Alberta Children's Hospital Research Articles

Few sex differences in regional gray matter volume growth trajectories across early childhood

Abstract Sex-specific developmental differences in brain structure have been documented in older children and adolescents, with females generally showing smaller overall brain volumes and earlier peak ages than males. However, sex differences in gray matter structural development in early childhood are less studied. We characterized sex-specific trajectories of gray matter volume development in children aged 2–8 years. We acquired anatomical magnetic resonance imaging (MRI) of the brain at the Alberta Children's Hospital in 123 typically developing children. Most children were scanned multiple times, for a total of 393 scans (mean = 3.2 scans/subject). We segmented T1-weighted structural MRI with MaCRUISE to define 116 regions and measured both absolute volumes (mm3) and proportional volumes (percent of intracranial volume). We characterized growth trajectories of gray matter volume for these brain regions between 2 and 8 years using mixed-effects models, showing volume increases, with most posterior and temporo-parietal regions peaking before 8 years. We found widespread main effects of sex, with males having larger volumes in 86% of brain regions. However, there were no significant sex differences in trajectories (age or age2 terms) for absolute volume. Proportional volumes of the right occipital fusiform gyrus and left medial postcentral gyrus showed significant age-by-sex interactions where females had steeper volume decreases than males. This study also confirms regional patterns observed in previous studies of older children, such as posterior-to-anterior timing of brain maturation. These results provide a comprehensive picture of gray matter volume development across early childhood, and suggest that sex differences do not emerge until later in development.

Gene Expression Profiling in Pediatric Appendicitis

Appendicitis is the most common indication for urgent surgery in the pediatric population, presenting across a range of severity and with variable complications. Differentiating simple appendicitis (SA) and perforated appendicitis (PA) on presentation may help direct further diagnostic workup and appropriate therapy selection, including antibiotic choice and timing of surgery. To provide a mechanistic understanding of the differences in disease severity of appendicitis with the objective of developing improved diagnostics and treatments, specifically for the pediatric population. The Gene Expression Profiling of Pediatric Appendicitis (GEPPA) study was a single-center prospective exploratory diagnostic study with transcriptomic profiling of peripheral blood collected from a cohort of children aged 5 to 17 years with abdominal pain and suspected appendicitis between November 2016 and April 2017 at the Alberta Children's Hospital in Calgary, Alberta, Canada, with data analysis reported in August 2023. There was no patient follow-up in this study. SA, PA, or nonappendicitis abdominal pain. Blood transcriptomics was used to develop a hypothesis of underlying mechanistic differences between SA and PA to build mechanistic hypotheses and blood-based diagnostics. Seventy-one children (mean [SD] age, 11.8 [3.0] years; 48 [67.6%] male) presenting to the emergency department with abdominal pain and suspected appendicitis were investigated using whole-blood transcriptomics. A central role for immune system pathways was revealed in PA, including a dampening of major innate interferon responses. Gene expression changes in patients with PA were consistent with downregulation of immune response and inflammation pathways and shared similarities with gene expression signatures derived from patients with sepsis, including the most severe sepsis endotypes. Despite the challenges in identifying early biomarkers of severe appendicitis, a 4-gene signature that was predictive of PA compared to SA, with an accuracy of 85.7% (95% CI, 72.8-94.1) was identified. This study found that PA was complicated by a dysregulated immune response. This finding should inform improved diagnostics of severity, early management strategies, and prevention of further postsurgical complications.

Busulfan with 400 centigray of total body irradiation and higher dose fludarabine: An alternative regimen for hematopoietic stem cell transplantation in pediatric acute lymphoblastic leukemia.

Hematopoietic stem cell transplantation can be curative for children with difficult-to-treat leukemia. The conditioning regimen utilized is known to influence outcomes. We report outcomes of the conditioning regimen used at the Alberta Children's Hospital, consisting of busulfan (with pharmacokinetic target of 3750μmol*min/L/day ±10%) for 4days, higher dose (250mg/m2 ) fludarabine and 400centigray (cGy) of total body irradiation. This retrospective study involved children receiving transplant for acute lymphoblastic leukemia (ALL). It compared children who fell within the target range for busulfan with those who were either not measured or were measured and fell outside this range. All other treatment factors were identical. Twenty-nine children (17 within target) were evaluated. All subjects engrafted neutrophils with a median [interquartile range] time of 14days [8-30days]. The cumulative incidence of acute graft-versus-host disease was 44.8% [95% confidence interval, CI: 35.6%-54.0%], while chronic graft-versus-host disease was noted in 16.0% [95% CI: 8.7%-23.3%]. At 2years, the overall survival was 78.1% [95% CI: 70.8%-86.4%] and event-free survival was 74.7% [95% CI: 66.4%-83.0%]. Cumulative incidence of relapse was 11.3% [95% CI: 5.1%-17.5%]. There were no statistically significant differences in between the group that received targeted busulfan compared with the untargeted group. Our conditioning regiment for children with ALL resulted in outcomes comparable to standard treatment with acceptable toxicities and significant reduction in radiation dose. Targeting busulfan dose in this cohort did not result in improved outcomes.

Use of rational subgrouping to understand variation and opportunity for improvement in time to ultrasound.

To understand factors that contribute to variation in time to abdominal and/or pelvic ultrasound in pediatric patients in an emergency department (ED) by utilizing rational subgrouping to assess opportunity for improvement. All abdominal and pelvic ultrasounds conducted in the Alberta Children's Hospital ED from May 2019 to April 2021 were included. Time of study order and time of study completion were obtained from the electronic health record. Statistical process control (SPC) I-charts were used to analyze the quarterly median number of minutes from ultrasound order to completion. Rational subgrouping was used to stratify the data based on sex, age, and ED shift type, and identify special cause variation between groups. Findings were used to inform local decision-making. Special cause variation was detected among subgroups for sex, age group, and shift type. The median time from order of an abdominal and/or pelvic ultrasound to completion of study was 155min. Females had a median order to completion time of 178min, while males had a completion time of 131min. From age 0 to 3, the median time was 110min, compared to 149min for ages 4 to 11 and 171min for ages 12 and older. Day shifts had a median order to completion time of 145min, compared to 129min for evening shifts and 269min for night shifts. Longer time to study completion was observed in female patients, older patients, and during night shifts. Use of rational subgrouping supported understanding of variation among subgroups of patients evaluated with abdominal and/or pelvic ultrasound. This allowed informed decision-making regarding opportunities for improvement. Rational subgrouping is a useful methodology in planning QI initiatives as it identifies sources of variation within a nonhomogeneous population and allows for judicious decision-making in a context of limited resources.

Families' perception of proposed nutrition screening on admission to pediatric hospitals: a qualitative analysis.

Nutrition screening is the first step in most acute care pediatric nutrition care pathways. However, there is a lack of understanding of patient and families' perception of nutrition screening in pediatric populations. The objective of this study was to explore the potential perceptions, feelings, and opinions of families if pediatric nutrition screening were to be completed during hospital admission. Nine members of the Family Advisory Council at the Alberta Children's Hospital participated in a focus group to discuss questions around nutrition screening practices, malnutrition, and the pediatric nutrition screening tool. Transcripts were analyzed using MAXQDA and thematic analysis using the Braun and Clarke methodology. Two major themes emerged: screening may raise sensitive emotions and understanding the purpose of nutrition screening and the questions. Participants agreed discussions around growth and nutrition are vital to comprehensive medical care; however, the timing and approach of nutrition screening can lead to anxiety and feelings of judgement. A lack of understanding of the purpose of screening, next steps, and benefit to the individual patient could limit acceptance of nutrition screening. The findings of this study can inform training and education of healthcare professionals involved in nutrition screening.

52 An Evaluation of Satisfaction with Emergency Department Care in Children and Adolescents with Mental Health Concerns

Abstract Background Increasingly, the emergency department (ED) is a vital safety net for children and adolescents with mental health concerns seeking crisis care. Evaluating patient and parent/caregiver experience and satisfaction with care is essential to improve the quality of mental health services provided. Objectives The primary objective was to evaluate total satisfaction with the delivery of ED mental health care in two paediatric EDs in Alberta, Canada (Stollery Children's Hospital and Alberta Children's Hospital). Secondary objectives included exploring aspects of ED mental health care (staff interpersonal skills, confidentiality/privacy, and patient-reported outcomes of care) associations with general satisfaction, patient and ED visit characteristic associations with total satisfaction score, and care experience themes. Design/Methods We enrolled patients <18 years of age presenting with a mental health concern—e.g., anxiety, disruptive behaviour, self-harm, depression, situational crisis—over a 12-month period (February 1, 2020—January 31, 2021). Satisfaction data were collected using the Service Satisfaction Scale, which includes quantitative and qualitative data on aspects of ED mental health care. ED visit (length of stay, mental health and psychiatry consultations, hospital admission) and patient (discharge diagnoses, age, sex) data were collected. We evaluated associations of general satisfaction with ED mental health care using Pearson’s correlation coefficient tests, and associations between total satisfaction score with patient and ED visit characteristics using multivariable regression analyses. Inductive thematic analysis of qualitative feedback identified satisfaction and patient experience themes. Results 646 participants were enrolled with most being Caucasian (71.2%; 460/646) and female (56.3%; 364/646); the median age was 13 years (IQR, 11-15 years). The most common discharge diagnosis was anxiety or stress-related disorders (39.5%; 245/620). Parents/caregivers and adolescents were most satisfied with confidentiality and respect in the ED and least satisfied with how the ED services helped reduce symptoms and/or problems. Greater satisfaction was reported for parents/caregivers whose child received care at Alberta Children’s Hospital (p=0.003). General satisfaction was strongly associated with the perceived amount of help received in the ED (r=0.85). ED visit characteristics associated with total satisfaction score included an evaluation by a mental health team member (p=0.004) and psychiatrist consultation (p=0.05). Written comments demonstrated satisfaction with ED provider attitudes and interpersonal skills and dissatisfaction with access to mental health and addictions care, wait time, and COVID-19. Conclusion The results reflect the need to improve the satisfaction with ED mental health care delivery, with a particular focus on enhancing access to care by appropriate mental health providers.

Interview With CSCI Joe Doupe Young Investigator Awardee, Dr. Amy Metcalfe.

Dr. Amy Metcalfe is an Associate Professor in the Departments of Obstetrics and Gynecology, Medicine, and Community Health Sciences at the University of Calgary. She is also the Maternal and Child Health Program Director with the Alberta Children's Hospital Research Institute. Dr. Metcalfe's training is a perinatal epidemiologist whose research broadly focuses on the management of chronic illness during pregnancy, and how events in pregnancy impact women's health and wellbeing throughout the life course. Current major projects include co-leading the P3 Cohort study (https://p3cohort.ca), a longitudinal pregnancy cohort study, and the GROWW (Guiding interdisciplinary Research On Women's and girls' health and Wellbeing) Training Program (https://www.growwprogram.com).

A clinically relevant selective ERK-pathway inhibitor reverses core deficits in a mouse model of autism

Extracellular signal-regulated kinase (ERK/MAPK) pathway in the brain is hypothesized to be a critical convergent node in the development of autism spectrum disorder. We reasoned that selectively targeting this pathway could reverse core autism-like phenotype in animal models. Here we tested a clinically relevant, selective inhibitor of ERK pathway, PD325901 (Mirdametinib), in a mouse model of idiopathic autism, the BTBR mice. We report that treating juvenile mice with PD325901 reduced ERK pathway activation, dose and duration-dependently reduced core disease-modeling deficits in sociability, vocalization and repetitive behavior, and reversed abnormal EEG signals. Further analysis revealed that subchronic treatment did not affect weight gain, locomotion, or neuronal density in the brain. Parallel treatment in the C57BL/6J mice did not alter their phenotype. Our data indicate that selectively inhibiting ERK pathway using PD325901 is beneficial in the BTBR model, thus further support the notion that ERK pathway is critically involved in the pathophysiology of autism. These results suggest that a similar approach could be applied to animal models of syndromic autism with dysregulated ERK signaling, to further test selectively targeting ERK pathway as a new approach for treating autism. This has beenwork was supported by Alberta Children's Hospital Research Foundation (JMR & NC), University of Calgary Faculty of Veterinary Medicine (NC), Kids Brain Health Network (NC), and Natural Sciences and Engineering Research Council of Canada (NC).

A18 INTERKINGDOM DYNAMICS AND NUTRITION ARE ASSOCIATED WITH DIVERGENT MATURATIONAL PATTERNS OF THE INFANT BACTERIAL AND FUNGAL GUT MICROBIOME

Abstract Background Early life has been identified as a critical window, during which time deviations from typical patterns of gut microbiome maturation have been associated with adverse health outcomes later in life. In the first 2-3 years of life, the infant gut microbiome undergoes ecological shifts characterized by increasing bacterial alpha diversity and variable changes in fungal alpha diversity. Research has shown not all infants follow these maturational trends, but our understandings of the factors linked to atypical microbiome maturation patterns are limited. Purpose We assessed bacterial and fungal gut microbiome maturation in early life to determine if atypical maturational patterns were observed in otherwise healthy infants and identify factors associated with these patterns. Method In 100 infants from the CHILD Cohort Study, we assessed the bacterial and fungal gut microbiome in stool samples collected at 3 and 12 months of age using 16S and ITS2 Illumina sequencing, respectively. We performed untargeted metabolomics on urine samples collected at 3 and 12 months using liquid chromatography-mass spectrometry/mass spectrometry. Microbiome and metabolomic measures were evaluated by ecological and multivariate analyses using RStudio. Result(s) Gut microbiome analyses revealed 24% and 20% of infants displayed atypical alpha diversity trajectories in the first year of life for bacteria or fungi, respectively. Atypical patterns were linked to reduced abundance of Bacteroides and increased Candida at 3 months. Functional analysis revealed an atypical bacterial alpha diversity trend was associated with elevated urinary trimethylamine N-oxide, creatine, indole acetic acid, and 2-furoylglycine, and an atypical fungal trend was associated with elevated urinary lactate. Using decision trees, the strongest predictors of atypical alpha diversity trends were interkingdom dynamics, breastfeeding duration, and maternal diet during pregnancy. Logistic regression revealed an atypical bacterial trend was positively associated with delivery via C-section and inversely associated with exclusive breastfeeding at 3 months, and an atypical fungal trend was positively associated with gestational consumption of artificially sweetened beverages and inversely associated with prenatal antibiotics. Interkingdom network analyses revealed the gut microbiome of infants with an atypical bacterial or fungal alpha diversity trend displayed a greater number of interkingdom interactions reflective of a less stable or immature gut microbiome. Conclusion(s) Our findings reveal a substantial proportion of infants display atypical patterns of gut microbiome maturation in the first year of life. While known microbiome-modifying factors were important determinants of maturational patterns, these factors were generally less influential than interkingdom influences. Together, this highlights the importance of interkingdom analyses at the individual level to generate more nuanced understandings of maturational trajectories in early life. Please acknowledge all funding agencies by checking the applicable boxes below CIHR, Other Please indicate your source of funding; Alberta Children's Hospital Research Institute Disclosure of Interest None Declared

Eosinophilic/T-cell Chorionic Vasculitis: Its Incidence Is Increasing but It Does Not Appear to Recur in Subsequent Pregnancies.

Eosinophilic/T-cell chorionic vasculitis (E/TCV), an incidental finding primarily in third trimester placentas, is characterized by eosinophils and CD3+ T lymphocytes infiltrating at least 1 chorionic and/or stem villous vessels. Its etiology and clinical significance are unclear. Placental pathology reports issued by 8 pediatric-perinatal pathologists at Alberta Children's Hospital were retrieved from the lab information system (2010-2022), and candidate reports were identified using a Perl script searching for "eosinophil." Candidate diagnoses of E/TCV were validated by pathologist review. 38,058 placenta reports from 34,643 patients were reviewed; 328 cases of E/TCV were identified, for an overall incidence of 0.86%. Incidence increased 23% per year, from 0.11% in 2010 to 1.5% in 2021 (P < .01). This temporal change was observed for all pathologists; the incidence of identified multifocality also increased over time (P < .01). Umbilical vascular involvement was exceedingly rare. No variation in incidence was attributable to season. We received more than 1 placenta from 46 mothers with an E/TCV placental diagnosis; examination of >1 placenta did not reveal any mother with >1 E/TCV diagnosis. The incidence of E/TCV increased steadily over a ~12-year period and no recurrent cases were observed.

The COVID-19 Pandemic and Canadian Pediatric Tertiary Care Hospitalizations for Anorexia Nervosa

PurposeGlobal studies show an increase in hospitalizations for pediatric eating disorders (EDs). No published Canadian studies have confirmed these findings in pediatric ED programs for one-year post onset of the COVID-19 pandemic. The primary objective was to examine health administrative data from two pediatric tertiary care ED programs: Alberta Children's Hospital (ACH) and Hospital for Sick Children (SickKids) to determine the number of pediatric hospitalizations with the most responsible discharge diagnosis of anorexia nervosa (AN). MethodsThis hospital-based design explored monthly pediatric hospitalizations in seven-year-olds to 18-year-olds between March 11, 2014 and March 11, 2021 using the Discharge Abstract databases. The analysis used negative binomial regression with robust standard errors to compare hospitalization counts in the months preceding and following the World Health Organization pandemic declaration (March 11, 2020). ResultsHospitalizations due to pediatric AN increased by 63% and 132% at SickKids (p < .001) and ACH (p < .001), respectively, in the first year of the pandemic compared to the previous six years. The total number of non-ED hospitalizations decreased by 29.3% and 2.4% at SickKids and ACH, respectively. DiscussionThis is the first Canadian study to show a rise in pediatric hospitalizations over one year due to AN in two tertiary care hospitals following the onset of the pandemic, confirming the impact that the pandemic has had on children and adolescents with AN in Canada.

Clinical features at diagnosis of sickle cell disease prior to universal newborn screening in Alberta.

Sickle cell disease (SCD) is an inherited multisystem disorder with complications starting in the first year of life. Newborn screening (NBS) can identify infants with SCD and is associated with decreased morbidity and mortality. Variation in availability of NBS in Canada, and lack of standardized screening for immigrant children, may lead to delayed diagnosis. This was a retrospective cohort study of 126 children aged 0-18 years with SCD registered with the SCD clinic at the Alberta Children's Hospital between January 2003 and January 2018, prior to province-wide universal NBS for SCD. Patient demographic information, circumstances of diagnosis, and other contextual information were collected from patient health records. Descriptive statistics were used to summarize data, with Mood's median test used to compare medians between groups. Forty-three (35%) patients were born in Alberta. Patients were mostly (95.3%) of African descent. Of patients born in Alberta, 63% (26/43) were diagnosed at >12 months of age, with a median age at diagnosis of 18 months (IQR = 4-39). This was significantly older (P < 0.001) than children born in the USA or in Canadian provinces with SCD NBS programs, where the median age at diagnosis was zero months (N = 36). Of the 42% of patients born outside North America, 64% were diagnosed following an acute complication. This study highlights the importance of NBS for early detection and management of SCD, and the importance of screening at-risk immigrants who may not have received NBS for SCD.

Video Review of Simulated Pediatric Cardiac Arrest to Identify Errors/Latent Safety Threats: A Mixed Methods Study.

Outcomes from pediatric in-hospital cardiac arrest depend on the treatment provided as well as resuscitation team performance. Our study aimed to identify errors occurring in this clinical context and develop an analytical framework to classify them. This analytical framework provided a better understanding of team performance, leading to improved patient outcomes. We analyzed 25 video recordings of pediatric cardiac arrest simulations from the pediatric intensive care unit at the Alberta Children's Hospital. We conducted a qualitative-dominant crossover mixed method analysis to produce a broad understanding of the etiology of errors. Using qualitative framework analysis, we identified and qualitatively described errors and transformed the data coded into quantitative data to determine the frequency of errors. We identified 546 errors/error-related actions and behaviors and 25 near misses. The errors were coded into 21 codes that were organized into 5 main themes. Clinical task-related errors accounted for most errors (41.9%), followed by planning, and executing task-related errors (22.3%), distraction-related errors (18.7%), communication-related errors (10.1%), and knowledge/training-related errors (7%). This novel analytical framework can robustly identify, classify, and describe the root causes of errors within this complex clinical context. Future validation of this classification of errors and error-related actions and behaviors on larger samples of resuscitations from various contexts will allow for a better understanding of how errors can be mitigated to improve patient outcomes.

Evaluation of a pediatric pre-chemotherapy rapid hydration protocol: A quality assurance project.

Intravenous hydration may be utilized to prevent nephrotoxicity and facilitate drug elimination in patients receiving high-dose chemotherapy. Prolonged hydration protocols may lead to delayed initiation and completion of therapy, lengthening hospital admissions. Rapid hydration protocols have been implemented to reduce the time required for patients to meet parameters for chemotherapy administration. This study aims to evaluate a rapid hydration protocol implemented at the Alberta Children's Hospital (ACH). Starting January 2018 through May 2018, data was prospectively collected for pediatric oncology acute care and ambulatory patients at ACH receiving methotrexate (MTX), cisplatin, cyclophosphamide, or ifosfamide. The primary outcome was the time to achieve pre-determined urine parameters prior to chemotherapy administration. Secondary outcomes included the proportion of cycles that achieved urine parameters and the efficacy of each rapid hydration step. A total of 22 cycles were included, 13 for MTX and 9 for non-MTX chemotherapy. Median time to meet all urine parameters was 120 min (range 30-600 min). Two cycles (15%) failed rapid hydration in the MTX group, while no cycles required further hydration in the non-MTX group. Adverse events potentially attributable to hydration were mild and did not require intervention. The ACH rapid hydration protocol resulted in reduced time to meet target urine parameters. The results of this quality assurance review support the continued use of rapid hydration prior to chemotherapy administration.

Probiotics counteract hepatic steatosis caused by ketogenic diet and upregulate AMPK signaling in a model of infantile epilepsy.

SummaryBackgroundInfantile spasms syndrome (IS) is a type of epilepsy affecting 1.6 to 4.5 per 10,000 children in the first year of life, often with severe lifelong neurodevelopmental consequences. Only two first-line pharmacological treatments currently exist for IS and many children are refractory to these therapies. In such cases, children are treated with the ketogenic diet (KD). While effective in reducing seizures, the diet can result in dyslipidemia over time.MethodsEmploying a neonatal Sprague-Dawley rat model of IS, we investigated how the KD affects hepatic steatosis and its modulation by a defined probiotic blend. A combination of multiple readouts, including malondialdehyde, fatty acid profiles, lipid metabolism-related enzyme mRNA expression, mitochondrial function, histone deacetylase activity, cytokines and chemokines were evaluated using liver homogenates.FindingsThe KD reduced seizures, but resulted in severe hepatic steatosis, characterized by a white liver, triglyceride accumulation, elevated malondialdehyde, polyunsaturated fatty acids and lower acyl-carnitines compared to animals fed a control diet. The KD-induced metabolic phenotype was prevented by the co-administration of a blend of Streptococcus thermophilus HA-110 and Lactococcus lactis subsp. lactis HA-136. This probiotic blend protected the liver by elevating pAMPK-mediated signaling and promoting lipid oxidation. The strains further upregulated the expression of caspase 1 and interleukin 18, which may contribute to their hepatoprotective effect in this model.InterpretationOur results suggest that early intervention with probiotics could be considered as an approach to reduce the risk of hepatic side effects of the KD in children who are on the diet for medically indicated reasons.FundingThis study was funded by the Alberta Children's Hospital Research Institute and Mitacs Accelerate Program (IT16942).

Seizure modulation by the gut microbiota and tryptophan-kynurenine metabolism in an animal model of infantile spasms.

SummaryBackgroundThe infantile spasms syndrome is an early-onset epileptic encephalopathy presenting in the first 2 years of life, often with severe developmental consequences. The role of the gut microbiota and metabolism in infantile spasms remains unexplored.MethodsEmploying a brain injury neonatal rat model of infantile spasms intractable to anticonvulsant medication treatments, we determined how the ketogenic diet and antibiotics affected specific microbial communities and the resultant circulating factors that confer spasms protection in the infantile spasms model. To confirm a role of kynurenine metabolism pathway in spasms protection, indoleamine 2,3-dioxygenase 1 was pharmacologically inhibited and comprehensive metabolomics was applied.FindingsWe show that antibiotics reduced spasms and improved the effectiveness of the ketogenic diet when given in combination. Examination of the gut microbiota and metabolomics showed the downregulation of indoleamine 2,3-dioxygenase 1 and upregulation of hippocampal kynurenic acid, a metabolite with antiepileptic effects. To further test the involvement of indoleamine 2,3-dioxygenase 1, a specific antagonist 1-methyltryptophan and minocycline, an antibiotic and inhibitor of kynurenine formation from tryptophan, were administered, respectively. Both treatments were effective in reducing spasms and elevating hippocampal kynurenic acid. A fecal microbiota transplant experiment was then performed to examine the contribution of the gut microbiota on spasm mitigation. Transplant of feces of ketogenic diet animals into normal diet animals was effective in reducing spasms.InterpretationThese results highlight the importance of tryptophan-kynurenine metabolism in infantile spasms and provide evidence for new-targeted therapies such as indoleamine 2,3-dioxygenase 1 inhibition or microbiota manipulation to promote kynurenic acid production as a strategy to reduce spasms in infantile spasms.FundingThis study was funded by the Alberta Children's Hospital Research Institute and the Owerko Centre.

The Diagnostic Journey of Childhood Idiopathic Nephrotic Syndrome: Perspectives of Children and Their Caregivers.

Childhood nephrotic syndrome is a rare kidney disease characterized by sudden onset of edema, massive proteinuria, and hypoalbuminemia. Rare diseases can have a long and difficult trajectory to diagnosis. We aimed to explore the experiences of children with nephrotic syndrome and their caregivers in their search of a nephrotic syndrome diagnosis. An exploratory, qualitative descriptive study design. The Alberta Children's Hospital outpatient nephrology program in Calgary, Alberta, Canada. Children aged 9 to 18 years with steroid-sensitive nephrotic syndrome and their caregivers. We undertook semi-structured interviews with children (alone or with a caregiver present) and their caregivers using a question guide suitable to their age and role. We used a thematic analysis approach to inductively code the data and characterize themes related to our research question. Participants included 10 children aged 9 to 18 years (6 boys and 4 girls) and 18 caregivers (8 men and 10 women). We characterized 3 themes related to participants' experiences in search of a diagnosis of nephrotic syndrome: (1) unexpected and distressing symptom onset, (2) elusiveness of a diagnosis, and (3) encountering a diagnosis. Children with nephrotic syndrome and their caregivers described experiencing initial anxiety due to their unusual and unexpected symptom onset and lack of awareness about the disease. Perceived diagnostic delays and incorrect diagnosis early in the course of the disease contributed to multiple consultations with a variety of care providers. Overall, participants expressed a desire to move past their diagnosis, learn about nephrotic syndrome, and engage in their treatment plans. The views expressed by participants may not reflect those of individuals from other settings. The time elapsed since participants' nephrotic syndrome diagnosis may have influenced their recall of events and reactions to this diagnosis. In characterizing the diagnostic experiences of children and their caregivers, our study provides insight into how patients with nephrotic syndrome and their caregivers can be supported by the healthcare team along this journey. Focused strategies to increase awareness and understanding of nephrotic syndrome among healthcare providers are needed to improve patients' and families' diagnostic experiences.

Psychosocial risk, symptom burden, and concerns in families affected by childhood cancer.

The revised Psychosocial Assessment Tool (PATrev) is a common family-level risk-based screening tool for pediatric oncology that has gained support for its ability to predict, at diagnosis, the degree of psychosocial support a family may require throughout the treatment trajectory. However, ongoing screening for symptoms and concerns (e.g., feeling alone, understanding treatment) remains underutilized. Resource limitations necessitate triaging and intervention based on need and risk. Given the widespread use of the PATrev, we sought to explore the association between family psychosocial risk, symptom burden (as measured by the revised Edmonton Symptom Assessment System (ESAS-r)), and concerns (as measured by the Canadian Problem Checklist (CPC)). Families (n = 87) with children ≤ 18years of age (M = 11.72, male: 62.1%) on or off treatment for cancer were recruited from the Alberta Children's Hospital. One parent from each family completed the PATrev and the CPC. Participants 8-18years of age completed the ESAS-r. Risk category (universal/low risk = 67.8%, targeted/intermediate risk = 26.4%, clinical/high risk = 5.7%) predicted symptom burden (F[2, 63.07] = 4.57, p = .014) and concerns (F[2, 82.06] = 16.79, p < .001), such that universal risk was associated with significantly lower symptom burden and fewer concerns. Family psychosocial risk is associated with cross-sectionally identified concerns and symptom burden, suggesting that resources might be prioritized for families with the greatest predicted need. Future research should evaluate the predictive validity of the PATrev to identify longitudinal concerns and symptom burden throughout the cancer trajectory.

Phenotype and pathology of the dilated cardiomyopathy with ataxia syndrome in children.

The dilated cardiomyopathy with ataxia syndrome (DCMA) is an autosomal recessive mitochondrial disease caused by mutations in the DnaJ heat shock protein family (Hsp40) member C19 (DNAJC19) gene. DCMA or 3-methylglutaconic aciduria type V is globally rare, but the largest number of patients in the world is found in the Hutterite population of southern Alberta in Canada. We provide an update on phenotypic findings, natural history, pathological findings, and our clinical experience. We analyzed all available records for 43 patients diagnosed with DCMA between 2005 and 2015 at the Alberta Children's Hospital. All patients studied were Hutterite and homozygous for the causative DNAJC19 variant (c.130-1G>C, IVS3-1G>C) and had elevated levels of 3-methyglutaconic acid. We calculated a birth prevalence of 1.54 cases per 1000 total births in the Hutterite community. Children were small for gestational age at birth and frequently required supplemental nutrition (63%) or surgical placement of a gastrostomy tube (35%). Early mortality in this cohort was high (40%) at a median age of 13 months (range 4-294 months). Congenital anomalies were common as was dilated cardiomyopathy (50%), QT interval prolongation (83%), and developmental delay (95%). Tissue pathology was analyzed in a limited number of patients and demonstrated subendocardial fibrosis in the heart, macrovesicular steatosis and fibrosis in the liver, and structural abnormalities in mitochondria. This report provides clinical details for a cohort of children with DCMA and the first presentation of tissue pathology for this disorder. Despite sharing common genetic etiology and environment, the disease is highly heterogeneous for reasons that are not understood. DCMA is a clinically heterogeneous systemic mitochondrial disease with significant morbidity and mortality that is common in the Hutterite population of southern Alberta.

The prevalence of feeding difficulties and potential risk factors in pediatric intestinal failure: Time to consider promoting oral feeds?

Although nutritional care is a cornerstone in the management of pediatric intestinal failure (IF), little is known about feeding difficulty (FD) prevalence. The aim of this study was to determine the frequency of FD and associated factors and to characterize eating behaviours in two pediatric IF rehabilitation centres (Hôpital-Necker Enfants Malades (NEM), France and Alberta Children's Hospital (ACH), Canada). Parents of children (aged 1-18 years) on home parenteral nutrition (PN) for >3 months followed at NEM and ACH completed two validated tools: Montreal Children's Feeding scale for severity of FD, Child Eating Behaviour Questionnaire and a pediatric IF-specific questionnaire for FD associated risk factors. In the entire cohort (n=59, median 5.2 years), 15% had mild, 19% had moderate and 25% had severe FD. No FD was seen in 53% vs 11% and severe FD was seen in 20% vs. 39% of the NEM and ACH cohorts respectively (p=0.003). Current ETF was less common at NEM vs. ACH (3% vs. 50%, p<0.001). The FD score was associated with current enteral tube feed (ETF) use (p=0.04). Compared to healthy reference children, the NEM cohort did not differ for the enjoyment of food, whereas the ACH cohort's enjoyment was lower (p<0.0001). The ACH cohort scored higher for food avoidance behaviours: food fussiness (p<0.02), satiety responsiveness (p<0.0001), and slowness in eating (p<0.0001) while the NEM cohort was not different from healthy reference children. In the entire cohort, according to parental recall, 60% were reported to be NPO for >12 weeks in the first 6 months of life, and late introduction of purees (>9 months) and lumpy textures (>1 year) were found in 40% and 58%, respectively. Parent-recalled ETF differed between NEM and ACH in the first 6 months of life (45% vs 76%, p=0.03). Feeding difficulty and associated risk factors, including early ETF, prolonged NPO and delays in achieving feeding milestones were frequently reported in pediatric IF. Feeding medicalization with the use of ETF may inadvertently contribute to FD and eating disorder behavioural characteristics. This study highlights the need for FD prevention and an increased focus on establishing healthy eating. Future prospective study of FD, associated risk factors and clinical outcomes are merited.