Metabolic Panel Research Articles

Utility of hydroxychloroquine laboratory monitoring in dermatologic and rheumatologic patients

Hydroxychloroquine (HCQ) is an immunomodulator used in dermatology and rheumatology. Side effects may be observed on routine monitoring studies before they become clinically apparent. The goal of this retrospective chart review was to assess laboratory abnormalities in dermatologic and rheumatologic patients taking HCQ. Medical records of patients prescribed HCQ were retrospectively reviewed. Demographics, reported side effects, and parameters on baseline and follow-up complete blood count (CBC) and comprehensive metabolic panel (CMP) were recorded and graded. Laboratory abnormalities were considered severe if they were grade 3 or greater according to Common Terminology Criteria for Adverse Events v3.0 and persistent if they continued beyond subsequent laboratory testing. Of 646 eligible charts, 289 had monitoring studies for review. There were 35 severe (grade 3 or 4, 35/289; 12%) adverse events that developed, as noted on CBC or CMP. Of these 35 severe adverse events, 25 self-corrected on subsequent testing, and 10 (10/289, 3%) across 9 patients were persistent, including glomerular filtration rate, alanine transferase, alkaline phosphatase, glucose, hemoglobin and lymphopenia abnormalities. Of these 10 abnormalities, 7/10 (70%) were unlikely due to hydroxychloroquine use according to the calculated Naranjo score for each patient. Severe laboratory abnormalities while taking hydroxychloroquine are rare, even in a population with a high rate of comorbidities. Among the abnormalities observed, the majority of them (70%) were likely due to disease progression or a medication other than hydroxychloroquine. CBC and CMP monitoring for the reason of observing abnormalities while on HCQ should be at the discretion of the prescribing physician.

Tennessee hospital noncompliance with price transparency legislation for 8 common laboratory tests.

The goal of this study was to assess hospital compliance with federal price transparency mandates and barriers to pricing information in Tennessee. All hospitals websites were queried for gross, cash, and BlueCross BlueShield of Tennessee prices for 8 high-frequency laboratory tests in 2 Centers for Medicare & Medicaid Services-mandated pricing sources: (1) a machine-readable file of all available services and (2) a consumer-friendly display of 300 shoppable services. Barriers, including click counts, data availability, and intrahospital price discrepancies, were noted. Of the 145 Tennessee hospitals assessed, 97.2% were noncompliant with the Centers for Medicare & Medicaid Services final rule. Subanalysis of available machine-readable files, price estimators, and shoppable services files demonstrated 49.6%, 95.1%, and 78.6% noncompliance, respectively. Barriers to pricing information included requiring protected health information (55.9%), missing at least 1 pricing source (7.6%), having no pricing sources available (6.2%), and involving more than 3 clicks to access the cash price in machine-readable files (54.1%) and price estimators (68.6%.) Average intrahospital discrepancy for basic metabolic panel cash prices across pricing sources was $101.30 (range, $0-1012.40). Our study showed high levels of noncompliance with price transparency laws, inconsistent and inaccessible pricing, and continued challenges facing patients in Tennessee.

Serum biomarker signature is predictive of the risk of hepatocellular cancer in patients with cirrhosis

BackgroundInflammatory and metabolic biomarkers have been associated with hepatocellular cancer (HCC) risk in phases I and II biomarker studies. We developed and internally validated a robust metabolic biomarker panel predictive...

PSIII-13 Putative metabolites for sow lifetime opportunity and production traits

Abstract Identifying females with favorable lifetime born alive (opportunity) and weaned (wn; production) traits requires extended observation. Estimate of lifetime (4 parities) difference in the economic margin over genetic cost between a high producing female (48 pigs weaned; wn) and a low producing female (31 wn) is approximately $1,000. Determining metabolic compounds present from females with favorable or unfavorable longevity traits may provide profiles that could be assessed in younger females prior to entry within the breeding system to indicate their potential productivity. Females within the USMARC breeding system were retained through four parities then harvested between 12 to 15 d following their post-weaning estrus. Liver, skeletal muscle, and subcutaneous adipose tissues were collected and stored at -80° C for later analyses. Females were categorically identified by the level of opportunity (born alive; ba) and production (wn) over their lifetime. Females with consistent opportunity and production traits at each parity were categorized as high (H; 61 ba), medium (M; 50 ba), or low (L; 39 ba) opportunity and H (50 wn), M (42 wn), or L (34 wn) production resulting in six categories (HH, HL, MH, ML, LH, LL). Tissue extracts were subjected to positive mode UPLC-MS and numerous features were detected. Using Progenesis Q software features were annotated and those with a fold-change ≥ 2.0 and P < 0.05 by category were then tested using a mixed model in SAS to determine LS Mean differences of raw abundances among the six categories. Of those compounds tested in SAS, a significance threshold was set at P < 0.01 as a false discovery adjustment. Within liver 877 compounds were analyzed with 152 yielding a significant (P < 0.01) categorical effect. Of those, 43 compounds predominantly identified either HH or LL from other categories. Within skeletal muscle 359 compounds were subjected to mixed models, 221 compounds had significance for a category effect, and 105 compounds were predominantly different for HH or LL from all other categories. Within adipose tissue, 406 compounds were submitted to mixed model testing, 186 compounds had a categorical effect with 44 compounds predominantly different for HH or LL categories. Annotation of these compounds suggest differences in metabolites associated with, but not limited to, bacteria by-products (pradmicin, adifolin, lactobacillic acid), alkyloids, sapogenins, amino acids (lysine, tyrosine), minerals (calcium, copper), lipids (sphingomyelin), and fatty acids (mono-, di-, tri-acylglycerol). Future confirmation and evaluation of these metabolites in young pre-breeding females will need to be done. Establishing a metabolic profile panel that could discern young pre-breeding gilts with a likelihood of becoming a LL female will improve economic productivity and animal welfare concerns.

Abstract PO3-06-12: Targeting Fatty Acid Synthase in Brain Metastatic Triple-negative Breast Cancer

Abstract Introduction: Treating triple-negative breast cancer (TNBC) is challenging due to the lack of clearly defined and targetable biomarkers, and treatment options become increasingly limited with TNBC brain metastases (BM). Since the brain microenvironment has relatively low lipid availability, breast cancer cells that colonize the brain increase their reliance on the endogenous biosynthesis of fatty acids. This reveals a potential metabolic vulnerability that can be targeted, and fatty acid synthase (FASN) inhibition has been shown to decrease breast cancer cell invasion in preclinical models. Methods: In our study, we utilized the TNBC cell line MDA-MB-231-Luc/GFP, its brain-seeking subclone, MDA-MB-231-BR-GFP, and two novel cell lines generated from patient-derived organoids obtained from serial collection of brain-metastatic TNBC resections from the same patient, denoted PDO-BC25 and PDO-BC25-2. Cell lines were screened with FASN inhibitors as single agents vs. combined with SN-38 (topoisomerase I inhibitor) and synergy was assessed by the Chou-Talalay method. To characterize signaling changes with FASN inhibition and identify any off-target signaling, we used a Nanostring metabolic pathways nCounter panel to perform differential expression analysis on cells treated with the FASN inhibitor, TVB-2640, vs. vehicle control across the four cell lines. This panel detects the expression of 768 metabolism-related genes. We used 4 biological replicates per sample and the Benjamini-Hochberg statistical method to control for the false discovery rate after performing a t-test to calculate P-values. In addition, we performed spheroid outgrowth assays to identify any phenotypic impacts of FASN inhibition on spheroid outgrowth. Results: Combinatory drug screening between FASN inhibitors and SN-38 revealed synergy in MDA-MB-231-BR-GFP, PDO-BC25, and PDO-BC25-2, but not in the parental MDA-MB-231-Luc/GFP. The Nanostring nCounter metabolic pathways panel identified direct target engagement where FASN, SCD, and the transcription factor SREBP1 were significantly upregulated in the cells treated with TVB-2640 compared to vehicle control (P-adjusted < 0.05). Other upregulated genes were related to the pentose phosphate pathway, nucleotide salvage and synthesis, reactive oxygen species response, amino acid synthesis and transport, and autophagy. Genes that were down-regulated are involved in cell cycle progression, deoxynucleotide synthesis, DNA damage repair, fatty acid oxidation, and cytokine and chemokine signaling. Moreover, despite no decrease in cell viability, TVB-2640 alone was able to slow the outgrowth and invasion of Matrigel-embedded spheroids in a spheroid outgrowth assay. Conclusions: In our study, we have shown that the combination of SN-38 and FASN inhibitors is synergistic in the TNBC brain-seeking cell lines, and that FASN inhibition alone causes on-target transcriptome-level changes and a decrease in spheroid invasion. Next, we plan on testing the brain-metastatic potential of these cell lines in the presence and absence of a FASN inhibitor using an organ-on-chip microfluidic device developed by our lab that mimics the blood-brain barrier, to identify if this strategy has a potential role in prevention of brain metastases. Further studies to refine the molecular basis of the mechanism of action of the combination are underway. Citation Format: Habib Serhan, Liwei Bao, Xu Cheng, Matthew Soellner, Sofia Merajver, Aki Morikawa, Nathan Merrill. Targeting Fatty Acid Synthase in Brain Metastatic Triple-negative Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-06-12.

Metabolic syndrome reduces cerebral blood flow more in women than men

One in three adults in the United States suffers from metabolic syndrome (MetSyn), a state of insulin resistance associated with reduced cerebral blood flow (CBF) and increased risk of stroke and neurologic diseases. Notably, females are at greater risk for cardiovascular and metabolic complications derived from insulin resistance. Still, it remains unclear whether the reduction in CBF seen in MetSyn is sex-specific or uniform between various brain regions. Additionally, fasting triglyceride (TG) levels are stronger predictors of cognitive disease in females than in males. However, little data exist examining the relationship between TG and CBF in females with MetSyn. Therefore, we aimed to examine the interaction between sex and MetSyn on global and regional CBF in young adults and to explore the relationship between fasting TG levels and CBF. We predict that males and females with MetSyn will have lower global and regional CBF compared to healthy controls of the same sex, but to a greater extent in females with MetSyn. Additionally, we predict fasting TG levels will have stronger relationships with CBF in females than in males with MetSyn. Twenty-five healthy controls (CON; 7 females; 24 ± 4 y) and 13 individuals with MetSyn (5 females; 27 ± 8 y) completed this study. Subjects were unmedicated, and females were studied on days 1-5 of their menstrual cycle. A metabolic panel, blood pressure, and waist circumference were collected in a fasted state. Magnetic resonance imaging (MRI, 3 Tesla) with arterial spin labeling was used to quantify global and regional CBF. Two-way (Group x Sex) linear models with Shaffer’s correction and Tukey adjusted post hocs were used to determine differences in CBF. In the MetSyn groups, Pearson correlation coeffcients were assessed between fasting TG levels and each global and regional CBF value. Global CBF was greater in female CON compared to all groups (p ≤ 0.01), and male CON had greater CBF than male MetSyn (p = 0.03), whereas there was no difference between male and female MetSyn (p = 0.43). Regional analyses resulted in the same pattern of between-group differences in the parietal lobe (p = 0.03), the precuneus (p = 0.01), and the frontal lobe (p = 0.01), outside of a nonsignificant difference between male CON and male MetSyn in the frontal lobe (p = 0.12). No interactions existed for the temporal lobe, occipital lobe, or thalamus (p ≥ 0.06). In females with MetSyn, fasting TG levels were moderately negatively correlated with CBF (r = -0.65), whereas a moderate positive relationship existed in males with MetSyn (r = 0.71). These data suggest that MetSyn reduces CBF to a greater extent in females than males, abolishing sex-dependent differences in CBF present in healthy young adults. While female sex is protective against cardiovascular disease in healthy young adults, this is not the case in individuals with MetSyn. Additionally, males and females with MetSyn had opposing relationships between fasting TG levels and CBF. These findings may help explain the greater cardiovascular risk in females with insulin resistance. American Diabetes Association (ADA1-16-ICTS-099 and ADA 1-12-IN-39); Clinical and Translational Science Award program (UL1TR002373); Wisconsin National Primate Research Center (P51OD011106). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Abstract 3047: Extracellular Vesicles Produced By IL4-polarized Human Macrophages Suppress Atherosclerosis By Reprograming Ly6c hi Monocytes

Introduction: Extracellular vesicles (EVs) produced by IL4-polarized macrophages (Mφ) suppress inflammation by communicating microRNA-controlled immunometabolic signaling to recipient immune cells and adipocytes. However, detailed cellular and molecular pathways responsible for these effects remain incompletely understood. Objectives: Examine transcriptional responses sensitive to IL4-polarized Mφ EVs among circulating Ly6C hi monocytes derived from mice with hyperlipidemia. Methods/Approach: EVs were produced by culturing THP1 macrophages with human IL4, and purified using cushioned-density gradient ultracentrifugation. Twenty-week old male LDL-receptor deficient mice fed high-fat diet for 16 weeks were treated to a 6-week course of 3-weekly intraperitoneal infusions of 10e 10 THP1-IL4 EVs or sham. Circulating Ly6C hi monocytes were collected using a cell sorter and RNA was examined using nanoString nCounter inflammatory and metabolic pathway panels. Plasma cytokines were detected with a V-Plex MesoScale assay, while atherosclerosis was assessed by detecting myeloid cell subsets in enzymatically-digested aortae and oil red O positive lesions in the aortic root. Results: THP1-IL4 EVs caused profound transcriptional reprogramming among Ly6C hi monocytes, resulting in reduced signaling pathways controlled by MAPK, PI3K, TLR and inflammasomes. We identified reduced levels of Casp-1, Nlrp1a, as well as Aim2, all recognized to drive atherosclerosis including in JAK2 vf clonal hematopoiesis. Furthermore, THP1-IL4 EVs upregulated metabolic pathways involved in arginine metabolism, IDH1/2 activity, redox stress control, nucleotide salvage, fatty acid oxidation and mitochondrial respiration. In contrast they reduced pathways involved in glucose transport, hypoxia, KEAP-NRF2 pathway and tryptophan metabolism. Control of these pathways in Ly6C hi monocytes contributed to reduced levels of IL-1β, IL-6, IFNγ and TNFα in plasma, as well as CD45 + aortic myeloid cells and oil red O positive aortic lesions. Conclusions: IL4-polarized Mφ EVs suppress atherosclerosis by communicating profound transcriptional reprogramming to Ly6C hi monocytes. Ongoing studies examine their capacity to drive atherosclerosis regression.

Continuous Glucose Monitoring Using the Dexcom G6 in Cardiac Surgery During the Postoperative Period

ObjectiveCardiac surgery is associated with hyperglycemia, which in turn is associated with adverse postsurgical outcomes such as wound infections, acute renal failure, and mortality. This pilot study seeks to determine if Dexcom G6Pro continuous glucose monitor (Dexcom G6Pro CGM) is accurate during the postoperative cardiac surgery period when fluid shifts, systemic inflammatory response syndrome, and vasoactive medications are frequently encountered, compared to standard glucose monitoring techniques. MethodsThis study received institutional review board approval. In this prospective study, correlation between clinical and Dexcom glucose readings was evaluated. Clinical glucose (blood gas, metabolic panel, and point of care) data set included 1428 readings from 29 patients, while the Dexcom G6Pro CGM data included 45 645 data points following placement to upper arm. Additionally, average clinical measurements of day and overnight temperatures and hemodynamics were evaluated.Clinical and Dexcom data were restricted to being at least 1 hour after prior clinical reading Matching Dexcom G6Pro CGM data were required within 5 minutes of clinical measure. Data included only if taken at least 2 hours after Dexcom G6Pro CGM insertion (warm-up time) and analyzed only following intensive care unit (ICU) admission. Finally, a data set excluding the first 24 hours after ICU admission was created to explore stability of the device. Patients remained on Dexcom G6Pro CGM until discharge or 10 days postoperatively. ResultsThe population was 71% male, 14% with known diabetes; 66% required intravenous insulin infusion. The Clarke error grid plot of all measures post-ICU admission showed 53.5% in zone A, 45.9% in zone B, and 0.6% (n = 5) in zones D or E. The restricted dataset that excluded the first 24 hours post-ICU admission showed 55.9% in zone A, 43.9% in zone B, and 0.2% in zone D. Mean absolute relative difference between clinical and Dexcom G6Pro CGM measures was 20.6% and 21.6% in the entire post-ICU admission data set, and the data set excluding the first 24 hours after ICU admission, respectively. In the subanalysis of the 12 patients who did not have more than a 5-minute tap in the operating room, a consensus error grid, demonstrated that after ICU admission, percentage in zone A was 53.9%, zone B 45.4%, and zone C 0.7%. Similar percentages were obtained removing the first 24 hours post-ICU admission. These numbers are very similar to the entire cohort.A consensus error grid created post-ICU admission demonstrated: (zone A) 54%, (zone B) 45%, (zone C) 0.9%, and the following for the dataset created excluding the first 24 hours: (zone A) 56%, (zone B) 44%, (zone C) 0.4%, which demonstrated very close agreement with the original Clarke error grid. No adverse events were reported. ConclusionsAlmost 100% of Dexcom G6Pro CGM and clinical data matching points fell within areas considered as giving clinically correct decisions (zone A) and clinically uncritical decisions (zone B). However, the relatively high mean absolute relative difference precludes its use for both monitoring and treatment in the clinical context. As technology evolves, interstitial glucose monitoring may become an important tool to limit iatrogenic anemia and mitigate glycemic fluctuations.

Diagnostic utility of capnography in emergency department triage for screening acidemia: a pilot study

BackgroundCapnography is a quantitative and reliable method of determining the ventilatory status of patients. We describe the test characteristics of capnography obtained during Emergency Department triage for screening acidemia.ResultsWe performed an observational, pilot study of adult patients presenting to Emergency Department (ED) triage. The primary outcome was acidemia, as determined by the basic metabolic panel and/or blood gas during the ED visit. Secondary outcomes include comparison of estimated and measured respiratory rates (RR), relationships between end-tidal CO2 (EtCO2) and venous partial pressure of CO2, admission disposition, in-hospital mortality during admission, and capnogram waveform analysis. A total of 100 adult ED encounters were included in the study and acidemia (\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$ \\left[HC{O}_{3}^{-}\\right]\\le 22 \ ext{mEq/L}$$\\end{document} or \\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$ pH< 7.35$$\\end{document}) was identified in 28 patients. The measured respiratory rate (20.3 ± 6.4 breaths/min) was significantly different from the estimated rate (18.4 ± 1.6 breaths/min), and its area under the receiver operating curve (c-statistic) to predict acidemia was only 0.60 (95% CI 0.51–0.75, p = 0.03). A low end-tidal CO2 (EtCO2 < 32 mmHg) had positive (LR+) and negative (LR−) likelihood ratios of 4.68 (95% CI 2.59–8.45) and 0.34 (95% CI 0.19–0.61) for acidemia, respectively—corresponding to sensitivity 71.4% (95% CI 51.3–86.8) and specificity 84.7% (95% CI 74.3–92.1). The c-statistic for EtCO2 was 0.849 (95% CI 0.76–0.94, p = 0.00). Waveform analysis further revealed characteristically abnormal capnograms that were associated with underlying pathophysiology.ConclusionsCapnography is a quantitative method of screening acidemia in patients and can be implemented feasibly in Emergency Department triage as an adjunct to vital signs. While it was shown to have only modest ability to predict acidemia, triage capnography has wide generalizability to screen other life-threatening disease processes such as sepsis or can serve as an early indicator of clinical deterioration.

522 Testosterone Supplementation in Patients with Burn Hypermetabolism

Abstract Introduction After major burn injuries, patients experience a hypermetabolic response that leads to hyperdynamic circulatory, physiologic, catabolic, and immune system responses. Many transdisciplinary approaches have been tested to mitigate this postburn hypermetabolic syndrome such as comprehensive burn rehabilitation, nutritional support, monitoring, and pharmacological interventions. Oxandrolone, a synthetic analog of testosterone, has been shown to have higher anabolic properties and minimal androgenic effects and studied intensely in burn care. In 2023, the FDA asked all manufacturers of oxandrolone to cease production and subsequently removed the drug from market on June 28, 2023. Our study examines the cost and operationalization of an intramuscular (IM) testosterone protocol as an alternative in male burn patients with ≥20% total body surface area (TBSA). Methods A cost analysis was conducted using the National Drug Codes (NDC) and commercially available benchmarking data. The cost of oxandrolone and testosterone were included in our analysis. Following a thorough literature review, a protocol was developed for adult male patients with &amp;gt;20% TBSA burn injuries. Patients undergoing gender affirming hormone therapy, untreated obstructive sleep apnea, or hormonal blockers for cancer were excluded from the protocol. Results The protocol begins with total serum testosterone levels at the time of admission and weekly thereafter for male patients with ≥20% TBSA injury. Once a testosterone level &amp;lt; 150 ng/dL is detected, supplementation of testosterone with 200 mg IM once weekly for two weeks is started. Weekly evaluations include total body weight, metabolic panels, and nutritional panels. Cost comparison between oxandrolone and testosterone show an equivalent unit cost of $8.62 versus $8.38, respectively. Conclusions Drug shortages and supply chain challenges are becoming more common in burn care. We hypothesize testosterone to be both a clinically effective and cost-effective alternative to oxandrolone in the setting of burn hypermetabolism in male patients with major burns. Currently, burn experts are working with endocrinologists to assess pharmacologic alternatives for female patients and have obtained IRB-approval to evaluate both safety and efficacy of testosterone supplementation in the setting of burn hypermetabolism. Applicability of Research to Practice This study evaluates the safety and efficacy of testosterone supplementation as an alternative to oxandrolone in the setting of burn hypermetabolism. This study helps provide guidance to other burn centers in filling the gap in therapy that now exists in the pharmacologic management of hypermetabolic syndrome in patients with severe burns.

MENKES DISEASE: A LITERATURE REVIEW AND CLINICAL CASE

Menkes Kinky Hair Disease (MKHD) is characterized by an abnormality in copper metabolism caused by a mutation in the ATP7A gene, which is located on Xq13.3 and has 23 exons. In addition, this gene encodes 1500 amino acids and is expressed in large quantities in various organs. It’s worth mentioning that about 357 diff erent mutations have been identifi ed in the ATP7A gene. It is a relatively rare disease with an incidence of 1 case per 100,000 to 250,000 live births. MKHD is an X-linked recessive trait that almost exclusively aff ects boys.The diagnosis of this rare disease is based on the genetic- molecular study of a metabolic disease panel, including the ATP7A gene and the biochemical phenotype (a decrease in serum copper and ceruloplasmin levels).In developing therapeutic strategies for individuals with Menkes disease, three fundamental problems are being addressed: 1) unlocking the absorption of copper in the intestine; 2) making copper available to enzymes in cells that require it as a cofactor; and 3) identifying infants with Menkes disease and initiating treatment at a very early stage of life, before irreversible neurodegeneration occurs. This article presents a clinical case of Menkes disease in a 7-month-old boy. The diagnosis was confi rmed by molecular genetic testing (NGS) of the Neurometabolic Disorders Panel, which included the ATP7A gene and biochemical phenotype. The described case illustrates the complexity of diagnosing Menkes disease in the neonatal period due to the non-specifi city of disease symptoms (lethargy, weak sucking, weight loss, etc.) and the importance of biochemical and molecular genetic methods of fetal investigation in subsequent pregnancies or in a newborn sibling for early diagnosis and treatment. This case will be published with the consent of the mother in accordance with bioethical principles.

Time-of-day dependence of running averages for some components of metabolic panels at our hospital: Relation to strategy for patient-based quality control

Background and objectivesWe assessed properties of running averages for our hospital's most common chemistry analytes, for use in real-time patient-based quality control (PBQC). We determined whether there was dependence of any running averages on 24-h clock time (time-of-day, TOD). Materials and methodsWe analyzed 3-months' data for measurements of 13 metabolic panel components. Running averages for 20 consecutive results (20-mers) were computed for data restricted to results within reference intervals. This produced an overall mean (X) and standard-deviation (SD) of 20-mers for each analyte. We then computed the average 20-mer result (Y) reported within 1-h bins across 24-hour clock time (t). Y(t) was regarded as having TOD-dependence if either nadir or apex values for |Y-X| exceeded 0.5 SD, occurring within a contiguous series of at least 4 Y(t) values on one side of the mean. ResultsSeven analytes (albumin, aspartate aminotransferase, calcium, chloride, CO2, potassium, total protein) demonstrated TOD-dependence of running means for 20-mers. ConclusionsAt our hospital, TOD-dependence of running means was identified for 7 of 13 metabolic panel analytes. TOD-dependence is likely to be hospital-specific. Utilization of TOD-dependent targets for PBQC, rather than fixed targets, would be appropriate in these cases.

Review of Urinary Diversion (Mainz II) for Women with Irreparable Vesico-Vaginal Fistula (VVF) In Eritrea, 2022: A Retrospective Study

Introduction: Mainz II urinary diversion procedures are increasingly being performed in the developing world for irreparable obstetric fistulas. Our goal was to review the long-term complications of continent urinary diversion and to evaluate the feasibility of the recommended follow-up protocols in a country with limited resources. Methods: The medical records of patients who underwent urinary diversion or who are under follow-up for irreparable vesico-vaginal fistula (VVF) at National Fistula center (NFC) in Mendefera, Eritrea, between February 2004 and December 2021, were reviewed. Descriptive statistics was used to depict the complications and surgical outcomes. Results: Urinary diversions were performed in 47 patients. The average duration of stay after surgery was 18 days. Metabolic panel and arterial blood gases (ABG) were found only in 26 of the records which showed hyperchloremic acidosis in 22 (84.7%) and decreased kidney function in 8 (30.7%) of the women. Night time incontinence was found in 24 (51.1%) of the cases with 9 (19.1%) experiencing symptomatic renal infections which required admission. Three of the patients developed pouch stones and two patients developed hydronephrosis. Five patients were able to conceive after diversion. Eleven (23.4 %) of the women were lost to follow-up and 10 (21.3 %) died, with majority (70%) of them with unknown cause of death. Conclusion: On top of the long-term complications following diversion, there was substantial loss to follow-up and death after urinary diversion. Therefore, innovative approaches and continuous financial support to ensure patient return or local follow-up in residential regions need to be developed to overcome barriers to guarantee continuity of care and to decrease the morbidity and mortality of these women.

Community pharmacist-led point-of-care eGFR screening: early detection of chronic kidney disease in high-risk patients

Adherence to scheduled physician screenings for renal function monitoring in patients with chronic kidney disease (CKD) or those at high risk remains suboptimal despite the endorsement of regular screenings by several clinical practice guidelines. Our study aims to assess the effectiveness of a point-of-care CKD screening program led by these pharmacists using the PICCOLO device while recognizing the unique position of community pharmacists in primary care. We conducted an 11-month prospective point-of-care interventional research study in the United Arab Emirates to evaluate the performance of a community pharmacist-led CKD screening program for high-risk patients. Six diverse community pharmacies were selected based on staff availability, patient volume, and their offered range of services. Eligible individuals with risk factors for CKD were identified during medication evaluations. The PICCOLO Comprehensive Metabolic Panel facilitated on-site blood analysis, delivering estimated Glomerular Filtration Rate (eGFR) results within 10 to 15 min. Data also included eGFR categories, demographic information, and insights into lifestyle and health habits collected through a questionnaire. Pharmacists conducted comprehensive medication reviews and offered referrals and lifestyle guidance as part of the program. The study encompassed a total of 400 patients, with an average age of 69 ± 13.4 years within the study cohort. Notably, 38.8% (155 individuals) of the 400 patients were found to have undiagnosed CKD stages 3–5. Univariate logistic regression analysis revealed a significant association between a higher incidence of CKD stages 3–5 and factors such as older age, a history of hypertension, vascular disease, and diabetes mellitus. In the multivariate regression model, age and a history of diabetes mellitus emerged as significant predictors of an elevated risk of CKD. This study sheds light on the viability and impact of CKD screening programs conducted by community pharmacists, particularly in detecting CKD stages 3–5. The findings have implications for healthcare policies, as they can influence the enhancement of early detection and management of CKD. Moreover, these insights may catalyze focused screening initiatives and strengthen collaboration between community pharmacies and healthcare systems to benefit patients at high risk of CKD.

Abstract 3392: Generation and characterization of transgenic oncopig model for lung cancer

Abstract Lung cancer (LC) is the leading cause of cancer-associated death in the United States. Preclinical findings in small animal models do not translate into human clinics. There is an urgent need to develop relevant preclinical large animal models for LC. We describe a novel method to induce LC in transgenic pigs carrying Cre-inducible KrasG12D and TrP53R167H mutations (Oncopigs). The Oncopigs (n=12; 9 females, and 3 males) at 9 weeks of age were anesthetized and adenovirus (1 × 1011 PFU) carrying Cre recombinase gene (Ad-Cre) ± polybrene (1:100) ± IL-8 (5 ng/ml) was injected via flexible bronchoscopy with two techniques: (1) Bronchial lavage (n=6) and (2) Transbronchial needle injection (n=6) into different lung lobes. As controls, a combination of polybrene ± IL-8 was injected without AdCre into the contralateral lobes in the same pigs (n=8). Oncopigs were monitored via clinical monitoring, blood counts, basic metabolic panel, and contrast-enhanced computed tomography (CT) imaging for LC progression and metastasis at 3-, 4-, 7-, 10-, 16-, and 26 weeks post-intervention. All animals tolerated the injections with expected weight gains. Blood counts and metabolic panels remained normal during LC progression. At the site of injection/lavage, lung masses were detected on CT imaging at 3 weeks post-injections. However, a decrease in masses was observed on CT at 7 weeks post-intervention. The decrease in size of the lung masses coincided with increasing attenuation. No distant metastases were observed on CT imaging. Lavage-based lesions appeared to be more heterogeneous with surrounding inflammatory changes. Transbronchial-injection-based lesions appeared more consolidated and coin-shaped without surrounding inflammatory changes. Control injection sites did not show any mass growth on CT imaging. Immunohistochemistry analysis on lung tumors revealed increased pancytokeratin, trichrome, E-cad, Ki-67, IBA, and CD3 expression. Further, immunofluorescence revealed decreased E-Cad, CK-19, and Zo-1 expression, whereas increased expression of N-Cad, FN1, snail, CD44, α-SMA, and γ-catenin, was observed in the LC and metastatic tissue compared to normal. We successfully generated and characterized a novel transgenic Oncopig LC model. There is robust tumor production status post AdCre delivery. One of four Oncopigs had carcinomatous metastatic skin growth. The remaining 7 Oncopigs are monitored longitudinally for tumor growth and development of metastasis. Citation Format: Kirtan Joshi, Nagabhishek Sirpu, Amanda Schmelzle, Ravikanth Poonooru, Benjamin Nelson, Pradeep Subramanyam, Colleen Garrett, Mariana Sponchiado, Sarah Schlink, Samantha Gerb, Jesse Porter, Dae Kim, Jeffrey Kunin, Jeffrey Bryan, Timothy Hoffman, Bhanu Telugu, Jussuf Kaifi, Satyanarayana Rachagani. Generation and characterization of transgenic oncopig model for lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3392.

Abstract 5645: HuR regulates aerobic glycolysis in triple negative breast cancer (TNBC)

Abstract Introduction: The RNA-binding protein Human Antigen R (HuR/ELAVL1) is ubiquitously expressed and exerts post-transcriptional regulation on mRNAs characterized by U/AU-rich sequences in their 3' UTR. Elevated cytoplasmic expression of HuR has been associated with various malignancies, influencing key cellular processes such as proliferation, apoptosis, angiogenesis, and metastasis. The involvement of HuR influences prognostic outcomes and hence is a potential biomarker and therapeutic target in cancer research. The present study investigates the oncogenic role of HuR in TNBCs, an aggressive subtype of breast cancer. Methods: Immunohistochemistry was performed on TNBC patient tumor tissue (n=40) to asses the expressions of HuR and MMP9. Human TNBC cell lines MDA-MB-231 and MDA-MB-468 were used for in vitro studies after confirming cytoplasmic HuR accumulation in these cells via Immunofluorescence. The RNA binding activity of HuR was disrupted using CMLD2, a specific inhibitor of HuR, and subsequent physiological changes were assessed through functional assays. An exploratory investigation of HuR-moderated metabolic changes was performed employing NANOSTRING nCounter XT gene expression assay using metabolic pathways panel. Investigation and/or validation of molecular changes were done via immunoblotting. Results: Meta-analysis using Liu-2014 TNBC dataset correlated high HuR protein expression with reduced patient survival (p=0.028). HuR (77%) and MMP9(55%) were found to be overexpressed in TNBC tissues. Inhibiting HuR with CMLD2 resulted in the downregulation of the protein and its downstream targets CDK2, MMP9, and β catenin. HuR inhibition compromised proliferation, migration, Matrigel invasion and EMT (downregulated E-Cadherin, N-Cadherin, and Vimentin) in TNBC cell lines. Further, HuR inhibition resulted in decreased clonogenicity in 2D and 3D TNBC cultures. Transcriptomics studies showed that HuR inhibition in MDA-MB-231 altered the profile of glycolytic genes in addition to other pathways such as cell cycle and DNA damage repair. In accordance, the expression of glycolytic proteins was reduced upon CMLD2 treatment. Similar results were obtained on HuR knockdown by siRNA suggesting that HuR-mediated effects on TNBC progression might be in part through its modulation of aerobic glycolysis. Conclusion: Overall, our results demonstrate HuR as a positive regulator of aerobic glycolysis in TNBCs and the ability of CMLD2 to inhibit HuR provides a rationale to consider it as a potential anticancer agent for TNBCs. Citation Format: Arundhathi Dev J R, Ajay Gogia, Sandeep R. Mathur, S.V.S. Deo, Chandra Prakash Prasad. HuR regulates aerobic glycolysis in triple negative breast cancer (TNBC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5645.

Abstract 559: Investigating DDX3X as a target to improve outcomes in Black and Native American endometrial cancer patients

Abstract Introduction: The goal of this project was to identify and test a new molecular target that will help reduce the worse outcomes of endometrial cancer, especially in Black and Native American patients. Endometrial cancer is rapidly on the rise in the developed world. It has overtaken many other types of cancer in both incidence and mortality. Black populations are disproportionately impacted by endometrial cancer, both in Oklahoma and across the United States. In Oklahoma specifically, Native Americans are the most heavily impacted group. Methods: Machine learning techniques were used to analyze comprehensive metabolic panel (CMP) data from electronic medical record of patients in the University of Oklahoma (OU) network of hospitals and clinics. This data was broken down by endometrial cancer status, race, and age. Plasma samples of endometrial cancer patients were collected from the OU Health Sciences Center Biobank. These samples were analyzed by mass spectrometry. Endometrial cancer cell lines Ishikawa (low-grade) and ARK-1 and ARK-4 (high grade) were cultured in EMEM. For treating the cells, we used RK-33, a small molecule inhibitor of DDX3X. MTT assays were performed in 96-well plates at increasing concentrations of RK-33 for 48 hours. Western blots were used to determine effect of the drug on cellular DDX3X and yH2AX protein levels. Results: Machine learning analysis EMR data revealed a difference between races in albumin levels of women with endometrial cancer. Black and Native American patients had lower albumin, which is known to correlate to worse outcomes. IPA analysis of plasma proteomics revealed several proteins that were differentially expressed between races. Among these was DDX3X, the X-linked form of DDX3, a DEAD-box RNA helicase which is involved in DNA damage repair. Patient data indicated that patients with high DDX3X expression tended to have lower survival rates. MTT analysis determined that Ishikawa has a lower IC50 than the high-grade cell lines, but all responded. Western blotting confirmed that treatment with RK-33 reduced the amount of DDX3X in the cells and increased y-H2AX, indicating more DNA damage. Conclusions: This study demonstrates that DDX3X is a valid molecular target in endometrial cancer. The differential expression across race groups indicates that Black and Native Americans may stand to benefit the most from a novel drug targeting this difference. Because DDX3X is involved in DNA damage repair, combining the treatment with a DNA-damaging drug may increase response to the drug as well. Citation Format: James D. Lausen, Doris M. Benbrook. Investigating DDX3X as a target to improve outcomes in Black and Native American endometrial cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 559.

Diagnostic threshold and performance of anion gap in screening for high anion gap metabolic acidosis.

The anion gap (AG) is commonly used to screen for acid-base disorders. It was proposed that the cut-off for high anion gap metabolic acidosis (HAGMA) may be lower with current laboratory techniques, although modern laboratory equipment are still calibrated to familiar reference ranges established with earlier techniques. The appropriate cut-off for HAGMA is unclear. This study aimed to assess the performance of AG as a screening test for HAGMA and to determine the optimal diagnostic threshold of AG for HAGMA. This was a retrospective analysis of a large, anonymised dataset extracted by computerised protocol from 2017 to 2019. All inpatients with blood samples taken for organic acids (lactate, ketone or salicylate) paired with a metabolic panel were included. The target condition was HAGMA secondary to elevated blood lactate, ketone and/or salicylate. Sensitivity for HAGMA was explored at various AG cut-off levels. Of 16,475 patients, 2,621 had organic acidosis. Median age was 65 years, and median estimated glomerular filtration rate was 70 mL/min/1.73 m2. With organic acidosis, the median AG was 23 (interquartile range [IQR] 20-29) mEq/L, while without organic acidosis, the median AG was 16 (IQR 14-19) mEq/L. The area under the curve-receiver operating characteristic of AG for HAGMA was 0.873. Desired sensitivity for HAGMA was set at ≥95%, and this was found with an AG threshold of ≥15 mEq/L (sensitivity 98.1%, specificity 34.0%). The recommended AG threshold value is ≥15 mEq/L with a high sensitivity for HAGMA. The AG should always be interpreted with the clinical context, and it should be repeated as the clinical picture evolves.

Gene expression profiling in elderly patients with familial hypercholesterolemia with and without coronary heart disease

Background and aimsElderly familial hypercholesterolemia (FH) patients are at high risk of coronary heart disease (CHD) due to high cholesterol burden and late onset of effective cholesterol-lowering therapies. A subset of these individuals remains free from any CHD event, indicating the potential presence of protective factors. Identifying possible cardioprotective gene expression profiles could contribute to our understanding of CHD prevention and future preventive treatment. Therefore, this study aimed to investigate gene expression profiles in elderly event-free FH patients. MethodsExpression of 773 genes was analysed using the Nanostring Metabolic Pathways Panel, in peripheral blood mononuclear cells (PBMCs) from FH patients ≥65 years without CHD (FH event-free, n = 44) and with CHD (FH CHD, n = 39), and from healthy controls ≥70 years (n = 39). ResultsNone of the genes were differentially expressed between FH patients with and without CHD after adjusting for multiple testing. However, at nominal p < 0.05, we found 36 (5%) differentially expressed genes (DEGs) between the two FH groups, mainly related to lipid metabolism (e.g. higher expression of ABCA1 and ABCG1 in FH event-free) and immune responses (e.g. lower expression of STAT1 and STAT3 in FH event-free). When comparing FH patients to controls, the event-free group had fewer DEGs than the CHD group; 147 (19%) and 219 (28%) DEGs, respectively. ConclusionsElderly event-free FH patients displayed a different PBMC gene expression profile compared to FH patients with CHD. Differences in gene expression compared to healthy controls were more pronounced in the CHD group, indicating a less atherogenic gene expression profile in event-free individuals. Overall, identification of cardioprotective factors could lead to future therapeutic targets.

Laboratory testing efficiency during the COVID pandemic: Findings from the Primary Health Care Corporation laboratories in the State of Qatar

BackgroundLittle is known about how the COVID-19 pandemic altered laboratory testing efficiency in the State of Qatar. The aim of this study was to assess laboratory testing efficiency with respect to the total number and proportion of C-reactive protein (CRP), complete blood count (CBC), and comprehensive metabolic panel (CMP) tests completed on time in 2019–2021 in several ordinary and COVID-converted Primary Health Care Corporation (PHCC) health centers across Qatar. MethodsSecondary data from 2019 to 2021 were accessed from the PHCC-Clinical Information System center. Six randomly selected centers from three regions of Qatar (Northern, Central, and Western), two of which were COVID-converted, were analyzed. ResultsA total of 404,316 laboratory tests were analyzed. There were decreasing, U-shaped, and inverted-U-shaped patterns in the numbers of tests conducted in different regions between 2019 and 2021 according to test type. The proportion of urgent (STAT) CBC and CMP tests increased from 2019 to 2021, and the proportion of tests completed by COVID-converted health centers increased for CRP and CBC and decreased for CMP between 2019 and 2021. Northern and Western regions in Qatar showed higher efficiency than the Central region with respect to the proportion of STAT tests completed on time in 2019–2021. COVID-converted centers completed fewer STAT CBC tests on time than ordinary centers. ConclusionPandemics such as COVID-19 shift the allocation of resources from routine tests to urgent tests, as exemplified by the increase in STAT test proportions in 2019 to 2021. High population densities, as noted in the Central region of Qatar, may require additional resources during pandemics to complete urgent tests more efficiently. The conversion of centers to COVID-converted centers may not necessarily translate into higher urgent test efficiency, as exemplified by the STAT CBC test results.