Genomic markers associated with successful treatment of hypertension with lisinopril: A pilot study.

OBJECTIVE: To identify single nucleotide variants (SNVs) associated with lisinopril effectiveness. MATERIALS AND METHODS: This was an observational study using a candidate gene approach to examine SNVs associated with lisinopril effectiveness. Drug effectiveness was defined as 10% decrease in systolic blood pressure at 1 week follow-up. We used the Illumina GWAS MEGA chip to examine variants in the renin/angiotensin pathway that may be associated with drug effectiveness. RESULTS: 61 subjects were enrolled, and 33 (54.1%) were responsive to lisinopril therapy. SNVs in AGT (p = 0.0141), REN (p = 0.0192), and ACE2 (p = 0.0002) were found to be associated with successful treatment on lisinopril. Conclusion and relevance: SNVs in the renin and angiotensin pathway are associated with lisinopril effectiveness in a pilot cohort of patients with uncontrolled hypertension.

Acute Illness Associated With Cannabis Use, by Route of Exposure: An Observational Study.

Background: Little is known about the relative harms of edible and inhalable cannabis products. Objective: To describe and compare adult emergency department (ED) visits related to edible and inhaled cannabis exposure. Design: Chart review of ED visits between 1 January 2012 and 31 December 2016. Setting: A large urban academic hospital in Colorado. Participants: Adults with ED visits with a cannabis-related International Classification of Diseases, Ninth or 10th Revision, Clinical Modification (ICD-9-CM or ICD-10-CM), code. Measurements: Patient demographic characteristics, route of exposure, dose, symptoms, length of stay, disposition, discharge diagnoses, and attribution of visit to cannabis. Results: There were 9973 visits with an ICD-9-CM or ICD-10-CM code for cannabis use. Of these, 2567 (25.7%) visits were at least partially attributable to cannabis, and 238 of those (9.3%) were related to edible cannabis. Visits attributable to inhaled cannabis were more likely to be for cannabinoid hyperemesis syndrome (18.0% vs. 8.4%), and visits attributable to edible cannabis were more likely to be due to acute psychiatric symptoms (18.0% vs. 10.9%), intoxication (48% vs. 28%), and cardiovascular symptoms (8.0% vs. 3.1%). Edible products accounted for 10.7% of cannabis-attributable visits between 2014 and 2016 but represented only 0.32% of total cannabis sales in Colorado (in kilograms of tetrahydrocannabinol) during that period. Limitation: Retrospective study design, single academic center, self-reported exposure data, and limited availability of dose data. Conclusion: Visits attributable to inhaled cannabis are more frequent than those attributable to edible cannabis, although the latter is associated with more acute psychiatric visits and more ED visits than expected. Primary Funding Source: Colorado Department of Public Health and Environment.

Predicting response to lisinopril in treating hypertension: a pilot study.

INTRODUCTION: Only ~ 50% of hypertensive patients will respond to treatment. OBJECTIVE: This pilot study aims to identify clinical and metabolite markers that predict response to lisinopril. METHODS: Hypertensive patients (n = 45) received lisinopril (10 mg) at their baseline visit. Blood pressures were reevaluated one week later. Responders to lisinopril (n = 19) were defined by a 10% decline in systolic blood pressure. Plasma metabolites were evaluated with mass spectrometry. RESULTS: BMI (p = 0.009), GFR (p = 0.015) and 2-oxoglutarate were included in a logistic regression model to predict response to lisinopril. CONCLUSIONS: Further validation cohorts are needed to confirm the predictive values of these clinical and metabolic markers.

Characteristics of Emergency Medicine Specimen Bank Participants Compared to the Overall Emergency Department Population.

INTRODUCTION: Biorepositories lack diversity both demographically and with regard to the clinical complaints of patients enrolled. The Emergency Medicine Specimen Bank (EMSB) seeks to enroll a diverse cohort of patients for discovery research in acute care conditions. Our objective in this study was to determine the differences in demographics and clinical complaints between participants in the EMSB and the overall emergency department (ED) population. METHODS: This was a retrospective analysis of participants of the EMSB and the entire UCHealth at University of Colorado Anschutz Medical Center (UCHealth AMC) ED population across three periods: peri-EMSB; post-EMSB; and COVID-19. We compared patients consented to the EMSB to the entire ED population to determine differences in age, gender, ethnicity, race, clinical complaints, and severity of illness. We used chi-square tests to compare categorical variables and the Elixhauser Comorbidity Index to determine differences in the severity of illness between the groups. RESULTS: Between February 5, 2018-January 29, 2022, there were 141,670 consented encounters in the EMSB, representing 40,740 unique patients and over 13,000 blood samples collected. In that same time, the ED saw approximately 188,402 unique patients for 387,590 encounters. The EMSB had significantly higher rates of participation from the following: patients 18-59 years old (80.3% vs 77.7%); White patients (52.3% vs 47.8%), and women (54.8% vs 51.1%) compared to the overall ED population. The EMSB had lower rates of participation from patients ≥70 years, Hispanic patients, Asian patients, and men. The EMSB population had higher mean comorbidity scores. During the six months after Colorado's first COVID-19 case, the rate of consented patients and samples collected increased. The odds of consent during the COVID-19 study period were 1.32 (95% CI 1.26-1.39), and the odds of sample capture were 2.19 (95% CI 2.0-2.41). CONCLUSION: The EMSB is representative of the overall ED population for most demographics and clinical complaints.

Accessing and utilizing clinical and genomic data from an electronic health record data warehouse.

Electronic health records (EHRs) and linked biobanks have tremendous potential to advance biomedical research and ultimately improve the health of future generations. Repurposing EHR data for research is not without challenges, however. In this paper, we describe the processes and considerations necessary to successfully access and utilize a data warehouse for research. Although imperfect, data warehouses are a powerful tool for harnessing a large amount of data to phenotype disease. They will have increasing relevance and applications in clinical research with growing sophistication in processes for EHR data abstraction, biobank integration, and cross-institutional linkage.

Metabolomic Evaluation of N-Acetyl-p-Benzoquinone Imine Protein Adduct Formation with Therapeutic Acetaminophen Administration: Sex-based Physiologic Differences.

BACKGROUND: Acetaminophen (APAP)-associated transaminase elevation, induced by N-acetyl-p-benzoquinone imine (NAPQI) protein adduction, remains an area of research interest. Distinct from known genetic, physiologic, and dosage associations dictating severity of hepatic injury, no known factors predict an absence of protein adduct formation at therapeutic APAP dosing. HYPOTHESIS: Sex-based physiology is predictive of APAP-induced protein adduct formation and differential metabolite expression at therapeutic doses. METHODS: This retrospective study interrogated serum samples collected for a prior study investigating fluctuations of alanine aminotransferase (ALT) over time with 4G daily APAP dosing for ≥ 16 days in subjects from Denver, Colorado. Subjects were grouped by adduct formation (n = 184) vs no adducts (n = 20). Samples were run on ultra-high-performance liquid chromatography mass spectrometry from study days 0, 7, 16, and 31. Significant metabolite expressions were identified using t-tests with false discovery rate correction (FDR), partial least squares discriminant, and ANOVA simultaneous comparison analyses. Demographic and clinical data were explored using t-tests with FDR (age, weight, BMI, ALT) and Chi-square (sex, ethnicity, race) analyses. RESULTS: In pre-treatment samples, relative quantitation caprylic acid was expressed ninefold higher and 6-carboxyhexanoate was expressed threefold lower in subjects who did not develop adducts. Lactate had greater expression in the no adducts group (p = 0.001). Using absolute quantitation, glutathione was expressed 2.6-fold greater among no adduct subjects. Odds of males developing NAPQI protein adducts at therapeutic APAP dosing were 5.91 times lower than females (95% CI = 2.3-14.9; p = 0.0001). CONCLUSION: Multiple metabolites were differentially expressed based on adduct group and sex. Metabolites were identified unique to adduct development independent of sex. At therapeutic APAP dosing, males were less likely to develop APAP protein adducts. Further research into lipid biosynthesis and metabolism may provide further insight into physiology associated with adduct production.

Block by block: Building on our knowledge to better care for LGBTQIA+ patients.

Background: Emergency physicians need to recognize the diversity of identities held by sexual and gender minorities, as well as the health implications and inequities experienced by these communities. Identities such as lesbian, gay, bisexual, transgender, queer, questioning, intersex, asexual, aromantic, and many others fall under the LGBTQIA+ acronym. This wide spectrum is seldom discussed in emergency medicine but nonetheless impacts both patient care and patient experience in acute and critical care settings. Aims: This commentary aims to provide a brief but nonexhaustive review of LGBTQIA+ identities and supply a critical framework for applying this understanding to patient encounters in the emergency department, as well as describe the challenges and educational aims at the level of medical school, residency, and postresidency. Materials and Methods: The commonly used and widely accepted definitions of LGBTQIA+ terms are described, as well as implications for patient care and emergency physician education. The authors of this writing group represent the Society for Academic Emergency Medicine, LGBTQ Task Force of the Academy of Diversity Inclusion in Medicine. Results: LGB terms are addressed, with LGBTQIA+ adding "intersex," "asexual," and "+," to include other gender identities and sexual orientations which are not already included. This paper also addresses the terms "transition," "nonbinary," "polyamorous." "two-spirit," "queer," and others. These acronyms and terms continually expand and evolve in the pursuit of inclusivity. Additionally, with some health issues potentially related to medications, hormones, surgery, or to internal or external genitalia, important EM physician tools include gathering an "organ inventory," asking about sexual history, and conducting a physical exam. Discussion: Most persons have congruent biological sex, gender identity, and attraction to the "opposite" gender. However, humans can have every imaginable variation and configuration of chromosomes, genitalia, gender identities, sexual attractions, and sexual behaviors. Terms and definitions are constantly changing and adapting; they may also vary by local culture. Obtaining relevant medical history, conducting an "organ inventory," asking about sexual history in a nonjudgmental way, and conducting a physical exam when warranted can all be important in delivering best possible medical care. Although there has been increased focus on education at the medical school, residency, and faculty level on LGBTQIA+ patient care in the ED, much work remains to be done. Conclusion: Emergency physicians should feel confident in providing a model of care that affirms the sexual and gender identities of all the patient populations we serve. Optimal patient-centric care requires a deeper understanding of the patient's biology, gender identity, and sexual behavior encapsulated into the ever-growing acronym LGBTQIA+.

Emergency care of LGBTQIA+ patients requires more than understanding the acronym.

Emergency physicians (EPs) frequently deliver care to members of the LGBTQIA+ community in the emergency department. This community suffers from many health disparities important to understand as part of comprehensive care, and these disparities are infrequently discussed in emergency medicine education. Previous data also suggest a need for broader education to increase the comfort of EPs caring for LGBTQIA+ patients. A group of content experts identified key disparities, opportunities for expanded education, and strategies for more inclusive care of LGBTQIA+ patients.

Metabolomic markers predictive of hepatic adaptation to therapeutic dosing of acetaminophen.

BACKGROUND: Drug induced liver injury (DILI) remains a prominent global issue and acetaminophen (APAP) overdose represents a common cause of hepatic injury and DILI. Transient alanine aminotransferase (ALT) elevations have been documented while adhering to recommended daily dosing. However, no metabolites have been identified in pre-treatment samples predicting which patients will develop these transient increases. METHODS: This was a secondary analysis of samples collected from a parent study describing the course of ALT levels in subjects receiving therapeutic APAP dosing. Two hundred and four subjects recruited from Denver, Colorado received 4 g APAP/daily for at least 16 days. Subjects were grouped by ALT at any monitored time point above 60 units/L (n = 25) vs. no increase (n = 179). Serum samples from days 0, 7, 16, and 31 were run on ultra-high performance liquid chromatography mass spectrometry. We report the metabolomic results of samples analyzed prior to APAP administration and over time. Significant changes in metabolite and demographic variable expressions were explored using t-tests with false discovery rate correction, chi square, and partial least squares discriminant analyses. RESULTS: Within pre-treatment day 0 samples, allantoate and ornithine were significantly elevated in subjects of the ALT elevation group (p = .032). Baseline ALT (p = .011) and alkaline phosphatase (p = .006) were also significant. These metabolites were significant independent of race, ethnicity, gender, or BMI. CONCLUSIONS: Allantoate and ornithine are directly involved in pathways related to nitrogen release and urea production. Further investigation into alterations in the glutathione metabolism and urea cycle pathways may lead to a greater understanding of the mechanisms associated with hepatic adaptation for a variety of pharmaceuticals.

The Genomics of Elevated ALT and Adducts in Therapeutic Acetaminophen Treatment: a Pilot Study.

INTRODUCTION: Therapeutic acetaminophen (APAP) ingestion causes asymptomatic drug-induced liver injury in some patients. In most cases, elevations in alanine aminotransferase (ALT) are transient and return to the normal range, even with continued APAP ingestion, though ALT elevation persists in some patients unpredictably. The etiology of this liver injury or adaption is unclear. Our objective was to identify new pharmacogenomic variants associated with elevated ALT or elevated protein adduct concentrations in patients receiving therapeutic acetaminophen. METHODS: We performed genome-wide sequencing analysis on eight patients using leftover blood samples from an observational study that administered four grams of acetaminophen for up to 16 days to all patients. Two patients with ALT elevations > two times the upper limit of normal, two patients with no adduct formation, and four control patients were sequenced. The genomes were aligned with the GRCh38 reference sequence, and variants with predicted low, moderate, or high impact on the subsequent proteins were first manually curated for biologic plausibility, then organized and examined in the REACTOME pathway analysis program. RESULTS: We found 394 variants in 107 genes associated with elevated ALT. Variants associated with ALT elevation predominantly involved genes in the immune system (MHC class II complex genes), endoplasmic reticulum stress response (SEC23B and XBP1), oxidative phosphorylation (NDUFB9), and WNT/beta-catenin signaling (FZD5). Variants associated with elevated adducts were primarily in signal transduction (MUC20) and DNA repair mechanisms (P53). CONCLUSIONS: While underpowered, genetic variants in immune system genes may be associated with drug-induced liver injury at therapeutic doses of acetaminophen.

The Emergency Medicine Specimen Bank: An Innovative Approach To Biobanking In Acute Care.

The Emergency Medicine Specimen Bank (EMSB) was developed to facilitate precision medicine in acute care. The EMSB is a biorepository of clinical health data and biospecimens collected from all adult English- or Spanish-speaking individuals who are able and willing to provide consent and are treated at the UCHealth-University of Colorado Hospital Emergency Department. The EMSB is the first acute care biobank that seeks to enroll all patients, with all conditions who present to the ED. Acute care biobanking presents many challenges that are unique to acute care settings such as providing informed consent in a uniquely stressful and fast-paced environment and collecting, processing, and storing samples for tens of thousands of patients per year. Here, we describe the process by which the EMSB overcame these challenges and was integrated into clinical workflow allowing for operation 24 hours a day, 7 days a week at a reasonable cost. Other institutions can implement this template, further increasing the power of biobanking research to inform treatment strategies and interventions for common and uncommon phenotypes in acute care settings.