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Cytochrome P450 2D6 (CYP2D6) activity is highly variable due to several factors, including genetic polymorphisms and drug-drug-gene interactions. Hydrocodone, oxycodone, codeine, and tramadol the most commonly prescribed CYP2D6-activated opioids for pain. However, the co-administration of CYP2D6 interacting drugs can modulate CYP2D6-medicated activation of these opioids, affecting drug analgesia, effectiveness, and safety, and can impact healthcare costs. A retrospective, observational cohort analysis was performed in a large (n = 50,843) adult population. This study used drug claims data to derive medication risk scores and matching propensity scores to estimate the effects of opioid use and drug-drug interactions (DDIs) on medical expenditures. 4088 individuals were identified as opioid users; 95% of those were prescribed CYP2D6-activated opioids. Among those, 15% were identified as being at risk for DDIs. Opioid users had a significant increase in yearly medical expenditure compared to non-opioid users ($2457 vs. $1210). In matched individuals, average healthcare expenditures were higher for opioid users with DDIs compared to those without DDIs ($7841 vs. $5625). The derived medication risk score was higher in CYP2D6 opioid users with interacting drug(s) compared to no DDI (15 vs. 12). Higher costs associated with CYP2D6 opioid use under DDI conditions suggest inadequate CYP2D6 opioid prescribing practices. Efforts to improve chronic opioid use in adults should reduce interacting drug combinations, especially among patients using CYP2D6 activated opioids.

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Polypharmacy is a common phenomenon among adults using opioids, which may influence the frequency, severity, and complexity of drug-drug interactions (DDIs) experienced. Clinicians must be able to easily identify and resolve DDIs since opioid-related DDIs are common and can be life-threatening. Given that clinicians often rely on technological aids-such as clinical decision support systems (CDSS) and drug interaction software-to identify and resolve DDIs in patients with complex drug regimens, this narrative review provides an appraisal of the performance of existing technologies. Opioid-specific CDSS have several system- and content-related limitations that need to be overcome. Specifically, we found that these CDSS often analyze DDIs in a pairwise manner, do not account for relevant pharmacogenomic results, and do not integrate well with electronic health records. In the context of polypharmacy, existing systems may encourage inadvertent serious alert dismissal due to the generation of multiple incoherent alerts. Future technological systems should minimize alert fatigue, limit manual input, allow for simultaneous multidrug interaction assessments, incorporate pharmacogenomic data, conduct iterative risk simulations, and integrate seamlessly with normal workflow.

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Aim: Estimate cost avoidance of pharmacist recommendations for participants enrolled in the Program of All-inclusive Care for the Elderly. Materials & methods: Convenience sample of 200 pharmacogenomics consultations from the PHARM-GENOME-PACE study. Genetic variants, drug-gene interactions, drug-drug-gene interactions and phenoconversions were interrogated. Cost avoidance was estimated and adjusted for inflation. Results: In total, 165 participants had at least one actionable drug-gene pair totaling 429 drug-gene pairs, of which 158 (36.8%) were clinically actionable. Most (70.5%) pharmacists' recommendations were accepted. Estimated cost avoidance was $233,945 when all recommendations were included but conservatively $162,031 based on acceptance rates. Overall mean cost avoidance per actionable drug-gene pair was $1063 or $1983 per participant. Conclusion: Pharmacist-led pharmacogenomics services added to the traditional medication review can avoid substantial costs for payers. Clinical trial registration number: NCT03257605.

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Treatment of behavioral and psychological symptoms of dementia (BPSD) and comorbidities often necessitates the concomitant use of antipsychotics and non-antipsychotic drugs, thereby potentiating the risk for drug-drug interactions (DDIs).The primary objective of our study was to identify potentially clinically relevant cytochrome P450 (CYP)-mediated DDIs involving antipsychotics among participants enrolled in the Program of All-Inclusive Care for the Elderly (PACE) with BPSD. Additionally, we wanted to determine the prevalence of antipsychotic use in this population. The study included 10,001 PACE participants. The practice setting used a proprietary clinical decision support system (CDSS) to analyze simultaneous multidrug interactions. A retrospective analysis of pharmacy claims data was conducted to identify DDIs involving antipsychotics prescribed for BPSD, using snapshots of medication profiles paired with the CDSS. Of the participants who met inclusion criteria, 1190 (11.9%) were prescribed an antipsychotic; of those, 1071 (90.0%) were prescribed an atypical antipsychotic. Aripiprazole commonly caused (being a perpetrator drug 94.6% of the time) potential DDIs with antidepressants (e.g., duloxetine, venlafaxine, mirtazapine), opioids (e.g., hydrocodone, oxycodone, tramadol) and metoprolol via the CYP2D6 isoform. Risperidone commonly caused (85.7%) potential DDIs with donepezil, lamotrigine and trazodone via the CYP3A4 isoform. Quetiapine exclusively suffered (100%) from potential DDIs with amlodipine, buspirone, omeprazole or topiramate via the CYP3A4 isoform. Antipsychotics are commonly prescribed to PACE participants for BPSD treatment and they may interact with other drugs used to treat comorbidities. A thorough review of concomitant medications will help mitigate the likelihood of potentially dangerous CYP-mediated DDIs involving antipsychotics.

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Precision medication entails selecting the precise medication, dose, and timing of administration. Multi-drug interactions and genetics significantly affect precision medication. In this article, we present two simulated cases for real-world applications of precision medication. Clinicians may need to acquire additional skills to apply the principles illustrated by these cases.

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Little is known about the types of drug information inquiries (DIIs) prescribers caring for older adults ask pharmacists during routine practice. The objective of this research was to analyze the types of DIIs prescribing clinicians of Programs of All-Inclusive Care for the Elderly (PACE) made to clinical pharmacists during routine patient care. This was a retrospective analysis of documented pharmacists' encounters with PACE prescribers between March through December, 2018. DIIs were classified using a developed taxonomy that describes prescribers' motivations for consulting with pharmacists and their drug information needs. Prescribers made 414 DIIs during the study period. Medication safety concerns motivated the majority of prescribers' inquiries (223, 53.9%). Inquiries received frequently involved modifying drug therapy (94, 22.7%), identifying or resolving adverse drug events (75, 18.1%), selecting or adjusting doses (61, 14.7%), selecting new drug therapies (57, 13.8%), and identifying or resolving drug interactions (52, 12.6%). Central nervous system medications (e.g., antidepressants and opioids), were involved in 38.6% (n = 160) of all DIIs. When answering DIIs, pharmacists made 389 recommendations. Start alternative medications (18.0%), start new medications (16.7%), and change doses (12.1%) were the most frequent recommendations rendered. Prescribers implemented at least 79.3% (n = 268) of recommendations based on pharmacy records (n = 338 verifiable recommendations). During clinical practice, PACE prescribers commonly ask pharmacists a variety of DIIs, largely related to medication safety concerns. In response to these DIIs, pharmacists provide medication management recommendations, which are largely implemented by prescribers.

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OBJECTIVE: To evaluate pharmacist-encountered medication-related problems (MRPs) among the participants of the Program of All-Inclusive Care for the Elderly (PACE). DESIGN: This was a retrospective analysis of proprietary pharmacy records detailing pharmacist encounters with PACE clinical staff. SETTING AND PARTICIPANTS: A national provider of pharmacy services to more than 75 PACE organizations. In total, 1057 PACE participants at 69 PACE sites across the United States with documented pharmacist encounters between March and May 2018. OUTCOME MEASURES: MRPs were classified using the Hepler-Strand taxonomy, and pharmacists' recommendations made to prescribers to resolve these MRPs were classified using a modified Hoth taxonomy. In addition, pharmacists' communication methods and prescribers' responses were analyzed. RESULTS: Overall, 2004 MRPs were encountered. The most frequent MRPs identified were related to medication safety concerns, including drug interactions (720, 35.9%), adverse drug reactions (ADRs, 356, 17.8%), high doses (270, 13.5%), and unindicated drugs (252, 12.6%). Drug interactions frequently involved competitive inhibition, 3 or more drugs, opioids, anticoagulants, antiplatelets, and antidepressants. Deprescribe medication (561, 24.8%), start alternative therapy (553, 24.4%), change doses (457, 20.2%), and monitor (243, 10.7%) were the top 4 types of recommendations made by pharmacists. Among 1730 responses obtained from PACE prescribers, 78.1% (n = 1351) of pharmacists' recommendations were accepted. Compared with electronic communication, telephonic communication was associated with more acceptance and less prescriber nonresponse (χ2 = 78.5, P < 0.001). CONCLUSION: Pharmacists identified a substantial number of MRPs in PACE, especially those related to medication safety such as drug interactions and ADRs. In this practice setting, significant collaboration occured between pharmacists and PACE prescribers, as evidenced by the rate of prescribers' acceptance of pharmacists' recommendations. Further research is needed to fully evaluate the economic, clinical, and humanistic outcomes associated with pharmacists' encounters in PACE.

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The use of opioids for chronic pain management is extraordinarily common despite substantial evidence of only modest benefits, when compared with nonopioid analgesics. Opioid use is also associated with serious risks, including overdose and death. A growing body of evidence suggests that opioids are involved in significant drug interactions that often go unrecognized in clinical practice. Understanding opioid-involved drug interactions is of great practical importance for all health care professionals caring for patients with chronic pain. In this article, we describe the mechanisms of opioid-involved drug interactions and their potential consequences, which have major public health implications. Additionally, this article provides practical strategies to aid health care professionals in avoiding and mitigating opioid-involved drug interactions in order to obtain a favorable balance in the risk-benefit ratio associated with opioid use. These strategies include using osteopathic principles for chronic pain management, separating the times of administration of the opioid(s) from the nonopioid(s) involved in the interaction, changing the opioid(s) adversely affected by the interaction, changing the nonopioid(s) causing the interaction, and partnering with pharmacists in clinical practice.

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Aim: Evaluate results of pharmacogenomics testing for participants enrolled in the Program of All-inclusive Care for the Elderly (PACE). Materials & methods: A convenience sample of 100 participants from the PHARM-GENOME-PACE study. Genetic variants were determined by pharmacogenomics testing. Drug-gene interactions (DGIs), drug-drug-gene interactions (DDGIs) and phenoconversions were interrogated from a clinical decision support system. Results: In total, 146 genetic variants, 169 DGIs and 125 DDGIs were detected. DGIs and DDGIs occurred most commonly with the CYP2D6 gene (36.1 and 39.2%, respectively). There were 280 instances of phenoconversions; majority (62.9%) affecting the CYP3A4 isoenzyme. Conclusion: Prevalence of exposures to DGIs and DDGIs among PACE participants is high. Pharmacists using a clinical decision support system can support PACE practitioners with assessing multidrug simultaneous interactions. Clinical trial registration: NCT03257605.

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OBJECTIVES: To determine the feasibility of implementing a pharmacist-led pharmacogenomics (PGx) service for the Program of All-Inclusive Care for the Elderly (PACE). SETTING: A national centralized pharmacy providing PGx services to community-based PACE centers. PRACTICE DESCRIPTION: Individuals 55 years of age and older enrolled in PACE who underwent PGx testing as part of their medical care (n = 296). PRACTICE INNOVATION: Pharmacist-led PGx testing, interpreting, and consulting. EVALUATION: Implementation processes and roles were ascertained by reviewing policies and procedures for the PGx service and documented observations made by pharmacists providing the service. Genetic variants and drug-gene interactions (DGIs) were determined by interpretations of PGx test results. Types of recommendations provided by pharmacists were ascertained from PGx consultations. Prescribers' acceptance of recommendations were ascertained by documented responses or drug changes made after PGx consultations. RESULTS: Challenges to implementation included lack of systems interoperability, limited access to medical electronic health records, determining prescribers' responses, and knowledge and competency gaps in PGx. Pharmacist roles most essential to overcoming challenges were interpreting and applying PGx data, determining how to disseminate those data to prescribers, advocating for appropriate PGx testing, and educating about the application of test results to clinical practice. Participants frequently used drugs posing DGI risks, with the majority (73.6%) reporting more than 1 interaction. The overwhelming majority (89.0%) of pharmacists' recommendations to mitigate risks were accepted by referring prescribers. CONCLUSION: Implementing a pharmacist-led PGx service for PACE is feasible. Implementation of this service highlights the leadership role of pharmacists in moving PGx from research to practice.

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PURPOSE: The purpose of this study was to implement a clinical pharmacist-led medication therapy management (MTM) service within a primary-care setting that is enhanced by 1) a clinical decision support system (CDSS) that includes a unique combination of medication risk mitigation factors, which aids the pharmacist in interpreting the medication profile, and 2) pharmacogenomics (PGx) testing. METHODS: This was a service implementation study, whereby Medicare beneficiaries were eligible if they were patients of Elmwood Family Physicians, a private family, primary care practice with 2 locations in New Jersey, and were on at least 7 medications. Patients had a medication reconciliation completed by a pharmacist and performed a PGx buccal swab. Patient information was run through a CDSS to aid the pharmacist with screening for multidrug interactions and assessing patient's medication-related risks. The output of the CDSS was used to create recommendations and provide a consult to the physicians. Recommendations were followed up by return of the consult. RESULTS: Enrolled patients used a mean (± standard deviation) of 12.1 (± 4.6) medications. The turnaround time for the MTM Plus consults was 11.7 (± 6.2) days. During the consults, the pharmacist identified 138 medication-related problems (MRPs). The most common MRPs were drug-drug interactions (29.0%) and drug-gene interactions (DGIs; 24.6%). CONCLUSION: Implementing a clinical pharmacist-led MTM Plus service in the primary care setting is feasible. This study highlights that DGIs are common in older adults in family practice and indicates that PGx testing identifies additional MRPs that may otherwise go unnoticed in these patients. The experiences we shared can aid other clinicians in establishing successful MTM Plus services. Future studies should also measure the impact of such personalized medicine services on economic, clinical, and humanistic outcomes. This study has been registered with ClinicalTrials.gov (study No. NCT02748148).

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The off-label use of antipsychotics for the management of behavioral and psychologic symptoms of dementia (BPSD) in older adults (age ≥65 years) is common, despite evidence of modest benefits and serious risks. Although national initiatives aimed at reducing antipsychotic use among older adults with BPSD in nursing homes have been successful, similar initiatives are lacking for community-dwelling adults with dementia. As a result, older adults with BPSD residing in the community may be at an even greater risk of being negatively affected by antipsychotic use. Physicians should be knowledgeable of this issue and understand the alternatives to antipsychotics, as well as how to reduce antipsychotic use in patients with dementia who are already taking antipsychotics.

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The high prevalence of inappropriate polypharmacy in geriatric populations is unacceptable. Traditional medication risk mitigation (MRM) strategies have proven to be effective at improving polypharmacy, but these strategies have not consistently translated into positive health outcomes. Enhanced MRM strategies, such as using pharmacogenomics information, are needed, and these strategies need to be tested. A formidable challenge is successfully integrating pharmacogenomic information into clinical practice. As the medication experts on health care teams, pharmacists have a clear role to play in developing, integrating, and assessing enhanced MRM strategies to improve therapeutic outcomes for geriatric patients.

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PURPOSE: The development and implementation of quality-improvement initiatives to enhance customer service in an outpatient pharmacy of a Veterans Affairs (VA) medical center are described. SUMMARY: Historically low customer service satisfaction rates with the outpatient pharmacy at the Philadelphia Veterans Affairs Medical Center prompted this quality-improvement project. A three-question survey was designed to be easily and quickly administered to veterans in the outpatient pharmacy waiting area. Using 5-point Likert scale, veterans were asked to rate (1) their overall experience with the outpatient pharmacy service and (2) their satisfaction with the customer service provided by the pharmacy department. They were also asked how they thought the pharmacy department could improve its customer service. After receiving feedback from the survey, several quality-improvement initiatives were developed. The initiatives were categorized as environmental, personnel, communicative, and technological. For each initiative, one or more tasks were developed and the initiatives were subsequently implemented over eight months. After each task was completed, veterans were surveyed to measure the impact of the change. A total of 79 veterans were surveyed before the implementation of the quality-improvement initiatives, and 49% and 68% rated their experience with the outpatient pharmacy and customer service favorably, respectively. Twenty-five veterans were surveyed after the implementation of numerous quality-improvement interventions, with 44% and 72% rating their experience with the outpatient pharmacy and customer service favorably. CONCLUSION: Customer service satisfaction with an outpatient pharmacy service at a VA medical center was enhanced through the implementation of various quality-improvement initiatives.

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Objective: A growing body of evidence provides proof that proton pump inhibitors (PPIs) are overused in the general population and that such use is associated with adverse risks and unnecessary costs. Our objective was to systematically evaluate PPI overuse in the veteran population. Data Sources: A literature search using MEDLINE and CINHAL databases (1946-December 2014) was performed using the search term proton pump inhibitors coupled with each of the following key words: inappropriate use, misuse, and overuse. Searches were limited to studies and reviews in English language and human subjects. Additional references were identified from a review of literature citations. Study Selection and Data Extraction: All articles that centrally addressed the issue of PPI overuse were evaluated, following the PRISMA guidelines for systematic reviews. Data were extracted into Microsoft Excel 2013. Articles that focused on the pediatric or non-US veteran populations were excluded. Data Synthesis: Among 30 articles included, 5 evaluated PPI overuse in veterans. The reported prevalence rate of PPI overuse in veterans ranged from 33% to 67%. Several cases reported PPI-associated Clostridium difficile-associated diarrhea and pneumonia. One Veterans Affairs center reported the total cost of PPI overuse to be more than $200 000 based on over-the-counter costs and more than $1.5 million based on average wholesale price cost. Conclusions: PPI overuse is common among veterans and exposes them to adverse risks and costs the system enormous dollars. Based on the findings of this review, we provide recommendations to curb PPI overuse among veterans and in the Veterans Affairs system.

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The nuclear pore complex (NPC), embedded in the nuclear envelope, is a large, dynamic molecular assembly that facilitates exchange of macromolecules between the nucleus and the cytoplasm. The yeast NPC is an eightfold symmetric annular structure composed of ~456 polypeptide chains contributed by ~30 distinct proteins termed nucleoporins. Nup116, identified only in fungi, plays a central role in both protein import and mRNA export through the NPC. Nup116 is a modular protein with N-terminal "FG" repeats containing a Gle2p-binding sequence motif and a NPC targeting domain at its C-terminus. We report the crystal structure of the NPC targeting domain of Candida glabrata Nup116, consisting of residues 882-1034 [CgNup116(882-1034)], at 1.94 Å resolution. The X-ray structure of CgNup116(882-1034) is consistent with the molecular envelope determined in solution by small-angle X-ray scattering. Structural similarities of CgNup116(882-1034) with homologous domains from Saccharomyces cerevisiae Nup116, S. cerevisiae Nup145N, and human Nup98 are discussed.

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Guidelines recommend hospice care for patients with advanced heart failure (HF) who are approaching end of life. However, little is known about the data available when HF patients are admitted to hospice. This pilot study surveyed the staff from 100 hospices in the United States and Canada about how frequently data were provided to or obtained by the hospice when admitting HF patients and how important they perceived the data. The survey response rate was 66%. Overall, data were less often provided or obtained than rated important (aggregate mean difference, P<.001, r=.75). Data important to prognostication or ongoing care were provided to or readily obtained by the hospices for blood pressure (50.0%), left ventricular ejection fraction (EF) (50.0%), edema (58.3%), HF medications, symptoms of dyspnea (63.2%), chest pain (57.2%), common comorbidities, and pacemaker (69.6%) or other devices (60.0%). Approximately half of the time, hospices reported that they rarely or never received information about medication intolerance. Significant amounts of clinically valid data are not provided to or obtained by hospice providers when admitting HF patients. Investigations are needed to corroborate these findings, understand information transfer at transitions in care, and to determine the impact of admission data on hospice care for HF patients. Congest Heart Fail.

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BACKGROUND: Heart failure (HF) management guidelines recommend that most patients with HF receive an ACE inhibitor or an angiotensin II type 1 receptor antagonist (angiotensin receptor blocker [ARB]) and a ß-blocker (ß-adrenoceptor antagonist), collectively referred to as 'cardiac drugs', based on results from randomized controlled trials showing that these drugs reduce mortality. However, the results of randomized controlled trials may not be generalizable to the population most likely (i.e. the elderly) to receive these drugs in clinical practice. OBJECTIVE: To determine the effectiveness of cardiac drugs for reducing mortality in the elderly Medicare HF population. STUDY DESIGN: Retrospective, survey-weighted, cohort analysis of the 2002 Medicare Current Beneficiary Survey Cost and Use files. PARTICIPANTS: 12 697 beneficiaries, of whom 1062 had a diagnosis of HF and 577 were eligible to receive cardiac drugs. MEASUREMENTS: Association between mortality and cardiac drugs, adjusted for sociodemographics, co-morbidity and propensity to receive cardiac drugs. RESULTS: The mortality rate among the 577 eligible beneficiaries with HF was 9.7%. The mortality rate for those receiving an ACE inhibitor or ARB alone, a ß-blocker alone, or both an ACE inhibitor or ARB and a ß-blocker, was 6.1%, 5.9% and 5.3%, respectively; in the absence of any of the three cardiac drugs, the mortality rate was 20.0% (p < 0.0001). In multivariable analyses, mortality rates remained significantly lower for beneficiaries receiving an ACE inhibitor or ARB alone (odds ratio [OR] 0.24; 95% CI 0.11, 0.50), a ß-blocker alone (OR 0.17; 95% CI 0.07, 0.41), or both an ACE inhibitor or ARB and a ß-blocker (OR 0.24; 95% CI 0.10, 0.55) compared with patients who did not receive any of the three cardiac drugs. CONCLUSIONS: Use of guideline-recommended cardiac drugs is associated with reduced mortality in the elderly Medicare HF population. Providing evidence of the benefit of cardiac drugs among the elderly with HF will become increasingly important as the size of the Medicare population grows.

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BACKGROUND: Guidelines recommend lifelong anticoagulation in patients with cancer and a history of thromboembolism, but the use of anticoagulation in hospice has not been described. A retrospective study of medication data was conducted to determine patterns of anticoagulant use and predictors of type of anticoagulant prescribed for hospice patients with lung cancer. METHODS: Medication data were evaluated for 16,896 hospice patients with lung cancer in 2006 to determine patient and hospice characteristics that predicted anticoagulant prescription. Independent predictors of warfarin versus low molecular weight heparin (LMWH) prescription were identified using a logistic regression model. RESULTS: One of every 11 patients was prescribed an anticoagulant, most commonly warfarin. Compared with patients prescribed LMWH, patients prescribed warfarin were older (71.6 vs 65.8 years, P<.001), were more likely white (81.2% vs 74.3%, P = .03), had a longer stay in hospice (median 21 days vs 17 days, P = .001), and were more likely to have ≥3 comorbid illnesses (37.5% vs 25.0%, P<.001). The strongest independent predictor of type of anticoagulant prescribed was geographic region, with hospices in the Northeast more likely to prescribe LMWH. CONCLUSIONS: Anticoagulant use is prevalent in patients with lung cancer enrolled in hospice. This study highlights the need to understand the benefits and risks of anticoagulation at the end of life.

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