Differentiating viral and bacterial infections: A machine learning model based on routine blood test values.

The growing threat of antibiotic resistance necessitates accurate differentiation between bacterial and viral infections for proper antibiotic administration. In this study, a Virus vs. Bacteria machine learning model was developed to distinguish between these infection types using 16 routine blood test results, C-reactive protein concentration (CRP), biological sex, and age. With a dataset of 44,120 cases from a single medical center, the model achieved an accuracy of 82.2 %, a sensitivity of 79.7 %, a specificity of 84.5 %, a Brier score of 0.129, and an area under the ROC curve (AUC) of 0.905, outperforming a CRP-based decision rule. Notably, the machine learning model enhanced accuracy within the CRP range of 10-40 mg/L, a range where CRP alone is less informative. These results highlight the advantage of integrating multiple blood parameters in diagnostics. The "Virus vs. Bacteria" model paves the way for advanced diagnostic tools, leveraging machine learning to optimize infection management.

Association between Prescribing and Intoxication Rates for Selected Psychotropic Drugs: A Longitudinal Observational Study.

Psychotropic prescription drugs are commonly involved in intoxication events. The study's aim was to determine a comparative risk for intoxication in relation to prescribing rates for individual drugs. This was a nationwide observational study in Slovenian adults between 2015 and 2021. Intoxication events with psychotropic drugs were collected from the National Register of intoxications. Dispensing data, expressed in defined daily doses, were provided by the Health Insurance Institute of Slovenia. Intoxication/prescribing ratio values were calculated. The correlation between trends in prescribing and intoxication rates was assessed using the Pearson correlation coefficient. In total, 2640 intoxication cases with psychotropic prescription drugs were registered. Anxiolytics and antipsychotics were the predominant groups. Midazolam, chlormethiazole, clonazepam, sulpiride, and quetiapine demonstrated the highest risk of intoxication, while all antidepressants had a risk several times lower. The best trend correlation was found for the prescribing period of 2 years before the intoxication events. An increase of 1,000,000 defined daily doses prescribed resulted in an increase of fifty intoxication events for antipsychotics, twenty events for antiepileptics, and five events for antidepressants. Intoxication/prescribing ratio calculation allowed for a quantitative comparison of the risk for intoxication in relation to the prescribing rates for psychotropic drugs, providing additional understanding of their toxicoepidemiology.

Viper envenomation in Central and Southeastern Europe: a multicentre study.

INTRODUCTION: Snakebite incidence varies across Europe. However, there is limited research from Central and Southeastern Europe. These regions are notable for the presence of the common European adder (Vipera berus) and the more venomous nose-horned viper (Vipera ammodytes). No standard European antivenom protocol exists. The aim was to assess the epidemiology and treatment of viper bites in this region, focusing on a comparison of bites from Vipera berus and Vipera ammodytes. METHODS: We conducted a prospective multicenter study in Central and Southeastern Europe from 2018 to 2020. This study included poison centres and toxicology-associated hospital wards in Poland, the Czech Republic, Slovakia, Hungary, Slovenia, Croatia, Serbia, and Bulgaria. The following data were collected: age, gender, Vipera species, snakebite site, clinical picture, laboratory results, Audebert's clinical severity grading score, and antivenom therapy. RESULTS: The annual incidence of viper bites in Central and Southeast Europe was estimated at 2.55 bites per million population. Within their respective geographical distribution areas, the incidence of Vipera ammodytes bites (1.61 bites per million population) was higher than Vipera berus bites (1.00 bites per million population). Patients bitten by Vipera ammodytes more frequently reported local pain and developed thrombocytopenia. Antivenom treatment was more commonly administered in Vipera ammodytes bites (72%) compared to Vipera berus bites (39%). The incidence of Vipera ammodytes bites treated with antivenom within its geographical distribution area was three times higher than Vipera berus bites treated with antivenom (1.16 bites per million population versus 0.39 bites per million population). No deaths were reported. CONCLUSIONS: The estimated incidence of viper bites in Central and Southeastern Europe is at least 2.55 per million population. Vipera ammodytes bites are more common and severe, characterized by higher frequencies of pain and thrombocytopenia. Antivenom is needed more often for Vipera ammodytes bites. It is vital that enough European Medicines Agency-approved Vipera ammodytes antivenom is produced and offered affordably.

Adverse drug reactions in the ambulatory internal patients at the emergency department: Focus on causality assessment and drug-drug interactions.

A non-interventional retrospective study in ambulatory patients was conducted at the emergency department of the Division of internal medicine. In 2 months, 266 suspected adverse drug reactions (ADRs) were identified in 224/3453 patients (6.5 %). In 158/3453 patients (4.6 %), an ADR was the reason for emergency department visit and in 49 patients (1.4 %), ADRs led to hospitalisation. A causality assessment algorithm was developed, which included Naranjo algorithm and levels of ADR recognition by the treating physician and the investigators. Using this algorithm, 63/266 ADRs (23.7 %) were classified as "certain", whereas using solely the Naranjo score calculation, only 19/266 ADRs (7.1 %) were assessed as "probable" or "certain", and the rest of ADRs (namely, 247/266 = 92.9 %) were assessed as "possible". There were 116/266 (43.6 %) ADRs related to potential drug-drug interactions (DDIs), stated in at least one of the literature sources used. Based on the causality relationship, the rate of the clinically expressed DDIs was 19.0 %, or 12/63 "certain" ADR cases. Of these, 10 cases presented serious DDI-related ADRs. In summary, ADR causality assessment based exclusively on Naranjo algorithm demonstrated low sensitivity at an ambulatory emergency setting. Additional clinical judgment, including the opinion of the treating physician, proved necessary to avoid under-rating of the causality relationship, and enabled the determination of clinically expressed DDIs.

Cytotoxic Effects of Cannabidiol on Neonatal Rat Cortical Neurons and Astrocytes: Potential Danger to Brain Development.

The influence of cannabidiol (CBD) on brain development is inadequately understood. Since CBD is considered a non-intoxicating drug, it has attracted great interest concerning its potential medical applicability, including in pregnant women and children. Here, we elucidated the response of perinatal rat cortical neurons and astrocytes to CBD at submicromolar (0.1, 0.5, 1, 5 µM) concentrations attainable in humans. The effect of CBD was concentration- and time-dependent and cell-specific. In neurons, 0.1 µM CBD induced an early and transient change in mitochondrial membrane potential (ΔΨm), ATP depletion, and caspase-8 activation, followed by rapid ATP recovery and progressive activation of caspase-9 and caspase-3/7, resulting in early apoptotic cell death with reduction and shortening of dendrites, cell shrinkage, and chromatin condensation. The decrease in neuronal viability, ATP depletion, and caspase activation due to CBD exposure was prevented by transient receptor potential vanilloid 1 (TRPV1) antagonist. In astrocytes, 0.5 µM CBD caused an immediate short-term dysregulation of ΔΨm, followed by ATP depletion with transient activation of caspase-8 and progressive activation of caspase-9 and caspase-3/7, leading to early apoptosis and subsequent necroptosis. In astrocytes, both TRPV1 and cannabinoid receptor 1 (CB1) antagonists protected viability and prevented apoptosis. Given that CBD is a non-intoxicating drug, our results clearly show that this is not the case during critical periods of brain development when it can significantly interfere with the endogenous cannabinoid system.

COVID-19 diagnosis by routine blood tests using machine learning.

Physicians taking care of patients with COVID-19 have described different changes in routine blood parameters. However, these changes hinder them from performing COVID-19 diagnoses. We constructed a machine learning model for COVID-19 diagnosis that was based and cross-validated on the routine blood tests of 5333 patients with various bacterial and viral infections, and 160 COVID-19-positive patients. We selected the operational ROC point at a sensitivity of 81.9% and a specificity of 97.9%. The cross-validated AUC was 0.97. The five most useful routine blood parameters for COVID-19 diagnosis according to the feature importance scoring of the XGBoost algorithm were: MCHC, eosinophil count, albumin, INR, and prothrombin activity percentage. t-SNE visualization showed that the blood parameters of the patients with a severe COVID-19 course are more like the parameters of a bacterial than a viral infection. The reported diagnostic accuracy is at least comparable and probably complementary to RT-PCR and chest CT studies. Patients with fever, cough, myalgia, and other symptoms can now have initial routine blood tests assessed by our diagnostic tool. All patients with a positive COVID-19 prediction would then undergo standard RT-PCR studies to confirm the diagnosis. We believe that our results represent a significant contribution to improvements in COVID-19 diagnosis.

Intravenous Vipera berus Venom-Specific Fab Fragments and Intramuscular Vipera ammodytes Venom-Specific F(ab')2 Fragments in Vipera ammodytes-Envenomed Patients.

Vipera ammodytes (V. ammodytes) is the most venomous European viper. The aim of this study was to compare the clinical efficacy and pharmacokinetic values of intravenous Vipera berus venom-specific (paraspecific) Fab fragments (ViperaTAb) and intramuscular V. ammodytes venom-specific F(ab')2 fragments (European viper venom antiserum, also called "Zagreb" antivenom) in V.ammodytes-envenomed patients. This was a prospective study of V.ammodytes-envenomed patients that were treated intravenously with ViperaTAb or intramuscularly with European viper venom antiserum that was feasible only due to the unique situation of an antivenom shortage. The highest venom concentration, survival, length of hospital stay and adverse reactions did not differ between the groups. Patients treated with intravenous Fab fragments were sicker, with significantly more rhabdomyolysis and neurotoxicity. The kinetics of Fab fragments after one or more intravenous applications matched better with the venom concentration in the early phase of envenomation compared to F(ab')2 fragments that were given intramuscularly only on admission. F(ab')2 fragments given intramuscularly had 25-fold longer apparent total body clearance and 14-fold longer elimination half-time compared to Fab fragments given intravenously (2 weeks vs. 24 h, respectively). In V.ammodytes-envenomed patients, the intramuscular use of specific F(ab')2 fragments resulted in a slow rise of antivenom serum concentration that demanded their early administration but without the need for additional doses for complete resolution of all clinical signs of envenomation. Intravenous use of paraspecific Fab fragments resulted in the immediate rise of antivenom serum concentration that enabled their use according to the clinical progress, but multiple doses might be needed for efficient therapy of thrombocytopenia due to venom recurrence, while the progression of rhabdomyolysis and neurotoxic effects of the venom could not be prevented.

Comparison of Preclinical Properties of Several Available Antivenoms in the Search for Effective Treatment of Vipera ammodytes and Vipera berus Envenoming.

Snakebites are a relatively rare medical emergency in Europe. In more than half of the annual cases caused by Vipera ammodytes, Vipera berus, and Vipera aspis, immunotherapy with animal-derived antivenom is indicated. Among eight products recently identified as available against European medically relevant species, only Zagreb antivenom, Viperfav, and ViperaTAb have been used almost exclusively for decades. Zagreb antivenom comprises V. ammodytes-specific F(ab')2 fragments. Viperfav is a polyspecific preparation based on F(ab')2 fragments against V. aspis, V. berus, and V. ammodytes venoms. ViperaTAb contains Fab fragments against the venom of V. berus. In 2014 the production of Zagreb antivenom was discontinued. Additionally, in the period of 2017 to 2018 a shortage of Viperfav occurred. Due to a lack of the product indicated for the treatment of V. ammodytes bites, other antivenoms were implemented into clinical practice without comparative assessment of their eligibility. The aim of our work was to identify a high-quality antivenom that might ensure the successful treatment of V. ammodytes and V. berus bites at the preclinical level. Differentiation between bites from these two species is difficult and unreliable in clinical practice, so the availability of a unique antivenom applicable in the treatment of envenoming caused by both species would be the most advantageous for Southeastern Europe. Zagreb antivenom, Viperfav, and ViperaTAb, as well as Viper venom antitoxin for V. berus envenoming and the in-development Inoserp Europe, which was designed to treat envenoming caused by all medically important European snakes, were comparatively tested for the first time. Emphasis was placed on their physicochemical properties, primarily purity and aggregate content, as well as their in vivo protective efficacies. As Zagreb antivenom is no longer available on the European market, Viperfav is the highest-quality product currently available and the only antivenom whose neutralisation potency against V. ammodytes and V. berus venoms was above regulatory requirements.

Accidental poisoning with autumn crocus (Colchicum autumnale): a case series.

INTRODUCTION: Colchicum autumnale (autumn crocus) is a plant that contains highly toxic alkaloid colchicine. The aim was to evaluate accidental C autumnale poisoning and assess serum troponin as a prognostic parameter. METHODS: In this study, we retrospectively included all adult patients with a history of accidental C autumnale ingestion and serum colchicine confirmation during the study period from 2000 to 2019. The medical files of enrolled patients were reviewed. Literature search of accidental ingestions of C autumnale was done. RESULTS: Over the study period of 20 years, 16 adult patients were admitted to the University Medical Centre Ljubljana due to acute colchicine poisoning after ingestion of C autumnale. They all mistakenly ingested C autumnale's leaves instead of Allium ursinum in the spring and had confirmed colchicine in serum by GC-MS or LC-MS/MS (15.5 µg/L (0.5-80 µg/L)). They developed vomiting and diarrhoea within 1-9 h after the meal. Vomiting within 2 h was associated with lethality (p=.04). Bone marrow suppression developed in 15 patients (94%). Acute myocardial injury with positive troponin I (>0.10 µg/L) developed in five patients; lethal cardiogenic shock with decreased cardiac output and hypotension occurred in four of these patients despite supportive therapy. Positive troponin I ultra (>0.10 µg/L) was associated with need for intensive support therapy (p=.01), decreased cardiac output (p=.01) and death (p=.01). The mortality was 4/16 (25%). On review, we found 58 cases; 95% cases accidently ingested leaves of C autumnale instead of A ursinum. Troponin I was reported in 3% cases. The lethality of this and reviewed cases was 35% (26/74). CONCLUSIONS: In unexplained gastroenterocolitis after ingestion of wild plants as a salad or spice in the spring, especially when wild garlic is mentioned, we should always consider C autumnale poisoning. Cardiogenic shock can be predicted by a positive serum troponin I measurement.

Occupational inhalation poisoning with the veterinary antibiotic tiamulin.

Introduction: Tiamulin is a semisynthetic pleuromutilin diterpene veterinary antibiotic, widely used in farms. We present a case of prolonged QT-interval and ventricular tachyarrhythmia after tiamulin inhalation.Case presentation: A 43-year-old veterinarian without previous medical history was dividing granulated powder of antibiotic gravimetrically without wearing personal protective equipment. Half an hour after exposure, nausea occurred; four hours later he started to vomit and soon after that he experienced syncope. He was unconscious three minutes; afterwards he became somnolent, dizzy and nauseated with sweating and salivation. On admission to hospital five hours after exposure, he was conscious and had heart rate 70 beats/min and blood pressure 140/80 mmHg. Initial laboratory results were normal. Electrocardiography showed a prolonged QTc-interval of 730 ms with numerous polymorphic ventricular extrasystoles and episodes of non-sustained polymorphic ventricular tachycardia that resolved after treatment with lidocaine and magnesium. Subsequent electrocardiography revealed gradual shortening of QTc-interval with QTc-interval normalization (430 ms) between 24 and 32 hours after tiamulin exposure. Laboratory tests, morphologic heart diagnostics and genetic testing excluded other potential causes of QTc-interval prolongation. Subsequent toxicology analysis by LC-MS/MS confirmed tiamulin in his serum samples on admittance (500 ng/mL).Conclusion: Tiamulin inhalation can be associated with prolonged QT-interval and ventricular tachyarrhythmia. QT-interval prolongation could be expected in overdoses of emerging human pleuromutilins.

Magnesium sulfate and calcium channel blocking drugs as antidotes for acute organophosphorus insecticide poisoning - a systematic review and meta-analysis.

INTRODUCTION: Treatment of acute organophosphorus or carbamate insecticide self-poisoning is often ineffective, with tens of thousands of deaths occurring every year. Researchers have recommended the addition of magnesium sulfate or calcium channel blocking drugs to standard care to reduce acetylcholine release at cholinergic synapses. OBJECTIVE: We aimed to review systematically the evidence from preclinical studies in animals exposed to organophosphorus or carbamate insecticides concerning the efficacy of magnesium sulfate and calcium channel blocking drugs as therapy compared with placebo in reducing mortality or clinical features of poisoning. We also systematically reviewed the evidence from clinical studies in patients self-poisoned with organophosphorus or carbamate insecticides concerning the efficacy of magnesium sulfate and calcium channel blocking drugs as therapy compared with placebo, in addition to standard therapy, in reducing mortality, atropine requirement, need for intubation and ventilation, and intensive care unit and hospital stay. METHODS: We performed a systematic review for articles on magnesium sulfate and calcium channel blocking drugs in organophosphorus or carbamate insecticide poisoning using PubMed and China Academic Journals Full-text (Medicine/Hygiene Series) databases and keywords: "organophosphorus or organophosphate poisoning", "cholinesterase inhibitor poisoning" OR "carbamate poisoning" AND "magnesium", "calcium channel blocker", or generic names of different calcium channel blocking drugs. Review of titles and abstracts revealed 2262 papers of potential relevance. After review of the full papers, a total of 19 papers relevant to the question were identified: five preclinical studies, nine case reports or small case series, and five clinical studies and trials. We also obtained primary data from three unpublished clinical trials of magnesium sulfate, providing data from a total of eight clinical studies and trials for analysis. All studies were of organophosphorus insecticides; no studies of carbamates were found. No pre-clinical or clinical studies of calcium channel blocking drugs and magnesium sulfate in combination were found. We extracted data on study type, treatment regimens, outcome, and side effects. Pre-clinical studies: Two rodent studies indicated a benefit of calcium channel blocking drugs treatment on mortality if given before or soon after organophosphorus exposure, in addition to atropine and/or oxime. In poisoned minipigs, treatment with magnesium sulfate after organophosphorus insecticide poisoning reduced cholinergic stimulation and hypertension. Of note, magnesium sulfate further suppressed serum butyrylcholinesterase activity in one rat study. Observational clinical studies: Calcium channel blocking drugs and magnesium sulfate have been used to treat cardiac dysrhythmias and hypertonic uterine contractions in organophosphorus poisoned patients. A small neurophysiological study of magnesium sulfate reported reversion of neuromuscular junction effects of organophosphorus insecticide exposure. Comparative clinical studies: Only four of eight studies were randomized controlled trials; all studies were of magnesium sulfate, of small to modest size, and at substantial risk of bias. They included 441 patients, with 239 patients receiving magnesium sulfate and 202 control patients. The pooled odds ratios for magnesium sulfate for mortality and need for intubation and ventilation for all eight studies were 0.55 (95% confidence interval [CI] 0.32-0.94) and 0.52 (95% CI 0.34-0.79), respectively. However, there was heterogeneity in the results of higher quality phase III randomized controlled trials providing more conservative estimates. Although a small dose-escalation study suggested benefit from higher doses of magnesium sulfate, there was no evidence of a dose effect across the studies. Adverse effects were reported rarely, with 11.1% of patients in the randomized controlled trials receiving the highest dose of magnesium sulfate requiring their infusion to be stopped due to hypotension. CONCLUSIONS: Both preclinical and clinical data suggest that magnesium sulfate and calcium channel blocking drugs might be promising adjunct treatments for acute organophosphorus insecticide poisoning. However, evidence is currently insufficient to recommend their use. Mechanistic and large multi-center randomized controlled trials testing calcium channel blocking drugs and magnesium sulfate are required to provide the necessary evidence, with careful identification of the insecticides ingested and measurement of surrogate markers of toxicity, including butyrylcholinesterase activity.

An application of machine learning to haematological diagnosis.

Quick and accurate medical diagnoses are crucial for the successful treatment of diseases. Using machine learning algorithms and based on laboratory blood test results, we have built two models to predict a haematologic disease. One predictive model used all the available blood test parameters and the other used only a reduced set that is usually measured upon patient admittance. Both models produced good results, obtaining prediction accuracies of 0.88 and 0.86 when considering the list of five most likely diseases and 0.59 and 0.57 when considering only the most likely disease. The models did not differ significantly, which indicates that a reduced set of parameters can represent a relevant "fingerprint" of a disease. This knowledge expands the model's utility for use by general practitioners and indicates that blood test results contain more information than physicians generally recognize. A clinical test showed that the accuracy of our predictive models was on par with that of haematology specialists. Our study is the first to show that a machine learning predictive model based on blood tests alone can be successfully applied to predict haematologic diseases. This result and could open up unprecedented possibilities for medical diagnosis.

Yellow sac spider (Cheiracanthium punctorium) bites in Slovenia: case series and review.

In Central Europe, reports of human envenomation by Cheiracanthium punctorium, commonly known as the yellow sac spider, are sporadic, despite the fact that this species is widespread in Europe. However, in recent years, C. punctorium has been repeatedly described globally in medical and toxicological literature. Its venom was found to possess insecticidal, haemolytic, cytotoxic, and membrane-damaging activities. Its bite is often very painful, frequently associated with local and transient cutaneous and neurotoxic effects, but sometimes also with systemic symptoms which require medical help. The main objective of this article is to introduce more details about C. punctorium, the clinical manifestations and circumstances of its bite, the characteristics of its venom and proposed clinical management. The authors provide case reports of patients bitten by C. punctorium during the 10-year observational period. All patients presented in this article showed generally mild clinical manifestations and recovered completely without sequelae. No further treatment in terms of hospital surveillance or specific clinical measures was necessary in any of the reported cases.

Comparative analysis of three drug-drug interaction screening systems against probable clinically relevant drug-drug interactions: a prospective cohort study.

PURPOSE: Drug-drug interaction (DDI) screening systems report potential DDIs. This study aimed to find the prevalence of probable DDI-related adverse drug reactions (ADRs) and compare the clinical usefulness of different DDI screening systems to prevent or warn against these ADRs. METHODS: A prospective cohort study was conducted in patients urgently admitted to medical departments. Potential DDIs were checked using Complete Drug Interaction®, Lexicomp® Online™, and Drug Interaction Checker®. The study team identified the patients with probable clinically relevant DDI-related ADRs on admission, the causality of which was assessed using the Drug Interaction Probability Scale (DIPS). Sensitivity, specificity, and positive and negative predictive values of screening systems to prevent or warn against probable DDI-related ADRs were evaluated. RESULTS: Overall, 50 probable clinically relevant DDI-related ADRs were found in 37 out of 795 included patients taking at least two drugs, most common of them were bleeding, hyperkalemia, digitalis toxicity, and hypotension. Complete Drug Interaction showed the best sensitivity (0.76) for actual DDI-related ADRs, followed by Lexicomp Online (0.50), and Drug Interaction Checker (0.40). Complete Drug Interaction and Drug Interaction Checker had positive predictive values of 0.07; Lexicomp Online had 0.04. We found no difference in specificity and negative predictive values among these systems. CONCLUSION: DDI screening systems differ significantly in their ability to detect probable clinically relevant DDI-related ADRs in terms of sensitivity and positive predictive value.

Antivenom for European Vipera species envenoming.

BACKGROUND: European viper bite is relatively uncommon but can cause serious envenoming, particularly swelling and hemorrhage spreading from limb to trunk that can cause long term disability. Systemic features are relatively mild compared to many other venomous species. Moderate-to-severe envenoming requires antivenom, which is given many hundreds of times each year across the continent. Several Vipera spp antivenoms are produced in Europe, but there is little comparative information available for the antivenoms and none is licensed with the European Medicines Agency. We aimed to collect descriptive data on European viper antivenoms and assess their relative effectiveness. METHODS: A systematic review of articles relating to antivenom in Europe was performed using the Medline medical database. The following keywords "Europ*" or the individual names of each European country and "antiven*" or "immun*" or "envenom*" and "snake" or "viper*" or "adder" were used. Articles published between 1 January 1996 and 11 March 2016 pertaining to clinical outcome, including case reports, were selected. Referenced articles in the indexed articles were explored for suitability and included if they met any of the criteria: specific antivenom used, route of antivenom administration, adverse reactions to antivenom therapy and length of hospital admission. All accepted abstracts from EAPCCT conferences since 2000 were searched and abstracts relating to Vipera spp envenoming were assessed for suitability. We extracted data on study type, safety and effectiveness. We sought information on antivenoms from manufacturers and individual patient data from authors of publications. Since individual patient data were only rarely available, we compared median length of stay between case series reporting each antivenom. We identified 40 papers and six published abstracts, and one unpublished paper that reported clinical cases and case series of envenomed patients treated with antivenom. No publication reported randomized controlled trials comparing any European Vipera antivenom with either placebo or another antivenom. 25 reports were of retrospective hospital- (n = 13) or poison center-based (n = 12) case series including five or more patients; a further 12 reports were either case reports or case series with less than five patients and one paper was a limited literature review. An additional nine papers reported prospective data; seven collected data remotely through poison service telephone communication with the attending physicians. Antivenoms available in Europe: Eight antivenoms are available for European Vipera spp envenoming; a material safety data sheet providing information on manufacture was available for seven. Six are raised against V. berus or V. ammodytes venom; the seventh is raised against a mixture of V. ammodytes, V. aspis and V. berus venom and the eighth is raised against V. ammodytes, Macrovipera lebetina and Montivipera xanthina venom. Six manufacturers recommended intramuscular administration while two recommended intravenous administration. No randomized control trials comparing the effectiveness of antivenoms were identified. Pre-clinical data: We found two papers presenting comparative preclinical data. Clinical data: Clinical studies were predominantly retrospective and contained clinical data on antivenom used in 2602 patients; where the antivenom was identified (n = 2174), 2061 (94.8%) received Zagreb, ViperFAV or ViperaTAb antivenoms. There were few published data on the other antivenoms. Repeated use of antivenom: Repeat doses were reported in 230/1491 of cases (15.4%) where this information was recorded. Outcome and length of hospital stay: Intravenous administration of antivenom was associated with shorter length of hospital stay (median length of hospital stay in studies of intravenous ViperFAV or ViperaTAb ranged from 1 to 4.8 days versus 2 to 18 days for intramuscular Bulbio or Zagreb antivenoms). Antivenom versus no antivenom: Some small studies demonstrated no difference in the length of hospital stay in patients with equivalent envenomation grading who either did or did not receive antivenom. Adverse events: Adverse reactions were reported in 37 of 2408 cases (1.5%) including seven cases of anaphylaxis. CONCLUSIONS: There are very limited pre-clinical comparative data and no randomised controlled trials assessing effectiveness of the antivenoms against different Vipera species. Most descriptive data suggest the efficacy of Zagreb, ViperFAV and ViperaTAb antivenoms by the intravenous route but not intramuscular route, although this is level D evidence. Reported adverse reactions were rare, suggesting that the modern intravenous antivenoms are of good quality. Better and more systematic data, including perhaps randomized controlled trials comparing different antivenoms, are required for the many hundreds of antivenom administrations that occur annually across Europe.

Occupational transdermal poisoning with synthetic cannabinoid cumyl-PINACA.

CONTEXT: Synthetic cannabinoids are getting more popular among young people and illicit manufacturers. We report a case series of occupational transdermal poisoning with synthetic cannabinoids. CASE DETAILS: Three customs inspectors got in contact with a sticky substance with their fingertips because they were not wearing protection gloves and the delivered package was damaged. Despite washing their hands with water, signs of synthetic cannabinoids intoxication started occurring half an hour after exposure. On arrival at the Emergency Department six hours later, they were somnolent, lethargic and confused. They showed signs of mydriasis, blurred vision, ataxia, weakness, numbness, tachycardia and one of them had orthostatic hypotension. Two days later, they were feeling much better and reported amnesia and slowed perception of time after exposure. Toxicology analysis by LC-MS/MS revealed synthetic cannabinoid cumyl-PINACA (SGT-24) in their blood samples taken on admission. cumyl-PINACA was also confirmed with NMR method in liquid samples seized at the airport. It was 98% pure substance with the purpose of being diluted and sold further in the drug market by drug dealer. DISCUSSION: This case series highlights the possible transdermal exposure to synthetic cannabinoids oil resulting in prolonged cannabinoid syndrome.

Vipera ammodytes bites treated with antivenom ViperaTAb: a case series with pharmacokinetic evaluation.

CONTEXT: In clinical practice it is difficult to differentiate between V. berus and V. ammodytes venomous bites. In the past this was not a concern, but due to the current shortage in Viperfav™ and European viper venom antiserum availability, V. a. ammodytes venomous bites have recently been treated with ViperaTAb®, which is a pharmaceutical formulation containing a monospecific ovine Fab fragments against the venom of V. berus. OBJECTIVE: To evaluate ViperaTAb® in V. a. ammodytes envenomations. MATERIALS AND METHODS: This is a prospective case series of three consecutive patients envenomed by V. a. ammodytes snakebite treated with ViperaTAb®. V. ammodytes venom, neurotoxic ammodytoxins, and Fab fragment levels were determined in serum samples and a pharmacokinetic analysis of the antivenom Fab fragments was carried out. RESULTS: Three patients bitten by V. a. ammodytes with extensive local swelling, neurological symptoms and recurrent thrombocytopenia were treated with ViperaTAb®. V. ammodytes venom was detected in serum of all three patients. Ammodytoxins were detected in the serum of only the most severely envenomed patient who developed neurological symptoms. In the presented moderate cases, a dose of 8 mL of ViperaTAb® reduced swelling and improved systemic effects, such as thrombocytopenia. However, this dose of ViperaTAb® was not effective in the most severely envenomed patient with the highest serum values of V. ammodytes venom. In this case ViperaTAb® did not stop local swelling and it had no effect on neurological signs. ViperaTAb®'s systemic clearance, distribution and elimination half-lives were 4.3-13.4 mL/h/kg, 1.2-3.2 h and 14.1-55.4 h, respectively. CONCLUSIONS: In patients envenomed by V. a. ammodytes venom, ViperaTAb® reduces moderate swelling and temporarily improves systemic effects, except neurological symptoms. ViperaTAb® application induces a decrement of V. ammodytes venom level in the blood, but did not affect serum concentration of neurotoxic ammodytoxins in the one patient with measurable concentrations.