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Supplementary Figure 2 from Genome-Wide Impact of Androgen Receptor Trapped clone-27 Loss on Androgen-Regulated Transcription in Prostate Cancer Cells

Supplementary Figure 3 from Genome-Wide Impact of Androgen Receptor Trapped clone-27 Loss on Androgen-Regulated Transcription in Prostate Cancer Cells

Supplementary Figure and Table Legends from Genome-Wide Impact of Androgen Receptor Trapped clone-27 Loss on Androgen-Regulated Transcription in Prostate Cancer Cells

Steroid-refractory chronic graft versus host disease (cGVHD) remains a significant cause of morbidity and mortality following allogeneic transplantation. Abatacept is a selective co-stimulation modulator, used for the treatment of rheumatologic disease, and was recently the first drug to be approved by the FDA for the prophylaxis of acute graft versus host disease. We conducted a Phase II study to evaluate the efficacy of Abatacept in steroid-refractory cGVHD (clinicaltrials.gov #NCT01954979). The overall response rate was 58%, with all responders achieving a partial response. Abatacept was well-tolerated with few serious infectious complications. Immune correlative studies showed a decrease in IL-1-alpha, IL-21, and TNF-alpha as well as decreased PD-1 expression by CD4+ T cells in all patients after treatment with Abatacept, demonstrating the effect of this drug on the immune microenvironment. The results demonstrate that Abatacept is a promising therapeutic strategy for the treatment of cGVHD.

We examine the spiral structure of the thinking and the work of Marshall McLuhan, which we believe will provide a new way of viewing McLuhan’s work. In particular, we believe that the way he reversed figure and ground, reversed content and medium, reversed cause and effect, and the relationship he established between the content of a new medium and the older media it obsolesced all contain a spiral structure going back and forth in time. Finally, the time structure of his Laws of Media in which a new medium obsolesced an older medium, while retrieving an even older medium and then when pushed far enough flipped into a still newer medium has the feeling of a spiral. We will also examine the spiral structure of the thinking and work of those thinkers and artists that most influenced McLuhan such as Vico, Hegel, Marx, Freud, Joyce, TS Eliot, Wyndham Lewis and the Vorticism movement. Keywords: spiral; McLuhan; reversal; figure/ground; Laws of Media; media; environment/anti-environment; cause; effect

COVID-19 disproportionately affects racial and ethnic minority populations, but comparatively few epidemiologic studies have been performed on children as compared to adults.To characterise factors associated with SARS-CoV-2 infections amongst children from Chicago, Illinois, USA.A test-negative case-control study of children tested for SARS-CoV-2 (0-18 years) at three medical centres of the Rush University System for Health between 12 March and 7 December 2020 was conducted. Of 8462 children, 1,302 tested positive by real-time PCR or rapid (NAAT) testing. Infection with SARS-CoV-2 was analysed as the outcome variable; effects of predictors were assessed by logistic regression analysis. A Paediatric Risk Score Index with a concordance index of 72% of accuracy was created to predict SARS-CoV-2 infection.The median age of cases was 13 years. On multivariable analysis, factors associated with SARS-CoV-2 infection were being Hispanic/Latinx (odds ratio [OR] 2.45, 95% CI 1.99, 3.03); Black/African-American (OR 1.31, 95% CI 1.03, 1.66); overweight/obese (OR 1.27, 95% CI 1.02, 1.58); older age, 10-14 years (OR 1.70, 95% CI 1.39, 2.08), 15-18 years (OR 2.06, 95% CI 1.71, 2.47); from households with income$50,000 (OR 1.36, 95% CI 1.17, 1.60); or residing in predominantly minority neighbourhoods (OR 1.45, 95% CI 1.17, 1.80). Infections were higher during the second "fall" wave (5 October 2020 onward) compared with the first "spring" wave (OR 2.30, 95% CI 2.01, 2.63). Within Chicago, racial/ethnic minority neighbourhoods had striking positivity rates, as high as 39% in majority Hispanic/Latinx West Lawn neighbourhood. In suburban Chicago, highest positivity rates (20%-28%) were in zip codes within Hispanic/Latinx communities.Infection with SARS-CoV-2 is more likely amongst children of Hispanic/Latinx ethnicity, Black/African-American race, aged 10-18 years, who are overweight/obese, from lower income households, and from minority neighbourhoods. Future studies should focus on the prevention of COVID-19 infection in children of highest risk.

Novel psychoactive substances (NPS) continue to represent a threat to public health and safety. The number of new drugs in the latest emergent synthetic opioid class—the 2-benzylbenzimidazole analogs—also called the nitazenes—has begun to dominate the current new synthetic opioid (NSO) subclass of NPS. We describe a liquid chromatography–tandem quadrupole mass spectrometry method for the quantification of nine analogs and/or metabolites of drugs in this series: isotonitazene, metonitazene, protonitazene, etonitazene, clonitazene, flunitazene, N-desethyl isotonitazene, 5-amino isotonitazene and 4ʹ-hydroxy nitazene in human whole blood, urine, and tissue. Samples were prepared for analysis using a basic liquid–liquid extraction. Chromatographic separation was achieved using a C-18 analytical column. Multiple reaction monitoring mode was used for detection. The calibration range for the analytes was 0.5–50 ng/mL (except for 5-amino isotonitazene, which was 1.0–50 ng/mL). The limit of detection was 0.1 ng/mL, and the limit of quantitation was 0.5 ng/mL. The method had no carryover or interferences. Ionization enhancement was observed but did not affect quantitation. All analytes passed the method validation assessment. Authentic human samples suspected of containing NSOs were obtained from a medical examiner and coroner offices, as well as partnering forensic toxicology laboratories. Isotonitazene was confirmed in 92 blood samples, and its metabolites were confirmed across various matrices. Metonitazene (n = 35), flunitazene (n = 5), protonitazene (n = 3), etodesnitazene (n = 2) and butonitazene (n = 1) were also detected in cases. These newly emerging 2-benzylbenzimidazole analogs were commonly found in combination with NPS benzodiazepines and opioids (e.g., flualprazolam, fentanyl). Nitazene analogs are potent esoteric drugs that may not be identified during routine toxicological screening, and specialized assays based on sensitive instrumentation are needed to accurately characterize these NSOs.

The purpose of this study was to examine the impact of 59 novel psychoactive compounds on common enzyme-linked immunosorbent assay (ELISA) testing kits. Concentrations above and below the individual kit reporting limits in each class were measured. Compounds that exhibited cross-reactivity were then spiked individually using a seven-point response curve to determine the level of cross-reactivity. Diclazepam, delorazepam, phenazepam, flualprazolam, bromazolam, adinazolam, 3-methoxy-PCP, 3-hydroxy-PCP (3-OH-PCP), phenylfentanyl, para-methylacetylfentanyl and para-fluorofuranylfentanyl were determined to cross-react in the respective kits below. Herein, we detail the cross-reactivity that was observed with the above novel psychoactive substances on Immunalysis Benzodiazepine (BEN), Phencyclidine (PCP), Fentanyl (FEN), Buprenorphine (BUP), Opiates (OPI) and Oxycodone (OXY) Direct ELISA kits.

The roosterfish (Nematistius pectoralis) is a piscivorous predator targeted extensively in recreational fisheries throughout the eastern tropical Pacific; however, its biology is poorly understood. To address these shortcomings, we investigated vertical habitat use and behaviour of roosterfish in coastal Panama using pop-up satellite archival tags. Nearly 5000 h of vertical movement data across 274 days from five fish showed that roosterfish largely used the upper 10 m and 20 m of the water column during the night-time and daytime respectively, and rarely left the mixed layer. Roosterfish diving behaviour showed a clear diurnal pattern, with oscillatory dives beginning during dawn and continuing through dusk. Accelerometer data showed that this period was also associated with a sharp increase in activity during dawn and a decrease around sunset. Whereas previous work in shallow systems (

Executive summaryTesting of asymptomatic patients for severe acute respiratory coronavirus virus 2 (SARS-CoV-2) (ie, “asymptomatic screening) to attempt to reduce the risk of nosocomial transmission has been extensive and resource intensive, and such testing is of unclear benefit when added to other layers of infection prevention mitigation controls. In addition, the logistic challenges and costs related to screening program implementation, data noting the lack of substantial aerosol generation with elective controlled intubation, extubation, and other procedures, and the adverse patient and facility consequences of asymptomatic screening call into question the utility of this infection prevention intervention. Consequently, the Society for Healthcare Epidemiology of America (SHEA) recommends against routine universal use of asymptomatic screening for SARS-CoV-2 in healthcare facilities. Specifically, preprocedure asymptomatic screening is unlikely to provide incremental benefit in preventing SARS-CoV-2 transmission in the procedural and perioperative environment when other infection prevention strategies are in place, and it should not be considered a requirement for all patients. Admission screening may be beneficial during times of increased virus transmission in some settings where other layers of controls are limited (eg, behavioral health, congregate care, or shared patient rooms), but widespread routine use of admission asymptomatic screening is not recommended over strengthening other infection prevention controls. In this commentary, we outline the challenges surrounding the use of asymptomatic screening, including logistics and costs of implementing a screening program, and adverse patient and facility consequences. We review data pertaining to the lack of substantial aerosol generation during elective controlled intubation, extubation, and other procedures, and we provide guidance for when asymptomatic screening for SARS-CoV-2 may be considered in a limited scope.

Background Black Americans have been disproportionately impacted by COVID-19, with systemic inequities contributing to increased incidence and mortality. In Chicago, access to COVID-19 testing was scarce in many predominantly Black neighborhoods early in the pandemic, exacerbating inequities. We aimed to assess uptake and yield of a COVID-19 testing campaign to increase access in high-risk, underserved Chicago communities. Methods The Alive Church Network (ACN) is a community-driven coalition of Black pastors and public health researchers developed to address health inequities in Chicago. For this initiative, ACN implemented two strategies to improve access to COVID-19 testing in underserved neighborhoods: 1) church-based testing, with nurses and community health workers (CHWs) stationed in churches to perform PCR testing for community members and church staff (Dec 2020-Dec 2021) and 2) community site testing, with nurses and CHWs deployed to 8 local sites (e.g., Salvation Army) to conduct weekly PCR testing for employees and clients (May 2021-Mar 2022). We assessed characteristics of individuals undergoing testing; symptom and exposure history; and COVID-19 positivity. In addition, we compared positivity for ACN sites with Chicago citywide positivity over time. Results A total of 3420 tests were performed for 1703 individuals. Of those tested, 931 (54.7%) were tested at churches and 772 (45.3%) were tested at community partner sites. Those presenting to churches were older (mean 44.8 vs. 39.1 years), more likely to be female (56.5% vs. 48.5%), and more likely to have a chronic medical condition (37.1% vs. 22.5%, Table). Prevalence of COVID-19 symptoms and exposure history were similar for those presenting to church and community sites (Table). Overall, ACN test positivity was similar to Chicago citywide positivity; however, ACN test positivity was much higher during the Omicron surge (24% vs. 11%, Figure). Characteristics of individuals tested for COVID-19 at church and community sites COVID-19 test positivity, ACN sites vs. Chicago citywide Conclusion The ACN testing campaign increased access to COVID-19 testing in underserved neighborhoods in Chicago and had high yield during the Omicron surge. Church-based testing was successful for reaching older, medically vulnerable individuals. Ensuring widespread access to testing is essential for health equity and to reduce COVID-19 morbidity and mortality. Disclosures All Authors: No reported disclosures.

Synthetic opioids constitute one of the fastest-growing groups of new psychoactive substances (NPS) worldwide. With fentanyl analogues being increasingly controlled via classwide scheduling, many non-fentanyl-related opioids are now emerging on the recreational opioid market, rendering the landscape highly complex and dynamic. While new compounds are entering the supply in rapid and unpredictable manners, some recent patterns have become apparent. Many of these newly emerging opioids are being pirated from early patent literature and/or research papers, synthesized and sold online through various channels. Burdened by the identification of every newly emerging drug, many toxicology labs struggle to keep up. Moreover, by the time a ‘new’ drug is controlled via legislative measures, illicit drug markets will have already adapted and diversified as manufacturers work to avoid the restricted product(s). Hence, the typical life cycle of an NPS opioid is generally short (less than 6 months to 1 year), with only a few drugs escalating to significant numbers of detections. In this review, we summarize the key events in the emergence, rise and subsequent decline of two non-fentanyl opioids—isotonitazene and brorphine. These two opioids sequentially dominated the NPS opioid market in 2019 and 2020. Both isotonitazene and brorphine remained in circulation for over a year, each contributing to hundreds of deaths and adverse events. By detailing the life cycles of these opioids from their earliest synthesis as described in scientific literature to their subsequent rise and fall on recreational markets, this review illustrates the new characteristic life cycle of synthetic opioids in the ‘post-fentanyl-analogue’ era.

Non-pharmaceutical fentanyl and its analogs have driven striking increases in opioid-associated overdose deaths. These highly potent opioids can be found at low concentrations in biological specimens. Little is known regarding the concentrations of these substances among survivors of non-fatal overdoses. In a locale where fentanyl is responsible for the majority of non-fatal opioid overdoses, we compared the concentration of fentanyl in blood to naloxone dosing in the presence and absence of a concurrent sedative-hypnotic exposure.In this pilot study, we enrolled adult patients presenting to the emergency department (ED) who: (1) arrived after an overdose requiring naloxone for the reversal of respiratory depression; and (2) who required venipuncture or intravenous access as part of their clinical care. Blood specimens (Nineteen of twenty participants (95%) were exposed to fentanyl prior to their overdose; the remaining participant tested positive for heroin metabolites. No participants reported pharmaceutical fentanyl use. Fentanyl analogs - acetylfentanyl or carfentanil - were present in three specimens. In 11 cases, fentanyl and its metabolites were the only opioids identified. Among the fentanyl-exposed, blood concentrations ranged from0.1-19 ng/mL with a mean of 6.2 ng/mL and a median of 3.6 ng/mL. There was no relationship between fentanyl concentration and naloxone dose administered for reversal. We detected sedative-hypnotics (including benzodiazepines, muscle relaxants, and antidepressants) in nine participants. Among the sedative-hypnotic exposed, fentanyl concentrations were lower, but naloxone dosing was similar to those without a concomitant exposure.In this study, we found that: 1) fentanyl was present in the blood of nearly all participants; 2) fentanyl concentrations were lower among study participants with concomitant sedative-hypnotic exposure; and 3) the dose of naloxone administered for overdose reversal was not associated with the measured fentanyl concentration in blood specimens. Our results underscore the role that tolerance and concomitant drug exposure play in the precipitation and resuscitation of management of opioid overdose.

Prostate cancers adapt to androgen receptor (AR) pathway inhibitors and progress to castration resistance despite the continued expression and function of the AR. We developed a new approach to antagonize the proliferative activity of AR and inhibit castration-resistant prostate cancer (CRPC) growth using multivalent peptoid conjugates (MPCs). Our strategy is to display multiple copies of the AR antagonist, ethisterone, on a peptoid scaffold. Such a multivalent display increases the ligand’s effective local concentration, thus targeting AR with high affinity and affecting AR interactions with coregulators. Here, we report a new potent MPC called MPC309, which displays three ethisterone groups and binds to AR with nanomolar affinity. MPC309 reduces the proliferation of enzalutamide-resistant prostate cancer cells, including those harboring AR splice variants, AR ligand binding mutations, and non-canonical AR gene expression programs. We provide evidence that MPC309 enters cells via macropinocytosis, which facilitates the fluid-phase uptake of extracellular macromolecules. Macropinocytotic uptake of MPC309 enhances cancer cell-specific delivery, thus limiting systemic toxicities. MPC309 displays favorable pharmacological properties and produced significantly greater tumor suppression in xenograft studies than enzalutamide, the standard of care anti-androgen in clinical use. Mechanistically, MPC309 inhibits prostate cancer growth by eliciting a unique gene expression program through alterations in AR chromatin occupancy compared to dihydrotestosterone (DHT) or enzalutamide. Thus, MPC309 represents a novel AR antagonist that activates an AR anti-proliferative program to repress the growth of CRPC and supports further investigation of the MPC compound class for treating CRPC. Citation Format: Justine Habault, Jeffrey A. Schneider, Susan Ha, Rachel Ruoff, Joseph Puccini, Dafna Bar-Sagi, Kwok-Kin Wong, Amina Zoubeidi, Frank Claessens, David R. Wise, Susan K. Logan, Kent Kirshenbaum, Michael J. Garabedian. A multivalent peptoid conjugate that inhibits therapy-resistant prostate cancer cell proliferation by modulating androgen receptor transcriptional activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3441.

This report describes updates to the National Safety Council’s Alcohol, Drugs and Impairment Division’s recommendations for drug testing in driving under the influence of drug (DUID) cases and motor vehicle fatalities. The updates are based on a survey of drug testing practices in laboratories in the USA and Canada, a comprehensive review of the prior recommendations and data and research on drugs most frequently detected in DUID cases. A consensus meeting was held with representative forensic science practitioners and the authors of this report to update recommendations. No changes were made to the Tier I scope; however, there were changes to cutoffs of some analytes for blood, urine and oral fluid. Due to increased prevalence in DUID cases, trazodone and difluoroethane were added to the Tier II scope. For clarification, Tier I cutoffs reflect free concentrations, and hydrolysis is recommended but not required. The consensus panel concluded that urine is an inferior matrix to blood and oral fluid as it may represent historical use or exposure unrelated to observed impairment; therefore, future iterations of these recommendations will not include urine as a recommended matrix. Laboratories currently testing urine should work with traffic safety partners to encourage the use of blood and oral fluid as more appropriate specimens and adjust their capabilities to provide that testing.

The present study examined the individual differences of radical anti-fascist sympathizers who were federally charged for crimes committed in Portland, Oregon, between May and October of 2020. Anti...

Isotonitazene is an illicit synthetic opioid associated with many intoxications and fatalities. Recent studies show that isotonitazene is a potent µ-opioid receptor (MOR) agonist in vitro, but little information is available about its in vivo effects.The aims of the present study were to investigate the pharmacokinetics of isotonitazene in rats, and relate pharmacokinetic parameters to pharmacodynamic effects.Isotonitazene and its metabolites were identified and quantified by liquid chromatography tandem quadrupole mass spectrometry (LC-QQQ-MS). Male Sprague-Dawley rats with jugular catheters and subcutaneous (s.c.) temperature transponders received isotonitazene (3, 10, 30 µg/kg, s.c.) or its vehicle. Blood samples were drawn at 15, 30, 60, 120, and 240 min post-injection, and plasma was assayed using LC-QQQ-MS. At each blood draw, body temperature, catalepsy scores, and hot plate latencies were recorded.Maximum plasma concentrations of isotonitazene rose in parallel with increasing dose (range 0.2-9.8 ng/mL) and half-life ranged from 23.4 to 63.3 min. The metabolites 4'-hydroxy nitazene and N-desethyl isotonitazene were detected, and plasma concentrations were below the limit of quantitation (0.5 ng/mL) but above the limit of detection (0.1 ng/mL). Isotonitazene produced antinociception (EDIn summary, isotonitazene is a potent MOR agonist whose pharmacodynamic effects are related to circulating concentrations of the parent drug. The high potency of isotonitazene portends substantial risk to users who are exposed to the drug.

The synthetic cannabinoid receptor agonist (SCRA) market is transnational, and the availability of individual SCRAs changes regularly in response to national and international legislative controls. This generates a cyclic pattern and near constant evolution of SCRA compounds. This study reports toxicology-based and/or seized sample-based prevalence data relating to SCRA use in prisons from Germany, the United Kingdom (UK; Scotland and Wales), and the United States (US), representing 4427 individual test results. The study examines SCRA detections in prisons from July 2018 to September 2020, and where possible, prison-based data are compared with SCRA prevalence data in the wider population. The relative influence of Chinese, other international, and national drug legislation on the prevalence of individual SCRAs in prisons is also considered. tert-Leucinate- and valinate-indole- and indazole-3-carboxamides were the most common SCRA detections, and MDMB-4en-PINACA was one of the most commonly detected SCRAs in all jurisdictions by September 2020. However, despite there being a global production and supply market, there were notable regional differences. Analog controls in German and US legislation may have led to increased compound diversity that is not reflected in the UK which has both analog controls and a blanket ban on psychoactive substances. While there were regional differences, SCRA prevalence in prisons closely aligned with the SCRAs detected on the local market, demonstrating that SCRA (and possibly other NPS) monitoring programs in prisons can act as early warning systems for the wider population in that given jurisdiction.

HighlightsCommercial truck drivers are a significant component of the logging workforce, and driver qualifications are an important component of managing risk.Some error types important in crash causation involve cognitive factors, which are effectively addressed by lecture or on-line training.There is evidence for the effectiveness of lecture-type driver training as an intervention for managing fatigue, situational awareness, and driving behavior.Adoption of trained behavior is supported by individual factors, a company safety culture, and supervisor feedback.Abstract. The logging industry relies on owner-operators and employed commercial drivers, who comprise up to 40% of logging employment, to transport products from the forest to the mill gate. Truck drivers are exposed to many of the same risks as logging workers as well as additional risks from vehicle crashes. Vehicle crash risks contribute to risk of personal injury and liability related to public safety, which are critical reasons for enhancing driver qualifications. Driver qualifications can be influenced by hiring better drivers and improving drivers’ skills through training even after they have received their commercial driver’s license. To explore the effectiveness of driver training in the logging industry, we reviewed studies of commercial driver training assessment and training interventions that included lectures (on-line or in-person) as a main component. Decision errors and violations are important in crash causation and involve cognitive skills, which are addressed by this type of training. Additionally, lecture training is more accessible than behind-the-wheel or simulator training for logging operations that employ just a few drivers. In their efforts to improve driver qualifications, large commercial carriers often provide driver training, reinforce the training through monitoring, and rely heavily on driver selection. The literature supports the effectiveness of training related to cognitive factors, including fatigue management, behavior, and situational awareness. Successful lecture training interventions are accompanied by individual feedback or coaching. Training that produces measurable outcomes (behavior or crash risk) is supported by a suite of factors involving the trainee, the training, and the company or supervisor. Keywords: Commercial vehicles, Logging, Training, Trucking.

Objective: In this study, we investigate extremists’ appraisals of and sensitivity to perceived sanction risk during the commission of arson. We pay specific attention to the decision-making processes of extremists leading up to and during the offending opportunity. Methods: We examined data collected from self-reported communiqués ( n = 275) describing acts of arson committed by radical environmental extremists. Results: We found that extremists, like other criminals, are sensitive to situational factors that affect the certainty of apprehension. Additionally, extremists work to reduce the risk of detection by engaging in crime-specific risk management techniques prior to and during the offending opportunity. Conclusions: Analysis of the communiqués is consistent with recent works on extremism, situational crime prevention, and restrictive deterrence. We discuss our findings in the context of rational choice and situational crime prevention theory and the advancement of preventative policies aimed at ideological and political crime.

Objective:To develop a pediatric research agenda focused on pediatric healthcare-associated infections and antimicrobial stewardship topics that will yield the highest impact on child health.Participants:The study included 26 geographically diverse adult and pediatric infectious diseases clinicians with expertise in healthcare-associated infection prevention and/or antimicrobial stewardship (topic identification and ranking of priorities), as well as members of the Division of Healthcare Quality and Promotion at the Centers for Disease Control and Prevention (topic identification).Methods:Using a modified Delphi approach, expert recommendations were generated through an iterative process for identifying pediatric research priorities in healthcare associated infection prevention and antimicrobial stewardship. The multistep, 7-month process included a literature review, interactive teleconferences, web-based surveys, and 2 in-person meetings.Results:A final list of 12 high-priority research topics were generated in the 2 domains. High-priority healthcare-associated infection topics included judicious testing for Clostridioides difficile infection, chlorhexidine (CHG) bathing, measuring and preventing hospital-onset bloodstream infection rates, surgical site infection prevention, surveillance and prevention of multidrug resistant gram-negative rod infections. Antimicrobial stewardship topics included β-lactam allergy de-labeling, judicious use of perioperative antibiotics, intravenous to oral conversion of antimicrobial therapy, developing a patient-level “harm index” for antibiotic exposure, and benchmarking and or peer comparison of antibiotic use for common inpatient conditions.Conclusions:We identified 6 healthcare-associated infection topics and 6 antimicrobial stewardship topics as potentially high-impact targets for pediatric research.

We report a method for the detection and quantitation of 12 drugs and 2 metabolites in the same structural class as the illicit mu-opioid agonist U-47700 in human whole blood. These substances are either known or suspected to be present as potential novel opioids in illicit drug markets. The general class of these drugs was developed in pharmaceutical research programs in the 1970s, but these drugs have recently become of concern for overdoses and death in opioid users in the USA and internationally. The scope of analysis included the following compounds: methylenedioxy U-47700, ethylenedioxy U-47700, ethylenedioxy U-51754, U-69593, U-47931E (bromadoline), U-47700, U-48800, U-49900, U-51754, U-50488, propyl U-47700 and isopropyl U-47700. Additionally, two metabolites N,N-didesmethyl U-47700 and desmethyl U-47700 were also included in the scope. Drugs were extracted from human whole blood using solid-phase extraction, and the extracts were analyzed by liquid chromatography--tandem mass spectrometry. The assay was validated with respect to bias, carryover, interference, within-run and between-run precision, and accuracy. Eight medicolegal death investigation cases that had screened positive for U-48800 by liquid chromatography--time-of-flight mass spectrometry were successfully confirmed and quantified using this method. The mean and median concentrations of U-48800 in these cases were 2.5 (±2.1) and 1.8 ng/mL, respectively, with a range of concentrations of 0.27–6.2 ng/mL. Case history information including the presence of other drugs in combination are described and discussed.

New synthetic opioids continue to appear as novel psychoactive substances (NPS) on illicit drug markets. Isotonitazene emerged in mid-2019, becoming the most prevalent NPS opioid in the United States within a few months. Notification by the Drug Enforcement Administration of its intent to schedule isotonitazene in mid-2020 led to its decline in popularity and replacement with a new NPS opioid: brorphine. Brorphine is a potent synthetic opioid, but little information was previously available regarding its toxicity or involvement in impairment and death. Our laboratory developed an assay for the identification and quantitative confirmation of brorphine using standard addition. Quantitative analysis was performed using liquid chromatography-tandem mass spectrometry (LC-MS/MS). In vitro and in vivo metabolism studies were performed using pooled human liver microsomes and authentic biological specimens, respectively, with analysis by liquid chromatography quadrupole time-of-flight mass spectrometry (LC-QTOF-MS). Brorphine was confirmed in 20 authentic forensic cases, commonly found in combination with fentanyl (100%) and flualprazolam (80%). The average concentration of brorphine in blood was 2.5 ± 3.1 ng/mL (median: 1.1 ng/mL, range: 0.1-10 ng/mL). The average concentration of brorphine in urine was 4.6 ± 7.6 ng/mL (median: 1.6 ng/mL, range: 0.2-23 ng/mL). The majority of cases originated from Midwestern states. Metabolism was verified to included N-dealkylation and hydroxylation. Detailed case histories and autopsy findings are presented herein. The prevalence of brorphine continues to increase in the United States. Forensic scientists should remain aware of the ongoing emergence of new opioids, especially those outside a standard scope of toxicology testing.

The giant sea bass Stereolepis gigas Ayres 1859 (GSB) is a critically endangered top marine predator in California. Since protection in 1982 and 1994, the population has appeared to increase, and individuals within a growing population may expand their ranges to new habitats to reduce intraspecific competition and increase foraging opportunities. In 2016-2018, two GSB tagged with acoustic transmitters were detected at artificial reefs for periods of up to 3 months during October-March, and one individual travelled 53 km from an offshore island to mainland California in 56 h. Artificial reefs may provide important foraging opportunities for these protected marine predators as they recover from exploitation.

A new class of synthetic cannabinoids has emerged as new psychoactive substances (NPS). Similar in structure to JWH-022, these substances contain alkene modifications to the tail region of the synthetic cannabinoid core structure, and nomenclature denotes these new analogues as pent-4en or but-3en species. Internationally, two analogues from this new series recently emerged: MDMB-4en-PINACA and MMB-4en-PICA. Previously, data regarding activity and potential toxicity were not available.In vitroassessment of cannabinoid receptor 1 (CB1) activation via the beta-arrestin 2 recruitment was studied for three (3) pent-4en analogues, one (1) but-3en analogue, and one (1) principal metabolite. MDMB-4en-PINACA (2.47 nM, 239%), MDMB-4en-PICA (11.5 nM, 302%), and MDMB-3en-BINACA (14.3 nM, 286%) were highly potent and efficacious (comparison: JWH-018, 25.3 nM, 100%), while the potencies of MMB-4en-PICA and MDMB-4en-PINACA 3,3-dimethylbutanoic acid were markedly lower. Modifications to core and tail structural features (i.e., indole vs. indazole) led to relatively small differences in potency, while changes among the head region led to larger differences. Sample-mining and data-mining conducted on toxicology samples led to the identification of MDMB-4en-PINACA in 25 forensic toxicology cases, including postmortem and impaired driving investigations, with case details and limited histories described herein. Moderate geographical distribution of MDMB-4en-PINACA was noted in the United States with emergence in the Northeast, Midwest, South, and West regions. Results from toxicology testing paired with case history show the potential for MDMB-4en-PINACA to cause or contribute to impairment or death. Forensic scientists, public health and public safety officials, law enforcement, clinicians, medical examiners, and coroners should consider involvement of emergent synthetic cannabinoids in their work and that new analogues containing an alkene tail can retain similar or increased potency and toxicity.

Magnetic resonance image guided adaptive radiation therapy (MRgART) represents a significant improvement in our ability to deliver therapeutic radiation. However, for the process of MRgART to be carried out safely and efficiently, the covering radiation oncologist must be aware of all aspects of a patient's case, because they will be required to recontour and replan the patient before each treatment. In this report, we will demonstrate our initial experience with a video sign-out process to convey the detailed level of information required for the covering physician to treat patients safely and effectively with MRgART. We then describe our optimized video sign-out process to allow for other centers to adopt a similar approach.