Project description:IntroductionOpioid and sedative/hypnotic drug overdoses are major causes of morbidity in the U.S. This study compares 12-month incidence of fatal unintentional drug overdose, suicide, and other mortality among emergency department patients presenting with nonfatal opioid or sedative/hypnotic overdose.MethodsThis is a retrospective cohort study using statewide, longitudinally linked emergency department patient record and mortality data from California. Participants comprised all residents presenting to a licensed emergency department at least once in 2009-2011 with nonfatal unintentional opioid overdose, sedative/hypnotic overdose, or neither (a 5% random sample). Participants were followed for 1 year after index emergency department presentation to assess death from unintentional overdose, suicide, or other causes, ascertained using ICD-10 codes. Absolute death rates per 100,000 person years and standardized mortality ratios relative to the general population were calculated. Data were analyzed February-August 2019.ResultsFollowing the index emergency department visit, unintentional overdose death rates per 100,000 person years were 1,863 following opioid overdose, 342 following sedative/hypnotic overdose, and 31 for reference patients without an index overdose (respective standardized mortality ratios of 106.1, 95% CI=95.2, 116.9; 24.5, 95% CI=21.3, 27.6; and 2.6, 95% CI=2.2, 3.0). Suicide mortality rates per 100,000 were 319, 174, and 32 following opioid overdose, sedative/hypnotic overdose, and reference visits, respectively. Natural causes mortality rates per 100,000 were 8,058 (opioid overdose patients), 17,301 (sedative/hypnotic overdose patients), and 3,097 (reference patients).ConclusionsEmergency department patients with nonfatal opioid or sedative/hypnotic drug overdose have exceptionally high risks of death from unintentional overdose, suicide, and other causes. Emergency department-based interventions offer potential for reducing these patients' overdose and other mortality risks.

Project description:Atmospheric particulate matter (PM) is a recognized risk factor for the global burden of disease in human populations. We are presenting here the application of toxicogenomics in the evaluation of the toxic effects of organic content of atmospheric particle matter (PM), from urban and rural environments (city of Barcelona and village of La Pobla, NE Spain), using the developing zebrafish embryo. The main goal is to identify the metabolic pathways involved in the adverse effects observed in zebrafish embryos exposed to PM organic content from urban and rural environments, also allowing the selection of genes of interest that are differentially expressed. The relevance of particle size to the PM toxicity is also addressed. Indeed, the zebrafish embryos were exposed to PM of aerodynamic diameter larger than 7.2 μm and smaller than 0.5 μm (PM10 and PM0.5, respectively). PM0.5 concentrated biological and toxic activities linked to organic substances. Transcriptomic analyses showed strong induction of the AhR signalling pathway (a.k.a. dioxin-like activity) for embryos exposed to both rural and urban extracts, correlating with the concentrations of PAHs. Urban extracts, with strong contribution of traffic emissions, specifically de-regulated oxidative stress-related genes, as well as pancreatic and eye-lens specific genes, two organs known to be affected by air pollution in humans. Exposure to rural extracts, with high contribution of wood burning emissions, affected genes implicated in basic cellular functions, in agreement with their strong embryotoxicity. Extracts from rural and urban samples elicited both common and specific transcriptome responses, suggesting different potentially adverse outcomes depending on PM source and composition. The authors thank the financial support of the Spanish Ministry (project TEA-PARTICLE, grant number CGL2011-29621) and the Portuguese Foundation for Science and Technology for the doctoral grant of Sofia R. Mesquita (SFRH/BD/80710/2011) funded by the Program POPH-QREN through the Portuguese Ministry of Education and Science and the European Social Fund, and support through project PEst-C/MAR/LA0015/2013.

Project description:Atmospheric particulate matter (PM) is a recognized risk factor for the global burden of disease in human populations. We are presenting here the application of toxicogenomics in the evaluation of the toxic effects of organic content of atmospheric particle matter (PM), from urban and rural environments (city of Barcelona and village of La Pobla, NE Spain), using the developing zebrafish embryo. The main goal is to identify the metabolic pathways involved in the adverse effects observed in zebrafish embryos exposed to PM organic content from urban and rural environments, also allowing the selection of genes of interest that are differentially expressed. The relevance of particle size to the PM toxicity is also addressed. Indeed, the zebrafish embryos were exposed to PM of aerodynamic diameter larger than 7.2 Î¼m and smaller than 0.5 Î¼m (PM10 and PM0.5, respectively). PM0.5 concentrated biological and toxic activities linked to organic substances. Transcriptomic analyses showed strong induction of the AhR signalling pathway (a.k.a. dioxin-like activity) for embryos exposed to both rural and urban extracts, correlating with the concentrations of PAHs. Urban extracts, with strong contribution of traffic emissions, specifically de-regulated oxidative stress-related genes, as well as pancreatic and eye-lens specific genes, two organs known to be affected by air pollution in humans. Exposure to rural extracts, with high contribution of wood burning emissions, affected genes implicated in basic cellular functions, in agreement with their strong embryotoxicity. Extracts from rural and urban samples elicited both common and specific transcriptome responses, suggesting different potentially adverse outcomes depending on PM source and composition. The authors thank the financial support of the Spanish Ministry (project TEA-PARTICLE, grant number CGL2011-29621) and the Portuguese Foundation for Science and Technology for the doctoral grant of Sofia R. Mesquita (SFRH/BD/80710/2011) funded by the Program POPH-QREN through the Portuguese Ministry of Education and Science and the European Social Fund, and support through project PEst-C/MAR/LA0015/2013. The PM filter samples used in the present study were PM10 and PM0.5 from the urban site - total of 4 samples from 2 sampling months; and PM0.5 from the rural site - total of 2 samples from 2 sampling months (PM10 samples from the rural site were not tested due to their very low concentration in organic compounds, and insignificant biological activity, previously measured). Sampling occurred during the cold periods of the year 2012/2013. The organic fraction of PM samples was extracted by sonication using a mixture of dichloromethane:methanol. Then, the extracts were filtered, evaporated and re-dissolved in Dimethyl sulfoxide (DMSO). Zebrafish fertilized eggs were exposed to PM organic extracts (0.2% DMSO) from the urban and rural sites from 24 to 120h post-fertilization. Total RNA was isolated from whole embryos (pools of 20 individuals), using Trizol reagent protocol (Invitrogen Life Technologies, Carlsberg, CA). The microarray study was performed using the Agilent Two-colour D. rerio Oligo Microarray v3 platform, following the Agilent Microarray â?? Based Gene Expression Analysis protocol. Three biological replicates were performed for each PM sample and controls. Biological replicates, a technical replicate and a self-to-self, were simultaneously amplified and labelled using Cyanine 3 (Cy3) and Cyanine 5 (Cy5) dye. After cRNA purification (RNeasy Kit, Quiagen GmbH, Hilden, Germany), the cRNA concentration and labelling were quantified in the NanoDrop spectrophotometer, obtaining incorporation rates in the range of 15-20pmol of cyanide dye/Âµl cRNA and yield values > 0.825ug, as recommended. cRNA was fragmented and hybridized in 4x44K arrays, for 17h at 65oC. After the hybridization the array slides were washed, and immediately scanned using Microarray Scanner Agilent G2505C system. Data was extracted using Agilent Feature Extraction Software v10.5.1.1, and the quality of microarray data was evaluated using the Quality Control report provided by Agilent Software. Based on the microarray data analysis, 22 primers were selected and designed using Primer Express 2.0 software (Applied Biosystems, Foster City, CA). Genes were quantified by real-time PCR to validate the microarray data, and a subset of 13 genes were further selected by their robust behaviour in the validation assays, allowing to differentiate the toxic potential of PM from urban and rural sources.

Project description:ImportanceOverdoses continue to increase in the US, but the contribution of methamphetamine use is understudied in rural communities.ObjectiveTo estimate the prevalence of methamphetamine use and its correlates among people who use drugs (PWUD) in rural US communities and to determine whether methamphetamine use is associated with increased nonfatal overdoses.Design, setting, and participantsFrom January 2018 through March 2020, the National Rural Opioid Initiative conducted cross-sectional surveys of PWUD in rural communities in 10 states (Illinois, Kentucky, New Hampshire, Massachusetts, North Carolina, Ohio, Oregon, Vermont, West Virginia, and Wisconsin). Participants included rural PWUD who reported any past-30-day injection drug use or noninjection opioid use to get high. A modified chain-referral sampling strategy identified seeds who referred others using drugs. Data analysis was performed from May 2021 to January 2022.ExposuresUse of methamphetamine alone, opioids alone, or both.Main outcomes and measuresUnweighted and weighted prevalence of methamphetamine use, any past-180-day nonfatal overdose, and number of lifetime nonfatal overdoses.ResultsAmong the 3048 participants, 1737 (57%) were male, 2576 (85%) were White, and 225 (7.4%) were American Indian; the mean (SD) age was 36 (10) years. Most participants (1878 of 2970 participants with any opioid or methamphetamine use [63%]) reported co-use of methamphetamine and opioids, followed by opioids alone (702 participants [24%]), and methamphetamine alone (390 participants [13%]). The estimated unweighted prevalence of methamphetamine use was 80% (95% CI, 64%-90%), and the estimated weighted prevalence was 79% (95% CI, 57%-91%). Nonfatal overdose was greatest in people using both methamphetamine and opioids (395 of 2854 participants with nonmissing overdose data [22%]) vs opioids alone (99 participants [14%]) or methamphetamine alone (23 participants [6%]). Co-use of methamphetamine and opioids was associated with greater nonfatal overdose compared with opioid use alone (adjusted odds ratio, 1.45; 95% CI, 1.08-1.94; P = .01) and methamphetamine use alone (adjusted odds ratio, 3.26; 95% CI, 2.06-5.14; P < .001). Those with co-use had a mean (SD) of 2.4 (4.2) (median [IQR], 1 [0-3]) lifetime overdoses compared with 1.7 (3.5) (median [IQR], 0 [0-2]) among those using opioids alone (adjusted rate ratio, 1.20; 95% CI, 1.01-1.43; P = .04), and 1.1 (2.9) (median [IQR], 0 [0-1]) among those using methamphetamine alone (adjusted rate ratio, 1.81; 95% CI, 1.45-2.27; P < .001). Participants with co-use most often reported having tried and failed to access substance use treatment: 827 participants (44%) for both, 117 participants (30%) for methamphetamine alone, and 252 participants (36%) for opioids alone (χ22 = 33.8; P < .001). Only 66 participants (17%) using methamphetamine alone had naloxone.Conclusions and relevanceThese findings suggest that harm reduction and substance use disorder treatment interventions must address both methamphetamine and opioids to decrease overdose in rural communities.

Project description:BackgroundPotentially inappropriate prescribing (PIP) may contribute to opioid overdose.ObjectiveTo examine the association between PIP and adverse events.DesignCohort study.ParticipantsThree million seventy-eight thousand thirty-four individuals age ≥ 18, without disseminated cancer, who received prescription opioids between 2011 and 2015.Main measuresWe defined PIP as (a) morphine equivalent dose ≥ 100 mg/day in ≥ 3 months; (b) overlapping opioid and benzodiazepine prescriptions in ≥ 3 months; (c) ≥ 4 opioid prescribers in any quarter; (d) ≥ 4 opioid-dispensing pharmacies in any quarter; (e) cash purchase of prescription opioids on ≥ 3 occasions; and (f) receipt of opioids in 3 consecutive months without a documented pain diagnosis. We used Cox proportional hazards models to identify PIP practices associated with non-fatal opioid overdose, fatal opioid overdose, and all-cause mortality, controlling for covariates.Key resultsAll six types of PIP were associated with higher adjusted hazard for all-cause mortality, four of six with non-fatal overdose, and five of six with fatal overdose. Lacking a documented pain diagnosis was associated with non-fatal overdose (adjusted hazard ratio [AHR] 2.21, 95% confidence interval [CI] 2.02-2.41), as was high-dose opioids (AHR 1.68, 95% CI 1.59-1.76). Co-prescription of benzodiazepines was associated with fatal overdose (AHR 4.23, 95% CI 3.85-4.65). High-dose opioids were associated with all-cause mortality (AHR 2.18, 95% CI 2.14-2.23), as was lacking a documented pain diagnosis (AHR 2.05, 95% CI 2.01-2.09). Compared to those who received opioids without PIP, the hazard for fatal opioid overdose with one, two, three, and ≥ four PIP subtypes were 4.24, 7.05, 10.28, and 12.99 (test of linear trend, p < 0.001).ConclusionsPIP was associated with higher hazard for all-cause mortality, fatal overdose, and non-fatal overdose. Our study implies the possibility of creating a risk score incorporating multiple PIP subtypes, which could be displayed to prescribers in real time.

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The Opioid Hydra: Understanding Overdose Mortality Epidemics and Syndemics Across the Rural-Urban Continuum.

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