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: Methamphetamine-related deaths have been rising along with those involving synthetic opioids, mostly fentanyl and fentanyl analogs (FAs). However, the extent to which methamphetamine involvement in deaths differs from those changes occurring in synthetic opioid involvement is unknown.: To determine the patterns and temporal changes in methamphetamine-related deaths with and without other drug involvement.: Data from all methamphetamine-related deaths in West Virginia from 2013 to 2018 were analyzed. Quasi-Poisson regression analyses over time were conducted to compare the rates of change in death counts among methamphetamine and fentanyl//FA subgroups.: A total of 815 methamphetamine-related deaths were analyzed; 572 (70.2%) were male and 527 (64.7%) involved an opioid. The proportion of methamphetamine only deaths stayed relatively flat over time although the actual numbers of deaths increased. Combined fentanyl/FAs and methamphetamine were involved in 337 deaths (41.3%) and constituted the largest increase from 2013 to 2018. The modeling of monthly death counts in 2017-2018 found that the average number of deaths involving fentanyl without methamphetamine significantly declined (rate of change -0.025, < .001), while concomitant fentanyl with methamphetamine and methamphetamine only death counts increased significantly (rate of change 0.056 and 0.057, respectively, < .001).: Fentanyl and FAs played an increasingly significant role in methamphetamine-related deaths. The accelerating number of deaths involving fentanyl/FAs and methamphetamine indicates the importance of stimulants and opioids in unintentional deaths. Comprehensive surveillance efforts should continue to track substance use patterns to ensure that appropriate prevention programs are undertaken.

The relative risk of major gastrointestinal bleeding (GIB) among different direct oral anticoagulants (DOACs) is debatable. Randomized controlled trials (RCTs) comparing DOACs with each other are lacking. We performed network meta-analysis to assess whether the risk of major GIB differs based on type and dose of DOAC. Literature search of PubMed, EMBASE and Cochrane databases from inception to August 2019, limited to English publications, was conducted to identify RCTs comparing DOACs with warfarin or enoxaparin for any indication. Primary outcome of interest was major GIB risk. We used frequentist network meta-analysis through the random-effects model to compare DOACs with each other and DOACs by dose to isolate the impact on major GIB. Twenty-eight RCTs, including 139 587 patients receiving six anticoagulants, were selected. The risk of major GIB for DOACs was equal to warfarin. Comparison of DOACs with each other did not show risk differences. After accounting for dose, rivaroxaban 20 mg, dabigatran 300 mg and edoxaban 60 mg daily had 47, 40 and 22% higher rates of major GIB versus warfarin, respectively. Apixaban 5 mg twice daily had lower major GIB compared to dabigatran 300 mg (OR, 0.63; 95% CI, 0.44-0.88) and rivaroxaban 20 mg (OR, 0.60; 95% CI, 0.43-0.83) daily. Heterogeneity was low, and the model was consistent without publication bias (Egger's test: P = 0.079). All RCTs were high-quality with low risk of bias. DOACs at standard dose, except apixaban, had a higher risk of major GIB compared to warfarin. Apixaban had a lower rate of major GIB compared to dabigatran and rivaroxaban.

Adverse drug reactions (ADRs) are a pervasive complication in the realm of pharmacotherapy. At the root of ADRs lies interindividual variability in drug response, which can range from allergic reactions, to genetic variability, to any factors that influence the pharmacokinetics of a drug. Nonalcoholic steatohepatitis (NASH) is the late-stage of non-alcoholic fatty liver disease (NAFLD), characterized by fat deposition, oxidative stress, inflammation, and fibrosis. Over the last several years, alterations in drug metabolizing enzymes and transporters have been broadly characterized through NAFLD progression. Multidrug resistance-associated protein 2 (MRP2) is a canalicular efflux transporter that directs the biliary elimination of a wide variety of xenobiotics and metabolites. In NASH, MRP2 is mislocalized away from the canalicular membrane in a post-translational event. The mechanism and extent of this mislocalization has yet to be elucidated. While transporter misregulation has been shown to influence the disposition of a variety of substrates, the direct impact of MRP2 mislocalization on its overall transport capacity, and pharmacologic consequence of this change, is unknown. The purpose of this study was to elucidate the mechanism behind, and functional consequence of, MRP2/Mrp2 mislocalization in NASH, predominantly using the rodent methionine-and-choline-deficient (MCD) dietary model.To identify the mechanism of MRP2/Mrp2 mislocalization, a comparison of the activation status of various mediators of MRP2/Mrp2 retrieval was conducted between healthy and NASH livers. Results in rat samples and human NASH samples indicate that activation changes of these mediators, including radixin, PKCα, PKCδ, and PKA, are consistent with a shift toward active retrieval of MRP2/Mrp2 from the membrane, and some evidence of impaired membrane insertion is also present. Measurement of Mrp2 transport capacity was completed using pemetrexed, a novel Mrp2 probe substrate. Comparison of biliary excretion of pemetrexed between wild-type and Mrp2^(-/-) rats shows a 100% decrease, confirming that it relies upon Mrp2 for biliary excretion. NASH rats exhibited a 60% decrease in pemetrexed levels in the bile compared to their control counterparts, indicating that Mrp2 transport capacity is severely impaired in NASH rats. Finally, to ascertain the pharmacologic consequence of impaired Mrp2 transport, a study was conducted measuring the effects of the active morphine glucuronide on control and NASH rats. NASH rats exhibited a decreased biliary excretion, and increased systemic retention, of M3G. While they did also exhibit increased antinociception of M6G, the definitive impact of altered disposition on pharmacologic response was masked due to the interference of an MCD dietary effect on antinociception. Overall, the data reported herein identify active membrane retrieval as a mechanism of MRP2/Mrp2 mislocalization in NASH, and that mislocalization results in a 60% decrease in overall Mrp2 transport capacity. This decrease significantly hinders biliary excretion of Mrp2 substrates, and may result in ADRs by contributing to interindividual variability in drug response.

INTRODUCTION: Approximately two-thirds of the U.S. population have had at least one adverse childhood experience (CDC-Kaiser Permanente Adverse Childhood Experiences [ACE] Study, 2009). Some consequences of ACEs are manifested as the child grows into late teenage years and young adulthood. Research suggests that children exposed to traumatic events during childhood subsequently experience negative health outcomes like substance abuse, engagement in risky and harmful sexual behavior, and STD occurrence. AIM: In this thesis I explore the associations of 18 year olds’ described use of alcohol, risky sexual behavior and sexually transmitted diseases (STDs) with childhood exposure to caregiver substance abuse, violence and family circumstances METHODS: Data were obtained from the Longitudinal Studies of Childhood Abuse and Neglect (LONGSCAN) Assessments 0 - 18 from the National Data Archive on Child Abuse and Neglect (NDACAN). Variables on adverse childhood experiences, sex behaviors, STDs and substance use were observed in SAS. Multiple logistic regression models were used to identify odds ratios and strength of associations. RESULTS: Results suggests significant associations among participants who were exposed to parent/caregiver use of illicit drugs during participant’s childhood and subsequent self-reported heavy alcohol use 1.60 (95% CI: 1.18, 2.22), having early sexual initiation (at age 13 or younger) 1.60 (95% CI: 1.18, 2.22), having 6 or more sexual partners 1.36 (95% CI: 1.09, 1.68) and having STDs 1.83 (95% CI: 1.36, 2.46). Eighteen year olds with who were African American, were at a greater odds of having greater than 6 sexual partners, having sexual intercourse at or before age 13 and having (an) STD(s). No significant associations were found between having a parent/caregiver or member of household who was incarcerated, being exposed to violence, being exposed to yelling often or parental often use of alcohol and subsequent alcohol abuse, having greater than 6 sexual partners, having sexual intercourse at or before age 13 and having (an) STD(s) . DISCUSSION: Based on the findings of these analyses, programs for adolescents should focus time and resources on young children who may be currently experiencing, or at risk for experiencing, parental/ caregiver illicit drug use in the home.

Thesis (LLM)--Stellenbosch University, 1982. / INLEIDING: Een van die gevolge van die besit van 'n saak is die feit dat die besitter op besitsbeskerming geregtig is. Onderliggend aan hierdie beskerming moet die doel wat die reg vervul, gesien word - die vreedsame ordening van die samelewing. Wanorde sal heers in 'n samelewing waar willekeurige en eiegeregtige inbreukmaking op besitsverhoudinge toegelaat word: "In the final analysis the protection of possession is part and parcel of the protection of the peace in a community, which could not be maintained if every person who asserts that he has a real right to a particular thing which is in another person's possession would be entitled to resort to selfhelp". In hierdie verband verwys skrywers onder meer na die "regspolitieke funksie" of die "beskermingsimplikasie" van besit.

The purpose of this dissertation was to use the theory of planned behavior (TPB) to predict Texas pharmacists’ intention to report serious adverse drug effects (ADEs) to the Food and Drug Administration (FDA). The study explored the utility of the TPB model constructs (attitude [A], subjective norm [SN], perceived behavioral control [PBC]), as well as past reporting behavior (PRB), and perceived moral obligation (PMO) to predict pharmacists’ intention to report serious ADEs to the FDA. The study also determined if the pharmacists’ A, SN and PBC were related to practice characteristics and demographic factors. A survey was developed based on two focus group interviews, pretested and mailed to 1,500 Texas practicing pharmacists. An overall response rate of 26.4 percent was obtained (n = 377 pharmacists). Overall, pharmacists intended to report serious ADEs, had a favorable attitude towards reporting, were somewhat influenced by social norms regarding reporting and perceived themselves to have some control over reporting serious ADEs to the FDA. For direct measures, A and SN were significant predictors of intention to report serious ADEs, but PBC was not. The TPB constructs together accounted for 34.0 percent of the variance in intention to report serious ADEs to the FDA. Using indirect measures, A, SN and PBC were significant predictors of intention and together accounted for 28.8 percent of the variance in intention to report serious ADEs. PRB and PMO improved the explanatory power of the regression models (direct and indirect measures) over and above the TPB constructs. Unlike most other practice characteristics and demographic factors examined, knowledge was significantly related with the TPB constructs. In summary, A, SN, PBC (indirect measures), PRB, and PMO influence the formation of pharmacists’ intention to report serious ADEs. The TPB has utility in predicting ADE reporting behavior. Pharmacy educators should explore pharmacists’ attitudes, beliefs, and expectations of important others in designing educational programs. Strategies to help pharmacists report more serious ADEs should focus on altering their perception of social pressure towards reporting and addressing the barriers towards ADE reporting (e.g., lack of knowledge). / text

<p>Genetically determined differences in drug metabolism and disposition and drug targets play a pivotal role in the interindividual variability in the clinical outcome of antipsychotic treatment. The aim of this thesis was to study the impact of polymorphisms in genes involved in the pharmacokinetics and pharmacodynamics of antipsychotics, with special focus on their extrapyramidal and metabolic adverse effects. </p><p>Polymorphisms in serotonin 2A and 2C receptor coding genes (<i>HTR2A</i> and <i>HTR2C</i>) were found to be associated with the risk to develop extrapyramidal side effects (EPS) in patients on short term perphenazine treatment. A further study in a larger group of patients on long term treatment with various classical antipsychotics confirmed the association between occurrence of EPS and <i>HTR2C</i> polymorphisms. In another study, dose corrected steady state serum clozapine and N-desmethylclozapine concentrations (C/D) and insulin elevation during clozapine therapy were found to correlate with <i>CYP1A2</i> but not with <i>CYP2D6</i> polymorphisms. Furthermore, <i>HTR2C</i> and <i>HTR2A</i> polymorphisms were found to have significant influences on BMI and C-peptide levels in patients treated with olanzapine and clozapine. Evaluation of the impact of polymorphisms in genes encoding CYP3A4, CYP3A5 and P-glycoprotein (<i>ABCB1</i>) in addition to CYP2D6 on the steady state plasma levels of risperidone, 9-hydroxyrisperidone and their active moiety revealed a significant influence of <i>ABCB1 </i>genotype on 9-hydroxyrisperidone and active moiety C/Ds, while <i>CYP2D6</i> genotype associated with risperidone C/Ds but not with 9-hydroxyrisperidone or active moiety C/D. </p><p>We have shown that polymorphisms in genes involved in the pharmacokinetics and the pharmacodynamics of antipsychotic drugs play a role in the occurrence of adverse effects, both EPS and metabolic disturbances, induced by antipsychotic treatment. Genotyping for <i>HTR2A</i>, <i>HTR2C</i>, <i>CYP1A2</i>, <i>CYP2D6</i> and <i>ABCB1</i> polymorphisms may therefore potentially provide useful information to identify patients at higher risk to develop EPS or metabolic adverse during schizophrenia treatment with antipsychotic drugs.</p>

Class of 2009 Abstract / OBJECTIVES: To compare possible differences in the proportion of serious potential ADEs associated with high-risk medications that were avoided by the use of AID technology in adult and pediatric ICU patients and to investigate the proportion of serious ADEs associated with high-risk medications as identified by root cause analyses (RCA) that occurred before and after AID implementation. METHODS: Study Site: This retrospective study was conducted at a tertiary care, academic medical center in Tucson Arizona. Design: This was a two-part retrospective study involving data obtained from an AID database and root-cause analyses. Information on high-risk medications obtained from the AID database was used to compare the proportion of serious ADEs avoided by the use of AID technology in adult and pediatric patients. Information on high-risk medications (administered by continuous infusion) obtained from root-cause analyses was used to compare the proportion of serious ADEs that occurred during the 5-year period before and the 5-year period after AID implementation. RESULTS: A total of 261 infusions (225 in the adult and 36 in the pediatric) generated an alert where the final outcome resulted in a reprogramming event when the limit was exceeded by 2.5 times or greater. The pediatric population was 1.68 time (95% CI=1.18 to 2.38) more likely to require a reprogramming event than the adult acute care population for all high-risk medications combined. Significantly more reprogramming events occurred in the pediatric patients with potassium (RR=2.77, 95 CI=1.15 to 6.68) and insulin (RR=2.73, 95% CI=1.15 to 6.45) infusions. Overrides accounted for 80% of the total reprogramming and override events when the maximum limit was exceeded by 10 times or more. There were significantly more overrides in the pediatric compared to the adult population for the high-risk medications (RR=1.82, 95% CI=1.32 to 2.53), however, there were significantly fewer overrides in the pediatric versus adult patients on fentanyl (RR=0.34, 95% CI=0.17 to 0.70). CONCLUSIONS: We found that medication errors involving high-risk medications with the potential to cause ADEs can occur frequently during the administration phase of drug delivery. While smart AIDs cannot intercept all errors, it did show that it was able to intercept certain errors, especially key=pad entry errors. We also determined that when an alert was generated involving our high-risk medications, clinicians were more apt to reprogram the AID when the alert occurred in our pediatric population. While smart pumps have shown great improvement and allow for safer drug delivery, more research is needed in this area before the ability of these smart AIDs to improve drug administration safety can be shown.

The purpose of the present study was to investigate the behavioral differences between over- and underachieving mental retardates and to provide an effective way of identifying over- and underachieving mental retardates.