Feasibility and acceptability of collecting umbilical cord tissue for prenatal cannabis research: A mixed-methods research study.

BACKGROUND: Large-scale longitudinal studies with biological samples are needed to examine the associations between prenatal cannabis use and birth and developmental outcomes. OBJECTIVES: The aim of this study was to understand the feasibility and acceptability of collecting umbilical cord tissue for the purpose of cannabis use testing in a community sample. DESIGN: This is a mixed methods research study consisted of a prospective cohort study and a qualitative descriptive study. METHODS: This study was conducted in Vancouver, British Columbia between January 2021 and August 2022. Participants were recruited during pregnancy, and the umbilical cord tissues were collected at birth and tested for the presence of cannabinoids. After the completion of the study, participants completed an online open-ended questionnaire about their overall experience. Data were analyzed using descriptive and thematic analyses. RESULTS: Among the 85 eligible individuals, 57 people (67%) consented to the study. The cord tissue was collected for 39 participants (68.4%). The collection rates for participants with vaginal, elective, and emergency cesarean delivery were 73.0%, 71.4%, and 53.8%, respectively, and for those with spontaneous and induced labor were 81.5% and 50%, respectively. Four (7.0%) and seven participants (12.3%) reported prenatal cannabis use in direct and probing self-report questions, respectively. The agreement between any self-report and cord tissue test was moderate (kappa 0.53, 95% confidence interval 0.06-0.99). Qualitative findings were classified into five themes. CONCLUSION: The collection of cord tissue was perceived acceptable by most participants. Implementation of collection protocols for complex labors, a central hospital unit to liaise direct communications and active participants' involvement might increase the feasibility of future studies.

Identification of Emerging Novel Psychoactive Substances by Retrospective Analysis of Population-Scale Mass Spectrometry Data Sets.

Over the last two decades, hundreds of new psychoactive substances (NPSs), also known as "designer drugs", have emerged on the illicit drug market. The toxic and potentially fatal effects of these compounds oblige laboratories around the world to screen for NPS in seized materials and biological samples, commonly using high-resolution mass spectrometry. However, unambiguous identification of a NPS by mass spectrometry requires comparison to data from analytical reference materials, acquired on the same instrument. The sheer number of NPSs that are available on the illicit market, and the pace at which new compounds are introduced, means that forensic laboratories must make difficult decisions about which reference materials to acquire. Here, we asked whether retrospective suspect screening of population-scale mass spectrometry data could provide a data-driven platform to prioritize emerging NPSs for assay development. We curated a suspect database of precursor and diagnostic fragment ion masses for 83 emerging NPSs and used this database to retrospectively screen mass spectrometry data from 12,727 urine drug screens from one Canadian province. We developed integrative computational strategies to prioritize the most reliable identifications and tracked the frequency of these identifications over a 3 year study period between August 2019 and August 2022. The resulting data were used to guide the acquisition of new reference materials, which were in turn used to validate a subset of the retrospective identifications. Last, we took advantage of matching clinical reports for all 12,727 samples to systematically benchmark the accuracy of our retrospective data analysis approach. Our work opens up new avenues to enable the rapid detection of emerging illicit drugs through large-scale reanalysis of mass spectrometry data.

Desalkylgidazepam blood concentrations in 63 forensic investigation cases.

Desalkylgidazepam, also known as bromonordiazepam, is the latest designer benzodiazepine to appear in postmortem blood samples in British Columbia. Our laboratory was first alerted to the presence of desalkylgidazepam in seized drug samples in May 2022, and the analyte was added to an in-house library shortly thereafter. Previously acquired spectra from routine death investigation cases were reprocessed using the updated library with the first presumptive identification of desalkylgidazepam occurring in a sample received in April 2022. A standard addition method for the quantitation of desalkylgidazepam in blood samples (from femoral, iliac, jugular and subclavian veins) was validated and consequently used to confirm presence and concentrations of the drug in 63 cases, with an average concentration of 42.2 ± 44.0 ng/mL (median concentration: 24.5 ng/mL; range: 3.7-220.6 ng/mL). Similar to detections of other novel benzodiazepines, co-occurrence of desalkylgidazepam with opioids and/or stimulants was common. To our knowledge, this paper is the first to report desalkylgidazepam concentrations in postmortem blood samples.

Bromazolam Blood Concentrations in Postmortem Cases-A British Columbia Perspective.

Bromazolam is a designer benzodiazepine that was first detected in British Columbia in January 2021. Postmortem cases were analyzed using a comprehensive blood drug screening procedure by liquid chromatography-high-resolution mass spectrometry before being retrospectively analyzed using an in-house novel psychoactive substances data processing method. Bromazolam was detected in 41 postmortem cases in 2021 and quantitatively confirmed by standard addition, using liquid chromatography-tandem mass spectrometry. The mean bromazolam concentration observed was 11.4 ± 53.7 ng/mL (median concentration: 1.6 ng/mL), with a range from 0.5 to 319.3 ng/mL and the majority of cases co-occurring with fentanyl. These low concentrations may be indicative of a presumed enhancement of opioid effects, rather than being used as a stand-alone drug. Bromazolam was always detected with opioids (fentanyl and carfentanil), stimulants (methamphetamine) and/or other benzodiazepines (etizolam and flualprazolam). To our knowledge, this is the first report to provide concentrations of bromazolam in postmortem blood samples in Canada.

Fatal ingestion of Taxus baccata: English yew.

Poisoning from consumption of foraged alternative medicine products is an uncommon yet recognized occurrence. Here, presented is the case of a 40-year-old woman who was witnessed to collapse with labored breathing and subsequently died despite emergency medical personnel attendance and resuscitation efforts. Autopsy revealed the presence of plant matter that was visually identified as leaves from Taxus baccata - the English Yew. Isolation of alkaloids from the plant material and subsequent identification of the same alkaloids in the decedent's blood by liquid chromatography-tandem mass spectrometry indicated a toxicological cause of death. This case illustrates a collaborative team approach among subject matter experts to unexpectedly discover and then confirm the sudden death of this woman from T. baccata toxicity.

Quantitation of γ-aminobutyric acid in equine plasma by hydrophilic interaction liquid chromatography with tandem mass spectrometry.

γ-Aminobutyric acid is the principal inhibitory neurotransmitter in the central nervous system and regulates the neuronal excitability. There has been anecdotal evidence that γ-aminobutyric acid has been used within a few hours prior to competition in equine sports to calm down nervous horses. However, regulating the use of γ-aminobutyric acid is challenging because it is an endogenous substance in the horse. γ-Aminobutyric acid is usually present at low ng/mL levels in equine plasma; therefore, a sensitive method has to be developed to quantify these low background levels. Measuring low concentrations of endogenous γ-aminobutyric acid is essential to establish a threshold that can be used to differentiate levels attributable to exogenous administrations of γ-aminobutyric acid. A hydrophilic interaction liquid chromatography coupled with tandem mass spectrometry method was developed and validated for the quantitation of γ-aminobutyric acid in equine plasma. Calibrators were prepared in artificial surrogate matrix consisting of 35 mg/mL equine serum albumin in phosphate buffered saline. Samples were prepared by protein precipitation with acetonitrile. Utilizing this methodology, a total of 403 equine plasma samples collected post-competition from horses participating in equestrian events in Canada were analyzed.

Studies of benzothiophene template as potent factor IXa (FIXa) inhibitors in thrombosis.

FIXa is a serine protease enzyme involved in the intrinsic pathway of the coagulation cascade. The upstream intervention of the coagulation cascade in selectively inhibiting FIXa would leave hemostasis intact via the extrinsic pathway, leading to an optimum combination of efficacy and safety with low incidence of bleeding. We have identified 2-amindinobenzothiophene template as a lead scaffold for FIXa inhibiton based on its homology with urokinase plasminogen activator (uPA). Subsequent SAR work on the template revealed a number of highly potent FIXa inhibitors, though with moderate selectivity against FXa. X-ray study with one of the analogues demonstrated active site binding interaction with the induced opening of the S1 beta pocket and a secondary binding at the S2-S4 sites, which is in direct contrast with the previous finding.

Generation of ligand conformations in continuum solvent consistent with protein active site topology: application to thrombin.

Using the crystal structure of an inhibitor complexed with the serine protease thrombin (PDB code ) and the functional group definitions contained within the Catalyst software, a representation of the enzyme's active site was produced (structure-based pharmacophore model). A training set of 16 homologous non-peptide inhibitors whose conformations had been generated in continuum solvent (MacroModel) and clustered into conformational families (XCluster) was regressed against this pharmacophore so as to obtain a 3D-QSAR model. To test the robustness of the resulting QSAR model, the synthesis of a series of non-peptide thrombin inhibitors based on arylsuphonyl derivatives of an aminophenol ring linked to a pyridyl-based S1 binding group was undertaken. These compounds served as a test set (20-24). The crystal structure for the novel symmetrical disulfonyl compound 24, in complex with thrombin, has been solved. Its calculated binding mode is in general agreement with the crystallographically observed one, and the predicted K(i) value is in close accord with the experimental value.