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Heather D Anderson,1 Vanessa Paul Patterson,1 Garth Wright,1 Julia E Rawlings,1 Gina D Moore,1 Jim Leonard,2 Robert L Page II1 1Department of Clinical Pharmacy, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Anschutz Medical Campus, Aurora, CO, USA; 2Colorado Department of Health Care Policy and Financing, Denver, CO, USACorrespondence: Robert L Page II, Clinical Pharmacy, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, 12850 E. Montview Blvd, Mail Stop C238, Aurora, CO, 80045, USA, Tel +1 303-724-2616, Fax +1 303-724-2627, Email robert.page@cuanschutz.eduObjective: COVID-19, coinciding with the opioid epidemic in the United States, has had significant impacts on health-care utilization. While mixed, early analyses signaled a potential resurgence in opioid use following the pandemic. The primary study objective was to assess the association of the COVID-19 pandemic with opioid utilization among Health First Colorado (Colorado’s Medicaid Program) members and a non-Medicaid managed care cohort who did not have a diagnosis of cancer or sickle cell disease.Patients and Methods: Using an interrupted time series and segmented regression analysis, this population-level study assessed the association of the COVID-19 pandemic on prescribed utilization of long- and short-acting opioid analgesics among Health First Colorado members and a random sample of non-Medicaid managed care members. Pharmacy claims data for both cohorts were assessed between October 1, 2018, and September 30, 2021, with April 2020 identified as the interruption of interest. We evaluated the following monthly opioid use measures separately for short-acting and long-acting opioids: number of members filling an opioid, total fills, and total days supplied.Results: Short- and long-acting opioid utilization was significantly decreasing among Health First Colorado members in the 18 months prior to the start of COVID-19. After the onset of the pandemic, utilization stabilized and slopes were not significantly different from zero. Among the non-Medicaid managed care cohort, short- and long-acting opioid utilization significantly decreased in the 18 months leading up to the onset of the pandemic. After the onset of the pandemic, utilization of long-acting opioids stabilized, while utilization of short-acting opioids significantly increased.Conclusion: While we observed an increase in opioid utilization measures post-pandemic in the non-Medicaid managed care cohort, a similar increase was not observed in Health First Colorado members suggesting that thoughtful opioid policies put in place pre-pandemic may have been effective at controlling potential inappropriate opioid utilization.Keywords: interrupted time series, segmented regression, pain management, health care utilization, Medicaid, managed care, opioids

Background: Identify opportunities to improve syphilis screening by describing changes in patient characteristics and risk factors among individuals with syphilis and by comparing cases with and without an indication for syphilis screening., Methods: This retrospective cohort study used Colorado public health surveillance data to identify 8,326 syphilis diagnoses from 2011-2020. Demographics, clinical characteristics, and risk factors were compared across 2-year groups and between individuals with and without an indication for screening. Indications for screening were based on national guidelines and included men who have sex with men, persons living with HIV, pregnant individuals, those who test positive for chlamydia, gonorrhea, or HIV, and partners of those who test positive for syphilis., Results: Across study years, there was a 234% increase in the proportion of syphilis cases that were females (5.3% to 17.7%; p < .01), a 78% increase in the proportion of cases living in rural areas (3.6% to 6.4%; p < .01), and a 15% increase in the proportion of cases among non-White individuals (47.9% to 54.9%; p < .01). The proportion of patients that had a guideline-recommended indication for screening decreased from 88% in 2011-2012 to 59% in 2019-2020 (p < .01). Females represented 5.5% of cases with an indication for screening and 29.8% of cases without an indication for screening (p < .01)., Conclusions: Syphilis cases increased annually from 2011-2020 yet the proportion of cases detected under current screening recommendations decreased. These findings reveal opportunities to expand syphilis screening., Competing Interests: Disclosures of Conflicts of Interest: The authors have no conflicts of interest related to this work to disclose., (Copyright © 2024 American Sexually Transmitted Diseases Association. All rights reserved.)

Objective: To learn how students in an accredited PharmD program in the United States are using ChatGPT for personal, academic, and clinical reasons, and whether students think ChatGPT training should be incorporated into their program's curriculum., Methods: In August 2023, an 18-item survey was developed, pilot tested, and sent to all students who were enrolled during the Spring 2023 semester in the entry-level PharmD program at the University of Colorado. E-mail addresses were separated from survey responses to maintain anonymity. Responses were described using descriptive statistics., Results: 206 pharmacy students responded to the survey for a 49% response rate. Nearly one-half (48.5%) indicated they had used ChatGPT for personal reasons; 30.2% had used it for academic reasons; and 7.5% had used it for clinical reasons. The most common personal use for ChatGPT was answering questions and looking-up information (67.0%). The top academic reason for using ChatGPT was summarizing information or a body of text (42.6%), while the top clinical reason was simplifying a complex topic (53.3%). Most respondents (61.8%) indicated they would be interested in learning about how ChatGPT could help them in pharmacy school, and 28.1% thought ChatGPT training should be incorporated into their pharmacy curriculum., Conclusion: At the time of the survey, ChatGPT was being used by approximately one-half of our pharmacy student respondents for personal, academic, or clinical reasons. Overall, many students indicated they want to learn how to use ChatGPT to help them with their education and think ChatGPT training should be integrated into their curriculum., Competing Interests: Declaration of competing interest None of the authors have any conflicts of interest to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Understand perceived barriers to and facilitators of using clinical informatics applications for pharmacogenomic (PGx) implementation in resource-limited settings., Materials and Methods: We conducted a qualitative research study using a semi-structured interview guide informed by the Consolidated Framework for Implementation Research (CFIR). Interview questions assessed CFIR contextual determinants related to: electronic health record (EHR) infrastructure; clinical informatics personnel and resources; EHR integration of PGx test results; PGx clinical decision support (CDS) tools; institutional resources; and partner receptivity. Transcripts were coded and analyzed to identify themes., Results: We interviewed 24 clinical informaticists and executive leaders working in rural or underserved health care settings in Montana ( n  = 15) and Colorado ( n  = 9) and identified three major themes: (1) EHR infrastructure limitations, (2) insufficient supporting resources, and (3) unique contextual considerations for resource-limited settings. EHR infrastructure limitations included limited agency related to EHR build and interoperability concerns. Theme 1 highlighted challenges associated with integrating structured data into the EHR and inadequate vendor support. Theme 2 included limited familiarity with PGx across the care team, cost concerns, and allocation of non-financial resources. Theme 3 highlighted perceptions about the clinical utility of PGx within rural and underrepresented populations. Potential facilitators, such as being able to act nimbly, were found to coexist among the reported barriers., Discussion and Conclusion: Our results provide insight into the clinical informatics infrastructure in resource-limited settings and identify unique considerations for clinical informatics-facilitated PGx implementation. Future efforts in these settings should consider innovative partnerships and strategies to leverage facilitators and minimize barriers associated with integrating PGx CDS applications., Competing Interests: The authors have no competing interests to declare., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Medical Informatics Association.)

Understanding the initiation of T-helper (Th)-2 immunity is crucial for addressing allergic diseases that have been linked to the commensal microbiota. However, Th2 responses are notably absent from known host-microbiota intestinal immune circuits. Notably, the commensal protist Tritrichomonas induces a transient innate ILC2 circuit rather than a chronic Th2 circuit. Canonical Th2 responses rely on the induction of IL-4 production by innate cells. This study shows that the absence of Tet2 , a DNA demethylase, reprograms naïve T cells to autonomously produce IL-4 upon T cell receptor stimulation, bypassing the need for IL-4 from innate cells for Th2 differentiation. Loss of this checkpoint induces chronic Th2 responses to Tritrichomonas , associated with IL-25-dependent barrier dysfunction and increased susceptibility to allergic pathology in response to dietary antigens., Sentence Summary: Regulation of cell autonomous IL-4 in T cells is critical to prevent dysregulated Th2 immunity to commensals and predisposition to allergy.

Natural killer (NK) cells traffic through the blood and mount cytolytic and interferon-γ (IFNγ)-focused responses to intracellular pathogens and tumors. Type 1 innate lymphoid cells (ILC1s) also produce type 1 cytokines but reside in tissues and are not cytotoxic. Whether these differences reflect discrete lineages or distinct states of a common cell type is not understood. Using single-cell RNA sequencing and flow cytometry, we focused on populations of TCF7 + cells that contained precursors for NK cells and ILC1s and identified a subset of bone marrow lineage-negative NK receptor-negative cells that expressed the transcription factor Eomes, termed Eomes hi NK neg cells. Transfer of Eomes hi NK neg cells into Rag2 -/- Il2rg -/- recipients generated functional NK cells capable of preventing metastatic disease. By contrast, transfer of PLZF + ILC precursors generated a mixture of ILC1s, ILC2s and ILC3s that lacked cytotoxic potential. These findings identified Eomes hi NK neg cells as the bone marrow precursor to classical NK cells and demonstrated that the NK and ILC1 lineages diverged early during development., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

The objective of this study was to estimate the cost-effectiveness of CYP3A5 genotype-guided tacrolimus dosing in kidney, liver, heart, and lung transplant recipients relative to standard of care (SOC) tacrolimus dosing, from a US healthcare payer perspective. We developed decision-tree models to compare economic and clinical outcomes between CYP3A5 genotype-guided and SOC tacrolimus therapy in the first six months post-transplant. We derived inputs for CYP3A5 phenotype frequencies and physician use of genotype test results to inform clinical care from literature; tacrolimus exposure [high vs low tacrolimus time in therapeutic range using the Rosendaal algorithm (TAC TTR-Rosendaal)] and outcomes (incidences of acute tacrolimus nephrotoxicity, acute cellular rejection, and death) from real-world data; and costs from the Medicare Fee Schedule and literature. We calculated cost per avoided event and performed sensitivity analyses to evaluate the robustness of the results to changes in inputs. Incremental costs per avoided event for CYP3A5 genotype-guided vs SOC tacrolimus dosing were $176,667 for kidney recipients, $364,000 for liver recipients, $12,982 for heart recipients, and $93,333 for lung recipients. The likelihood of CYP3A5 genotype-guided tacrolimus dosing leading to cost-savings was 19.8% in kidney, 32.3% in liver, 51.8% in heart, and 54.1% in lung transplant recipients. Physician use of genotype results to guide clinical care and the proportion of patients with a high TAC TTR-Rosendaal were key parameters driving the cost-effectiveness of CYP3A5 genotype-guided tacrolimus therapy. Relative to SOC, CYP3A5 genotype-guided tacrolimus dosing resulted in a slightly greater benefit at a higher cost. Further economic evaluations examining intermediary outcomes (e.g., dose modifications) are needed, particularly in populations with higher frequencies of CYP3A5 expressers., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Objective: This study aimed to describe the purpose, implementation, and perceived utility of course evaluations in pharmacy programs., Methods: After a literature review, a 34-item survey was developed, pretested, and sent to assessment administrators at accredited pharmacy programs (N = 139) with at least 3 follow-ups. Descriptive and inferential statistics were performed in IBM SPSS Statistics software., Results: A total of 90 programs responded (64.7% response rate). Most students (94%) were offered the opportunity to complete course evaluations. Some students completed evaluations during the course (47%), while others did so within 1 week of completion of the course (49%). Whether or not class time was given for students to complete the survey was often dependent on faculty choice (52.2%). Results were typically released after final grades were posted (92%), in time to use for the next semester of teaching (77%). Faculty were chosen to be evaluated by the number of teaching hours (50%) followed by all instructors (45.6%). Programs used the results for performance reviews by chairs (91%), course coordinator reviews (84%), and committee continuous quality improvement efforts (72%). Most programs did not provide faculty guidance on using evaluations (78%) nor development/mentoring (57%); only 22% of programs offered student development in completing evaluations., Conclusion: While most programs invite feedback from all students via evaluations, most did not provide guidance to faculty on how to use this feedback for faculty or course development purposes. A more robust process to optimize the use of course evaluations should be developed., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: The prevalence of exposure to pharmacogenomic medications is well established but little is known about how long patients are exposed to these medications., Aim: Our objective was to describe the amount of exposure to actionable pharmacogenomic medications using patient-level measures among a large nationally representative population using an insurance claims database., Methods: Our retrospective cohort study included adults (18+ years) from the IQVIA PharMetrics ® Plus for Academics claims database with incident fills of 72 Clinical Pharmacogenetics Implementation Consortium level A, A/B, or B medications from January 2012 through September 2018. Patient-level outcomes included the proportion of days covered (PDC), number of fills, and average days supplied per fill over a 12-month period., Results: Over 1 million fills of pharmacogenetic medications were identified for 605,355 unique patients. The mean PDC for all medications was 0.21 (SD 0.3), suggesting patients were exposed 21% (77 days) of the year. Medications with the highest PDC (0.55-0.89) included ivacaftor, tamoxifen, clopidogrel, HIV medications, transplant medications, and statins; with the exception of statins, these medications were initiated by fewer patients. Pharmacogenomic medications were filled an average of 2.8 times (SD 3.0, range 1-81) during the year following the medication's initiation, and the average days supplied for each fill was 22.3 days (SD 22.4, range 1-180 days)., Conclusion: Patient characteristics associated with more medication exposure were male sex, older age, and comorbid chronic conditions. Prescription fill data provide patient-level exposure metrics that can further our understanding of pharmacogenomic medication utilization and help inform opportunities for pharmacogenomic testing.

Glucose metabolism is critical for the African trypanosome, Trypanosoma brucei , serving as the lone source of ATP production for the bloodstream form (BSF) parasite in the glucose-rich environment of the host blood. Recently, phosphonate inhibitors of human enolase (ENO), the enzyme responsible for the interconversion of 2-phosphoglycerate (2-PG) to phosphoenolpyruvate (PEP) in glycolysis or PEP to 2-PG in gluconeogenesis, have been developed for the treatment of glioblastoma multiforme (GBM). Here, we have tested these agents against T. brucei ENO ( Tb ENO) and found the compounds to be potent enzyme inhibitors and trypanocides. For example, (1-hydroxy-2-oxopyrrolidin-3-yl) phosphonic acid (deoxy-SF2312) was a potent enzyme inhibitor (IC 50 value of 0.60 ± 0.23 µM), while a six-membered ring-bearing phosphonate, (1-hydroxy-2-oxopiperidin-3-yl) phosphonic acid (HEX), was less potent (IC 50 value of 2.1 ± 1.1 µM). An analog with a larger seven-membered ring, (1-hydroxy-2-oxoazepan-3-yl) phosphonic acid (HEPTA), was not active. Molecular docking simulations revealed that deoxy-SF2312 and HEX had binding affinities of -6.8 and -7.5 kcal/mol, respectively, while the larger HEPTA did not bind as well, with a binding of affinity of -4.8 kcal/mol. None of these compounds were toxic to BSF parasites; however, modification of enzyme-active phosphonates through the addition of pivaloyloxymethyl (POM) groups improved activity against T. brucei , with POM-modified (1,5-dihydroxy-2-oxopyrrolidin-3-yl) phosphonic acid (POMSF) and POMHEX having EC 50 values of 0.45 ± 0.10 and 0.61 ± 0.08 µM, respectively. These findings suggest that HEX is a promising lead against T. brucei and that further development of prodrug HEX analogs is warranted.

Introduction/background: Patients with heart failure and reduced ejection fraction (HFrEF) are consistently underprescribed guideline-directed medications. Although many barriers to prescribing are known, identification of these barriers has relied on traditional a priori hypotheses or qualitative methods. Machine learning can overcome many limitations of traditional methods to capture complex relationships in data and lead to a more comprehensive understanding of the underpinnings driving underprescribing. Here, we used machine learning methods and routinely available electronic health record data to identify predictors of prescribing., Methods: We evaluated the predictive performance of machine learning algorithms to predict prescription of four types of medications for adults with HFrEF: angiotensin converting enzyme inhibitor/angiotensin receptor blocker (ACE/ARB), angiotensin receptor-neprilysin inhibitor (ARNI), evidence-based beta blocker (BB), or mineralocorticoid receptor antagonist (MRA). The models with the best predictive performance were used to identify the top 20 characteristics associated with prescribing each medication type. Shapley values were used to provide insight into the importance and direction of the predictor relationships with medication prescribing., Results: For 3,832 patients meeting the inclusion criteria, 70% were prescribed an ACE/ARB, 8% an ARNI, 75% a BB, and 40% an MRA. The best-predicting model for each medication type was a random forest (area under the curve: 0.788-0.821; Brier score: 0.063-0.185). Across all medications, top predictors of prescribing included prescription of other evidence-based medications and younger age. Unique to prescribing an ARNI, the top predictors included lack of diagnoses of chronic kidney disease, chronic obstructive pulmonary disease, or hypotension, as well as being in a relationship, nontobacco use, and alcohol use., Discussion/conclusions: We identified multiple predictors of prescribing for HFrEF medications that are being used to strategically design interventions to address barriers to prescribing and to inform further investigations. The machine learning approach used in this study to identify predictors of suboptimal prescribing can also be used by other health systems to identify and address locally relevant gaps and solutions to prescribing., Competing Interests: DCM reports consulting fees from Biomarin, Abbott/Pharmacylics, Novartis, Pear Therapeutics, Seres, and Sarepta. LAA reports consulting fees from Abbott, ACI Clinical, Amgen, Boston Scientific, Cytokinetics, and Novartis. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Kim, Suresh, Rosenberg, Tan, Malone, Allen, Kao, Anderson, Tiwari and Trinkley.)

Pathological remodeling of atrial tissue renders the atria more prone to arrhythmia upon arrival of electrical triggers. Activation of the renin-angiotensin system is an important factor that contributes to atrial remodeling, which may result in atrial hypertrophy and prolongation of P-wave duration. In addition, atrial cardiomyocytes are electrically coupled via gap junctions, and electrical remodeling of connexins may result in dysfunction of coordinated wave propagation within the atria. Currently, there is a lack of effective therapeutic strategies that target atrial remodeling. We previously proposed that cannabinoid receptors (CBR) may have cardioprotective qualities. CB13 is a dual cannabinoid receptor agonist that activates AMPK signaling in ventricular cardiomyocytes. We reported that CB13 attenuates tachypacing-induced shortening of atrial refractoriness and inhibition of AMPK signaling in the rat atria. Here, we evaluated the effects of CB13 on neonatal atrial rat cardiomyocytes (NRAM) stimulated by angiotensin II (AngII) in terms of atrial myocyte enlargement and mitochondrial function. CB13 inhibited AngII-induced enhancement of atrial myocyte surface area in an AMPK-dependent manner. CB13 also inhibited mitochondrial membrane potential deterioration in the same context. However, AngII and CB13 did not affect mitochondrial permeability transition pore opening. We further demonstrate that CB13 increased Cx43 compared to AngII-treated neonatal rat atrial myocytes. Overall, our results support the notion that CBR activation promotes atrial AMPK activation, and prevents myocyte enlargement (an indicator that suggests pathological hypertrophy), mitochondrial depolarization and Cx43 destabilization. Therefore, peripheral CBR activation should be further tested as a novel treatment strategy in the context of atrial remodeling., Competing Interests: The authors declare 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 Altieri, Etzion and Anderson.)

Background: Since the mid-1990s, more than 500,000 deaths have been attributed to the opioid overdose epidemic, which has created a serious national crisis affecting public health and social and economic welfare. To mitigate these opioid-related overdoses and deaths, interventions targeted at both the patient and community level are needed., Objective: This demonstration project sought to determine whether implementation of a provider-to-provider opioid pain teleconsultation service with a pain specialist was correlated with a reduction in inappropriate opioid use and improve health outcomes., Methods: Individual-level claims data for Health First Colorado Medicaid members were collected between March 1, 2017, and September 30, 2021, for individuals who triggered a provider-to-provider pain management teleconsultation based on receipt of a prescription for an opioid where the member was receiving a high-dose opioid (n = 125) or was opioid-naive (n = 819). The primary outcome measures were a patient's opioid dose less than 200 morphine milligram equivalent (MME) by 6 months after the consult if consult was triggered for high-dose use or discontinuation of an opioid by 12 weeks after consult if the consult was triggered for opioid naivety. Secondary opioid-related health outcomes were also assessed., Results: In the high-dose opioid cohort, 87% of the members had their monthly average MME reduced to less than 200 by 180 days after their consult. More than half of the opioid-naive group had discontinued their opioid by 90 days after their consult., Conclusion: Results indicate that provider-to-provider teleconsultation services with a pain specialist can be an effective intervention at reducing total inappropriate opioid use., (Copyright © 2022 American Pharmacists Association®. All rights reserved.)

Blueberry is considered a functional food due to various beneficial health effects associated with its consumption. Therefore, we examined the cardiovascular benefits of a blueberry polyphenolic extract in spontaneously hypertensive rats (SHR). Male SHR and Wistar-Kyoto (WKY) rats were administered with blueberry polyphenolic extract for 15 weeks. SHR showed significant augmented media-to-lumen ratio compared to WKY rats and blueberry polyphenolic extract significantly improved media-to-lumen ratio. SHR also had high blood pressure (BP), cardiac remodeling, and diastolic dysfunction and treatment did not affect BP or cardiac structure and function. SHR showed significantly increased the levels of malondialdehyde (MDA) and blueberry polyphenolic extract did not lower MDA. The levels of interleukin 6 and nitrate/nitrite ratio were unaltered in SHR. SHR showed a significant increase in the pro-apoptotic marker, Bax. Blueberry polyphenolic extract significantly lowered Bax. Our study shows that blueberry polyphenolic extract is beneficial in preventing vascular remodeling and cardiac apoptosis. PRACTICAL APPLICATIONS: Similar to many other berries, blueberries are repertoire of many phytochemicals including polyphenols. Along with its considerably well-established role as a sought after berry, blueberries have been at the forefront of approaches to hharnessing health benefits from plant food sources. Several studies have attempted to unravel the role of blueberry and their major phytochemicals in reducing the risk of cardiovascular diseases and reported their beneficial effects. Our pre-clinical study found that blueberry polyphenolic extract can reduce vascular remodeling in the setting of hypertension. This new finding further suggests the potential of blueberry-based phytochemicals. Further exploration of blueberries and their phytochemicals and positive outcomes from such studies can lead to substantial benefits for consumers and economy as a whole., (© 2022 Wiley Periodicals LLC.)

Actionable drug-gene pairs relevant to depression treatment include CYP2D6 and CYP2C19 with specific antidepressants. While clinical use of pharmacogenetic testing is growing, little is known about pharmacogenetic testing for depression treatment in managed care. We determined the incidence of single-gene CYP2D6 and CYP2C19 testing following a new depression episode among US managed care patients, and described characteristics and antidepressant use of patients receiving tests. We used paid medical and pharmacy claims for patients from commercial health plans in the US. For adult patients with a new depression episode from January 1, 2013 to June 30, 2018, we identified covered claims for single-gene CYP2D6 and CYP2C19 pharmacogenetic tests and antidepressant fills. Fewer than 1% (n = 1795) of the depressed cohort (n = 438,534) received a single-gene CYP2D6 or CYP2C19 test through their insurance within 365 days of their earliest depression episode. The percentage of patients who received a test nearly tripled from 0.2% in 2013 to 0.5% in 2014 before plateauing at 0.4% from 2014 to 2017. Among the patients who received a single-gene CYP2D6 or CYP2C19 test and filled an antidepressant within 365 days of their depression diagnosis, up to 30% may have had their initial antidepressant informed by the test result. Our findings describe the use of antidepressants before and after pharmacogenetic testing, which is clinically relevant as pharmacogenomic testing becomes more common in clinical practice. Our study also emphasizes the need for procedure and billing codes that capture multiple-gene panel tests to be more widely implemented in administrative databases., (© 2022 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background: Harvard Pilgrim Health Care expanded coverage for non-invasive prenatal testing (NIPT) to include all pregnant, single-gestation women aged < 35 years, through a performance-based risk-sharing (PBRS) agreement with Illumina to offset costs from coverage expansion. NIPT analyzes cell-free DNA fragments from a maternal blood sample to screen for fetal aneuploidies and is considered a more accurate screening method than conventional serum biochemical screening and nuchal translucency ultrasound-based approaches., Objective: This study assessed the impact of NIPT coverage expansion on prenatal screening strategies and payer expenditures., Methods: This was a real-world comparison of utilization and expenditures of prenatal screening and diagnostic testing in pregnant women aged < 35 years pre- (1 March 2016-28 February 2018) and post- (1 March 2018-30 September 2019) coverage expansion. Incidence rate ratios (IRRs) with 95% confidence intervals (CIs) were estimated to compare changes in utilization of conventional and NIPT-based prenatal screening methods. Change in per member per month (PMPM) expenditures in $US year 2020 were assessed post-coverage expansion using a budget impact model., Results: A total of 5041 and 4109 distinct pregnancies were identified in pre- and post-coverage expansion periods, respectively. Mean ± standard deviation maternal age was consistent between pre- and post-coverage expansion periods (30.35 ± 3.35 and 30.33 ± 3.28, respectively). Screening orders for conventional methods decreased, with an adjusted IRR in the post-expansion period of 0.87 (95% CI 0.85-0.90) times the rate in the pre-expansion period; orders for NIPT increased, with an adjusted IRR in the post-expansion period of 1.41 (95% CI 1.32-1.51) times the rate in the pre-expansion period. Invasive diagnostic testing was low at baseline (1.0%) and did not change post-coverage expansion. The change in PMPM is estimated at $US0.026 post-coverage expansion., Conclusion: The PBRS agreement to expand NIPT coverage for women aged < 35 years was associated with an increase in NIPT utilization, decreases in conventional screening methods, and a modest increase in PMPM expenditures., (© 2021. The Author(s).)

The use of electronic health records allows for the application of a novel medication risk score for the rapid identification of ambulatory patients at risk of adverse drug events. We sought to examine the longitudinal association of medication risk score with mortality. This retrospective cohort study included patients whose data were available through electronic health records from multiple health care organizations in the United States that provided data as part of a Patient Safety Organization. Patients were included if they had ≥1 visit and ≥1 medication in their record between January 1, 2011, to June 30, 2017. Cox proportional hazards regression was used to examine the association between continuous and categorized medication risk score with all-cause mortality. Among 427,103 patients, the median age was 50 years (interquartile range, 29-64 years); 61% were female; 50% were White, 11% were Black, and 38% were Hispanic; and 6873 had a death date recorded. Patients 30 to 49 years old had the highest hazard ratios (HRs), followed by the 50- to 64-year-olds and lastly those 65 years or older. Controlling for all covariates, 30- to 49-year-olds with a score of 20 to 30 (versus <10) had a 604% increase in the hazard of death (HR, 7.04; 95% confidence interval [CI], 3.86-12.85), 50- to 64-year-olds had a 254% increase (HR, 3.54; 95% CI, 2.71-4.63), and ≥65-year-olds had an 87% increase (HR, 1.87; 95% CI, 1.67-2.09). The medication risk score was independently associated with death, adjusting for multimorbidities and other conditions. Risk was found to vary by age group and score. Results suggest that pharmaceutical interventions among those with elevated scores could improve medication safety for patients taking multiple medications., Competing Interests: Tabula Rasa HealthCare has funded the research included in this article, of which V.M., J.T., and R.B. are all employees and shareholders. The rest of the authors disclose no conflict of interest., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.)

Introduction: Atrial fibrillation (AF) leads to rate-dependent atrial changes collectively defined as atrial remodelling (AR). Shortening of the atrial effective refractory period (AERP) and decreased conduction velocity are among the hallmarks of AR. Pharmacological strategies to inhibit AR, thereby reducing the self-perpetual nature of AF, are of great clinical value. Cannabinoid receptor (CBR) ligands may exert cardioprotective effects; CB13, a dual CBR agonist with limited brain penetration, protects cardiomyocytes from mitochondrial dysfunction induced by endothelin-1. Here, we examined the effects of CB13 on normal physiology of the rat heart and development of tachypacing-induced AR. Methods: Rat hearts were perfused in a Langendorff set-up with CB13 (1 µM) or vehicle. Hemodynamic properties of non-paced hearts were examined conventionally. In a different set of hearts, programmed stimulation protocol was performed before and after atrial tachypacing for 90 min using a mini-hook platinum quadrupole electrode inserted on the right atrium. Atrial samples were further assessed by western blot analysis. Results: CB13 had no effects on basal hemodynamic properties. However, the compound inhibited tachypacing-induced shortening of the AERP. Protein expression of PGC1α was significantly increased by CB13 compared to vehicle in paced and non-paced hearts. Phosphorylation of AMPKα at residue threonine 172 was increased suggesting upregulation of mitochondrial biogenesis. Connexin43 was downregulated by tachypacing. This effect was diminished in the presence of CB13. Conclusion: Our findings support the notion that peripheral activation of CBR may be a new treatment strategy to prevent AR in patients suffering from AF, and therefore warrants further study., Competing Interests: The authors declare 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 © 2021 Lee, Murninkas, Elyagon, Etzion and Anderson.)

How insects navigate complex odor plumes, where the location and timing of odor packets are uncertain, remains unclear. Here we imaged complex odor plumes simultaneously with freely-walking flies, quantifying how behavior is shaped by encounters with individual odor packets. We found that navigation was stochastic and did not rely on the continuous modulation of speed or orientation. Instead, flies turned stochastically with stereotyped saccades, whose direction was biased upwind by the timing of prior odor encounters, while the magnitude and rate of saccades remained constant. Further, flies used the timing of odor encounters to modulate the transition rates between walks and stops. In more regular environments, flies continuously modulate speed and orientation, even though encounters can still occur randomly due to animal motion. We find that in less predictable environments, where encounters are random in both space and time, walking flies navigate with random walks biased by encounter timing., Competing Interests: MD, NK, HA, DC, TE No competing interests declared, (© 2020, Demir et al.)

Purpose: Identify administrative claims-based algorithms for capturing out-of-hospital ventricular arrhythmias (VA) and cardiac arrests (CA) due to cardiac causes in the pediatric population with high positive-predictive value (PPV)., Methods: Within a single pediatric center, a retrospective cohort of patients hospitalized or seen in the emergency room for VA or CA were identified from the electronic health records. Eligible encounters were blindly reviewed and linked to administrative data, including ICD-9/ICD-10 codes. Test characteristics, including PPV, for different diagnostic and procedure codes were generated using a 50% training sample. The gold standard was definite or suspected out-of-hospital VA or CA due to cardiac cause verified based on clinical criteria. Algorithms with the highest PPV were then applied to a 50% validation sample to validate performance., Results: From 2004-2017, 598 encounters met eligibility criteria. 174 (29%) had an outcome of interest, with remainder being an inpatient event or CA due to other cause. Within the training sample (n = 263), VA codes in primary position had a PPV 94% (95%CI 81%-99%) with low sensitivity (44%, 95%CI 33%-56%). CA codes in any position or VA codes in nonprimary positions had low PPV (18%-19%, 31% respectively). Applying the top three performing algorithms to the validation sample (n = 252) yielded similar PPV values., Conclusions: Contrary to adults, algorithms including a CA code do not perform well for identifying out-of-hospital VA and CA due to cardiac cause in the pediatric populations. Researchers should be aware of the potential implications for future pediatric drug safety studies for these outcomes., (© 2020 John Wiley & Sons Ltd.)

Objective: To measure the association between selective serotonin reuptake inhibitor (SSRI) use and out-of-hospital ventricular arrhythmia among the pediatric and young adult population., Study Design: Case-control study using US claims data from 2007 to 2018. Cases were subjects with at least 1 event between ages 2 and 24 years. Controls (matched 10:1 on index date, age, sex, and continuous enrollment) had no events during study period. Independent association between current SSRI use (prescription fill with continuous exposure ending on, or after, the index date) and incident out-of-hospital ventricular arrhythmia (hospitalization or emergency room encounter with primary diagnostic code for ventricular arrhythmia) was estimated using multivariable conditional logistic regression. Separate analyses were performed for pediatric (2-17 years of age) vs young adult (18-24 years of age) subjects and between citalopram/escitalopram vs other SSRIs., Results: During the study period, 237 eligible cases were identified with 2370 matched controls. Cases were more likely to have government insurance and have a mental health, cardiac, or other complex chronic condition. Thirteen cases (5%) and 15 controls (<1%) had current SSRI exposure. After adjustment for mental health and chronic conditions, there was an increased odds of current SSRI use among cases compared with controls (OR 5.11, 95% CI 1.22-21.37). No difference was observed between pediatric and young adult ages, nor between citalopram/escitalopram and other SSRIs., Conclusions: These findings demonstrate increased odds of out-of-hospital ventricular arrhythmia associated with SSRI use in the pediatric and young adult population, suggesting a need for heightened awareness and ongoing monitoring of this potential adverse effect., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: Little is known about how many insured patients receive pharmacogenetic testing. We describe trends of single-gene pharmacogenetic testing in a US managed care population, and demographic and clinical characteristics of patients who received a test., Methods: We leveraged a random sample of nearly 11 million patients from a data set of paid medical and pharmacy claims to identify patients with at least one claim indicating receipt of at least one of these single-gene pharmacogenetic tests: CYP2C19, CYP2D6, CYP2C9, VKORC1, UGT1A1, and HLA class 1 typing., Results: From 1 January 2013 to 30 September 2017, 5712 patients received at least one pharmacogenetic test (55% female; mean age = 43 years). The median number of tests per patient was 3 (mean = 2.7, max = 12); 54% were processed through Managed Medicare/Medicaid, while 45% were processed through commercial insurance. The total number of pharmacogenetic tests received more than doubled from 2013 (n = 1955) to 2015 (n = 4192), then decreased slightly in 2016 (n = 3946). The most common test was CYP2C19 (n = 4719), and "long-term (current) use of other medications" was the most common diagnosis., Conclusion: Pharmacogenetic testing through patients' insurance was low, but more than doubled from 2013 to 2016. This study highlights the need to better understand utilization patterns and insurance coverage for pharmacogenetic tests.

Background: Counseling on access to lethal means is highly recommended for patients with suicide risk, but there are no formal evaluations of its impact in real-world settings., Objective: Evaluate whether lethal means assessment reduces the likelihood of suicide attempt and death outcomes., Design: Quasi-experimental design using an instrumental variable to overcome confounding due to unmeasured patient characteristics that could influence provider decisions to deliver lethal means assessment., Setting: Kaiser Permanente Colorado, an integrated health system serving over 600,000 members, with comprehensive capture of all electronic health records, medical claims, and death information., Participants: Adult patients who endorsed suicide ideation on the Patient Health Questionnaire-9 (PHQ-9) depression screener administered in behavioral health and primary care settings from 2010 to 2016., Interventions: Provider documentation of lethal means assessment in the text of clinical notes, collected using a validated Natural Language Processing program., Measurements: Main outcome was ICD-9 or ICD-10 codes for self-inflicted injury or suicide death within 180 days of index PHQ-9 event., Results: We found 33% of patients with suicide ideation reported on the PHQ-9 received lethal means assessment in the 30 days following identification. Lethal means assessment reduced the risk of a suicide attempt or death within 180 days from 3.3 to 0.83% (p = .034, 95% CI = .069-.9)., Limitations: Unmeasured suicide prevention practices that co-occur with lethal means assessment may contribute to the effects observed., Conclusions: Clinicians should expand the use of counseling on access to lethal means, along with co-occurring suicide prevention practices, to all patients who report suicide ideation.

Edible legume seeds, such as lentils, have been shown to modulate the structural and functional properties of hypertensive blood vessels, however, the effects of dried beans have not been similarly evaluated. To determine whether beans could attenuate hypertension-induced vascular changes (remodeling and stiffness) in relation to their phytochemical content, spontaneously hypertensive rats (SHR) were fed diets containing black beans (BB; high phytochemical content as indicated by their dark seed coat colour) or navy (white) beans (NB; low phytochemical content) for eight weeks. An additional follow-up phase was included to determine how long the alterations in vascular properties are maintained after bean consumption is halted. Assessments included blood pressure (BP), pulse wave velocity (PWV), vessel compliance (small-artery) and morphology (large-artery), and body composition. Neither BBs nor NBs altered BP or PWV in SHR. SHR-BB demonstrated greater medial strain (which is indicative of greater elasticity) at higher intraluminal pressures (80 and 140 mmHg) compared to SHR-NB. BB consumption for 8 weeks enhanced vascular compliance compared to SHR-NB, as demonstrated by a rightward shift in the stress-strain curve, but this improvement was lost within 2 weeks after halting bean consumption. BB and NB increased lean mass after 8 weeks, but halting BB consumption increased fat mass. In conclusion, regular consumption of BBs may be appropriate as a dietary anti-hypertensive strategy via their positive actions on vascular remodeling and compliance., Competing Interests: The authors declare no conflict of interest.

Objective: Guidelines for management of anxiety and sleep disorders emphasize antidepressant medications and/or psychotherapy as first/second-line and benzodiazepines as third-line treatments. We evaluated the association between suicide death and concordance with benzodiazepine guidelines., Methods: Retrospective case-control study of patients with anxiety and/or sleep disorders from health systems across 8 U.S. states within the Mental Health Research Network. Suicide death cases were matched to controls on year and health system. Appropriate benzodiazepine prescribing defined as: no monotherapy, no long duration, and/or age < 65 years. The association between guideline concordance and suicide death was evaluated, adjusting for diagnostic and treatment covariates., Results: Sample included 6960 patients with anxiety disorders (2363 filled benzodiazepine) and 6215 with sleep disorders (1237 filled benzodiazepine). Benzodiazepine guideline concordance was associated with reduced odds for suicide in patients with anxiety disorders (OR = 0.611, 95% CI = 0.392-0.953, p = 0.03) and was driven by shorter duration of benzodiazepine use with concomitant psychotherapy or antidepressant medication. The association of benzodiazepine guideline concordance with suicide death did not meet statistical significance in the sleep disorder group (OR = 0.413, 95% CI = 0.154-1.11, p = 0.08)., Conclusions: We found reduced odds for suicide in those with anxiety disorders who filled benzodiazepines in short-moderate duration with concomitant psychotherapy or antidepressant treatment., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Evidence suggests that the activation of the endocannabinoid system offers cardioprotection. Aberrant energy production by impaired mitochondria purportedly contributes to various aspects of cardiovascular disease. We investigated whether cannabinoid (CB) receptor activation would attenuate mitochondrial dysfunction induced by endothelin-1 (ET1). Acute exposure to ET1 (4 hours) in the presence of palmitate as primary energy substrate induced mitochondrial membrane depolarization and decreased mitochondrial bioenergetics and expression of genes related to fatty acid oxidation (ie, peroxisome proliferator-activated receptor-gamma coactivator-1α, a driver of mitochondrial biogenesis, and carnitine palmitoyltransferase-1β, facilitator of fatty acid uptake). A CB1/CB2 dual agonist with limited brain penetration, CB-13, corrected these parameters. AMP-activated protein kinase (AMPK), an important regulator of energy homeostasis, mediated the ability of CB-13 to rescue mitochondrial function. In fact, the ability of CB-13 to rescue fatty acid oxidation-related bioenergetics, as well as expression of proliferator-activated receptor-gamma coactivator-1α and carnitine palmitoyltransferase-1β, was abolished by pharmacological inhibition of AMPK using compound C and shRNA knockdown of AMPKα1/α2, respectively. Interventions that target CB/AMPK signaling might represent a novel therapeutic approach to address the multifactorial problem of cardiovascular disease.

Aims: To assess stakeholder perspectives regarding the clinical utility of pharmacogenomic (PGx) testing following kidney, liver, and heart transplantation. Methods: We conducted individual semi-structured interviews and focus groups with kidney, liver, and heart transplantation patients and providers. We analyzed the qualitative data to identify salient themes. Results: The study enrolled 36 patients and 24 providers. Patients lacked an understanding about PGx, but expressed interest in PGx testing. Providers expressed willingness to use PGx testing, but reported barriers to implementation, such as lack of knowledge, lack of evidence demonstrating clinical utility, and patient healthcare burden. Conclusion: Patient and provider educational efforts, including foundational knowledge, clinical evidence, and applications to patient care beyond just immunosuppression, may be useful to facilitate the use of PGx testing in transplant medicine.

Objective: Whether physical access to psychotropic medication via prescription (ie, prescribed access) is associated with use of psychotropic medication as a means of subsequent suicide attempt remains unclear. In a population of suicide attempters, we investigated whether prescribed access to any psychotropic medication increased the likelihood of using any psychotropic drug in a suicide attempt and whether prescribed access to a specific psychotropic drug type increased the likelihood of using that specific psychotropic drug type in an attempt., Methods: Case-control study design was used. We identified individuals receiving care for a suicide attempt (fatal or nonfatal) in emergency department and inpatient settings from a US insurance claims dataset (2006-2013) using relevant ICD-9-CM codes. Cases used a psychotropic drug in their suicide attempt, while controls used another method. Exposed individuals filled a psychotropic drug prescription within 90 days prior to the attempt. Multivariable logistic regression estimated odds ratios., Results: A population of 27,876 (cases = 10,158, controls = 17,718) was included. Anxiolytics were used most in attempts (n = 6,037, 59.4%), followed by antidepressants (n = 3,573, 35.2%), antipsychotics or mood stabilizers (n = 1,168, 11.5%), and stimulants (n = 368, 3.6%). Thirteen percent (n = 1,316) used more than 1 type of psychotropic drug in the attempt. Across all psychotropic drug groups evaluated, individuals using psychotropic medication in a suicide attempt were significantly more likely to have had prescribed access (adjusted odds ratio [aOR] = 1.7; 95% CI, 1.6-1.9), with the highest drug type-specific odds ratios for antipsychotics or mood stabilizers (aOR = 6.5; 95% CI, 5.4-7.7) and stimulants (aOR = 7.6; 95% CI, 5.5-10.5)., Conclusions: Individuals at high risk for suicide with prescribed access to any psychotropic medication should be targeted for means safety interventions., (© Copyright 2018 Physicians Postgraduate Press, Inc.)

In the XML of the original article, M. Laird Forrest's name was tagged incorrectly. M. Laird is his first name.

Background: Despite strong recommendations to use metformin as first-line therapy for type 2 diabetes (T2DM), its use has been suboptimal, likely due to concerns of lactic acidosis. This study compared the association of acidosis in patients with T2DM prescribed metformin with those prescribed other antihyperglycemic medications or no medications., Methods: This was a retrospective cohort study of patients with newly diagnosed T2DM utilizing an administrative database, which includes medical and prescription claims. Eligible patients had a diagnosis of T2DM, had continuous health plan enrollment 3 months prior to study enrollment and during the study period, and were at least 18 years of age. Mutually exclusive exposure groups were metformin only, other antihyperglycemic medications, and no medication. Acidosis cases were stratified by exposure group and risk factors for lactic acidosis (chronic obstructive pulmonary disease, hepatic dysfunction, alcohol abuse, heart failure, renal insufficiency, age of 80 years or older, and a history of acidosis). Degree of renal insufficiency was not available. Associations between exposure and acidosis were estimated, and risk factors evaluated., Results: A total of 132,780 patients met inclusion criteria: 24,936 (20%) metformin only group, 15,059 (11%) other antihyperglycemic medication group, and 92,785 (70%) no medication group. Acidosis was observed in 1.45 per 10,000 patient months (0.78 metformin, 1.59 other antihyperglycemic medication, 1.51 no medication). The unadjusted relative risk of acidosis was 0.5 for patients prescribed metformin only compared with the other exposure groups (95% confidence interval = 0.2-1.2). There was no significant difference in risk of acidosis between exposure groups, irrespective of risk factors for lactic acidosis., Conclusions: Risk of acidosis was similar with metformin only compared with those prescribed other antihyperglycemic medications or no medication. These results support expanded use of metformin for T2DM. Additional studies are needed to understand the impact of risk factor severity on risk of lactic acidosis., Competing Interests: Conflict of interest statement: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Stilbenoids are a group of naturally occurring phenolic compounds found in various plant species. They share a common backbone structure known as stilbene, but differ in the nature and position of substituents. Stilbenoids are classified as phytoalexins, which are antimicrobial compounds produced de novo in plants to protect against fungal infection and toxins. In this review, the biological effects of stilbenoids such as resveratrol, pterostilbene, gnetol and piceatannol are discussed. Stilbenoids exert various biological activities ranging from cardioprotection, neuroprotection, anti-diabetic properties, depigmentation, anti-inflammation, cancer prevention and treatment. The results presented cover a myriad of models, from cell culture to animal studies as well as clinical human trials. Although positive results were obtained in most cell culture and animal studies, further human studies are needed to substantiate beneficial effects of stilbenoids. Resveratrol remains the most widely studied stilbenoid. However, there is limited information regarding the potential of less common stilbenoids. Therefore, further research is warranted to evaluate the salutary effects of various stilbenoids., Competing Interests: The authors declare no conflict of interest.

We tested whether inhibiting mechanically responsive articular chondrocyte mitochondria after severe traumatic injury and preventing oxidative damage represent a viable paradigm for posttraumatic osteoarthritis (PTOA) prevention. We used a porcine hock intra-articular fracture (IAF) model well suited to human-like surgical techniques and with excellent anatomic similarities to human ankles. After IAF, amobarbital or N -acetylcysteine (NAC) was injected to inhibit chondrocyte electron transport or downstream oxidative stress, respectively. Effects were confirmed via spectrophotometric enzyme assays or glutathione/glutathione disulfide assays and immunohistochemical measures of oxidative stress. Amobarbital or NAC delivered after IAF provided substantial protection against PTOA at 6 months, including maintenance of proteoglycan content, decreased histological disease scores, and normalized chondrocyte metabolic function. These data support the therapeutic potential of targeting chondrocyte metabolism after injury and suggest a strong role for mitochondria in mediating PTOA., (Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and overlap syndrome (SJS-TEN) are rare, serious skin and mucosa break-down conditions frequently associated with antibiotic use. The role of nonprescription medications alone, or in combination with antibiotics in triggering SJS/TEN, is largely unknown. This study summarized data collected from patient surveys about nonprescription and antibiotic use prior to a SJS/TEN diagnosis. The survey was administered online to members of the U.S. SJS Foundation who had been diagnosed with SJS/TEN or were the parent of a child who had been diagnosed with SJS/TEN. Respondents were asked about nonprescription medications taken within the year before diagnosis, and the approximate point in time before diagnosis that they had taken them. They were also asked about specific prescription medications, including antibiotics, that they took before diagnosis. An estimated 4500 patients received an invitation to complete the survey. 251 patients completed it, resulting in a response rate of 5.6%. The mean age of respondents was 43 years (SD (standard deviation) = 17.3) and 70% were female. 32.3% of respondents indicated that a prescription antibiotic triggered their reaction. 14.1% indicated a nonprescription medication had triggered their SJS/TEN, and 18.1% said a nonprescription medication may have triggered their SJS/TEN. 85.5% of respondents said they took a nonprescription medication within three months of their SJS/TEN diagnosis. Of those respondents who reported that an antibiotic triggered their SJS/TEN, 35.2% reported taking a nonprescription medication within the three months prior to their diagnosis. This survey captured valuable information about nonprescription and antibiotic use in SJS/TEN patients. It is important for future studies to estimate the impact of antibiotics on SJS/TEN, and account for nonprescription medication use in that relationship., Competing Interests: The authors declare no conflicts of interest.

Astrocytes are glial cells that are distributed throughout the central nervous system in an arrangement optimal for chemical and physical interaction with neuronal synapses and brain blood supply vessels. Neurotransmission modulates astrocytic excitability by activating an array of cell surface receptors and transporter proteins, resulting in dynamic changes in intracellular Ca 2+ or Na + . Ionic and electrogenic astrocytic changes, in turn, drive vital cell nonautonomous effects supporting brain function, including regulation of synaptic activity, neuronal metabolism, and regional blood supply. Alzheimer disease (AD) is associated with aberrant oligomeric amyloid β generation, which leads to extensive proliferation of astrocytes with a reactive phenotype and abnormal regulation of these processes. Astrocytic morphology, Ca 2+ responses, extracellular K + removal, glutamate transport, amyloid clearance, and energy metabolism are all affected in AD, resulting in a deleterious set of effects that includes glutamate excitotoxicity, impaired synaptic plasticity, reduced carbon delivery to neurons for oxidative phosphorylation, and dysregulated linkages between neuronal energy demand and regional blood supply. This review summarizes how astrocytes are affected in AD and describes how these changes are likely to influence brain function. © 2017 Wiley Periodicals, Inc., (© 2017 Wiley Periodicals, Inc.)

Background: Anticholinergic (AC) adverse drug events (ADEs) are caused by inhibition of muscarinic receptors as a result of designated or off-target drug-receptor interactions. In practice, AC toxicity is assessed primarily based on clinician experience. The goal of this study was to evaluate a novel concept of integrating big pharmacological and healthcare data to assess clinical AC toxicity risks., Methods: AC toxicity scores (ATSs) were computed using drug-receptor inhibitions identified through pharmacological data screening. A longitudinal retrospective cohort study using medical claims data was performed to quantify AC clinical risks. ATS was compared with two previously reported toxicity measures. A quantitative structure-activity relationship (QSAR) model was established for rapid assessment and prediction of AC clinical risks., Results: A total of 25 common medications, and 575,228 exposed and unexposed patients were analyzed. Our data indicated that ATS is more consistent with the trend of AC outcomes than other toxicity methods. Incorporating drug pharmacokinetic parameters to ATS yielded a QSAR model with excellent correlation to AC incident rate ( R 2 = 0.83) and predictive performance (cross validation Q 2 = 0.64). Good correlation and predictive performance ( R 2 = 0.68/ Q 2 = 0.29) were also obtained for an M2 receptor-specific QSAR model and tachycardia, an M2 receptor-specific ADE., Conclusions: Albeit using a small medication sample size, our pilot data demonstrated the potential and feasibility of a new computational AC toxicity scoring approach driven by underlying pharmacology and big data analytics. Follow-up work is under way to further develop the ATS scoring approach and clinical toxicity predictive model using a large number of medications and clinical parameters., Competing Interests: Conflict of interest statement: The authors declare that there is no conflict of interest.

Doxorubicin is an effective anticancer drug; however, it is cardiotoxic and has poor oral bioavazilability. Quercetin is a plant-based flavonoid with inhibitory effects on P-glycoprotein (P-gp) and CYP3A4 and also antioxidant properties. To mitigate these therapeutic barriers, DoxQ, a novel derivative of doxorubicin, was synthesized by conjugating quercetin to doxorubicin. The purpose of this study is to mechanistically elucidate the in vitro safety and efficacy of DoxQ. Drug release in vitro and cellular uptake by multidrug-resistant canine kidney (MDCK-MDR) cells were quantified by HPLC. Antioxidant activity, CYP3A4 inhibition, and P-gp inhibitory effects were examined using commercial assay kits. Drug potency was assessed utilizing triple-negative murine breast cancer cells, and cardiotoxicity was assessed utilizing adult rat and human cardiomyocytes (RL-14). Levels of reactive oxygen species and gene expression of cardiotoxicity markers, oxidative stress markers, and CYP1B1 were determined in RL-14. DoxQ was less cytotoxic to both rat and human cardiomyocytes and retained anticancer activity. Levels of ROS and markers of oxidative stress demonstrate lower oxidative damage induced by DoxQ compared to doxorubicin. DoxQ also inhibited the expression and catalytic activity of CYP1B1. Additionally, DoxQ inhibited CYP3A4 and demonstrated higher cellular uptake by MDCK-MDR cells than doxorubicin. DoxQ provides a novel therapeutic approach to mitigate the cardiotoxicity and poor oral bioavailability of doxorubicin. The cardioprotective mechanism of DoxQ likely involves scavenging ROS and CYP1B1 inhibition, while the mechanism of improving the poor oral bioavailability of doxorubicin is likely related to inhibiting CYP3A4 and P-gp.

Cannabis sativa has long been used for medicinal purposes. To improve safety and efficacy, compounds from C. sativa were purified or synthesized and named under an umbrella group as cannabinoids. Currently, several cannabinoids may be prescribed in Canada for a variety of indications such as nausea and pain. More recently, an increasing number of reports suggest other salutary effects associated with endogenous cannabinoid signaling including cardioprotection. The therapeutic potential of cannabinoids is therefore extended; however, evidence is limited and mechanisms remain unclear. In addition, the use of cannabinoids clinically has been hindered due to pronounced psychoactive side effects. This review provides an overview on the endocannabinoid system, including known physiological roles, and conditions in which cannabinoid receptor signaling has been implicated.

Purpose: Research has a prominent role within the field of pharmacy practice. However, no studies have assessed the importance of research methods in pharmacy education from the perspective of students, residents, or residency directors., Methods: Questionnaires were administered online in spring 2014 to four respondent groups: University of Colorado fourth year PharmD (P4) students, post graduate year 1 (PGY1) residents, and PGY1 and post-graduate year 2 (PGY2) residency directors. Descriptive statistics were used to characterize respondents; t-tests and chi-square tests were used to compare groups of respondents., Results: Respondents included 255 PGY1 residency directors, 155 PGY2 residency directors, 35 PGY1 residents, and 87 P4 students. Response rates ranged from 26% (residency directors) to nearly 60% (P4 students and PGY1 residents). PGY1 residents and PGY1/PGY2 residency directors ranked research experience lowest among ten characteristics with respect to their importance when competing for a residency or being a successful resident. Among six specific clinical research skills, PGY1 residents and PGY1/PGY2 residency directors ranked "identifying and writing a research question" as the most important for successfully completing a residency research project or when selecting a PGY1/PGY2 resident., Conclusions: Perceived importance of clinical research skills by P4 students, current residents, and residency program directors is low. This is in opposition to opinions from several national organizations that proclaim the importance of clinical research skills in doctor of pharmacy curricula. Pharmacy programs must continue to further develop clinical research skills and abilities of future graduates while being cognizant of these perception barriers when developing strategies to enhance research experiences within their curricular programs., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Hypertension is associated with aberrant structure and mechanical properties of resistance arteries. We determined the effects of resveratrol, a non-flavonoid polyphenol found in foods such as red grapes, and structurally-similar analogues (pterostilbene and gnetol) on systolic blood pressure (SBP) and resistance arteries from the spontaneously hypertensive heart failure (SHHF) rat. SBP was elevated in 17-week-old SHHF vs. Sprague-Dawley rats (normotensive control; 194 ± 3 vs. 142 ± 6 mmHg, p < 0.01) and was unaffected by resveratrol, pterostilbene, or gnetol (2.5 mg/kg/d). Geometry and mechanical properties of pressurized mesenteric resistance arteries and middle cerebral arteries were calculated from media and lumen dimensions measured at incremental intraluminal pressures. SHHF arteries exhibited remodeling which consisted of augmented media-to-lumen ratios, and this was attenuated by stilbenoid treatment. Compliance was significantly reduced in SHHF middle cerebral arteries but not mesenteric arteries vis-à-vis increased wall component stiffness; stilbenoid treatment failed to normalize compliance and wall component stiffness. Our data suggest that neither AMPK nor ERK mediate stilbenoid effects. In conclusion, we observed arterial bed-specific abnormalities, where mesenteric resistance arteries exhibited remodeling and cerebral arteries exhibited remodeling and stiffening. Resveratrol, pterostilbene, and gnetol exhibited similar abilities to attenuate vascular alterations.