Implementation of preemptive DNA sequence-based pharmacogenomics testing across a large academic medical center: The Mayo-Baylor RIGHT 10K Study.

PURPOSE: The Mayo-Baylor RIGHT 10K Study enabled preemptive, sequence-based pharmacogenomics (PGx)-driven drug prescribing practices in routine clinical care within a large cohort. We also generated the tools and resources necessary for clinical PGx implementation and identified challenges that need to be overcome. Furthermore, we measured the frequency of both common genetic variation for which clinical guidelines already exist and rare variation that could be detected by DNA sequencing, rather than genotyping. METHODS: Targeted oligonucleotide-capture sequencing of 77 pharmacogenes was performed using DNA from 10,077 consented Mayo Clinic Biobank volunteers. The resulting predicted drug response-related phenotypes for 13 genes, including CYP2D6 and HLA, affecting 21 drug-gene pairs, were deposited preemptively in the Mayo electronic health record. RESULTS: For the 13 pharmacogenes of interest, the genomes of 79% of participants carried clinically actionable variants in 3 or more genes, and DNA sequencing identified an average of 3.3 additional conservatively predicted deleterious variants that would not have been evident using genotyping. CONCLUSION: Implementation of preemptive rather than reactive and sequence-based rather than genotype-based PGx prescribing revealed nearly universal patient applicability and required integrated institution-wide resources to fully realize individualized drug therapy and to show more efficient use of health care resources.

COVID-19 Transmission, Current Treatment, and Future Therapeutic Strategies.

At the stroke of the New Year 2020, COVID-19, a zoonotic disease that would turn into a global pandemic, was identified in the Chinese city of Wuhan. Although unique in its transmission and virulence, COVID-19 is similar to zoonotic diseases, including other SARS variants (e.g., SARS-CoV) and MERS, in exhibiting severe flu-like symptoms and acute respiratory distress. Even at the molecular level, many parallels have been identified between SARS and COVID-19 so much so that the COVID-19 virus has been named SARS-CoV-2. These similarities have provided several opportunities to treat COVID-19 patients using clinical approaches that were proven to be effective against SARS. Importantly, the identification of similarities in how SARS-CoV and SARS-CoV-2 access the host, replicate, and trigger life-threatening pathological conditions have revealed opportunities to repurpose drugs that were proven to be effective against SARS. In this article, we first provided an overview of COVID-19 etiology vis-à-vis other zoonotic diseases, particularly SARS and MERS. Then, we summarized the characteristics of droplets/aerosols emitted by COVID-19 patients and how they aid in the transmission of the virus among people. Moreover, we discussed the molecular mechanisms that enable SARS-CoV-2 to access the host and become more contagious than other betacoronaviruses such as SARS-CoV. Further, we outlined various approaches that are currently being employed to diagnose and symptomatically treat COVID-19 in the clinic. Finally, we reviewed various approaches and technologies employed to develop vaccines against COVID-19 and summarized the attempts to repurpose various classes of drugs and novel therapeutic approaches.

Temporal and spatial requirements for Nodal-induced anterior mesendoderm and mesoderm in anterior neurulation.

Zebrafish with defective Nodal signaling have a phenotype analogous to the fatal human birth defect anencephaly, which is caused by an open anterior neural tube. Previous work in our laboratory found that anterior open neural tube phenotypes in Nodal signaling mutants were caused by lack of mesendodermal/mesodermal tissues. Defects in these mutants are already apparent at neural plate stage, before the neuroepithelium starts to fold into a tube. Consistent with this, we found that the requirement for Nodal signaling maps to mid-late blastula stages. This timing correlates with the timing of prechordal plate mesendoderm and anterior mesoderm induction, suggesting these tissues act to promote neurulation. To further identify tissues important for neurulation, we took advantage of the variable phenotypes in Nodal signaling-deficient sqt mutant and Lefty1-overexpressing embryos. Statistical analysis indicated a strong, positive correlation between a closed neural tube and presence of several mesendoderm/mesoderm-derived tissues (hatching glands, cephalic paraxial mesoderm, notochord, and head muscles). However, the neural tube was closed in a subset of embryos that lacked any one of these tissues. This suggests that several types of Nodal-induced mesendodermal/mesodermal precursors are competent to promote neurulation.

The potential influence of estrogen-containing oral contraception on clozapine metabolism in a patient with known pharmacogenomic status.

Clozapine is primarily metabolized via cytochrome P450(CYP)1A2 and to a lesser extent CYP3A4, CYP2C19, and CYP2D6. Metabolic inhibitors of clozapine, such as fluvoxamine and ciprofloxacin, are important to recognize to avoid adverse drug events. Estrogen-containing oral contraceptives (eOCPs) are weaker CYP1A2 and CYP2C19 inhibitors but are associated with a 2-fold increase of clozapine concentrations. The potential for phenoconversion due to a CYP genetic polymorphism can add additional complexities when considering drug interactions. A case report is presented of a suspected interaction between newly initiated clozapine and a prescribed eOCP for which the patient's pharmacogenomic status was known. A 17-year-old, nonsmoking, White female with a history of schizophrenia was initiated on clozapine 12.5 mg at bedtime with a plan to increase by 25 mg every 4 days in the outpatient setting. The patient was a known rapid CYP1A2 metabolizer without identified sources of CYP1A2 induction and a CYP2C19 rapid metabolizer. Based on pharmacogenomic testing, there was no suspicion for significant gene-drug interactions. Yet, as the patient was prescribed an eOCP, a clozapine concentration was obtained after reaching 150 mg at bedtime. This steady-state clozapine concentration was found to be 560 ng/mL, correlating with worsening sedation and constipation. Given ongoing side effects, clozapine was lowered to 100 mg at bedtime; however, ongoing intolerance ultimately led to clozapine discontinuation. This case highlights the potential interaction between clozapine and eOCP in a CYP1A2 and CYP2C19 rapid metabolizer, leading to clozapine intolerance and discontinuation. The concomitant use of clozapine and eOCPs should be undertaken judiciously.

Most patients with disorders of gut-brain interaction receive pharmacotherapy with major or moderate drug-gene interactions.

BACKGROUND: How variations predicted by pharmacogenomic testing to alter drug metabolism and therapeutic response affect outcomes for patients with disorders of gut- brain interaction is unclear. AIMS: To assess the prevalence of pharmacogenomics-predicted drug-gene interactions and symptom outcomes for patients with disorders of gut-brain interaction. METHODS: Patients who were treated in our clinical practice for functional dyspepsia/bowel disorder underwent pharmacogenomic testing. The change in symptoms from baseline to 6 months was compared for patients with variations in CYP2D6 and CYP2C19, which metabolize neuromodulators, and SLC6A4, which encodes the sodium- dependent serotonin transporter. RESULTS: At baseline, 79 of 94 participants (84%) had at least one predicted major drug- gene interaction, and all 94 (100%) had at least one predicted moderate interaction. For the 44 participants who completed a survey of their symptoms at 6 months, the mean (SD) irritable bowel syndrome-symptom severity score decreased from 284 (71) at baseline to 231 (95) at 6 months (p < 0.001). Among patients taking selective serotonin reuptake inhibitors, the decrease in symptom severity (p = 0.03) and pain (p = 0.002) scores from baseline to 6 months was greater for patients with a homozygous SLC6A4 long/long genotype (n = 30) (ie, increased serotonin transporter activity) than for patients with homozygous short/short or heterozygous long/short genotypes (n = 64). Symptom outcomes were not affected by CYP2D6 or CYP2C19 variations. CONCLUSIONS: The homozygous SLC6A4 long/long genotype confers better symptom resolution for patients with disorders of gut-brain interaction who take selective serotonin reuptake inhibitors than do the homozygous short/short or heterozygous long/short genotypes.

Vincristine-Induced Acrocyanosis and Erythema Pernio.

INTRODUCTION: Acrocyanosis and erythema pernio are 2 dermatologic manifestations of vasospastic changes. Primary care providers should consider that these conditions can occur as primary or idiopathic conditions and as secondary conditions related to another disease or medication. Herein we describe a case of acrocyanosis and erythema pernio attributed to vincristine therapy. CASE DESCRIPTION: A 22-year-old man was evaluated for discomfort and red lesions involving the toes of both feet for several weeks. He had completed chemotherapy 1 month earlier for Ewing sarcoma in the right femur. Local control for the primary tumor included wide local excision and reconstruction with a vascularized fibular allograft from the right fibula. On examination, his right foot was dark blue and cool. Toes on both feet had nonpainful erythematous papules. After the case was discussed with the patient's oncology team, the diagnosis was medication-induced acrocyanosis of the right foot and bilateral erythema pernio. Treatment consisted of supportive care to keep the feet warm and promote circulation to the feet. At 2-week follow-up, the patient's symptoms and the appearance of his feet had markedly improved. DISCUSSION: Primary care clinicians should be able to recognize dermatologic manifestations of vasospastic changes, including acrocyanosis and erythema pernio, and rule out possible secondary causes, such as pharmacologic agents. This patient's history of therapy for Ewing sarcoma prompted consideration of medication-induced vasospastic changes most likely related to the adverse vasospastic effects of vincristine. Symptoms should improve with cessation of the offending medication.

Gabapentinoid Prescribing Practices at a Large Academic Medical Center.

Objective: To evaluate indications for gabapentinoid prescription at an academic medical center. Patients and Methods: We retrospectively reviewed patients aged 18 years or older who were prescribed gabapentinoids (gabapentin or pregabalin) during the 2019 calendar year at an academic medical center in the US Midwest. Patient demographic characteristics, indications for gabapentinoid prescription, and prescribing clinician specialities were abstracted from a random sample, and the findings were extrapolated to the overall cohort. Results: A total of 6205 prescriptions for gabapentinoids were initially identified. In the random sample of prescriptions (n=721), 89.5% were for gabapentin and 10.5% were for pregabalin. More women than men were prescribed gabapentinoids, and the mean ± SD patient age was 58.6±16.9 years. The top 5 indications for gabapentinoid prescriptions were neuropathic pain, musculoskeletal pain, restless legs syndrome, anxiety, and headache. A majority (66.7%) of prescriptions had substantial-to-modest evidence, but 29.0% of prescriptions had conflicting or insufficient evidence. Conclusion: To our knowledge, this study is one of the first to manually review clinical notes from multiple clinical specialities to ascertain indications for gabapentinoid prescriptions. Although most prescriptions had modest evidence to support their use, a high percentage of gabapentinoid prescriptions were issued for indications not supported by robust evidence. This suggests that prescribers are gravitating toward gabapentinoid use for reasons that are currently not fully understood. Clinician intent for off-label gabapentinoid prescriptions at the point of care should be further studied to understand the factors that lead to these clinical decisions.

Impact of sex on antidepressant discontinuation in groups of similar cytochrome P450 phenotypes.

Introduction: Although there are studies assessing reasons for antidepressant discontinuation, little is known about the impact of sex differences or cytochrome P450 phenotypes. Our objective is to assess discontinuation rates between males and females and whether CYP450 phenotype influences discontinuation. Methods: This is a retrospective review of patients previously enrolled in the Right Drug, Right Dose, Right Time: Using Genomic Data to Individualize Treatment database with major depressive disorder. Patients were evaluated for antidepressants trialed between January 1, 2009, and September 30, 2019. Survival analyses with competing risks were used to analyze discontinuation reasons. A Kaplan-Meier estimation method was used to assess the time to discontinuation and discontinuation rates. Analyses were also completed to assess discontinuation between men and women by phenotypic groups. All tests were two-sided, and p-values ≤ .05 were considered statistically significant. Results: There were 620 antidepressant discontinuation events discovered from 1015 antidepressant trials included. Overall, the median time to discontinuation for males was 2.6 years and 1.9 years for females (hazard ratio [HR] 0.97 [95% confidence interval (CI): 0.80, 1.19], p = .77). The risk of discontinuation was not different between males and females in any of the phenotype groups, which was consistent in the multivariable analyses. Concomitant use of medications that inhibited or induced antidepressant metabolism increased the overall risk of discontinuation (HR 1.45, 95% CI [1.06, 1.99], p = .020) in a time-dependent analysis. Discussion: We did not detect a significant difference in risk of antidepressant discontinuation rates between males and females even when accounting for cytochrome P450 phenotype. Future studies should account for whether medications that inhibit or induce antidepressant metabolism may be a crucial factor in antidepressant discontinuation.

Pharmacogenomic panel testing provides insight and enhances medication management in people with HIV.

OBJECTIVE: Our study aimed to assess the impact of pharmacogenomic panel testing in people with HIV (PWH). DESIGN: Prospective, observational intervention assessment. METHODS: One hundred PWH were provided a comprehensive pharmacogenomic panel during routine care visits within the HIV specialty clinic of a large academic medical center. The panel determined the presence of specific genetic variants that could predict response or toxicity to commonly prescribed antiretroviral therapy (ART) and non-ART medications. An HIV specialty pharmacist reviewed the results with participants and the care team. The pharmacist (1) recommended clinically actionable interventions based on the participants' current drug therapy, (2) assessed for genetic explanations for prior medication failures, adverse effects, or intolerances, and (3) advised on potential future clinically actionable care interventions based on individual genetic phenotypes. RESULTS: Ninety-six participants (median age 53 years, 74% white, 84% men, 89% viral load <50 copies/ml) completed panel testing, yielding 682 clinically relevant pharmacogenomic results (133 major, 549 mild-moderate). Ninety participants (89 on ART) completed follow-up visits with 65 (72%) receiving clinical recommendations based on current medication profiles. Of the 105 clinical recommendations, 70% advised additional monitoring for efficacy or toxicity, and 10% advised alteration of drug therapy. Panel results offered explanation for prior ART inefficacy in one participant and ART intolerance in 29%. Genetic explanation for non-ART toxicity was seen in 21% of participants, with genetic contributors to inefficacy of non-ART therapy identified in 39% of participants. CONCLUSION: Preliminary data in a small cohort of PWH demonstrates benefit of routine pharmacogenomic panel testing.

Considerations When Applying Pharmacogenomics to Your Practice.

Many practitioners who have not had pharmacogenomic education are required to apply pharmacogenomics to their practices. Although many aspects of pharmacogenomics are similar to traditional concepts of drug-drug interactions, there are some differences. We searched PubMed with the search terms pharmacogenomics and pharmacogenetics (January 1, 2005, through December 31, 2019) and selected articles that supported the application of pharmacogenomics to practice. For inclusion, we gave preference to national and international consortium guidelines for implementation of pharmacogenomics. We discuss special considerations important in the application of pharmacogenomics to assist clinicians with ordering, interpreting, and applying pharmacogenomics in their practices.

Pharmacogenomics testing in patients with liver transplant and potential impact on prospective management.

Aim: Pharmacogenomics (PGx) tests are performed on whole-blood or saliva specimens. In patients with a transplanted liver, PGx results may be discordant with hepatic drug metabolizing enzyme activity. We evaluate the incidence and impact of PGx testing in liver transplant recipients, detail potential errors and describe clinical decision support (CDS) solution implemented. Materials & methods: A retrospective cohort study of liver transplant recipients at Mayo Clinic who underwent PGx testing between 1 January 1996 and 7 October 2019 were characterized. Impact of a CDS solution was evaluated. Results: There were 129 PGx tests in 117 patients. PGx testing incidence increased before (per year incidence rate ratio = 1.45, 95% CI: 1.20-1.74, p < 0.001) and after transplant (incidence rate ratio = 1.48, 95% CI: 1.27-1.72, p < 0.001). Three erroneous PGx tests were avoided 6 months following CDS implementation. Conclusion: Incidence of PGx testing in liver transplant recipients is increasing, leading to erroneous therapeutic decisions. CDS interventions and education are needed to prevent errors.

Pharmacogenetic testing in psychiatric inpatients with polypharmacy is associated with decreased medication side effects but not via medication changes.

In psychiatric patients, medication adverse effects are regularly attributed to psychosomatic causes. However, many psychotropic medications are metabolized by cytochrome P450 (CYP450) enzymes. In the setting of polypharmacy, the activity of these enzymes may produce unfavorable drug-drug interactions (DDI) and drug-genotype interactions (DGI) that contribute to morbidity and mortality. This study sought to estimate the risk of adverse DDI and DGI in psychiatric inpatients with polypharmacy. We assessed whether medication changes made after pharmacogenetics (PGx) testing correlated with changes in side effects and overall improvement. Adult psychiatry inpatients with polypharmacy, defined as 5 or more scheduled prescription medications, completed the 24-item Antidepressant Side Effect Checklist (ASEC) questionnaire on enrollment and underwent PGx testing. Analysis of PGx results focused on whether the CYP2D6 and CYP2C19 phenotypes were "extreme," defined as poor, poor to intermediate, or ultrarapid. Approximately 30 days after PGx results were sent to outpatient providers, patients were contacted to obtain their current medication list and ASEC and Clinical Global Impression Improvement (CGI-I) scores. A total of 80 patients were enrolled, and 52 (65%) completed follow-up. ASEC scores improved from 11.5 (±8.1) to 7.2 (±6.0) (p = 0.0009). Mean CGI-I score was 2.7 (±1.4), between "minimal" to "much improved." However, linear regression revealed that these improvements were not correlated with whether medications were changed. We concluded that the impact of drug-genotype interactions in this small sample of inpatients with polypharmacy was low, and that patient improvement was related not to PGx-guided medication changes but to other treatments during hospitalization.

Integrating pharmacogenomics into the electronic health record by implementing genomic indicators.

Pharmacogenomics (PGx) clinical decision support integrated into the electronic health record (EHR) has the potential to provide relevant knowledge to clinicians to enable individualized care. However, past experience implementing PGx clinical decision support into multiple EHR platforms has identified important clinical, procedural, and technical challenges. Commercial EHRs have been widely criticized for the lack of readiness to implement precision medicine. Herein, we share our experiences and lessons learned implementing new EHR functionality charting PGx phenotypes in a unique repository, genomic indicators, instead of using the problem or allergy list. The Gen-Ind has additional features including a brief description of the clinical impact, a hyperlink to the original laboratory report, and links to additional educational resources. The automatic generation of genomic indicators from interfaced PGx test results facilitates implementation and long-term maintenance of PGx data in the EHR and can be used as criteria for synchronous and asynchronous CDS.

Prolonged survival after invasive aspergillosis: a single-institution review of 11 cases.

PURPOSE: To perform a retrospective review of the authors' experience with invasive aspergillosis (IA) in a pediatric population treated with conventional chemotherapy. Case series of IA in the pediatric oncology population are limited but generally report poor overall survival. METHODS: Medical records were reviewed of all patients receiving conventional chemotherapy for malignant disease who developed IA at Children's Hospital and Regional Medical Center, Seattle, Washington, between January 1, 1995, and January 1, 2002. RESULTS: During the study period there were 11 cases of IA in pediatric cancer patients treated with conventional chemotherapy. All patients had pulmonary IA; two also had evidence of disseminated disease. All patients underwent diagnostic tissue biopsy. Sixty-four percent required further surgery to excise bulky disease. Medical therapy varied with disease presentation and the overall clinical picture, although prolonged treatment with amphotericin B and itraconazole was the mainstay of therapy. Resolution of clinical disease was seen in 91% of patients. Seventy-three percent received further chemotherapy. The 3-year estimated survival was 82%, with a median follow-up of 32.5 months. CONCLUSIONS: Early diagnosis and aggressive intervention improve long-term survival from IA in immunocompromised pediatric oncology patients. Aggressive surgical resection, prolonged medical therapy after gross resolution of disease, and chemoprophylaxis during subsequent chemotherapy decrease the likelihood of recurrent IA despite subsequent cytotoxic therapy. The ability to proceed with intensive chemotherapy despite a history of IA may improve long-term survival.