Effect modification by socioeconomic conditions on the effects of prescription opioid supply on drug poisoning deaths in the United States

The rise in America’s drug poisoning rates has been described as a public health crisis and has long been attributed to the rapid rise in opioid supply due to increased volumes of medical prescribing in the United States that began in the mid-1990s and peaked in 2012. In 2016, the introduction of the “deaths of despair” hypothesis provided a more nuanced explanation for the rising rates of drug poisoning deaths: increasing income inequality and stagnation of middle-class worker wages, driven by long-term shifts in the labor market, reduced employment opportunities and overall life prospects for persons with a high school degree or less, driving increases in “deaths of despair” (i.e., deaths from suicide, cirrhosis of the liver, and drug poisonings). This focus on economic and social conditions as capable of shaping geospatial differences in drug demand and attendant drug-related harms (e.g., drug poisonings) provides a larger context to factors potentially underlying the heterogeneous distribution of prescription opioid supply across the United States. However, despite the likelihood that economic and social conditions may be important demand-side factors that also interact with supply-side factors to produce the rates of fatal drug poisonings, little information exists about the effect of area-level socioeconomic conditions on fatal drug poisoning rates, and no study has investigated whether socioeconomic conditions interact with prescription opioid supply to affect area-level rates of fatal drug poisonings. The overarching goal of this dissertation was to test the independent and joint effects of supply- and demand-side factors, operationalized as prescription opioid supply and socioeconomic conditions, on fatal drug poisoning in the U.S. First, a systematic review of the literature was conducted to critically evaluate the evidence on the ecological relationship of prescription opioid supply and socioeconomic conditions on rates of drug poisoning deaths. The systematic review provides robust evidence of the independent effect of each prescription opioid supply and socioeconomic conditions on rates of drug poisoning deaths. The gap in the literature on the joint effects of prescription opioid supply and socioeconomic conditions was clear, with no study examining the interaction between supply- and demand-side factors on rates of fatal drug poisonings. Moreover, although greater prescription opioid supply was associated with higher rates of fatal drug poisonings in most of the studies, two studies presented contradictory findings, with one study showing no effect of supply on drug poisoning deaths and the other showing locations with higher levels of prescription opioid supply were associated with fewer drug-related deaths. Three limitations were also identified in the reviewed studies that could partially explain the observed associations. First, although studies aggregated data on drug poisoning deaths to a range of administrative spatial levels, including census tract, 5-digit ZIP code, county, 3-digit ZIP code, and state, no study investigated the sensitivity of findings to the level of geographic aggregation. Second, spatial modeling requires the assessment of spatial autocorrelation in both the unadjusted and adjusted data, but few studies even assessed spatial autocorrelation in the data, and fewer still incorporated spatial dependencies in the model. This is important because when spatial autocorrelation is present, the independence assumption in standard statistical regression models is violated, potentially causing bias and loss of efficiency. Third, studies operationalized prescription opioid supply and socioeconomic conditions using a variety of different measures, and no study assessed the sensitivity of findings to the different measures of supply and socioeconomic conditions. Second, the ecological relationship between prescription opioid supply and fatal drug poisonings was examined. For this, pooled cross-sectional time series data from 3,109 U.S. counties in 49 states (2006-2016) were used in Bayesian Poisson conditional autoregressive models to estimate the effect of county prescription opioid supply on four types of drug poisoning deaths: any drug (drug-related death), any opioid (opioid-related death), any prescription opioid but not heroin (prescription opioid-related death), and heroin (heroin-related death), adjusting for compositional and contextual differences across counties. Comparisons were made by type of drug poisoning (any drug, any opioid, prescription opioids only, heroin), level of geographic aggregation (county versus state), and measure of prescription opioid supply (rate of opioid-prescribing per 100 persons and morphine milligram equivalents per-capita). Results indicated a positive association between prescription opioid supply and rates of fatal drug poisonings consistent across changes in type of drug poisoning, level of aggregation, and measure of prescription opioid supply. However, removing confounders from the model caused the direction of the effect estimate to reverse for drug poisoning deaths from any drug, any opioid, and heroin. These results suggested that differences in adjustment for confounding could explain most of the inconsistent findings in the literature. Finally, a rigorous test of the hypothesis that worse socioeconomic conditions increase risk of fatal drug poisonings at the county level, and interact with prescription opioid supply was conducted. This analysis used the same pooled cross-sectional time series data from 3,109 U.S. counties in 49 states (2006-2016). The analysis modeled the effect of five key socioeconomic variables, including three single socioeconomic variables (unemployment, poverty rate, income inequality) and two index variables (Rey index, American Human Development Index [HDI]) on four types of drug poisoning deaths: any drug (drug-related death), any opioid (opioid-related death), any prescription opioid but not heroin (prescription opioid-related death), and heroin (heroin-related death). Using a hierarchical Bayesian modeling approach to account for spatial dependence and the variability of fatal drug poisoning rates due to the small number of events, the independent effect of socioeconomic conditions on rates of drug poisoning deaths and their joint multiplicative and additive effect with prescription opioid supply were estimated. Results showed that rates of fatal drug poisonings were higher in more economically and socially disadvantaged counties; the five key indicator variables were differentially associated with drug poisoning rates; and the American Human Development Index (HDI) and income inequality were most strongly associated with fatal drug poisoning rates. Finally, the results indicate that both HDI and income inequality interact with county-level prescription opioid supply to affect drug poisoning rates. Specifically, the effect of higher prescription opioid supply on rates of fatal drug poisonings was greater in counties with higher HDI and more equal income distributions than counties with lower HDI and less equal income distributions. Overall, this dissertation increased knowledge about the separate and conjoint roles of supply- and demand-side factors in the geospatial distribution of fatal drug poisonings in the U.S. The idea that area-level prescription opioid supply are key drivers of prescription drug use, misuse, and addiction and the attendant consequences, including nonfatal and fatal drug poisonings, has been in the literature for well over a decade. However, no study to date has shown that area-level socioeconomic conditions modify the effect of prescription opioid supply on fatal drug poisonings. By identifying important contextual factors capable of modifying the effect of prescription opioid supply reductions on mortality, high-risk geographic areas can be prioritized for interventions to counter any unintended effects of reducing the prescription opioid supply in an area. As federal and state policies continue to target the rising rates of fatal drug poisonings, these findings show that area-level socioeconomic conditions may represent an important target for policy intervention during the current drug poisoning crisis and a critical piece of information necessary for predicting any future drug-related crises

Increase in suicides the months after the death of Robin Williams in the US

Investigating suicides following the death of Robin Williams, a beloved actor and comedian, on August 11th, 2014, we used time-series analysis to estimate the expected number of suicides during the months following Williams’ death. Monthly suicide count data in the US (1999–2015) were from the Centers for Disease Control and Prevention Wide-ranging ONline Data for Epidemiologic Research (CDC WONDER). Expected suicides were calculated using a seasonal autoregressive integrated moving averages model to account for both the seasonal patterns and autoregression. Time-series models indicated that we would expect 16,849 suicides from August to December 2014; however, we observed 18,690 suicides in that period, suggesting an excess of 1,841 cases (9.85% increase). Although excess suicides were observed across gender and age groups, males and persons aged 30–44 had the greatest increase in excess suicide events. This study documents associations between Robin Williams’ death and suicide deaths in the population thereafter

Ezh2-dCas9 and KRAB-dCas9 enable engineering of epigenetic memory in a context-dependent manner.

BackgroundRewriting of the epigenome has risen as a promising alternative to gene editing for precision medicine. In nature, epigenetic silencing can result in complete attenuation of target gene expression over multiple mitotic divisions. However, persistent repression has been difficult to achieve in a predictable manner using targeted systems.ResultsHere, we report that persistent epigenetic memory required both a DNA methyltransferase (DNMT3A-dCas9) and a histone methyltransferase (Ezh2-dCas9 or KRAB-dCas9). We demonstrate that the histone methyltransferase requirement can be locus specific. Co-targeting Ezh2-dCas9, but not KRAB-dCas9, with DNMT3A-dCas9 and DNMT3L induced long-term HER2 repression over at least 50 days (approximately 57 cell divisions) and triggered an epigenetic switch to a heterochromatic environment. An increase in H3K27 trimethylation and DNA methylation was stably maintained and accompanied by a sustained loss of H3K27 acetylation. Interestingly, substitution of Ezh2-dCas9 with KRAB-dCas9 enabled long-term repression at some target genes (e.g., SNURF) but not at HER2, at which H3K9me3 and DNA methylation were transiently acquired and subsequently lost. Off-target DNA hypermethylation occurred at many individual CpG sites but rarely at multiple CpGs in a single promoter, consistent with no detectable effect on transcription at the off-target loci tested. Conversely, robust hypermethylation was observed at HER2. We further demonstrated that Ezh2-dCas9 required full-length DNMT3L for maximal activity and that co-targeting DNMT3L was sufficient for persistent repression by Ezh2-dCas9 or KRAB-dCas9.ConclusionsThese data demonstrate that targeting different combinations of histone and DNA methyltransferases is required to achieve maximal repression at different loci. Fine-tuning of targeting tools is a necessity to engineer epigenetic memory at any given locus in any given cell type

Patterns of major depression and nonmedical use of prescription opioids in the United States

Introduction: Recent epidemiologic studies have shown that nonmedical use of prescription opioids (NMUPO) and major depression frequently co-occur. Comorbid forms of drug use and mental illness such as NMUPO and depression pose a greater disease burden than either condition alone. However, sociodemographic and substance use differences between individuals with either NMUPO or depression and those with comorbid conditions have not yet been fully investigated. Methods: Data came from the 2011 and 2012 National Survey on Drug Use and Health (NSDUH). Adolescents and adults were examined independently because of differences in screening for major depressive episodes (MDE). Weighted multinomial logistic regression investigated differences between persons with either past-year NMUPO (4.0%) or MDE (5.5%) and those with comorbid NMUPO and MDE (0.6%), compared to persons with neither condition. Results: Females were more likely than males to report either MDE-alone and comorbid NMUPO and MDE, whereas adult men were marginally more likely to report NMUPO-alone (not significant among adolescents). Polydrug use and alcohol use disorders were more pronounced among those with comorbid NMUPO and MDE than persons with either NMUPO-alone or MDE-alone. Persons with independent and comorbid NMUPO and MDE were more likely to report lower income and unemployment versus employment. Conclusions: This study found that independent and comorbid NMUPO and MDE were disproportionately clustered with burdens of lower socioeconomic position, suggesting that a population-based approach to address NMUPO would target these social determinants of health, whereas a high-risk approach to prevention should be tailored to females experiencing MDE symptoms and polydrug users

THERMAL AND SPECTROSCOPIC ANALYSES OF CAUSTIC LIDE SOLVENT EXTRACTION SOLVENT CONTACTED WITH 16 MOLAR AND 8 MOLAR NITRIC ACID

Thermal and spectroscopic analyses were performed on multiple layers formed from contacting Caustic Side Solvent Extraction (CSSX) solvent with 1 M or 3 M nitric acid. A slow chemical reaction occurs (i.e., over several weeks) between the solvent and 1 M or 3 M nitric acid as evidenced by color changes and the detection of nitro groups in the infrared spectrum of the aged samples. Thermal analysis revealed that decomposition of the resulting mixture does not meet the definition of explosive or deflagrating material

THERMAL AND SPECTROSCOPIC ANALYSES OF CAUSTIC SIDE SOLVENT EXTRACTION SOLVENT CONTACTED WITH 1 MOLARAND 3 MOLAR NITRIC ACID

Thermal and spectroscopic analyses were performed on multiple layers formed from contacting Caustic Side Solvent Extraction (CSSX) solvent with 1 M or 3 M nitric acid. A slow chemical reaction occurs (i.e., over several weeks) between the solvent and 1 M or 3 M nitric acid as evidenced by color changes and the detection of nitro groups in the infrared spectrum of the aged samples. Thermal analysis revealed that decomposition of the resulting mixture does not meet the definition of explosive or deflagrating material

DEVELOPMENT OF A ROTARY MICROFILTER FOR RADIOACTIVE WASTE APPLICATIONS

The processing rate of Savannah River Site (SRS) high-level waste decontamination processes are limited by the flow rate of the solid-liquid separation. The baseline process, using a 0.1 micron cross-flow filter, produces {approx}0.02 gpm/sq. ft. of filtrate under expected operating conditions. Savannah River National Laboratory (SRNL) demonstrated significantly higher filter flux for actual waste samples using a small-scale rotary filter. With funding from the U. S. Department of Energy Office of Cleanup Technology, SRNL personnel are evaluating and developing the rotary microfilter for radioactive service at SRS. The authors improved the design for the disks and filter unit to make them suitable for high-level radioactive service. They procured two units using the new design, tested them with simulated SRS wastes, and evaluated the operation of the units. Work to date provides the following conclusions and program status: (1) The authors modified the design of the filter disks to remove epoxy and Ryton{reg_sign}. The new design includes welding both stainless steel and ceramic coated stainless steel filter media to a stainless steel support plate. The welded disks were tested in the full-scale unit. They showed good reliability and met filtrate quality requirements. (2) The authors modified the design of the unit, making installation and removal easier. The new design uses a modular, one-piece filter stack that is removed simply by disassembly of a flange on the upper (inlet) side of the filter housing. All seals and rotary unions are contained within the removable stack. (3) While it is extremely difficult to predict the life of the seal, the vendor representative indicates a minimum of one year in present service conditions is reasonable. Changing the seal face material from silicon-carbide to a graphite-impregnated silicon-carbide is expected to double the life of the seal. Replacement of the current seal with an air seal could increase the lifetime to 5 years and is undergoing testing in the current work. (4) The bottom bushing showed wear due to a misalignment during the manufacture of the filter tank. Replacing the graphite bushing with a more wear resistant material such as a carbide material will increase the lifetime of the bushing. This replacement requires a more wear resistant part or coating to prevent excessive wear of the shaft. The authors are currently conducting testing with the more wear resistant bushing. (5) The project team plans to use the rotary microfilter as a filter in advance of an ion exchange process under development for potential deployment in SRS waste tank risers

Cosmic Ray Acceleration at the Forward Shock in Tycho's Supernova Remnant: Evidence from Chandra X-ray Observations

We present evidence for cosmic ray acceleration at the forward shock in Tycho's supernova remnant (SNR) from three X-ray observables: (1) the proximity of the contact discontinuity to the forward shock, or blast wave, (2) the morphology of the emission from the rim of Tycho, and (3) the spectral nature of the rim emission. We determine the locations of the blast wave (BW), contact discontinuity (CD), and reverse shock (RS) around the rim of Tycho's supernova remnant using a principal component analysis and other methods applied to new Chandra data. The azimuthal-angle-averaged radius of the BW is 251". For the CD and RS we find average radii of 241" and 183", respectively. Taking account of projection effects, we find ratios of 1:0.93:0.70 (BW:CD:RS). We show these values to be inconsistent with adiabatic hydrodynamical models of SNR evolution. The CD:BW ratio can be explained if cosmic ray acceleration of ions is occurring at the forward shock. The RS:BW ratio, as well as the strong Fe Ka emission from the Tycho ejecta, imply that the RS is not accelerating cosmic rays. We also extract radial profiles from ~34% of the rim of Tycho and compare them to models of surface brightness profiles behind the BW for a purely thermal plasma with an adiabatic shock. The observed morphology of the rim is much more strongly peaked than predicted by the model, indicating that such thermal emission is implausible here. Spectral analysis also implies that the rim emission is non-thermal in nature, lending further support to the idea that Tycho's forward shock is accelerating cosmic rays.Comment: 39 pages, 10 figures, accepted by Ap

Mental Health Over Time in a Military Sample: The Impact of Alcohol Use Disorder on Trajectories of Psychopathology After Deployment

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/116086/1/jts22055.pd

DEVELOPMENT OF A CROSSFLOW FILTER TO REMOVE SOLIDS FROM RADIOACTIVE LIQUID WASTE: COMPARISON OF TEST DATA WITH OPERATING EXPERIENCE - 9119

In 2008, the Savannah River Site (SRS) began treatment of liquid radioactive waste from its Tank Farms. To treat waste streams containing {sup 137}Cs, {sup 90}Sr, and actinides, SRS developed the Actinide Removal Process (ARP) and the Modular Caustic Side Solvent Extraction Unit (MCU). The Actinide Removal Process contacts the waste with monosodium titanate (MST) to sorb strontium and select actinides. After MST contact, the process filters the resulting slurry to remove the MST (with sorbed strontium and actinides) and any entrained sludge. The filtrate is transported to the MCU to remove cesium. The solid particle removed by the filter are concentrated to {approx} 5 wt %, washed to reduce the concentration of dissolved sodium, and transported to the Defense Waste Processing Facility (DWPF) for vitrification. The authors conducted tests with 0.5 {micro} and 0.1 {micro} Mott sintered stainless steel crossflow filter at bench-scale (0.19 ft{sup 2} surface area) and pilot-scale (11.2 ft{sup 2}). The collected data supported design of the filter for the process and identified preferred operating conditions for the full-scale process (230 ft{sup 2}). The testing investigated the influence of operating parameters, such as filter pore size, axial velocity, transmembrane pressure, and solids loading, on filter flux, and validated the simulant used for pilot-scale testing. The conclusions from this work follow: (1) The 0.1 {micro} Mott sintered stainless steel filter produced higher flux than the 0.5 {micro} filter. (2) The filtrate samples collected showed no visible solids. (3) The filter flux with actual waste is comparable to the filter flux with simulated waste, with the simulated waste being conservative. This result shows the simulated sludge is representative of the actual sludge. (4) When the data is adjusted for differences in transmembrane pressure, the filter flux in the Actinide Removal Process is comparable to the filter flux in the bench-scale and pilot-scale testing. (5) Filter flux increased with transmembrane pressure, increased with axial velocity, and decreased with concentration in agreement with classical crossflow filtration theories