Search

Tolcapone and entacapone are catechol-O-methyltransferase (COMT) inhibitors developed as adjunct therapies for treating Parkinson's disease. While both drugs have been shown to cause mitochondrial dysfunction and inhibition of the bile salt export protein (BSEP), liver injury has only been associated with the use of tolcapone. Here we used a multiscale, mechanistic model (DILIsym®) to simulate the response to tolcapone and entacapone. In a simulated population (SimPops™) receiving recommended doses of tolcapone (200 mg t.i.d.), increases in serum alanine transaminase (ALT) >3× the upper limit of normal (ULN) were observed in 2.2% of the population. In contrast, no simulated patients receiving recommended doses of entacapone (200 mg 8× day) experienced serum ALT >3× ULN. Further, DILIsym® analyses revealed patient-specific risk factors that may contribute to tolcapone-mediated hepatotoxicity. In summary, the simulations demonstrated that differences in mitochondrial uncoupling potency and hepatic exposure primarily account for the difference in hepatotoxic potential for tolcapone and entacapone. [ABSTRACT FROM AUTHOR]

Purpose: To assess the hemodynamic forces on a bifurcated abdominal aortic stent-graft under realistic conditions of flow, blood pressure, and sac pressure. Methods: Computational fluid dynamics was used to study the temporal and spatial variations in surface pressure and shear through the cardiac cycle on models of bifurcated stent-grafts derived from computed tomography in 4 patients who had previously undergone endovascular repair of abdominal aortic aneurysm (AAA). The trunk, bifurcation, and limbs of the graft were analyzed separately and as parts of a unified whole. Analyses were repeated under varying conditions of sac pressure, reflecting different conditions of perigraft flow and sac diameter change. Results: Pressure-related forces were far larger than flow-related forces in all 3 segments of all 4 cases. The largest forces acted at the bifurcation of the stent-graft. High sac pressures, seen in patients with endoleak or aneurysm dilatation, were associated with reduced transmural pressure and low-pressure-derived forces. Conclusion: Several parameters of stent-graft design affect the magnitude and distribution of forces on a bifurcated stent-graft. The forces on a stent-graft are also affected by the pressure within the aneurysm sac, which depends on stent-graft performance. [ABSTRACT FROM AUTHOR]

Polymeric materials have been a great boon to the development and wellbeing of mankind. However, in the main, these materials are flammable and must be flame retarded for most applications. Many substances have been utilized to impart a measure of flame retardancy. The most widely used and most effective have been organic: organohalogen and organophosphorus compounds. Organohalogen compounds have been popular, low-cost, very effective flame retardants for polymeric materials. However, with the recognition that these compounds readily migrate from a polymer matrix into which they have been incorporated, persist in the environment and pose serious risks to human health, the use of organophosphorus compounds has become prominent. In particular, organophosphorus compounds of appropriate structure derived from readily-available, renewable, low-cost, non-toxic biobased precursors are attractive. Avoidance of the issues of environmental persistence and toxicity associated with organohalogen compounds is possible with these materials. Migration from a polymer matrix may be removed as a deficiency through the use of reactive compounds, i.e., compounds that may be incorporated directly into the polymer structure either by copolymerization or grafting, or oligomeric compounds. Oligomeric materials of branched structure display characteristics of broad compatibility, high effectiveness and lack of migration., Competing Interests: The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Howell.)

Objective: The opioid overdose crisis continues within the United States, and the role of prescribed opioids and prescribing patterns in overdose deaths remains an important area of research. This study investigated patterns of prescription opioids dispensed in the 12 months before opioid-detected overdose death in Connecticut between May 8, 2016, and January 2, 2018, considering differences by demographic characteristics., Method: The sample included decedents who had an opioid dispensed within 30 days preceding death. Using multilevel modeling, we estimated the slope of change in mean morphine equivalent (MME) daily dose over 12 months before death, considering linear and quadratic effects of time. We also estimated the main effects of age, sex, race, and ethnicity and their interactions with time on MME. A sensitivity analysis examined how excluding decedents who did not receive long-term (≥90 days) opioid therapy affected mean MME slopes. The secondary analysis explored differences according to toxicology results., Results: Among 1,580 opioid-detected deaths, 179 decedents had prescribed opioids dispensed within 30 days preceding death. Decedents' mean age was 47.3 years ( SD = 11.5), 65.5% were male, 81% were White non-Hispanic, 9.5% were Black non-Hispanic, and 9.5% were Hispanic. In the time-only model, linear (beta = 6.25, p < .01) and quadratic (beta = 0.49, p = .02) effects of time were positive, indicating exponentially increasing dose before death. Linear change in MME was significantly attenuated in men compared with women (beta = -4.87, p = .03); however, men were more likely to have nonprescription opioids in their toxicology results ( p = .02). Sensitivity analysis results supported the primary findings., Conclusions: Rapid dose increases in dispensed opioids may be associated with opioid-detected overdose deaths, especially among women.

Introduction: There is uncertainty about whether criminal legal involvement (CLI) impacts the effectiveness of medications for opioid use disorder (MOUD). We aimed to determine whether CLI modifies the association between buprenorphine-naloxone (BUP-NX) vs. extended-release naltrexone (XR-NTX) and MOUD treatment outcomes., Methods: We conducted a secondary analysis of X:BOT, a 24-week multi-center randomized controlled trial comparing treatment outcomes between BUP-NX (n = 287) and XR-NTX (n = 283) in the general population. We used baseline Additional Severity-Index Lite responses to identify patients with recent CLI (n = 342), defined as active CLI and/or CLI in the past 30 days, and lifetime incarceration (n = 328). We explored recent CLI and lifetime incarceration as potential effect modifiers of BUP-NX vs. XR-NTX effectiveness on relapse, induction, and overdose. We conducted both intention-to-treat and per-protocol analyses for each outcome., Results: In intention-to-treat analyses, recent CLI modified the effect of BUP-NX vs. XR-NTX on odds of successful induction (p = 0.03) and hazard of overdose (p = 0.04), but it did not modify the effect on hazard of relapse (p = 0.23). All participants experienced lower odds of successful induction with XR-NTX compared to BUP-NX, but the relative likelihood of successful induction with BUP-NX was lower than XR-NTX among individuals with recent CLI (OR: 0.25, 95 % CI: 0.13-0.47, p < 0.001) compared to those without recent CLI (OR: 0.04, 95 % CI: 0.01-0.19, p < 0.001). Participants with recent CLI experienced similar hazard of overdose with XR-NTX and BUP-NX (HR: 1.12, 95 % CI: 0.42-3.01, p = 0.82), whereas those without recent CLI experienced greater hazard of overdose with XR-NTX compared to BUP-NX (HR: 12.60, 95 % CI: 1.62-98.03, p = 0.02). In per-protocol analyses, recent CLI did not modify the effect of MOUD on hazard of overdose (p = 0.10) or relapse (p = 0.41). Lifetime incarceration did not modify any outcome., Conclusions: Compared to individuals without recent CLI, individuals with recent CLI experienced decreased relative effectiveness of BUP-NX compared to XR-NTX for induction and overdose outcomes. This highlights the importance of considering the impact of recent CLI on opioid use disorder treatment outcomes. Future research should explore the mechanisms through which recent CLI modifies MOUD effectiveness and aim to improve MOUD effectiveness for individuals with recent CLI., Competing Interests: Declaration of competing interest The authors have no declared conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objectives. To determine mortality risk among those recently released from a Minnesota jail or prison. Methods. Using linked prison, jail, and death records, our retrospective cohort study followed 99 065 people who were released from Minnesota jails and prisons between March 1, 2020, and December 31, 2021. We explored differences between jail and prison exposures regarding mortality using standardized mortality ratios. Results. Adjusting for age and gender, we estimated that the rate of overdose death for people released from jail was 15.5 times that of the Minnesota general population. Overdose death rates for people released from prison were even higher at 28.3 times the rate of the Minnesota general population. Conclusions. Drug overdose was the leading cause of death for people reentering their communities from both jail and prison in Minnesota-with opioids being the leading cause of overdoses. Overdose death relative to the general population was double the estimates from earlier studies among people leaving prison. Providing seamless access to medications for opioid use disorder during and after incarceration is important to lower the risk of death following release. ( Am J Public Health . 2024;114(9):913-922. https://doi.org/10.2105/AJPH.2024.307723).

The novel myeloperoxidase inhibitor verdiperstat was developed as a treatment for neuroinflammatory and neurodegenerative diseases. During development, a computational prediction of verdiperstat liver safety was performed using DILIsym v8A, a quantitative systems toxicology (QST) model of liver safety.A physiologically-based pharmacokinetic (PBPK) model of verdiperstat was constructed in GastroPlus 9.8, and outputs for liver and plasma time courses of verdiperstat were input into DILIsym. In vitro experiments measured the likelihood that verdiperstat would inhibit mitochondrial function, inhibit bile acid transporters, and generate reactive oxygen species (ROS); these results were used as inputs into DILIsym, with two alternate sets of parameters used in order to fully explore the sensitivity of model predictions. Verdiperstat dosing protocols up to 600 mg BID were simulated for up to 48 weeks using a simulated population (SimPops) in DILIsym.Verdiperstat was predicted to be safe, with only very rare, mild liver enzyme increases as a potential possibility in highly sensitive individuals. Subsequent Phase 3 clinical trials found that ALT elevations in the verdiperstat treatment group were generally similar to those in the placebo group. This validates the DILIsym simulation results and demonstrates the power of QST modelling to predict the liver safety profile of novel therapeutics.

Background: As overdose deaths continue to rise, public health officials need comprehensive surveillance data to design effective prevention, harm reduction, and treatment strategies. Disparities across race and ethnicity groups, as well as trends in substance use, treatment, or overdose deaths, have been examined individually, but reports rarely compare findings across multiple substances or data sources., Objective: To provide a broad assessment of the overdose crisis, we describe trends in substance use, treatment, and overdose mortality across racial and ethnic groups for multiple substances., Research Design: We conducted a longitudinal, cross-sectional analysis comparing trends., Subjects: We identified self-reported use from the National Survey on Drug Use and Health, substance use treatment admissions from the Treatment Episode Data Set-Admissions, and overdose deaths from the CDC's Multiple Cause of Death files., Measures: We measured rates of substance use, treatment, and deaths involving heroin, methamphetamine, and cocaine among United States adults from 2010 to 2019., Results: Heroin, methamphetamine, and cocaine use increased, though not all changes were statistically significant. Treatment admissions indicating heroin and methamphetamine increased while admissions indicating cocaine decreased. Overdose deaths increased among all groups: methamphetamine (257%-1,115%), heroin (211%-577%), and cocaine (88%-259%). Changes in rates of use, treatment, and death for specific substances varied by racial and ethnic group., Conclusions: Substance use, treatment, and overdose mortality changed considerably, though not always equivalently. Identifying diverging trends in substance-related measures for specific substances and racial and ethnic groups can inform targeted investment in treatment to reduce disparities and respond to emerging changes in the overdose crisis., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Clinical investigation of emvododstat for the treatment of solid tumors was halted after two patients who were heavily treated with other anticancer therapies experienced drug-induced liver failure. However, preclinical investigations supported that emvododstat at lower doses might be effective in treating acute myeloid leukemia (AML) and against severe acute respiratory syndrome-coronavirus 2 as a dihydroorotate dehydrogenase inhibitor. Therefore, a quantitative systems toxicology model, DILIsym, was used to predict liver safety of the proposed dosing of emvododstat in AML clinical trials. In vitro mechanistic toxicity data of emvododstat and its desmethyl metabolite were integrated with in vivo exposure within DILIsym to predict hepatotoxicity responses in a simulated human population. DILIsym simulations predicted alanine aminotransferase elevations observed in prior emvododstat clinical trials in patients with solid tumors, but not in the prospective AML clinical trial with the proposed dosing regimens. Exposure predictions based on physiologically-based pharmacokinetic modeling suggested that reduced doses of emvododstat would produce clinical exposures that would be efficacious to treat AML. In the AML clinical trial, only eight patients experienced aminotransferase elevations, all of which were mild (grade 1), all resolving within a short period of time, and no patient showed symptoms of hepatotoxicity, confirming the prospective prediction of liver safety. Overall, retrospective DILIsym simulations adequately predicted the liver safety liabilities of emvododstat in solid tumor trials and prospective simulations predicted the liver safety of reduced doses in an AML clinical trial. The modeling was critical to enabling regulatory approval to proceed with the AML clinical trial wherein the predicted liver safety was confirmed., (© 2023 Simulations Plus Inc., PTC Therapeutics, Inc. and The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Objective: To determine the relative risk of death following exposure to treatments for OUD compared to no treatment., Methods: In this retrospective cohort study we compiled and merged state agency data on accidental and undetermined opioid overdose deaths in 2017 and exposures to OUD treatment in the prior six months to determine incidence rates following exposure to different treatment modalities. These rates were compared to the estimated incidence among those exposed to no treatment to determine relative risk of death for each treatment exposure., Results: Incidence rates for opioid poisoning deaths for those exposed to treatment ranged from 6.06±1.40 per 1000 persons exposed to methadone to 17.36±3.22 per 1000 persons exposed to any non-medication treatment. The estimated incidence rate for those not exposed to treatment was 9.80±0.72 per 1000 persons. With no exposure to treatment as referent, exposure to methadone or buprenorphine reduced the relative risk by 38% or 34%, respectively; the relative risk of non-medication treatments was equal to or worse than no exposure to treatment (RR = 1.27-1.77)., Principal Conclusions: Exposure to non-MOUD treatments provided no protection against fatal opioid poisoning whereas the relative risk was reduced following exposures to MOUD treatment, even if treatment was not continued. Population level efforts to reduce opioid overdose deaths need to focus on expanding access to agonist-based MOUD treatments and are unlikely to succeed if access to non-MOUD treatments is made more available., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to declare. The authors also state that the work described has not been published previously nor is under consideration for publication elsewhere., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: As overdose rates increase for multiple substances, policymakers need to identify geographic patterns of substance-specific deaths. In this study, we describe county-level opioid and psychostimulant overdose patterns and how they correlate with county-level social vulnerability measures., Methods: A cross-sectional observational study, we used nationwide 2016-2018 restricted access Centers for Disease Prevention and Control county-level mortality files for 1,024 counties. We estimated quartiles of opioid and psychostimulant overdose mortality and provided estimates of their association with county-level Social Vulnerability Index (SVI) percentile., Results: There was high opioid and psychostimulant overdose mortality in the Middle Atlantic, South Atlantic, East North Central, and Mountain regions. The Central US had the lowest opioid and psychostimulant overdose mortality rates. Counties with higher SVI scores (i.e. higher social vulnerability) were significantly more likely to experience high opioid and high psychostimulant overdose (high-high) mortality. A 10-percentile increase in SVI score was associated with a 3.1 percentage point increase in the likelihood of being a high-high county (p < 0.001) in unadjusted models and a 1.5 percentage point increase (p < 0.05) in models adjusting for region., Conclusion: Our results illustrated the heterogenous geographic distribution of the growing concurrent opioid and psychostimulant overdose crisis. The substantial regional variation we identified highlights the need for local data to guide policymaking and treatment planning. The association of opioid-psychostimulant overdose mortality with social vulnerability demonstrates the critical need in impacted counties for tailored treatment that addresses the complex medical and social needs of people who use both opioids and psychostimulants.

In clinical trials of cannabidiol (CBD) for the treatment of seizures in patients with Dravet syndrome, Lennox-Gastaut syndrome, and tuberous sclerosis complex, elevations in serum alanine aminotransferase (ALT) > 3× the upper limit of normal were observed in some patents, but the incidence was much greater in patients who were receiving treatment with valproate (VPA) before starting CBD. To explore potential mechanisms underlying this interaction, we used DILIsym, a quantitative systems toxicology model, to predict ALT elevations in a simulated human population treated with CBD alone, VPA alone, and when CBD dosing was starting during treatment with VPA. We gathered in vitro data assessing the potential for CBD, the two major CBD metabolites, and VPA to cause hepatotoxicity via inhibition of bile acid transporters, mitochondrial dysfunction, and production of reactive oxygen species (ROS). Physiologically-based pharmacokinetic models for CBD and VPA were used to predict liver exposure. DILIsym simulations predicted dose-dependent ALT elevations from CBD treatment and this was predominantly driven by ROS production from the parent molecule. DILIsym also predicted VPA treatment to cause ALT elevations which were transient when mitochondrial biogenesis was incorporated into the model. Contrary to the clinical experience, simulation of 2 weeks treatment with VPA prior to introduction of CBD treatment did not predict an increase of the incidence of ALT elevations relative to CBD treatment alone. We conclude that the marked increased incidence of CBD-associated ALT elevations in patients already receiving VPA is unlikely to involve the three major mechanisms of direct hepatotoxicity., (© 2023 The Authors. Clinical Pharmacology & Therapeutics © 2023 American Society for Clinical Pharmacology and Therapeutics.)

Objective: Individuals with criminal legal involvement have high rates of substance use and other mental disorders. Before implementation of the Affordable Care Act's Medicaid expansion, they also had low health insurance coverage. The objective of this study was to assess the impact of Medicaid expansion on health insurance coverage and use of treatment for substance use or other mental disorders in this population., Methods: The authors used restricted data (2010-2017) from the National Survey on Drug Use and Health (NSDUH). Using a difference-in-differences approach, the authors estimated the impact of Medicaid expansion on health insurance coverage and treatment for substance use or other mental disorders among individuals with recent criminal legal involvement., Results: The sample consisted of 9,910 NSDUH respondents who were ages 18-64 years, had a household income ≤138% of the federal poverty level, and reported past-year criminal legal involvement. Medicaid expansion was associated with an 18 percentage-point increase in insurance coverage but no change in receipt of substance use treatment among individuals with substance use disorder. Individuals with any other mental illness had a 16 percentage-point increase in insurance coverage but no change in receipt of mental health treatment., Conclusions: Despite a large increase in health insurance coverage among individuals with criminal legal involvement and substance use or other mental disorders, Medicaid expansion was not associated with a significant change in treatment use for these conditions. Insurance access alone appears to be insufficient to increase treatment for substance use or other mental disorders in this population., Competing Interests: The authors report no financial relationships with commercial interests.

BMS-932481 was designed to modulate ɣ-secretase activity to produce shorter and less amyloidogenic peptides, potentially averting liabilities associated with complete enzymatic inhibition. Although it demonstrated the intended pharmacology in the clinic, BMS-932481 unexpectedly caused drug-induced liver injury (DILI) in a multiple ascending dose study characterized by dose- and exposure-dependence, delayed onset manifestation, and a high incidence of hepatocellular damage. Retrospective studies investigating the disposition and probable mechanisms of toxicity of BMS-932481 are presented here. These included a mass balance study in bile-duct-cannulated rats and a metabolite profiling study in human hepatocytes, which together demonstrated oxidative metabolism followed by biliary elimination as the primary means of disposition. Additionally, minimal protein covalent binding in hepatocytes and lack of bioactivation products excluded reactive metabolite formation as a probable toxicological mechanism. However, BMS-932481 and 3 major oxidative metabolites were found to inhibit the bile salt export pump (BSEP) and multidrug resistance protein 4 (MRP4) in vitro. Considering human plasma concentrations, the IC50 values against these efflux transporters were clinically meaningful, particularly in the high dose cohort. Active uptake into human hepatocytes in vitro suggested the potential for hepatic levels of BMS-932481 to be elevated further above plasma concentrations, enhancing DILI risk. Conversely, measures of mitochondrial functional decline in hepatocytes treated with BMS-932481 were minimal or modest, suggesting limited contributions to DILI. Collectively, these findings suggested that repeat administration of BMS-932481 likely resulted in high hepatic concentrations of BMS-932481 and its metabolites, which disrupted bile acid transport via BSEP and MRP4, elevating serum biomarkers of liver injury., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Individuals with criminal legal involvement (CLI), housing instability, or Medicaid insurance may experience barriers accessing substance use treatment in certain settings. Previous research has found individuals in these groups are less likely to receive medications for opioid use disorder (MOUD), but the role treatment setting may play in low rates of MOUD is unclear., Methods: We conducted a cross-sectional study using nationally representative survey data from 2015 to 2021. We estimated the proportion of individuals who had CLI, housing instability, or Medicaid insurance who received substance use treatment in a variety of settings. We used multivariable logistic regressions to estimate the associations between group and the receipt of MOUD across treatment settings., Results: Individuals with CLI, housing instability, or Medicaid insurance were more likely to receive substance use treatment in hospitals, rehabilitation, and mental health facilities compared with individuals not in these groups. However, all groups accessed substance use treatment in doctors' offices at similar rates. Treatment at a doctor's office was associated with the highest likelihood of receiving MOUD (aOR 4.73 [95% CI: 2.2.15-10.43]). Across multiple treatment settings, Individuals with CLI or housing instability were less likely to receive MOUD., Conclusions: Individuals with CLI, housing instability, or Medicaid insurance are more likely to access substance use treatment at locations associated with lower rates of MOUD use. MOUD access across treatment settings is needed to improve engagement and retention in treatment for patients experiencing structural disadvantage or who have low incomes., Competing Interests: None, (© 2023 The Authors.)

Biologics address a range of unmet clinical needs, but the occurrence of biologics-induced liver injury remains a major challenge. Development of cimaglermin alfa (GGF2) was terminated due to transient elevations in serum aminotransferases and total bilirubin. Tocilizumab has been reported to induce transient aminotransferase elevations, requiring frequent monitoring. To evaluate the clinical risk of biologics-induced liver injury, a novel quantitative systems toxicology modeling platform, BIOLOGXsym™, representing relevant liver biochemistry and the mechanistic effects of biologics on liver pathophysiology, was developed in conjunction with clinically relevant data from a human biomimetic liver microphysiology system. Phenotypic and mechanistic toxicity data and metabolomics analysis from the Liver Acinus Microphysiology System showed that tocilizumab and GGF2 increased high mobility group box 1, indicating hepatic injury and stress. Tocilizumab exposure was associated with increased oxidative stress and extracellular/tissue remodeling, and GGF2 decreased bile acid secretion. BIOLOGXsym simulations, leveraging the in vivo exposure predicted by physiologically-based pharmacokinetic modeling and mechanistic toxicity data from the Liver Acinus Microphysiology System, reproduced the clinically observed liver signals of tocilizumab and GGF2, demonstrating that mechanistic toxicity data from microphysiology systems can be successfully integrated into a quantitative systems toxicology model to identify liabilities of biologics-induced liver injury and provide mechanistic insights into observed liver safety signals.

Purpose: Older adults who are or have been incarcerated constitute a growing population in the USA. The complex health needs of this group are often inadequately addressed during incarceration and equally so when transitioning back to the community. The purpose of this paper is to discuss the literature on challenges older adults (age 50 and over) face in maintaining health and accessing social services to support health after an incarceration and to outline recommendations to address the most urgent of these needs., Design/methodology/approach: This study conducted a narrative literature review to identify the complex health conditions and health services needs of incarcerated older adults in the USA and outline three primary barriers they face in accessing health care and social services during reentry., Findings: Challenges to healthy reentry of older adults include continuity of health care; housing availability; and access to health insurance, disability and other support. The authors recommend policy changes to improve uniformity of care, development of support networks and increased funding to ensure that older adults reentering communities have access to resources necessary to safeguard their health and safety., Originality/value: This review presents a broad perspective of the current literature on barriers to healthy reentry for older adults in the USA and offers valuable system, program and policy recommendations to address those barriers., (© Rose Onyeali, Benjamin A. Howell, D. Keith McInnes, Amanda Emerson and Monica E. Williams.)

Background: Opioid overdoses are a leading cause of preventable death in the United States. There is limited research linking decedents' receipt of controlled substances and presence of controlled substances on post-mortem toxicology (PMT)., Methods: We linked data on opioid-detected deaths in Connecticut between May 3, 2016, and December 31, 2017 from the Office of the Chief Medical Examiner, Department of Consumer Protection, and Department of Mental Health and Addiction Services. Exposure was defined as receipt of an opioid or benzodiazepine prescription within 90 days prior to death. Our primary outcome was concordance between medication received and metabolites in PMT., Results: Our analysis included 1412 opioid-detected overdose deaths. 47 % received an opioid or benzodiazepine 90 days prior to death; 36 % received an opioid and 27 % received a benzodiazepine. Concordance between receipt of an opioid or benzodiazepine and its presence in PMT was observed in 30 % of opioid-detected deaths. Concordance with an opioid was present in 17 % of opioid-detected deaths and concordance with a benzodiazepine was present in 21 % of opioid-detected deaths. Receipt of an opioid or benzodiazepine and concordance with PMT were less common in fentanyl or heroin-detected deaths and more common in pharmaceutical opioid-detected deaths., Discussion: Our results suggest medically supplied opioids and benzodiazepines potentially contributed to a substantial number, though minority, of opioid-detected deaths during the study period. Efforts to reduce opioid and benzodiazepine prescribing may reduce risk of opioid-detected deaths in this group, but other approaches will be needed to address most opioid-detected deaths that involved non-pharmaceutical opioids., Competing Interests: Disclosures/Conflict of Interest The authors have no financial conflicts of interest to disclose., (Copyright © 2023 Elsevier B.V. All rights reserved.)

In 2011, the U.S. Department of Veterans Health (VA) implemented a homeless-tailored primary care medical home model called the Homeless Patient Aligned Care Teams (HPACTs). The impact of HPACTs on health and healthcare outcomes of veterans experiencing homelessness has not been adequately synthesized. This narrative review summarized peer-reviewed studies published in databases Ovid MEDLINE, Ovid EMBASE, and APA PsycInfo from 1946 to February 2022. Only original research studies that reported outcomes of the HPACT model were included in the review. Of 575 studies that were initially identified and screened, 26 studies met inclusion criteria and were included in this review. Included studies were categorized into studies that described the following: (1) early HPACT pilot implementation; (2) HPACT's association with service quality and utilization; and (3) specialized HPACT programs. Together, studies in this review suggest HPACT is associated with reductions in emergency department utilization and improvements in primary care utilization, engagement, and positive patient experiences; however, the methodological rigor of the included studies was low, and thus, these findings should only be considered preliminary. There is a need for randomized controlled trials assessing the impact of the PACT model on key outcomes of interest, as well as to determine whether the model is a viable way to manage healthcare for persons experiencing homelessness outside of the VA system., (© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Inhibition of the canalicular phospholipid floppase multidrug resistance protein 3 (MDR3) has been implicated in cholestatic drug-induced liver injury (DILI), which is clinically characterized by disrupted bile flow and damage to the biliary epithelium. Reduction in phospholipid excretion, as a consequence of MDR3 inhibition, decreases the formation of mixed micelles consisting of bile acids and phospholipids in the bile duct, resulting in a surplus of free bile acids that can damage the bile duct epithelial cells, i.e., cholangiocytes. Cholangiocytes may compensate for biliary increases in bile acid monomers via the cholehepatic shunt pathway or bicarbonate secretion, thereby influencing viability or progression to toxicity. To address the unmet need to predict drug-induced bile duct injury in humans, DILIsym, a quantitative systems toxicology model of DILI, was extended by representing key features of the bile duct, cholangiocyte functionality, bile acid and phospholipid disposition, and cholestatic hepatotoxicity. A virtual, healthy representative subject and population ( n = 285) were calibrated and validated utilizing a variety of clinical data. Sensitivity analyses were performed for 1) the cholehepatic shunt pathway, 2) biliary bicarbonate concentrations and 3) modes of MDR3 inhibition. Simulations showed that an increase in shunting may decrease the biliary bile acid burden, but raise the hepatocellular concentrations of bile acids. Elevating the biliary concentration of bicarbonate may decrease bile acid shunting, but increase bile flow rate. In contrast to competitive inhibition, simulations demonstrated that non-competitive and mixed inhibition of MDR3 had a profound impact on phospholipid efflux, elevations in the biliary bile acid-to-phospholipid ratio, cholangiocyte toxicity, and adaptation pathways. The model with its extended bile acid homeostasis representation was furthermore able to predict DILI liability for compounds with previously studied interactions with bile acid transport. The cholestatic liver injury submodel in DILIsym accounts for several processes pertinent to bile duct viability and toxicity and hence, is useful for predictions of MDR3 inhibition-mediated cholestatic DILI in humans., Competing Interests: Authors JB, KY, JA, GT, SS, BH, and JW were employed by the company Simulations Plus Inc. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Beaudoin, Yang, Adiwidjaja, Taneja, Watkins, Siler, Howell and Woodhead.)

Introduction: Overdose deaths involving opioids and stimulants continue to reach unprecedented levels in the United States. Although significant attention has been paid to the relationship between prescription and illicit opioid use, little work has focused on the association between prescription and illicit stimulant use. Thus, this study explores characteristics of those who use or misuse prescription stimulants and/or opioids and associations with use of cocaine, methamphetamine, and heroin., Methods: We used 2015-2020 data from the National Survey on Drug Use and Health. Using adjusted multivariable logistic regression, we estimated the associations between past year prescription stimulant or prescription opioid prescribed use and misuse; various demographic characteristics; and past-year cocaine, methamphetamine, or heroin use., Results: From 2015 to 2020, 4.9 and 9.8 million US adults annually reported misusing prescription stimulants and opioids, respectively. Individuals who misused prescription stimulants were more likely to be ages 18-25 (45.8 %; 95 % CI: 44.0-47.5) than individuals who misused prescription opioids (21.7 %; 95 % CI: 20.7-22.7). We observed higher rates of cocaine use among individuals reporting prescription stimulant misuse (12.0 %; 95 % CI: 11.0-12.9) compared to those reporting prescription opioid misuse (5.7 %; 95 % CI: 5.1-6.3, p < 0.001). Heroin use was more common among individuals with prescription opioid misuse (2.1 %; 95 % CI: 1.7-2.2) than prescription stimulant misuse (0.6 %; 95 % CI: 0.4-0.7, p < 0.001). However, rates of methamphetamine use among individuals with prescription stimulant misuse (2.4 %; 95 % CI: 1.9-3.0) did not differ from individuals with prescription opioid misuse (2.1 %; 95 % CI: 1.7-2.5, p = 0.67)., Conclusions: Prescription stimulant misuse, compared to prescription opioid misuse, was associated with higher levels of cocaine use but not methamphetamine use. Treatment providers should consider screening for other substance use disorders among people who report prescription stimulant use or misuse. Additional research should seek to understand the mechanism underlying the different associations between prescription stimulant misuse and cocaine or methamphetamine use., Competing Interests: Declaration of competing interest None., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The development of new organophosphorus flame retardants for polymeric materials is spurred by relatively low toxicity, effectiveness, and demand for replacement of more traditional materials. To function, these compounds must decompose in a degrading polymer matrix to form species which promote modification of the solid phase or generate active radical moieties that escape to the gas phase and interrupt combustion propagating reactions. An understanding of the decomposition process for these compounds may provide insight into the nature of flame retardant action which they may offer and suggest parameters for the synthesis of effective new organophosphorus flame retardants. The thermal degradation of a series of organophosphorus esters varying in the level of oxygenation at phosphorus-alkyl phosphate, aryl phosphate, phosphonate, phosphinate-has been examined. Initial degradation in all cases corresponds to elimination of a phosphorus acid. However, the facility with which this occurs is strongly dependent on the level of oxygenation at phosphorus. For alkyl phosphates elimination occurs rapidly at relatively low temperature. The same process occurs at somewhat higher temperature for aryl phosphates. Elimination of a phosphorus acid from phosphonate or phosphinate occurs more slowly and at much higher temperature. Further, the acids formed from elimination rapidly degrade further to evolve volatile species.

Calcitonin gene-related peptide (CGRP) signaling inhibitors have shown efficacy in both the acute and preventive treatment of migraine. Telcagepant, a first-generation CGRP receptor antagonist, was effective but failed in clinical trials due to hepatotoxicity. Subsequently, although 4 next-generation CGRP receptor antagonists (rimegepant, zavegepant, atogepant, and ubrogepant) were being advanced into late-stage clinical trials, due to telcagepant's failure, more confidence in the liver safety of these compounds was needed. DILIsym v6A, a quantitative systems toxicology (QST) model of drug-induced liver injury (DILI), was used to model all 5 compounds and thus to compare the 4 next-generation CGRP receptor antagonists to telcagepant. In vitro experiments were performed to measure the potential for each compound to inhibit bile acid transporters, produce oxidative stress, and cause mitochondrial dysfunction. Physiologically based pharmacokinetic models were produced for each compound in order to appropriately estimate liver exposure. DILIsym predicted clinical elevations of liver enzymes and bilirubin for telcagepant, correctly predicting the observed DILI liability of the first-generation compound. By contrast, DILIsym predicted that each of the 4 next-generation compounds would be significantly less likely to cause DILI than telcagepant. Subsequent clinical trials have validated these predictions for each of the 4 compounds, and all 3 of the compounds submitted to FDA to date (rimegepant, ubrogepant, and atogepant) have since been approved by the FDA with no warning for hepatotoxicity. This work demonstrates the potential for QST modeling to prospectively differentiate between hepatotoxic and nonhepatotoxic molecules within the same class., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society of Toxicology.)

Purpose: With a rapidly growing population of older adults with chronic illness in US prisons, the number of people who die while incarcerated is increasing. Support for patients' medical decision-making is a cornerstone of quality care for people at the end of life (EOL). This study aims to identify, describe, and analyze existing policies regarding EOL decision-making in U.S. Departments of Corrections., Design/methodology/approach: This study performed an iterative content analysis on all available EOL decision-making policies in US state departments of corrections and the Federal Bureau of Prisons., Findings: This study collected and reviewed available policies from 37 of 51 prison systems (73%). Some areas of commonality included the importance of establishing health-care proxies and how to transfer EOL decision documents, although policies differed in terms of which patients can complete advance care planning documents, and who can serve as their surrogate decision-makers., Practical Implications: Many prison systems have an opportunity to enhance their patient medical decision-making policies to bring them in line with community standard quality of care. In addition, this study was unable to locate policies regarding patient decision-making at the EOL in one quarter of US prison systems, suggesting there may be quality-of-care challenges around formalized approaches to documenting patient medical wishes in some of those prison systems., Originality/value: To the best of the authors' knowledge, this is the first content analysis of EOL decision-making policies in US prison systems., (© Emerald Publishing Limited.)

This cross-sectional study compares changes in health insurance coverage from 2010 to 2017 for low-income US adults with criminal legal involvement in states that did and did not adopt the Medicaid expansion provision of the Affordable Care Act., Competing Interests: Conflict of Interest Disclosures: None reported., (Copyright 2022 Howell BA et al. JAMA Health Forum.)

Background: People who have been incarcerated have high rates of cardiovascular risk factors, such as hypertension and smoking, and cardiovascular disease (CVD) is a leading cause of hospitalizations and mortality in this population. Despite this, little is known regarding what pathways mediate the association between incarceration exposure and increased rates of CVD morbidity and especially what incarceration specific factors are associated with this risk. The objective of this study is to better understand CVD risk in people exposed to incarceration and the pathways by which accumulate cardiovascular risk over time., Methods and Analysis: The Justice-Involved Individuals Cardiovascular Disease Epidemiology (JUSTICE) study is a prospective cohort study of individuals released from incarceration with known cardiovascular risk factors. We are recruiting 500 individuals within three months after release from jail/prison. At baseline we are assessing traditional risk factors for CVD, including diet, exercise, and smoking, and exposure to incarceration-related policies, psychosocial stress, and self-efficacy. Cardiovascular risk factors are measured at baseline through point of care testing. We are following these individuals for the 12 months following the index release from incarceration with re-evaluation of psychosocial factors and clinical risk factors every 6 months. Using these data, we will estimate the direct and indirect latent effects of incarceration on cardiovascular risk factors and the paths via which these effects are mediated. We will also model the anticipated 10-year burden of CVD incidence, health care use, and mortality associated with incarceration., Discussion: Our study will identify factors associated with CVD risk factor control among people released from incarceration. Our measurement of incarceration-related exposures, psychosocial factors, and clinical measures of cardiovascular risk will allow for identification of unique targets for intervention to modify CVD risk in this vulnerable population., (© 2022. The Author(s).)

The USA incarcerates more people than any other nation in the world. Exposure to the criminal legal system has been associated with a myriad of health outcomes but less is understood about what drives these associations. We argue that stigma due to criminal legal involvement, what we call criminal legal stigma, likely has a larger role in the association between incarceration and negative health outcomes than has been previously appreciated. There is limited research on the impact on health of criminal legal stigma despite abundant research on its negative social consequences. In this paper, we describe a conceptual framework of the health effects of criminal legal stigma drawing on previous research of criminal legal stigma and advances in other areas of stigma research. We outline key concepts related to stigma mechanisms, how they function at structural and individual levels, and how they might cause health outcomes. Finally, we identify potential areas for future research and opportunities for clinical interventions to remediate negative effects of stigma., (© 2021. The New York Academy of Medicine.)

Background: In 2016, at least 20% of people with opioid use disorder (OUD) were involved in the criminal justice system, with the majority of individuals cycling through jails. Opioid overdose is the leading cause of death and a common cause of morbidity after release from incarceration. Medications for OUD (MOUD) are effective at reducing overdoses, but few interventions have successfully engaged and retained individuals after release from incarceration in treatment., Objective: To assess whether follow-up care in the Transitions Clinic Network (TCN), which provides OUD treatment and enhanced primary care for people released from incarceration, improves key measures in the opioid treatment cascade after release from jail. In TCN programs, primary care teams include a community health worker with a history of incarceration, and they attend to social needs, such as housing, food insecurity, and criminal legal system contact, along with patients' medical needs., Methods and Analysis: We will bring together six correctional systems and community health centers with TCN programs to conduct a hybrid type-1 effectiveness/implementation study among individuals who were released from jail on MOUD. We will randomize 800 individuals on MOUD released from seven local jails (Bridgeport, CT; Niantic, CT; Bronx, NY; Caguas, PR; Durham, NC; Minneapolis, MN; Ontario County, NY) to compare the effectiveness of a TCN intervention versus referral to standard primary care to improve measures within the opioid treatment cascade. We will also determine what social determinants of health are mediating any observed associations between assignment to the TCN program and opioid treatment cascade measures. Last, we will study the cost effectiveness of the approach, as well as individual, organizational, and policy-level barriers and facilitators to successfully transitioning individuals on MOUD from jail to the TCN., Ethics and Dissemination: Investigation Review Board the University of North Carolina (IRB Study # 19-1713), the Office of Human Research Protections, and the NIDA JCOIN Data Safety Monitoring Board approved the study. We will disseminate study findings through peer-reviewed publications and academic and community presentations. We will disseminate study data through a web-based platform designed to share data with TCN PATHS participants and other TCN stakeholders. Clinical trials.gov registration: NCT04309565., (Copyright © 2021. Published by Elsevier Inc.)

To decrease opioid overdose mortality, prisons and jails in the US are increasingly offering medications for opioid use disorder (OUD) to incarcerated people. It is unknown how receipt of these medications in a correctional setting affects health services use after release. In this article we analyze changes in postrelease health care use after the implementation of a statewide medications for OUD program in the unified jail and prison system of the Rhode Island Department of Corrections. Using Medicaid claims data, we examined individual health care use in the community before and after receipt of medications for OUD while incarcerated. We found that inpatient admissions did not change, emergency department visits decreased, and both nonacute outpatient services and pharmacy claims increased after people received medications for OUD while incarcerated. There was no change in total health care costs paid by Medicaid. Our findings provide evidence that people's use of health care services paid for by Medicaid did not increase after they started medications for OUD in correctional settings. Given the frequent interaction of people with OUD with the criminal justice system, offering evidence-based treatment of OUD in correctional settings is an important opportunity to initiate addiction treatment.

Background: Social connections can lead to contagion of healthy behaviors. Successful treatment of patients with opioid use disorder may lay in rebuilding social networks. Strong social networks of support can reinforce the benefits of medication treatments that are the current standard of care and the most effective tool physicians have to fight the opioid epidemic., Methods: The research team conducted a systematic review of electronic research databases, specialist journals and grey literature up to August 2020 to identify randomized controlled trials of social network support in patient populations receiving medication for opioid use disorder (MOUD). The research team placed the studies into a framework of dynamic social networks, examining the role of networks before MOUD treatment is initiated, during the treatment, and in the long-term following the treatment. The research team analyzed the results across three sources of social network support: partner relationships, family, and peer networks., Results: Of 5193 articles screened, eight studies were identified as meeting inclusion criteria. Five studies indicated that social network support had a statistically significant effect on improved MOUD treatment outcomes. We find the strongest support for the positive impact of family social network support., Conclusions: Social networks significantly shape effectiveness of opioid use disorder treatments. While negative social ties reinforce addiction, positive social support networks can amplify the benefits of medication treatments. Targeted interventions to improve treatment outcomes can be designed and added to MOUD treatment with their effects evaluated in improving patients' odds of recovery from opioid use disorder and reversing the rising trend in opioid deaths., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: An important strategy to address the opioid overdose epidemic involves identifying people at elevated risk of overdose, particularly those with opioid use disorder (OUD). However, it is unclear to what degree OUD diagnoses in administrative data are inaccurate., Objective: To estimate the prevalence of inaccurate diagnoses of OUD among patients with incident OUD diagnoses., Subjects: A random sample of 90 patients with incident OUD diagnoses associated with an index in-person encounter between October 1, 2016, and June 1, 2018, in three Veterans Health Administration medical centers., Design: Direct chart review of all encounter notes, referrals, prescriptions, and laboratory values within a 120-day window before and after the index encounter. Using all available chart data, we determined whether the diagnosis of OUD was likely accurate, likely inaccurate, or of indeterminate accuracy. We then performed a bivariate analysis to assess demographic or clinical characteristics associated with likely inaccurate diagnoses., Key Results: We identified 1337 veterans with incident OUD diagnoses. In the chart verification subsample, we assessed 26 (29%) OUD diagnoses as likely inaccurate; 20 due to systems error and 6 due to clinical error; additionally, 8 had insufficient information to determine accuracy. Veterans with likely inaccurate diagnoses were more likely to be younger and prescribed opioids for pain. Clinical settings associated with likely inaccurate diagnoses were non-mental health clinical settings, group visits, and non-patient care settings., Conclusions: Our study identified significant levels of likely inaccurate OUD diagnoses among veterans with incident OUD diagnoses. The majority of these cases reflected readily addressable systems errors. The smaller proportion due to clinical errors and those with insufficient documentation may be addressed by increased training for clinicians. If these inaccuracies are prevalent throughout the VHA, they could complicate health services research and health systems responses.

Background: Adult drug courts are growing in popularity within the Unites States, but the quality of substance use treatment within drug court programs and the impact of drug courts on health and substance use treatment outcomes is largely unknown. We appraised the quality of United States adult drug court process evaluations and the inclusion of measures of substance use treatment quality., Methods: We systematically reviewed the adult drug court evaluations between 2008 and 2018 in accordance with recommended strategies for systematic gray literature search. We appraised evaluation quality using the Evidence for Policy and Practice Information and Coordination Center tool for process evaluations. We extracted recommended measures of substance use treatment quality, including measures related to screening and monitoring, diagnosis, service availability, service utilization, and outcomes., Results: Our search identified 112 evaluations. Process measures were included within 68 evaluations, 45% of which had poor data reliability. We found that less than 10% of evaluations reported substance use treatment quality measures related to service utilization, overdose, and mortality, while more than 75% contained criminal justice measures, including program graduation (completion of criminal justice proceedings) and participant recidivism., Conclusions: We found low uptake of measures of substance use treatment quality. The absence of data call into question the ability of drug courts to stem harmful substance use related health outcomes., (Copyright © 2020. Published by Elsevier B.V.)

Individuals involved with the US criminal justice system have high rates of opioid use disorder (OUD) but face significant barriers to evidence-based treatment. Using 2008-17 data from the Treatment Episode Data Set-Admissions, we examined trends in receipt of medications for OUD among individuals referred by criminal justice agencies and other sources both before and after Medicaid expansion. Individuals referred by criminal justice agencies were less likely to receive medications for OUD than were those referred by other sources during our study period, although this disparity narrowed slightly after Medicaid expansion. Receipt of medications for OUD increased more for individuals referred by criminal justice agencies in states that expanded Medicaid compared with those in states that did not. Medicaid expansion may improve evidence-based treatment for individuals with criminal justice involvement and OUD, although additional policy change outside the health care sector is likely needed to reduce persistent treatment disparities.

Background: The fourth wave of the opioid crisis is characterized by increased use and co-use of methamphetamine. How opioid and methamphetamine co-use is associated with health care use, housing instability, social service use, and criminal justice involvement has not been studied and could inform future interventions and partnerships., Objectives: To estimate service involvement across sectors among people who reported past year opioid and methamphetamine co-use, methamphetamine use, opioid use, or neither opioid nor methamphetamine use., Research Design: We examined 2015-2018 data from the National Survey on Drug Use and Health. We used multivariable negative binomial and logistic regression models and predictive margins, adjusted for sociodemographic and clinical characteristics., Subjects: Nonelderly US adults aged 18 or older., Measures: Hospital days, emergency department visits, housing instability, social service use, and criminal justice involvement in the past year., Results: In adjusted analyses, adults who reported opioid and methamphetamine co-use had 99% more overnight hospital days, 46% more emergency department visits, 2.1 times more housing instability, 1.4 times more social service use, and 3.3 times more criminal justice involvement compared with people with opioid use only. People who used any methamphetamine, with opioids or alone, were significantly more likely be involved with services in 2 or more sectors compared with those who used opioids only (opioids only: 11.6%; methamphetamine only: 19.8%; opioids and methamphetamine: 27.6%)., Conclusions: Multisector service involvement is highest among those who use both opioids and methamphetamine, suggesting that partnerships between health care, housing, social service, and criminal justice agencies are needed to develop, test, and implement interventions to reduce methamphetamine-related morbidity., Competing Interests: The authors declare no conflict of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

In 2019 the California Office of Environmental Health Hazard Assessment (OEHHA) initiated a review of the carcinogenic hazard potential of acetaminophen, including an assessment of the long-term rodent carcinogenicity and tumor initiation/promotion studies. The objective of the analysis herein was to inform this review process with a weight-of-evidence assessment of these studies and an assessment of the relevance of these models to humans. In most of the 14 studies, there were no increases in the incidences of tumors in any organ system. In the few studies in which an increase in tumor incidence was observed, there were factors such as absence of a dose response and a rodent-specific tumor supporting that these findings are not relevant to human hazard identification. In addition, we performed qualitative analysis and quantitative simulations of the exposures to acetaminophen and its metabolites and its toxicity profile; the data support that the rodent models are toxicologically relevant to humans. The preclinical carcinogenicity results are consistent with the broader weight of evidence assessment and evaluations of multiple international health authorities supporting that acetaminophen is not a carcinogenic hazard., (Copyright © 2020. Published by Elsevier Inc.)

In 2019, the California Office of Environmental Health Hazard Assessment (OEHHA) initiated a review of the carcinogenic hazard potential of acetaminophen. The objective of the analysis herein was to inform this review by assessing whether variability in patient baseline characteristics (e.g. baseline glutathione (GSH) levels, pharmacokinetics, and capacity of hepatic antioxidants) leads to potential differences in carcinogenic hazard potential at different dosing schemes: maximum labeled doses of 4 g/day, repeated doses above the maximum labeled dose (>4-12 g/day), and acute overdoses of acetaminophen (>15 g). This was achieved by performing simulations of acetaminophen exposure in thousands of diverse virtual patients scenarios using the DILIsym® Quantitative Systems Toxicology (QST) model. Simulations included assessments of the dose and exposure response for toxicity and mode of cell death based on evaluations of the kinetics of changes of: GSH, N-acetyl-p-benzoquinone-imine (NAPQI), protein adducts, mitochondrial dysfunction, and hepatic cell death. Results support that, at therapeutic doses, cellular GSH binds to NAPQI providing sufficient buffering capacity to limit protein adduct formation and subsequent oxidative stress. Simulations evaluating repeated high-level supratherapeutic exposures or acute overdoses indicate that cell death precedes DNA damage that could result in carcinogenicity and thus acetaminophen does not present a carcinogenicity hazard to humans at any dose., (Copyright © 2020. Published by Elsevier Inc.)