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Abstract Background Prenatal glyphosate (GLY) exposure is associated with adverse reproductive outcomes in animal studies. Little is known about the effects of GLY exposure during pregnancy in the human population. This study aims to establish baseline urine GLY levels in a high-risk and racially diverse pregnancy cohort and to assess the relationship between prenatal GLY exposure and fetal development and birth outcomes. Methods Random first trimester urine specimens were collected from high risk pregnant women between 2013 and 2016 as part of the Indiana Pregnancy Environmental Exposures Study (PEES). Demographic and clinical data were abstracted from mother and infant medical records. Urine glyphosate levels were measured as a proxy for GLY exposure and quantified using liquid chromatography-tandem mass spectrometry. Primary outcome variables included gestation-adjusted birth weight percentile (BWT%ile) and neonatal intensive care unit (NICU) admission. Relationships between primary outcome variables and GLY exposure were assessed using univariate and multivariate linear and logistic regression models. Results Urine GLY levels above the limit of detection (0.1 ng/mL) were found in 186 of 187 (99%) pregnant women. Further analyses were limited to 155 pregnant women with singleton live births. The mean age of participants was 29 years, and the majority were non-Hispanic white (70%) or non-Hispanic Black (21%). The mean (± SD) urine GLY level was 3.33 ± 1.67 ng/mL. Newborn BWT%iles were negatively related to GLY (adjusted slope ± SE = -0.032 + 0.014, p = 0.023). Infants born to women living outside of Indiana’s large central metropolitan area were more likely to have a lower BWT%ile associated with mother’s first trimester GLY levels (slope ± SE = -0.064 ± 0.024, p = 0.007). The adjusted odds ratio for NICU admission and maternal GLY levels was 1.16 (95% CI: 0.90, 1.67, p = 0.233). Conclusion GLY was found in 99% of pregnant women in this Midwestern cohort. Higher maternal GLY levels in the first trimester were associated with lower BWT%iles and higher NICU admission risk. The results warrant further investigation on the effects of GLY exposure in human pregnancies in larger population studies.

Objective measures of adherence for antiretrovirals used as pre-exposure prophylaxis (PrEP) are critical for improving preventative efficacy in both clinical trials and real-world application. Current objective adherence measures either reflect only recent behavior (eg days for plasma or urine) or cumulative behavior (eg months for dried blood spots). Here, we measured the accumulation of the antiretroviral drug maraviroc (MVC) in hair strands by infrared matrix-assisted laser desorption electrospray ionization (IR-MALDESI) mass spectrometry imaging (MSI) to evaluate adherence behavior longitudinally at high temporal resolution. An MSI threshold for classifying daily adherence was established using clinical samples from healthy volunteers following directly observed dosing of 1 to 7 doses MVC/week. We then used the benchmarked MSI assay to classify adherence to MVC-based PrEP regimens in hair samples collected throughout the 48-week HPTN069/ACTGA5305 study. We found that only ~32% of investigated hair samples collected during the study's active dosing period showed consistent daily PrEP adherence throughout a retrospective period of 30 days, and also found that profiles of daily individual adherence from MSI hair analysis could identify when patients were and were not taking study drug. The assessment of adherence from MSI hair strand analysis was 62% lower than adherence classified using paired plasma samples, the latter of which may be influenced by white-coat adherence. These findings demonstrate the ability of MSI hair analysis to examine daily variability of adherence behavior over a longer-term measurement and offer the potential for longitudinal comparison with risk behavior to target patient-specific adherence interventions and improve outcomes.

Synthetic cannabinoid receptor agonists (SCRAs) continue to make up a significant portion new psychoactive substances (NPS) detected and seized worldwide. Due to their often potent activation of central cannabinoid receptors in vivo, use of SCRAs can result in severe intoxication, in addition to other adverse health effects. Recent detections of AB-4CN-BUTICA, MMB-4CN-BUTINACA, MDMB-4F-BUTICA and MDMB-4F-BUTINACA mark a continuation in the appearance of SCRAs bearing novel tail substituents. The proactive characterization campaign described here has facilitated the detection of several new SCRAs in toxicological case work. Here we detail the synthesis, characterization, and pharmacological evaluation of recently detected SCRAs, as well as a systematic library of 32 compounds bearing head, tail, and core group combinations likely to appear in future. In vitro radioligand binding assays revealed most compounds showed moderate to high affinity at both CB1 (pKi = < 5 to 8.89 ± 0.09 M) and CB2 (pKi = 5.49 ± 0.03 to 9.92 ± 0.09 M) receptors. In vitro functional evaluation using a fluorescence-based membrane potential assay showed that most compounds were sub-micromolar to sub-nanomolar agonists at CB1 (pEC50 = < 5 to 9.48 ± 0.14 M) and CB2 (pEC50 = 5.92 ± 0.16 to 8.64 ± 0.15 M) receptors. An in silico receptor-ligand docking approach was utilized to rationalize binding trends for CB2 with respect to the tail substituent, and indicated that rigidity in this region (i.e., 4-cyanobutyl) was detrimental to affinity.

Abstract Given the complex exposures from both exogenous and endogenous sources that an individual experiences during life, exposome-wide association studies that interrogate levels of small molecules in biospecimens have been proposed for discovering causes of chronic diseases. We conducted a study to explore associations between environmental chemicals and endogenous molecules using Gaussian graphical models (GGMs) of non-targeted metabolomics data measured in a cohort of California women firefighters and office workers. GGMs revealed many exposure-metabolite associations, including that exposures to mono-hydroxyisononyl phthalate, ethyl paraben and 4-ethylbenzoic acid were associated with metabolites involved in steroid hormone biosynthesis, and perfluoroalkyl substances were linked to bile acids—hormones that regulate cholesterol and glucose metabolism—and inflammatory signaling molecules. Some hypotheses generated from these findings were confirmed by analysis of data from the National Health and Nutrition Examination Survey. Taken together, our findings demonstrate a novel approach to discovering associations between chemical exposures and biological processes of potential relevance for disease causation.

The present study was conducted in pregnant rhesus monkeys to determine the rapidity and extent to which BPA reaches the fetal compartment following oral ingestion, and the 24-hr fate of BPA. To assess metabolism changes during the course of pregnancy, we compared BPA biotransformation during the second and third trimesters in the same animals, measuring the levels of sulfated, gluronidated, and free BPA in maternal serum, amniotic fluid, and fetal serum. All animals showed measurable unconjugated and conjugated BPA in the fetal compartment and slow clearance compared to maternal serum. There were higher levels of BPA-G in amniotic fluid at 150 days gestation compared to 100 days gestation, as well as higher levels of BPA-G than BPA-S. We also monitored 3H-BPA (and metabolites) in key tissues and excreta from a mother and fetus and from a non-pregnant female. The elimination of radioactivity was rapid, but residues were still detectable 24 hr after dosing in all tissues analyzed. These data suggest that, in primates, rapid maternal processing of BPA does not alleviate the risk of exposure to the developing fetus. This study elevates concerns about levels of current BPA human exposure from potentially a large number of unknown sources and the risks posed to developing fetuses.

Rivaroxaban is a newer anticoagulant initially approved by the Food and Drug Administration to treat nonvalvular atrial fibrillation. Rivaroxaban has several characteristics that are more favorable than warfarin. One of the characteristics is decreased risk of hemorrhage. We report one of the first case reports of severe intracranial hemorrhage associated with rivaroxaban in an elderly patient with decreased renal function. We aim to alert emergency medicine providers regarding the likelihood of encountering these patient as newer anticoagulants rise in popularity.

Introduction: The ability to objectively measure chronic stress has important implications for research, prevention, and treatment. Cortisol is currently the most used biological marker in the investigation of stress and can be measured via blood, saliva, and urine; however, these methods have disadvantages. The measurement of cortisol in hair is a more recently developed method that quantifies the cumulative production of cortisol over longer periods of time. Given the potential benefits of hair as a chronic stress biometric, research with this novel method is burgeoning, yet rarely involves transgender ("trans") populations, despite high levels of reported stress among trans people due to experiences of stigma and discrimination. Since hair is a key part of gender presentation, trans people might be less likely than cisgender people to donate hair for research. To explore the feasibility and acceptability of hair collection for use as a stress biometric with trans women, we nested a study into an ongoing clinical trial in São Paulo, Brazil, "Manas por Manas" (Sisters for Sisters). Here, we describe the hair biometric substudy protocol, as well as the feasibility and acceptability of collecting hair in the study cohort., Methods: We randomly selected a subsample (n = 180) from the Manas por Manas cohort (n = 392), all of whom are trans women, age 18 or older. We messaged participants via phone, WhatsApp, or social media for at least three attempted contacts. Study visits included four components: (1) video introduction, including a demonstration of hair sampling; (2) informed consent; (3) a brief survey with the validated Short Stress Overload Scale (translated to Portuguese) and questions on hair care that could moderate stress hormone results; and (4) hair sample collection. Hair samples were collected and stored using validated protocols. Participants were reimbursed for travel costs., Results: Between April and December 2022, we messaged with 143 individuals out of the 180 sampled (79%) and invited them to participate in the study. Of those invited to participate, we scheduled study visits with 102 people (71.3% of those invited to participate), of whom 100 attended their study visits and completed all activities. Two people did not attend their study visits and stopped communication. Of those who were invited to participate and declined a study visit, four individuals declined due to the hair sample collection procedures (2.8% of those invited to participate). Other reasons for declining to participate included having moved (n = 7), lack of time (n = 11), not interested in research participation (n = 8), or unknown/stopped responding to messages (n = 11). Most participants reported that they chemically treated their hair to bleach, color, or straighten it, which could impact laboratory assays., Conclusion: We found hair sampling for stress measurement to be feasible and acceptable to our participants. We successfully completed all study activities for our desired sample size, and most recruited individuals volunteered to participate. Reasons provided for declining study participation reflected general barriers to research participation, with only four people declining due to hair sample collection procedures., (© 2024 The Author(s). Brain and Behavior published by Wiley Periodicals LLC.)

Objective: There is a need to characterize exposures associated with the pathogenesis of systemic lupus erythematosus (SLE). In this pilot study, we explore a hypothesis-free approach that can measure thousands of exogenous chemicals in blood ("exposome") in patients with SLE and unaffected controls., Methods: This cross-sectional study analyzed a cohort of patients with prevalent SLE (n = 285) and controls (n = 106). Plasma was analyzed by liquid chromatography-quadrupole time-of-flight mass spectrometry (LC-QTOF/MS). Mass spectrometry features present in at least 25% of all samples were selected for association analysis (n = 2,737). Features were matched to potential chemicals using available databases. Association analysis of abundances of features with SLE status was performed, adjusting for age and sex. We also explored features associated with SLE phenotypes, sociodemographic factors, and current medication use., Results: We found 30 features significantly associated with SLE status (Bonferroni P < 0.05). Of these, seven matched chemical names based on databases. These seven features included phthalate metabolites, a formetanate metabolite, and eugenol. The abundance of acid pesticides differed between patients with SLE and controls (Bonferroni P < 0.05). Two unmatched features were associated with a history of lupus nephritis, and one with anti-double-stranded DNA antibody production (Bonferroni P < 0.05). Seventeen features varied by self-reported race and ethnicity, including a polyfluoroalkyl substance (analysis of variance P < 1.69 × 10 -5 ). Eleven features correlated with antimalarials, 6 with mycophenolate mofetil, and 29 with prednisone use., Conclusion: This proof-of-concept study demonstrates that LC-QTOF/MS is a powerful tool that agnostically detects circulating exogenous compounds. These analyses can generate hypotheses of disease-related exposures for future prospective, longitudinal studies., (© 2023 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. No potential conflicts of interest were disclosed.

Estrogenic overstimulation is carcinogenic to the human breast. Personal care products (PCPs) commonly contain xenoestrogens (XE), such as parabens and phthalates. Here, we identified the adverse effects of persistent exposure to such PCPs directly within human estrogen responsive breast tissue of subjects enrolled in a regimen of reduced XE use (REDUXE). Pre- and post-intervention fine needle aspirates (FNAs) of the breast were collected from healthy volunteers who discontinued the use of paraben and phthalate containing PCPs over a 28 d period. Based on high-dimensional gene expression data of matched FNA pairs of study subjects, we demonstrate a striking reversal of cancer-associated phenotypes, including the PI3K-AKT/mTOR pathway, autophagy, and apoptotic signaling networks within breast cells of REDUXE compliant subjects. These, and other altered phenotypes were detected together with a significant reduction in urinary parabens and phthalate metabolites. Moreover, in vitro treatment of paired FNAs with 17β-estradiol (E2), displayed a 'normalizing' impact of REDUXE on gene expression within known E2-modulated pathways, and on functional endpoints, including estrogen receptor alpha: beta ratio, and S-phase fraction of the cell cycle. In a paradigm shifting approach facilitated by community-based participatory research, REDUXE reveals unfavorable consequences from exposure to XEs from daily-use PCPs. Our findings illustrate the potential for REDUXE to suppress pro-carcinogenic phenotypes at the cellular level towards the goal of breast cancer prevention., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)

Dried blood spot (DBS) has been used as an alternative matrix in drug testing. In forensic testing it offers enhanced stability of analytes and ease of storage that requires minimal space. This is compatible with long term archiving of large numbers of samples for future investigation. We employed liquid chromatography-tandem mass spectrometry (LC-MS/MS) to quantify alprazolam, α-hydroxyalprazolam, and hydrocodone in a DBS sample that has been stored for 17 years. We achieved linear dynamic ranges (0.1-50 ng/mL) that capture wide ranges of concentration of the analytes below and above their reported reference ranges, and limits of detection (0.05 ng/mL) of 40-100X lower than the lower limit of the analyte's reference ranges. The method was validated according to FDA and CLSI guidelines and successfully confirmed and quantified alprazolam and α-hydroxyalprazolam in a forensic DBS sample., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Roy Gerona reports financial support was provided by Federal Public Defender for District of Middle Tennessee]., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Introduction: Delta-8-tetrahydrocannabinol (THC) is a known isomer of delta-9-THC, both found naturally in the Cannabis sativa plant and thought to have similar potency. Delta-8-THC products are widely accessible in retail shops which may lead to a rise in pediatric exposures with substantial clinical effects., Case Report: This is a case series of four pediatric patients that were seen between June and September 2021. The patients presented with varied clinical symptoms including confusion, somnolence, seizure-like activity, hypotension, and tachycardia after exposure to delta-8-THC products obtained in retail shops. Basic urine drug screen immunoassays revealed positive results for cannabinoids in all patients. Subsequent confirmatory drug analysis of residual biological samples of blood and/or urine was sent to the University of California San Francisco Clinical Toxicology and Environment Biomonitoring Laboratory with the assistance of the Drug Enforcement Administration's Toxicology Testing Program (DEA TOX). Confirmatory testing revealed 11-nor-9-carboxy-delta-8-THC, the metabolite of delta-8-THC. Delta-9-THC and its metabolites were not detected on confirmatory testing in any of the cases., Discussion: Clinical effects of delta-8-THC in children include but are not limited to altered mental status, seizure-like activity, and vital sign abnormalities. Delta-8-THC exposure may lead to a positive urine drug screen for cannabinoids, but confirmatory testing is needed to differentiate from delta-9-THC., (© 2023. American College of Medical Toxicology.)

Background: Although hyperthermia is described after cocaine intoxication, the two hyperthermic cases discussed were unusual in severity and duration for cocaine alone. Synephrine was found in biological samples of these patients in high concentrations and was suspected to be an adulterant in illicitly obtained drugs., Case Report: Two patients presented to a tertiary care university hospital within 2 days of each other after recreational drug use with delayed and protracted hyperthermia. Synephrine was later found in high concentrations in biological samples as an unexpected drug adulterant. The first patient's presentation came with delayed recognition of hyperthermia and implementation of aggressive cooling measures; he entered multisystem organ failure with prolonged intensive care unit stay and significant morbidity. The second patient's hyperthermia was recognized promptly, and she received early, aggressive cooling, including deep sedation and ice water submersion. She left against medical advice from the hospital at her baseline 3 days after presentation. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Synephrine is a suspected adulterant that may be associated with profound hyperthermia. Early recognition of drug overdose and working knowledge of common adulterants can facilitate early targeted management, such as aggressive cooling measures, which may prevent morbidity and mortality., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Isoniazid (INH) preventative therapy is recommended for people with HIV (PWH) in resource-constrained settings. Valid measures are needed to assess adherence. We aimed to examine agreement between measures overall and by level of social desirability., Methods: PWH with latent tuberculosis (TB) were recruited in Mbarara, Uganda. Past 30-day adherence was measured by the number of days with pill bottle openings using a medication event monitoring system (MEMS) and self-reported number of days pills taken. INH concentration (INH plus acetyl INH and their ratio) in hair samples was measured. We used Bland-Altman plots to examine agreement between adherence measures and calculated the area under the receiver operating characteristics curve (AUROC) to determine if INH hair concentration predicted optimal MEMS-measured adherence (≥90%)., Results: A total of 301 participants enrolled; 92% were virologically suppressed, and adherence was high. The median (interquartile range [IQR]) number of pill bottle openings in 30 days was 28 (24-30) compared with 30 (28-30) via self-report. The median INH concentration (IQR) was 36.2 (17.2-62.4), and the INH:acetyl ratio was 2.43 (0.99-3.92). Agreement between self-reported and MEMS adherence was greater at more optimal adherence levels. INH:acetyl INH ratio was not predictive of optimal adherence according to MEMS (AUROC, 0.62; 95% CI, 0.52-0.72) in a subset (n = 161)., Conclusions: Lower MEMS adherence levels compared with self-report suggest the need for objective adherence measures. Biologic measures have potential, although in this study INH concentration was not predictive of MEMS measured adherence. More data are needed to assess the accuracy of biologic measures., Competing Interests: Potential conflicts of interest. All authors: no reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Maternal psychological stress has been linked to preterm birth. However, the differential contribution of psychological stress versus stress hormones is not clear. Studies focus primarily on perceived stress and cortisol, with few assessing its inter-convertible hormone cortisone. Furthermore, little is known about the potential moderating roles of obstetric risk and fetal sex in the relationship between maternal stress and gestational length. This gap in knowledge is particularly evident for rural women who typically experience chronic multiple stressors during pregnancy. We explored the relationship of hormonal and psychological stress to gestational length and the effects of obstetric risks and fetal sex on this relationship among Kenyan pregnant women., Methods: The sample included 130 women recruited between 22 to 28 weeks gestation. They completed a clinical and sociodemographic questionnaire together with the Perceived Stress Scale and provided a hair sample for cortisol and cortisone assay. Women underwent an ultrasound to assess weeks of gestation. At delivery, their pregnancy-related health problems were identified using information extracted from medical records to compile each woman's number of pregnancy risks on the Obstetric Medical Risk Index (OMRI)., Results: Perceived stress and hair cortisol were not significant predictors of gestational length. However, a greater number of obstetric risks on the OMRI was associated with shorter gestational length. This effect was further explained by the interaction between obstetric risk and hair cortisone ( B = 0.709, p = 0.02). Hair cortisone levels of mothers who had a shorter gestation were significantly higher in mothers with 2 or more risks on the OMRI but not among mothers with only one or no risks ( t = 2.39, p = 0.02). Fetal sex had no relationship to gestational length and also had no moderating effect on the relationship between any stress-related metric and gestational length., Conclusion: Cortisone levels may increase in anticipation of shorter gestation as a compensatory response to increased obstetric risk. Elevated cortisone may be a more sensitive marker of risk for early delivery than cortisol or psychological stress, with salience for both the male and female fetus., (Copyright © 2022 Musana, Cohen, Kuppermann, Gerona, Wanyoro, Aguilar, Santos, Temmerman and Weiss.)

Introduction: Phenibut is used to treat anxiety, insomnia, alcohol withdrawal and other conditions in Russia. The drug, however, has abuse potential and may cause lethargy, delirium, psychosis and coma. In the United States (US), the US Food and Drug Administration (FDA) has never approved the use of phenibut as a prescription medication, but the drug is available over-the-counter in dietary supplements. More than 80 cases of coma and death have been associated with phenibut consumption and withdrawal, and the FDA recently warned that the drug is not permitted in over-the-counter supplements. We designed our study to determine the presence and quantity of phenibut in over-the-counter supplements before and after the FDA warnings., Methods: Phenibut products were included if they (a) listed phenibut or a synonym as an ingredient on the label, (b) were labeled as a dietary supplement, and (c) were available for sale both before and after the FDA warning. Supplements were analyzed by liquid chromatography time-of-flight mass spectrometry; quantification was performed by isotope dilution method., Results: Four brands of dietary supplements labeled as containing phenibut met the inclusion criteria. Prior to the FDA warnings, two of the four brands contained phenibut, at dosages of 484 mg and 487 mg per serving. After the FDA warning, all four products contained phenibut, ranging in dosages from 21 mg to 1,164 mg per serving. Phenibut was first detected only after the FDA warnings in two brands, and the quantity of phenibut increased in three of four products after the FDA warnings. Quantities detected per dose were as much as 450% greater than a typical 250 mg pharmaceutical tablet manufactured in Russia., Conclusion: Following FDA issuing an advisory that phenibut is not permitted in dietary supplements, the quantity of phenibut increased in 3 of 4 brands of over-the-counter phenibut supplements.

Occupational exposures to flame retardants (FRs), a class of suspected endocrine-disrupting compounds, are of health concern for firefighters. We sought to characterize exposure to FR compounds and evaluate their association with thyroid hormone levels, a biomarker of early effect, in female firefighters and office workers in San Francisco. In a cross-sectional study, we measured replacement organophosphate and organohalogen FRs in spot urine samples from firefighters ( N = 86) and office workers ( N = 84), as well as total thyroxine (T 4 ) and thyroid-stimulating hormone in plasma for 84 firefighters and 81 office workers. Median bis(1,3-dichloro-2-propyl)phosphate (BDCPP) levels were 5 times higher in firefighters than office workers. Among firefighters, a doubling of BDCPP was associated with a 2.88% decrease (95% confidence interval -5.28, -0.42) in T 4 . We did not observe significant associations between FRs and T 4 among office workers. In the full group, intermediate body mass index and a college education were associated with higher FR levels. The inverse association observed between FRs and T 4 coupled with the lack of studies on women workers and evidence of adverse health effects from FR exposure─including endocrine disruption and breast cancer risk─warrant further research on occupational exposures and identification of opportunities for exposure reduction.

BACKGROUND Delta-8 tetrahydrocannabinol (delta-8 THC) is an isomer of delta-9-tetrahydrocannabinol (delta-9 THC), the primary psychoactive cannabinoid in the marijuana plant. Typically found at lower concentrations in marijuana, delta-8 THC exhibits psychoactive properties similar to delta-9 THC. Products containing delta-8 THC are readily available across the US and currently there is a lack of available confirmatory testing specific to delta-8 THC as there is cross-reactivity to other naturally occurring cannabinoids in standard immunoassays. Pediatric exposures to this substance are on the rise. CASE REPORT We present a case with laboratory confirmation of a previously healthy 2-year-old girl ingesting approximately 15 mg/kg of delta-8 THC gummies. The patient arrived minimally responsive and requiring intubation for encephalopathy. Laboratory confirmation of delta-8 THC exposure is not routinely available with common testing modalities. A urine drug screen preformed in the hospital was positive for delta-9 THC. With the collaboration of the Drug Enforcement Administration's Toxicology Testing Program, detection and confirmation of delta-8 THC was performed in the serum and urine using liquid chromatography-quadrupole time-of-flight mass spectrometry. CONCLUSIONS The prevalence of delta-8 THC-containing products in the illicit drug market is increasing rapidly. Delta-8 THC products are now available in gas stations and in headshops. The clinical presentation of delta-8 THC exposure is similar to known effects of delta-9 THC exposure. These similarities limit the clinicians' abilities to determine the specific substance ingested. Symptomatic and supportive care remains an effective treatment for cannabinoid toxicity.

Synthetic cannabinoid receptor agonists (SCRAs) remain a prolific class of new psychoactive substances (NPS) and continue to expand rapidly. Despite the recent identification of hydroxybenzotriazole (HOBt) containing SCRAs in synthetic cannabis samples, there is currently no information regarding the pharmacological profile of these NPS with respect to human CB 1 and CB 2 receptors. In the current study, a series consisting of seven HOBt indole-, indazole-, and 7-azaindole-carboxylates bearing a range of N -alkyl substituents were synthesized and pharmacologically evaluated. Competitive binding assays at CB 1 and CB 2 demonstrated that all analogues except a 2-methyl-substituted derivative had low affinity for CB 1 ( K i = 3.80-43.7 μM) and CB 2 ( K i = 2.75-18.2 μM). A fluorometric functional assay revealed that 2-methylindole- and indole-derived HOBt carboxylates were potent and efficacious agonists of CB 1 (EC 50 = 12.0 and 63.7 nM; E max = 118 and 120%) and CB 2 (EC 50 = 10.9 and 321 nM; E max = 91 and 126%). All other analogues incorporating indazole and 7-azaindole cores and bearing a range of N1-substituents showed relatively low potency for CB 1 and CB 2 . Additionally, a reporter assay monitoring β-arrestin 2 (βarr2) recruitment to the receptor revealed that the 2-methylindole example was the most potent and efficacious at CB 1 (EC 50 = 131 nM; E max = 724%) and the most potent at CB 2 (EC 50 = 38.2 nM; E max = 51%). As with the membrane potential assay, the indazole and other indole HOBt carboxylates were considerably less potent at both receptors, and analogues comprising a 7-azaindole core showed little activity. Taken together, these data suggest that NNL-3 demonstrates little CB1 receptor activity and is unlikely to be psychoactive in humans. NNL-3 is likely an unintended SCRA manufacturing byproduct. However, the synthesis of NNL-3 analogues proved simple and general, and some of these showed potent cannabimetic profiles in vitro , indicating that HOBt esters of this type may represent an emerging class of SCRA NPS.

Background: Environmental chemical exposures can affect telomere length, which in turn has been associated with adverse health outcomes including cancer. Firefighters are occupationally exposed to many hazardous chemicals and have higher rates of certain cancers. As a potential biomarker of effect, we assessed associations between chemical exposures and telomere length in women firefighters and office workers from San Francisco, CA., Methods: We measured serum concentrations of polyfluoroalkyl substances (PFAS), urinary metabolites of flame retardants, including organophosphate flame retardants (OPFRs), and telomere length in peripheral blood leukocytes in women firefighters (N = 84) and office workers (N = 79) who participated in the 2014-15 Women Workers Biomonitoring Collaborative. Multiple linear regression models were used to assess associations between chemical exposures and telomere length., Results: Regression results revealed significant positive associations between perfluorooctanoic acid (PFOA) and telomere length and perfluorooctanesulfonic acid (PFOS) and telomere length among the whole cohort. Models stratified by occupation showed stronger and more significant associations among firefighters as compared to office workers. Among firefighters in models adjusted for age, we found positive associations between telomere length and log-transformed PFOA (β (95%CI) = 0.57(0.12, 1.02)), PFOS (0.44 (0.05, 0.83)), and perfluorodecanoic acid (PFDA) (0.43 (0.02, 0.84)). Modeling PFAS as categories of exposure showed significant associations between perfluorononanoic acid (PFNA) and telomere length among firefighters. Significant associations between OPFR metabolites and telomere length were seen for bis (1,3-dichloro-2-propyl) phosphate (BDCPP) and telomere length among office workers (0.21(0.03, 0.40)) and bis (2-chloroethyl) phosphate (BCEP) and telomere length among firefighters (- 0.14(- 0.28, - 0.01)). For OPFRs, the difference in the direction of effect by occupational group may be due to the disparate detection frequencies and concentrations of exposure between the two groups and/or potential unmeasured confounding., Conclusion: Our findings suggest positive associations between PFAS and telomere length in women workers, with larger effects seen among firefighters as compared to office workers. The OPFR metabolites BDCPP and BCEP are also associated with telomere length in firefighters and office workers. Associations between chemical exposures and telomere length reported here and by others suggest mechanisms by which these chemicals may affect carcinogenesis and other adverse health outcomes., (© 2021. The Author(s).)

Synthetic cannabinoid receptor agonists (SCRAs) are one of the largest and most structurally diverse classes of new psychoactive substances (NPS). Despite this, pharmacological data are often lacking following the identification of a new SCRA in drug markets. In this first of a three-part series, we describe the synthesis, analytical characterization, and binding affinity of a proactively generated, systematic library of 30 indole, indazole, and 7-azaindole SCRAs related to MMB-4en-PICA, MDMB-4en-PINACA, ADB-4en-PINACA, and MMB-4CN-BUTINACA featuring a 4-pentenyl (4en-P), butyl (B/BUT), or 4-cyanobutyl (4CN-B/BUT) tail and a methyl l-valinate (MMB), methyl l-tert-leucinate (MDMB), methyl l-phenylalaninate (MPP), l-valinamide (AB), l-tert-leucinamide (ADB), l-phenylalaninamide (APP), adamantyl (A), or cumyl head group. Competitive radioligand binding assays demonstrated that the indazole core conferred the highest CB 1 binding affinity (K i  = 0.17-39 nM), followed by indole- (K i  = 0.95-160 nM) and then 7-azaindole-derived SCRAs (K i  = 5.4-271 nM). Variation of the head group had the greatest effect on binding, with tert-leucine amides and methyl esters (K i  = 0.17-14 nM) generally showing the greatest affinities, followed by valine derivatives (K i  = 0.72-180 nM), and then phenylalanine derivatives (K i  = 2.5-271 nM). Adamantyl head groups (K i  = 8.8-59 nM) were suboptimal for binding, whereas the cumyl analogues consistently conferred high affinity (K i  = 0.62-36 nM). Finally, both butyl (K i  = 3.1-163 nM) and 4-cyanobutyl (K i  = 5.5-44 nM) tail groups were less favorable for CB 1 binding than their corresponding 4-pentenyl counterparts (K i  = 0.72-25 nM)., (© 2021 John Wiley & Sons, Ltd.)

Background: As global confirmed cases and deaths from coronavirus disease 2019 (COVID-19) surpass 100 and 2.2 million, respectively, quantifying the effects of the widespread treatment of remdesivir (GS-5734, Veklury) and the steroid dexamethasone is becoming increasingly important. Limited pharmacokinetic studies indicate that remdesivir concentrations in serum decrease quickly after dosing, so its primary serum metabolite GS-441524 may have more analytical utility., Objectives: We developed and validated a method to quantify remdesivir, its metabolite GS-441524 and dexamethasone in human serum., Methods: We used LC-MS/MS and applied the method to 23 serum samples from seven patients with severe COVID-19., Results: The method has limits of detection of 0.0375 ng/mL for remdesivir, 0.375 ng/mL for GS-441524 and 3.75 ng/mL for dexamethasone. We found low intra-patient variability, but significant inter-patient variability, in remdesivir, GS-441524 and dexamethasone levels., Conclusions: The significant inter-patient variability highlights the importance of therapeutic drug monitoring of COVID-19 patients and possible dose adjustment to achieve efficacy., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

New all-oral regimens for rifampin-resistant tuberculosis (RR-TB) are being scaled up globally. Measurement of drug concentrations in hair assesses long-term drug exposure. Delamanid (DLM) is likely to be a key component of future RR-TB treatment regimens, but a method to describe its quantification in hair via liquid chromatography-tandem mass spectrometry (LC-MS/MS) has not previously been described. We developed and validated a simple, fast, sensitive, and accurate LC-MS/MS method for quantifying DLM and its metabolite DM-6705 in small hair samples. We pulverized and extracted two milligrams of hair in methanol at 37 °C for two hours, and diluted 1:1 with water. A gradient elution method eluted DLM, DM-6705, and the internal standard OPC 14714 within 3 min, bringing overall analysis time to 5.5 min. The method has limits of detection (LOD) of 0.0003 ng/mg for DLM and 0.003 ng/mg for DM-6705. The established linear dynamic ranges are 0.003-2.1 ng/mg and 0.03-21 ng/mg for DLM and DM-6705, respectively. Eleven of 12 participant hair samples had concentrations within DLM's linear dynamic range, while all 12 samples had concentrations within the quantifiable range for DM-6705. The ranges of concentrations observed in these clinical samples for DLM and DM-6705 were 0.004-0.264 ng/mg hair and 0.412-12.041 ng/mg hair respectively. We demonstrate that while DLM was detected in hair at very low levels, its primary metabolite DM-6705 had levels approximately 100 times higher. Measuring DM-6705 in hair may accurately reflect long-term adherence to DLM-containing regimens for drug-resistant TB., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Gamma-hydroxybutyrate (GHB) is misused as an intoxicant, either alone or concurrently with other substances. Because GHB is illegal, the precursor chemicals 1,4-butanediol and gamma-butyrolactone are also misused for the same effect, either through pre-ingestion alteration or endogenous metabolism to GHB. We describe a case of a 50-year-old man with a history of polysubstance misuse who experienced an overdose of GHB from gamma-butyrolactone ingestion. The patient also co-ingested a common industrial solvent, N-methyl-2-pyrrolidone (NMP). This co-ingested substance raised theoretical concern of metabolism to a GHB congener, underscoring that the emergence of new psychoactive substance use patterns requires ongoing vigilance and toxicologic confirmation., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Treatment monitoring of drug-resistant tuberculosis (DR-TB) in resource-limited settings is challenging. We developed a multi-analyte assay for eleven anti-TB drugs in small hair samples as an objective metric of drug exposure., Methods: Small hair samples were collected from participants at various timepoints during directly observed RR-TB treatment at an inpatient tertiary referral facility in South Africa (DR-TB cohort). We assessed qualitative determination (i.e., detection above limit of detection) of bedaquiline, linezolid, clofazimine, pretomanid, levofloxacin, moxifloxacin, pyrazinamide, isoniazid, ethambutol, ethionamide, and prothionamide in an LC-MS/MS index panel assay against a reference standard of inpatient treatment records. Because treatment regimens prior to hospitalization were not available, we also analyzed specificity (for all drugs except isoniazid) using an external cohort of HIV-positive patients treated for latent TB infection with daily isoniazid (HIV/LTBI cohort) in Uganda., Results: Among the 57 DR-TB patients (58% with pre-XDR/XDR-TB; 70% HIV-positive) contributing analyzable hair samples, the sensitivity of the investigational assay was 94% or higher for all drugs except ethionamide (58.5, 95% confidence interval [CI], 40.7-99.9). Assay specificity was low across all tested analytes within the DR-TB cohort; conversely, assay specificity was 100% for all drugs in the HIV/LTBI cohort., Conclusions: Hair drug concentrations reflect long-term exposure, and multiple successive regimens commonly employed in DR-TB treatment may result in apparent false-positive qualitative and falsely elevated quantitative hair drug levels when prior treatment histories within the hair growth window are not known.

Phthalates are reproductive toxicants in experimental animal studies and exposure has been associated with infertility in human populations, although the results have been inconsistent. To help to address the data gap, we conducted a hypothesis-generating investigation of associations between urinary phthalate metabolites and reproductive outcomes among women (n = 56) and their male partners (n = 43) undergoing in vitro fertilization (IVF). Urine was collected from participants on the day of oocyte retrieval. Samples were analyzed for a series of phthalates, MEP, MBP, MPP, MHxP, MEHP, MEHHP, MECPP, MiNP, MiDP, MCHP, and MBzP, using liquid chromatography-tandem mass spectrometry. We employed Poisson regression with robust variance estimation to estimate associations between urinary phthalate levels and biochemical pregnancy and live birth, adjusted for partner's concentration and confounding factors. Doublings in women's MBP (relative risk (RR) = 0.32, 95 % CI: 0.13, 0.78), and men's MEHP (RR = 0.28, 95 % CI: 0.09, 0.83), were associated with a lower likelihood for pregnancy. Doublings in women's (RR = 0.08, 95 % CI: 0.01, 0.67) and men's (RR = 0.13, 95 % CI: 0.02, 0.92) MHxP were associated with a lower likelihood of live birth. Our results suggest that phthalate exposure may impact IVF outcomes, and underscore the importance of including male partners when investigating the impact of phthalate exposure on IVF. These results also suggest that clinical recommendations should include male partners for limiting phthalate exposure. Still, a larger and more comprehensive investigation is necessary to more definitively assess the risks., Competing Interests: Declaration of Competing Interest The authors report no declarations of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Synthetic cannabinoid receptor agonists (SCRAs) are an evolving class of new psychoactive substances (NPS) with structurally diverse compounds emerging each year. Due to the rapid pace at which these drugs enter the market, there is often little or nil information regarding the pharmacology of these substances despite widespread human use. In this study, 12 recently emerged SCRAs (reported between 2018 and 2020) were synthesized, analytically characterized, and pharmacologically evaluated using a live cell-based nanoluciferase complementation reporter assay that monitors in vitro cannabinoid receptor type 1 (CB1) activation via its interaction with β-arrestin 2 (βarr2). All synthesized SCRAs acted as agonists of CB1, although differences in potency (EC 50 = 2.33-5475 nM) and efficacy ( E max = 37-378%) were noted, and several structure-activity relationships were identified. SCRAs featuring indazole cores (EC 50 = 2.33-159 nM) were generally of equal or greater potency than indole analogues (EC 50 = 32.9-330 nM) or 7-azaindole derivatives (EC 50 = 64.0-5475 nM). Interestingly, with the exception of APP-BINACA ( E max = 75.7%) and 5F-A-P7AICA ( E max = 37.4%), all SCRAs showed greater efficacy than the historical SCRA JWH-018 to which responses were normalized ( E max = 142-378%). The most potent CB1 agonists in the study were ADB-BINACA (EC 50 = 6.36 nM), 4F-MDMB-BINACA (EC 50 = 7.39 nM), and MDMB-4en-PINACA (EC 50 = 2.33 nM). Notably, all of these SCRAs featured an indazole core as well as a "bulky" tert -butyl moiety in the pendant amino acid side chain. This study confirms that recently detected SCRAs 4F-MDMB-BICA, 5F-MPP-PICA, MMB-4en-PICA, CUMYL-CBMICA, ADB-BINACA, APP-BINACA, 4F-MDMB-BINACA, MDMB-4en-PINACA, A-CHMINACA, 5F-AB-P7AICA, 5F-MDMB-P7AICA, and 5F-AP7AICA were all able to activate the CB1 receptor in vitro, albeit to different extents, and are potentially psychoactive in vivo. These results indicate that further evaluation of these widely used NPS is warranted to better understand the risks associated with human consumption of these drugs.

Objectives: The purpose of this study was to characterize the stress experienced by pregnant women in Kenya and assess the relationship between perceived stress and stress-related biomarkers of cortisol and cortisone. Background: Kenyan women are exposed to multiple stressors that may result in chronic stress. However, antenatal stress has not been examined and characterized in Kenya; nor has the relationship between pregnant women's self-reported stress and stress biomarkers been established. Methods: One hundred and fifty women were recruited between 22 and 28 weeks gestation. Participants completed the Perceived Stress Scale (PSS) and a sociodemographic questionnaire. Hair samples were obtained for analysis of cortisol and cortisone. Factor analysis was used to extract unique clusters of stress symptoms from items in the PSS. Regression models were computed to examine relationships of stress to cortisone and cortisol, controlling for obstetric risk. Results: Mean age of the women was 25 years (SD = 5, ±16-41). Their degree of perceived stress and cortisol/cortisone concentrations both indicated moderate levels of stress. There was no association between general perceived stress and either hair cortisol or cortisone. However, factor analysis of the PSS identified three clusters of stress symptoms and one cluster - a woman's negative frame of mind regarding life and inefficacy in handling its problems - was associated with higher levels of cortisone (β= -.231, p  = 0.011). Conclusions: Specific stress symptoms may have unique relationships to specific biomarkers and be more useful in assessment than general perceived stress. Assays of both hair cortisol and cortisone might enable a more comprehensive assessment of glucocorticoid activity and better prediction of health risks from stress.Lay summaryUnderstanding stress among rural pregnant Kenyan women may help in addressing risks during pregnancy that lead to adverse birth outcomes. Findings suggest that a woman's tendency to think negatively about life and to doubt her ability to handle life's problems are symptoms of stress that may contribute to higher levels of stress hormones. Assessing women's specific symptoms of stress and different stress hormones during pregnancy may more effectively identify women who need intervention to reduce their health risk.

Phthalates have been implicated as reproductive toxicants in animal models and in human populations. This study examined associations between potential exposure sources and urinary phthalate metabolite concentrations among women (n = 56) and their male partners (n = 43) undergoing in vitro fertilization (IVF). On the day of oocyte retrieval, participants provided urine samples and completed questionnaires detailing use of personal care products (PCPs), and consumption of medications, foods, and beverages in the preceding 24 h. Urine was analyzed for MEP, MBP, MPP, MHxP, MEHP, MEHHP, MECPP, MiNP, MiDP, MCHP, and MBzP, via liquid chromatography-tandem mass spectrometry. We employed principal component analysis (PCA) to summarize exposure sources and regression models to estimate associations between exposure patterns and urinary phthalate metabolites, adjusted for confounding variables. Among women, application of more body washes and eye creams, and consumption of more supplements, was associated with greater urinary MECPP [relative difference = 1.36 (95% CI: 1.28, 1.45)] and the molar sum of DEHP metabolites, including MEHP, MEHHP, and MECPP [∑DEHP; 1.26 (95% CI: 1.17, 1.34)]. Among men, consumption of more supplements and allergy medications was associated with greater urinary MECPP, MEHHP, and ∑DEHP [relative difference = 1.13 (95% CI: 1.02, 1.23)] concentrations. Identifying differences in sources of phthalate exposure may help clinicians to intervene to reduce exposure as part of a comprehensive strategy to help improve IVF outcomes., (Copyright © 2020 Elsevier GmbH. All rights reserved.)

Flualprazolam is a nonregistered drug in the benzodiazepine family and constitutes a new psychoactive substance (NPS). Since 2014, a growing number of designer benzodiazepines have become available over the Internet and on the counterfeit drug market. In June 2019, a cluster of patients intoxicated with flualprazolam was identified by the Oregon Poison Center. As an emerging drug of abuse, the clinical characteristics of flualprazolam have been poorly characterized thus far. Over a one-week period, 6 teenagers presented to local emergency departments after ingesting illegally obtained counterfeit alprazolam, which led to sedation. Other symptoms included slurred speech, confusion, and mild respiratory depression. All 6 patients had resolution of their symptoms within 6 hours of ingestion. Blood and urine samples, as well as a tablet fragment, were obtained from 3 patients. The tablet and biological samples were analyzed by using liquid chromatography-quadrupole time-of-flight mass spectrometry and were found to contain the NPS flualprazolam without other drugs or intoxicants. With this case series, we add to the medical literature a clinical description of an emerging drug of abuse. Flualprazolam appears to share the clinical properties of other benzodiazepines. As flualprazolam and other NPSs become more common, physicians must be aware of their availability and characteristics. Sedation lasting <6 hours was observed in 6 of 6 patients exposed to flualprazolam. No effects that would be unexpected from benzodiazepine intoxication were seen among the patients. Specifically, none developed prolonged symptoms or required intubation and mechanical ventilation, ICU admission, or antidotal therapy., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2020 by the American Academy of Pediatrics.)

Drug resistant-tuberculosis (DR-TB) is a growing public health threat, and assessment of therapeutic drug levels may have important clinical benefits. Plasma drug levels are the current gold standard assessment, but require phlebotomy and a cold chain, and capture only very recent adherence. Our method uses hair, a matrix that is easily collected and reflective of long-term adherence, to test for 11 anti-TB medications. Previous work by our group shows that antiretroviral drug levels in hair are associated with HIV outcomes. Our method for DR-TB drugs uses 2 mg of hair (3 cm proximal to the root), which is pulverized and extracted in methanol. Samples are analyzed with a single LC-MS/MS method, quantifying 11 drugs in a 16 min run. Lower limits of quantification (LLOQs) for the 11 drugs range from 0.01 ng/mg to 1 ng/mg. Drug presence is confirmed by comparing ratios of two mass spectrometry transitions. Samples are quantified using the area ratio of the drug to the deuterated, 15 N-, or 13 C-labeled drug isotopologue. We used a calibration curve ranging from 0.001-100 ng/mg. Application of the method to a convenience sample of hair samples collected from DR-TB patients on directly observed therapy (DOT) indicated drug levels in hair within the linear dynamic range of nine of the eleven drugs (isoniazid, pyrazinamide, ethambutol, linezolid, levofloxacin, moxifloxacin, clofazimine, bedaquiline, pretomanid). No patient was on prothionamide, and the measured levels for ethionamide were close to its LLOQ (with further work instead examining the suitability of ethionamide's metabolite for monitoring exposure). In summary, we describe the development of a multi-analyte panel for DR-TB drugs in hair as a technique for therapeutic drug monitoring during drug-resistant TB treatment.