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ObjectiveExploration of a novel therapeutic drug monitoring (TDM) strategy to personalise use of ibuprofen for closure of patent ductus arteriosus (PDA) in preterm neonates.DesignProspective, single-centre, open-label, pharmacokinetics study in preterm neonates.SettingNeonatal intensive care unit at McMaster Children’s Hospital.PatientsNeonates with a gestational age ≤28+6 weeks treated with oral ibuprofen for closure of a PDA.MethodsPopulation pharmacokinetic parameters, concentration-time profiles and exposure metrics were obtained using pharmacometric modelling and simulation.Main outcome measureAssociation between ibuprofen plasma concentrations measured at various sampling time points on the first day of treatment and attainment of the target exposure over the first 3 days of treatment (AUC0–72h >900 mg·hour/L).ResultsTwenty-three preterm neonates (median birth weight 780 g and gestational age 25.9 weeks) were included, yielding 155 plasma ibuprofen plasma samples. Starting from 8 hours’ postdose on the first day, a strong correlation between ibuprofen concentrations and AUC0–72h was observed. At 8 hours after the first dose, an ibuprofen concentration >20.5 mg/L was associated with a 90% probability of reaching the target exposure.ConclusionWe designed a novel and practical TDM strategy and have shown that the chance of reaching the target exposure (AUC0–72h >900 mg·hour/L) can be predicted with a single sample collection on the first day of treatment. This newly acquired knowledge can be leveraged to personalise ibuprofen dosing regimens and improve the efficacy of ibuprofen use for pharmacological closure of a PDA.

The development of specific drug therapy for children was a paradigm-changing event that transformed paediatric medical practice. However, a series of tragedies involving drug treatment for children resulted in a gap developing between drug regulation and practice, with the majority of drugs used in child healthcare being used off-label, rendering children therapeutic orphans. Over the past two decades changes in drug regulation led by the US Food and Drug Administration and followed by the European Union's European Medicines Agency have led to substantial changes in how new drugs with potential use in children are studied and labelled. While these changes have substantially improved labelling for new drugs, there has been much less progress with older drugs. Although the unique challenges of conducting clinical research in children have been addressed by novel clinical trial designs, many of these innovations have not been translated into approaches accepted for the drug approval process. The regulations applying to the need for paediatric studies currently are only applicable in the United States and the European Union, and there is less impetus for paediatric labelling in other jurisdictions. This impacts on a number of issues beyond labelling, including the availability of child-friendly formulations. Finally, the impact of Brexit on paediatric drug studies in the UK remains unclear and is subject to ongoing negotiations between the UK government and the European Union.

Background Drug reaction with eosinophilia and systemic symptoms (DRESS) is a rare but serious delayed hypersensitivity reaction that can be caused by antibiotic exposure. The reaction typically develops in 2 to 6 weeks. The pathophysiology is thought to involve toxic drug metabolites acting as a hapten, triggering a systemic response. The diagnosis is made clinically but can be confirmed using assays such as the lymphocyte toxicity assay (LTA), which correlates cell death upon exposure to drug metabolites with susceptibility to hypersensitivity reactions. Case presentations Case 1 involves a previously healthy 11-month-old male with first exposure to amoxicillin-clavulanate, prescribed for seven days to treat a respiratory infection. The patient developed DRESS fourteen days after starting the drug and was successfully treated with corticosteroids. LTA testing confirmed patient susceptibility to hypersensitivity reactions with amoxicillin-clavulanate. Parental samples were also tested, showing both maternal and paternal susceptibility. Neither parent reported prior hypersensitivity reactions. Lifelong penicillin avoidance for the patient was advised along with the notation in medical records of penicillin allergy. The parents were advised to avoid penicillin class antibiotics and be monitored closely for DRESS if they are exposed. Case 2 involves an 11-year-old female with atopic dermatitis with first exposure to amoxicillin-clavulanate, prescribed for ten days to treat a secondary bacterial skin infection. She developed DRESS eleven days after starting antibiotics and was successfully treated with corticosteroids. LTA testing confirmed patient susceptibility to hypersensitivity reactions with amoxicillin-clavulanate. Maternal samples were also tested and showed sensitivity. The mother reported no prior hypersensitivity reactions. Lifelong penicillin avoidance for the patient was advised along with the notation in medical records of penicillin allergy. Conclusions Amoxicillin-clavulanate is a commonly used antibiotic and the cases we have described suggest that it should be recognized as a potential cause of DRESS in pediatric patients. Furthermore, these cases contribute to current literature supporting that there may be a shorter latent period in DRESS induced by antibiotics. We have also shown that the LTA can be a helpful tool to confirm DRESS reactions, and that testing may have potential implications for family members.

Résumé La douleur est un problème courant chez les enfants. Des mesures pharmacologiques et non pharmacologiques sont utilisées pour la prendre en charge. Depuis quelques décennies, les opioïdes par voie orale sont populaires pour soulager la douleur modérée à grave. La codéine a longtemps été l’opioïde par voie orale le plus connu pour les enfants. Pour des raisons de sécurité, elle est désormais nettement moins accessible et moins employée. Divers autres opioïdes la remplacent, mais les données sur leur efficacité et leur sécurité sont limitées chez les enfants. L’oxycodone par voie orale emprunte les mêmes voies métaboliques que la codéine, mais sa pharmacocinétique est très variable. Les données sur la sécurité et l’efficacité de l’hydromorphone et du tramadol par voie orale chez les enfants sont également limitées. Lorsqu’on y recourt au lieu de la codéine, la morphine par voie orale est l’opiacé dont la sécurité et l’efficacité sont les mieux démontrées chez les enfants. Des recherches devront être réalisées pour explorer d’autres approches relatives aux médicaments opioïdes et non opioïdes, afin d’orienter les traitements analgésiques fondés sur des données probantes qui soulageront la douleur modérée à grave chez les enfants.

Pain is a common problem for children, and pain management comprises both pharmacologic and nonpharmacologic measures. For moderate to severe pain, oral opioids have been a popular choice for the last few decades. Codeine has historically been the best-known oral opioid for use in children. However, availability and use of codeine have sharply declined due to safety concerns. A variety of other opioids have been used in place of codeine, but data are limited regarding their efficacy and safety in children. While the same pathways metabolize oral oxycodone as codeine, oxycodone’s pharmacokinetics varies widely. There are also limited data on the safety and efficacy of oral hydromorphone and tramadol use for children. Oral morphine is the opiate alternative to codeine for which there is the most evidence of safety and efficacy in children. Research is needed to investigate both other opioids and non-opioid approaches to guide evidence-based analgesic therapy and treatment for moderate-to-severe pain in children.

Generalized bullous fixed drug eruptions (GBFDEs) are rare in the paediatric population. We present the case of a 7-year-old girl with GBFDE believed to be secondary to oral ibuprofen, who experienced rapid resolution of lesions and cessation of blistering with a 3-week course of oral cyclosporine. To the best of our knowledge, this is the first report of a paediatric case of GBFDE treated with cyclosporine. In our report, we review published cases of GBFDE in children, and all adult cases managed with cyclosporine.

BackgroundSerum sickness-like reaction (SSLR) is an acute inflammatory condition affecting predominantly children. The pathophysiology remains unclear, but drugs are considered the main trigger.ObjectiveThe aim of this study was to describe the clinical and laboratory features, triggers, and treatment modalities in children diagnosed with SSLR.MethodsWe conducted a 10-year retrospective cohort study including all paediatric patients (0 to 18 years old) with query SSLR referred to the Adverse Drug Reactions Clinic at the Children’s Hospital of Western Ontario. Diagnostic criteria included acute skin rash plus joint inflammation with or without fever.ResultsWe included 83 patients (47 females). Age ranged from 11 months to 12 years (mean 3.2 years). Amoxicillin was the trigger in 82.7% of patients. The mean time between the exposure to the triggering drug and the development of the symptoms was 8.5 days. Urticaria-like and Erythema multiforme-like lesions were present in 35% and 38.5% of the cases, respectively. Joint inflammation affecting hands/feet was present in 60%. Pruritus, lip/eye swelling, and fever were reported in 33, 31, and 45% of patients, respectively. The lymphocyte toxicity assay (LTA) showed incremental T-cell toxicity in 32 of 34 patients. Children that received treatment with antihistamines/nonsteroidal anti-inflammatory drugs (NSAIDs) plus oral steroids had a mean recovery time shorter than those treated only with antihistamines/NSAIDs (6 versus 8 days; P=0.09).ConclusionsIn our study, SSLR was mostly triggered by amoxicillin and had a mean time presentation of 8.5 days. Further prospective and well-conducted studies are needed.

Primary Subject area Rheumatology Background Prednisone is a glucocorticoid (GC) medication commonly used in moderate (>7.5 mg/day) to high doses (≥ 1 mg/kg/day to maximum 60 mg/day) for children with moderate to severe presentations of rheumatic disease, including systemic lupus erythematosus (SLE), juvenile idiopathic arthritis (JIA), and juvenile dermatomyositis (JDM). Adverse effects (AE) to GCs impose a significant burden on health and quality of life including frequent development of weight gain, mood changes, sleep difficulties, osteoporosis, and Cushingoid features, amongst others. Objectives We sought to evaluate a possible relationship between baseline patient body-mass-index (BMI) measure and development of select GC-mediated toxicity within the first 12 months of starting moderate or high-dose prednisone therapy using conventional weight-based dosing of prednisone. Secondary outcomes were to examine rates of GC-mediated hypertension, osteopenia, and osteoporosis. Design/Methods We performed a retrospective chart review on children with rheumatic disease aged ≤ 17 years treated with moderate and high-dose prednisone therapy at a single Canadian academic hospital between January 1, 2010 and December 31, 2019. Demographic variables collected included diagnosis, age, sex, ethnicity. Clinical variables collected include weight, height, and body-mass-index (BMI), hepatitis (AST>41 U/L, ALT>40 U/L, or GGT>60 U/L), proteinuria (>0.1 g/L), and presence of hypoalbuminemia ( Baseline characteristics, which were significant for the subsequent development of obesity during the first 12 months at the bivariate level (p < 0 .05), were included as predictors of obesity in separate logistic regression analyses. In each regression analysis, we also adjusted for baseline BMI, and for confounding variables of hepatitis, hypoalbuminemia (albumin less than 38 grams per litre), proteinuria and prednisone dose. We conducted a complete case analysis, and all analyses were performed using SPSS v.26 (IBM Corp., Armonk, NY, USA), and p-values < 0 .05 were considered statistically significant. Results Seventy-four charts were reviewed, and 72 patients met criteria for analysis. The median prednisone dose was 35 mg per day (IQR 20 to 60 mg), and median duration of therapy was 302 days (IQR 126.75 to 581.25). Thirty-five (48.6%) patients developed obesity, 33 (45.8%) hypertension, five (7.0%) osteopenia, and three (4.2%) osteoporosis. Greater BMI at baseline was associated with greater total weight gain (OR 4.04, 95% CI = [1.98-8.33], p < 0 .001). Conclusion Greater baseline patient BMI may be a predictor of weight gain on high-dose prednisone therapy in children with rheumatic disease requiring high-dose therapy. Further work is required to determine methods for individualized prednisone dosing and counseling and behavioral interventions to mitigate risk for weight gain.

Key points Children with chronic debilitating illness and pain are increasingly using cannabis for medical purposes, particularly when conventional treatment options have limited benefit or substantial adverse effects. Caregivers are becoming aware of evidence that suggests medical cannabis provides

Early prediction of patient mortality risks during a pandemic can decrease mortality by assuring efficient resource allocation and treatment planning. This study aimed to develop and compare prognosis prediction machine learning models based on invasive laboratory and noninvasive clinical and demographic data from patients’ day of admission. Three Support Vector Machine (SVM) models were developed and compared using invasive, non-invasive, and both groups. The results suggested that non-invasive features could provide mortality predictions that are similar to the invasive and roughly on par with the joint model. Feature inspection results from SVM-RFE and sparsity analysis displayed that, compared with the invasive model, the non-invasive model can provide better performances with a fewer number of features, pointing to the presence of high predictive information contents in several non-invasive features, including SPO2, age, and cardiovascular disorders. Furthermore, while the invasive model was able to provide better mortality predictions for the imminent future, non-invasive features displayed better performance for more distant expiration intervals. Early mortality prediction using non-invasive models can give us insights as to where and with whom to intervene. Combined with novel technologies, such as wireless wearable devices, these models can create powerful frameworks for various medical assignments and patient triage.

Cisplatin, a chemotherapy used to treat solid tumors, causes acute kidney injury (AKI), a known risk factor for chronic kidney disease and mortality. AKI diagnosis relies on biomarkers which are only measurable after kidney damage has occurred and functional impairment is apparent; this prevents timely AKI diagnosis and treatment. Metabolomics seeks to identify metabolite patterns involved in cell tissue metabolism related to disease or patient factors. The A Canadian study of Cisplatin mEtabolomics and NephroToxicity (ACCENT) team was established to harness the power of metabolomics to identify novel biomarkers that predict risk and discriminate for presence of cisplatin nephrotoxicity, so that early intervention strategies to mitigate onset and severity of AKI can be implemented.Describe the design and methods of the ACCENT study which aims to identify and validate metabolomic profiles in urine and serum associated with risk for cisplatin-mediated nephrotoxicity in children and adults.Observational prospective cohort study.Six Canadian oncology centers (3 pediatric, 1 adult and 2 both).Three hundred adults and 300 children planned to receive cisplatin therapy.During two cisplatin infusion cycles, serum and urine will be measured for creatinine and electrolytes to ascertain AKI. Many patient and disease variables will be collected prospectively at baseline and throughout therapy. Metabolomic analyses of serum and urine will be done using mass spectrometry. An untargeted metabolomics approach will be used to analyze serum and urine samples before and after cisplatin infusions to identify candidate biomarkers of cisplatin AKI. Candidate metabolites will be validated using an independent cohort.Patients will be recruited before their first cycle of cisplatin. Blood and urine will be collected at specified time points before and after cisplatin during the first infusion and an infusion later during cancer treatment. The primary outcome is AKI, defined using a traditional serum creatinine-based definition and an electrolyte abnormality-based definition. Chart review 3 months after cisplatin therapy end will be conducted to document kidney health and survival.It may not be possible to adjust for all measured and unmeasured confounders when evaluating prediction of AKI using metabolite profiles. Collection of data across multiple sites will be a challenge.ACCENT is the largest study of children and adults treated with cisplatin and aims to reimagine the current model for AKI diagnoses using metabolomics. The identification of biomarkers predicting and detecting AKI in children and adults treated with cisplatin can greatly inform future clinical investigations and practices.Le cisplatine, un agent utilisé en chimiothérapie pour traiter les tumeurs solides, entraîne de l’insuffisance rénale aiguë (IRA); un facteur de risque connu de néphropathie chronique et de mortalité. Le diagnostic de l’IRA repose sur des biomarqueurs qui ne sont mesurables qu’après l’apparition d’une lésion rénale et d’une déficience fonctionnelle; ce qui empêche le diagnostic et le traitement précoce de la maladie. La métabolomique s’efforce d’établir le profil des métabolites impliqués dans le métabolisme des tissus cellulaires en relation avec des facteurs liés à la maladie ou au patient. Une étude canadienne portant sur la métabolomique et la néphrotoxicité du cisplatine (ACCENT) s’est amorcée, elle explore la puissance de la métabolomique dans l’identification de nouveaux biomarqueurs permettant de prédire le risque de néphrotoxicité du cisplatine et d’en distinguer la présence. L’objectif étant de mettre en œuvre des stratégies d’intervention précoce, dès l’apparition de l’IRA, et de limiter la gravité de la maladie.Décrire la conception et la méthodologie de l’étude ACCENT. Cette étude vise à établir et à valider des profils métabolomiques, dans l’urine et le sérum, associés au risque de néphrotoxicité médiée par le cisplatine chez les enfants et les adultes.Étude de cohorte prospective.Six centres canadiens d’oncologie (trois centres pédiatriques, un centre pour adultes et deux centres mixtes).L’étude porte sur 300 adultes et 300 enfants pour qui un traitement par cisplatine est prévu.L’IRA sera confirmée par mesure de la créatinine et des électrolytes dans le sérum et l’urine au cours de deux cycles de perfusion de cisplatine. De nombreuses variables relatives au patient et à la maladie seront recueillies prospectivement avant et pendant le traitement. Les analyses métabolomiques des échantillons de sérum et d’urine seront effectuées par spectrométrie de masse. Une approche métabolomique non ciblée sera utilisée pour analyser les échantillons avant et après les perfusions de cisplatine pour identifier les biomarqueurs candidats d’une IRA découlant du traitement par cisplatine. Les métabolites candidats seront validés dans une cohorte indépendante.Les patients seront recrutés avant le premier cycle de cisplatine. Le sang et l’urine seront recueillis à des moments précis, soit avant et pendant le traitement; plus précisément lors de la première perfusion, puis d’une perfusion subséquente au cours du traitement contre le cancer. Le principal critère d’évaluation est la présence d’IRA, laquelle sera établie selon la définition classique fondée sur la mesure de la créatinine sérique et d’une autre définition fondée sur les anomalies électrolytiques. Un examen des dossiers trois mois après la fin du traitement par cisplatine sera effectué afin de documenter la santé rénale et la survie des patients.Il pourrait être impossible de corriger tous les facteurs confusionnels mesurés et non mesurés lors de l’évaluation de la prédiction de l’IRA à l’aide de profils de métabolites. La collecte de données sur plusieurs sites sera un défi.ACCENT est la plus vaste étude portant sur des enfants et des adultes traités avec le cisplatine; cette étude tente de revoir le modèle actuel en utilisant la métabolomique pour diagnostiquer l’IRA. L’identification de biomarqueurs permettant de prédire et de détecter l’IRA chez les enfants et les adultes traités par cisplatine pourrait grandement éclairer les futures études et pratiques cliniques.ClinicalTrials.gov, insuffisance rénale induite par le cisplatine, NCT04442516.

Objective We compared pain and degree of disability in patients with acute ankle sprains receiving regular scheduled ibuprofen versus pro re nata (PRN). Methods This study is a randomized single-blinded controlled trial of children aged 7 to 17 years presenting with acute ankle sprain to an emergency department. Patients were randomized to receive 10 mg/kg of ibuprofen per dose (maximum 600 mg) every 6 hours regular scheduled versus PRN. Outcome measures included a 100-mm visual analog scale pain and degree of disability at day 4. A sample size of 72 children had a power of 80% to detect a clinically meaningful difference of 20 mm between the regular and PRN group. Results We randomly assigned 99 patients to receive regular scheduled (n = 50) or PRN (n = 49) ibuprofen. Pain scores and degree of disability at day 4 showed no significant differences between groups. The rate of reported adverse effects was higher in the regular scheduled group (11.4% vs 9.5%) versus the PRN group. Conclusions Our study suggests that there is little benefit from routinely using a regular scheduled ibuprofen regimen for acute pediatric ankle sprains.

Ukraineis a republic formed from someof the former Soviet Union's territory. Primary care for children in Ukraine is delivered by paediatricians in polyclinics. Specialty and tertiary care for children is based at children's hospitals, as is postgraduate training in paediatrics. Many challenges to child health care in Ukraine accompanied the collapse of the Soviet Union, includinga lack of resources devoted topublic health and community care, environmental contamination and a system of medical education and delivery of care that is not suited to meet evolving changes in medical care.L'Ukraine est une république formée d'une partie du territoire de l'ancienne Union soviétique. Dans ce pays, les soins de premier recours aux enfants sont assurés par des pédiatres situés dans des polycliniques. Les soins spécialisés et tertiaires sont offerts dans des hôpitaux pour enfants, de même que la formation surspécialisée en pédiatrie. De nombreux défis aux soins infantiles ont émergé en Ukraine par suite du démantèlement de l'Union soviétique, dont le manque de ressources vouées à la santé publique et aux soins communautaires, la contamination de l'environnement et un systême d’éducation médicale et de prestation des soins mal adapté pour répondre à l’évolution constante des soins médicaux.

Cancer is the leading cause of death in American children older than 1 year of age. Major developments in drugs such as thiopurines and optimization in clinical trial protocols for treating cancer in children have led to a remarkable improvement in survival, from approximately 30% in the 1960s to more than 80% today. Short-term and long-term adverse effects of chemotherapy still affect most survivors of childhood cancer. Pharmacogenetics plays a major role in predicting the safety of cancer chemotherapy and, in the future, its effectiveness. Treatment failure in childhood cancer—due to either serious adverse effects that limit therapy or the failure of conventional dosing to induce remission—warrants development of new strategies for treatment. Here, we summarize the current knowledge of the pharmacogenomics of cancer drug treatment in children and of statistically and clinically relevant drug–gene associations and the mechanistic understandings that underscore their therapeutic value in the treatment of childhood cancer.

Purpose The purpose of this study was to test fluorine-19 (19F) cellular magnetic resonance (MRI) as a non-invasive imaging modality to track therapeutic cell migration as a surrogate marker of immunotherapeutic effectiveness. Materials and methods Human peripheral blood mononuclear cell- (PBMC)-derived antigen presenting cell (APC) were labeled with a 19F-perfluorocarbon (PFC) and/or activated with granulocyte macrophage colony-stimulating factor (GM-CSF). Viability, phenotype and cell lineage characterization preceded 19F cellular MRI of PFC+ PBMC under both pre-clinical 9.4 Tesla (T) and clinical 3T conditions in a mouse model. Results A high proportion of PBMC incorporated PFC without affecting viability, phenotype or cell lineage composition. PFC+ PBMC were in vivo migration-competent to draining and downstream lymph nodes. GM-CSF addition to culture increased PBMC migration to, and persistence within, secondary lymphoid organs. Conclusion 19F cellular MRI is a non-invasive imaging technique capable of detecting and quantifying in vivo cell migration in conjunction with an established APC-based immunotherapy model. 19F cellular MRI can function as a surrogate marker for assessing and improving upon the therapeutic benefit that this immunotherapy provides.

Background:While the pathophysiology of chronic disorders varies there are three basic mechanisms - inflammation, oxidative stress and endothelial dysfunction – that are common in many chronic diseases. These mechanisms, which have a dynamic structure, are key to homeostasis. However, the failure of these mechanisms to work synchronously can lead to morbidity complicating the course of many chronic diseases.Objectives:To evaluate the effect of anti-atherosclerotic liquid (AAL), anti-inflammatory capsules (AIC) and anti-oxidant liquid (AOL) supplementation on the flow-mediated dilatation (FMD), inflammatory, oxidative stress and endothelial dysfunction markers in patients with selected chronic diseasesMethods:We analyzed data of 178 patients from cohorts with selected chronic diseases (Rheumatoid arthritis, familial Mediterranean fever, DM type-2, Hypertension, Multiple sclerosis, Chronic obstructive pulmonary disease, Alzheimer disease and Cancer) in this quasi-experimental study. Endothelial dysfunction was determined by FMD and serum asymmetric dimethylarginine (ADMA) levels. Serum ADMA, high sensitive C-reactive protein (hs-CRP), serum PTX3, malondialdehyde (MDA), Cu/Zn-superoxide dismutase (Cu/Zn-SOD), glutathione peroxidase (GSH-Px) levels and FMD were studied in baseline and after 12 weeks of Morinda citrifolia (AAL, 3 ml once per day), omega-3 (AIC, 3 capsules once per day) and extract with Alaskan blueberry and 21 different red purple fruit vegetables (AOL, 30 ml once per day). Stepwise multivariate regression analysis evaluated the association of FMD with clinical and serologic parameters.Results:Serum ADMA, MDA, PTX3, hsCRP and albumin levels, and proteinuria were significantly decreased and CuZn-SOD, GSH-Px and FMD levels were significantly increased following AAL, AIC and AOL therapies. FMD was negatively correlated with serum ADMA, MDA, PTX3, hsCRP levels, SBP and DBP and positively correlated to CuZn-SOD and eGFR levels both at baseline and after the 12-weeks treatment period. Multivariate regression analysis revealed that ADMA and PTX3 levels were independently related to FMD both before and after AAL, AIC and AOL therapies (Table 1, Figure 1).Conclusion:Our study shows that serum ADMA, MDA, PTX3 levels are associated with endothelial dysfunction in patients with selected chronic diseases. Short-term AAL, AIC and AOL therapies significantly improves FMD and normalizes ADMA, PTX3, hsCRP and MDA. This may have implications for adjunctive therapy in a number of chronic disorders.References:[1] Yilmaz MI, Saglam M, Caglar K, Cakir E, Sonmez A, Ozgurtas T et al. The determinants of endothelial dysfunction in CKD: oxidative stress and asymmetric dimethylarginine. Am J Kidney Dis. 2006;47(1):42-50. doi:10.1053/j.ajkd.2005.09.029.Disclosure of Interests:None declared

While the pathophysiology of chronic disorders varies there are three basic mechanisms - inflammation, oxidative stress and endothelial dysfunction – that are common in many chronic diseases. However, the failure of these mechanisms to work synchronously can lead to morbidity complicating the course of many chronic diseases. We analyzed data of 178 patients from cohorts with selected chronic diseases in this quasi-experimental study. Endothelial dysfunction was determined by flow-mediated dilatation (FMD) and asymmetric dimethylarginine (ADMA) levels. Serum ADMA, high sensitive C-reactive protein (hs-CRP), serum PTX3, malondialdehyde (MDA), Cu/Zn-superoxide dismutase (Cu/Zn-SOD), glutathione peroxidase (GSH-Px) levels and FMD were studied in baseline and after 12 weeks of Morinda citrifolia (anti-atherosclerotic liquid- AAL), omega-3 (anti-inflammatory capsules- AIC) and extract with Alaskan blueberry (anti-oxidant liquid- AOL). Stepwise multivariate regression analysis was used to evaluate the association of FMD with clinical and serologic parameters. Serum ADMA, MDA, PTX3, hsCRP and albumin levels, and proteinuria were significantly decreased while CuZn-SOD, GSH-Px and FMD levels were significantly increased following AAL, AIC and AOL therapies. The FMD was negatively correlated with serum ADMA, MDA, PTX3, and hsCRP levels and positively correlated with CuZn-SOD and eGFR levels. ADMA and PTX3 levels were independently related to FMD both before and after AAL, AIC and AOL therapies. Our study shows that serum ADMA, MDA, PTX3 levels are associated with endothelial dysfunction in patients with selected chronic diseases. In addition, short-term AAL, AIC and AOL therapies significantly improves a number of parameters in our cohort and can normalize ADMA, PTX3, hsCRP and MDA levels.

Résumé L’organisme a besoin de très petites quantités de sodium alimentaire pour soutenir le volume sanguin et la tension artérielle. Selon les données de surveillance nutritionnelle disponibles, la plupart des enfants canadiens consomment une quantité de sodium supérieure à leurs besoins nutritionnels. Environ 80 % du sodium que consomment les Canadiens proviennent d’aliments transformés et emballés. Chez les enfants, un fort apport en sodium peut être indicateur d’un régime alimentaire de piètre qualité. Les résultats d’analyses systématiques et de méta-analyses démontrent que la diminution du sodium alimentaire chez les enfants entraîne une réduction modeste, mais cliniquement non significative, de la tension artérielle. Les stratégies en population pour limiter la consommation de sodium, telles que la reformulation des produits alimentaires, la modification des processus d’approvisionnement alimentaire et les politiques fédérales de saine alimentation, sont d’importantes initiatives en santé publique qui peuvent réduire considérablement la consommation de sodium et contribuer à prévenir des maladies chroniques à l’âge adulte.

Adverse drug reactions (ADRs) are common and important complications of drug therapy for children. The risk for ADRs changes over childhood, as do the nature and types of ADRs. Importantly, the risk and nature of ADRs in children are markedly different from those of adults, and adult data cannot be relied on to guide safe drug therapy in children. There are groups of children, notably those with complex and chronic diseases, who are at substantial risk for ADRs. The evaluation of an undesired effect during therapy is ideally accomplished by an organized approach that is a skill that clinicians who care for children-especially those children at high risk for ADRs must have. Additionally, clinicians as well as drug regulatory agencies and industry need to be both vigilant and astute as well as aware that ADRs in children are often different in nature and frequency from those in adults. The increasing use of pharmacogenomics to guide drug dosing and the increasing number of biological agents will provide new sets of challenges to clinicians over the next decade.

Contains fulltext : 193438.pdf (Publisher’s version ) (Open Access) Optimising the dosing of medicines for neonates and children remains a challenge. The importance of pharmacokinetic (PK) and pharmacodynamic (PD) research is recognised both in medicines regulation and paediatric clinical pharmacology, yet there remain barriers to undertaking high-quality PK and PD studies. While these studies are essential in understanding the dose-concentration-effect relationship and should underpin dosing recommendations, this review examines how challenges affecting the design and conduct of paediatric pharmacological studies can be overcome using targeted pharmacometric strategies. Model-based approaches confer benefits at all stages of the drug life-cycle, from identifying the first dose to be used in children, to clinical trial design, and optimising the dosing regimens of older, off-patent medications. To benefit patients, strategies to ensure that new PK, PD and trial data are incorporated into evidence-based dosing recommendations are needed. This review summarises practical strategies to address current challenges, particularly the use of model-based (pharmacometric) approaches in study design and analysis. Recommendations for practice and directions for future paediatric pharmacological research are given, based on current literature and our joint international experience. Success of PK research in children requires a robust infrastructure, with sustainable funding mechanisms at its core, supported by political and regulatory initiatives, and international collaborations. There is a unique opportunity to advance paediatric medicines research at an unprecedented pace, bringing the age of evidence-based paediatric pharmacotherapy into sight.

Drug therapy for children is one of the cornerstone developments that have sharply reduced childhood mortality. Despite this, many challenges remain in ensuring that children receive safe and effective drug therapy. There are unique issues in treating children with oral medication relating to development, existing formulations and medication acceptability. Medication acceptability in children is complex relating to a wide range of factors, including drug palatability. Over the past decade there has been an increasing interest in and research as to how to improve and enhance child-specific drug formulations including the development of specific instruments for assessing drug palatability in children and new approaches to teaching medication literacy to families. Approaches to enhancing drug acceptability have also included organoleptic (taste masking) strategies as well as the creation of a number of innovative taste-blocking strategies and new technologies for formulation preparation. Polymer coating, microencapsulation and heat melt technologies have resulted in drug formulations that are now being assessed in children while soft melt and gel formulations are now commonly used. Mini-tablets offer the potential of using solid delivery systems in even very young infants. This work has resulted in a number of highly promising developments that are being evaluated for clinical use as well as providing insights into new directions in pursuit of the common goal of effective and safe drug therapy for children. On-going challenges include the need for drug regulatory agencies to work closely with drug regulatory agencies in facilitating innovation in formulation design and approval.

Adverse drug reactions (ADRs) represent a major health problem worldwide, with high morbidity and mortality rates. ADRs are classified into Type A (augmented) and Type B (bizarre) ADRs, with the former group being more common and the latter less common but often severe and clinically more problematic due to their unpredictable nature and occurrence at any dose. Pediatric populations are especially vulnerable to ADRs due to the lack of data for this age group from the drug development process and because of the wide use of off-label and unlicensed use of drugs. Children are more prone to specific types of ADRs because of the level of maturity of body systems involved in absorption, metabolism, transportation, and elimination of drugs. This state-of-the-art review provides an overview of definitions, classifications, epidemiology, and pathophysiology of ADRs and discusses the available evidence for related risk factors and causes of ADRs in the pediatric population.

Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) are potentially life-threatening, immune-mediated adverse reactions characterized by widespread erythema, epidermal necrosis, and detachment of skin and mucosa. Efforts to grow and develop functional international collaborations and a multidisciplinary interactive network focusing on SJS/TEN as an uncommon but high burden disease will be necessary to improve efforts in prevention, early diagnosis and improved acute and long-term management. SJS/TEN 2019: From Science to Translation was a 1.5-day scientific program held April 26-27, 2019, in Vancouver, Canada. The meeting successfully engaged clinicians, researchers, and patients and conducted many productive discussions on research and patient care needs.

OBJECTIVES: Proton pump inhibitors (PPIs) are often used in pediatrics to treat common gastrointestinal disorders, and there are growing concerns for infectious adverse events. Because CYP2C19 inactivates PPIs, genetic variants that increase CYP2C19 function may decrease PPI exposure and infections. We tested the hypothesis that CYP2C19 metabolizer phenotypes are associated with infection event rates in children exposed to PPIs. METHODS: This retrospective biorepository cohort study included individuals aged 0 to 36 months at the time of PPI exposure. Respiratory tract and gastrointestinal tract infection events were identified by using International Classification of Diseases codes in the year after the first PPI mention. Variants defining CYP2C19 *2, *3, *4, *8, *9, and *17 were genotyped, and all individuals were classified as CYP2C19 poor or intermediate, normal metabolizers (NMs), or rapid or ultrarapid metabolizers (RM/UMs). Infection rates were compared by using univariate and multivariate analyses. RESULTS: In all, 670 individuals were included (median age 7 months; 44% girls). CYP2C19 NMs (n = 267; 40%) had a higher infection rate than RM/UMs (n = 220; 33%; median 2 vs 1 infections per person per year; P = .03). There was no difference between poor or intermediate (n = 183; 27%) and NMs. In multivariable analysis of NMs and RM/UMs adjusting for age, sex, PPI dose, and comorbidities, CYP2C19 metabolizer status remained a significant risk factor for infection events (odds ratio 0.70 [95% confidence interval 0.50–0.97] for RM/UMs versus NMs). CONCLUSIONS: PPI therapy is associated with higher infection rates in children with normal CYP2C19 function than in those with increased CYP2C19 function, highlighting this adverse effect of PPI therapy and the relevance of CYP2C19 genotypes to PPI therapeutic decision-making.

BACKGROUND: Over the past decade a number of highly promising new therapeutic entities have become available. Many of these new treatments are biologicals or antibodies rather than conventional small molecules. These drugs offer great promise but come with the potential for potent adverse effects as well as creating challenges for access. Many of these new treatments are very expensive and are frequently not on hospital formularies. There is no comprehensive pan-Canadian strategy on how to best provide access to these drugs for the children at most need and how to address the rapidly evolving world of novel therapeutics for children. To evaluate how this issue is being addressed nationally we conducted a survey among the 17 Departments of Paediatrics across Canada. OBJECTIVES: In Paediatrics high cost drugs are most commonly used in academic child health care centres. Our objectives were to; I) Determine what the policies as to provision of high cost drugs in Canada’s academic child health care centres, ii) Determine what the challenges facing Canada’s academic health care centres were in providing access to novel therapies to children at most need and iii) Explore possible solutions to these challenges. DESIGN/METHODS: To explore these questions we conducted a survey of the 17 Departments of Paediatrics across Canada through the Paediatric Chairs of Canada and faciliated through Childrens Healthcare Canada. A questionnaire was sent to all Department Chairs asking the following four questions; 1) Does your hospital have a policy for how to deal with high cost drugs that are not covered by provincial health insurance or are not on the hospital formulary? 2) If so, how does this policy work? 3) If not, how are these therapies addressed? 4) What do you think is the best approach to provide access to high cost drugs for children? Department Chairs agreed to voluntarily participate in the survey. After completion of the survey areas of uncertainty were followed up by interviews with the respective Department Chairs. RESULTS: The issue of high cost drugs for children was noted to be a growing issue by all Departments of Paediatrics across Canada. There was a wide variability in how requests for high cost drugs were dealt with, ranging from a somewhat ad hoc case-specific response to a formal process involving decision making groups representing physicians, hospital administration and hospital pharmacy. No single best practice was identified. There was a concensus that this has emerged as a major problem in terms of access having a significant impact on hospital budgets with no end in sight as the therapeutic revolution in biological, factor and molecular therapy continued. It was acknowledged that traditional payment measures have failed to address this and some changes in provincial policy towards drugs for children may have negatively impacted access to these therapies. There was also a wide concensus that a pan-Canadian approach was needed, with suggestions including a national formulary for drugs for children that could provide evidence and recommendations to provincial funders as well as the suggestion of a pan-Canadian pharmacare plan for children. An urgent need for national leadership on this issue was also identified. CONCLUSION: Historically the per capita expenditure for pharmaceuticals for a Canadian child was in the range of $450. With the advent of new therapies that cost in the tens of thousands of dollars new approaches to drug evaluation and drug access for Canada’s children are urgently needed. This is a concern for all Departments of Paediatrics across Canada and pan-Canadian solutions are needed to address how to best treat Canada’s children at highest need.

Background: The knowledge and ability to prescribe safely and effectively is a core competency for every graduating medical student. Our previous research suggested concerns about medical student prescribing abilities, and interest in a standardized assessment process. Methods: A multi-year cross-sectional study evaluating the feasibility, acceptability, and discriminative ability of an online prescribing competency assessment for final year Canadian medical students was conducted. Students at nine sites of four Ontario medical schools were invited to participate in an online one-hour exam of eight domains related to prescribing safely. Student feedback on perceived fairness, clarity, and ease of use formed the primary outcome. Exam performance and parity between schools were the secondary outcome. Results: A total of 714 students completed the assessment during spring final review courses between 2016 and 2018. Student feedback was more favourable than not for appropriateness of content (53.5% agreement vs 18.3% disagreement), clarity of questions (65.5% agreement vs 11.6% disagreement), question layout and presentation (70.8% agreement vs 12.2% disagreement), and ease of use of online interface (67.1% agreement vs 13.6% disagreement). Few (23.6% believed their course work had prepared them for the assessment. Mean total exam score was 70.0% overall (SD 10.4%), with 47.6% scoring at or above the pass threshold of 70%. Conclusion: Our prescribing competency assessment proved feasible, acceptable, and discriminative, and indicated a need for better medical school training to improve prescribing competency. Further evaluation in a larger sample of medical schools is warranted.

Many paediatric patients require sedation and analgesia for diagnostic testing and therapeutic procedures outside the operating room. This statement reviews the literature on procedural sedation, focusing on the prevention of adverse events through the selection of appropriate patients, advance preparation for emergency situations, and adequate monitoring during and after the administration of pharmacologic agents. Procedural sedation should only be performed by clinicians who are competent in airway management and resuscitation, as part of a hospital program with active and engaged quality assurance and safety initiatives. Recommendations include the development of institutional policies and procedures for the safe delivery of procedural sedation in infants, children, and adolescents.

Background Oral morphine has been proposed as an effective and safe alternative to codeine for after-discharge pain in children following surgery but there are few data guiding an optimum safe oral dose. Aims The aim of this study was to characterize the absorption pharmacokinetics of enteral morphine in order to simulate time–concentration profiles in children given common oral morphine dose regimens. Methods Children (2–6 years, n = 34) undergoing elective surgery and requiring opioid analgesia were randomized to receive preoperative oral morphine (100 mcg·kg−1, 200 mcg·kg−1, 300 mcg·kg−1). Blood sampling for morphine assay was performed at 30, 60, 90, 120, 180, and 240 min. Morphine serum concentrations were determined by liquid chromatography–mass spectroscopy and pharmacokinetic parameters were calculated using nonlinear mixed effects models. Current data were pooled with published time–concentration profiles from children (n = 1059, age 23 weeks postmenstrual age – 3 years) administered intravenous morphine, to determine oral bioavailability (F), absorption lag time (TLAG), and absorption half-time (TABS). These parameter estimates were used to predict concentrations in children given oral morphine (100, 200, 300, 400, 500 mcg·kg−1) at different dosing intervals (3, 4, 5, 6, 8, 12 h). Results The oral morphine formulation had F 0.298 (CV 36.5%), TLAG 0.45 (CV 63.6%) h and TABS 0.71 (CV 55%) h. A single-dose morphine 100 mcg·kg−1 achieved a mean CMAX 10 mcg·l−1. Repeat 4-hourly dosing achieved mean steady-state concentration 13–18 mcg·l−1; concentrations associated with good analgesia after intravenous administration. Serum concentration variability was large ranging from 5 to 55 mcg·l−1 at steady state. Conclusions Oral morphine 200 mcg·kg−1 then 100 mcg·kg−1 4 h or 150 mcg·kg−1 6 h achieves mean concentrations associated with analgesia. There was high serum concentration variability suggesting that respiration may be compromised in some children given these doses.

BACKGROUND Children's aversions to poor and mostly bitter tastes and their inability to swallow tablets and capsules are major challenges in pediatric medicine. Sodium phenylbutyrate (NaPB) is a lifesaving waste nitrogen, alternative to urea nitrogen, for individuals suffering from urea cycle disorders. A major issue in the use of NaPB is its highly foul taste, which often leads to children being unable to consume it, resulting in ineffective treatment, or alternatively, necessitating the application of the drug through a nasogastric tube or gastrostomy. METHODS This study reviews the published data on a novel formulation of NaPB, Pheburane® granules, which begin to release their NaPB after a lag time of ~10 seconds followed by a slow release over several minutes. RESULTS The taste-masked granule formulation of NaPB dramatically improves the acceptability of the drug by children and appears in initial studies to be both safe and effective. CONCLUSION While more studies are needed to substantiate and enrich these initial trials, the available data provide a telling example where masking the drug taste of medicine for children can sometimes be the difference between life and death.

It has historically been very difficult to conduct early phase drug studies in children for a number of reasons related to ethics, acceptability, rarity, standardization, end points, safety, dosing and feasibility. Over the past decade there have been a number of developments including novel clinical trial design, in silico pharmacology and microdosing that have significantly enhanced the ability of investigators to conduct early phase drug studies in children. While the evolution of drug therapy is creating a series of new challenges, there has never been a better time for conducting drug studies in children.

AIM Anthracycline-induced cardiotoxicity (ACT) occurs in 57% of treated patients and remains an important limitation of anthracycline-based chemotherapy. In various genetic association studies, potential genetic risk markers for ACT have been identified. Therefore, we developed evidence-based clinical practice recommendations for pharmacogenomic testing to further individualize therapy based on ACT risk. METHODS We followed a standard guideline development process; including a systematic literature search, evidence synthesis and critical appraisal, and the development of clinical practice recommendations with an international expert group. RESULTS RARG rs2229774, SLC28A3 rs7853758 and UGT1A6 rs17863783 variants currently have the strongest and the most consistent evidence for association with ACT. Genetic variants in ABCC1, ABCC2, ABCC5, ABCB1, ABCB4, CBR3, RAC2, NCF4, CYBA, GSTP1, CAT, SULT2B1, POR, HAS3, SLC22A7, SCL22A17, HFE and NOS3 have also been associated with ACT, but require additional validation. We recommend pharmacogenomic testing for the RARG rs2229774 (S427L), SLC28A3 rs7853758 (L461L) and UGT1A6*4 rs17863783 (V209V) variants in childhood cancer patients with an indication for doxorubicin or daunorubicin therapy (Level B - moderate). Based on an overall risk stratification, taking into account genetic and clinical risk factors, we recommend a number of management options including increased frequency of echocardiogram monitoring, follow-up, as well as therapeutic options within the current standard of clinical practice. CONCLUSIONS Existing evidence demonstrates that genetic factors have the potential to improve the discrimination between individuals at higher and lower risk of ACT. Genetic testing may therefore support both patient care decisions and evidence development for an improved prevention of ACT.

Periconceptional folic acid significantly reduces the risk of neural tube defects. It is difficult to achieve optimal levels of folate by diet alone, even with fortification of flour, especially because flour consumption in Canada is slightly decreasing. Intermittent concerns have been raised concerning possible deleterious effects of folate supplementation, including the masking of symptoms of vitamin B12 deficiency and an association with cancer, especially colorectal cancer. Both concerns have been disproved. The Canadian Paediatric Society endorses the following steps to enhance folate intake in women of child-bearing age: encouraging the consumption of folate-rich foods such as leafy vegetables, increasing the level of folate food fortification, taking a supplement containing folate and B12, and providing free folate supplementation to disadvantaged women of child-bearing age. These recommendations are consistent with those of the Society of Obstetricians and Gynaecologists of Canada.La consommation d’acide folique pendant la période périconcep- tionnelle réduit considérablement le risque d’anomalie du tube neural. Il est difficile d’atteindre un taux optimal de folate à partir du seul régime alimentaire, malgré l’enrichissement de la farine, surtout que la consommation de ce produit diminue légèrement au Canada. Les effets délétères possibles des suppléments de folate ont suscité sporadiquement des inquiétudes, y compris le camouflage des symptômes de carence en vitamine B

Needle fear typically begins in childhood and represents an important health-related issue across the lifespan. Individuals who are highly fearful of needles frequently avoid health care. Although guidance exists for managing needle pain and fear during procedures, the most highly fearful may refuse or abstain from such procedures. The purpose of a clinical practice guideline (CPG) is to provide actionable instruction on the management of a particular health concern; this guidance emerges from a systematic process. Using evidence from a rigorous systematic review interpreted by an expert panel, this CPG provides recommendations on exposure-based interventions for high levels of needle fear in children and adults. The AGREE-II, GRADE, and Cochrane methodologies were used. Exposure-based interventions were included. The included evidence was very low quality on average. Strong recommendations include the following. In vivo (live/in person) exposure-based therapy is recommended (vs. no treatment) for children seven years and older and adults with high levels of needle fear. Non-in vivo (imaginal, computer-based) exposure (vs. no treatment) is recommended for individuals (over seven years of age) who are unwilling to undergo in vivo exposure. Although there were no included trials which examined children < 7 years, exposure-based interventions are discussed as good clinical practice. Implementation considerations are discussed and clinical tools are provided. Utilization of these recommended practices may lead to improved health outcomes due to better health care compliance. Research on the understanding and treatment of high levels of needle fear is urgently needed; specific recommendations are provided. Canadian Institutes of Health Research, The Mayday Fund

Cannabis is a psychoactive compound with a long history of recreational and therapeutic use. Current considerations regarding cannabis use for medical purposes in children have been stimulated by recent case reports describing its beneficial effect with refractory epilepsy. Overall, there are insufficient data to support either the efficacy or safety of cannabis use for any indications in children, and an increasing body of data suggests possible harm, most importantly in specific conditions. The potential for cannabis as a therapeutic agent must be evaluated carefully for both efficacy and safety in treating specific paediatric health conditions. Smoking is not an acceptable mode of drug delivery for children. The use of cannabis for medical purposes in specific cases should not be construed as a justification for recreational cannabis use by adolescents. Recommendations for therapeutic use in exceptional paediatric cases are offered, always providing that this treatment course is carefully evaluated in individuals and in ongoing, well-designed research studies to determine safety and efficacy.Le cannabis est une substance psychoactive utilisée depuis très longtemps dans un cadre récréatif et thérapeutique. Les considérations actuelles à l’égard de l’utilisation du cannabis à des fins médicales en pédiatrie découlent de récents rapports de cas sur son effet bénéfique lors d’une épilepsie réfractaire. Dans l’ensemble, les données sont insuffisantes pour en corroborer l’efficacité ou l’innocuité pour quelque indication que ce soit au sein de cette population, mais les données s’accumulent sur son potentiel néfaste, particulièrement pour traiter certaines affections. Il faut en évaluer soigneusement l’efficacité et l’innocuité comme agent thérapeutique contre certaines affections infantiles. L’inhalation sous forme de cigarette n’est pas un mode d’administration acceptable chez les enfants. L’utilisation de cannabis à des fins médicales dans des situations particulières ne doit pas en justifier l’utilisation à des fins récréatives chez les adolescents. Des recommandations sont formulées quant à son utilisation à des fins thérapeutiques dans des cas exceptionnels en pédiatrie, à condition d’assurer une évaluation étroite des sujets traités et de poursuivre des recherches bien conçues pour en déterminer l’innocuité et l’efficacité.

Beta-lactam allergy is commonly diagnosed in paediatric patients, but over 90% of individuals reporting this allergy are able to tolerate the medications prescribed after evaluation by an allergist. Beta-lactam allergy labels are associated with negative clinical and administrative outcomes, including use of less desirable alternative antibiotics, longer hospitalizations, increasing antibiotic-resistant infections, and greater medical costs. Also, children with true IgE-mediated allergy to penicillin medications are often advised to avoid all beta-lactam antibiotics, including cephalosporins, which is likely unnecessary in greater than 97% of those reporting penicillin allergies. Most patients can be safely treated with penicillin or amoxicillin if they do not have a history compatible with IgE-mediated or systemic, delayed reactions such as Stevens-Johnson syndrome (SJS), serum sickness-like reactions, drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome, or acute generalized exanthematous pustulosis (AGEP). Guidance is provided on how to stratify risk of beta-lactam allergy, and on test dosing and monitoring in the outpatient setting for patients deemed low risk. Guidance for patients at higher risk of beta-lactam allergy includes criteria for appropriate referral to allergists and the use of alternative antimicrobials, such as cephalosporins, while awaiting specialist assessment.

L’allergie aux bêta-lactamines est souvent diagnostiquée chez les patients pédiatriques, mais plus de 90 % de ceux qui déclarent en être victimes peuvent tolérer les médicaments prescrits après avoir été évalués par un allergologue. Une « étiquette » d’allergie aux bêta-lactamines est liée à des résultats cliniques et administratifs négatifs, y compris l’utilisation d’autres antibiotiques moins indiqués, des hospitalisations plus longues, une augmentation des infections antibiorésistantes et des coûts médicaux plus élevés. De plus, pour les enfants ayant une véritable allergie à médiation IgE aux pénicillines, on conseille souvent d’éviter toutes les bêta-lactamines, y compris les céphalosporines, ce qui n’est probablement pas nécessaire chez plus de 97 % de ceux qui déclarent être allergiques à la pénicilline. La plupart des patients peuvent recevoir un traitement à la pénicilline ou à l’amoxicilline en toute sécurité s’ils n’ont pas d’antécédents compatibles avec des réactions à médiation IgE ni avec des réactions systémiques tardives comme le syndrome de Stevens-Johnson, une réaction de type maladie sérique, le syndrome d’éruption médicamenteuse avec éosinophilie et manifestations systémiques ou la pustulose exanthématique aiguë généralisée. Des directives sont proposées pour stratifier le risque d’allergie aux bêta-lactamines ainsi que pour administrer des doses tests aux patients considérés comme à faible risque et les surveiller en milieu ambulatoire. Les directives sur les patients à plus haut risque d’allergie aux bêta-lactamines comprennent les critères pour les diriger vers des allergologues et l’utilisation d’autres antimicrobiens tels que les céphalosporines, en attendant l’évaluation par un spécialiste.

Background Hair cortisol analysis is increasingly being appreciated and applied in both research and medicine, aiding endocrinologists with diagnosis. Content We provide an overview of hair cortisol research in general and an update on methodological considerations including the incorporation of cortisol into hair, hair growth rates, and sampling procedures, mincing vs. grinding of samples during preparation for extraction, various extraction protocols, and quantification techniques. We compare the clinical utility and application of hair cortisol with traditional methods of measurement while acknowledging the limitations of analysis including variations in hair growth parameters. We explore the value of hair cortisol in cases of Cushing syndrome (particularly Cyclical Cushing), Adrenal insufficiency (including Addison's disease), therapy monitoring, cardiovascular disease, stress, and mental illness. Summary Hair cortisol provides a unique objective biomarker for the analysis of endogenous cortisol levels for not only clinical diagnostic purposes but also in research. The use of hair cortisol has great potential for advancing patient care.

Purpose: Ketamine is the most commonly used agent for procedural sedation in children in the emergency department. Evidence suggests ketamine can be administered intranasally, obviating the need for intravenous access. However, studies are conflicting with regards to dosing and indications, limiting the ability of clinicians to extrapolate findings to practice. We sought to summarize the pediatric literature on the effectiveness of intranasal (IN) ketamine for sedation, analgesia, and adverse effects. Methods: Trials were identified through electronic searches of MEDLINE (1946-2015), EMBASE (1980-2015), Google Scholar (2015), CINAHL (1981-2015), Cochrane Central Register …

BACKGROUND: Since the removal of codeine from hospital formularies, clinicians have increasingly turned to oral morphine to manage acute pain in children. However, recent evidence highlights a high prevalence of adverse effects and variable efficacy. Characterization of oral morphine pharmacokinetics and pharmacogenomics is necessary to guide the safe and effective use of oral morphine. OBJECTIVES: We sought to explore the pharmacokinetics and pharmacogenomics of oral morphine in otherwise healthy children with fractures. DESIGN/METHODS: We included a convenience sample of children age 5–17 years in the Paediatric Emergency Department with a deformed extremity fracture. Repeated blood samples were taken from an intravenous (IV) line for 120 minutes. Key pharmacokinetic parameters included time to maximum concentration (Tmax), peak serum concentration (Cmax), half-life, and area under the curve (AUC) for morphine and its metabolites: morphine-6-glucuronide (M6G) and morphine-3-glucuronide (M3G). Concentrations were determined by ultra performance liquid chromatography (UPLC) coupled to quadrupole time of flight (QTOF) mass spectrometry. Genotyping of single nucleotide polymorphisms (SNPs) was performed by TaqMan assay. Pain scores were collected using the Faces Pain Scale – Revised. RESULTS: We recruited 13 children (11 males) ranging from 4–16 (median 11.6) years. All participants received a single dose of oral morphine 0.5 mg/kg (maximum 20 mg). For morphine, M6G, and M3G, Tmax ranged from 30–120 minutes, 60–180 minutes, and 60–180 minutes, respectively; Cmax ranged from ranged from 6.2–52.6 ng/mL, 14.7–86 ng/mL, and 89.3–483.4 ng/mL, respectively; half-life ranged from 47.9–271.5 minutes, 71.2–400.5 minutes, and 94.7–278.3 minutes, respectively; AUC ranged from 250.1–6760.1 ng/mL*hr, 1129.4–9893.2 ng/mL*hr, and 8030.6–56246.5 ng/mL*hr, respectively. In one patient who reported no reduction from a pain score of 6, a SNP (RS563649) on the OPRMIgene locus previously shown to confer reduced receptor efficiency (less analgesia) was identified. In two patients, we identified a SNP (RS1799971) on the OPRMIgene locus previously shown to confer reduced metabolism, blood-brain barrier penetration, and receptor activity (less analgesia but fewer adverse effects). In 11 patients, we identified a SNP (RS1045642) on the ABCB1 gene locus previously shown to confer reduced intestinal p-glycoprotein expression (greater analgesia). Five patients were homozygous for a SNP (RS7439366) on the UGT2B7*2gene locus previously shown to confer reduced metabolism of M6G, an active metabolite (greater analgesia and nausea). CONCLUSION: Several SNPs confer variability in oral morphine’s pharmacokinetic and pharmacodynamic profile and may explain the wide variability in analgesic efficacy and adverse effects in children.

OBJECTIVES:To determine whether lidocaine is superior to nonanesthetic lubricant (NAL) for relieving pain in children undergoing urethral catheterization (UC).METHODS:Children 0 to 24 months requiring UC were randomized to NAL or topical and intraurethral 2% lidocaine gel. Primary outcome was facial grimacing in the pre to during drug administration and catheterization phases. Secondary outcome was caregiver satisfaction by using a Visual Analog Scale.RESULTS:There were 133 participants (n = 68 lidocaine, n = 65 NAL). There were no significant differences in mean (SD) scores during UC between lidocaine and NAL (86.4% [121.5%] vs 85.2% [126.6%]), respectively (Δ [confidence interval (CI)] = −1.2 [−21.0 to 49.0], P = .4). There was a significantly greater difference in mean (SD) scores during instillation of lidocaine versus NAL (61.8% [105.6%] vs 3.2% [84.9%]), respectively (Δ [CI] –58.6 [–95.0 to –32.0], P < .001). There were no significant differences in mean (SD) parental satisfaction scores between lidocaine and NAL (4.8 [3.2] vs 5.9 [2.9]), respectively (CI–0.1 to 2.2; P = .06). In the subgroup analysis, age, gender, and positive urine culture did not significantly influence between-group differences in facial grimacing.CONCLUSIONS:Compared with NAL, topical and intraurethral lidocaine is not associated with significant pain reduction during UC, but significantly greater pain during instillation. Therefore, clinicians may consider using noninvasive pain-reducing strategies for young children who require UC.

Aims Adverse drug reactions are a common problem affecting adults and children. The economic impact of the adverse drug reactions has been widely evaluated; however, studies of the impact on the quality of life of children with adverse drug reactions are scarce. The aim was to evaluate studies assessing the health-related quality of life of children with adverse drug reactions. Methods We conducted a systematic review that included the following electronic databases: MEDLINE, EMBASE and the Cochrane Library (including the Cochrane Database of Systematic Reviews, the Database of Abstracts of Reviews of Effects, the Cochrane Controlled Trials Register and the Health Technology Assessment Databases). Results Nine studies were included. Four of the studies were conducted in children with epilepsy; the rest of them involved children with chronic viral hepatitis, Crohn's disease, paediatric cancer and multiple adverse drug reactions compared with healthy children. Based on their findings, authors of all studies concluded that adverse drug reactions had a negative impact on the quality of life of children. No meta-analysis was conducted given the heterogeneous nature of the studies. Conclusions To date, there is no specific instrument that measures quality of life of children with adverse drug reactions, and the information available is poor and variable. In general, adverse drug reactions have a negative impact on the quality of life of affected children. For those interested in this area, more work needs to be done to improve tools that help to evaluate efficiently the health-related quality of life of children with adverse drug reactions and chronic diseases.

Idiosyncratic drug reactions (IDRs) represent a major health problem, as they are unpredictable, often severe and can be life threatening. The low incidence of IDRs makes their detection during drug development stages very difficult causing many post-marketing drug withdrawals and black box warnings. The fact that IDRs are always not predictable based on the drug's known pharmacology and have no clear dose-effect relationship with the culprit drug renders diagnosis of IDRs very challenging, if not impossible, without the aid of a reliable diagnostic test. The drug provocation test (DPT) is considered the gold standard for diagnosis of IDRs but it is not always safe to perform on patients. In vitro tests have the advantage of bearing no potential harm to patients. However, available in vitro tests are not commonly used clinically because of lack of validation and their complex and expensive procedures. This review discusses the current role of in vitro diagnostic testing for diagnosis of IDRs and gives a brief account of their technical and mechanistic aspects. Advantages, disadvantages and major challenges that prevent these tests from becoming mainstream diagnostic tools are also discussed here.

Acute kidney injury (AKI) is a serious problem occurring in anywhere between 8 and 30% of children in the intensive care unit. Up to 25% of these cases are believed to be the result of pharmacotherapy. In this review we have focused on several relevant drugs and/or drug classes, which are known to cause AKI in children, including cancer chemotherapeutics, non-steroidal anti-inflammatory drugs and antimicrobials. AKI demonstrates a steady association with increased long term risk of poor outcomes including chronic kidney disease and death as determined by the extent of injury. For this reason it is important to understand the causality and implications of these drugs and drug classes. Children occupy a unique patient population, advocating the importance of understanding how they are affected dissimilarly compared with adults. While the kidney itself is likely more susceptible to injury than other organs, the inherent toxicity of these drugs also plays a major role in the resulting AKI. Mechanisms involved in the toxicity of these drugs include oxidative damage, hypersensitivity reactions, altered haemodynamics and tubule obstruction and may affect the glomerulus and/or the tubules. Understanding these mechanisms is critical in determining the most effective strategies for treatment and/or prevention, whether these strategies are less toxic versions of the same drugs or add-on agents to mitigate the toxic effect of the existing therapy.