Clinicians' use of Health Information Exchange technologies for medication reconciliation in the U.S. Department of Veterans Affairs: a qualitative analysis.

BACKGROUND: Medication reconciliation is essential for optimizing medication use. In part to promote effective medication reconciliation, the Department of Veterans Affairs (VA) invested substantial resources in health information exchange (HIE) technologies. The objectives of this qualitative study were to characterize VA clinicians' use of HIE tools for medication reconciliation in their clinical practice and to identify facilitators and barriers. METHODS: We recruited inpatient and outpatient prescribers (physicians, nurse practitioners, physician assistants) and pharmacists at four geographically distinct VA medical centers for observations and interviews. Participants were observed as they interacted with HIE or medication reconciliation tools during routine work. Participants were interviewed about clinical decision-making pertaining to medication reconciliation and use of HIE tools, and about barriers and facilitators to use of the tools. Qualitative data were analyzed via inductive and deductive approaches using a priori codes. RESULTS: A total of 63 clinicians participated. Over half (58%) were female, and the mean duration of VA clinical experience was 7 (range 0-32) years. Underlying motivators for clinicians seeking data external to their VA medical center were having new patients, current patients receiving care from an external institution, and clinicians' concerns about possible medication discrepancies among institutions. Facilitators for using HIE software were clinicians' familiarity with the HIE software, clinicians' belief that medication information would be available within HIE, and their confidence in the ability to find HIE medication-related data of interest quickly. Six overarching barriers to HIE software use for medication coordination included visual clutter and information overload within the HIE display; challenges with HIE interface navigation; lack of integration between HIE and other electronic health record interfaces, necessitating multiple logins and application switching; concerns with the dependability of HIE medication information; unfamiliarity with HIE tools; and a lack of HIE data from non-VA facilities. CONCLUSIONS: This study is believed to be the first to qualitatively characterize clinicians' HIE use with respect to medication reconciliation. Results inform recommendations to optimize HIE use for medication management activities. We expect that healthcare organizations and software vendors will be able to apply the findings to develop more effective and usable HIE information displays.

Epidermal growth factor receptor signaling in precancerous keratinocytes promotes neighboring head and neck cancer squamous cell carcinoma cancer stem cell-like properties and phosphoinositide 3-kinase inhibitor insensitivity.

Head and neck squamous cell carcinoma (HNSCC) is commonly associated with tobacco and alcohol consumption that induce a "precancerous field," with phosphoinositide 3-kinase (PI3K) signaling being a common driver. However, the preclinical effectiveness of PI3K inhibitors has not necessarily translated to remarkable benefit in HNSCC patients. Thus, we sought to determine how precancerous keratinocytes influence HNSCC proliferation, cancer stem cell (CSC) maintenance, and response to PI3K inhibitors. We used the NOK keratinocyte cell line as a model of preneoplastic keratinocytes because it harbors two frequent genetic events in HNSCC, CDKN2A promoter methylation and TP53 mutation, but does not form tumors. NOK cell coculture or NOK cell-conditioned media promoted HNSCC proliferation, PI3K inhibitor resistance, and CSC phenotypes. SOMAscan-targeted proteomics determined the relative levels of >1300 analytes in the media conditioned by NOK cells and HNSCC cells ± PI3K inhibitor. These results demonstrated that NOK cells release abundant levels of ligands that activate epidermal growth factor receptor (EGFR) and fibroblast growth factor receptor (FGFR), two receptor tyrosine kinases with oncogenic activity. Inhibition of EGFR, but not FGFR, blunted PI3K inhibitor resistance and CSC phenotypes induced by NOK cells. Our results demonstrate that precancerous keratinocytes can directly support neighboring HNSCC by activating EGFR. Importantly, PI3K inhibitor sensitivity was not necessarily a cancer cell-intrinsic property, and the tumor microenvironment impacts therapeutic response and supports CSCs. Additionally, combined inhibition of EGFR with PI3K inhibitor diminished EGFR activation induced by PI3K inhibitor and potently inhibited cancer cell proliferation and CSC maintenance.

Utilizing a user-centered approach to develop and assess pharmacogenomic clinical decision support for thiopurine methyltransferase.

BACKGROUND: A pharmacogenomic clinical decision support tool (PGx-CDS) for thiopurine medications can help physicians incorporate pharmacogenomic results into prescribing decisions by providing up-to-date, real-time decision support. However, the PGx-CDS user interface may introduce errors and promote alert fatigue. The objective of this study was to develop and evaluate a prototype of a PGx-CDS user interface for thiopurine medications with user-centered design methods. METHODS: This study had two phases: In phase I, we conducted qualitative interviews to assess providers' information needs. Interview transcripts were analyzed through a combination of inductive and deductive qualitative analysis to develop design requirements for a PGx-CDS user interface. Using these requirements, we developed a user interface prototype and evaluated its usability (phase II). RESULTS: In total, 14 providers participated: 10 were interviewed in phase I, and seven providers completed usability testing in phase II (3 providers participated in both phases). Most (90%) participants were interested in PGx-CDS systems to help improve medication efficacy and patient safety. Interviews yielded 11 themes sorted into two main categories: 1) health care providers' views on PGx-CDS and 2) important design features for PGx-CDS. We organized these findings into guidance for PGx-CDS content and display. Usability testing of the PGx-CDS prototype showed high provider satisfaction. CONCLUSION: This is one of the first studies to utilize a user-centered design approach to develop and assess a PGx-CDS interface prototype for Thiopurine Methyltransferase (TPMT). This study provides guidance for the development of a PGx-CDS, and particularly for biomarkers such as TPMT.

A comprehensive review and meta-analysis of risk factors for statin-induced myopathy.

PURPOSE: To aid prescribers in assessing a patient's risk for statin-induced myopathy (SIM), we performed a comprehensive review of currently known risk factors and calculated aggregated odds ratios for each risk factor through a meta-analysis. METHODS: This meta-analysis was done through four phases: (1) Identification of the relevant primary literature; (2) abstract screening using inclusion and exclusion criteria; (3) detailed review and data extraction; and (4) synthesis and statistical analysis. RESULTS: Out of 44 papers analyzed from 836 papers searched from MEDLINE, 18 different potential risk factors were collected, divided into three categories: three demographics (11 papers), ten clinical factors (31 papers), and five pharmacogenetics/biomarkers (12 papers). Risk factors significant for myopathy and/or rhabdomyolysis included age, gender, diabetes, renal impairment, cardiovascular disease, certain interacting drugs, and mutations of the SLCO1B1 gene, which encodes a transporter protein in the liver. Several factors, such as gender, race, cardiovascular disease, and the GATM gene, which encodes a protein for creatine synthesis, appeared to be protective in terms of the outcomes of interest. CONCLUSIONS: This comprehensive assessment of risk factors can help support clinicians in reducing the incidence of SIM in their patient population on statins.

Usability evaluation of a medication reconciliation tool: Embedding safety probes to assess users' detection of medication discrepancies.

OBJECTIVE: An electronic medication reconciliation tool was previously developed by another research team to aid provider-patient communication for medication reconciliation. To evaluate the usability of this tool, we integrated artificial safety probes into standard usability methods. The objective of this article is to describe this method of using safety probes, which enabled us to evaluate how well the tool supports users' detection of medication discrepancies. MATERIALS AND METHODS: We completed a mixed-method usability evaluation in a simulated setting with 30 participants: 20 healthcare professionals (HCPs) and 10 patients. We used factual scenarios but embedded three artificial safety probes: (1) a missing medication (i.e., omission); (2) an extraneous medication (i.e., commission); and (3) an inaccurate dose (i.e., dose discrepancy). We measured users' detection of each probe to estimate the probability that a HCP or patient would detect these discrepancies. Additionally, we recorded participants' detection of naturally occurring discrepancies. RESULTS: Each safety probe was detected by ≤50% of HCPs. Patients' detection rates were generally higher. Estimates indicate that a HCP and patient, together, would detect 44.8% of these medication discrepancies. Additionally, HCPs and patients detected 25 and 45 naturally-occurring discrepancies, respectively. DISCUSSION: Overall, detection of medication discrepancies was low. Findings indicate that more advanced interface designs are warranted. Future research is needed on how technologies can be designed to better aid HCPs' and patients' detection of medication discrepancies. CONCLUSION: This is one of the first studies to evaluate the usability of a collaborative medication reconciliation tool and assess HCPs' and patients' detection of medication discrepancies. Results demonstrate that embedded safety probes can enhance standard usability methods by measuring additional, clinically-focused usability outcomes. The novel safety probes we used may serve as an initial, standard set for future medication reconciliation research. More prevalent use of safety probes could strengthen usability research for a variety of health information technologies.

The action of endo-xylanase and endo-glucanase on cereal cell wall polysaccharides and its implications for starch digestion kinetics in an in vitro poultry model.

Endo-xylanase and endo-glucanase are supplemented to poultry diets in order to improve nutrient digestion and non-starch polysaccharide (NSP) fermentation. Here, the action of these enzymes on alcohol insoluble solids (AIS) from wheat and maize grains as well as its implications for starch digestion in milled grains were evaluated in vitro, under conditions mimicking the poultry digestive tract. For wheat AIS, GH11 endo-xylanase depolymerized soluble arabinoxylan (AX) during the gizzard phase, and proceeded to release insoluble AX under small intestine conditions. At the end of the in vitro digestion (480 min), the endo-xylanase, combined with a GH7 endo-ß-1,4-glucanase, released 30.5 % of total AX and 18.1 % of total glucan in the form of arabinoxylo- and gluco-oligosaccharides, as detected by HPAEC-PAD and MALDI-TOF-MS. For maize AIS, the combined enzyme action released 2.2 % and 7.0 % of total AX and glucan, respectively. Analogous in vitro digestion experiments of whole grains demonstrated that the enzymatic release of oligomers coincided with altered grain microstructure, as examined by SEM. In the present study, cell wall hydrolysis did not affect in vitro starch digestion kinetics for cereal grains. This study contributes to understanding the action of feed enzymes on cereal NSP under conditions mimicking the poultry digestive tract.

Droplet size dependency and spatial heterogeneity of lipid oxidation in whey protein isolate-stabilized emulsions.

Spatiotemporal assessment of lipid and protein oxidation is key for understanding quality deterioration in emulsified food products containing polyunsaturated fatty acids. In this work, we first mechanistically validated the use of the lipid oxidation-sensitive fluorophore BODIPY 665/676 as a semi-quantitative marker for local peroxyl radical formation. Next, we assessed the impact of microfluidic and colloid mill emulsification (respectively producing mono- and polydisperse droplets) on local protein and lipid oxidation kinetics in whey protein isolate (WPI)-stabilized emulsions. We further used BODIPY 581/591 C11 and CAMPO-AFDye 647 as colocalisation markers for lipid and protein oxidation. The polydisperse emulsions showed an inverse relation between droplet size and lipid oxidation rate. Further, we observed less protein and lipid oxidation occurring in similar sized droplets in monodisperse emulsions. This observation was linked to more heterogeneous protein packing at the droplet surface during colloid mill emulsification, resulting in larger inter-droplet heterogeneity in both protein and lipid oxidation. Our findings indicate the critical roles of emulsification methods and droplet sizes in understanding and managing lipid oxidation.

Engineering the substrate specificity and regioselectivity of Burkholderia thailandensis lipoxygenase.

Lipoxygenases (LOXs) catalyze the regioselective dioxygenation of polyunsaturated fatty acids (PUFAs), generating fatty acid hydroperoxides (FAHPs) with diverse industrial applications. Bacterial LOXs have garnered significant attention in recent years due to their broad activity towards PUFAs, yet knowledge about the structural factors influencing their substrate preferences remains limited. Here, we characterized a bacterial LOX from Burkholderia thailandensis (Bt-LOX), and identified key residues affecting its substrate preference and regioselectivity through site-directed mutagenesis. Bt-LOX preferred ω-6 PUFAs and exhibited regioselectivity at the ω-5 position. Mutations targeting the substrate binding pocket and the oxygen access channel led to the production of three active variants with distinct catalytic properties. The A431G variant bifurcated dioxygenation between the ω-5 and ω-9 positions, while F446V showed reduced regioselectivity with longer PUFAs. Interestingly, L445A displayed altered substrate specificity, favoring ω-3 over ω-6 PUFAs. Furthermore, L445A shifted the regioselectivity of dioxygenation to the ω-2 position in ω-3 PUFAs, and, for some substrates, facilitated dioxygenation closer to the carboxylic acid terminus, suggesting an altered substrate orientation. Among these variants, L445A represents a significant milestone in LOX research, as these alterations in substrate specificity, dioxygenation regioselectivity, and substrate orientation were achieved by a single mutation only. These findings illuminate key residues governing substrate preference and regioselectivity in Bt-LOX, offering opportunities for synthesizing diverse FAHPs and highlighting the potential of bacterial LOXs as biocatalysts with widespread applications.

Assessing user perspectives on clinical pharmacogenomics consultation documentation: a user-centered evaluation.

The University of Florida Health Precision Medicine Program plays a crucial role in delivering pharmacogenomics (PGx) result notes to providers who request PGx testing. Despite this, there is currently a lack of a formal assessment of provider needs and established best practice design principles to guide the ongoing development of PGx result notes. This study aims to enhance the content and format of the PGx consult note at UF Health by incorporating valuable feedback from healthcare providers. Through in-depth user sessions involving 11 participants, we evaluated the usability of our consult note template. While overall satisfaction with the content was noted, specific sections, including those addressing phenoconversion and the medication list, were identified for revision to enhance clarity based on insightful provider feedback.

A mechanistic kinetic model for lipid oxidation in Tween 20-stabilized O/W emulsions.

Models predicting lipid oxidation in oil-in-water (O/W) emulsions are a requirement for developing effective antioxidant solutions. Existing models do, however, not include explicit equations that account for composition and structural features of O/W emulsions. To bridge this gap, a mechanistic kinetic model for lipid oxidation in emulsions is presented, describing the emulsion as a one-dimensional three phase (headspace, water, and oil) system. Variation in oil droplet sizes, overall surface area of oil/water interface, oxidation of emulsifiers, and the presence of catalytic transition metals were accounted for. For adequate predictions, the overall surface area of oil/water interface needs to be determined from the droplet size distribution obtained by dynamic and static light scattering (DLS, SLS). The kinetic model predicted well the formation of oxidation products in both mono- and polydisperse emulsions, with and without presence of catalytic transition metals.

Association between Opioid-Benzodiazepine Trajectories and Injurious Fall Risk among US Medicare Beneficiaries.

Background/Objectives: Concurrent opioid (OPI) and benzodiazepine (BZD) use may exacerbate injurious fall risk (e.g., falls and fractures) compared to no use or use alone. Yet, patients may need concurrent OPI-BZD use for co-occurring conditions (e.g., pain and anxiety). Therefore, we examined the association between longitudinal OPI-BZD dosing patterns and subsequent injurious fall risk. Methods: We conducted a retrospective cohort study including non-cancer fee-for-service Medicare beneficiaries initiating OPI and/or BZD in 2016-2018. We identified OPI-BZD use patterns during the 3 months following OPI and/or BZD initiation (i.e., trajectory period) using group-based multi-trajectory models. We estimated the time to first injurious falls within the 3-month post-trajectory period using inverse-probability-of-treatment-weighted Cox proportional hazards models. Results: Among 622,588 beneficiaries (age ≥ 65 = 84.6%, female = 58.1%, White = 82.7%; having injurious falls = 0.45%), we identified 13 distinct OPI-BZD trajectories: Group (A): Very-low OPI-only (early discontinuation) (44.9% of the cohort); (B): Low OPI-only (rapid decline) (15.1%); (C): Very-low OPI-only (late discontinuation) (7.7%); (D): Low OPI-only (gradual decline) (4.0%); (E): Moderate OPI-only (rapid decline) (2.3%); (F): Very-low BZD-only (late discontinuation) (11.5%); (G): Low BZD-only (rapid decline) (4.5%); (H): Low BZD-only (stable) (3.1%); (I): Moderate BZD-only (gradual decline) (2.1%); (J): Very-low OPI (rapid decline)/Very-low BZD (late discontinuation) (2.9%); (K): Very-low OPI (rapid decline)/Very-low BZD (increasing) (0.9%); (L): Very-low OPI (stable)/Low BZD (stable) (0.6%); and (M): Low OPI (gradual decline)/Low BZD (gradual decline) (0.6%). Compared with Group (A), six trajectories had an increased 3-month injurious falls risk: (C): HR = 1.78, 95% CI = 1.58-2.01; (D): HR = 2.24, 95% CI = 1.93-2.59; (E): HR = 2.60, 95% CI = 2.18-3.09; (H): HR = 2.02, 95% CI = 1.70-2.40; (L): HR = 2.73, 95% CI = 1.98-3.76; and (M): HR = 1.96, 95% CI = 1.32-2.91. Conclusions: Our findings suggest that 3-month injurious fall risk varied across OPI-BZD trajectories, highlighting the importance of considering both dose and duration when assessing injurious fall risk of OPI-BZD use among older adults.

Implementing a pragmatic clinical trial to tailor opioids for chronic pain on behalf of the IGNITE ADOPT PGx investigators.

Chronic pain is a prevalent condition with enormous economic burden. Opioids such as tramadol, codeine, and hydrocodone are commonly used to treat chronic pain; these drugs are activated to more potent opioid receptor agonists by the hepatic CYP2D6 enzyme. Results from clinical studies and mechanistic understandings suggest that CYP2D6-guided therapy will improve pain control and reduce adverse drug events. However, CYP2D6 is rarely used in clinical practice due in part to the demand for additional clinical trial evidence. Thus, we designed the ADOPT-PGx (A Depression and Opioid Pragmatic Trial in Pharmacogenetics) chronic pain study, a multicenter, pragmatic, randomized controlled clinical trial, to assess the effect of CYP2D6 testing on pain management. The study enrolled 1048 participants who are taking or being considered for treatment with CYP2D6-impacted opioids for their chronic pain. Participants were randomized to receive immediate or delayed (by 6 months) genotyping of CYP2D6 with clinical decision support (CDS). CDS encouraged the providers to follow the CYP2D6-guided trial recommendations. The primary study outcome is the 3-month absolute change in the composite pain intensity score assessed using Patient-Reported Outcomes Measurement Information System (PROMIS) measures. Follow-up will be completed in July 2024. Herein, we describe the design of this trial along with challenges encountered during enrollment.

Clinician Response to Pharmacogenetic Clinical Decision Support Alerts.

The objective of this study was to characterize clinician response following standardization of pharmacogenetic (PGx) clinical decision support alerts at University of Florida (UF) Health. A retrospective analysis of all PGx alerts that fired at a tertiary academic medical center from August 2020 through May 2022 was performed. Alert acceptance rate was calculated and compared across six gene-drug pairs, patient care setting, and clinician specialty. The disposition of the triggering medication was compared with the alert response and evaluated for congruence. There were a total of 818 alerts included for analysis of alert response, 557 alerts included in acceptance rate calculations, and 392 alerts with sufficient information to assess clinical response. The overall acceptance rate was 63%. The alert response and clinical response were congruent for 47% of alerts. Alert response was influenced by the triggering gene-drug pair, clinician specialty, patient care setting, and specialty of the provider who initially ordered the PGx test. Clinical response was mostly incongruent with alert response. Alert acceptance is influenced by the triggering gene-drug pair, clinician specialty, and care setting. Alert response is not a reliable surrogate marker for clinical action. Any future research into the impact of clinical decision support (CDS) alerts should focus on clinical response rather than alert response. Given the reliance on CDS alerts to enhance uptake of PGx, it is worthwhile to further investigate their impact on prescribing and patient outcomes.

Polymorphonuclear myeloid-derived suppressor cells and phosphatidylinositol-3 kinase gamma are critical to tobacco-mimicking oral carcinogenesis in mice.

BACKGROUND: Oral squamous cell carcinoma (OSCC) is a devastating disease most often associated with tobacco consumption that induces a field of mutations from which a tumor arises. Identification of ways to prevent the emergence of cancer in high-risk patients is an ultimate goal for combatting all types of cancer, including OSCC. METHODS: Our study employs a mouse model of tongue carcinogenesis induced by tobacco carcinogen mimetic, 4-nitroquinoline 1-oxide (4NQO), to establish tongue dysplasia and OSCC. We use conventional histology, immunohistochemistry, multispectral imaging, mass cytometry, novel cell lines, pharmaceutical inhibition of PI3Kγ, T-cell suppression assays and mouse transplant models in our functional experimentation. RESULTS: In our study, we identify Ly6G+ granulocytes as the most abundant immune cell type in a model of tongue carcinogenesis induced by tobacco carcinogen mimetic 4NQO. Targeting Ly6G+ granulocytes with a pharmacologic inhibitor of PI3Kγ, an isoform of PI3K exclusively expressed by myeloid cells, resulted in reduced tongue dysplasia severity, and reduced rates of OSCC. Importantly, we performed functional assays with the Ly6G+ granulocytes induced in cell line models of 4NQO carcinogenesis to demonstrate that these granulocytes have increased polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) activity against T-cell proliferation and these PMN-MDSCs play a functional role in promoting tumor formation by inhibiting tumor regression in a PI3Kγ-dependent manner. CONCLUSIONS: Overall, our data suggest that recruitment of PMN-MDSCs to sites of dysplasia is critical to immune suppression of CD8 T cells, thereby permitting malignancy, and PI3Kγ inhibitors are one mechanism to reduce PMN-MDSC recruitment, immunosuppression and tumorigenesis in OSCC.

Lessons from clinical implementation of a preemptive pharmacogenetic panel as part of a testing pilot program with an employer-sponsored medical plan.

Introduction: This manuscript reports on a pilot program focused on implementing pharmacogenetic testing within the framework of an employer-sponsored medical plan at University of Florida (UF) Health. The aim was to understand the challenges associated with program implementation and to gather insights into patient attitudes towards PGx testing. Methods: The pilot program adopted a partially preemptive approach, targeting patients on current prescriptions for medications with relevant gene-drug associations. Patients were contacted via phone or through the MyChart system and offered pharmacogenetic testing with no additional direct costs. Results: Of 244 eligible patients, 110 agreed to participate. However, only 61 returned the mailed DNA collection kits. Among these, 89% had at least one potentially actionable genotype-based phenotype. Post-test follow-up revealed that while the majority viewed the process positively, 71% preferred a consultation with a pharmacogenetic specialist for better understanding of their results. Barriers to implementation ranged from fatigue with the healthcare system to a lack of understanding of the pharmacogenetic testing and concerns about privacy and potential misuse of genetic data. Conclusion: The findings underscore the need for clearer patient education on pharmacogenetic results and suggest the importance of the role of pharmacogenetic-trained pharmacists in delivering this education. They also highlight issues with relying on incomplete or inaccurate medication lists in patients' electronic health record. The implementation revealed less obvious challenges, the understanding of which could be beneficial for the success of future preemptive pharmacogenetic implementation programs. The insights from the pilot program served to bridge the information gap between patients, providers, and pharmacogenetic -specialists, with the ultimate goal of improving patient care.

Assessment of a Manual Method versus an Automated, Probability-Based Algorithm to Identify Patients at High Risk for Pharmacogenomic Adverse Drug Outcomes in a University-Based Health Insurance Program.

We compared patient cohorts selected for pharmacogenomic testing using a manual method or automated algorithm in a university-based health insurance network. The medication list was compiled from claims data during 4th quarter 2018. The manual method selected patients by number of medications by the health system's list of medications for pharmacogenomic testing. The automated method used YouScript's pharmacogenetic interaction probability (PIP) algorithm to select patients based on the probability that testing would result in detection of one or more clinically significant pharmacogenetic interactions. A total of 6916 patients were included. Patient cohorts selected by each method differed substantially, including size (manual n = 218, automated n = 286) and overlap (n = 41). The automated method was over twice as likely to identify patients where testing may reveal a clinically significant pharmacogenetic interaction than the manual method (62% vs. 29%, p < 0.0001). The manual method captured more patients with significant drug-drug or multi-drug interactions (80.3% vs. 40.2%, respectively, p < 0.0001), higher average number of significant drug interactions per patient (3.3 vs. 1.1, p < 0.0001), and higher average number of unique medications per patient (9.8 vs. 7.4, p < 0.0001). It is possible to identify a cohort of patients who would likely benefit from pharmacogenomic testing using manual or automated methods.

Dosing profiles of concurrent opioid and benzodiazepine use associated with overdose risk among US Medicare beneficiaries: group-based multi-trajectory models.

BACKGROUND AND AIMS: One-third of opioid (OPI) overdose deaths involve concurrent benzodiazepine (BZD) use. Little is known about concurrent opioid and benzodiazepine use (OPI-BZD) most associated with overdose risk. We aimed to examine associations between OPI-BZD dose and duration trajectories, and subsequent OPI or BZD overdose in US Medicare. DESIGN: Retrospective cohort study. SETTING: US Medicare. PARTICIPANTS: Using a 5% national Medicare data sample (2013-16) of fee-for-service beneficiaries without cancer initiating OPI prescriptions, we identified 37 879 beneficiaries (age ≥ 65 = 59.3%, female = 71.9%, white = 87.6%, having OPI overdose = 0.3%). MEASUREMENTS: During the 6 months following OPI initiation (i.e. trajectory period), we identified OPI-BZD dose and duration patterns using group-based multi-trajectory models, based on average daily morphine milligram equivalents (MME) for OPIs and diazepam milligram equivalents (DME) for BZDs. To label dose levels in each trajectory, we defined OPI use as very low (< 25 MME), low (25-50 MME), moderate (51-90 MME), high (91-150 MME) and very high (>150 MME) dose. Similarly, we defined BZD use as very low (< 10 DME), low (10-20 DME), moderate (21-40 DME), high (41-60 DME) and very high (> 60 DME) dose. Our primary analysis was to estimate the risk of time to first hospital or emergency department visit for OPI overdose within 6 months following the trajectory period using inverse probability of treatment-weighted Cox proportional hazards models. FINDINGS: We identified nine distinct OPI-BZD trajectories: group A: very low OPI (early discontinuation)-very low declining BZD (n = 10 598; 28.0% of the cohort); B: very low OPI (early discontinuation)-very low stable BZD (n = 4923; 13.0%); C: very low OPI (early discontinuation)-medium BZD (n = 4997; 13.2%); D: low OPI-low BZD (n = 5083; 13.4%); E: low OPI-high BZD (n = 3906; 10.3%); F: medium OPI-low BZD (n = 3948; 10.4%); G: very high OPI-high BZD (n = 1371; 3.6%); H: very high OPI-very high BZD (n = 957; 2.5%); and I: very high OPI-low BZD (n = 2096; 5.5%). Compared with group A, five trajectories (32.3% of the study cohort) were associated with increased 6-month OPI overdose risks: E: low OPI-high BZD [hazard ratio (HR) = 3.27, 95% confidence interval (CI) = 1.61-6.63]; F: medium OPI-low BZD (HR = 4.04, 95% CI = 2.06-7.95); G: very high OPI-high BZD (HR = 6.98, 95% CI = 3.11-15.64); H: very high OPI-very high BZD (HR = 4.41, 95% CI = 1.51-12.85); and I: very high OPI-low BZD (HR = 6.50, 95% CI = 3.15-13.42). CONCLUSIONS: Patterns of concurrent opioid and benzodiazepine use most associated with overdose risk among fee-for-service US Medicare beneficiaries initiating opioid prescriptions include very high-dose opioid use (MME > 150), high-dose benzodiazepine use (DME > 40) or medium-dose opioid with low-dose benzodiazepine use.

Implementing a pragmatic clinical trial to tailor opioids for acute pain on behalf of the IGNITE ADOPT PGx investigators.

Opioid prescribing for postoperative pain management is challenging because of inter-patient variability in opioid response and concern about opioid addiction. Tramadol, hydrocodone, and codeine depend on the cytochrome P450 2D6 (CYP2D6) enzyme for formation of highly potent metabolites. Individuals with reduced or absent CYP2D6 activity (i.e., intermediate metabolizers [IMs] or poor metabolizers [PMs], respectively) have lower concentrations of potent opioid metabolites and potentially inadequate pain control. The primary objective of this prospective, multicenter, randomized pragmatic trial is to determine the effect of postoperative CYP2D6-guided opioid prescribing on pain control and opioid usage. Up to 2020 participants, age ≥8 years, scheduled to undergo a surgical procedure will be enrolled and randomized to immediate pharmacogenetic testing with clinical decision support (CDS) for CYP2D6 phenotype-guided postoperative pain management (intervention arm) or delayed testing without CDS (control arm). CDS is provided through medical record alerts and/or a pharmacist consult note. For IMs and PM in the intervention arm, CDS includes recommendations to avoid hydrocodone, tramadol, and codeine. Patient-reported pain-related outcomes are collected 10 days and 1, 3, and 6 months after surgery. The primary outcome, a composite of pain intensity and opioid usage at 10 days postsurgery, will be compared in the subgroup of IMs and PMs in the intervention (n = 152) versus the control (n = 152) arm. Secondary end points include prescription pain medication misuse scores and opioid persistence at 6 months. This trial will provide data on the clinical utility of CYP2D6 phenotype-guided opioid selection for improving postoperative pain control and reducing opioid-related risks.

Design and rationale of GUARDD-US: A pragmatic, randomized trial of genetic testing for APOL1 and pharmacogenomic predictors of antihypertensive efficacy in patients with hypertension.

RATIONALE AND OBJECTIVE: APOL1 risk alleles are associated with increased cardiovascular and chronic kidney disease (CKD) risk. It is unknown whether knowledge of APOL1 risk status motivates patients and providers to attain recommended blood pressure (BP) targets to reduce cardiovascular disease. STUDY DESIGN: Multicenter, pragmatic, randomized controlled clinical trial. SETTING AND PARTICIPANTS: 6650 individuals with African ancestry and hypertension from 13 health systems. INTERVENTION: APOL1 genotyping with clinical decision support (CDS) results are returned to participants and providers immediately (intervention) or at 6 months (control). A subset of participants are re-randomized to pharmacogenomic testing for relevant antihypertensive medications (pharmacogenomic sub-study). CDS alerts encourage appropriate CKD screening and antihypertensive agent use. OUTCOMES: Blood pressure and surveys are assessed at baseline, 3 and 6 months. The primary outcome is change in systolic BP from enrollment to 3 months in individuals with two APOL1 risk alleles. Secondary outcomes include new diagnoses of CKD, systolic blood pressure at 6 months, diastolic BP, and survey results. The pharmacogenomic sub-study will evaluate the relationship of pharmacogenomic genotype and change in systolic BP between baseline and 3 months. RESULTS: To date, the trial has enrolled 3423 participants. CONCLUSIONS: The effect of patient and provider knowledge of APOL1 genotype on systolic blood pressure has not been well-studied. GUARDD-US addresses whether blood pressure improves when patients and providers have this information. GUARDD-US provides a CDS framework for primary care and specialty clinics to incorporate APOL1 genetic risk and pharmacogenomic prescribing in the electronic health record. TRIAL REGISTRATION: ClinicalTrials.govNCT04191824.

Utilizing a Human-Computer Interaction Approach to Evaluate the Design of Current Pharmacogenomics Clinical Decision Support.

A formal assessment of pharmacogenomics clinical decision support (PGx-CDS) by providers is lacking in the literature. The objective of this study was to evaluate the usability of PGx-CDS tools that have been implemented in a healthcare setting. We enrolled ten prescribing healthcare providers and had them complete a 60-min usability session, which included interacting with two PGx-CDS scenarios using the "Think Aloud" technique, as well as completing the Computer System Usability Questionnaire (CSUQ). Providers reported positive comments, negative comments, and suggestions for the two PGx-CDS during the usability testing. Most provider comments were in favor of the current PGx-CDS design, with the exception of how the genotype and phenotype information is displayed. The mean CSUQ score for the PGx-CDS overall satisfaction was 6.3 ± 0.95, with seven strongly agreeing and one strongly disagreeing for overall satisfaction. The implemented PGx-CDS at our institution was well received by prescribing healthcare providers. The feedback collected from the session will guide future PGx-CDS designs for our healthcare system and provide a framework for other institutions implementing PGx-CDS.