Residents' Knowledge regarding Recreational Drug Screening Immunoassays at a Swiss Hospital Group.

Introduction: In case of suspected acute recreational drug toxicity, immunoassays are commonly used as diagnostic tools. Although easy to handle, understanding of their limitations is necessary for a correct interpretation of the results. The aim of this project was to investigate residents' knowledge regarding drug screening immunoassays at a Swiss hospital group. Methods: All residents of a large hospital group in Switzerland were invited by e-mail to participate in an anonymous survey. Following ten multiple choice questions on drug screening tests, the participants were also asked about their demographics, whether they used drug screening tests on a regular basis, and how confident they felt in their ability to interpret test results. Results: The ten knowledge questions were answered by 110 of the 1026 residents (11%). Among the 108 participants with available demographics, 90% were 25-35 years old, 63% were female, and 70% were at least in their 4th year of residency. The median score of correct answers was 4 out of 10 (range 0-7) and in 50% of the questions, the correct answer was the most frequently selected response. No significant differences in the knowledge scores were found based on the training, confidence level, or the frequency of drug tests used in daily work. Conclusion: This survey revealed widespread knowledge gaps among residents regarding the interpretation of immunoassay-based drug test results. These findings can be used to implement educational measures on this topic and might provide a basis for targeted information on common pitfalls to be included in laboratory reports.

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.

Anticoagulation reversal (vitamin K, prothrombin complex concentrates, idarucizumab, andexanet-α, protamine).

Bleeding events are common in patients prescribed anticoagulants and can have devastating consequences. Several specific and nonspecific agents have been developed to reverse the effects of anticoagulant drugs or toxins. Vitamin K, as the oldest of these antidotes, specifically counteracts the effects of pharmaceuticals and rodenticides designed to deplete stores of vitamin K-dependent factors. In cases of life-threatening bleeding, the addition of prothrombin complex concentrates (PCCs) allows for the immediate replacement of coagulation factors. While the use of PCCs has been extended to the non-specific reversal of the effects of newer direct oral anticoagulants, the specific agents idarucizumab, targeting dabigatran and andexanet-α, binding factor Xa inhibitors, have recently been developed and are being preferentially recommended by most guidelines. However, despite having rapid effects on correcting coagulopathy, there is to date a lack of robust evidence establishing the clear superiority of direct oral anticoagulant-specific reversal agents over PCCs in terms of haemostatic efficacy, safety or mortality. For andexanet-α, a potential signal of increased thromboembolic risks, comparatively high costs and low availability might also limit its use, even though emerging evidence appears to bolster its role in intracranial haemorrhage. Protamine is the specific agent for the reversal of unfractionated heparin anticoagulation used mainly in cardiovascular surgery. It is much less effective for low molecular weight heparin fragments and is usually reserved for cases with life-threatening bleeding.

Pharmacokinetics and pharmacodynamics of inhaled nicotine salt and free-base using an e-cigarette: A randomized crossover study.

BACKGROUND: Popular "pod-style" e-cigarettes commonly use nicotine salt-based e-liquids that cause less irritation when inhaled and can deliver higher nicotine concentrations than free-base nicotine. We aimed to investigate the pharmacokinetic and pharmacodynamic effects of different nicotine formulations (salt vs. free-base) and concentrations that might influence systemic nicotine absorption and appeal of e-cigarettes. METHODS: In this randomized, double-blind, within-subject crossover study, 20 non nicotine-naïve participants were switched among three e-liquids (free-base nicotine 20mg/mL, nicotine salt 20mg/mL, nicotine salt 40mg/mL) using a refillable pod system and a standardized vaping protocol (one puff every 30 seconds, 10 puffs total). Serum nicotine concentrations and vital signs were assessed over 180 minutes; direct effects, craving, satisfaction, withdrawal, and respiratory symptoms were measured using questionnaires. CYP2A6 genotypes and the nicotine metabolite ratio were also assessed. RESULTS: Eleven (55%) participants were male and the median age was 23.5 years (range 18-67). All three formulations differed significantly in peak serum nicotine concentration (baseline adjusted Cmax, median (range): 12.0ng/mL (1.6-27.3), 5.4ng/mL (1.9-18.7) and 3.0ng/mL (1.3-8.8) for nicotine salt 40mg/mL, nicotine salt 20mg/mL and free-base 20mg/mL, respectively). All groups reached Cmax 2.0-2.5min (median) after their last puff. Differences in subjective effects were not statistically significant. No serious adverse events were observed. CONCLUSION: Free-base 20mg/mL formulations achieved lower blood nicotine concentrations than nicotine salt 20mg/mL, while 40mg/mL nicotine salt yielded concentrations similar to cigarette smoking. The findings can inform regulatory policy regarding e-liquids and their potential use in smoking cessation. IMPLICATIONS: Nicotine salt formulations inhaled by an e-cigarette led to higher nicotine delivery compared to nicotine free-base formulations with the same nicotine concentration. These findings should be considered in future regulatory discussions. The 40mg/mL nicotine salt formulation showed similar nicotine delivery as combustible cigarettes, albeit at concentrations over the maximum limit for e-liquids allowed in the European Union. Nicotine delivery resembling combustible cigarettes might be beneficial for smokers willing to quit to adequately alleviate withdrawal symptoms. However, increased nicotine delivery can also pose a public health risk, raising concerns about abuse liability, especially among youth and non-smokers.

Self-discharge during treatment for acute recreational drug toxicity: an observational study from emergency departments in seven European countries.

BACKGROUND: Self-discharge is a risk factor for readmission and excess mortality. We assess the rate of self-discharge from the emergency department (ED) among presentations for acute recreational drug toxicity and identify factors associated with self-discharge. METHODS: From the Euro-DEN Plus database of presentations to the ED with acute recreational drug toxicity, we extracted data from 11 centres in seven European countries from 2014 to 2017. Self-discharge was defined as taking one's own discharge or escaping from the ED before being medically cleared. We used multiple logistic regression analyses to look for factors associated with self-discharge. RESULTS: Among 15,135 included presentations, 1807 (11.9%) self-discharged. Self-discharge rates varied from 1.7 to 17.1% between centres. Synthetic cannabinoids were associated with self-discharge, adjusted odds ratio 1.44 (95% confidence interval 1.10-1.89), as were heroin, 1.44 (1.26-1.64), agitation, 1.27 (1.10-1.46), and naloxone treatment, 1.27 (1.07-1.51), while sedation protected from self-discharge, 0.38 (0.30-0.48). CONCLUSION: One in eight presentations self-discharged. There was a large variation in self-discharge rates across the participating centres, possibly partly reflecting different discharge procedures and practices. Measures to improve the management of agitation and cautious administration of naloxone to avoid opioid withdrawal symptoms may be approaches worth exploring to reduce self-discharge.

Characteristics of emergency department presentations following ingestion of Taxus baccata (yew).

OBJECTIVE: Presentations of Taxus baccata (yew) poisoning can range between asymptomatic cases and life-threatening cardiotoxicity - depending on the amount ingested. This study aimed to describe emergency department (ED) presentations after yew exposure, and covers their clinical presentation, diagnostic and specific treatment, to contribute to optimising intreatment and prophylaxis. METHODS: Retrospective observational study of cases (≥ 16 years of age) presenting at the ED of the University Hospital of Bern, Switzerland, from 1 May 2012 to 31 May 2020 following reported yew exposure. Cases were retrieved from the electronic patient database using full-text terms. RESULTS: During the study period, 55 presentations (11 patients) of the 350,381 ED attendances were included. All patients were female and the median age on first presentation was 22 years (range 16-48). All 10 patients with intentional intake had previous diagnoses of psychiatric disorders. Commonly reported symptoms on presentation were gastrointestinal disturbances (31 presentations, 56%), neurological (six presentations, 11%) and subjective cardiovascular symptoms (five presentations, 9%). The most frequent clinical findings on presentation were tachycardia (15 presentations, 27%) and hypotension (11 presentations, 20%). In 52 presentations (95%), gastroscopic extraction of the leaves was performed, activated charcoal was administered in 25 cases (45%), and there were no fatalities. In the majority of the cases (40, 73%), the patient was admitted to psychiatric care and in 10 (18%) the patient was discharged home. CONCLUSION: ED presentations after yew exposure appear to be rare, but potentially life-threatening and commonly observed in this study in young female patients with underlying psychiatric diseases. In this case series, gastroscopic extraction and activated charcoal application were commonly performed and there were no fatalities.

Tobacco use disorder and cardiovascular health.

This narrative review examines the impact of cigarette smoking and the use of other tobacco and nicotine products on cardiovascular disease. Smoking increases the incidence of both acute and chronic cardiovascular diseases, and the harmful effects are substantially and relatively quickly reversible after quitting. Recommended cessation treatment includes offering pharmacotherapy, counseling which should emphasize the rapid risk reduction that occurs after quitting and adequate follow-up contacts. Although most research on cardiovascular disease in relation to tobacco use has focused upon cigarette smoking, we also review available data related to other combustible tobacco products, smokeless tobacco, electronic nicotine delivery systems and second-hand smoke. We discuss the implications of smoking on clinical management of patients with heart disease and newer developments with potential relevance to treatment of such patients.

Presentations with reported methamphetamine use to an urban emergency department in Switzerland.

AIMS OF THE STUDY: The stimulant methamphetamine (e.g., "crystal meth") is a commonly abused drug in many parts of the world and can cause significant health problems. The present study aims to describe presentations with reported methamphetamine use at an urban emergency department (ED) in Switzerland, to investigate prevalence, patterns and susceptible groups. METHODS: Retrospective study at the ED of the University Hospital of Bern, Switzerland. Cases from June 2012 to July 2019 were retrieved from the electronic patient database using full-text terms and were categorised into three groups based on patient history: "acute", if patients presented within 72 hours of last reported use, "chronic" in cases of regular use but not within the previous 72 hours, and "past" in cases of discontinued consumption. Cases with a positive methamphetamine urine drug screening test with no further information available were described separately. RESULTS: During the study period, 40 cases were categorised as "acute". Among those, the mean age was 29.5 years (standard deviation [SD] 8.7), 75% (n = 30) were male, and agitation (n = 11, 28%), hypertension (n = 11, 28%), tachycardia (n = 11, 28%), sleep disturbances (n = 10, 25%) and aggression (n = 8, 20%) were the most common symptoms. Most patients (n = 22, 55%) were medically discharged, but 35% (n = 14) were admitted to a psychiatric clinic. Most (n = 33, 82.5%) were polydrug users, with alcohol, cocaine and cannabis being the most frequent co-used substances. The "chronic" group included 37 cases. Those patients were mostly male (n = 26, 70%), with a mean age of 31 years (SD 11.0), and 46% (n = 17) presented because of psychiatric symptoms, such as psychosis, depression or aggression. Of the 45 cases in the "past" group (mean age of 30 years, SD 8.6), 69% (n = 31) were male, and 49% (n = 22) and 24% (n = 11), respectively, had medical and psychiatric symptoms as the reason for admission. Of 61 cases with a positive urine drug screening test as the sole indicator of methamphetamine use, 19 patients reported MDMA use (cross-reactivity with methamphetamine in the urine immunoassay used). In the 42 remaining cases, it was unclear if the positive result was due to unreported methamphetamine use or cross-reactivity. CONCLUSIONS: Most patients with reported methamphetamine use were young and male, with signs of sympathomimetic arousal and/or psychiatric symptoms. Although ED visits with reports of methamphetamine use appear to be uncommon, consumption-related health problems can require significant pre- and in-hospital resources.

Characteristics of Presentations to the Emergency Department Following Attempted Suicide with Drugs.

A relatively high proportion of attempted suicides employ self-poisoning with medication. Data from emergency department presentations can help to identify possible risk drug classes and provide a basis for preventive measures. This retrospective analysis included cases presenting at the emergency department of the University Hospital of Bern, Switzerland, from May 2012 to August 2016, after attempted suicide with drugs. We excluded attempted suicides with only alcohol or other non-medical substances. During the study period, there were 488 cases (466 patients) of attempted suicide with medical substances. The median patient age was 33 years (range 16-93) and 354 (73%) cases were female. The most commonly involved substances/drug classes were benzo-diazepines (n = 167, 34%), neuroleptics (n = 114, 23%) and paracetamol (n = 111, 23%). A total of 231 (47%) cases employed only a single substance. Common symptoms included somnolence (n = 245, 50%), tachycardia (n = 119, 24%) and nausea/vomiting (n = 76, 16%). In most cases, the poisoning was of minor severity (n = 231, 47%) and the patients were admitted to a psychiatric hospital (n = 264, 54%). Important preventive measures may include careful monitoring for suicidal behaviour when prescribing psychotropic drugs, in addition to restrictions in pack size. Efforts should also be made to enhance the awareness of health professionals qualified to prescribe or supply paracetamol.

Comparative Effects of Metamizole (Dipyrone) and Naproxen on Renal Function and Prostacyclin Synthesis in Salt-Depleted Healthy Subjects - A Randomized Controlled Parallel Group Study.

Aim: The objective was to investigate the effect of metamizole on renal function in healthy, salt-depleted volunteers. In addition, the pharmacokinetics of the four major metamizole metabolites were assessed and correlated with the pharmacodynamic effect using urinary excretion of the prostacyclin metabolite 6-keto-prostaglandin F1α. Methods: Fifteen healthy male volunteers were studied in an open-label randomized controlled parallel group study. Eight subjects received oral metamizole 1,000 mg three times daily and seven subjects naproxen 500 mg twice daily for 7 days. All subjects were on a low sodium diet (50 mmol sodium/day) starting 1 week prior to dosing until the end of the study. Glomerular filtration rate was measured using inulin clearance. Urinary excretion of sodium, potassium, creatinine, 6-keto-prostaglandin F1α, and pharmacokinetic parameters of naproxen and metamizole metabolites were assessed after the first and after repeated dosing. Results: In moderately sodium-depleted healthy subjects, single or multiple dose metamizole or naproxen did not significantly affect inulin and creatinine clearance or sodium excretion. Both drugs reduced renal 6-keto-prostaglandin F1α excretion after single and repeated dosing. The effect started 2 h after intake, persisted for the entire dosing period and correlated with the concentration-profile of naproxen and the active metamizole metabolite 4-methylaminoantipyrine (4-MAA). PKPD modelling indicated less potent COX-inhibition by 4-MAA (EC50 0.69 ± 0.27 µM) compared with naproxen (EC50 0.034 ± 0.033 µM). Conclusions: Short term treatment with metamizole or naproxen has no significant effect on renal function in moderately sodium depleted healthy subjects. At clinically relevant doses, 4-MAA and naproxen both inhibit COX-mediated renal prostacyclin synthesis.

Clinical Pharmacology of Electronic Nicotine Delivery Systems (ENDS): Implications for Benefits and Risks in the Promotion of the Combusted Tobacco Endgame.

Electronic nicotine delivery systems (ENDS) such as e-cigarettes and heated tobacco products are novel battery-operated devices that deliver nicotine without combustion of tobacco. Because cigarette smoking is sustained by nicotine addiction and the toxic combustion products are mainly responsible for the harmful effects of smoking, ENDS could be used to promote smoking cessation while exposing users to lower levels of toxicants compared with conventional cigarettes. The currently available evidence from clinical and observational studies indicates a potential role of e-cigarettes as smoking cessation aids, although many continue to use e-cigarettes long after quitting smoking. Nicotine and toxicant delivery vary considerably by device and depend on the characteristics of the e-liquid formulation. Because smokers tend to titrate their nicotine intake to maintain their desired pharmacologic effects, device and liquid characteristics need to be considered when using ENDS as an aid to quit smoking. Factors potentially limiting their use are the currently still unknown long-term safety of these products and concerns regarding widespread use among youth. Implications of clinical pharmacology data on ENDS for the cigarette endgame and regulation by the U.S. Food and Drug administration are discussed.

Effect of race and glucuronidation rates on the relationship between nicotine metabolite ratio and nicotine clearance.

OBJECTIVES: To investigate if the nicotine metabolite ratio (NMR, the ratio of nicotine metabolites 3'-hydroxycotinine/cotinine) is a reliable phenotypic biomarker for nicotine clearance across races, and as a function of differences in the rate of nicotine, cotinine and 3'-hydroxycotinine glucuronidation and UGT genotypes. METHODS: Participants [Caucasians (Whites), African Americans (Blacks) and Asian-Americans (Asians)] received an oral solution of deuterium-labeled nicotine and its metabolite cotinine. Plasma and saliva concentrations of nicotine and cotinine were used to determine oral clearances. Rates of glucuronidation were assessed from urine glucuronide/parent ratios, and UGT2B10 and UGT2B17 genotypes from DNA. RESULTS: Among the 227 participants, 96 (42%) were White, 67 (30%) Asian and 64 (28%) Black. Compared to the other two races, Whites had higher nicotine and cotinine total oral clearance, Blacks had lower nicotine and cotinine glucuronidation rates and Asians had lower 3'-hydroxycotinine glucuronidation rates. A strong positive correlation (correlations coefficients 0.77-0.84; P < 0.001) between NMR and nicotine oral clearance was found for all three races, and NMR remained a strong predictor for the nicotine oral clearance while adjusting for race, sex and age. Neither the metabolite glucuronidation ratios nor the UGT genotypes had significant effects on the ability of NMR to predict nicotine oral clearance. CONCLUSION: NMR appears to be a reliable phenotypic biomarker for nicotine clearance across races, glucuronidation phenotypes and genotypes. Racial differences in the relationships between NMR, smoking behaviors and addiction are unlikely to be related to an inadequate estimation of nicotine clearance on the basis of NMR.

The Risk of Muscular Events Among New Users of Hydrophilic and Lipophilic Statins: an Observational Cohort Study.

BACKGROUND: Statins are effective lipid-lowering drugs for the prevention of cardiovascular disease, but muscular adverse events can limit their use. Hydrophilic statins (pravastatin, rosuvastatin) may cause less muscular events than lipophilic statins (e.g. simvastatin, atorvastatin) due to lower passive diffusion into muscle cells. OBJECTIVE: To compare the risk of muscular events between statins at comparable lipid-lowering doses and to evaluate if hydrophilic statins are associated with a lower muscular risk than lipophilic statins. DESIGN/SETTING: Propensity score-matched cohort study using data from the United Kingdom-based Clinical Practice Research Datalink (CPRD) GOLD. PATIENTS: New statin users. Cohort 1: pravastatin 20-40 mg (hydrophilic) vs simvastatin 10-20 mg (lipophilic), cohort 2: rosuvastatin 5-40 mg (hydrophilic) vs atorvastatin 10-80 mg (lipophilic), and cohort 3: simvastatin 40-80 mg vs atorvastatin 10-20 mg. MAIN MEASURES: The outcome was a first record of a muscular event (myopathy, myalgia, myositis, rhabdomyolysis) during a maximum follow-up of 1 year. KEY RESULTS: The propensity score-matched cohorts consisted of 1) 9,703, 2) 7,032, and 3) 37,743 pairs of statin users. Comparing the risk of muscular events between low-intensity pravastatin vs low-intensity simvastatin yielded a HR of 0.86 (95% CI 0.64-1.16). In the comparison of moderate- to high-intensity rosuvastatin vs equivalent doses of atorvastatin, we observed a HR of 1.17 (95% CI 0.88-1.56). Moderate- to high-intensity simvastatin was associated with a HR of 1.33 (95% CI 1.16-1.53), when compared with atorvastatin at equivalent doses. LIMITATIONS: We could not conduct other pairwise comparisons of statins due to small sample size. In the absence of a uniform definition on the comparability of statin doses, the applied dose ratios may not fully match with all literature sources. CONCLUSIONS: Our results do not suggest a systematically lower risk of muscular events for hydrophilic statins when compared to lipophilic statins at comparable lipid-lowering doses.

Variation of drugs involved in acute drug toxicity presentations based on age and sex: an epidemiological approach based on European emergency departments.

OBJECTIVE: To analyse the relative percentage of acute recreational drug toxicity emergency department (ED) presentations involving the main drug groups according to age and sex and investigate different patterns based on sex and age strata. METHODS: We analysed all patients with acute recreational drug toxicity included by the Euro-DEN Plus dataset (22 EDs in 14 European countries) between October 2013 and December 2016 (39 months). Drugs were grouped as: opioids, cocaine, cannabis, amphetamines, gamma-hydroxybutyrate (GHB), hallucinogens, new psychoactive substances (NPS), benzodiazepines and ketamine. Descriptive data by age and sex are presented and compared among age/sex categories and among drug families. RESULTS: Of 17,371 patients were included during the 39-month period, 17,198 (99.0%) had taken at least one of the investigated drugs (median age: 31 years; 23.9% female; ethanol co-ingestion recorded in 41.5%, unknown in 31.2%; multiple drug use in 37.9%). Opioids (in 31.4% of patients) and amphetamines (23.3%) were the most frequently involved and hallucinogens (1.9%) and ketamine (1.7%) the least. Overall, female patients were younger than males, both in the whole cohort (median age 29 vs. 32 years; p < 0.001) and in all drug groups except benzodiazepines (median age 36 vs. 36 years; p = 0.83). The relative proportion of each drug group was different at every age strata and some patterns could be clearly described: cannabis, NPS and hallucinogens were the most common in patients <20 years; amphetamines, ketamine and cocaine in the 20- to 39-year group; GHB/GBL in the 30- to 39-year group; and opioids and benzodiazepines in patients ≥40 years. Ethanol and other drug co-ingestion was more frequent at middle-ages, and multidrug co-ingestion was more common in females than males. CONCLUSION: Differences in the drugs involved in acute drug toxicity presentations according to age and sex may be relevant for developing drug-prevention and education programs for some particular subgroups of the population based on the increased risk of adverse events in specific sex and/or age strata.

Development and validation of a prognostic COVID-19 severity assessment (COSA) score and machine learning models for patient triage at a tertiary hospital.

BACKGROUND: Clinical risk scores and machine learning models based on routine laboratory values could assist in automated early identification of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) patients at risk for severe clinical outcomes. They can guide patient triage, inform allocation of health care resources, and contribute to the improvement of clinical outcomes. METHODS: In- and out-patients tested positive for SARS-CoV-2 at the Insel Hospital Group Bern, Switzerland, between February 1st and August 31st ('first wave', n = 198) and September 1st through November 16th 2020 ('second wave', n = 459) were used as training and prospective validation cohort, respectively. A clinical risk stratification score and machine learning (ML) models were developed using demographic data, medical history, and laboratory values taken up to 3 days before, or 1 day after, positive testing to predict severe outcomes of hospitalization (a composite endpoint of admission to intensive care, or death from any cause). Test accuracy was assessed using the area under the receiver operating characteristic curve (AUROC). RESULTS: Sex, C-reactive protein, sodium, hemoglobin, glomerular filtration rate, glucose, and leucocytes around the time of first positive testing (- 3 to + 1 days) were the most predictive parameters. AUROC of the risk stratification score on training data (AUROC = 0.94, positive predictive value (PPV) = 0.97, negative predictive value (NPV) = 0.80) were comparable to the prospective validation cohort (AUROC = 0.85, PPV = 0.91, NPV = 0.81). The most successful ML algorithm with respect to AUROC was support vector machines (median = 0.96, interquartile range = 0.85-0.99, PPV = 0.90, NPV = 0.58). CONCLUSION: With a small set of easily obtainable parameters, both the clinical risk stratification score and the ML models were predictive for severe outcomes at our tertiary hospital center, and performed well in prospective validation.

Retrospective analysis of adverse drug reactions leading to short-term emergency hospital readmission.

AIMS OF THE STUDY: Adverse drug reactions (ADRs) are an important cause of hospital admissions. Insufficient data are available about the frequency and characteristics of ADR-related emergency readmissions in Switzerland. The aim of this retrospective study was to characterise ADRs related to short-term emergency readmissions in a large Swiss University Hospital and to assess their reporting frequency. METHODS: Electronic records of all patients discharged from the University Hospital Bern within a 12-month period (1 January to 31 December 2012) and emergency readmission within 30 calendar days were reviewed. Case inclusion required a known ADR. Cases with intentional overdosing, lack of compliance or insufficient documentation were excluded. Identified ADR-related readmission cases were searched in the Swiss ADR reporting system to assess reporting rate. RESULTS: There were 1294 emergency readmissions among the 4792 readmissions (14% of all admissions) within 30 days after discharge. We identified 270 cases of ADR-related readmissions, corresponding to 21% of emergency readmissions and 6% of all readmissions within 30 days. The most frequent ADRs were gastrointestinal disorders (26%), infections and infestations (19%), and nervous system disorders (10%). The most frequent drug classes leading to ADRs were antineoplastic/immunomodulating (35%) and antithrombotic agents (25%). Only 8 (3%) of the 270 cases were reported to the Swiss ADR reporting system. CONCLUSION: ADR-related readmissions constituted a considerable part of short-term emergency readmissions. Despite being a relevant cause for rehospitalisation, only a minority of the ADRs were reported to the regulatory authorities. Strategies to prevent ADR-related readmissions and to improve reporting rates are needed.

Effects of Hypericum perforatum (St John's wort) on the pharmacokinetics and pharmacodynamics of rivaroxaban in humans.

AIMS: To investigate the influence of a cytochrome P450 CYP3A4 and efflux transporter P-glycoprotein (P-gp) inducing Hypericum perforatum extract on the pharmacokinetics and pharmacodynamics of rivaroxaban. METHODS: Open-label, nonrandomized, sequential treatment interaction study. Following CYP3A4 and P-gp phenotyping using low-dose midazolam and fexofenadine, 12 healthy volunteers received a single oral dose of 20 mg rivaroxaban and rivaroxaban plasma concentrations and inhibition of the activated coagulation factor X (factor Xa) activity were measured prior to and up to 48 h postdosing. The procedures were repeated after 2 weeks' treatment with the H. perforatum extract. RESULTS: The geometric mean ratios for the area under the concentration-time curve and Cmax of rivaroxaban after/before induction with the H. perforatum extract were 0.76 (90% confidence interval [CI] 0.70, 0.82) and 0.86 (90% CI 0.76, 0.97), respectively. Inhibition of factor Xa activity was reduced with a geometric mean area under the effect-time curve ratio after/before induction of 0.80 (90% CI 0.71, 0.89). No clinically significant differences were found regarding Tmax (median 1.5 vs 1 h, P = .26) and terminal elimination half-life (mean 10.6 vs 10.8 h, P = .93) of rivaroxaban. The H. perforatum extract significantly induced CYP3A4 and P-gp activity, as evidenced by phenotyping. CONCLUSION: The CYP3A4/P-gp inducing H. perforatum extract caused a decrease of rivaroxaban exposure with a proportional decrease of the pharmacodynamic effect. Although the data do not justify a contraindication for the combination or a systematic adjustment of rivaroxaban dosage, avoidance of the combination or laboratory monitoring should be considered in patients taking hyperforin-containing H. perforatum extracts with rivaroxaban.

MDMA-related presentations to the emergency departments of the European Drug Emergencies Network plus (Euro-DEN Plus) over the four-year period 2014-2017.

CONTEXT: 3,4-Methylenedioxymethamphetamine (MDMA) remains one of the most commonly used recreational drugs in Europe. Monitoring of Emergency Department (ED) presentations with acute toxicity associated with MDMA is important to determine trends in MDMA use and harms. METHODS: Data were extracted from the European Drug Emergencies Network (Euro-DEN) Plus database for all ED presentations with acute toxicity involving MDMA use, alone or in combination with other substances, between 1 January 2014 and 31 December 2017. Geographical distribution, time trends, patient demographics, clinical features, management and outcome were analysed. RESULTS: Out of 23,947 presentations, 2013 (8.4%) involved MDMA, used alone (88, 4.4%) or with other substances (1925, 95.6%). The proportion of MDMA presentations varied by country, from over 15% in France to less than 5% in Norway. For the 15 sentinel centres where data were available for all four years, MDMA-related presentations peaked in 2016 (10.4% versus 8.1% in 2015, p < 0.0001), thereafter decreasing in 2017 (8.2%, p = 0.0002). 1436 (71.3%) presentations involved males. Females were significantly younger than males (median 23 years, interquartile range, IQR, 20-27 years, versus median 25 years, IQR 21-30 years, p < 0.0001). Compared to presentations of acute toxicity with lone-use cocaine, presentations with lone-use MDMA occurred more frequently during the weekend (58.0% versus 43.9%, p = 0.02), were more frequently medically discharged directly from the ED (74.7% versus 62.4%, p = 0.03), and less frequently received sedation (43.5% versus 66.5%, p = 0.003). CONCLUSIONS: This large multicentre series of MDMA presentations to EDs showed geographical variation and changes in time trends and in patient demographics. Triangulation with data from complementary sources including seizures, prevalence of use and wastewater analysis, will enable a greater understanding of the public health implications of MDMA use in Europe.

Genome-Wide Association Study of Metamizole-Induced Agranulocytosis in European Populations.

Agranulocytosis is a rare yet severe idiosyncratic adverse drug reaction to metamizole, an analgesic widely used in countries such as Switzerland and Germany. Notably, an underlying mechanism has not yet been fully elucidated and no predictive factors are known to identify at-risk patients. With the aim to identify genetic susceptibility variants to metamizole-induced agranulocytosis (MIA) and neutropenia (MIN), we conducted a retrospective multi-center collaboration including cases and controls from three European populations. Association analyses were performed using genome-wide genotyping data from a Swiss cohort (45 cases, 191 controls) followed by replication in two independent European cohorts (41 cases, 273 controls) and a joint discovery meta-analysis. No genome-wide significant associations (p < 1 × 10-7) were observed in the Swiss cohort or in the joint meta-analysis, and no candidate genes suggesting an immune-mediated mechanism were identified. In the joint meta-analysis of MIA cases across all cohorts, two candidate loci on chromosome 9 were identified, rs55898176 (OR = 4.01, 95%CI: 2.41-6.68, p = 1.01 × 10-7) and rs4427239 (OR = 5.47, 95%CI: 2.81-10.65, p = 5.75 × 10-7), of which the latter is located in the SVEP1 gene previously implicated in hematopoiesis. This first genome-wide association study for MIA identified suggestive associations with biological plausibility that may be used as a stepping-stone for post-GWAS analyses to gain further insight into the mechanism underlying MIA.