REPRESENT: REPresentativeness of RESearch data obtained through the 'General Informed ConsENT'.

BACKGROUND: We assessed potential consent bias in a cohort of > 40,000 adult patients asked by mail after hospitalization to consent to the use of past, present and future clinical and biological data in an ongoing 'general consent' program at a large tertiary hospital in Switzerland. METHODS: In this retrospective cohort study, all adult patients hospitalized between April 2019 and March 2020 were invited to participate to the general consent program. Demographic and clinical characteristics were extracted from patients' electronic health records (EHR). Data of those who provided written consent (signatories) and non-responders were compared and analyzed with R studio. RESULTS: Of 44,819 patients approached, 10,299 (23%) signed the form. Signatories were older (median age 54 [IQR 38-72] vs. 44 years [IQR 32-60], p < .0001), more comorbid (2614/10,299 [25.4%] vs. 4912/28,676 [17.1%] with Charlson comorbidity index ≤ 4, p < .0001), and more often of Swiss nationality (6592/10,299 [64%] vs. 13,813/28,676 [48.2%], p < .0001). CONCLUSIONS: Our results suggest that actively seeking consent creates a bias and compromises the external validity of data obtained via 'general consent' programs. Other options, such as opt-out consent procedures, should be further assessed.

Impact of computerised physician order entry (CPOE) on the incidence of chemotherapy-related medication errors: a systematic review.

PURPOSE: Computerised prescriber (or physician) order entry (CPOE) implementation is one of the strategies to reduce medication errors. The extent to which CPOE influences the incidence of chemotherapy-related medication errors (CMEs) was not previously collated and systematically reviewed. Hence, this study was designed to collect, collate, and systematically review studies to evaluate the effect of CPOE on the incidence of CMEs. METHODS: A search was performed of four databases from 1 January 1995 until 1 August 2019. English-language studies evaluating the effect of CPOE on CMEs were selected as per inclusion and exclusion criteria. The total CMEs normalised to total prescriptions pre- and post-CPOE were extracted and collated to perform a meta-analysis using the 'meta' package in R. The systematic review was registered with PROSPERO CRD42018104220. RESULTS: The database search identified 1621 studies. After screening, 19 studies were selected for full-text review, of which 11 studies fulfilled the selection criteria. The meta-analysis of eight studies with a random effects model showed a risk ratio of 0.19 (95% confidence interval: 0.08-0.44) favouring CPOE (I2 = 99%). CONCLUSION: The studies have shown consistent reduction in CMEs after CPOE implementation, except one study that showed an increase in CMEs. The random effects model in the meta-analysis of eight studies showed that CPOE implementation reduced CMEs by 81%.

Toward precision medicine in pediatric population using cytochrome P450 phenotyping approaches and physiologically based pharmacokinetic modeling.

The activity of drug-metabolizing enzymes (DME) shows high inter- and intra-individual variability. Genetic polymorphisms, exposure to drugs, and environmental toxins are known to significantly alter DME expression. In addition, the activity of these enzymes is highly age-dependent due to maturation processes that occur during development. Currently, there is a vast choice of phenotyping methods in adults using exogenous probes to characterize the activity of these enzymes. However, this can hardly be applied to children since it requires the intake of non-therapeutic xenobiotics. In addition, sampling may be challenging in the pediatric population for a variety of reasons: limited volume (e.g., blood), inappropriate sampling methods for age (e.g., urine), and metric requiring invasive or multiple blood samples. This review covers the main existing methods that can be used in the pediatric population to determine DME activity, with a particular focus on cytochrome P450 enzymes. Less invasive tools are described, including phenotyping using endogenous probes. Finally, the potential of pediatric model-informed precision dosing using physiologically based pharmacokinetic modeling is discussed.

Cost-effectiveness of HLA-DQB1/HLA-B pharmacogenetic-guided treatment and blood monitoring in US patients taking clozapine.

Less than 1% of adult patients with schizophrenia taking clozapine develop agranulocytosis, and most of these cases occur within the first weeks of treatment. The human leukocyte antigen (HLA) region has been associated with genetic susceptibility to clozapine-induced agranulocytosis (single amino acid changes in HLA-DQB1 (126Q) and HLA-B (158T)). The current study aimed to evaluate the cost-effectiveness, from a healthcare provider's perspective, of an HLA genotype-guided approach in patients with treatment-resistant schizophrenia who were taking clozapine and to compare the results with the current absolute neutrophil count monitoring (ANCM) schemes used in the USA. A semi-Markovian model was developed to simulate the progress of a cohort of adult men and women who received clozapine as a third-line antipsychotic medication. We compared current practices using two genotype-guided strategies: (1) HLA genotyping followed by clozapine, with ANCM only for patients who tested positive for one or both alleles (genotype-guided blood sampling); (2) HLA genotyping followed by clozapine for low-risk patients and alternative antipsychotics for patients who tested positive (clozapine substitution scheme). Up to a decision threshold of $3.9 million per quality-adjusted life-year (90-fold the US gross domestic product per capita), the base-case results indicate that compared with current ANCM, genotype-guided blood sampling prior to clozapine initiation appeared cost-effective for targeted blood monitoring only in patients with HLA susceptibility alleles. Sensitivity analysis demonstrated that at a cost of genotype testing of up to USD700, HLA genotype-guided blood monitoring remained a cost-effective strategy compared with either current ANCM or clozapine substitution.

The European Association for Clinical Pharmacology and Therapeutics-25 years' young and going strong.

Clinical pharmacology as a scientific discipline and medical specialty was unarguably born in the twentieth century. Whilst pharmacology-the science behind the treatment of disease-had been in evolution since at least medieval times, the clinical discipline of pharmacology has had a more recent genesis and rather insidious evolution. During the 1900s, there were some clear father (parent) figures of clinical pharmacology in Europe that emerged and were responsible for the development of the specialty in this continent. This was a time when there were parallel developments in geographically dispersed academic departments (around the globe), during an age of excitement in drug discovery and clinical application of new therapeutic agents. It was the meeting of minds of some of these progenitors of the specialty that led to the development of the European Association for Clinical Pharmacology and Therapeutics (EACPT) 25 years ago arising from a working party supported by the World Health Organization in Europe. The EACPT now includes all major national organizations for clinical pharmacology in Europe, representing over 4000 individual professionals interested in clinical pharmacology and therapeutics. The EACPT has a major interest in promoting the safe use of medicines across Europe and internationally and has supported these aims since 1995, through biennial international scientific congresses and summer schools with delegates and presenters from around the world as well as various working group activities. In this article, the current executive committee members of EACPT recall this history, describe the evolution of the association over the last quarter of a century, and provide an update on the activities and ambitions of the association today.

Apixaban Pharmacokinetics at Steady State in Hemodialysis Patients.

It is unclear whether warfarin is protective or harmful in patients with ESRD and atrial fibrillation. This state of equipoise raises the question of whether alternative anticoagulants may have a therapeutic role. We aimed to determine apixaban pharmacokinetics at steady state in patients on hemodialysis. Seven patients received apixaban 2.5 mg twice daily for 8 days. Blood samples were collected before and after apixaban administration on days 1 and 8 (nondialysis days). Significant accumulation of the drug was observed between days 1 and 8 with the 2.5-mg dose. The area under the concentration-time curve from 0 to 24 hours increased from 628 to 2054 ng h/ml (P<0.001). Trough levels increased from 45 to 132 ng/ml (P<0.001). On day 9, after a 2.5-mg dose, apixaban levels were monitored hourly during dialysis. Only 4% of the drug was removed. After a 5-day washout period, five patients received 5 mg apixaban twice daily for 8 days. The area under the concentration-time curve further increased to 6045 ng h/ml (P=0.03), and trough levels increased to 218 ng/ml (P=0.03), above the 90th percentile for the 5-mg dose in patients with preserved renal function. Apixaban 2.5 mg twice daily in patients on hemodialysis resulted in drug exposure comparable with that of the standard dose (5 mg twice daily) in patients with preserved renal function and might be a reasonable alternative to warfarin for stroke prevention in patients on dialysis. Apixaban 5 mg twice daily led to supratherapeutic levels in patients on hemodialysis and should be avoided.

Screening for genotypic and phenotypic variations in CYP450 activity in patients with therapeutic problems in a psychiatric setting, a retrospective study.

OBJECTIVES: This retrospective study aimed to assess to what extent an adverse drug reaction (ADR), an abnormal therapeutic drug monitoring (TDM) or a non-response, was attributable to an abnormal cytochrome P450 activity in a psychiatric setting. METHOD: We collected the results of investigations performed in these situations related to psychotropic drugs between January 2005 and November 2014. Activities of different cytochrome P450 were assessed by genotyping and/or phenotyping. Two experienced clinical pharmacologists assessed independently the possible association between the event and the results of the investigations. RESULTS: One hundred and thirty eight clinical or biological situations had a complete assessment of all major metabolic pathways of the target drug. A majority of clinical or biological situations were observed with antidepressants (n=93, 67.4%), followed by antipsychotics (n=28, 20.3%), benzodiazepines and hypnotics (n=13, 9.4%), and psychostimulants (n=4, 2.9%). Genotype and/or phenotype determination was mainly performed because of ADRs (n=68, 49.3%) or non-response (n=46, 33.3%). Inter-rate reliability of the scoring system between the pharmacologists was excellent (kappa=0.94). The probability of an association between ADR, TDM or non-response and metabolic status was rated as intermediate to high in 34.7% of all cases, with proportions of 30.4% and 36.7%, for non-response and ADR respectively. CONCLUSION: When indicated by clinical pharmacologists, ADR, TDM or non-response may be attributable to a variation of the metabolic status with an intermediate to high probability in 34.7% of patients, based on the congruent assessment made by two clinical pharmacologists. Further studies assessing the clinical relevance of prospective explorations and clarifying the appropriate method according to the clinical context are needed.

Hepatic fat loss in advanced nonalcoholic steatohepatitis: are alterations in serum adiponectin the cause?

UNLABELLED: Advanced liver fibrosis in nonalcoholic steatohepatitis (NASH) is often accompanied by a reduction in hepatic fat to the point of complete fat loss (burnt-out NASH), but the mechanisms behind this phenomenon have not been elucidated. Adiponectin is raised in cirrhosis of any cause and has potent antisteatotic activity. In this study we examined 65 patients with advanced biopsy-proven NASH (fibrosis stage 3-4) and 54 with mild disease (fibrosis stage 0-1) to determine if disappearance of steatosis correlated with changes in serum adiponectin. All patents had fasting blood tests and anthropometric measures at the time of liver biopsy. Liver fat was accurately quantitated by morphometry. Serum adiponectin was measured by immunoassay. When compared to those with early disease, patients with advanced NASH were more insulin-resistant, viscerally obese, and older, but there was no difference in liver fat content or adiponectin levels. Adiponectin had a significant negative correlation with liver fat percentage in the whole cohort (r = -0.28, P < 0.01), driven by patients with advanced NASH (r = -0.40, P < 0.01). In advanced NASH, for each 4 µg/L increase in adiponectin there was an odds ratio OR of 2.0 (95% confidence interval [CI]: 1.3-3.0, P < 0.01) for a 5% reduction in hepatic fat. Adiponectin was highly and significantly associated with almost complete hepatic fat loss or burnt-out NASH (12.1 versus 7.4 µg/L, P = 0.001) on multivariate analysis. A relationship between adiponectin, bile acids, and adipocyte fexaramine activation was demonstrated in vivo and in vitro, suggestive of hepatocyte-adipocyte crosstalk. CONCLUSION: Serum adiponectin levels in advanced NASH are independently associated with hepatic fat loss. Adiponectin may in part be responsible for the paradox of burnt-out NASH. (HEPATOLOGY 2012).

Therapeutic drug monitoring of voriconazole: a case report of multiple drug interactions in a patient with an increased CYP2C19 activity.

BACKGROUND: Voriconazole is metabolized by cytochrome P450 (CYP) 2C19 and CYP 3A4. Drug-drug interactions and genetic polymorphisms modulate their activities. CASE PRESENTATION: A 35-year old African female patient with resistant HIV and a cerebral mass of unknown origin was treated with voriconazole for a suspicion of disseminated Aspergillosis infection. Voriconazole trough concentrations (C0) were within target range while the patient was under esomeprazole, a CYP2C19 inhibitor. Phenotyping showed decreased CYP2C19 activity, whereas genotyping showed a variant allele associated with increased enzyme activity. The patient was switched to ranitidine because of the introduction of atazanavir. CYP3A4 inhibition by atazanavir combined with uninhibited CYP2C19 activity resulted in subtherapeutic voriconazole C0. The reintroduction of esomeprazole allowed restoring voriconazole C0 back to target range. CONCLUSION: The integration of drug-drug interactions and pharmacogenetics data is crucial to interpret drug concentrations correctly, thus preventing suboptimal exposure to voriconazole.

Consent as a compositional act - a framework that provides clarity for the retention and use of data.

BACKGROUND: Informed consent is one of the key principles of conducting research involving humans. When research participants give consent, they perform an act in which they utter, write or otherwise provide an authorisation to somebody to do something. This paper proposes a new understanding of the informed consent as a compositional act. This conceptualisation departs from a modular conceptualisation of informed consent procedures. METHODS: This paper is a conceptual analysis that explores what consent is and what it does or does not do. It presents a framework that explores the basic elements of consent and breaks it down into its component parts. It analyses the consent act by first identifying its basic elements, namely: a) data subjects or legal representative that provides the authorisation of consent; b) a specific thing that is being consented to; and c) specific agent(s) to whom the consent is given. RESULTS: This paper presents a framework that explores the basic elements of consent and breaks it down into its component parts. It goes beyond only providing choices to potential research participants; it explains the rationale of those choices or consenting acts that are taking place when speaking or writing an authorisation to do something to somebody. CONCLUSIONS: We argue that by clearly differentiating the goals, the procedures of implementation, and what is being done or undone when one consent, one can better face the challenges of contemporary data-intensive biomedical research, particularly regarding the retention and use of data. Conceptualising consent as a compositional act enhances more efficient communication and accountability and, therefore, could enable more trustworthy acts of consent in biomedical science.

Stereoselective separation of omeprazole and 5-hydroxy-omeprazole using dried plasma spots and a heart-cutting 2D-LC approach for accurate CYP2C19 phenotyping.

Omeprazole (OME) is a widely used gastric proton pump inhibitor, marketed as a racemic mixture comprising (S)- and (R)-enantiomers, with distinct pharmacokinetic profiles. OME is primarily metabolized by the cytochrome P450 enzymes 2C19 (CYP2C19) and 3A4 (CYP3A4). OME is a conventional probe for CYP2C19 phenotyping. Accurate measurement of these enantiomers and their metabolites is essential for pharmacokinetic studies. This article presents a sensitive and accurate two-dimensional liquid chromatography-mass spectrometry (LC-MS/MS) method for the simultaneous quantification of OME enantiomers and its hydroxylated metabolite (5-hydroxyomeprazole) in human plasma. The method involves an online extraction using an achiral Discovery HS C18 trapping column for purification (20 × 2.1 mm ID, 5µm particle size, Supelco) and subsequent forward flush elution onto a chlorinated phenylcarbamate cellulose-based chiral column (150x2mm ID, 3 µm particle size, Lux Cellulose-4, Phenomenex). The assay was fully validated and met international validation criteria for accuracy, precision, and stability and ensured high selectivity and sensitivity within a short runtime (<8 min). Application of this method to clinical samples demonstrated its utility in studying OME enantiomer pharmacokinetics, particularly its potential for phenotyping the activity of the CYP2C19 isoenzyme. This robust analytical approach offers a valuable tool for clinicians and researchers studying OME's pharmacokinetics, providing insights into its metabolism and potential implications for personalized medicine.

Local anaesthetics risks perception: A web-based survey.

Background: The use of local anaesthetics (LAs) is usually associated with few adverse effects, but local anaesthetic systemic toxicity (LAST) can result in serious harm and even death. However, practitioner awareness regarding this risk has been little studied. Methods: This was a closed, web-based study carried out at two Swiss university hospitals using a fully automated questionnaire. The main objective was to evaluate LAST awareness and LA use among various medical practitioners. The secondary objective was to determine whether these physicians felt that a tool designed to compute maximum safe LA doses should be developed. Results: The overall participation rate was 40.2 % and was higher among anaesthesiologists (154/249, 61.8 % vs 159/530, 30.0 %; P < .001). Anaesthesiologists identified the risk of LAST and the systems involved more frequently than non-anaesthesiologists (85.1 % vs 43.4 %, P < .001). After adjusting for years of clinical experience, age, country of diploma, frequency of LA use, clinical position and being an anaesthesiologist, the only significant associations were this latter factor (P < .001) and clinical position (P = .016 for fellows and P = .046 for consultants, respectively). Most respondents supported the development of a tool designed to compute maximum safe LA doses (251/313, 80.2 %) and particularly of a mobile app (190/251, 75.7 %). Conclusions: LAST awareness is limited among practitioners who use LAs on a regular basis. Educational interventions should be created, and tools designed to help calculate maximum safe LA doses developed. The actual frequency of unsafe LA doses administration would also deserve further study.

Impact of a Mobile App (LoAD Calc) on the Calculation of Maximum Safe Doses of Local Anesthetics: Protocol for a Randomized Controlled Trial.

BACKGROUND: Local anesthetics (LAs) are regularly used to alleviate pain during medical or surgical procedures. Their use is generally considered safe, but exceeding the maximum recommended doses can lead to LA systemic toxicity, a rare but potentially lethal complication. Determining maximum safe doses is therefore mandatory before performing local anesthesia, but rules are often unclear and the factors affecting dose calculation are numerous. Mobile health apps have been shown to help clinical decision-making, but most currently available apps present significant limitations. The Local Anesthetics Dose Calculator (LoAD Calc) app was designed to overcome these limitations by taking all relevant parameters into account. Before deploying this app in a clinical setting, it should be tested to determine its effectiveness and whether clinicians would be willing to use it. OBJECTIVE: The primary objective will be to evaluate the effectiveness of the LoAD Calc app through written simulated cases. The secondary objective will be to determine whether physicians find this app easier, faster, and safer than the methods they generally use. METHODS: We describe a parallel-group randomized controlled trial protocol. Anesthesiologists working at the Geneva University Hospitals will be invited to participate. Participants will be asked to compute the maximum dose of LA in 10 simulated clinical cases using 3 different LAs. The maximum safe dose will be determined manually using the same calculation rules that were used to develop LoAD Calc, without using the app itself. An overdose will be considered any dose higher than the correct dose, rounded to the superior integer, while an underdose will be defined as the optimal calculated dose minus 20%, rounded to the inferior integer. Randomization will be stratified according to current position (resident vs registrar). The participants allocated to the LoAD Calc (experimental) group will use the LoAD Calc app to compute the maximum safe LA doses. Those allocated to the control group will be asked to use the method they generally use. The primary outcome will be the overall overdose rate. Secondary outcomes will include the overdose rate according to ideal and actual body weight and to each specific LA, the overall underdose rate, and the time taken to complete these calculations. The app's usability will also be assessed. RESULTS: A sample size of 46 participants will be needed to detect a difference of 10% with a power of 90%. Thus, a target of 50 participants was set to allow for attrition and exclusion criteria. We expect recruitment to begin during the winter of 2023, data analysis in the spring of 2024, and results by the end of 2024. CONCLUSIONS: This study should determine whether LoAD Calc, a mobile health app designed to compute maximum safe LA doses, is safer and more efficient than traditional LA calculation methods. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/53679.

Antiviral Use in Mild-to-Moderate SARS-CoV-2 Infections during the Omicron Wave in Geriatric Patients.

(1) Background: Geriatric patients are at high risk of complications of Coronavirus disease-2019 (COVID-19) and are good candidates for antiviral drugs. (2) Methods: A retrospective study of electronic health records (EHRs) aiming to describe antiviral (nirmatrelvir and ritonavir (nirmatrelvir/r) or remdesivir) use, drug-drug interactions (DDIs) and adverse drug reactions (ADRs) in elderly patients (75 and over), hospitalized with mild-to-moderate COVID-19 between July 2022 and June 2023. (3) Results: Out of 491 patients (mean age: 86.9 years), 180 (36.7%) received nirmatrelvir/r, 78 (15.9%) received remdesivir, and 233 (47.4%) received no antiviral therapy. No association was found between the choice of antiviral and the demographic or medical data. No serious ADR was observed. Nirmatrelvir/r dosage adjustment was inadequate in 65% of patients with renal impairment. In total, 128 patients (71%) on nirmatrelvir/r had potential pharmacokinetic DDIs, with 43 resulting in a possibly related ADR. In the remdesivir group, pharmacodynamic DDIs were more frequent, with QTc prolongation risk in 56 patients (72%). Only 20 patients underwent follow-up ECG, revealing QTc prolongation in 4. (4) Conclusions: There is an underutilization of antivirals despite their justified indications. Nirmatrelvir/r dosage was rarely adjusted to renal function. Dose adjustments and closer monitoring are needed due to the high risk of drug interactions.

Vitamin D Receptor Regulates Liver Regeneration After Partial Hepatectomy in Male Mice.

Vitamin D signals through the vitamin D receptor (VDR) to induce its end-organ effects. Hepatic stellate cells control development of liver fibrosis in response to stressors and vitamin D signaling decreases fibrogenesis. VDR expression in hepatocytes, however, is low in healthy liver, and the role of VDR in hepatocyte proliferation is unclear. Hepatocyte-VDR null mice (hVDR) were used to assess the role of VDR and vitamin D signaling in hepatic regeneration. hVDR mice have impaired liver regeneration and impaired hepatocyte proliferation associated with significant differential changes in bile salts. Notably, mice lacking hepatocyte VDR had significant increases in expression of conjugated bile acids after partial hepatectomy, consistent with failure to normalize hepatic function by the 14-day time point tested. Real-time PCR of hVDR and control livers showed significant changes in expression of cell cycle genes including cyclins D1 and E1 and cyclin-dependent kinase 2. Gene expression profiling of hepatocytes treated with vitamin D or control showed regulation of groups of genes involved in liver proliferation, hepatitis, liver hyperplasia/hyperproliferation and liver necrosis/cell death. Together these studies demonstrate an important functional role for VDR in hepatocytes during liver regeneration. Combined with the known profibrotic effects of impaired VDR signaling in stellate cells, the studies provide a mechanism whereby vitamin D deficiency would both reduce hepatocyte proliferation and permit fibrosis, leading to significant liver compromise.

Clinical Pharmacogenetics Implementation Consortium Guideline for CYP2B6 Genotype and Methadone Therapy.

Methadone is a mu (µ) opioid receptor agonist used clinically in adults and children to manage opioid use disorder, neonatal abstinence syndrome, and acute and chronic pain. It is typically marketed as a racemic mixture of R- and S-enantiomers. R-methadone has 30-to 50-fold higher analgesic potency than S-methadone, and S-methadone has a greater adverse effect (prolongation) on the cardiac QTc interval. Methadone undergoes stereoselective metabolism. CYP2B6 is the primary enzyme responsible for catalyzing the metabolism of both enantiomers to the inactive metabolites, S- and R-2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (S- and R-EDDP). Genetic variation in the CYP2B6 gene has been investigated in the context of implications for methadone pharmacokinetics, dose, and clinical outcomes. Most CYP2B6 variants result in diminished or loss of CYP2B6 enzyme activity, which can lead to higher plasma methadone concentrations (affecting S- more than R-methadone). However, the data do not consistently indicate that CYP2B6-based metabolic variability has a clinically significant effect on methadone dose, efficacy, or QTc prolongation. Expert analysis of the published literature does not support a change from standard methadone prescribing based on CYP2B6 genotype (updates at www.cpicpgx.org).

Clinical effects of cannabis compared to synthetic cannabinoid receptor agonists (SCRAs): a retrospective cohort study of presentations with acute toxicity to European hospitals between 2013 and 2020.

INTRODUCTION: Cannabis is the most common recreational drug worldwide and synthetic cannabinoid receptor agonists are currently the largest group of new psychoactive substances. The aim of this study was to compare the clinical features and outcomes of lone acute cannabis toxicity with lone acute synthetic cannabinoid receptor agonist toxicity in a large series of presentations to European emergency departments between 2013-2020. METHODS: Self-reported drug exposure, clinical, and outcome data were extracted from the European Drug Emergencies Network Plus which is a surveillance network that records data on drug-related emergency department presentations to 36 centres in 24 European countries. Cannabis exposure was considered the control in all analyses. To compare the lone cannabis and lone synthetic cannabinoid receptor agonist groups, univariate analysis using chi squared testing was used for categorical variables and non-parametric Mann-Whitney U- testing for continuous variables. Statistical significance was defined as a P value of < 0.05. RESULTS: Between 2013-2020 there were 54,314 drug related presentations of which 2,657 were lone cannabis exposures and 503 lone synthetic cannabinoid receptor agonist exposures. Synthetic cannabinoid receptor agonist presentations had statistically significantly higher rates of drowsiness, coma, agitation, seizures and bradycardia at the time of presentation. Cannabis presentations were significantly more likely to have palpitations, chest pain, hypertension, tachycardia, anxiety, vomiting and headache. DISCUSSION: Emergency department presentations involving lone synthetic cannabinoid receptor agonist exposures were more likely to have neuropsychiatric features and be admitted to a psychiatric ward, and lone cannabis exposures were more likely to have cardiovascular features. Previous studies have shown variability in the acute toxicity of synthetic cannabinoid receptor agonists compared with cannabis but there is little comparative data available on lone exposures. There is limited direct comparison in the current literature between lone synthetic cannabinoid receptor agonist and lone cannabis exposure, with only two previous poison centre series and two clinical series. Whilst this study is limited by self-report being used to identify the drug(s) involved in the presentations, previous studies have demonstrated that self-report is reliable in emergency department presentations with acute drug toxicity. CONCLUSION: This study directly compares presentations with acute drug toxicity related to the lone use of cannabis or synthetic cannabinoid receptor agonists. It supports previous findings of increased neuropsychiatric toxicity from synthetic cannabinoid receptor agonists compared to cannabis and provides further data on cardiovascular toxicity in lone cannabis use.

Carbimazole-induced, ANCA-associated, crescentic glomerulonephritis: case report and literature review.

Anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis is a rare complication of antithyroid drug use that was first described with propylthiouracil. We describe an ANCA-associated rapidly progressive glomerulonephritis in a patient treated with carbimazole during 6 months for Graves disease that resulted in end-stage renal disease. A 66-year-old man treated with carbimazole for Graves disease was admitted for macroscopic hematuria and edema of the lower extremities. Laboratory work-up showed elevated serum creatinine (435 µmol/L), mixed hematuria, nephrotic range proteinuria, and a low positive c-ANCA titer with proteinase-3 specificity. Renal biopsy showed necrotizing, crescentic, pauci-immune glomerulonephritis. Carbimazole was discontinued and hemodialysis was initiated as well as high-dose glucocorticoids and pulses of intravenous cyclophosphamide. Despite immunosuppressive treatment, the patient remained dialysis-dependent at 6 months after diagnosis. Graves disease remained in remission after carbimazole withdrawal. ANCA-associated vasculitis manifesting as glomerulonephritis is a potential adverse effect of all antithyroid drugs. Although prognosis is usually good, end-stage renal disease may ensue in rare cases. Physicians should have a high index of suspicion in patients receiving antithyroid drugs who present with symptoms or signs suggestive of progressive renal disease.

[Efficient treatment of breakthrough pain in adults: the importance of timing and medication choice]. / Traiter efficacement la douleur incidente chez l'adulte: donner le bon antalgique au bon moment!

Diagnostic or therapeutic procedures can lead to breakthrough pain. Thanks to a wise choice of analgesic medication started in due time, this type of pain can be avoided or decreased. The therapeutic options of this preventive approach are presented according to the expected breakthrough pain type and intensity. Specific situations are presented through case discussions. The main pharmacokinetic information needed to prescribe the right analgesic at the right time is summarized in a convenient table. When associated to non-pharmacological measures such as empathy, patient positioning and high quality procedures, preventive analgesia provides patients the best possible relief from breakthrough pain.