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An animal a day
Dip in each day to discover a new animal to enjoy sharing with friends or family - make sure to find YOUR birthday animal! Travel through the incredible ecosystems and habitats of our beautiful planet, and meet some of the most fascinating animals that call them home. Dive into the oceans to find whales and giant squid, journey across the icy poles with penguins and polar bears, race across the African savanna with lions and wildebeest - and so much more.
CHILDBOOK
CYP2D6-guided opioid therapy improves pain control in CYP2D6 intermediate and poor metabolizers: a pragmatic clinical trial
Purpose
CYP2D6 bioactivates codeine and tramadol, with intermediate and poor metabolizers (IMs and PMs) expected to have impaired analgesia. This pragmatic proof-of-concept trial tested the effects of CYP2D6-guided opioid prescribing on pain control.
Methods
Participants with chronic pain (94% on an opioid) from seven clinics were enrolled into CYP2D6-guided (
n
= 235) or usual care (
n
= 135) arms using a cluster design. CYP2D6 phenotypes were assigned based on genotype and CYP2D6 inhibitor use, with recommendations for opioid prescribing made in the CYP2D6-guided arm. Pain was assessed at baseline and 3 months using PROMIS
®
measures.
Results
On stepwise multiple linear regression, the primary outcome of composite pain intensity (composite of current pain and worst and average pain in the past week) among IM/PMs initially prescribed tramadol/codeine (
n
= 45) had greater improvement in the CYP2D6-guided versus usual care arm (-1.01 ± 1.59 vs. -0.40 ± 1.20; adj
P
= 0.016); 24% of CYP2D6-guided versus 0% of usual care participants reported ≥30% (clinically meaningful) reduction in the composite outcome. In contrast, among normal metabolizers prescribed tramadol or codeine at baseline, there was no difference in the change in composite pain intensity at 3 months between CYP2D6-guided (-0.61 ± 1.39) and usual care (-0.54 ± 1.69) groups (adj
P
= 0.540).
Conclusion
These data support the potential benefits of CYP2D6-guided pain management.
Journal Article
A dinosaur a day
Dip in each day to discover a new dinosaur and enjoy sharing with friends or family. Immerse yourself in this unforgettable year-long encounter with the most astonishing creatures ever to walk the Earth. From ferocious Tyrannosaurus to gentle giant Titanosaurus. You'll find familiar and lesser-known names, alongside newly discovered species, all brought to life with illustrations and fascinating facts.
CHILDBOOK
Determining the potential clinical value of panel-based pharmacogenetic testing in patients with chronic pain or gastroesophageal reflux disease
We aimed to determine the potential value of panel-based pharmacogenetic (PGx) testing in patients with chronic pain or gastroesophageal reflux disease (GERD) who underwent single-gene PGx testing to guide opioid or proton pump inhibitor (PPI) therapy, respectively. Of 448 patients included (chronic pain, n = 337; GERD, n = 111), mean age was 57 years, 68% were female, and 73% were white. Excluding opiates for the pain cohort and PPIs for the GERD cohort, 76.6% of patients with pain and 71.2% with GERD were prescribed at least one additional medication with a high level of PGx evidence, most commonly ondansetron or selective serotonin reuptake inhibitors. The most common genes that could inform PGx drug prescribing were CYP2C19, CYP2D6, CYP2C9, and SLCO1B1. Our findings suggest that patients with chronic pain or GERD are commonly prescribed drugs with a high level of evidence for a PGx-guided approach, supporting panel-based testing in these populations.
Journal Article
Challenges and lessons learned from clinical pharmacogenetic implementation of multiple gene–drug pairs across ambulatory care settings
Purpose
Incorporating a patient’s genotype into the clinical decision-making process is one approach to precision medicine. The University of Florida (UF) Health Precision Medicine Program is a pharmacist-led multidisciplinary effort that has led the clinical implementation of six gene–drug(s) pairs to date. This study focuses on the challenges encountered and lessons learned with implementing pharmacogenetic testing for three of these:
CYP2D6
-opioids,
CYP2D6
/
CYP2C19
-selective serotonin reuptake inhibitors, and
CYP2C19
-proton pump inhibitors within six pragmatic clinical trials at UF Health and partners.
Methods
We compared common measures collected within each of the pharmacogenetic implementations as well as solicited feedback from stakeholders to identify challenges, successes, and lessons learned.
Results
We identified several challenges related to trial design and implementation, and learned valuable lessons. Most notably, case discussions are effective for prescriber education, prescribers need clear concise guidance on genotype-based actions, having genotype results available at the time of the patient–prescriber encounter helps optimize the ability to act on them, children prefer noninvasive sample collection, and study participants are willing to answer patient-reported outcomes questionnaires if they are not overly burdensome, among others.
Conclusion
The lessons learned from implementing three gene–drug pairs in ambulatory care settings will help shape future pharmacogenetic clinical trials and clinical implementations.
Journal Article
Multisite investigation of strategies for the clinical implementation of pre-emptive pharmacogenetic testing
ABSTRACT
Purpose
The increased availability of clinical pharmacogenetic (PGx) guidelines and decreasing costs for genetic testing have slowly led to increased utilization of PGx testing in clinical practice. Pre-emptive PGx testing, where testing is performed in advance of drug prescribing, is one means to ensure results are available at the time of prescribing decisions. However, the most efficient and effective methods to clinically implement this strategy remain unclear.
Methods
In this report, we compare and contrast implementation strategies for pre-emptive PGx testing by 15 early-adopter institutions. We surveyed these groups, collecting data on testing approaches, team composition, and workflow dynamics, in addition to estimated third-party reimbursement rates.
Results
We found that while pre-emptive PGx testing models varied across sites, institutions shared several commonalities, including methods to identify patients eligible for testing, involvement of a precision medicine clinical team in program leadership, and the implementation of pharmacogenes with Clinical Pharmacogenetics Implementation Consortium guidelines available. Finally, while reimbursement rate data were difficult to obtain, the data available suggested that reimbursement rates for pre-emptive PGx testing remain low.
Conclusion
These findings should inform the establishment of future implementation efforts at institutions considering a pre-emptive PGx testing program.
Journal Article
Multi-site investigation of strategies for the clinical implementation of CYP2D6 genotyping to guide drug prescribing
Purpose
A number of institutions have clinically implemented
CYP2D6
genotyping to guide drug prescribing. We compared implementation strategies of early adopters of
CYP2D6
testing, barriers faced by both early adopters and institutions in the process of implementing
CYP2D6
testing, and approaches taken to overcome these barriers.
Methods
We surveyed eight early adopters of
CYP2D6
genotyping and eight institutions in the process of adoption. Data were collected on testing approaches, return of results procedures, applications of genotype results, challenges faced, and lessons learned.
Results
Among early adopters,
CYP2D6
testing was most commonly ordered to assist with opioid and antidepressant prescribing. Key differences among programs included test ordering and genotyping approaches, result reporting, and clinical decision support. However, all sites tested for copy-number variation and nine common variants, and reported results in the medical record. Most sites provided automatic consultation and had designated personnel to assist with genotype-informed therapy recommendations. Primary challenges were related to stakeholder support,
CYP2D6
gene complexity, phenotype assignment, and sustainability.
Conclusion
There are specific challenges unique to
CYP2D6
testing given the complexity of the gene and its relevance to multiple medications. Consensus lessons learned may guide those interested in pursuing similar clinical pharmacogenetic programs.
Journal Article
Clinical implementation of rapid CYP2C19 genotyping to guide antiplatelet therapy after percutaneous coronary intervention
Background
The
CYP2C19
nonfunctional genotype reduces clopidogrel effectiveness after percutaneous coronary intervention (PCI). Following clinical implementation of
CYP2C19
genotyping at University Florida (UF) Health Shands Hospital in 2012, where genotype results are available approximately 3 days after PCI, testing was expanded to UF Health Jacksonville in 2016 utilizing a rapid genotyping approach. We describe metrics with this latter implementation.
Methods
Patients at UF Health Jacksonville undergoing left heart catheterization with intent to undergo PCI were targeted for genotyping using the Spartan RX™ system. Testing metrics and provider acceptance of testing and response to genotype results were examined, as was antiplatelet therapy over the 6 months following genotyping.
Results
In the first year, 931 patients, including 392/505 (78%) total patients undergoing PCI, were genotyped. The median genotype test turnaround time was 96 min. Genotype results were available for 388 (99%) PCI patients prior to discharge. Of 336 genotyped PCI patients alive at discharge and not enrolled in an antiplatelet therapy trial, 1/6 (17%) poor metabolizers (PMs, with two nonfunctional alleles), 38/93 (41%) intermediate metabolizers (IMs, with one nonfunctional allele), and 119/237 (50%) patients without a nonfunctional allele were prescribed clopidogrel (p = 0.110). Clopidogrel use was higher among non-ACS versus ACS patients (78.6% vs. 42.2%, p < 0.001). Six months later, among patients with follow-up data, clopidogrel was prescribed in 0/4 (0%) PMs, 33/65 (51%) IMs, and 115/182 (63%) patients without a nonfunctional allele (p = 0.008 across groups; p = 0.020 for PMs versus those without a nonfunctional allele).
Conclusion
These data demonstrate that rapid genotyping is clinically feasible at a high volume cardiac catheterization facility and allows informed chronic antiplatelet prescribing, with lower clopidogrel use in PMs at 6 months.
Trial registration
ClinicalTrials.gov Identifier: NCT02724319; registered March 31, 2016;
https://www.clinicaltrials.gov/ct2/show/NCT02724319?term=angiolillo&rank=7
Journal Article
HiFrAMes: A Framework for Hierarchical Fragmentation and Abstraction of Molecular Graphs
Recent advances in computational chemistry, machine learning, and large-scale virtual screening have rapidly expanded the accessible chemical space, increasing the need for interpretable molecular representations that capture the hierarchical topological structure of molecules. Existing formats, such as Simplified Molecular Input Line Entry System (SMILES) strings and MOL files, effectively encode molecular graphs but provide limited support for representing the multi-level structural information needed for complex downstream tasks. To address these challenges, we introduce HiFrAMes, a novel graph–theoretic hierarchical molecular fragmentation framework that decomposes molecular graphs into chemically meaningful substructures and organizes them into hierarchical scaffold representations. HiFrAMes is implemented as a four-stage pipeline consisting of leaf and ring chain extraction, ring mesh reduction, ring enumeration, and linker detection, which iteratively transforms raw molecular graphs into interpretable abstract objects. The framework decomposes molecules into chains, rings, linkers, and scaffolds while retaining global topological relationships. We apply HiFrAMes to both complex and drug-like molecules to generate molecular fragments and scaffold representations that capture structural motifs at multiple levels of abstraction. The resulting fragments are evaluated using selection criteria established in the fragment-based drug discovery literature and qualitative case studies to demonstrate their suitability for downstream computational tasks.
Journal Article