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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.

Student engagement refers to a broad range of activities where students participate in management, education, research, and community activities within their institutions. It is a mutually beneficial collaborative approach between students and their institutions. This article provides practical advice for the implementation or further development of student engagement at medical, dental, and veterinary schools. The tips provided are based on the experiences of a group of universities recently recognized for best practice in student engagement, and are supported by evidence from the literature. The tips cover overarching themes which include the creation of an institutional culture and formal framework for student engagement, and maximize communication routes between students with peers and faculty. Tips are for specific areas of active student engagement, covering curriculum design and development, peer teaching, governance processes, research activities, peer support programs, and interaction with the local community., (undefined), info:eu-repo/semantics/acceptedVersion

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.

De nombreux patients pédiatriques ont besoin de sédation et d’analgésie lors de tests diagnostiques et d’actes thérapeutiques hors de la salle d’opération. Le présent document de principes contient une analyse bibliographique de la sédation interventionnelle (qu’on appelle aussi sédation procédurale), axée sur la prévention des événements indésirables grâce à la sélection des patients appropriés, à la préparation aux situations d’urgence et à la surveillance nécessaire pendant et après l’administration des agents pharmacologiques. Seuls des cliniciens formés en assistance respiratoire et en réanimation devraient être autorisés à l’effectuer, dans le cadre d’un programme hospitalier comportant des initiatives à la fois dynamiques et soutenues en matière de sécurité et d’assurance de la qualité. La rédaction de politiques et de protocoles sur la sédation interventionnelle sécuritaire chez les nourrissons, les enfants et les adolescents fait partie des recommandations.

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.

L’acide folique (vitamine B9) est une vitamine hydrosoluble du groupe B. On le trouve dans les aliments sous forme de folate et dans les supplements sous forme d’acide folique, dont la biodisponibilite est plus importante. Le folate joue un role essentiel dans la synthese et la reparation de l’ADN, ainsi que dans la croissance et la division cellulaires. Il contribue egalement a la methylation de l’ADN et est donc important pour la regulation epigenomique.

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.

Drug-induced gingival enlargement (DIGE) is a fibrotic condition associated with systemic administration of the anti-epileptic drug, phenytoin. We have previously demonstrated that periostin, which is transforming growth factor-beta (TGF-β) inducible gene, is upregulated in various fibrotic conditions including gingival enlargement associated with nifedipine. The objective of this study was to assess periostin expression in phenytoin-induced gingival enlargement (PIGE) tissues and to investigate the mechanisms underlying periostin expression. Human PIGE tissues were assessed using Masson's trichrome, with cell infiltration and changes in extracellular matrix composition characterized through labeling with antibodies to periostin, phospho-SMAD 3, TGF-β, as well as the macrophage markers CD68 and RM3/1. Using human gingival fibroblasts (HGFs) in vitro we examined the pathways through which phenytoin acts on fibroblasts. In PIGE tissues, which demonstrate altered collagen organization and increased inflammatory cell infiltration, periostin protein was increased compared with healthy tissues. p-SMAD2/3, the transcription factor associated with canonical TGF-β signaling, is localized to the nuclei in both gingival fibroblasts and oral epithelial cells in PIGE tissues, but not in healthy tissue. In vitro culture of HGFs with 15 and 30 μg/ml of phenytoin increased periostin protein levels, which correlated with p-SMAD3 phosphorylation. Inhibition of canonical TGF-β signaling with SB431542 significantly reduced phenytoin induction of SMAD3 phosphorylation and periostin expression in HGFs. Analysis of PIGE tissues showed a subset of CD68 stained macrophages were TGF-β positive and that RM1/3 regenerative macrophages were present in the tissues. Our results demonstrate that phenytoin up-regulates periostin in HGFs in a TGF-β-dependent manner.

Background Adverse drug reactions (ADRs) are a significant problem for HIV patients, with the risk of developing ADRs increasing as the infection progresses to AIDS. However, the pathophysiology underlying ADRs remains unknown. Sulphamethoxazole (SMX) via its active metabolite SMX-hydroxlyamine, when used prophylactically for pneumocystis pneumonia in HIV-positive individuals, is responsible for a high incidence of ADRs. We previously demonstrated that the HIV infection and, more specifically, that the HIV-1 Tat protein can exacerbate SMX-HA-mediated ADRs. In the current study, Jurkat T cell lines expressing Tat and its deletion mutants were used to determine the effect of Tat on the thiol proteome in the presence and absence of SMX-HA revealing drug-dependent changes in the disulfide proteome in HIV infected cells. Protein lysates from HIV infected Jurkat T cells and Jurkat T cells stably transfected with HIV Tat and Tat deletion mutants were subjected to quantitative slot blot analysis, western blot analysis and redox 2 dimensional (2D) gel electrophoresis to analyze the effects of SMX-HA on the thiol proteome. Results Redox 2D gel electrophoresis demonstrated that untreated, Tat-expressing cells contain a number of proteins with oxidized thiols. The most prominent of these protein thiols was identified as peroxiredoxin. The untreated, Tat-expressing cell lines had lower levels of peroxiredoxin compared to the parental Jurkat E6.1 T cell line. Conversely, incubation with SMX-HA led to a 2- to 3-fold increase in thiol protein oxidation as well as a significant reduction in the level of peroxiredoxin in all the cell lines, particularly in the Tat-expressing cell lines. Conclusion SMX-HA is an oxidant capable of inducing the oxidation of reactive protein cysteine thiols, the majority of which formed intermolecular protein bonds. The HIV Tat-expressing cell lines showed greater levels of oxidative stress than the Jurkat E6.1 cell line when treated with SMX-HA. Therefore, the combination of HIV Tat and SMX-HA appears to alter the activity of cellular proteins required for redox homeostasis and thereby accentuate the cytopathic effects associated with HIV infection of T cells that sets the stage for the initiation of an ADR. Electronic supplementary material The online version of this article (10.1186/s12985-018-0991-x) contains supplementary material, which is available to authorized users.

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.

Drug-induced gingival enlargement (DIGE) is a fibrotic condition that can be caused by the antihypertensive drug nifedipine and the anti-seizure drug phenytoin, but the molecular etiology of this type of fibrosis is not well understood and the role of confounding factors such as inflammation remains to be fully investigated. The aim of this study was to develop an ex vivo gingival explant system to allow investigation of the effects of nifedipine and phenytoin alone on human gingival tissue. Comparisons were made to the histology of human DIGE tissue retrieved from individuals with DIGE. Increased collagen, fibronectin, and proliferating fibroblasts were evident, but myofibroblasts were not detected in DIGE samples caused by nifedipine and phenytoin. In healthy gingiva cultured in nifedipine or phenytoin-containing media, the number of cells positive for p-SMAD2/3 increased, concomitant with increased CCN2 and periostin immunoreactivity compared to untreated explants. Collagen content assessed through hydroxyproline assays was significantly higher in tissues cultured with either drug compared to control tissues, which was confirmed histologically. Matrix fibronectin levels were also qualitatively greater in tissues treated with either drug. No significant differences in proliferating cells were observed between any of the conditions. Our study demonstrates that nifedipine and phenytoin activate canonical transforming growth factor-beta signaling, CCN2 and periostin expression, as well as increase collagen density, but do not influence cell proliferation or induce myofibroblast differentiation. We conclude that in the absence of confounding variables, nifedipine and phenytoin alter matrix homeostasis in gingival tissue explants ex vivo, and drug administration is a significant factor influencing ECM accumulation in gingival enlargement.

Anthracyclines are used in over 50% of childhood cancer treatment protocols, but their clinical usefulness is limited by anthracycline-induced cardiotoxicity (ACT) manifesting as asymptomatic cardiac dysfunction and congestive heart failure in up to 57% and 16% of patients, respectively. Candidate gene studies have reported genetic associations with ACT, but these studies have in general lacked robust patient numbers, independent replication or functional validation. Thus, the individual variability in ACT susceptibility remains largely unexplained. We performed a genome-wide association study in 280 patients of European ancestry treated for childhood cancer, with independent replication in similarly treated cohorts of 96 European and 80 non-European patients. We identified a nonsynonymous variant (rs2229774, p.Ser427Leu) in RARG highly associated with ACT (P = 5.9 × 10(-8), odds ratio (95% confidence interval) = 4.7 (2.7-8.3)). This variant alters RARG function, leading to derepression of the key ACT genetic determinant Top2b, and provides new insight into the pathophysiology of this severe adverse drug reaction.

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.

Currently, the majority of the surgical procedures performed in paediatric hospitals are done on a day care basis, with post-operative pain being managed by caregivers at home. Pain after discharge of these post-operative children has historically been managed with oral codeine in combination with paracetamol (acetaminophen). Codeine is an opioid, which elicits its analgesic effects via metabolism to morphine and codeine-6-glucuronide. Oral morphine is a feasible alternative for outpatient analgesia; however, the pharmacokinetics of morphine after oral administration have been previously described only sparsely, and there is little information in healthy children. The clinical trial included 40 children from 2 to 6 years of age, with an American Society of Anaesthesiologists physical status classification of 1 or 2, who were undergoing surgical procedures requiring opioid analgesia. Morphine was orally administered prior to surgery in one of three doses: 0.1 mg/kg, 0.2 mg/kg and 0.3 mg/kg. Blood samples were collected for plasma morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) concentrations at 30, 60, 90, 120, 180 and 240 min after administration. All analyses were performed with the non-linear mixed-effect modelling software NONMEM version 7.2, using the first-order conditional estimation (FOCE) method. A pharmacokinetic model was developed to simultaneously describe the plasma profiles of morphine and its metabolites M3G and M6G after a single dose of oral morphine in young children (2–6 years of age). The disposition of morphine, M3G and M6G in plasma was best described by a one-compartment model. M3G and M6G metabolite formation was best described by a delay transit compartment, indicating a delay in the appearance of these two major metabolites. This model provides a foundation on which to further evaluate the use of oral morphine and its safety in young children. Longer follow-up time for morphine oral doses and incorporation of other important covariates, such as phenotype, will add value and will help overcome the limitations of the presented population pharmacokinetic analysis.

Aim: To identify novel variants associated with anthracycline-induced cardiotoxicity and to assess these in a genotype-guided risk prediction model. Patients & methods: Two cohorts treated for childhood cancer (n = 344 and 218, respectively) were genotyped for 4578 SNPs in drug ADME and toxicity genes. Results: Significant associations were identified in SLC22A17 (rs4982753; p = 0.0078) and SLC22A7 (rs4149178; p = 0.0034), with replication in the second cohort (p = 0.0071 and 0.047, respectively). Additional evidence was found for SULT2B1 and several genes related to oxidative stress. Adding the SLC22 variants to the prediction model improved its discriminative ability (AUC 0.78 vs 0.75 [p = 0.029]). Conclusion: Two novel variants in SLC22A17 and SLC22A7 were significantly associated with anthracycline-induced cardiotoxicity and improved a genotype-guided risk prediction model, which could improve patient risk stratification. Original submitted 26 November 2014; Revision submitted 12 May 2015.

BACKGROUND: Oral morphine for postoperative pain after minor pediatric surgery, while increasingly popular, is not supported by evidence. We evaluated whether oral morphine was superior to ibuprofen for at-home management of children’s postoperative pain. METHODS: We conducted a randomized superiority trial comparing oral morphine (0.5 mg/kg) with ibuprofen (10 mg/kg) in children 5 to 17 years of age who had undergone minor outpatient orthopedic surgery (June 2013 to September 2016). Participants took up to 8 doses of the intervention drug every 6 hours as needed for pain at home. The primary outcome was pain, according to the Faces Pain Scale – Revised, for the first dose. Secondary outcomes included additional analgesic requirements, adverse effects, unplanned health care visits and pain scores for doses 2 to 8. RESULTS: We analyzed data for 77 participants in each of the morphine and ibuprofen groups. Both interventions decreased pain scores with no difference in efficacy. The median difference in pain score before and after the first dose of medication was 1 (interquartile range 0–1) for both morphine and ibuprofen (p = 0.2). For doses 2 to 8, the median differences in pain score before and after the dose were not significantly different between groups. Significantly more participants taking morphine reported adverse effects (45/65 [69%] v. 26/67 [39%], p INTERPRETATION: Morphine was not superior to ibuprofen, and both drugs decreased pain with no apparent difference in efficacy. Morphine was associated with significantly more adverse effects, which suggests that ibuprofen is a better first-line option after minor surgery. Trial registration: ClinicalTrials.gov, no. NCT01686802.

Adverse drug reactions (ADRs) are a common problem in children. Health-related quality of life in patients with such conditions has not been well studied. In this study we found that health-related quality of life is adversely affected in children who developed ADRs with cutaneous manifestations.

Objectives Dexamethasone is associated with adrenal insufficiency in adults and children with chronic disease. This association has not been studied after single-dose oral dexamethasone, the standard of care for children with croup. We hypothesized that single-dose oral dexamethasone in children with croup is associated with a transient decrease in endogenous glucocorticoids. Methods We conducted a prospective, 2-arm, pharmacodynamic study of single-dose oral dexamethasone 0.6 mg/kg (maximum, 12 mg) in children older than 2 years with croup compared with controls (children with febrile upper respiratory tract infections who did not receive dexamethasone). Primary outcome was urinary 6β-hydroxycortisol-cortisol ratio. Results Twenty-seven children were analyzed (22 with croup and 5 with upper respiratory tract infections). Median 6β-hydroxycortisol-cortisol ratios before dexamethasone, the following morning, and on days 1, 3, and 7 were 2.8, 2.2, 2.0, 2.8, and 2.6, respectively. Among controls, the median 6β-hydroxycortisol-cortisol ratios at the same time intervals was 1.9, 1.5, 1.8, 2.5, and 1.7, respectively. There were no significant differences in the change from time 0 between groups at any time point. There were no serious adverse events or infectious complications. Conclusions Single-dose oral dexamethasone is not associated with decreased endogenous corticosteroid levels in children with croup. Future studies should use criterion standard tests to rule out suppression of the hypothalamic-pituitary-adrenal axis and be powered sufficiently to identify adverse clinical outcomes.

Background Ketamine is commonly used for procedural sedation and analgesia (PSA) in children. Evidence suggests it can be administered intranasally (IN). We sought to review the evidence for IN ketamine for PSA in children. Methods We performed a systematic review of randomized trials of IN ketamine in PSA that reported any sedation-related outcome in children 0 to 19 years. Trials were identified through electronic searches of MEDLINE (1946-2016), EMBASE (1947-2016), Google Scholar (2016), CINAHL (1981-2016), The Cochrane Library (2016), Web of Science (2016), Scopus (2016), clinical trial registries, and conference proceedings (2000-2016) without language restrictions. The methodological qualities of studies and the overall quality of evidence were evaluated using the Cochrane Collaboration's Risk of Bias tool, and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system, respectively. Results The review included 7 studies (n = 264) of children ranging from 0 to 14 years. Heterogeneity in study design precluded meta-analysis. Most studies were associated with a low or unclear risk of bias and outcome-specific ratings for quality of evidence were low or very low. In four of seven studies, IN ketamine provided superior sedation to comparators and resulted in adequate sedation for 148/175 (85%) of participants. Vomiting was the most common adverse effect; reported by 9/91 (10%) of participants. Conclusions IN ketamine administration is well tolerated and without serious adverse effects. Although most participants were deemed adequately sedated with IN ketamine, effectiveness of sedation with respect to superiority over comparators was inconsistent, precluding a recommendation for PSA in children.

An infant boy with steroid-resistant nephrotic syndrome (idiopathic membranous glomerulonephropathy) achieved remission with ciclosporin but developed eosinophilia and high IgE levels (max 19 000 iU/mL). Conversion to tacrolimus resulted in chronic diarrhoea (eosinophilic gastroenteritis), muscle weakness, polyserositis and failure-to-thrive. In contrast, a trial without tacrolimus resulted in a ciclosporin-responsive relapse, therapy-resistant focal seizures with generalised spikes, worsening muscle weakness and diarrhoea. The patient was weaned off of ciclosporin and completely normalised. In vitro testing demonstrated decreased viability of the patient9s cells when incubated with calcineurin inhibitors (ciclosporin, 70%; tacrolimus, 80% compared to control cells), supporting their role in this adverse drug reaction.

Access to health care remains suboptimal for Indigenous people in Canada. One contributing factor is the longstanding undersupply of Indigenous physicians. Despite awareness of this issue, underrepresentation in medical schools continues. In 2002, Schulich School of Medicine and Dentistry (SSMD) policies were modified to enhance access for Indigenous students. This article describes our school’s continuing journey of policy and process revision, formative collaborations, early learner outcomes, and lessons learned towards this goal. In the first 10 years, SSMD matriculated 15 additional Indigenous students via this new stream. All candidates were successful in the undergraduate medical curriculum, licensing examinations, and residency match. The majority were attracted to primary care specialties, training programs affiliated with SSMD, and practices in southern Ontario. While the process and curriculum have revealed their potential, its capacity is not being maximized.

Background: One medication commonly used by HIV-1-infected individuals is the antimicrobial sulphamethoxazole (SMX), which is used in the treatment and prophylaxis of pneumocystis pneumonia. However, SMX is responsible for a very high incidence of hypersensitivity adverse drug reactions (ADRs) in the HIV-1 population. While the pathophysiology of ADRs in general is unknown, sulphamethoxazole-mediated ADRs have been linked to its reactive metabolite sulphamethoxazole-hydroxylamine (SMX-HA). Our previous work has shown that increased expression of the HIV-1 Tat protein in T cells correlated with increased apoptosis after incubation with SMX-HA. In this study we sought to determine the region of the Tat protein responsible for this effect and the mechanism by which Tat contributed to SMX-HA mediated apoptosis. Methods: We established Jurkat T and Cos 7 cell lines that stably expressed full-length Tat (Tat101) and deletion mutants (Tat86, Tat72, Tat48 and TatΔ). These cell lines were then incubated with SMX-HA and assayed for cell viability and production of reactive oxygen species (ROS). We further used confocal microscopy to assess the intracellular distribution of the Tat proteins and to determine if changes in the expression and/or localization of key cytoskeleton proteins contributed to Tat-mediated apoptosis after SMX-HA treatment. Results: Deletion of regions of Tat that lead to increased cytoplasmic accumulation significantly contributed to increased cell death in the presence of SMX-HA. The increased cell death did not require induction of ROS. Quantitative analysis also showed that the Tat-expressing cell lines had significantly lower levels of β-actin and α-tubulin present both before and after treatment with SMX-HA. Increased cytoplasmic localization of Tat correlated with greater disturbances in the distribution of actin filaments. Conclusion: The presence of cytoplasmic Tat in T and epithelial cell lines increases their sensitivity to SMX-HA induced cell death, an effect mediated by the first 48 amino acids of TAT.

Bronchiolitis is the most common reason for admission to hospital in the first year of life. There is tremendous variation in the clinical management of this condition across Canada and around the world, including significant use of unnecessary tests and ineffective therapies. This statement pertains to generally healthy children ≤2 years of age with bronchiolitis. The diagnosis of bronchiolitis is based primarily on the history of illness and physical examination findings. Laboratory investigations are generally unhelpful. Bronchiolitis is a self-limiting disease, usually managed with supportive care at home. Groups at high risk for severe disease are described and guidelines for admission to hospital are presented. Evidence for the efficacy of various therapies is discussed and recommendations are made for management. Monitoring requirements and discharge readiness from hospital are also discussed.La bronchiolite est la principale cause d’hospitalisation avant l’âge de un an. La prise en charge clinique de cette maladie varie considérablement selon les régions du Canada et du monde, y compris une grande utilisation de tests inutiles et de thérapies inefficaces. Le présent document de principes porte sur des enfants en santé de deux ans ou moins qui sont atteints d’une bronchiolite. Le diagnostic de bronchiolite repose d’abord sur l’anamnèse de la maladie et sur les résultats de l’examen physique. En général, les examens de laboratoire sont inutiles. La bronchiolite est une maladie spontanément résolutive, qui est généralement prise en charge par des soins de soutien à domicile. Par ailleurs, les groupes très vulnérables à une bronchiolite grave sont décrits, et les indications d’admission à l’hôpital sont présentées. Les données probantes sur l’efficacité des diverses thérapies et les recommandations de prise en charge sont exposées. La surveillance requise et le moment du congé de l’hôpital sont également abordés.

Objective: To report a novel approach to the management of tacrolimus intoxication that leads to rapid normalization of serum tacrolimus concentrations. Case Summary: A 9-year-old female renal transplant recipient developed a severe tacrolimus intoxication as a result of prolonged diarrhea, which resulted in acute kidney injury, severe dehydration, and neurological symptoms. We used a combination of intravenous steroids and intravenous phenytoin to normalize the tacrolimus level from 32 to 5 ng/mL in less than 24 hours, with complete resolution of symptoms and signs. Discussion: Tacrolimus intoxication is a rare event but may result in life-threatening complications. Treatment recommendations beyond holding the drug and enzyme induction with phenytoin or phenobarbital are elusive. This approach leads to a relatively slow normalization of the tacrolimus level over 72 hours. The authors hypothesized that additional induction of the p-glycoprotein through steroids was synergistic. Conclusions: The combination of phenytoin and a corticosteroid may be an effective approach that leads to rapid normalization of severely elevated tacrolimus levels.

BACKGROUND AND OBJECTIVES: Pharmacogenetics (PGx) promises to optimize patient response to therapy. However, the public’s acceptance of PGx is not well known, notably when this applies to children. Our objective was to explore perceptions of PGx testing among individuals, who differ from each other by either parental status or educational exposure to PGx, and to explore parents’ views between PGx testing for oneself and PGx testing for their children. METHODS: An exploratory survey was conducted among parents and other adults. Surveys P and C were completed by parents, survey NP by middle-aged nonparents, and survey MS by medical students. RESULTS: Proper explanation before PGx testing appeared to be the most important issue to the respondents (eg, P = 1.55 × 10−38 for survey NP). Respondents who were more knowledgeable about PGx were also more comfortable with PGx testing (eg, P = 2.53 × 10−7 in case of mild disease). When PGx testing was for one’s child, parents valued their own understanding more than their child’s assent (P = 1.57 × 10−17). CONCLUSIONS: The acceptability of PGx testing, either for oneself or for one’s child, seemed to depend on baseline PGx knowledge, but not on parenthood.

BACKGROUND Cannabis use for medical purposes has gathered growing interest from the public through its purported benefits. Since 2001, Health Canada has authorized availability from health practitioners, even for paediatric patients, despite concerns regarding efficacy and adverse effects among children and adolescents. It is likely that a lack of knowledge regarding the substance and indications for use, tempered by known and unknown side effects, dictate paediatricians’ practice toward cannabis. OBJECTIVES This study examines the views and knowledge of Canadian paediatricians regarding the use of cannabis for medical purposes among children and adolescents. Differences between general paediatricians and sub-specialists were explored. DESIGN/METHODS Data was collected using a Canadian Paediatric Surveillance Program (CPSP) one-time survey performed in 2017. A total of 864 paediatric physicians (33% participation rate) were asked about medical use of cannabis. They were also asked personal and professional characteristics. Descriptive statistics regarding their views and knowledge towards cannabis use for medical purposes are reported, as well as significant differences (p RESULTS General paediatricians represented 55.4% of the analyzed sample, with 36.7% having ≥ 20 years of practice. Half (50.4%) of all surveyed paediatricians had encountered in the past year patients who used cannabis for medical purposes (authorized or not). Half (50.6%) were also aware that Canadian physicians could authorize cannabis to children for medical purposes. More (61.3%) knew they could authorize it to adolescents (significantly more among sub-specialists, p=0.03). Nearly half (46.5%) believed that there are appropriate indications to support the authorization of cannabis for medical reasons to the paediatric population (significantly more among sub-specialists, p CONCLUSION Cannabis use for medical purposes is a situation frequently encountered by paediatricians. While they are generally supportive of certain medical indications for its authorization, most have minimal knowledge on its use and, report concerns about efficacy and safety. Differences between general paediatricians and sub-specialists probably emerge from conditions treated by these two groups. Our study highlights the need for timely continuing education for all paediatricians on this topic.

BackgroundReported allergy to penicillins is a major clinical problem. Over 10% of parents report drug allergy resulting in higher cost and less than optimum management of infectious diseases.ObjectivesTo determine the relative likelihood of true allergy in patients suspected to have a penicillin allergy and to investigate the risk factors involved. We hypothesized that the vast majority of self-reported penicillin allergies are less likely to be true allergies when proper immunological work up is performed.MethodsPaediatric patients aged 0–18 years presenting to the ADR clinic at the Children Hospital of Western Ontario (CHWO) with suspected antibiotic allergies were included. A retrospective review of charts was conducted to obtain demographic information and results from allergological and in vitro testing. Subjects were evaluated with a radioallergosorbent test (RAST) or the lymphocyte toxicity assay (LTA)/the invitro platelet toxicity assay (iPTA) depending on whether the history was most consistent with an immediate allergy or a delayed hypersensitivity, respectively. Patients with negative RAST or LTA/iPTA were recommended to undergo confirmatory oral challenge test (OCT).ResultsNinety subjects were identified including 75 with possible penicillin allergy and 10 with suspected allergy to a non-penicillin antibiotic. Five subjects presented with a mixed allergy. Based on the results from RAST, in vitro testing and OCTs, the prevalence of a true allergy in the penicillin group was 6.25% vs. 66.67% in the non-penicillin group (p< 0.001). Patients presenting with severe reactions were more likely to be truly allergic (p< 0.01). In-patients were more likely to present with non-penicillin allergies and were subsequently more likely to have a true allergy (p< 0.001).ConclusionsTrue allergy is very rare in patients with suspected penicillin allergies and can be determined with a proper work-up including OCT. Shorter protocols for the evaluation of these patients would be beneficial.Disclosure(s)Nothing to disclose

Drug hypersensitivity reactions (DHRs) are rare but potentially fatal adverse drug reactions (ADRs). A reliable test to diagnose DHRs would be a major advance in the clinical care for patients and in the evaluation of ADRs during drug development as well as for mechanistic studies of drug hypersensitivity. Available in vitro tests including the lymphocyte toxicity assay (LTA) have been used but are time-consuming, cumbersome, and expensive. We have developed a novel diagnostic test for DHRs, the in vitro platelet toxicity assay (iPTA). The aim of this study was to evaluate the predictive value of the iPTA in diagnosis of DHRs to sulfonamides. We recruited 66 individuals (36 DHS-sulfa patients and 30 healthy controls) to participate in the study. Blood samples were obtained and LTA and iPTA were performed in parallel. There was concentration-dependent toxicity in the cells of patients when incubated with the reactive hydroxylamine metabolite of sulfamethoxazole for both the LTA and iPTA (P

The occurrence of hypersensitivity reactions including rare but life-threatening Stevens-Johnson syndrome (SJS) and drug-induced hypersensitivity syndrome (HSS) limits the use of the anticonvulsant carbamazepine (CBZ). Human leukocyte antigen-B (HLA)-B 15:02 and HLA-A 31:01 have been identified as predictive genetic markers for CBZ hypersensitivity in Asian and European patients. To replicate these genetic associations in pediatric patients from North America with a diverse ethnic background, we investigated HLA-A 31:01 and HLA-B 15:02 in 42 children with CBZ hypersensitivity and 91 CBZ-tolerant children from across Canada. HLA-A 31:01 was significantly associated with CBZ-HSS (odds ratio (OR): 26.4, P = 0.0025) and maculopapular exanthema (MPE) (OR: 8.6, P = 0.0037) but not with CBZ-SJS. Conversely, HLA-B 15:02 was associated with CBZ-SJS (OR: 38.6, P = 0.002) but not HSS or MPE. This study is the first to demonstrate the association of HLA-A 31:01 with CBZ hypersensitivity in children, providing important replication of this association and highlighting the importance of HLA-A 31:01 as a predictive biomarker across various ancestries.

Background . The use of anthracyclines as effective antineoplastic drugs is limited by the occurrence of cardiotoxicity. Multiple genetic variants predictive of anthracycline-induced cardiotoxicity (ACT) in children were recently identified. The current study was aimed to assess replication of these findings in an independent cohort of children. Procedure . Twenty-three variants were tested for association with ACT in an independent cohort of 218 patients. Predictive models including genetic and clinical risk factors were constructed in the original cohort and assessed in the current replication cohort. Results . We confirmed the association of rs17863783 in UGT1A6 and ACT in the replication cohort (P = 0.0062, odds ratio (OR) 7.98). Additional evidence for association of rs7853758 (P = 0.058, OR 0.46) and rs885004 (P = 0.058, OR 0.42) in SLC28A3 was found (combined P = 1.6 × 10−5 and P = 3.0 × 10−5, respectively). A previously constructed prediction model did not significantly improve risk prediction in the replication cohort over clinical factors alone. However, an improved prediction model constructed using replicated genetic variants as well as clinical factors discriminated significantly better between cases and controls than clinical factors alone in both original (AUC 0.77 vs. 0.68, P = 0.0031) and replication cohort (AUC 0.77 vs. 0.69, P = 0.060). Conclusions . We validated genetic variants in two genes predictive of ACT in an independent cohort. A prediction model combining replicated genetic variants as well as clinical risk factors might be able to identify high- and low-risk patients who could benefit from alternative treatment options. Pediatr Blood Cancer 2013;601375-1381. © 2013 Wiley Periodicals, Inc.