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Dan M Wood,1,&ast; Brad Beauvais,2,&ast; Rodney X Sturdivant,3,&ast; Forest S Kim4,&ast; 1Graduate Program in Health and Business Administration, Army-Baylor University, San Antonio, TX, USA; 2School of Health Administration, Texas State University, San Marcos, TX, USA; 3Department of Statistical Science, Baylor University, Waco, TX, USA; 4Department of Economics, Baylor University, Waco, TX, USA&ast;These authors contributed equally to this workCorrespondence: Dan M Wood, Army-Baylor University MHA/MBA Program, 3630 Stanley Road, San Antonio, TX, 78234, USA, Email dan_wood@baylor.eduPurpose: This study explores the effects of CMS reimbursement financial penalties from the Hospital-Acquired Condition Reduction Program (HACRP) on hospital-acquired infections (HAI) in hospitals across the United States.Methods: Hospital-level data for 2896 hospitals in the United States were evaluated using multiple linear regression models with random effects analysis through a difference-in-differences study design to examine HAIs under the HACRP between hospitals that were financially penalized or not from calendar years 2013 to 2020.Results: This study showed significant differences from the pre-program Total HAC scores to the most recent reviewed year, validating the efficacy of the HACRP, and showing a reduction of overall HAIs over the years evaluated in the study. The multiple linear regression model with random effects analysis produced a significant (p < 0.001) interaction term between hospitals expected to be penalized in 2013 and each year evaluated in the study (− 0.412 estimate) confirming decreases in HAI scores, and overall decreases in HAIs across the years of the study. Notably, 98% of hospitals in the worst-performing, expected to be financially penalized quartile from 2013, were found to have decreased their HAIs in their facilities, while only 38.8% of hospital in the performing, non-penalized quartiles showed decreases in HAIs across their facilities, by 2020.Conclusion: Our research indicates that implementing financial disincentives through reimbursement reductions could potentially decrease the incidence of HAIs. Our study further suggests that incorporating financial penalties and incentives for HAIs annually across all hospitals may lead to significant reductions in HAIs throughout the US healthcare system.Keywords: HACRP, medicare, reimbursements, CMS PSI-90 scores

Sarbjeet S Kalsi1,2, Paul I Dargan2–4, W Stephen Waring5, David M Wood2–41Emergency Department, Guy’s and St Thomas’ NHS Foundation Trust, London, UK; 2Clinical Toxicology, Guy’s and St Thomas’ NHS Foundation Trust, London, UK; 3King’s Health Partners, London, UK; 4King’s College London, London, UK; 5York Teaching Hospital NHS Foundation Trust, York, UKAbstract: Paracetamol (acetaminophen) poisoning is common throughout the world. The management of nonstaggered (acute) paracetamol overdose is based on the plasma paracetamol concentration plotted on a treatment nomogram. In the UK there are two treatment lines on this nomogram, with the lower treatment line used for individuals felt to be at ‘high risk’ of paracetamol-related hepatotoxicity either as a result of induction of cytochrome P450 isoenzymes or reduction of intrahepatic glutathione. In this article we review the risk factors that, in current guidelines, are felt to increase risk due to a reduction in intrahepatic glutathione concentrations. Based on our review of the published literature, we feel that cystic fibrosis, acute viral illness, malnutrition, and eating disorders such as anorexia nervosa are likely to be associated with reduction in intrahepatic glutathione concentrations, and that this risk is likely to be related to malnutrition secondary to the disease. Chronic hepatitis C infection is also associated with reduced glutathione concentrations, although this appears to be independent of any associated malnutrition. Ageing and acute fasting are not associated with an increased risk of paracetamol-related hepatotoxicity due to reductions in glutathione concentrations. Finally, the evidence for HIV infection is inconclusive, particularly as the majority of studies were conducted in the pre-anti-viral treatment (HAART) era; however it is likely that patients with symptomatic HIV/AIDS have reduced glutathione concentrations due to associated malnutrition. Although there have been few studies which have specifically investigated whether there is an association between reduced intrahepatic glutathione concentrations and increased risk of paracetamol-related hepatotoxicity, in our opinion, it is likely that the above conditions that are associated with reduced glutathione concentrations, will be associated with an increased risk of paracetamol-related hepatotoxicity.Keywords: glutathione, GSH, paracetamol, acetaminophen, hepatotoxicity, NAPQI

Sarbjeet S Kalsi1,2, David M Wood2–4, W Stephen Waring5, Paul I Dargan2–4 1Emergency Department, 2Clinical Toxicology, Guy's and St Thomas' NHS Foundation Trust, London; 3King's Health Partners, 4King's College London, London; 5York Teaching Hospital NHS Foundation Trust, York, UK Abstract: Paracetamol (acetaminophen, N-acetyl-p-aminophenol, 4-hydroxyacetanilide) is the most common cause of acute liver failure in developed countries. There are a number of factors which potentially impact on the risk of an individual developing hepatotoxicity following an acute paracetamol overdose. These include the dose of paracetamol ingested, time to presentation, decreased liver glutathione, and induction of cytochrome P450 (CYP) isoenzymes responsible for the metabolism of paracetamol to its toxic metabolite N-acetyl-p-benzoquinoneimine (NAPQI). In this paper, we review the currently published literature to determine whether induction of relevant CYP isoenzymes is a risk factor for hepatotoxicity in patients with acute paracetamol overdose. Animal and human in vitro studies have shown that the CYP isoenzyme responsible for the majority of human biotransformation of paracetamol to NAPQI is CYP2E1 at both therapeutic and toxic doses of paracetamol. Current UK treatment guidelines suggest that patients who use a number of drugs therapeutically should be treated as “high-risk” after paracetamol overdose. However, based on our review of the available literature, it appears that the only drugs for which there is evidence of the potential for an increased risk of hepatotoxicity associated with paracetamol overdose are phenobarbital, primidone, isoniazid, and perhaps St John's wort. There is no evidence that other drugs often quoted as increasing risk, such as carbamazepine, phenytoin, primidone, rifampicin, rifabutin, efavirenz, or nevirapine, should be considered risk factors for hepatotoxicity in patients presenting with acute paracetamol overdose. Keywords: paracetamol, overdose, hepatotoxicity, isoenzymes

Laura J Hunter, David M Wood, Paul I DarganClinical Toxicology, Guy’s and St Thomas’ NHS Foundation Trust, London, UKAbstract: The nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used for their analgesic, anti-inflammatory and antipyretic actions. They are commonly taken in overdose in many areas of the world. The majority of patients with acute NSAID overdose will remain asymptomatic or develop minor self-limiting gastrointestinal symptoms. However, serious clinical sequelae have been reported in patients with acute NSAID overdose and these include convulsions, metabolic acidosis, coma and acute renal failure. There appear to be some differences between the NSAIDs in terms of the relative risk of these complications; in particular mefenamic acid is most commonly associated with convulsions. The management of these serious clinical features is largely supportive and there are no specific antidotes for acute NSAID toxicity.Keywords: nonsteroidal anti-inflammatory drugs (NSAID), ibuprofen, toxicity, poisoning, overdose, management

Acetaminophen (paracetamol-APAP) is the most common cause of drug-induced liver injury in the Western world. Reactive metabolite production by cytochrome P450 enzymes (CYP-metabolites) causes hepatotoxicity. We explored the toxicokinetics of human circulating APAP metabolites following overdose. Plasma from patients treated with acetylcysteine (NAC) for a single APAP overdose was analyzed from discovery ( n = 116) and validation ( n = 150) patient cohorts. In the discovery cohort, patients who developed acute liver injury (ALI) had higher CYP-metabolites than those without ALI. Receiver operator curve (ROC) analysis demonstrated that at hospital presentation CYP-metabolites were more sensitive/specific for ALI than alanine aminotransferase (ALT) activity and APAP concentration (optimal CYP-metabolite receiver operating characteristic area under the curve (ROC-AUC): 0.91 (95% confidence interval (CI) 0.83-0.98); ALT ROC-AUC: 0.67 (0.50-0.84); APAP ROC-AUC: 0.50 (0.33-0.67)). This enhanced sensitivity/specificity was replicated in the validation cohort. Circulating CYP-metabolites stratify patients by risk of liver injury prior to starting NAC. With development, APAP metabolites have potential utility in stratified trials and for refinement of clinical decision-making. [ABSTRACT FROM AUTHOR]

AIMS: To test, by completion of a simple questionnaire, patient knowledge of whether 15 commonly used over-the-counter and prescription analgesics and cough/cold remedies contained paracetamol and patient knowledge of the 4g maximum daily dose of paracetamol. METHODS: Patients in the emergency department triage waiting area of a busy London teaching hospital were asked to complete a standardised one-page questionnaire. From a list of 15 commonly used over-the-counter and prescription products, patients were asked which contained paracetamol, responding 'yes', 'no' or 'not sure' for each. They were also asked to state the recommended maximum daily dose of paracetamol. RESULTS: 910 patients were enrolled in the study (mean age 39years, 53% women). The mean±SD score was 6.5±2.5. The maximum score was 14 (n=2) and the minimum score was 0 (n=11). For the recommended maximum daily dose, 93.7% (n=853) of patients gave an answer. Of these, 53.8% answered correctly, 4.7% quoted a supratherapeutic dose and 41.5% a subtherapeutic dose. CONCLUSIONS: Patient knowledge of paracetamol-containing products and of the maximum daily dose is currently insufficient to ensure safe use of the drug. Interventions are required to address these knowledge gaps to prevent unintentional repeated supratherapeutic ingestion of paracetamol. These interventions could include targeted public education and/or appropriate and effective medication labelling. [ABSTRACT FROM AUTHOR]

Background: Recreational drug use in common, particularly in those attending nightclubs. Their knowledge about the potential toxicity of drugs and how to manage this is variable. Methods: We therefore established a multidisciplinary local network of key stakeholders interested in the prevention and management of recreational drug toxicity. Through this network we designed a unique outreach educational concept, 'Drug Idle', for recreational drug users and their friends. This was run within nightclub environments in a user-friendly, non-judgemental forum. We describe here the development of this educational concept and how it was evaluated and adapted on the basis of feedback from attendees. Results: 149 attended the three Drug Idle events as part of this study. All of those trialling the finalized concept thought all three components of the concept were useful, 96.0% that it was of appropriate duration and 98.8% that they would recommend future events to a friend. Conclusions: We believe that wider use of this outreach educational concept will help to improve the knowledge of those using recreational drugs, especially concerning management of drug toxicity. Additionally, it will provide them with information that will enable them to make informed decisions about the risk of continuing use of recreational drugs. [ABSTRACT FROM AUTHOR]

Pathophysiological stress from acute illness causes metabolic disturbance, including altered hepatic glucose metabolism, increased peripheral insulin resistance and hyperglycaemia. Acute hyperglycaemia is associated with increased morbidity and mortality in patients in intensive care units and patients with acute respiratory disease. The present review will consider mechanisms underlying this association. In normal lungs the glucose concentration of airway secretions is approximately 10-fold lower than that of plasma. Low airway glucose concentrations are maintained against a concentration gradient by active glucose transport. Airway glucose concentrations become elevated if normal homeostasis is disrupted by a rise in blood glucose concentrations or inflammation of the airway epithelium. Elevated airway glucose concentrations are associated with and precede increased isolation of respiratory pathogens, particularly methicillin-resistant Staphylococcus aureus, from bronchial aspirates of patients intubated on intensive care. Markers of elevated airway glucose are associated with similar patterns of respiratory infection in patients admitted with acute exacerbations of chronic obstructive pulmonary disease. Glucose at airway concentrations stimulates the growth of respiratory pathogens, over and above the effect of other nutrients. Elevated airway glucose concentrations may also worsen respiratory disease by promoting local inflammation. Hyperglycaemia may thus promote pulmonary infection, at least in part, by an effect on airway glucose concentrations. Therapeutic options, including systemic control of blood glucose and local manipulation of airway glucose homeostasis, will be considered. [ABSTRACT FROM AUTHOR]

There is increasing evidence for the use of Intralipid in the management of acute local anaesthetic toxicity. This is supported by the recent Association of Anaesthetists of Great Britain and Ireland (AAGBI) guidelines for the management of local anaesthetic toxicity. Acute hospitals in England and Wales were surveyed to determine the proportion that currently stocked Intralipid, the locations of stocks within the hospital, guidelines related to its use and previous use in the last 12 months. The majority of hospitals surveyed stocked Intralipid in multiple locations, although not in all areas using high volumes of local anaesthetics. Guidelines were typically in place, although these were often local rather than those from the AAGBI. Use in the last 12 months was uncommon, but typically information was not available on indications for its use. More systematic data collection is required on the safety and efficacy of Intralipid in the management of acute drug toxicity. [ABSTRACT FROM AUTHOR]

BACKGROUND: Patient-initiated alternative treatments in the management of chronic conditions are common and increasing in the United Kingdom. To date, there have been no reports of herbal medicine use alone in the management of diabetes mellitus. We report here the case of a man who attained excellent glycaemic control using a 'herbal' medicine and reveal how important it was to identify the products of active constituents. CASE REPORT: A 48-year-old man attending our clinic in Tooting, South London with known Type 2 diabetes, with evidence of both micro- and macro-vascular diabetes-related complications, was poorly controlled despite a drug regimen consisting of oral metformin and twice daily insulin. He went to India for at least 1 year and on returning to the clinic had excellent glycaemic control off all diabetic medication. While away he had started himself on a regimen of three different 'herbal' balls. Samples of blood were found to contain chlorpropamide in a therapeutic concentration; chlorpropamide was also found in one of the balls. He has been counselled on the potential risks associated with chlorpropamide and his treatment reverted to a more conventional treatment regimen. CONCLUSIONS: General practitioners and hospital physicians should be alert to those patients returning from abroad on effective 'herbal' medications that these may in fact contain an active ingredient. [ABSTRACT FROM AUTHOR]

Life time smoking of ready made cigarettes can be readily quantified as 'pack years' smoked, but methods for measuring loose tobacco use are less well established. In this study the frequency of loose tobacco use by 247 hospital in-patients was determined; 64% were current or ex-smokers, 41.3% of whom (25.9% of participants) had smoked loose tobacco. A formula was developed for converting loose tobacco use to pack years smoked, based on the weight of tobacco in ready made cigarettes; 12.5 g or half an ounce of loose tobacco was approximately equivalent to one packet of 20 cigarettes. Using a questionnaire it was found that hospital physicians of all grades were able to convert smoking histories of ready made cigarettes, but not loose tobacco, into number of 'pack years' smoked. [ABSTRACT FROM AUTHOR]

Background: Spice is the iconic brand name of a smokeable herbal mixture containing synthetic cannabinoid receptor agonists. It has been available on the Internet/in head shops in Europe since at least 2006. The synthetic cannabinoid receptor agonist constituents of Spice were classified in the UK as Class B agents in December 2009. This study assessed the impact of this legislation on the synthetic cannabinoid receptor agonists present in Spice products and whether new synthetic cannabinoid receptor agonists outside of the legislation are now available. Methods: Spice products were bought, prior to and after the change in the UK legislation, from a range of Internet legal high websites selling to UK consumers. Products were analysed using liquid chromatography high-resolution tandem mass spectrometry (LCMSMS). Identification of the synthetic cannabinoid receptor agonist(s) detected was made by comparison to existing databases or by 'in silico' methods. Results: Sixteen products were purchased prior to the UK control of synthetic cannabinoid receptor agonists; all contained at least one synthetic cannabinoid receptor agonist. 20 products were purchased after the UK control; no active compounds were detected in 3 (15%). The remaining 17 (85%) all contained at least one classified synthetic cannabinoid receptor agonist. Additionally, 2 synthetic cannabinoid receptor agonists not covered under current UK generic legislation (AM-694 and the 'novel Belarus compound') were detected. Conclusion: Despite the UK 'Spice' classification, classified synthetic cannabinoid receptor agonists continue to be supplied over the Internet to UK users. Furthermore, new synthetic cannabinoid receptor agonists not covered by the legislation are appearing. Consideration needs to be given to reviewing the UK legislation so that suppliers cannot circumvent it by supplying legal alternatives to the classified synthetic cannabinoid receptor agonists. [ABSTRACT FROM AUTHOR]

Introduction: Clinicians managing patients with acute recreational drug or new psychoactive substance toxicity typically depend on self-reported drug(s) used. This study compares patient self-report (and/or from other sources) to the substance(s) that were subsequently identified in serum., Methods: A prospective sample of 1,000 adults presenting to a tertiary care, urban emergency department in London, United Kingdom, with acute recreational drug/new psychoactive substance toxicity was collected from 1 February 2019 to 2 February 2020. A total of 939 appropriate samples underwent qualitative analysis by high-resolution mass spectrometry with comparison to a database of drugs/metabolites. Data on the stated drug(s) used were extracted from the routine medical chart/records; results were batched by drug class, when appropriate, and analysis was performed using R software., Results: Seven hundred and ninety-nine (85.1%) patients were male with a median (IQR) age of 34 years (27 to 42 years). Six hundred and thirty-five (67.6%) patients reported using two or more drugs. The median (IQR) positive predictive value of a self-report substance having been taken was 0.68 (IQR: 0.44-0.86); conversely, the median negative predictive value of a substance having not been taken was 0.90 (IQR: 0.53-0.95). There was variability in the accuracy of reporting. For example, self-reported opioid use had a 90.5% likelihood that opioids were detected on analysis, whereas hallucinogens were only detected in 18.8% of samples when use was reported. Individuals were also mostly accurate in not underreporting substances. For example, those not explicitly reporting gamma-hydroxybutyrate use were 97.5% truly negative., Discussion: Overall, most users were relatively accurate in their self-report of what class of drugs they had used, although there was variability in this accuracy. However, other drugs were present even when not reported, for example, opioids with disproportionate detection of prescription and over-the-counter (non-prescription) opioids that were unreported., Conclusions: Self-report (and/or collateral reports) had overall relatively high concordance with the likelihood that a substance was, or was not, recently used. Therefore, clinicians can make initial treatment decisions based on the self-reported drug(s) used in most cases.

In 2015, the United States Food and Drug Administration (FDA) approved uridine triacetate to treat overdose and severe toxicity of the fluoropyrimidine chemotherapy agents 5-fluorouracil (5-FU) and its oral prodrug capecitabine. Uridine triacetate is as an oral prodrug of uridine that competes with cytotoxic fluoropyrimidine metabolites for incorporation into nucleotides. Two million people worldwide start fluoropyrimidine chemotherapy each year, with 20-30% developing severe or life-threatening adverse effects, often attributable to a genetic predisposition such as dihydropyrimidine dehydrogenase deficiency. Whilst genetic prescreening is recommended prior to starting fluoropyrimidine agents, this only prevents 20-30% of early-onset life-threatening toxicity and so does not obviate the need for an antidote. Initial in-human studies established that uridine triacetate more than doubles the maximum tolerated weekly 5-FU bolus dose. A lack of clinical equipoise meant a placebo-controlled phase III trial was not ethical and so the phase III trials used historical controls. These found that uridine triacetate improved survival in those with fluoropyrimidine overdose and severe toxicity from 16% to 94%, with 34% able to resume chemotherapy within 30 days. Five case reports of delayed fluoropyrimidine toxicity demonstrate improvement following uridine triacetate treatment 120-504 h after last fluoropyrimidine administration, suggesting efficacy beyond the FDA licencing indications. Mechanistically uridine triacetate would be expected to be effective for overdose and severe toxicity of tegafur (a 5-FU prodrug), but there are no published case reports describing this. Uridine triacetate is available internationally through an expanded access scheme and has been available in the UK since 2019 on a named patient basis., (© 2024 British Pharmacological Society.)

Introduction: Vortioxetine is an antidepressant with a multimodal mechanism of action. It is used as a treatment option for patients with major depressive episodes. There have only been two previously reported non-fatal overdoses of vortioxetine; neither of these were analytically confirmed There has also been one case of serotonin syndrome potentially related to vortioxetine and two deaths where vortioxetine was detected. We report here a non-fatal analytically confirmed case of vortioxetine overdose., Case Report: A 32-year-old male presented to the emergency department (ED) 12-13 h after oral ingestion of 1,260 mg of vortioxetine and 350 mg of diazepam. A family member reported that he had been drowsy after the overdose, but his level of consciousness and observations (heart rate, blood pressure and temperature) were normal on review by the pre-hospital emergency services and on arrival to the ED. During a period of observation, he did not develop any features of serotonin syndrome or any other significant toxicity. Toxicological analysis of a blood sample taken in the ED detected vortioxetine (plasma concentration 457 ng/mL 10 h after ingestion) and sub-therapeutic concentrations of diazepam and pregabalin., Discussion: Despite having a plasma vortioxetine concentration nearly 15-times therapeutic vortioxetine concentrations, this patient did not develop any significant toxicity. In particular he did not develop any clinical or biochemical features of serotonin toxicity that would be expected with this class of antidepressant. Additional reporting of analytically confirmed vortioxetine overdoses will allow clinicians and licensing authorities to further understand the safety of this medication in overdose., (© 2024. The Author(s).)

Background: There is currently no practice-based, multicenter database of poisoned patients admitted to intensive care units (ICUs). The INTOXICATE study, endorsed by the ESICM and EAPCCT, aimed to determine the rate of eventful admissions among acutely intoxicated adult ICU patients., Methods: Ethical approval was obtained for this multicenter, prospective observational study, and data-sharing agreements were signed with each participating center. An electronic case report form was used to collect data on patient demographics, exposure, clinical characteristics, investigations, treatment, and in-hospital mortality data. The primary outcome, 'eventful admission', was a composite outcome defined as the rate of patients who received any of the following treatments in the first 24 h after the ICU admission: oxygen supplementation with a FiO2 > 40%, mechanical ventilation, vasopressors, renal replacement therapy (RRT), cardiopulmonary resuscitation, antidotes, active cooling, fluid resuscitation (> 1.5 L of intravenous fluid of any kind), sedation, or who died in the hospital., Results: Seventy-eight ICUs, mainly from Europe, but also from Australia and the Eastern Mediterranean, participated. A total of 2,273 patients were enrolled between November 2020 and June 2023. The median age of the patients was 41 years, 72% were exposed to intoxicating drugs. The observed rate of patients with an eventful ICU admission was 68% (n = 1546/2273 patients). The hospital mortality was 4.5% (n = 103/2273)., Conclusions: The vast majority of patients survive, and approximately one third of patients do not receive any ICU-specific interventions after admission in an intensive care unit for acute intoxication. High-quality detailed clinical data have been collected from a large cohort of acutely intoxicated ICU patients, providing information on the pattern of severe acute poisoning requiring intensive care admission and the outcomes of these patients., Trial Registration: OSF registration ID: osf.io/7e5uy., (© 2024. The Author(s).)

Drugs that induce reversible slowing of metabolic and physiological processes would have great value for organ preservation, especially for organs with high susceptibility to hypoxia-reperfusion injury, such as the heart. Using whole-organism screening of metabolism, mobility, and development in Xenopus , we identified an existing drug, SNC80, that rapidly and reversibly slows biochemical and metabolic activities while preserving cell and tissue viability. Although SNC80 was developed as a delta opioid receptor activator, we discovered that its ability to slow metabolism is independent of its opioid modulating activity as a novel SNC80 analog (WB3) with almost 1000 times less delta opioid receptor binding activity is equally active. Metabolic suppression was also achieved using SNC80 in microfluidic human organs-on-chips, as well as in explanted whole porcine hearts and limbs, demonstrating the cross-species relevance of this approach and potential clinical relevance for surgical transplantation. Pharmacological induction of physiological slowing in combination with organ perfusion transport systems may offer a new therapeutic approach for tissue and organ preservation for transplantation, trauma management, and enhancing patient survival in remote and low-resource locations., Competing Interests: MS Inventor on a relevant patentapplication held by Harvard University (PCT/US2021/012626), BC, HF, KP, ZI, TL, AK, SK, ML, SL, RM, SM, JM, MP, AS, KS, KS, DD, TP, JY, JP, DW, ZH, CH, JC, OP, JS, EW, MS No competing interests declared, EG Inventor on a relevant patentapplication held by Harvard University (PCT/US2021/012626). Hold equity in and is employed by Unravel Biosciences, Inc, TT Inventor on a relevant patent807 application held by Harvard University (PCT/US2021/012626), KA, EC, RL, IC, ZM, IJ, RV, LB Employee of Vascular Perfusion Solutions, ML Inventor on a relevant patent application held by Harvard University (PCT/US2021/012626). Hold equity in and is a member of the scientific advisory board of Unravel Biosciences, Inc, RN Inventor on a relevant patent application held by Harvard University (PCT/US2021/012626). Holds equity in, is a member of the board of directors, and is a current employee of Unravel Biosciences, Inc, DI Founder, board member and Scientific Advisory Board chair of, and holds equity in, Emulate Inc Inventors on a relevant patent application held by Harvard University (PCT/US2021/012626). Holds equity and is a member of the board of directors of Unravel Biosciences, Inc Member of the scientific advisory board of Vascular Perfusion Solutions

Introduction: Synthetic cannabinoid receptor agonists (SCRAs) are associated with significant toxicity and are increasingly used in electronic vaping devices. We assessed the availability of SCRA vaping products to UK purchasers on the surface web., Methods: An internet snapshot survey was performed between October 2022 and January 2023 on 'google.com' using the search terms "buy c-liquid vape", "buy herbal incense vape liquid", "buy cannabis vape liquid", "buy hashish vape liquid", "buy K2 vape liquid"., Results: 62 websites selling 128 SCRA vaping brands were identified. Most were purportedly based in the USA (41 websites, 66%) and most sold other controlled substances. Purchase incentives offered included discreet packaging (38, 61%), discounts for bulk purchase (34, 55%) and tracked delivery (30, 48%). Many websites stated SCRA products were: not for human consumption (41, 66%), for research purposes only (15, 24%), or legal (28, 45%). Websites sold a median (IQR) of 16 (7-25) SCRA vaping brands. Almost all were bottles of vaping liquid (1220/1225, 99.6%). The most common bottle size was 5mL (60%), the median (IQR) total volume of SCRA liquid per sale was 50mL (10-200mL). Median (IQR) price was £3.39/mL (£2.01/mL- £5.29/mL). Price decreased with increasing volume purchased (£6.58/mL for ≤ 5mL, £1.60/mL for > 200mL)., Conclusion: SCRA vaping products are easily obtainable online, in both small and bulk quantities. Information provided to purchasers on safety and legality is lacking or misleading. Further studies are needed to confirm the chemistry of these products. Policymakers should consider steps to limit the potential harm caused by the purchase and use of these products., (© 2024. The Author(s).)

Introduction: Intravenous lipid emulsion is used in the rescue treatment of certain poisonings. A complication is interference with laboratory analyses. The aim of this study was to determine the impact of intravenous lipid emulsion on routine laboratory analysis of coagulation parameters ex vivo and determine if any of the analytical techniques remain reliable., Methods: Samples were obtained from 19 healthy volunteers and divided in triplicate. One sample served as a control, and the other two were diluted to simulate the treatment of an average adult with Intralipid ® 20 per cent Fresenius Kabi 100 mL (dilution-1) or 500 mL (dilution-2). Coagulation tests performed were prothrombin time, activated prothrombin time, D-dimer concentration and fibrinogen. Coagulation testing was performed by three techniques. Test-1 was performed on a Sysmex CN6000 analyzer. Test-2 was performed with a manual mechanical endpoint method using the semi-automated Stago KC4 Delta. Test-3 involved high-speed centrifugation before repeat testing on the Sysmex CN6000 analyzer., Results: For test-1, only nine (47 per cent) samples in dilution-1 could be analyzed for coagulation tests, and no coagulation tests could be analyzed for dilution-2 because of lipaemia. For test-2 and test-3, all samples could be analyzed, and all results of both testing methods fell within the limits of the laboratory reference range., Discussion: Difficulties in laboratory analysis of patients having received intravenous lipid emulsion are due to multiple factors. Most automated coagulation analyzers use optical measurements, which can be unreliable in the presence of a high intravenous lipid concentration. By altering the lipaemia in the testing solution using high-speed centrifugation or by using manual mechanical endpoint detection, we were able to obtain reliable results. These findings are limited by the use of an ex vivo method and healthy volunteers., Conclusions: This ex vivo model confirms that Intralipid ® interferes with routine coagulation studies. It is important that clinicians are aware and inform their laboratories of its administration.

The Royal College of Emergency Medicine Toxicology Special Interest Group in collaboration with the UK National Poisons Information Service and the Clinical Toxicology Department at Guy's and St Thomas' NHS Foundation Trust has produced guidance to support clinicians working in the ED with the assessment and management of adults with acute opioid toxicity.Considerations regarding identification of acute opioid toxicity are discussed and recommendations regarding treatment options and secondary prevention are made. There is a focus on making recommendations on the best available evidence., Competing Interests: Competing interests: MB—unpaid member of RCEM Toxicology Advisory Group. RG has no declarations of interest. DMW is a member of the UK Advisory Council on the Misuse of Drugs and an expert advisor to the European Monitoring Centre for Drugs and Drug Addiction and the United Nations Office on Drugs and Crime. He is also a clinical coordinator at the UK National Confidential Enquiry into Patient Outcomes and Death (NCEPOD), and on the editorial board of the Journal of Medical Toxicology. His work on these guidelines was independent of his roles with these organisations. RT—his work on these guidelines was in his role as director of NPIS (Newcastle). CH is an editor for the Emergency Medicine Journal, has received payments from Elsevier for educational articles, has been reimbursed for travel expenses by RCEM and is a recipient of grants from the Centre for Precision Cell Therapy for the Liver. His work on these guidelines was in his role as a member of the RCEM Toxicology Special Interest Group. PID is an adviser to the UK Advisory Council on the Misuse of Drugs, the European Monitoring Centre for Drugs and Drug Addiction the United Nations Office on Drugs and Crime, and the WHO. He is also a commissioner to the UK Commission Human Medicines, on the senior editorial board of Clinical Toxicology, and is the president elect of the European Association of Poisons Control Centres and Clinical Toxicologists. His work on these guidelines was independent of his roles with these organisations., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

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.

This paper aims to explore the possibility of employing large language models (LLMs) - a type of artificial intelligence (AI) - in clinical pharmacology, with a focus on its possible misuse in bioweapon development. Additionally, ethical considerations, legislation and potential risk reduction measures are analysed. The existing literature is reviewed to investigate the potential misuse of AI and LLMs in bioweapon creation. The search includes articles from PubMed, Scopus and Web of Science Core Collection that were identified using a specific protocol. To explore the regulatory landscape, the OECD.ai platform was used. The review highlights the dual-use vulnerability of AI and LLMs, with a focus on bioweapon development. Subsequently, a case study is used to illustrate the potential of AI manipulation resulting in harmful substance synthesis. Existing regulations inadequately address the ethical concerns tied to AI and LLMs. Mitigation measures are proposed, including technical solutions (explainable AI), establishing ethical guidelines through collaborative efforts, and implementing policy changes to create a comprehensive regulatory framework. The integration of AI and LLMs into clinical pharmacology presents invaluable opportunities, while also introducing significant ethical and safety considerations. Addressing the dual-use nature of AI requires robust regulations, as well as adopting a strategic approach grounded in technical solutions and ethical values following the principles of transparency, accountability and safety. Additionally, AI's potential role in developing countermeasures against novel hazardous substances is underscored. By adopting a proactive approach, the potential benefits of AI and LLMs can be fully harnessed while minimizing the associated risks., (© 2023 British Pharmacological Society.)

Background: Recent work in the UK estimated the prevalence of current cannabinoid-based vaping to be higher than in the USA, a factor previously associated with e-cigarette or vaping-associated lung injury (EVALI). Research in the USA has demonstrated that attendances to emergency departments relating to e-cigarettes began to rise before the EVALI outbreak, suggesting that vapers also experience milder forms of vaping-related illness., Aim: Quantify symptom prevalence and healthcare utilization amongst current UK vapers., Design: Voluntary online survey of individuals aged 16 and over within the UK., Methods: Anonymized data were collected on demographics, vaping/smoking status and vaping substances used. Current vapers were asked about the presence of 10 prevalent symptoms from previous US EVALI case series, healthcare attendances and diagnoses given. Risk-ratios were calculated to compare the likelihood of symptoms and attendances between substances., Results: A total of 2477 complete responses were analysed. In all, 397 respondents were current vapers. Symptom prevalence within the previous 12 months ranged from 3.8% to 30.5% (bloody sputum, cough). Healthcare attendances per symptomatic respondent ranged from 0.1 to 1.4 (bloody sputum, shortness of breath). Current vapers of cannabinoid-based products (alone/in combination) had the most attendances per symptomatic respondent for 9/10 symptoms and were more likely to report symptoms aside from 'cough' (nicotine-free e-liquids [risk ratio = 1.7]). Clinicians reportedly never diagnosed vaping-related illness., Conclusions: UK vapers experience symptoms previously reported in EVALI cases for which they also seek healthcare. Users of cannabinoid-based products were more likely to report symptoms and accounted for a higher healthcare burden. UK vapers may also experience vaping-related illness that does not meet EVALI case criteria., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Association of Physicians.)