Assessing the quality and value of metabolic chart data for capturing core outcomes for pediatric medium-chain acyl-CoA dehydrogenase (MCAD) deficiency.

BACKGROUND: Generating rigorous evidence to inform care for rare diseases requires reliable, sustainable, and longitudinal measurement of priority outcomes. Having developed a core outcome set for pediatric medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, we aimed to assess the feasibility of prospective measurement of these core outcomes during routine metabolic clinic visits. METHODS: We used existing cohort data abstracted from charts of 124 children diagnosed with MCAD deficiency who participated in a Canadian study which collected data from birth to a maximum of 11 years of age to investigate the frequency of clinic visits and quality of metabolic chart data for selected outcomes. We recorded all opportunities to collect outcomes from the medical chart as a function of visit rate to the metabolic clinic, by treatment centre and by child age. We applied a data quality framework to evaluate data based on completeness, conformance, and plausibility for four core MCAD outcomes: emergency department use, fasting time, metabolic decompensation, and death. RESULTS: The frequency of metabolic clinic visits decreased with increasing age, from a rate of 2.8 visits per child per year (95% confidence interval, 2.3-3.3) among infants 2 to 6 months, to 1.0 visit per child per year (95% confidence interval, 0.9-1.2) among those ≥ 5 years of age. Rates of emergency department visits followed anticipated trends by child age. Supplemental findings suggested that some emergency visits occur outside of the metabolic care treatment centre but are not captured. Recommended fasting times were updated relatively infrequently in patients' metabolic charts. Episodes of metabolic decompensation were identifiable but required an operational definition based on acute manifestations most commonly recorded in the metabolic chart. Deaths occurred rarely in these patients and quality of mortality data was not evaluated. CONCLUSIONS: Opportunities to record core outcomes at the metabolic clinic occur at least annually for children with MCAD deficiency. Methods to comprehensively capture emergency care received at outside institutions are needed. To reduce substantial heterogeneous recording of core outcome across treatment centres, improved documentation standards are required for recording of recommended fasting times and a consensus definition for metabolic decompensations needs to be developed and implemented.

Relationship Between Gestational Weight Gain and Health Service Utilization in Early Childhood: A Retrospective Cohort Study.

OBJECTIVE: Gestational weight gain (GWG) outside recommended ranges can negatively impact both the woman and child. The long-term effects of below-recommended or above-recommended GWG on the child are unclear. METHODS: This retrospective cohort study used a population-based birth registry of 258,005 live births to evaluate the relationship between maternal GWG and paediatric health service use. RESULTS: The results suggest below recommended GWG in underweight women in particular is associated with an increased rate of hospitalizations and specialist visits for the child in the first 24 months. CONCLUSION: Findings indicate that GWG may impact paediatric outcomes in ways that depend on pre-pregnancy body mass index, as derived from maternal height and weight measures.

Exome and genome sequencing for rare genetic disease diagnosis: A scoping review and critical appraisal of clinical guidance documents produced by genetics professional organizations.

PURPOSE: Exome and genome sequencing have rapidly transitioned from research methods to widely used clinical tests for diagnosing rare genetic diseases. We sought to synthesize the topics covered and appraise the development processes of clinical guidance documents generated by genetics professional organizations. METHODS: We conducted a scoping review of guidance documents published since 2010, systematically identified in peer-reviewed and gray literature, using established methods and reporting guidelines. We coded verbatim recommendations by topic using content analysis and critically appraised documents using the Appraisal of Guidelines Research and Evaluation (AGREE) II tool. RESULTS: We identified 30 guidance documents produced by 8 organizations (2012-2022), yielding 611 recommendations covering 21 topics. The most common topic related to findings beyond the primary testing indication. Mean AGREE II scores were low across all 6 quality domains; scores for items related to rigor of development were among the lowest. More recently published documents generally received higher scores. CONCLUSION: Guidance documents included a broad range of recommendations but were of low quality, particularly in their rigor of development. Developers should consider using tools such as AGREE II and basing recommendations on living knowledge syntheses to improve guidance development in this evolving space.

The Impact of Patient and Family Engagement in Child Health Research: A Scoping Review.

OBJECTIVE: To identify impacts of patient and family engagement in child health research on the research process, research teams, and patient and family partners. STUDY DESIGN: A scoping review was conducted using the MEDLINE, Embase, Cumulative Index to Nursing and Allied Health Literature, PsycINFO, and Web of Science databases. English-language studies were included if they described ≥1 impact of patient and family engagement on child health research (age <18 years), researchers, or patient and family partners. Data were retrieved by 2 independent extractors. RESULTS: Of the 7688 studies identified, 25 were included in our analysis. Impacts of patient and family engagement were mostly on the research process (n = 24 studies; 96%), 11 (44%) determined impacts on the research team, and 17 (68%) reported impacts on patient and family partners. Less than one-half (n = 11; 44%) had a primary purpose of determining the impact of patient engagement, and no study used a specific evaluation tool. CONCLUSIONS: Patient and family engagement can strengthen the relevance and feasibility of research and empower researchers and patient partners. Measuring and reporting the impact of engagement is rare. Systematic and standardized evaluation of engagement is needed to understand how, when, and why to engage patients and families.

Association between toxic metals, vitamin D and preterm birth in the Maternal-Infant research on environmental chemicals study.

BACKGROUND: Toxic metals, like lead, are risk factors for preterm birth (PTB), but few studies have examined low levels found in most Canadians. Vitamin D, which may have antioxidant activity, protects against PTB. OBJECTIVES: In this study, we investigated the impact of toxic metals (lead, mercury, cadmium and arsenic) on PTB and examined if maternal plasma vitamin D concentrations modify these associations. METHODS: We investigated whether concentrations of metals in whole blood measured in early and late pregnancy were associated with PTB (<37 weeks) and spontaneous PTB in 1851 live births from the Maternal-Infant Research on Environmental Chemicals Study using discrete time survival analysis. We also investigated whether the risk of PTB was modified by first-trimester plasma 25-hydroxyvitamin D (25OHD) concentrations. RESULTS: Of 1851 live births, 6.1% (n = 113) were PTBs and 4.9% (n = 89) were spontaneous PTB. A 1 µg/dL increase in blood lead concentrations during pregnancy was associated with an increased risk of PTB (relative risk [RR] 1.48, 95% confidence interval [CI] 1.00, 2.20) and spontaneous PTB (RR 1.71, 95% CI 1.13, 2.60). The risk was higher in women with insufficient vitamin D concentrations (25OHD <50 nmol/L) for both PTB (RR 2.42, 95% CI 1.01, 5.79) and spontaneous PTB (RR 3.04, 95% CI 1.15, 8.04). However, an interaction on the additive scale was not present. Arsenic was associated with a higher risk of PTB (RR 1.10, 95% CI 1.02, 1.19) and spontaneous PTB (RR 1.11, 95% CI 1.03, 1.20) per 1 µg/L. CONCLUSIONS: Gestational exposure to low levels of lead and arsenic may increase the risk of PTB and spontaneous PTB; individuals with insufficient vitamin D may be more susceptible to the adverse effects of lead. Given our relatively small number of cases, we encourage testing of this hypothesis in other cohorts, especially those with vitamin D-deficient populations.

Ethical and practical considerations related to data sharing when collecting patient-reported outcomes in care-based child health research.

PURPOSE: The collection and use of patient reported outcomes (PROs) in care-based child health research raises challenging ethical and logistical questions. This paper offers an analysis of two questions related to PROs in child health research: (1) Is it ethically obligatory, desirable or preferable to share PRO data collected for research with children, families, and health care providers? And if so, (2) What are the characteristics of a model best suited to guide the collection, monitoring, and sharing of these data? METHODS: A multidisciplinary team of researchers, providers, patient and family partners, and ethicists examined the literature and identified a need for focus on PRO sharing in pediatric care-based research. We constructed and analyzed three models for managing pediatric PRO data in care-based research, drawing on ethical principles, logistics, and opportunities to engage with children and families. RESULTS: We argue that it is preferable to share pediatric PRO data with providers, but to manage expectations and balance the risks and benefits of research, this requires a justifiable data sharing model. We argue that a successful PRO data sharing model will allow children and families to have access to and control over their own PRO data and be engaged in decision-making around how PROs collected for research may be integrated into care, but require support from providers. CONCLUSION: We propose a PRO data sharing model that can be used across diverse research settings and contributes to improved transparency, communication, and patient-centered care and research.

Maternal weight and paediatric health use: mediating role of adverse birth outcomes: a retrospective cohort study.

BACKGROUND: Maternal pre-pregnancy body mass index (BMI) and gestational weight gain (GWG) above or below recommendations have been associated with increased paediatric health service utilization as well as increased risk of adverse birth outcomes, including small for gestational age (SGA) and preterm birth (PTB). SGA and PTB are associated with numerous adverse health outcomes in the child, including delayed growth, motor and cognitive impairment. Previous research has identified birth weight and gestational age on the causal pathway in the association between maternal pre-pregnancy BMI and child hospital admissions, there are no studies to date to quantify this relationship across other areas of health service utilization, nor the impact of gestational weight gain. This study aimed to assess if SGA or PTB partially explain the association between maternal weight and paediatric health service utilization. METHODS: The study population consisted of all women who delivered a singleton, live infant in Ontario between 2012 and 2014, and was assembled from data contained in the provincial birth registry. Health service utilization over the first 24 months following birth was examined by linking data from the registry with other provincial health administrative databases housed at ICES. The mediating roles of PTB and SGA were assessed using the Baron-Kenny method and causal mediation analysis. RESULTS: A total of 204,162 infants were included in the analysis of maternal pre-pregnancy BMI and 171,127 infants were included in the GWG analysis. The small magnitude of association between maternal BMI and paediatric health service utilization impacted our ability to estimate the indirect effect of maternal BMI through adverse birth outcomes (adjusted indirect effect = 0.00). 56.7% of the association between below recommended GWG and increased hospitalizations was attributed to PTB, while 6.8% of the association was attributed to SGA. CONCLUSION: Paediatric hospitalizations may be partially attributable to PTB and SGA in children born to mothers with below-recommended GWG. However, maternal weight also appears to be related to increased paediatric health service utilization independent of PTB and SGA.

Blood metals and vitamin D status in a pregnancy cohort: A bidirectional biomarker analysis.

Low 25-hydroxyvitamin D (25OHD), a biomarker of vitamin D status, is associated with reduced immune function and adverse pregnancy outcomes, such as preterm birth. Observational studies indicate that long-term, high level exposure to metals such as cadmium (Cd) and lead (Pb) can impact a person's vitamin D status. However, the directionality of the association is uncertain, particularly for low-level exposures. We used three distinct longitudinal data analysis methods to investigate cross-sectional, longitudinal and bidirectional relationships of Cd and Pb biomarkers with 25-hydroxyvitamin D (25OHD) in a Canadian pregnancy cohort. Maternal whole blood Cd and Pb and plasma 25OHD concentrations were measured in the 1st (n = 1905) and 3rd (n = 1649) trimester and at delivery (25OHD only, n = 1542). Our multivariable linear regression analysis showed weak inverse associations between Cd and 25OHD concentrations cross-sectionally and longitudinally while the latent growth curve models showed weak associations with Pb on the 25OHD intercept. In the bidirectional analysis, using cross lagged panel models, we found no association between 1st trimester metals and 3rd trimester 25OHD. Instead, 1st trimester 25OHD was associated with 9% (-15%, -3%) lower 3rd trimester Cd and 3% (-7, 0.1%) lower Pb. These findings suggest the 25OHD may modify metal concentrations in pregnancy and demonstrates the value of controlling for contemporaneous effects and the persistence of a biomarker over time, in order to rule out reverse causation.

Patient Engagement in a Multi-Stakeholder Workshop to Plan the Collection of Patient-Oriented Outcomes for Children with Inherited Metabolic Diseases.

Building on a study to develop core outcome sets for children with rare inherited metabolic diseases, the purpose of this workshop was to inform the design of longitudinal pediatric registries that support registry-based clinical trials. This workshop was co-designed by two patient/family partner investigators and attended by two family advisors who received preparatory training. Patient partners and advisors recommended integrating the collection of registry data into everyday life and highlighted the importance of transparent communication and attention to the issue of integration of patient-reported data into clinical care. We propose a need to explore strategies for engaging patients in post-project knowledge translation.

Developments in evidence creation for treatments of inborn errors of metabolism.

Inborn errors of metabolism (IEM) represent the first group of genetic disorders, amenable to causal therapies. In addition to traditional medical diet and cofactor treatments, new treatment strategies such as enzyme replacement and small molecule therapies, solid organ transplantation, and cell-and gene-based therapies have become available. Inherent to the rare nature of the single conditions, generating high-quality evidence for these treatments in clinical trials and under real-world conditions has been challenging. Guidelines developed with standardized methodologies have contributed to improve the practice of care and long-term clinical outcomes. Adaptive trial designs allow for changes in sample size, group allocation and trial duration as the trial proceeds. n-of-1 studies may be used in small sample sized when participants are clinically heterogeneous. Multicenter observational and registry-based clinical trials are promoted via international research networks. Core outcome and standard data element sets will enhance comparative analysis of clinical trials and observational studies. Patient-centered outcome-research as well as patient-led research initiatives will further accelerate the development of therapies for IEM.

Health services use by children identified as heterozygous hemoglobinopathy mutation carriers via newborn screening.

BACKGROUND: Newborn screening (NBS) for sickle cell disease incidentally identifies heterozygous carriers of hemoglobinopathy mutations. In Ontario, Canada, these carrier results are not routinely disclosed, presenting an opportunity to investigate the potential health implications of carrier status. We aimed to compare rates of health services use among children identified as carriers of hemoglobinopathy mutations and those who received negative NBS results. METHODS: Eligible children underwent NBS in Ontario from October 2006 to March 2010 and were identified as carriers or as screen-negative controls, matched to carriers 5:1 based on neighbourhood and timing of birth. We used health care administrative data to determine frequencies of inpatient hospitalizations, emergency department (ED) visits, and physician encounters through March 2012, using multivariable negative binomial regression to compare rates of service use in the two cohorts. We analyzed data from 4987 carriers and 24,935 controls. RESULTS: Adjusted incidence rate ratios (95% CI) for service use in carriers versus controls among children < 1 year of age were: 1.11 (1.06-1.17) for ED visits; 0.97 (0.89-1.06) for inpatient hospitalization; and 1.02 (1.00-1.04) for physician encounters. Among children ≥1 year of age, adjusted rate ratios were: 1.03 (0.98-1.07) for ED visits; 1.14 (1.03-1.25) for inpatient hospitalization and 0.92 (0.90-0.94) for physician encounters. CONCLUSIONS: While we identified statistically significant differences in health services use among carriers of hemoglobinopathy mutations relative to controls, effect sizes were small and directions of association inconsistent across age groups and health service types. Our findings are consistent with the assumption that carrier status is likely benign in early childhood.

A Retrospective Cohort Study Investigating the Impact of Maternal Pre-Pregnancy Body Mass Index on Pediatric Health Service Utilization.

OBJECTIVE: Maternal weight during pregnancy impacts the health of both mother and baby. This project investigated associations between maternal pre-pregnancy body mass index (BMI) and the child's future health service utilization. METHODS: The study population comprised all women who delivered a singleton, live infant in Ontario between 2012 and 2014, and was assembled from data contained in the provincial birth registry. Health service utilization in the 24 months following birth was examined by linking data from the registry with other provincial health administrative databases housed at ICES. RESULTS: A total of 258 005 records were available for analysis. After adjusting for infant sex and maternal age, smoking status, income quintile, and pre-existing or gestational diabetes or hypertension, children born to mothers who were overweight or had obesity prior to pregnancy had increased rates of hospitalization (overweight adjusted incidence rate ratio [aIRR] 1.09, 95% confidence interval [CI] 1.06-1.12; obesity aIRR 1.20, 95% CI 1.17-1.24), physician visits (overweight aIRR 1.03, 95% CI 1.03-1.04; obesity aIRR 1.05, 95% CI 1.04-1.05) and emergency department visits (overweight aIRR 1.12, 95% CI 1.10-1.13; obesity aIRR 1.27, 95% CI 1.25-1.29) than infants born to mothers with normal pre-pregnancy BMI. CONCLUSION: Excess maternal weight was associated with greater pediatric health service utilization. Rates of health service utilization appeared to increase with maternal pre-pregnancy BMI. Future study of the reasons behind this increase may allow for early education, diagnosis, and intervention in this at-risk population.

Primary care providers' role in newborn screening result notification for cystic fibrosis.

OBJECTIVE: To explore primary care providers' (PCPs') role in result notification for newborn screening (NBS) for cystic fibrosis (CF), given that expanded NBS has increased the number of positive screening test results, drawing attention to the role of PCPs in supporting families. DESIGN: Cross-sectional survey and qualitative interviews. SETTING: Ontario. PARTICIPANTS: Primary care providers (FPs, pediatricians, and midwives) who received a positive CF NBS result for an infant in their practice in the 6 months before the study. MAIN OUTCOME MEASURES: Whether the PCP notified the family of the initial positive CF screening result. RESULTS: Data from 321 PCP surveys (response rate of 51%) are reported, including 208 FPs, 68 pediatricians, and 45 midwives. Interviews were completed with 34 PCPs. Most (65%) surveyed PCPs reported notifying the infant's family of the initial positive screening result; 81% agreed that they have an important role to play in NBS; and 88% said it was important for PCPs, rather than the NBS centre, to notify families of initial positive results. With support and information from NBS centres, 68% would be extremely or very confident in doing so; this dropped to 54% when reflecting on their recent reporting experience. More than half (58%) of all PCPs said written point-of-care information from the NBS centre was the most helpful format. Adjusted for relevant factors, written educational information was associated with a lower rate of notifying families than written plus verbal information (risk ratio of 0.79; 95% CI 0.69 to 0.92). In the interviews, PCPs emphasized the challenge of balancing required content knowledge with the desire for the news to come from a familiar provider. CONCLUSION: Most PCPs notify families of NBS results and value this role. These data are relevant as NBS programs and other genomic services expand and consider ways of keeping PCPs confident and actively involved.

Newborn screening for cystic fibrosis: Role of primary care providers in caring for infants with positive screening results.

OBJECTIVE: To explore primary care providers' (PCPs') preferred roles and confidence in caring for infants receiving a positive cystic fibrosis (CF) newborn screening (NBS) result, as well as management of CF family planning issues, given that expanded NBS has resulted in an increase in positive results. DESIGN: Mailed questionnaire. SETTING: Ontario. PARTICIPANTS: Ontario FPs, pediatricians, and midwives identified by Newborn Screening Ontario as having had an infant with a positive CF NBS result in their practice in the previous 6 months. MAIN OUTCOME MEASURE: Primary care providers' preferred roles in providing well-baby care for infants with positive CF screening results. RESULTS: Overall, 321 of 628 (51%) completed surveys (208 FPs, 68 pediatricians, 45 midwives). For well-baby care for infants confirmed to have CF, 77% of PCPs indicated they would not provide total care (ie, 68% would share care with other specialists and 9% would refer to specialists completely); for infants with an inconclusive CF diagnosis, 50% of PCPs would provide total care, 45% would provide shared care, and 5% would refer to a specialist; for CF carriers, 89% of PCPs would provide total care, 9% would provide shared care, and 2% would refer. Half (54%) of PCPs were extremely or very confident in providing reassurance about CF carriers' health. Only 25% knew how to order parents' CF carrier testing; 67% knew how to refer for prenatal diagnosis. Confidence in reassuring parents about the health of CF carrier children was associated with providing total well-baby care for CF carriers (risk ratio of 1.50; 95% CI 1.14 to 1.97) and infants with an inconclusive diagnosis (risk ratio of 3.30; 95% CI 1.34 to 8.16). CONCLUSION: Most PCPs indicated willingness to treat infants with a range of CF NBS results in some capacity. It is concerning that some indicated CF carriers should have specialist involvement and only half were extremely or very confident about reassuring families about carrier status. This raises issues about possible medicalization of those with carrier status, prompting the need for PCP education about genetic disorders and the meaning of genetic test results.

Coaching Caregivers of Children who are Deaf or Hard of Hearing: A Scoping Review.

Caregiver coaching is an expected practice in early intervention. However, little is known about coaching with caregivers of children who are deaf or hard of hearing, receiving services for listening and spoken language (LSL). A systematic review of 7 databases, the gray literature, and consultation with 7 expert LSL practitioners yielded 506 records for full-text review, 22 of which were ultimately included in the review. Our findings are presented as 3 themes: coaching practices, training for coaching, and effectiveness of coaching. Eight models of coaching were identified in the literature, from which we identified commonalities to propose a consolidated model that illustrates the recommendations and process of caregiver coaching found in the LSL literature.

Health-care providers' perspectives on uncertainty generated by variant forms of newborn screening targets.

PURPOSE: Despite the public health successes of newborn bloodspot screening, uncertainty associated with variant forms of primary screening targets has led to discrepancies in medical management. This study explored health-care providers' approaches to managing atypical forms of inherited metabolic diseases (IMDs) in the absence of evidence-based guidelines. METHODS: Semistructured telephone interviews were conducted with metabolic specialists. 3-Methylcrotonyl CoA deficiency and variant forms of phenylketonuria, biotinidase deficiency, and fatty acid oxidation disorders were considered. Data were analyzed inductively and deductively using a novel taxonomy of uncertainty. RESULTS: Health-care providers (n = 12) navigate diagnostic, prognostic, and therapeutic challenges of uncertainty while interpreting patient and family attitudes, preferences, and ideas in the care of children with these result types. Participants explained the limits of classifying mild and atypical metabolic phenotypes. Participants also described the challenge of finding balance between cautious care and overmedicalization. Developing consistent care plans and honest communication with families were perceived as effective strategies when navigating uncertainty. CONCLUSION: Providers' experiences suggest a need for transparent and accessible guidelines that account for challenges associated with uncertainty generated by screening. Timely consideration of this challenge is warranted with increasing emergence of genotype-first approaches to screening.

Barriers in accessing medical cannabis for children with drug-resistant epilepsy in Canada: A qualitative study.

INTRODUCTION: The use of medical cannabis to treat drug-resistant epilepsy in children is increasing; however, there has been limited study of the experiences of parents with the current system of accessing medical cannabis for their children. METHODS: In this qualitative study, we used a patient-centered access to care framework to explore the barriers faced by parents of children with drug-resistant epilepsy when trying to access medical cannabis in Canada. We conducted semistructured interviews with 19 parents to elicit their experiences with medical cannabis. We analyzed the data according to five dimensions of access, namely approachability, acceptability, availability, affordability, and appropriateness. RESULTS: Parents sought medical cannabis as a treatment because of a perceived unmet need stemming from the failure of antiepileptic drugs to control their children's seizures. Medical cannabis was viewed as an acceptable treatment, especially compared with adding additional antiepileptic drugs. After learning about medical cannabis from the media, friends and family, or other parents, participants sought authorization for medical use. However, most encountered resistance from their child's neurologist to discuss and/or authorize medical cannabis, and many parents experienced difficulty in obtaining authorization from a member of the child's existing care team, leading them to seek authorization from a cannabis clinic. Participants described spending up to $2000 per month on medical cannabis, and most were frustrated that it was not eligible for reimbursement through public or private insurance programs. CONCLUSIONS: Parents pursue medical cannabis as a treatment for their children's drug-resistant epilepsy because of a perceived unmet need. However, parents encounter barriers in accessing medical cannabis in Canada, and strategies are needed to ensure that children using medical cannabis receive proper care from healthcare professionals with training in epilepsy care, antiepileptic drugs, and medical cannabis.

Postnatal gestational age estimation via newborn screening analysis: application and potential.

Introduction: Preterm birth is a major global health concern, contributing to 35% of all neonatal deaths in 2016. Given the importance of accurately ascertaining estimates of preterm birth and in light of current limitations in postnatal gestational age (GA) estimation, novel methods of estimating GA postnatally in the absence of prenatal ultrasound are needed. Previous work has demonstrated the potential for metabolomics to estimate GA by analyzing data captured through routine newborn screening. Areas covered: Circulating analytes found in newborn blood samples vary by GA. Leveraging newborn screening and demographic data, our group developed an algorithm capable of estimating GA postnatally to within approximately 1 week of ultrasound-validated GA. Since then, we have built on the model by including additional analytes and validating the model's performance through internal and external validation studies, and through implementation of the model internationally. Expert opinion: Currently, using metabolomics to estimate GA postnatally holds considerable promise but is limited by issues of cost-effectiveness and resource access in low-income settings. Future work will focus on enhancing the precision of this approach while prioritizing point-of-care testing that is both accessible and acceptable to individuals in low-resource settings.

Cannabis-based products for pediatric epilepsy: A systematic review.

OBJECTIVE: To assess the benefits and harms of cannabis-based products for pediatric epilepsy. METHODS: We identified in this living systematic review randomized controlled trials (RCTs) and nonrandomized studies (NRSs) involving children with epilepsy treated with cannabis-based products. We searched MEDLINE, Embase, PsycINFO, Cochrane Library, and gray literature (April 25, 2018). The primary outcome was seizure freedom; secondary outcomes were seizure frequency (total, ≥50% reduction), quality of life, sleep, status epilepticus, death, gastrointestinal adverse events, and visits to the emergency room. Data were pooled by random-effects meta-analysis. Risk of bias was assessed for each study, and GRADE was used to assess the quality of evidence for each outcome. RESULTS: Four RCTs and 19 NRSs were included, primarily involving cannabidiol. All RCTs were at low risk of bias, whereas all NRSs were at high risk. Among RCTs, there was no statistically significant difference between cannabidiol and placebo in seizure freedom (relative risk [RR] = 6.77, 95% confidence interval [CI] = 0.36-128.38; 1 RCT), quality of life (mean difference = 0.6, 95% CI = -2.6 to 3.9; 3 RCTs), sleep disruption (mean difference = -0.3, 95% CI = -0.8 to 0.2; 3 RCTs), or vomiting (RR = 1.00, 95% CI = 0.51-1.96; 4 RCTs). There was a statistically significant reduction in the median frequency of monthly seizures with cannabidiol compared with placebo (-19.8%, 95% CI = -27.0% to -12.6%; 3 RCTs) and an increase in the number of participants with at least a 50% reduction in seizures (RR = 1.76, 95% CI = 1.07-2.88; 1 RCT) and diarrhea (RR = 2.25, 95% CI = 1.38-3.68; 3 RCTs). Death and status epilepticus were infrequently reported. SIGNIFICANCE: Evidence from high-quality RCTs suggests that cannabidiol probably reduces seizures among children with drug-resistant epilepsy (moderate certainty). At this time, the evidence base is primarily limited to cannabidiol, and these findings should not be extended to all cannabis-based products.

Health Care for Mitochondrial Disorders in Canada: A Survey of Physicians.

BACKGROUND: An improved understanding of diagnostic and treatment practices for patients with rare primary mitochondrial disorders can support benchmarking against guidelines and establish priorities for evaluative research. We aimed to describe physician care for patients with mitochondrial diseases in Canada, including variation in care. METHODS: We conducted a cross-sectional survey of Canadian physicians involved in the diagnosis and/or ongoing care of patients with mitochondrial diseases. We used snowball sampling to identify potentially eligible participants, who were contacted by mail up to five times and invited to complete a questionnaire by mail or internet. The questionnaire addressed: personal experience in providing care for mitochondrial disorders; diagnostic and treatment practices; challenges in accessing tests or treatments; and views regarding research priorities. RESULTS: We received 58 survey responses (52% response rate). Most respondents (83%) reported spending 20% or less of their clinical practice time caring for patients with mitochondrial disorders. We identified important variation in diagnostic care, although assessments frequently reported as diagnostically helpful (e.g., brain magnetic resonance imaging, MRI/MR spectroscopy) were also recommended in published guidelines. Approximately half (49%) of participants would recommend "mitochondrial cocktails" for all or most patients, but we identified variation in responses regarding specific vitamins and cofactors. A majority of physicians recommended studies on the development of effective therapies as the top research priority. CONCLUSIONS: While Canadian physicians' views about diagnostic care and disease management are aligned with published recommendations, important variations in care reflect persistent areas of uncertainty and a need for empirical evidence to support and update standard protocols.

Les soins de santé prodigués au Canada à des individus atteints de troubles mitochondriaux : une enquête menée auprès de médecins. Contexte: Dans le cas de patients atteints de troubles mitochondriaux rares, il est permis de croire qu'une meilleure compréhension des pratiques en matière de diagnostic et de traitement peut contribuer, au moyen des lignes directrices, à l'étalonnage et à l'établissement de priorités en ce qui regarde la recherche évaluative. Notre intention a été de décrire les soins prodigués au Canada par des médecins, notamment leur variabilité, dans le cas de ces patients. Méthodes: Pour ce faire, nous avons effectué une enquête transversale auprès de médecins canadiens qui posent des diagnostics de troubles mitochondriaux et qui prodiguent des soins continus aux patients qui en sont atteints. À cet effet, nous avons fait appel à la méthode d'enquête dite « en boule de neige ¼ (snowball sampling) afin d'identifier des participants possiblement admissibles. Ces derniers ont été ensuite contactés par la poste, et ce, à cinq reprises au maximum. Ils ont été invités à remplir un questionnaire et à le retourner par la poste ou en ligne. Ce questionnaire abordait les aspects suivants : leur expérience personnelle à titre de prestataire de soins ; leurs pratiques en matière de diagnostic et de traitement ; les défis se présentant à eux au moment d'avoir accès à des tests ou à des traitements ; et finalement leurs points de vue en ce qui regarde les priorités de la recherche. Résultats: Dans le cadre de cette enquête, nous avons reçu 58 réponses, ce qui représente un taux de 52 %. Une majorité de répondants (83 %) ont indiqué allouer 20 % ou moins de leur temps de pratique clinique aux soins de patients atteints de ces troubles. Nous avons également noté d'importantes variations concernant les soins et les diagnostics, et ce, même si les outils d'évaluation fréquemment considérés utiles sur le plan diagnostic (p. ex. : des IRM du cerveau/la spectroscopie par RM) étaient également recommandés dans des lignes directrices déjà publiées. Environ la moitié de nos répondants (49 %) recommanderaient volontiers un « cocktail ¼ de vitamines pour tous leurs patients ou la plupart d'entre eux. Quand il est question de vitamines spécifiques et de cofacteurs, nous avons cependant identifié une variation dans leurs réponses. Interrogés quant à la priorité numéro un en matière de recherche, une majorité de répondants a dit recommander la poursuite d'études portant sur la mise sur pied de traitements thérapeutiques efficaces. Conclusions: Bien que les points de vue de ces médecins canadiens en ce qui regarde les diagnostics et la prise en charge des troubles mitochondriaux soient en phase avec des recommandations publiées, d'importantes variations reflètent la persistance d'aspects incertains ainsi qu'un besoin de données empiriques afin de renforcer et de mettre à jour les protocoles de rééférence.