Elevated Serum Concentrations Research Articles

FGF-21 and GDF-15 are increased in migraine and associated with the severity of migraine-related disability

BackgroundMigraine is a prevalent disorder with significant socioeconomic impact. The impairment of metabolic homeostasis in migraine warrants further investigation. Changes in serum levels of Fibroblast-growth-factor 21 (FGF-21) and Growth-differentiation-factor 15 (GDF-15) are characteristic of some metabolic and mitochondrial diseases. This study aimed to assess whether the presence of migraine affects serum levels of FGF-21 and GDF-15, and taking metabolic disorders into account as potential confounding factors.MethodsWe collected serum samples from 221 migraine patients (153 episodic migraineurs and 68 chronic migraineurs) and 124 healthy controls. The serum concentrations of FGF-21 and GDF-15 were measured using an enzyme-linked immunosorbent assay (ELISA) based approach. Clinical variables, including monthly headache days, peak headache pain intensity, the 6-item Headache Impact Test (HIT-6), and the Migraine Disability Assessment (MIDAS), were also addressed. The associations between the clinical variables of migraine patients and serum levels of FGF-21 and GDF-15 were studied.ResultsIn the multiple regression that corrected for age, we found that the serum levels of FGF-21 and GDF-15 were significantly higher in migraine sufferers than in healthy controls. A significant elevation in serum concentration of FGF-21, but not GDF-15, was observed in patients with chronic migraine (CM) compared to those with episodic migraine (EM). Regarding migraine-related disability, higher scores on the HIT-6 and MIDAS were associated with higher levels of FGF-21 and GDF-15. For the receiver operating characteristic (ROC) analysis, the diagnosis of migraine using GDF-15 showed that the area under the ROC curve (AUC) was 0.801 and the AUC of chronic migraine was 0.880.ConclusionSerum GDF-15 and FGF-21 levels are increased in patients with migraine and associated with the severity of migraine-related disability.

Urinary endogenous peptides as biomarkers for prostate cancer.

Prostate cancer (PCa) is one of the most prevalent types of cancer in men worldwide; however, the main diagnostic tests available for PCa have limitations and a biopsy is required for histopathological confirmation of the disease. Prostate-specific antigen (PSA) is the main biomarker used for the early detection of PCa, but an elevated serum concentration is not cancer-specific. Therefore, there is a need for the discovery of new non-invasive biomarkers that can accurately diagnose PCa. The present study used trichloroacetic acid-induced protein precipitation and liquid chromatography-mass spectrometry to profile endogenous peptides in urine samples from patients with PCa (n=33), benign prostatic hyperplasia (n=25) and healthy individuals (n=28). Receiver operating characteristic curve analysis was performed to evaluate the diagnostic performance of urinary peptides. In addition, Proteasix tool was used for in silico prediction of protease cleavage sites. Five urinary peptides derived from uromodulin were revealed to be significantly altered between the study groups, all of which were less abundant in the PCa group. This peptide panel showed a high potential to discriminate between the study groups, resulting in area under the curve (AUC) values between 0.788 and 0.951. In addition, urinary peptides outperformed PSA in discriminating between malignant and benign prostate conditions (AUC=0.847), showing high sensitivity (81.82%) and specificity (88%). From in silico analyses, the proteases HTRA2, KLK3, KLK4, KLK14 and MMP25 were identified as potentially involved in the degradation of uromodulin peptides in the urine of patients with PCa. In conclusion, the present study allowed the identification of urinary peptides with potential for use as non-invasive biomarkers in PCa diagnosis.

Blood neurofilament light chain in different types of dementia.

The study aimed to evaluate diagnostic values of circulating neurofilament light chain (NFL) levels in different types of dementia. Previous studies reported inconsistent change of blood NFL for different types of dementia, including Alzheimer's disease (AD), frontotemporal dementia (FTD), Parkinson's disease dementia (PDD) and Creutzfeldt-Jakob disease (CJD) and Lewy body dementia (LBD). Meta-analysis was conducted to summarize the results of studies evaluating diagnostic values of circulating NFL levels in different types of dementia to enhance the strength of evidence. Articles evaluating change in blood NFL levels in dementia and published before July 2022 were searched on the following databases (PubMed, Web of Science, EMBASE, Medline and Google Scholar). The computed results were obtained by using STATA 12.0 software. AD patients showed increased NFL concentrations in serum and plasma, compared to healthy controls (HC) [standard mean difference (SMD) = 1.09, 95% confidence interval (CI): 0.48, 1.70, I2 = 97.4%, p < 0.001]. In AD patients, higher NFL concentrations in serum and plasma were associated with reduced cerebrospinal fluid (CSF) Aβ1-42, increased CSF t-tau, increased CSF p-tau, reduced Mini-Mental State Examination (MMSE) and decreased memory. Additionally, mild cognitive impairment (MCI) showed elevated NFL concentrations in serum and plasma, compared to HC (SMD = 0.53, 95% CI: 0.18, 0.87, I2 = 93.8%, p < 0.001). However, in MCI, no significant association was found between NFL concentrations in serum, plasma and memory or visuospatial function. No significant difference was found between preclinical AD and HC (SMD = 0.18, 95% CI: -0.10, 0.47, I2 = 0.0%, p = 0.438). FTD patients showed increased NFL concentrations in serum and plasma, compared to HC (SMD = 1.08, 95% CI: 0.72, 1.43, I2 = 83.3%, p < 0.001). Higher NFL concentrations in serum and plasma were associated with increased CSF NFL in FTD. Additionally, the pooled parameters calculated were as follows: sensitivity, 0.82 (95% CI: 0.72, 0.90); specificity, 0.91 (95% CI: 0.83, 0.96). CJD patients showed increased NFL concentrations in serum and plasma, compared to HC. No significant difference in NFL level in serum and plasma was shown between AD and FTD (SMD = -0.03, 95% CI: -0.77, 0.72, I2 = 83.3%, p = 0.003). In conclusion, the study suggested abnormal blood NFL level in AD and MCI, but not in preclinical AD. FTD and CJD showed abnormal blood NFL levels.

Evaluation of miRNA-371a-3p (miR371a) assay to predict final pathohistology in patients undergoing primary nerve-sparing retroperitoneal lymphadenectomy (nsRPLND) for stage IIA/B seminomas and non-seminomas.

427 Background: NS-RPLND represents a guideline recommended treatment option in marker negative low volume metastatic seminomas and nonseminomas (NSGCT). However, about 30% of clinical stage IIA patients demonstrate equivocal findings of uncertain dignity so that they might undergo unnecessary treatment. Elevated serum concentrations of the molecular marker miR371 have been reported to correlate with the clinical stage even in small volume metastases. It was the purpose of our pilot study to evaluate the predictive accuracy of miR371 in a cohort of patients who underwent nsRPLND for clinical stage IIA/B germ cell tumors of the testis. Methods: Between 1-9/2022, 16 patients with marker negative clinical stage IIA/B seminomas (n=10) and NSGCT (n=6) underwent primary nsRPLND with a modified template resection via an open surgical approach. Blood specimens (20ml) were drawn on the day immediately prior to surgery and processed according to the manufacturer’s protocol. miRNA is extracted and purified with the Maxwell RSC MiRNA Plasma and Serum Kits prior to its transcription into cDNA using cDNA Solution, Reverse Transcriptase and RNase Inhibitor. Subsequently, this cDNA is amplified. Using qPCR techniques, the miRNA 371a is quantified using Roche Lightcycler 480 II. Using the Lightcycler software, the median Cp (CP = crossing points) of the triplicates is calculated and converted into a RQ value (RQ= relative abundance). Results: nsRPND was performed in all patients without significant Clavien-Dindo IIIa-V complications. Mean OR time was 131 (105-195) minutes, mean blood loss was &lt; 150ml, transfusion rate was 0%. Mean number of dissected lymph nodes was 17 (7-32), mean diameter of positive lymph nodes was 2.1 (0.8-4.1) cm. Histology revealed metastatic seminoma or nonseminoma in 12/16 (75%). In 4 patients histology revealed non-malignant disease (n=2), teratoma, and lymphoma. miR371 was positive in all 12 (100%) pts with metastases and it was negative in 3/4 (75%) pts without metastases. One patient with small volume CS IIA seminoma was false negative. Conclusions: This is the first report to demonstrate that miR371can be used as a personalized and individual biomarker to predict the presence of small volume retroperitoneal lymph node metastases in CS IIA/B seminomas and in nonseminomas. Patients with positive findings should undergo active treatment whereas negative findings should result in close follow-up. Date are currently validated in a multi-institutional trial.

Monocyte chemoattractant protein 1 as a potential biomarker for immune checkpoint inhibitor-associated neurotoxicity.

Oncological patients can benefit substantially from treatment with immune checkpoint inhibitors (ICI). However, there is a growing awareness of immune-related adverse events (irAE). Especially ICI-mediated neurological adverse events (nAE(+)), are tough to diagnose and biomarkers to identify patients at risk are missing. A prospective register with prespecified examinations was established for ICI treated patients in December 2019. At the time of data cut-off, 110 patients were enrolled and completed the clinical protocol. Herein, cytokines and serum neurofilament light chain (sNFL) from 21 patients were analyzed. nAE of any grade were observed in 31% of the patients (n= 34/110). In nAE(+) patients a significant increase in sNFL concentrations over time was observed. Patients with higher-grade nAE had significantly elevated serum-concentrations of monocyte chemoattractant protein 1 (MCP-1) and brain-derived neurotrophic factor (BDNF) at baseline compared to individuals without any nAE (p< 0.01 and p< 0.05). Here, we identified nAE to occur more frequently than previously reported. Increase of sNFL during nAE confirms the clinical diagnosis of neurotoxicity and might be a suitable marker for neuronal damage associated with ICI therapy. Furthermore, MCP-1 and BDNF are potentially the first clinical-class nAE predictors for patients under ICI therapy.

Iodine in the Therapy of Graves' Disease: A Century After Henry S. Plummer.

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Serum liver enzymes and metabolic syndrome from the Rafsanjan Cohort Study.

Our investigation aimed at evaluating the relationship between metabolic syndrome, alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma glutamyl transferase (GGT), and alkaline phosphatase (ALP) in the Rafsanjan cohort study (RCS). We used data obtained from the RCS, as a part of the prospective epidemiological research studies in Iran. In this cross-sectional research, 9895 participants from the baseline phase of RCS who completed medical questionnaire were included. Metabolic syndrome (MetS) defined using NCEP-ATP III criteria. The relationship between elevated serum liver enzymes levels even within the normal range and metabolic syndrome was evaluated by logistic regressions. The prevalence of MetS was 34.42% in the participants of study. The mean concentrations of AST, ALT, ALP, and GGT increased with increasing MetS components. After adjusting for all potential confounders, elevated serum concentrations of ALT, AST, GGT, and ALP even within the normal range were related with an increased odds of MetS. MetS was associated with increased levels of liver enzymes even within the normal range. These results indicated the potential for elevated liver enzymes as biomarkers for the possible presence of MetS.

Markers of malnutrition, inflammation, and tissue remodeling are associated with 1-year outcomes in patients with advanced heart failure.

A number of predictive models and biomarkers are used to assess outcomes in patients with advanced heart failure (HF). We sought to evaluate whether markers of malnutrition, inflammation, and tissue remodeling are associated with 1‑year mortality in patients with advanced HF. We analyzed 200 consecutive patients with advanced HF. We assessed markers of inflammation and malnutrition, such as the neutrophil percentage‑to-albumin ratio (NPAR), the advanced lung cancer inflammation index (ALI), and the level of high‑sensitivity C-reactive protein (hsCRP). We also evaluated the level of tenascin‑C (TNC), as well as known markers of HF, such as N‑terminal pro-B-type natriuretic peptide (NT-proBNP), creatinine, and bilirubin. Receiver operating characteristic (ROC) and Kaplan-Meier survival analyses were performed to evaluate the association of each parameter with 1‑year mortality. The median (interquartile range) age of the patients was 58 (51-64) years. The independent predictors of death were ALI (odds ratio [OR], 0.966; 95% CI, 0.941-0.992; P = 0.01) and NPAR (OR, 1.373; 95% CI, 1.126-1.674; P = 0.002), as well as serum levels of TNC (OR, 1.04; 95% CI, 1.020-1.050; P <0.001), hsCRP (OR, 1.187; 95% CI, 1.037-1.360; P = 0.01), NT‑ proBNP (OR, 1.110; 95% CI, 1.100-1.200; P = 0.02), creatinine (OR, 1.034; 95% CI, 1.013-1.055; P = 0.001), and bilirubin (OR, 1.079; 95% CI, 1.014-1.149; P = 0.02). The ROC analysis indicated a good discriminatory power of TNC (area under the curve [AUC] = 0.807), NT‑ proBNP (AUC = 0.760), hsCRP (AUC = 0.706), ALI (AUC = 0.749), and NPAR (AUC = 0.785) in predicting mortality during the 1‑year follow up. Our study demonstrated that a decreased ALI value, increased NPAR value, as well as elevated serum concentrations of TNC, NT‑proBNP, hsCRP, creatinine, and bilirubin are associated with 1‑year mortality in patients with advanced HF.

Virgin coconut oil reverses behavioral phenotypes of letrozole-model of PCOS in Wistar rats via modulation of NRF2 upregulation

ObjectivesPolycystic ovarian syndrome (PCOS) is an endocrine disorder associated with insulin resistance, hyperandrogenism, and sub-infertility. Virgin coconut oil (VCO) has been reported to have health benefits, such as anti-inflammatory, anti-oxidant, and antiviral properties. This study investigated the effects of dietary VCO supplementation on memory and cognitive impairment in female rats with letrozole induced PCOS. MethodsThirty female rats were randomly divided into five groups. All rats except controls were treated with letrozole for 21 days to induce PCOS and were subsequently treated for 14 days with 10% VCO, clomiphene (CLO), or VCO + CLO. Three neurobehavioral tests were conducted: elevated plus maze, Y maze, and novel object recognition tests. ResultsOur results indicated statistically elevated serum concentrations of sex hormones in rats with PCOS, compared with the control and treated groups. In addition, all treated groups showed significant reversal of the low serum concentrations of catalase and down-regulated gene expression of Nrf2 in the hippocampus seen in the PCOS rats. In addition, gene expression of acetylcholine esterase was up-regulated in PCOS rats, and was statistically reverted in the VCO treated groups. ConclusionAnxiety-like behavior and impaired short-term memory were observed in PCOS rats; however, VCO supplementation reversed these effects by modulating the gene expression of Nrf2 and AchE.

Systemic inflammation and obstructive sleep apnea syndrome (OSA): the role of C–reactive protein (CRP)

Abstract The presence of sleep-related disorders, particularly obstructive sleep apnea syndrome (OSA), instigates pathological changes during sleep, giving rise to frequent hypoxic episodes that generate elevated levels of a broad spectrum of inflammatory cytokines. C-reactive protein (CRP), a biomarker signifying the presence and intensity of inflammation, is frequently detected in elevated serum or plasma concentrations, correlating with the number of respiratory events, especially in moderate and severe forms, across both adults and children. Various available therapeutic approaches demonstrate the capacity to diminish serum levels, although the minimum duration of usage typically extends between 2-6 months. In the case of older individuals, OSA commonly coexists with additional conditions, further augmenting the baseline inflammatory level. This accelerated disease progression amplifies mortality rates, incurs heightened costs, and significantly diminishes the overall quality of life.

Correlation of Acute Inflammatory Markers with Oxidative Stress Markers in Patients with Chronic Pancreatitis: A Cross-sectional Study

Introduction: Chronic Pancreatitis (CP) is a long-standing inflammation of the pancreas that presents as episodes of acute inflammation or chronic damage, leading to alterations in the organ’s normal structure and function. Numerous studies have focused on inflammatory and oxidative stress markers in Acute Pancreatitis (AP), but similar studies in CP are rare. Aim: The aim of this study was to compare the serum levels of acute inflammatory and oxidative stress markers in CP patients with healthy controls, and to investigate the correlation between acute inflammatory markers and oxidative stress markers. Materials and Methods: This cross-sectional study was conducted at Jawaharlal Institute of Postgraduate Medical Education Research (JIPMER), Puducherry, India, from January 2018 to December 2021. Forty-five patients diagnosed with CP, based on clinical manifestations, Contrast-Enhanced Computed Tomography (CECT) of the abdomen, and histopathology reports, were enrolled along with 45 healthy controls. Serum biochemical parameters, including inflammatory markers such as high-sensitive C-Reactive Protein (hs-CRP), Interleukin-6 (IL-6), and Tumour Necrosis Factor-alpha (TNF-α), as well as oxidative stress parameters such as Malondialdehyde (MDA), Total Antioxidant Status (TAO), and Total Oxidant Status (TOS), were measured. The Oxidative Status Index (OSI) was calculated. Statistical analysis was performed using the Statistical Package for the Social Sciences (SPSS) version 21.0. Results: There were no significant differences in age and gender between the two groups. None of the individuals in the control group had diabetes, and their Body Mass Index (BMI) was within normal limits. Patients exhibited leukocytosis, hypoproteinemia, and hypoalbuminemia. Although all patients presented with pain, none had recent acute pain episodes or elevated serum amylase levels. Compared to healthy individuals, CP patients showed significantly elevated serum concentrations of inflammatory and oxidative stress markers, as well as OSI. Serum antioxidant (TAO) levels were significantly reduced in patients compared to controls. Inflammatory and oxidative stress markers were positively correlated with age, smoking and alcohol intake. There was a positive correlation between acute inflammatory markers and oxidative stress markers in patients with CP. Conclusion: Serum inflammatory and oxidative stress markers were significantly elevated in patients with CP as compared to controls, indicating key roles in patients with CP.

Функционирование АВСВ1-белка при беременности

Objective. To study the functioning of ABCB1 protein in pregnancy, namely, to evaluate its amount in the organs that play a significant role in pharmacokinetics and its functional activity at the whole organism level. Materials and methods. The study was performed on 52 female rabbits divided into two groups. Serum concentrations of progesterone, estradiol, testosterone, and prolactin were determined in animals before the experiment and on days 7, 14, 21, and 28 of pregnancy by the radioimmunoassay method. In group 1, the amount of ABCB1 protein was assessed in the jejunum, liver, kidneys, and cerebral cortex at the indicated gestational ages by enzyme immunoassay. In group 2, the functional activity of ABCB1 protein was studied during the same periods by evaluating the pharmacokinetics of its marker substrate fexofenadine. Results. Elevated serum concentrations of progesterone were detected at all gestational ages. There was an increase in the amount of ABCB1 protein compared to non-pregnant animals in the jejunum on days 7, 14, 21, and 28, in the liver – on day 7 with a tendency to increase on day 14, in kidneys and large cerebral cortex – on day 28. Pharmacokinetic parameters of fexofenadine did not differ significantly from those of intact animals, except for elevated T1/2 values on day 14. The results indicate an increase in the amount of ABCB1 protein in the studied organs, which is leveled by a decrease in its activity, which is probably due to the effect of progesterone. Conclusion. The functioning of ABCB1 protein does not change throughout the gestational period; therefore, pharmacotherapy with ABCB1 protein substrates during pregnancy does not require dose adjustments. Key words: ABCB1 protein (P-glycoprotein, Pgp), activity, amount, pharmacotherapy during pregnancy, function

Quantitative relationships of perfluoroalkyl acids in drinking water associated with serum concentrations above background in adults living near contamination hotspots in Sweden

Contaminated drinking water (DW) is a major source of exposure to per- and polyfluoroalkyl substances (PFAS) at locations around PFAS production/use facilities and military airports. This study aimed to investigate quantitative relationships between concentrations in DW and serum of nine perfluoroalkyl acids (PFAAs) in Swedish adult populations living near contamination hotspots. Short-chained (PFPeA, PFHxA, PFHpA, and PFBS) and long-chained PFAAs (PFOA, PFNA, PFDA, PFHxS and PFOS) were measured in DW and serum. We matched DW and serum concentrations for a total of 398 subjects living or working in areas receiving contaminated DW and in one non-contaminated area. Thereafter, linear regression analysis with and without adjustments for co-variates was conducted. This enabled to derive (i) serum concentrations at background exposure (CB) from sources other than local DW exposure (i.e. food, dust and textiles) at 0 ng/L DW concentration, (ii) population-mean PFAA serum:water ratios (SWR) and (iii) PFAA concentrations in DW causing observable elevated serum PFAA concentrations above background variability. Median concentrations of the sum of nine PFAAs ranged between 2.8 and 1790 ng/L in DW and between 7.6 and 96.9 ng/mL in serum. DW concentration was the strongest predictor, resulting in similar unadjusted and adjusted regression coefficients. Mean CB ranged from <0.1 (PFPeA, PFHpA, PFBS) to 5.1 ng/mL (PFOS). Serum concentrations increased significantly with increasing DW concentrations for all PFAAs except for PFPeA with SWRs ranging from <10 (PFHxA, PFHpA and PFBS) to 111 (PFHxS). Observed elevated serum concentrations above background variability were reached at DW concentrations between 24 (PFOA) and 357 ng/L (PFHxA). The unadjusted linear regression predictions agreed well with serum concentrations previously reported in various populations exposed to low and high DW levels of PFOA, PFHxS and PFOS. The quantitative relationships derived herein should be helpful to translate PFAA concentrations in DW to concentrations in serum at the population level.

The impact of haemodialysis treatment on high-sensitivity troponin I among end-stage kidney disease patients

High-sensitivity Troponin I (hs-Trop I) is used to detect myocardial necrosis, leading to an earlier diagnosis of myocardial infarction. However, most patients with end-stage kidney disease (ESKD) were observed to have slightly elevated serum concentrations of troponin. Furthermore, the magnitude of changes in serum concentration of hs-Trop I after haemodialysis has remained unknown.

Hyperuricemia during Pregnancy Leads to a Preeclampsia-Like Phenotype in Mice.

Hyperuricemia is a common feature in pregnancies compromised by pre-eclampsia, a pregnancy disease characterized by hypertension and proteinuria. The role of uric acid in the pathogenesis of pre-eclampsia remains largely unclear. The aim of this study was to investigate the effect of elevated uric acid serum levels during pregnancy on maternal blood pressure and neonatal outcome using two different murine knockout models. Non-pregnant liver-specific GLUT9 knockout (LG9KO) mice showed elevated uric acid serum concentrations but no hypertensive blood pressure levels. During pregnancy, however, blood pressure levels of these animals increased in the second and third trimester, and circadian blood pressure dipping was severely altered when compared to non-pregnant LG9KO mice. The impact of hyperuricemia on fetal development was investigated using a systemic GLUT9 knockout (G9KO) mouse model. Fetal hyperuricemia caused distinctive renal tissue injuries and, subsequently an impaired neonatal growth pattern. These findings provide strong evidence that hyperuricemia plays a major role in the pathogenesis of hypertensive pregnancy disorders such as pre-eclampsia. These novel insights may enable the development of preventive and therapeutic strategies for hyperuricemia-related diseases.

MAST CELL ACTIVATION SYNDROME AND ANTI -IMMUNOGLOBULIN E THERAPY FOR THERAPY-RESISTANT MCAS

<h3>Introduction</h3> Patients with mast cell activation syndrome (MCAS) may present with a variety of symptoms including flushing, urticaria, GI symptoms and headaches. In about 40% of patients, there is a failure of response to the recommended traditional therapy with anti H1/H2 and leukotriene modulating agents (LMAs) and a definitive effective treatment for MCAS has yet to be established. The aim of the current report is to present a medically challenging patient with therapy-resistant MCAS who responded favorably to omalizumab. <h3>Case Description</h3> A 53-year-old white female was evaluated for recurrent episodes of flushing, dermographism, urticaria, headaches, GI complaints and episodes of syncope, symptoms congruent with a diagnosis of MCAS. Our evaluation revealed elevated tryptase serum concentrations of 21.1 mcg per liter and a negative KIT D816 mutation test assay. Since there was no improvement following an initial course of therapy with anti H1/H2 and LMAs, treatment with omalizumab 300 mg SQ q4 weeks was initiated that led to resolution of her flushing, urticaria, GI symptoms and episodes of syncope. <h3>Discussion</h3> MCAS is a disorder that affects multiple systems including the skin, gastrointestinal, cardiovascular and the respiratory system with a small subgroup of patients who do not respond to traditional therapies. Our patient's favorable response to omalizumab, significantly improving her quality of life, should prompt the performance of larger well-controlled studies evaluating its potential use for patients with MCAS resistant to conventional therapies.

PMON180 Extremely Elevated Serum Copeptin Concentrations Following Venipuncture Occur in Approximately 5% of Children and May Affect Proper Interpretation of Copeptin Measurement

Abstract Introduction The secretion of copeptin, an easily measurable surrogate of arginine vasopressin (AVP), is mainly regulated by osmotic and volume stimuli, but also increases in situations of physical stress. Venipuncture has been found to be a stressful procedure, due to physical pain and anxiety, particularly in children. Falsely elevated copeptin concentrations can substantially affect establishment of reference intervals and interpretation of results in conditions such as syndrome of inappropriate antidiuresis, sepsis, infections. We thus tested the hypothesis that venipuncture, as a stressful stimulus, could stimulate copeptin secretion in children. Subjects &amp; Methods We evaluated 92 children (75% males, 5-19 years) enrolled in a study assessing fasting and stimulated serum copeptin concentrations in response to arginine-hydrochloride (500 mg/kg IV in 30 minutes, ArgST) or insulin (0.1 U/Kg IV, insulin tolerance test/ITT) during GH stimulation tests in healthy short children. Subjects underwent phlebotomy for placement of an IV cannula (angiocath) by trained nurses, without percutaneous anesthesia. Copeptin was measured at 0 min. and at sampling times of the expected copeptin peak (60 min post arginine; 45, 60 min post-insulin) by the immunometric B.R.A.H.M.S. Kryptor assay (Quest laboratories) Results Two distinct groups of fasting copeptin values were identified. The majority of subjects, 86/92 (93.5%, "controls") had serum copeptin concentrations in the expected range for overnight fasting (median 9, IQR 6-12, range 2-29 pM/L). Six subjects (6.5%) were outliers with very elevated copeptin values (&amp;gt;50 in one, &amp;gt;100 pM/L in five of them). In 50 controls who underwent ArgST, copeptin increased from a median of 9 (IQR 6-13, range 2-25) to 11 (IQR 8-15, range 2-28) pM/L at 60 min; In the 5 outliers who underwent ArgST, it paradoxically decreased, but remained elevated, from 272 (IQR 154-406, range 62-1361) to 95.5 (IQR58-128, range 42-282) pM/L at 60 min. Similarly, in 8 controls who underwent ITT, copeptin increased minimally from a median of 8 (IQR 7-11, range 5-12) to 10 (IQR10-14, range 6-17) at 45 min, and 9(IQR 2-13, range 8-12) pM/L at 60 min. In the outlier who underwent ITT, copeptin decreased from 202 (0 min) to 63 (45 min) and 51(60 min) pM/L. None of these children had abnormalities of fluid regulation (polydipsia, polyuria, abnormal serum Na+ levels). The highest copeptin level (&amp;gt;1000 pM/L) occurred in a subject who had 3 successive attempts at phlebotomy. Conclusions Very elevated serum concentrations of copeptin occur in a minority of pediatric subjects undergoing phlebotomy, suggesting that pain of venipuncture can be a potent stimulus of copeptin secretion. Unexplained high values were observed in another pediatric study (Bonnet, Clin Endocrinol 2022;96: 47-53). This information is relevant to clinicians measuring copeptin for diagnostic or prognostic purposes or to establish reference values. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

ODP221 Late-Onset Hypoglycemia in a Patient with Fatty Acid Oxidation Disorder

Abstract Background Multiple acyl-CoA dehydrogenase deficiency (MADD) is a disorder of fatty acid and protein metabolism due to a defect in electron transfer flavoprotein or in electron transfer flavoprotein dehydrogenase, and can present with hypoglycemia as a component of its clinical phenotype. We describe a rare case of hypoglycemia due to MADD with unusually late onset at age of 63 years. Clinical case: 63-year-old female with history of hypertension and depression, admitted to the hospital with a several month history of progressive weakness resulting in inability to walk, lightheadedness, unintentional 40-pound weight loss and oropharyngeal dysphagia to solids. On exam, she was noted to have predominant cranial neuropathies and proximal muscle weakness. Patient was found to be hypoglycemic to 47 mg/dL [75-200], with a lactic acidosis of 2.1 mmol/L [0.5-1.9], elevated CK of 630 U/L [22-269], elevated aldolase of 12.7 U/L [1.5-8.1], and increased beta-hydroxybutyrate of 2.9 mmol/L [&amp;lt;0.3] along with transaminitis without cholestatic pattern. Fasting insulin level was 6 uIU/mL [3-19], C-peptide was low normal 1.1 ng/dl [0.8-3.5] with corresponding glucose of 57 mg/dl. Proinsulin level and sulfonylurea panel were unremarkable, and insulin antibodies were negative. Adrenal insufficiency was ruled out with normal cosyntropin stimulation test. IGF-1 and IGF-2 levels were also within normal limits. CT scan of the head, abdomen and pelvis did not evidence any issues. Furthermore, prior to this admission, patient had extensive work-up done for generalized weakness including evaluation for myasthenia gravis, myositis, HIV, thyroid disease, and other autoimmune conditions which was unrevealing. A muscle biopsy was performed with patology suggestive of a lipid storage disorder. Genetic testing only demonstrated variants of uncertain significance in LARGE1, PLEC and TTN genes. Additional testing revealed elevated serum concentrations of short, medium and long chain acylcarnitine species. Urinary organic acids were also increased with predominant elevation of 2-hydroxy-glutaric, ethylmalonic, adipic and suberic acids. This pattern, along with increased plasma acylcarnitine is typically associated with multiple acyl-CoA dehydrogenase deficiency. Serum free fatty acids were also high, supportive of MADD as previously reported in some cases. She was started on high-dose riboflavin replacement and advised to ingest a low-fat, low-protein diet, with frequent feeding and blood glucose monitoring. Conclusion MADD is a rare cause of hypoglycemia in adults. It is important to consider this condition as a differential diagnosis of hypoglycemia associated with generalized weakness even in older individuals. Presentation: No date and time listed

Characteristics and Outcomes of Suspected Digoxin Toxicity and Immune Fab Treatment Over the Past Two Decades—2000-2020

The role of digoxin in clinical practice has narrowed over time. Data on digoxin toxicity trends and outcomes are variable and lack granularity for treatment outcomes. This study aimed to address data gaps in digoxin toxicity trends and outcomes in patients treated with or without digoxin immune fab (DIF). This single-center analysis examined patients with signs/symptoms concerning digoxin toxicity, defined as hospital admission or emergency department visit with elevated digoxin serum concentrations (>2ng/ml) and/or a primary diagnosis code of digoxin toxicity and/or DIF order. Between 2000 and 2020, 727 patients were identified with signs concerning for digoxin toxicity with a mortality rate of 12.7% during admission and 42.7% at 1year. DIF was ordered in 9% of cases. Incidence of digoxin toxicity per 1,000 patients with a digoxin prescription and frequency of DIF treatment fluctuated over time without a clear trend toward increase or reduction. DIF-treated patients demonstrated a heavier co-morbidity burden and lower presenting heart rates (median 53 [39.5 to 69.5] vs 77 [64.0 to 91.5]beats/min, p <0.001), worse renal function (median estimated glomerular filtration rate, 30.3 [14.8 to 48.6] vs 40.0 [24.2 to 61.2]ml/min/1.73m2, p=0.013), and higher potassium (median 4.5 [4.0 to 5.3] vs 4.3 [3.9 to 4.8]mEq/L, p=0.022). Compared with a matched cohort, DIF-treated patients experienced a nonsignificant, numerically lower in-hospital mortality (8.2% vs 15.8%, p=0.199) and 30-day all-cause hospitalization (14.3% vs 24.7%, p=0.112) and similar 6-month and 1-year hospitalization and mortality. In conclusion, digoxin toxicity remains a pertinent public health issue despite reduction in digoxin utilization. DIF therapy is used in a medically complex population with a high-acuity illness at presentation and is associated with nonsignificant trends toward reduced in-hospital mortality and early readmission that are attenuated over time.

MicroRNA-4516 in Urinary Exosomes as a Biomarker of Premature Ovarian Insufficiency.

Premature ovarian insufficiency (POI) is a typical disorder of amenorrhea that lasts for a minimum of four months in women < 40 years old and is typically characterized by reduced estrogen levels and elevated serum concentrations of follicle-stimulating hormone. We collected urine samples from two participant cohorts from Gil Hospital of Gachon University (Incheon, Korea): a sequencing cohort of 19 participants (seven patients with POI (POI patients without Turner syndrome), seven patients with Turner syndrome (POI patients with Turner syndrome), and five control individuals (age-matched controls with confirmed ovarian sufficiency)) and a validation cohort of 46 participants (15 patients with POI, 11 patients with Turner syndrome, and 20 control individuals). Among differentially expressed miRNAs, hsa-miR-4516 was significantly upregulated in patients with POI in both cohorts, independent of the presence of Turner syndrome. Moreover, the upregulation of miR-4516 was confirmed in the ovary—but not in the uterus—of a cyclophosphamide and busulfan-induced POI mouse model. This was accompanied by a decrease in STAT3 protein level, a predicted target of miR-4516, via miRTarBase2020. Our study provides compelling evidence that miR-4516 is highly expressed in patients with POI and POI mouse models, suggesting that miR-4516 is a diagnostic marker of POI.