Appearance of hexahydrocannabinols as recreational drugs and implications for cannabis drug testing - focus on HHC, HHC-P, HHC-O and HHC-H.

This study investigated the effects of hexahydrocannabinol (HHC) and other unclassified cannabinoids, which were recently introduced to the recreational drug market, on cannabis drug testing in urine and oral fluid samples. After the appearance of HHC in Sweden in 2022, the number of posts about HHC on an online drug discussion forum increased significantly in the spring of 2023, indicating increased interest and use. In parallel, the frequency of false positive screening tests for tetrahydrocannabinol (THC) in oral fluid, and for its carboxy metabolite (THC-COOH) in urine, rose from <2% to >10%. This suggested that HHC cross-reacted with the antibodies in the immunoassay screening, which was confirmed in spiking experiments with HHC, HHC-COOH, HHC acetate (HHC-O), hexahydrocannabihexol (HHC-H), hexahydrocannabiphorol (HHC-P), and THC-P. When HHC and HHC-P were classified as narcotics in Sweden on 11 July 2023, they disappeared from the online and street shops market and were replaced by other unregulated variants (e.g. HHC-O and THC-P). In urine samples submitted for routine cannabis drug testing, HHC-COOH concentrations up to 205 (mean 60, median 27) µg/L were observed. To conclude, cannabis drug testing cannot rely on results from immunoassay screening, as it cannot distinguish between different tetra- and hexahydrocannabinols, some being classified but others unregulated. The current trend for increased use of unregulated cannabinols will likely increase the proportion of positive cannabis screening results that need to be confirmed with mass spectrometric methods. However, the observed cross-reactivity also means a way to pick up use of new cannabinoids that otherwise risk going undetected.

Urine Drug Tests Indicate Higher Prevalence of Combined Alcohol and Cocaine Use Compared to Alcohol Together with Cannabis or Amphetamine-A Possible Link to Cocaethylene.

AIM: This retrospective study examined the prevalence of combined ethanol and cocaine use, which produces an enhanced psychoactive effect through formation of the active metabolite cocaethylene, compared to combined use of ethanol and two other common recreational drugs, cannabis and amphetamine, based on urine drug test results. METHODS: The study was based on >30,000 consecutive samples from routine urine drug testing in 2020, and 2627 samples from acute poisonings in the STRIDA project (2010-2016), in Sweden. Drug testing for ethanol (i.e. ethyl glucuronide and ethyl sulfate), cocaine (benzoylecgonine), cannabis (Δ9-THC-COOH) and amphetamine was done by routine immunoassay screening and LC-MS/MS confirmatory methods. Seven samples testing positive for cocaine and ethyl glucuronide were also analyzed for cocaethylene by LC-HRMS/MS. RESULTS: Among routine samples for which testing of ethanol and cocaine had been requested, 43% tested positive for both substances, compared with 24% for ethanol and cannabis and 19% for ethanol and amphetamine (P < 0.0001). Among the drug-related intoxications, 60% of cocaine-positive samples were also positive for ethanol, compared to 40% for cannabis and ethanol and 37% for amphetamine and ethanol. Cocaethylene was detected (range 1.3-150 µg/L) in all randomly selected samples testing positive for ethanol and cocaine use. CONCLUSIONS: These results, which were based on objective laboratory measures, indicated that combined ethanol and cocaine exposure was more prevalent than expected from drug use statistics. This may relate both to the common use of these substances in party and nightlife settings, and the amplified and prolonged pharmacological effect by the active metabolite cocaethylene.

Increasing prevalence of illicit drug use among employees at Swedish workplaces over a 25-year period.

BACKGROUND: Reports indicate that the proportion of adults using drugs of abuse has been increasing in recent years in Europe. Although there are various indicators of increased drug use in Sweden over time, few studies could demonstrate an increase in the proportion of adults using drugs. To investigate changes in drug use prevalence over time, drug testing at the workplace has been used for a 25-year period. METHODS: The urine samples of employees sent by occupational health services from all over Sweden during a 25-year period were analyzed. The analyzing capacity increased over time (from 3411 in 1994 to 60 315 samples analyzed in 2019), and the majority of the samples was analyzed for the following drugs: cannabis (tetrahydrocannabinol), amphetamine, opiates, cocaine, and benzodiazepines. RESULTS: There was an overall increase in the proportion of samples that tested positive for illicit drugs over a 25-year period. This increase seemed to take place step-wise, with phases of linear increases and plateaus that over time became shorter. About 1.3% of samples tested positive for drugs in 1994, whereas 5.6% tested positive in 2019. Since 2007, the rate of positive samples has increased for cannabis and decreased for benzodiazepines. Although the rate of samples tested positive for opiates had remained relatively stable over the last 20 years, this rate had increased for amphetamine and cocaine between 2013 and 2019. CONCLUSION: The results indicate that the use of illicit drugs among employees at Swedish workplaces has increased during a 25-year period.

Multi-organ point-of-care ultrasound for COVID-19 (PoCUS4COVID): international expert consensus.

COVID-19 has caused great devastation in the past year. Multi-organ point-of-care ultrasound (PoCUS) including lung ultrasound (LUS) and focused cardiac ultrasound (FoCUS) as a clinical adjunct has played a significant role in triaging, diagnosis and medical management of COVID-19 patients. The expert panel from 27 countries and 6 continents with considerable experience of direct application of PoCUS on COVID-19 patients presents evidence-based consensus using GRADE methodology for the quality of evidence and an expedited, modified-Delphi process for the strength of expert consensus. The use of ultrasound is suggested in many clinical situations related to respiratory, cardiovascular and thromboembolic aspects of COVID-19, comparing well with other imaging modalities. The limitations due to insufficient data are highlighted as opportunities for future research.

Alternative routine for reporting chiral amphetamine test results in assessment of attention-deficit/hyperactivity disorder medication: experiences from 2013 to 2023.

This study evaluated an alternative routine for reporting urinary chiral amphetamine results in assessment of attention-deficit/hyperactivity disorder (ADHD) treatment with amphetamine medications and for detecting side-use of illicit racemic amphetamine. Currently in Sweden, only enantiopure d-amphetamine-based ADHD medications (lisdexamphetamine dimesylate and dexamphetamine sulfate) are approved. It is therefore unsuitable to express the chiral result as the l/d-ratio, as before, because l-amphetamine should not be present provided treatment compliance. A new routine for LC-MS/MS chiral amphetamine testing was therefore introduced in 2020, whereby the relative proportion (%) of l-amphetamine and the total amphetamine and creatinine concentrations are reported. Evaluation of the new routine on 24,354 results from 2013 to 2023 revealed that it was useful to distinguish ADHD medication adherence from illicit drug use as the source for a positive test. The l-amphetamine proportion also reflected the enantiomeric content of the medications used. Overall, most results confirmed adherence to ADHD medication, as the l-amphetamine percentage was <1% in 76% of samples (2023) which is the recommended cutoff with enantiopure d-amphetamine medications. However, in all years, illicit drug use was indicated (>40% l-amphetamine) in 8.3%-14.5% of cases. In conclusion, this study demonstrated the clinical value and utility of a new routine for reporting urinary chiral amphetamine results to differentiate adherence to ADHD medication from illicit drug use. Unlike the l/d-amphetamine ratio, it considers differences in total amphetamine concentration and urine dilution, factors that can affect the interpretation.

Results of the implementation of a double-check protocol with point-of-care ultrasound for acute heart failure in the emergency department.

OBJECTIVE: To determine the effectiveness of a double-check protocol using Point-of-Care Ultrasound in the management of patients diagnosed with Acute Heart Failure in an Emergency Department. METHOD: Prospective analytical cross-sectional observational study with patients diagnosed with Acute Heart Failure by the outgoing medical team, who undergo multi-organ ultrasound evaluation including cardiac, pulmonary, and inferior vena cava ultrasound. RESULTS: 96 patients were included. An alternative diagnosis was found in 33% of them. Among the 77% where AHF diagnosis was confirmed, 73.4% had an underlying cause or condition not previously known (Left Ventricular Ejection Fraction less than 40% or moderate-severe valvulopathy). The introduction of the protocol had a clinically relevant impact on 47% of all included patients. CONCLUSIONS: The implementation of a double-check protocol using POCUS, including cardiac, pulmonary, and inferior vena cava assessment in patients diagnosed with Acute Heart Failure, demonstrates a high utility in ensuring accurate diagnosis and proper classification of these patients.

Detection of anabolic agents including selective androgen receptor modulators in samples outside of sport.

Selective androgen receptor modulators (SARMs) are prohibited by the World Anti-Doping Agency (WADA) since 2008. Similarly, to anabolic androgenic steroids (AAS), SARMs are detrimental to health not only in athletes but also in the general population. However, studies of the occurrence of SARMs outside of sport are scarce. Swedish healthcare samples from the Drugs of Abuse Laboratory at Karolinska were analyzed using WADA-accredited screening methods at the Doping Control Laboratory in Stockholm to estimate the frequency of SARM use outside of the WADA laboratories. Twenty (4%) of the male urine samples (n = 542) were positive for SARMs, whereas none of the analyzed female samples (n = 100) contained any SARMs. The top three SARMs found were LGD-4033 followed by RAD140 and ostarine. Two or more SARMs were found in >50% of the SARM-positive samples. AASs were identified in 40% of samples containing SARMs. A difference between genders was observed where 34% male and 7% female samples contained AAS. Many samples displayed testosterone/epitestosterone values indicative of testosterone intake, without presence of other AAS, and hence, there is a risk that these samples are being falsely reported as negative. Our results indicate that SARM use might be a concern outside of sport. Subsequently, in addition to AAS, the healthcare system should also be informed about SARM abuse and the associated adverse side effects.

Analytical and medico-legal problems linked to the presence of delta-8-tetrahydrocannabinol (delta-8-THC): Results from urine drug testing in Sweden.

During routine urine drug testing for cannabis use targeting delta-9-tetrahydrocannabinol carboxylic acid (delta-9-THC-COOH) at the Karolinska University Laboratory in Sweden, an unknown interfering peak was observed in the liquid-chromatographic-tandem mass-spectrometric (LC-MS/MS) confirmative analysis. The peak showed the same exact mass and most abundant fragments as delta-9-THC-COOH but a slightly shorter retention time, thereby not fulfilling all requirements for a positive identification. The analytical results suggested that it was a similar compound, and with access to reference material, it could be identified as the double bond isomer delta-8-THC-COOH. Delta-8-THC has recently become popular as a recreational drug, although its legality varies and is sometimes unclear. In Sweden, all THC isomers are classified substances. The slight difference in retention times was sufficient to distinguish the THC-COOH isomers in the routine LC-MS/MS method, but another LC method allowed better peak separation and individual quantification. At the Karolinska University Laboratory, delta-8-THC-COOH was first observed in April 2020, and the highest incidence was noted in June 2020 when it was present in 5.3% of all THC-COOH-positive samples. The incidence later decreased to today only occasional findings. Large differences in the relative presence of the isomers in the urine samples indicated different origin, for example, synthetically produced pure delta-8-THC, or mixtures of both THC isomers formed during combustion of cannabidiol (CBD). In conclusion, the appearance of delta-8-THC and other isomers on the recreational drug market risks causing analytical and medico-legal problems, due to confusion with delta-9-THC.

International consensus conference recommendations on ultrasound education for undergraduate medical students.

OBJECTIVES: The purpose of this study is to provide expert consensus recommendations to establish a global ultrasound curriculum for undergraduate medical students. METHODS: 64 multi-disciplinary ultrasound experts from 16 countries, 50 multi-disciplinary ultrasound consultants, and 21 medical students and residents contributed to these recommendations. A modified Delphi consensus method was used that included a systematic literature search, evaluation of the quality of literature by the GRADE system, and the RAND appropriateness method for panel judgment and consensus decisions. The process included four in-person international discussion sessions and two rounds of online voting. RESULTS: A total of 332 consensus conference statements in four curricular domains were considered: (1) curricular scope (4 statements), (2) curricular rationale (10 statements), (3) curricular characteristics (14 statements), and (4) curricular content (304 statements). Of these 332 statements, 145 were recommended, 126 were strongly recommended, and 61 were not recommended. Important aspects of an undergraduate ultrasound curriculum identified include curricular integration across the basic and clinical sciences and a competency and entrustable professional activity-based model. The curriculum should form the foundation of a life-long continuum of ultrasound education that prepares students for advanced training and patient care. In addition, the curriculum should complement and support the medical school curriculum as a whole with enhanced understanding of anatomy, physiology, pathophysiological processes and clinical practice without displacing other important undergraduate learning. The content of the curriculum should be appropriate for the medical student level of training, evidence and expert opinion based, and include ongoing collaborative research and development to ensure optimum educational value and patient care. CONCLUSIONS: The international consensus conference has provided the first comprehensive document of recommendations for a basic ultrasound curriculum. The document reflects the opinion of a diverse and representative group of international expert ultrasound practitioners, educators, and learners. These recommendations can standardize undergraduate medical student ultrasound education while serving as a basis for additional research in medical education and the application of ultrasound in clinical practice.

[Drug use and drug trends in Sweden 2010-2020 - results from urine drug testing in the workplace]. / Ökad droganvändning i arbetslivet ­ vart tjugonde urinprov positivt.

Workplace alcohol and drug testing is increasingly used at employment, for regular checks, and in case of accident, incident, or suspicion of drug exposure. The test results provide valuable objective information about drug use in the society. At the Karolinska University Laboratory (Stockholm, Sweden), the number of samples from drug testing in the workplace has quadrupled in the last decade. Almost all urine samples are tested for amphetamines (amphetamine, methamphetamine and MDMA), benzodiazepines (prescribed substances), cannabis, cocaine and opiates, and some also for alcohol (i.e. the metabolites ethyl glucuronide and ethyl sulfate) and drugs such as tramadol and oxycodone. The proportion of samples that test positive for one or more drugs has increased steadily in recent years to over 5%. Substances commonly detected are, in order of appearance, cannabis, amphetamines (amphetamine and MDMA), benzodiazepines, opiates (mainly codeine and only few due to heroin use), and cocaine. Other common substances are alcohol, tramadol, and oxycodone, but these are only tested for in a limited, and possibly selected, proportion of samples. After an MRO has reviewed the positive laboratory results, about 30% of cases are excluded mainly due to legal prescription as medicine. In 2020, the proportion of positive test results decreased, possibly due to reduced access to illicit drugs during the corona pandemic. In summary, results from drug testing in the workplace indicate that illicit use of drugs shows an increasing trend in Sweden.

Lung ultrasound for the early diagnosis of COVID-19 pneumonia: an international multicenter study.

PURPOSE: To analyze the application of a lung ultrasound (LUS)-based diagnostic approach to patients suspected of COVID-19, combining the LUS likelihood of COVID-19 pneumonia with patient's symptoms and clinical history. METHODS: This is an international multicenter observational study in 20 US and European hospitals. Patients suspected of COVID-19 were tested with reverse transcription-polymerase chain reaction (RT-PCR) swab test and had an LUS examination. We identified three clinical phenotypes based on pre-existing chronic diseases (mixed phenotype), and on the presence (severe phenotype) or absence (mild phenotype) of signs and/or symptoms of respiratory failure at presentation. We defined the LUS likelihood of COVID-19 pneumonia according to four different patterns: high (HighLUS), intermediate (IntLUS), alternative (AltLUS), and low (LowLUS) probability. The combination of patterns and phenotypes with RT-PCR results was described and analyzed. RESULTS: We studied 1462 patients, classified in mild (n = 400), severe (n = 727), and mixed (n = 335) phenotypes. HighLUS and IntLUS showed an overall sensitivity of 90.2% (95% CI 88.23-91.97%) in identifying patients with positive RT-PCR, with higher values in the mixed (94.7%) and severe phenotype (97.1%), and even higher in those patients with objective respiratory failure (99.3%). The HighLUS showed a specificity of 88.8% (CI 85.55-91.65%) that was higher in the mild phenotype (94.4%; CI 90.0-97.0%). At multivariate analysis, the HighLUS was a strong independent predictor of RT-PCR positivity (odds ratio 4.2, confidence interval 2.6-6.7, p < 0.0001). CONCLUSION: Combining LUS patterns of probability with clinical phenotypes at presentation can rapidly identify those patients with or without COVID-19 pneumonia at bedside. This approach could support and expedite patients' management during a pandemic surge.

[Harmonized measurement and reporting of chiral amphetamine in the follow-up of ADHD treatment]. / Ny testrutin för kiralt amfetamin minskar risken att missa sidobruk.

Amphetamine is an illicit central nervous system stimulant that is also used for the treatment of attention-decific/hyperacticity disorder (ADHD). Amphetamine exits as two enantiomers, dex(tro)amphetamine (D-amphetamine; also called S-amphetamine) and levoamphetamine (L-amphetamine; or R-amphetamine), of which mainly the former is used as medication for ADHD, whereas illicit street amphetamine is a racemic mixture. To monitor patient compliance with treatment and detect (side) intake of racemic amphetamine, chiral analysis in samples of urine, oral fluid, or blood is used and has traditionally involved reporting of the L/D ratio. Today in Sweden, however, only ADHD medications based on D-amphetamine (lisdexamphetamine lysate and dexamphetamine sulfate) are approved, so no L-amphetamine should be found in the samples provided treatment compliance. It is therefore advisable to instead report the total amphetamine concentration and the relative amount of L-amphetamine. A proposed L-amphetamine cutoff for compliance with ADHD medication is less than 1%, or as low as possible in samples with low amphetamine concentration, as there may be traces of L-amphetamine in the approved pharmaceutical products. Since (supervised) urine sampling is sometimes considered sensitive to ADHD patients without any underlying drug problem, using oral fluid testing is a less invasive alternative and would facilitate sampling for both patients and healthcare professionals. However, an analytical disadvantage is that the amphetamine concentration is generally lower in oral fluid than in urine.

[Simplified laboratory analysis of ethylene glycol allows improved management of poisoning cases]. / Förenklad analys av etylenglykol kan ge snabbare diagnos vid förgiftningsfall.

Toxicological analysis constitutes an important part of the acute treatment of poisonings. Timely laboratory results are essential for the patient to be diagnosed and treated appropriately, but also to exclude poisoning and avoid unnecessary overtreatment. Ingestion of ethylene glycol may cause acute kidney injury and, in severe cases, death, unless treated early with an antidote (ethanol infusion or fomepizole) to inhibit the formation of toxic metabolites. Diagnosis of poisoning is based on detection of ethylene glycol in plasma or serum, but a challenge remains that acute toxicology service is only available at major hospital laboratories using gas chromatography. A simple enzymatic method for the quantification of ethylene glycol (Catachem) was evaluated as a complement to currently used methods and demonstrated to provide fast and accurate measurement in a clinically relevant concentration range (1-80 mmol/l) with a minimal risk of analytical interference. The method is suitable for use on several automated clinical chemistry analyzers. Use of the enzymatic method can improve availability of acute toxicology service for ethylene glycol and contribute to better healthcare from both a patient and health resource perspective.

Accuracy and Interobserver Reliability of the Simplified Pulmonary Embolism Severity Index Versus the Hestia Criteria for Patients With Pulmonary Embolism.

OBJECTIVES: The objective was to assess and compare the accuracy and interobserver reliability of the simplified Pulmonary Embolism Severity Index (sPESI) and the Hestia criteria for predicting short-term mortality in patients with pulmonary embolism (PE). METHODS: This prospective cohort study evaluated consecutive eligible adults with PE diagnosed in the emergency department (ED) at a large, tertiary, academic medical center in the era January 1, 2015, to December 30, 2017. We assessed and compared sPESI and Hestia criteria prognostic accuracy for 30-day all-cause mortality after PE diagnosis and their interobserver reliability for classifying patients as low risk or high risk. Two clinician investigators scored both prediction tools during the ED evaluation. We used the kappa statistic to test for agreement. RESULTS: The 488-patient cohort had a mean (±SD) age of 69.0 (±17.1) years and an approximately even sex distribution. The investigators classified one-quarter of patients as low risk using the sPESI and Hestia criteria (28% vs. 27%, respectively). During the 30-day follow-up, 31 of the 488 (6.4%) patients died. Patients classified as low risk according to the sPESI and the Hestia criteria had a similar 30-day mortality (sPESI 0.7% [1/135], 95% confidence interval [CI] = 0.0%-4.0%; Hestia 2.3% [3/132], 95% CI = 0.5%-6.5%). The two observers had good agreement (κ = 0.80) for the Hestia criteria and very good agreement (κ = 0.97) for the sPESI. CONCLUSION: The sPESI and the Hestia criteria had similar risk classification determination and prognostic accuracy for 30-day mortality after PE. However, the succinct and more objective sPESI had higher interobserver reliability than the Hestia criteria.

Comparison of All-Cause Mortality Following VTE Treatment Between Propensity Score-Adjusted Observational Studies and Matched Randomized Controlled Trials: Meta-Epidemiologic Study.

BACKGROUND: It is unknown whether propensity score-adjusted observational studies produce results comparable to those of randomized controlled trials (RCTs) that address similar VTE treatment issues. METHODS: The PubMed and Web of Science databases were systematically searched for propensity score-adjusted observational studies, RCTs, and meta-analyses of RCTs that estimated all-cause mortality following VTE treatment. After identifying distinct clinical treatment issues evaluated in the eligible observational studies, a standardized algorithm was used to identify and match at least one RCT or RCT meta-analysis publication for paired study design analyses. Meta-analyses were used to summarize groups of studies. Treatment efficacy statistics (relative ORs) were compared between the paired observational and RCT studies, and the summary relative ORs for all study design pairs were also calculated. RESULTS: The observational and RCT study pairs assessed seven clinical treatment issues. Overall, the observational study-RCT pairs did not exhibit significantly different mortality estimates (summary relative OR, 0.89; 95% CI, 0.32-1.46; I2 = 23%). However, two of the seven treatment issue study pairs (thrombolysis vs anticoagulation for pulmonary embolism; once- vs twice-daily enoxaparin for VTE) exhibited a significantly different treatment effect direction, and there was a substantial (nonsignificant) difference in the magnitude of the effect in another two of the study pairs (rivaroxaban vs vitamin K antagonists for VTE; home treatment vs hospitalization for DVT). CONCLUSIONS: This systematic comparison across seven VTE treatment topics suggests that propensity score-adjusted observational studies and RCTs often exhibit similar all-cause mortality, although differences in the direction or the magnitude of estimated treatment effects may occasionally occur. TRIAL REGISTRY: PROSPERO; CRD42018087819; URL: http://www.crd.york.ac.uk/PROSPERO.

Detectability of fentanyl and designer fentanyls in urine by 3 commercial fentanyl immunoassays.

In recent times, structural variants of fentanyl (designer fentanyls) have appeared on the recreational drug market for new psychoactive substances (NPS). These potent opioids have caused harmful intoxications and increased opioid-related mortality in many countries. This work evaluated 3 commercial immunoassays for fentanyl screening in urine and investigated whether they are useful also for screening of designer fentanyls. The assays examined were the Thermo DRI® Fentanyl Enzyme Immunoassay, the ARK™ Fentanyl Assay homogeneous enzyme immunoassay, and the Immunalysis® Fentanyl Urine SEFRIA™ Drug Screening Kit. A liquid chromatography-high-resolution mass spectrometry method was used as reference. The DRI fentanyl immunoassay generated somewhat higher assay imprecision values (%CV) compared with the ARK™ and SEFRIA™ assays, but all assays showed %CV values acceptable for routine use. The 3 assays showed overall good detectability (33%-95% cross-reactivity) for blank urine samples spiked with acetylfentanyl, acrylfentanyl, butyrfentanyl, 4-chloroisobutyrfentanyl, 4-fluorobutyrfentanyl, 4-fluorofentanyl, 4-fluoroisobutyrfentnyl, isobutyrfentanyl, methoxyacetylfentanyl, or tetrahydrofuranfentanyl, whereas 4-methoxybutyrfentanyl (all assays) and 2-fluorofentanyl (DRI assay) showed low cross-reactivity. A good detectability of designer fentanyls was confirmed in urine samples from authentic acute intoxications. In conclusion, the present results demonstrate that the urinary fentanyl immunoassays are generally useful also for preliminary screening of fentanyl analogs sold as NPS. When the SEFRIA™ assay was applied for testing of 980 urine samples from patients treated for drug dependence in Sweden, only 1 sample was confirmed positive for fentanyl.