionary relationships of smallpox vaccination viruses within the poxviruses as a whole.