Differences in gross motor and fine motor outcomes for toddlers after early complex cardiac surgery.

OBJECTIVES: To determine whether gross motor scores of toddlers after complex cardiac surgery were different from fine motor scores and were adequately represented by motor composite scores and, whether acute care predictors and chronic childhood health markers of gross motor scores differed from those of fine motor. METHODS: This prospective inception-cohort outcomes study included 171 toddlers after complex cardiac surgery with cardiopulmonary bypass at age <6 months, born in Northern Alberta from 2009 to 2019, and without known chromosomal abnormalities. At a mean (standard deviation) age of 21.7 (3.7) months, the Bayley Scales of Infant and Toddler Development-III determined motor composite and scaled scores (normative values, 100 (15), 10 (3), respectively). The same variables from surgery and assessment were analysed using multivariate regression to predict gross and fine motor scores; results expressed as effect size (95% confidence interval) with % variance. RESULTS: Composite, fine, and gross motor scores were 89.7 (14.2), 9.4 (2.5), and 7.2 (2.7), respectively. Predictive variables accounted for 21.2% of the variance for fine motor, and 36.9% for gross motor. Multivariate analysis for gross motor scores included toddlers need for cardiac medication, effect size (95% confidence interval) -0.801 (-1.62, -0.02), gastrostomy, -1.35 (-2.39, -0.319), and single ventricle, -0.93 (-1.71, -0.15). These same variables did not predict fine motor scores. CONCLUSION: Gross motor skills commonly were lower than fine motor skills for toddlers after complex cardiac surgery. Predictors for gross motor scores differed from fine motor scores. Separate reporting of gross motor scores could lead to improved identification of predictors of delay and to optimised early intervention.

The Alberta Infant Motor Scale as an Outcomes Measure of Gross Motor Abilities after Early Complex Cardiac Surgery.

To address the research hypothesis that the Alberta Infant Motor Scale (AIMS) completed following complex cardiac surgery (CCS) is a useful outcomes measure this study determined: (1) AIMS scores at age 8 months after CCS; (2) predictive validity of AIMS at 8 months for Bayley Scales of Infant and Toddler Development-III Gross Motor-scaled scores (GMSS) and diagnosis of cerebral palsy (CP) at 21 months; and (3) predictive demographic and surgical variables of AIMS scores. A prospective cohort study of 250/271 (92.3%) surviving children from Northern Alberta (born 2009-2020) who had CCS at age < 6 months determined AIMS scores at age mean (SD) 8.6 (2.4) and the GMSS at 21.9 (3.8) months. Gross motor delay was defined as AIMS < 5th percentile and GMSS as < 4 (-2SD). Predictions using multiple logistic regressions were expressed as Odds Ratios (OR) and 95% Confidence Interval (CI). Of children, 100/250 (40%) had AIMS < 5th predicting GMSS < 4 (n = 43); sensitivity, specificity, positive, and negative predictive values were 88%, 71%, 40%, and 97%. Hospitalization days were independently associated with AIMS < 5th, OR 1.02 (95% CI 1.007, 1.032; p = 0.005). Excluding hospital days, ventilation days independently predicted AIMS < 5th, OR 1.08 (95% CI 1.038, 1.125, p < 0.001. Gross motor delay determine by AIMS scores of < 5th percentile occurred in 40% of survivors with good prediction of continued delay. Delay determined by AIMS was predicted by longer hospitalization and ventilation; further investigations about the causes are required. AIMS results provide opportunity for early motor intervention.

Introducing novel key genes and transcription factors associated with rectal cancer response to chemoradiation through co-expression network analysis.

Preoperative radiochemotherapy is a promising therapeutic method for locally advanced rectal cancer patients. However, the response of colorectal cancer (CRC) patients to preoperative radiotherapy varies widely. In this study, we aimed to identify novel biomarkers that could predict the response of colorectal tumors to treatment using a systems biology approach. We applied the Weighted Gene Co-Expression Network Analysis to construct co-expression networks and evaluated the correlation of these networks with radiation using the module-trait relationship. We then identified hub genes and related transcription factors in the selected co-expression module. Our analysis of seven constructed modules revealed that one module, which contained 113 nodes and 6066 edges, had the strongest correlation with radiation effects on CRC (correlation = 0.85; p-value = 6e-7). By analyzing the selected module with the CytoHubba plugin, we identified four hub genes, including ZEB2, JAM2, NDN, and PPAP2A. We also identified seven important transcription factors, including KLF4, SUZ12, TCF4, NANOG, POU5F1, SOX2, and SMARCA4, which may play essential roles in regulating the four hub genes. In summary, our findings suggest that ZEB2, JAM2, NDN, and PPAP2A, along with the seven transcription factors related to these hub genes, may be associated with the response of colorectal tumors to chemoradiotherapy.

Infants less than or equal to 2.5 kg have increased mortality and worse motor neurodevelopmental outcomes at 2 years of age after Norwood-Sano palliation.

Objectives: In infants with single-ventricle congenital heart disease, prematurity and low weight at the time of the Norwood operation are risk factors for mortality. Reports assessing outcomes (including neurodevelopment) post Norwood palliation in infants ≤2.5 kg are limited. Methods: All infants who underwent a Norwood-Sano procedure between 2004 and 2019 were identified. Infants ≤2.5 kg at the time of the operation (cases) were matched 3:1 with infants >3.0 kg (comparisons) for year of surgery and cardiac diagnosis. Demographic and perioperative characteristics, survival, and functional and neurodevelopmental outcomes were compared. Results: Twenty-seven cases (mean ± standard deviation: weight 2.2 ± 0.3 kg and age 15.6 ± 14.1 days at surgery) and 81 comparisons (3.5 ± 0.4 kg and age 10.9 ± 7.9 days at surgery) were identified. Post-Norwood, cases had a longer time to lactate ≤2 mmol/L (33.1 ± 27.5 vs 17.9 ± 12.2 hours, P < .001), longer duration of ventilation (30.5 ± 24.5 vs 18.6 ± 17.5 days, P = .005), greater need for dialysis (48.1% vs 19.8%, P = .007), and greater need for extracorporeal membrane oxygenation support (29.6% vs 12.3%, P = .004). Cases had significantly greater postoperative (in-hospital) (25.9% vs 1.2%, P < .001) and 2-year (59.2% vs 11.1%, P < .001) mortality. Neurodevelopmental assessment showed the following for cases versus comparisons, respectively: cognitive delay (18.2% vs 7.9%, P = .272), language delay (18.2% vs 11.1%, P = .505), and motor delay (27.3% vs 14.3%, P = .013). Conclusions: Infants ≤2.5 kg at Norwood-Sano palliation have significantly increased postoperative morbidity and mortality up to 2-year follow-up. Neurodevelopmental motor outcomes were worse in these infants. Additional studies are warranted to assess the outcome of alternative medical and interventional treatment plans in this patient population.

Maternal co-exposure to mercury and perfluoroalkyl acid isomers and their associations with child neurodevelopment in a Canadian birth cohort.

BACKGROUND: Perfluoroalkyl acids (PFAAs) within the broader class of per- and polyfluoroalkyl substances (PFAS) are present in human serum as isomer mixtures, but epidemiological studies have yet to address isomer-specific associations with child development and behavior. OBJECTIVES: To examine associations between prenatal exposure to 25 PFAAs, including perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) isomers, and child neurodevelopment among 490 mother-child pairs in a prospective Canadian birth cohort, the Alberta Pregnancy Outcomes and Nutrition (APrON) study. To consider the influence of a classic neurotoxicant, total mercury (THg), based on its likelihood of co-exposure with PFAAs from common dietary sources. METHODS: Maternal blood samples were collected in the second trimester and child neurodevelopment was assessed at 2 years of age using the Bayley Scales of Infant and Toddler Development, 3rd Edition (Bayley-III). Linear or curvilinear multiple regression models were used to examine associations between exposures and neurodevelopment outcomes. RESULTS: Select PFAAs were associated with lower Cognitive composite scores, including perfluoroheptanoate (PFHpA) (ß = -0.88, 95% confidence interval (CI): -1.7, -0.06) and perfluorododecanoate (PFDoA) (ß = -2.0, 95% CI: -3.9, -0.01). Non-linear relationships revealed associations of total PFOS (ß = -4.4, 95% CI: -8.3, -0.43), and linear-PFOS (ß = -4.0, 95% CI: -7.5, -0.57) and 1m-PFOS (ß = -1.8, 95% CI: -3.3, -0.24) isomers with lower Language composite scores. Although there was no effect modification, including THg interaction terms in PFAA models revealed negative associations between perfluorononanoate (PFNA) and Motor (ß = -3.3, 95% CI: -6.2, -0.33) and Social-Emotional (ß = -3.0, 95% CI: -5.6, -0.40) composite scores. DISCUSSION: These findings reinforce previous reports of adverse effects of maternal PFAA exposure during pregnancy on child neurodevelopment. The unique hazards posed from isomers of PFOS justify isomer-specific analysis in future studies. To control for possible confounding, mercury co-exposure may be considered in studies of PFAAs.

Neurodevelopmental Outcomes of Infants after Neonatal Surgical Intervention for Tetralogy of Fallot or Pulmonary Atresia.

OBJECTIVE: To determine the 2-year neurodevelopmental outcomes for survivors of neonatal cardiac surgery for the most common right ventricular outflow tract obstructive lesions: tetralogy of Fallot and pulmonary atresia with a ventricular septal defect. STUDY DESIGN: A single-center consecutive cohort of 77 children underwent neonatal surgery for tetralogy of Fallot or pulmonary atresia with a ventricular septal defect at ≤6 weeks of age between 2006 and 2017. The patients underwent a multidisciplinary neurodevelopmental assessment at 18-24 months of age. Survivor outcomes were compared by univariable and multivariable analyses. RESULTS: The 2-year mortality was 7.8% (6/77) with a postoperative in-hospital mortality of 3.9% (3/77). Freedom from reintervention by cardiac catheterization or surgical intervention at 2 years was 36%. Functional and neurodevelopmental assessment for 69 of 71 survivors was completed at a mean age of 22.6 ± 4.0 months using the Bayley Scales of Infant and Toddler Development III. The mean neurodevelopmental outcome scores were 83.4 ± 16.5 for cognitive skills, 82.2 ± 18.7 for language skills, and 81.4 ± 18.1 for motor skills. Cognitive, language, and motor delay, defined as a score of <70, was identified in 25%, 25%, and 23% of patients, respectively. Multivariable analyses for factors associated with worse neurodevelopmental outcomes identified chromosomal anomalies (P < .001) and postoperative complications (P < .03). CONCLUSIONS: Cyanotic tetralogy of Fallot and pulmonary atresia with ventricular septal defect requiring neonatal repair showed similar 2-year neurodevelopmental outcomes below normative values and a high prevalence of cognitive, language and motor delays.

Infants' gut microbiome data: A Bayesian Marginal Zero-inflated Negative Binomial regression model for multivariate analyses of count data.

The infants' gut microbiome is dynamic in nature. Literature has shown high inter-individual variability of gut microbial composition in the early years of infancy compared to adulthood. Although next-generation sequencing technologies are rapidly evolving, several statistical analysis aspects need to be addressed to capture the variability and dynamic nature of the infants' gut microbiome. In this study, we proposed a Bayesian Marginal Zero-inflated Negative Binomial (BAMZINB) model, addressing complexities associated with zero-inflation and multivariate structure of the infants' gut microbiome data. Here, we simulated 32 scenarios to compare the performance of BAMZINB with glmFit and BhGLM as the two other widely similar methods in the literature in handling zero-inflation, over-dispersion, and multivariate structure of the infants' gut microbiome. Then, we showed the performance of the BAMZINB approach on a real dataset using SKOT cohort (I and II) studies. Our simulation results showed that the BAMZINB model performed as well as those two methods in estimating the average abundance difference and had a better fit for almost all scenarios when the signal and sample size were large. Applying BAMZINB on SKOT cohorts showed remarkable changes in the average absolute abundance of specific bacteria from 9 to 18 months for infants of healthy and obese mothers. In conclusion, we recommend using the BAMZINB approach for infants' gut microbiome data taking zero-inflation and over-dispersion properties into account in multivariate analysis when comparing the average abundance difference.

Third Trimester Umbilical Arterial Pulsatility Index is Associated with Neurodevelopmental Outcomes at 2-Years in Major Congenital Heart Disease.

Major congenital heart disease (CHD) is associated with impaired neurodevelopment (ND), partly from prenatal insults. In this study we explore associations between 2nd and 3rd trimester umbilical (UA) and middle cerebral artery (MCA) pulsatility index (PI = systolic-diastolic velocities/mean velocity) in fetuses with major CHD and 2-year ND and growth outcomes. Eligible patients included those with a prenatal diagnosis of CHD from 2007 to 2017 without a genetic syndrome who underwent previously defined cardiac surgeries and 2-year biometric and ND assessments in our program. UA and MCA-PI Z-scores at fetal echocardiography were examined for relationships with 2-year Bayley Scales of Infant and Toddler Development and biometric Z-scores. Data from 147 children was analyzed. Second and 3rd trimester fetal echocardiograms were performed at 22.4 ± 3.7 and 34.7 ± 2.9 weeks (mean ± SD), respectively. Multivariable regression analysis showed an inverse relationship between 3rd trimester UA-PI for all CHD and cognitive - 1.98 (- 3.37, - 0.59), motor - 2.57 (- 4.15, - 0.99), and language - 1.67 (- 3.3, - 0.03) (effect size and 95th confidence interval) ND domains (p < 0.05), with the strongest relationships in the single ventricle and hypoplastic left heart syndrome subgroups. No association was found for 2nd trimester UA-PI or any trimester MCA-PI and ND or between UA or MCA-PI and 2-year growth parameters. Increased 3rd trimester UA-PI, reflecting an altered late gestation fetoplacental circulation, relates to worse 2-year ND in all domains.

Geographically weighted linear combination test for gene-set analysis of a continuous spatial phenotype as applied to intratumor heterogeneity.

Background: The impact of gene-sets on a spatial phenotype is not necessarily uniform across different locations of cancer tissue. This study introduces a computational platform, GWLCT, for combining gene set analysis with spatial data modeling to provide a new statistical test for location-specific association of phenotypes and molecular pathways in spatial single-cell RNA-seq data collected from an input tumor sample. Methods: The main advantage of GWLCT consists of an analysis beyond global significance, allowing the association between the gene-set and the phenotype to vary across the tumor space. At each location, the most significant linear combination is found using a geographically weighted shrunken covariance matrix and kernel function. Whether a fixed or adaptive bandwidth is determined based on a cross-validation cross procedure. Our proposed method is compared to the global version of linear combination test (LCT), bulk and random-forest based gene-set enrichment analyses using data created by the Visium Spatial Gene Expression technique on an invasive breast cancer tissue sample, as well as 144 different simulation scenarios. Results: In an illustrative example, the new geographically weighted linear combination test, GWLCT, identifies the cancer hallmark gene-sets that are significantly associated at each location with the five spatially continuous phenotypic contexts in the tumors defined by different well-known markers of cancer-associated fibroblasts. Scan statistics revealed clustering in the number of significant gene-sets. A spatial heatmap of combined significance over all selected gene-sets is also produced. Extensive simulation studies demonstrate that our proposed approach outperforms other methods in the considered scenarios, especially when the spatial association increases. Conclusion: Our proposed approach considers the spatial covariance of gene expression to detect the most significant gene-sets affecting a continuous phenotype. It reveals spatially detailed information in tissue space and can thus play a key role in understanding the contextual heterogeneity of cancer cells.

Identification of Prognostic Biomarkers for Breast Cancer Metastasis Using Penalized Additive Hazards Regression Model.

Background: Breast cancer (BC) has been reported as one of the most common cancers diagnosed in females throughout the world. Survival rate of BC patients is affected by metastasis. So, exploring its underlying mechanisms and identifying related biomarkers to monitor BC relapse/recurrence using new statistical methods is essential. This study investigated the high-dimensional gene-expression profiles of BC patients using penalized additive hazards regression models. Methods: A publicly available dataset related to the time to metastasis in BC patients (GSE2034) was used. There was information of 22 283 genes expression profiles related to 286 BC patients. Penalized additive hazards regression models with different penalties, including LASSO, SCAD, SICA, MCP and Elastic net were used to identify metastasis related genes. Results: Five regression models with penalties were applied in the additive hazards model and jointly found 9 genes including SNU13, CLINT1, MAPK9, ABCC5, NKX3-1, NCOR2, COL2A1, and ZNF219. According the median of the prognostic index calculated using the regression coefficients of the penalized additive hazards model, the patients were labeled as high/low risk groups. A significant difference was detected in the survival curves of the identified groups. The selected genes were examined using validation data and were significantly associated with the hazard of metastasis. Conclusion: This study showed that MAPK9, NKX3-1, NCOR1, ABCC5, and CD44 are the potential recurrence and metastatic predictors in breast cancer and can be taken into account as candidates for further research in tumorigenesis, invasion, metastasis, and epithelial-mesenchymal transition of breast cancer.

A complicated Glenn procedure: risk factors and association with adverse long-term neurodevelopmental and functional outcomes.

OBJECTIVES: To determine potentially modifiable risk factors for a complicated Glenn procedure (cGP) and whether a cGP predicted adverse neurodevelopmental and functional outcomes. A cGP was defined as post-operative death, heart transplant, extracorporeal life support, Glenn takedown, or prolonged ventilation. METHODS: All 169 patients having a Glenn procedure from 2012 to 2017 were included. Neurodevelopmental assessments were performed at age 2 years in consenting survivors (n = 156/159 survivors). The Bayley Scales of Infant and Toddler Development-3rd Edition (Bayley-III) and the Adaptive Behavior Assessment System-2nd Edition (ABAS-II) were administered. Adaptive functional outcomes were determined by the General Adaptive Composite (GAC) score from the ABAS-II. Predictors of outcomes were determined using univariate and multiple variable linear or Cox regressions. RESULTS: Of patients who had a Glenn procedure, 10/169 (6%) died by 2 years of age and 27/169 (16%) had a cGP. Variables statistically significantly associated with a cGP were the inotrope score on post-operative day 1 (HR 1.04, 95%CI 1.01, 1.06; p = 0.010) and use of inhaled nitric oxide post-operatively (HR 7.31, 95%CI 3.19, 16.76; p < 0.001). A cGP was independently statistically significantly associated with adverse Bayley-III Cognitive (ES -10.60, 95%CI -17.09, -4.11; p = 0.002) and Language (ES -11.43, 95%CI -19.25, -3.60; p = 0.004) scores and adverse GAC score (ES -14.89, 95%CI -22.86, -6.92; p < 0.001). CONCLUSIONS: Higher inotrope score and inhaled nitric oxide used post-operatively were associated with a cGP. A cGP was independently associated with adverse 2-year neurodevelopmental and functional outcomes. Whether early recognition and intervention for risk of a cGP can prevent adverse outcomes warrants study.

Evaluating the Prevalence and Factors Associated With an Optimal Neurodevelopmental Outcome in 4- to 6-Year-Old Children With Fontan Circulation.

BACKGROUND: We sought to evaluate the prevalence and factors associated with "optimal" neurodevelopmental outcomes in 4- to 6-year-old children with Fontan circulation. METHODS: Patients followed through the Western Canadian Complex Pediatric Therapies Follow-Up Program, and born between September 1996 and December 2015, were included. Optimal neurodevelopmental outcome was defined as full-scale intelligence quotient; visual-motor integration; adaptive behaviour assessment system-general adaptive composite scores of ≥ 80 each; and the absence of chronic motor disability, permanent hearing loss, visual impairment, and seizure disorder. Multivariable regression models and decision algorithms evaluated variables associated with optimal outcomes. RESULTS: The Fontan procedure was completed on 225 children, with neurodevelopmental outcome data available for 205 (mean [standard deviation]) age at Fontan 3.4 (0.9) years, 37% female). Optimal neurodevelopmental outcome was identified in 55% (112 of 205). Factors independently associated with optimal neurodevelopmental outcome were female sex (odds ratio [OR], 2.1; 95% confidence interval [CI] 1.1-4.1), years of maternal schooling (OR, 1.2 [1.1-1.4]), age at Fontan (years) (OR, 0.97 [0.94-1.0]), need for concomitant atrioventricular valve (AVV) intervention (OR, 0.4 [0.2-1.0]), and time (hours) for lactate to be ≤ 2 mmol/L (OR, 0.9 [0.8-1.0]). Of those with Fontan completion < 3.25 years, without concomitant AVV intervention and lactate normalization within 8 hours post-Fontan, 87% (27 of 31) had optimal neurodevelopmental outcomes. CONCLUSIONS: Optimal neurodevelopmental outcome was present in more than one-half of 4- to 6-year-old children with Fontan circulation in this cohort study, with important associated factors identified, including potentially modifiable factors such as younger age at Fontan surgery and lack of concomitant AVV intervention.

Geostatistical Modeling and Heterogeneity Analysis of Tumor Molecular Landscape.

Intratumor heterogeneity (ITH) is associated with therapeutic resistance and poor prognosis in cancer patients, and attributed to genetic, epigenetic, and microenvironmental factors. We developed a new computational platform, GATHER, for geostatistical modeling of single cell RNA-seq data to synthesize high-resolution and continuous gene expression landscapes of a given tumor sample. Such landscapes allow GATHER to map the enriched regions of pathways of interest in the tumor space and identify genes that have spatial differential expressions at locations representing specific phenotypic contexts using measures based on optimal transport. GATHER provides new applications of spatial entropy measures for quantification and objective characterization of ITH. It includes new tools for insightful visualization of spatial transcriptomic phenomena. We illustrate the capabilities of GATHER using real data from breast cancer tumor to study hallmarks of cancer in the phenotypic contexts defined by cancer associated fibroblasts.

The rise to power of the microbiome: power and sample size calculation for microbiome studies.

A priori power and sample size calculations are crucial to appropriately test null hypotheses and obtain valid conclusions from all clinical studies. Statistical tests to evaluate hypotheses in microbiome studies need to consider intrinsic features of microbiome datasets that do not apply to classic sample size calculation. In this review, we summarize statistical approaches to calculate sample sizes for typical microbiome study scenarios, including those that hypothesize microbiome features to be the outcome, the exposure or the mediator, and provide relevant R scripts to conduct some of these calculations. This review is intended to be a resource to facilitate the conduct of sample size calculations that are based on testable hypotheses across several dimensions of the microbiome. Implementation of these methods will improve the quality of human or animal microbiome studies, enabling reliable conclusions that will generalize beyond the study sample.

An updated reference for age-sex-specific birth weight percentiles stratified for ethnicity based on data from all live birth infants between 2005 and 2014 in Alberta, Canada.

OBJECTIVE: This study aims to update the current reference for sex-specific birth weight percentiles by gestational age, overall and for specific ethnic groups, based on data from all singleton live-birth deliveries from 2005 to 2014 in Alberta, Canada. METHODS: Infant and maternal information were captured in the Alberta Vital Statistics-Births Database for 473,115 singleton infants born to 311,800 women between January 1, 2005 and December 31, 2014. Within each sex, and each sex-ethnic group, birth weights were modelled by gestational age using generalized additive models and natural cubic splines. Crude and corrected estimates for birth weight percentiles including cut-off values for large for gestational age (LGA) and small for gestational age (SGA) were calculated by sex and sex-ethnic group, and gestational age for singleton live births. RESULTS: LGA and SGA cut-offs were lower for females than for males for all gestational ages. The SGA and LGA percentiles were greater for both male and female very preterm infants in Alberta compared to previous national references. Ethnicity-specific LGA and SGA cut-offs for term Chinese and preterm and at-term South Asian infants were consistently lower than those for both the general population in Alberta and the previous national reference. South Asian infants had lower birth weights at almost all gestational ages compared with the other groups. CONCLUSION: The updated birth weight percentiles presented in this study highlight the differences in SGA and LGA cut-offs among infants from South Asian, Chinese, and the general population, which may be important for clinical perinatal care.

RéSUMé: OBJECTIFS: L'objectif de cette étude est d'actualiser la référence actuelle pour les percentiles de poids à la naissance spécifique au sexe par l'âge gestationnel, globalement et pour des groupes ethniques spécifiques, basé sur les données de tous les accouchements de naissances vivante uniques entre 2005 et 2014 en Alberta, au Canada. MéTHODES: L'information infantile et maternelle ont été capturées dans les statistiques de l'état civil ­ base de données sur les naissances, en Alberta, pour 473 115 nourrissons uniques nés de 311 800 femmes entre le 1er janvier 2005 et le 31 décembre 2014. Dans chaque sexe, et dans chaque groupe sexe-ethnique, les poids de naissances ont été modélisés par l'âge gestationnel grâce à l'utilisation de modèles additifs généralisés et de splines cubiques naturelles. Des estimations grossières et corrigées pour les percentiles de poids à la naissance, y compris les valeurs seuils pours les nourrissons gros pour l'âge gestationnel (GAG) et petits pour l'âge gestationnel (PAG), ont été calculées par sexe et groupe sexe-ethnique, et par l'âge gestationnel pour les naissances vivantes uniques. RéSULTATS: Les critères pour GAG et PAG étaient plus bas pour les femelles que pour les mâles pour tous les âges gestationnels. Les percentiles pour PAG et GAG étaient plus élevés pour les nourrissons mâles et femelles nés très prématurés en Alberta en comparaison avec les références nationales précédentes. Les critères pour GAG et PAG spécifiques à l'ethnicité chinoise, pour les nourrissons nés à termes, et sud-asiatiques, pour les nourrissons nés avant et à termes, étaient régulièrement plus basses que ceux de la population générale en Alberta et de la référence nationale précédente. Les nourrissons sud-asiatiques avaient des poids de naissances plus basses à presque tous les âges gestationnels en comparaison avec les autres groupes. CONCLUSION: Les percentiles de poids à la naissance actualisés présentés dans cette étude mettent en évidence les différences de PAG et GAG entre les nourrissons sud-asiatiques, chinoises et de la population générale, qui peuvent êtres importantes pour les soins cliniques périnatales.

Interaction of prenatal bisphenols, maternal nutrients, and toxic metal exposures on neurodevelopment of 2-year-olds in the APrON cohort.

BACKGROUND: Epidemiological studies suggest that Bisphenol-A (BPA) is a developmental neurotoxicant, but the modifying effects of maternal nutrient status or neurotoxicant metal co-exposures have not been reported. Bisphenol-S (BPS) is being used as a BPA-alternative, but few epidemiological studies have evaluated its effects. OBJECTIVES: To examine if prenatal maternal BPA or BPS exposure are associated with children's neurodevelopment at two years of age while adjusting for effect-measure modification by sex, maternal nutrients, and co-exposure to neurotoxic metals. METHODS: Total BPA and BPS concentrations were analyzed in spot maternal urine from the second trimester; metals and maternal nutrient status were analyzed in blood. Child neurodevelopment was evaluated with the Bayley Scales of Infant Development-III (Bayley-III) at age 2 (394 maternal-child pairs) and linear regression was used to investigate associations. RESULTS: Among nutrients and neurotoxic metals, selenium (Se) and cadmium (Cd) were the most significant predictors of Bayley-III scale scores. Higher maternal Cd was significantly correlated with poorer motor performance (p < 0.01), and higher levels of maternal Se were significantly associated with poorer performance on the cognitive, motor, and adaptive behavior scales (p < 0.05). While maternal Cd did not modify relationships between bisphenol exposures and Bayley-III scores, both maternal Se and child sex were significant effect-measure modifiers. Associations between BPA exposure and social emotional scores were negative for boys (p = 0.056) but positive for girls (p = 0.046). Higher exposure to bisphenols was associated with lower motor scores among children with lower levels of maternal Se. CONCLUSION: Higher maternal Cd was associated with poorer motor development, but it was not an effect-measure modifier of bisphenols' effects on motor development. Maternal Se may be protective against adverse effects of bisphenols, and additional nutrient-bisphenol interaction studies examining sex-specific effects of BPA and BPS on child development are warranted.

Efficacy of metformin and fermentable fiber combination therapy in adolescents with severe obesity and insulin resistance: study protocol for a double-blind randomized controlled trial.

BACKGROUND: Accumulating evidence suggests that the metabolic effects of metformin and fermentable fibers are mediated, in part, through diverging or overlapping effects on the composition and metabolic functions of the gut microbiome. Pre-clinical animal models have established that the addition of fiber to metformin monotherapy improves glucose tolerance. However, possible synergistic effects of combination therapy (metformin plus fiber) have not been investigated in humans. Moreover, the underlying mechanisms of synergy have yet to be elucidated. The aim of this study is to compare in adolescents with obesity the metabolic effects of metformin and fermentable fibers in combination with those of metformin or fiber alone. We will also determine if therapeutic responses correlate with compositional and functional features of the gut microbiome. METHODS: This is a parallel three-armed, double-blinded, randomized controlled trial. Adolescents (aged 12-18 years) with obesity, insulin resistance (IR), and a family history of type 2 diabetes mellitus (T2DM) will receive either metformin (850 mg p.o. twice/day), fermentable fibers (35 g/day), or a combination of metformin plus fiber for 12 months. Participants will be seen at baseline, 3, 6, and 12 months, with a phone follow-up at 1 and 9 months. Primary and secondary outcomes will be assessed at baseline, 6, and 12 months. The primary outcome is change in IR estimated by homeostatic model assessment of IR; key secondary outcomes include changes in the Matsuda index, oral disposition index, body mass index z-score, and fat mass to fat-free mass ratio. To gain mechanistic insight, endpoints that reflect host-microbiota interactions will also be assessed: obesity-related immune, metabolic, and satiety markers; humoral metabolites; and fecal microbiota composition, short-chain fatty acids, and bile acids. DISCUSSION: This study will compare the potential metabolic benefits of fiber with those of metformin in adolescents with obesity, determine if metformin and fiber act synergistically to improve IR, and elucidate whether the metabolic benefits of metformin and fiber associate with changes in fecal microbiota composition and the output of health-related metabolites. This study will provide insight into the potential role of the gut microbiome as a target for enhancing the therapeutic efficacy of emerging treatments for T2DM prevention. TRIAL REGISTRATION: ClinicalTrials.gov NCT04578652 . Registered on 8 October 2020.

Music Use for Sedation in Critically ill Children (MUSiCC trial): a pilot randomized controlled trial.

OBJECTIVE: To demonstrate feasibility of a music medicine intervention trial in pediatric intensive care and to obtain information on sedation and analgesia dose variation to plan a larger trial. MATERIAL AND METHODS: Pilot randomized controlled trial (RCT) was conducted at the Stollery Children's Hospital general and cardiac intensive care units (PICU/PCICU). The study included children 1 month to 16 years of age on mechanical ventilation and receiving sedation drugs. Patients were randomized in a 1:1:1 ratio to music, noise cancellation or control. The music group received classical music for 30 min three times/day using headphones. The noise cancellation group received the same intervention but with no music. The control group received usual care. RESULTS: A total of 60 patients were included. Average enrollment rate was 4.8 patients/month, with a consent rate of 69%. Protocol adherence was achieved with patients receiving > 80% of the interventions. Overall mean (SD) daily Sedation Intensity Score was 52.4 (30.3) with a mean (SD) sedation frequency of 9.75 (7.21) PRN doses per day. There was a small but statistically significant decrease in heart rate at the beginning of the music intervention. There were no study related adverse events. Eighty-eight percent of the parents thought the headphones were comfortable; 73% described their child more settled during the intervention. CONCLUSIONS: This pilot RCT has demonstrated the feasibility of a music medicine intervention in critically ill children. The study has also provided the necessary information to plan a larger trial.

Fetal Umbilical Arterial Pulsatility Correlates With 2-Year Growth and Neurodevelopmental Outcomes in Congenital Heart Disease.

BACKGROUND: Children with congenital heart disease (CHD) are at risk of adverse long-term neurodevelopmental outcomes, believed to be, in part, secondary to prenatal insults. Placental pathology and altered fetal middle cerebral arterial (MCA) flow suggestive of brain sparing have been documented in fetal CHD. In the present study we investigated the relationship between MCA and umbilical arterial (UA) flow patterns in fetal transposition of the great arteries (d-TGA) and hypoplastic left heart syndrome (HLHS) and growth and 2-year neurodevelopmental outcomes. METHODS: We included children with d-TGA and HLHS who had third-trimester fetal echocardiograms between 2004 and 2014, at which time umbilical artery (UA) and MCA pulsatility indices (PIs) were measured, and who underwent 2-year growth and neurodevelopmental assessments. RESULTS: We identified 24 children with d-TGA and 36 with HLHS. Mean age at fetal echocardiography was 33.8 ± 3.5 weeks. At 2-year follow-up, head circumference z score (standard deviation [SD]) was -0.09 (1.07) and 0.17 (1.7) for the d-TGA and HLHS groups, respectively. Bayley III mean (SD) cognitive, language, and motor scores were 97.7 (10.8), 94.7 (13.4), and 98.6 (8.6) for the d-TGA group and 90.3 (13.9), 87.2 (17.5), and 85.3 (16.2) for the HLHS group. On multivariate linear regression analysis, UA-PI was associated (effect sizes [95% CI]) with length (-1.45 [-2.7, -0.17], P = 0.027), weight (-1.46 [-2.6 to -0.30], P = 0.015) and cognitive scores (-14.86 [-29.95 to 0.23], P = 0.05) at 2 years of age. MCA PI showed no statistically significant correlation. CONCLUSIONS: In fetal d-TGA and HLHS, a higher UA-PI in the third trimester, suggestive of placental insufficiency-but not MCA-PI-is associated with worse 2-year growth and neurodevelopment.

Health-related quality of life after pediatric heart transplantation in early childhood.

BACKGROUND: There is limited information about HRQL after pediatric heart transplantation at a young age. METHODS: Prospective follow-up study of children who received a heart transplant at age ≤4 years. HRQL was assessed using the PedsQLTM 4.0 at age 4.5 years. This cohort was compared with healthy children, children with CHD, and with chronic conditions. Peri-operative factors associated with HRQL were also explored. RESULTS: Of 66 eligible patients, 15 (23%) died prior to the HRQL assessment and 2 (3%) were lost to follow-up, leaving 49 patients. Indication for transplantation was CHD in 27 (55%) and CMP in 22 (45%). Median age (IQR) at transplant was 9 (5-31) months. HRQL was significantly lower in transplanted children compared to population norms (65.3 vs 87.3, P < .0001), children with chronic conditions (65.3 vs 76.1, P = .001), and children with CHD (65.3 vs 81.1, P < .0001). Transplanted children with CHD had lower HRQL than those with a prior diagnosis of CMP (59.5 vs 72.5, P-value = .020). Higher creatinine pretransplant and higher lactate post-operatively were associated with lower HRQL. CONCLUSION: Children after heart transplant had significantly lower HRQL, as reported by their parents, than the normative population, children with chronic conditions, and children with CHD.