Sulfonic Functionalized Polydopamine Coatings with pH-Independent Surface Charge for Optimizing Capillary Electrophoretic Separations.

Enhancing the pH-independence and controlling the magnitude of electroosmotic flow (EOF) are critical for highly efficient and reproducible capillary electrophoresis (CE) separations. Herein, we present a novel capillary modification method utilizing sulfonated periodate-induced polydopamine (SPD) coating to achieve pH-independent and highly reproducible cathodic EOF in CE. The SPD-coated capillaries were obtained through post-sulfonation treatment of periodate-induced PDA (PDA-SP) coatings adhered on the capillary inner surface. The successful immobilization of the SPD coating and the substantial grafting of sulfonic acid groups were confirmed by a series of characterization techniques. The excellent capability of PDA-SP@capillary in masking silanol groups and maintaining a highly robust EOF mobility was verified. Additionally, the parameters of sulfonation affecting the EOF mobilities were thoroughly examined. The obtained optimum SPD-coated column offered the anticipated highly pH-independent and high-strength cathodic EOF, which is essential for enhancing the CE separation performance and improving analysis efficiency. Consequently, the developed SPD-coated capillaries enabled successful high-efficiency separation of aromatic acids and nucleosides and rapid cyclodextrin-based chiral analysis of racemic drugs. Moreover, the SPD-coated columns exhibited a long lifetime and demonstrated good intra-day, inter-day, and column-to-column repeatability.

Plasma and serum metabolic analysis of healthy adults shows characteristic profiles by subjects' sex and age.

INTRODUCTION: Pre-analytical factors like sex, age, and blood processing methods introduce variability and bias, compromising data integrity, and thus deserve close attention. OBJECTIVES: This study aimed to explore the influence of participant characteristics (age and sex) and blood processing methods on the metabolic profile. METHOD: A Thermo UPLC-TSQ-Quantiva-QQQ Mass Spectrometer was used to analyze 175 metabolites across 9 classes in 208 paired serum and lithium heparin plasma samples from 51 females and 53 males. RESULTS: Comparing paired serum and plasma samples from the same cohort, out of the 13 metabolites that showed significant changes, 4 compounds related to amino acids and derivatives had lower levels in plasma, and 5 other compounds had higher levels in plasma. Sex-based analysis revealed 12 significantly different metabolites, among which most amino acids and derivatives and nitrogen-containing compounds were higher in males, and other compounds were elevated in females. Interestingly, the volcano plot also confirms the similar patterns of amino acids and derivatives higher in males. The age-based analysis suggested that metabolites may undergo substantial alterations during the 25-35-year age range, indicating a potential metabolic turning point associated with the age group. Moreover, a more distinct difference between the 25-35 and above 35 age groups compared to the below 25 and 25-35 age groups was observed, with the most significant compound decreased in the above 35 age groups. CONCLUSION: These findings may contribute to the development of comprehensive metabolomics analyses with confounding factor-based adjustment and enhance the reliability and interpretability of future large-scale investigations.

Challenges of insulin-like growth factor-1 testing.

Insulin-like growth factor 1 (IGF-1), primarily synthesized in the liver, was initially discovered due to its capacity to replicate the metabolic effects of insulin. Subsequently, it emerged as a key regulator of the actions of growth hormone (GH), managing critical processes like cell proliferation, differentiation, and apoptosis. Notably, IGF-1 displays a longer half-life compared to GH, making it less susceptible to factors that may affect GH concentrations. Consequently, the measurement of IGF-1 proves to be more specific and sensitive when diagnosing conditions such as acromegaly or GH deficiency. The recognition of the existence of IGFBPs and their potential to interfere with IGF-1 immunoassays urged the implementation of various techniques to moderate this issue and provide accurate IGF-1 results. Additionally, in response to the limitations associated with IGF-1 immunoassays and the occurrence of discordant IGF-1 results, modern mass spectrometric methods were developed to facilitate the quantification of IGF-1 levels. Taking advantage of their ability to minimize the interference caused by IGF-1 variants, mass spectrometric methods offer the capacity to deliver robust, reliable, and accurate IGF-1 results, relying on the precision of mass measurements. This also enables the potential detection of pathogenic mutations through protein sequence analysis. However, despite the analytical challenges, the discordance in IGF-1 reference intervals can be attributed to a multitude of factors, potentially leading to distinct interpretations of results. The establishment of reference intervals for each assay is a demanding task, and it requires nationwide multicenter collaboration among laboratorians, clinicians, and assay manufacturers to achieve this common goal in a cost-effective and resource-efficient manner. In this comprehensive review, we examine the challenges associated with the standardization of IGF-1 measurement methods, the minimization of pre-analytical factors, and the harmonization of reference intervals. Particular emphasis will be placed on the development of IGF-1 measurement techniques using "top-down" or "bottom-up" mass spectrometric methods.

Distinct plasma molecular profiles between early-onset and late-onset colorectal cancer patients revealed by metabolic and lipidomic analyses.

Colorectal cancer (CRC) incidence in younger adults has been steadily rising, warranting an in-depth investigation into the distinctions between early-onset CRC (EOCRC, < 50 years) and late-onset CRC (LOCRC, ≥ 50 years). Despite extensive study of clinical, pathological, and molecular traits, differentiating EOCRC from LOCRC and identifying potential biomarkers remain elusive. We analyzed plasma samples from healthy individuals, EOCRC, and LOCRC patients using liquid-chromatography mass spectrometry (LC/MS)-based metabolomics and lipidomics. Distinct polar metabolite and lipid profiles with significant metabolites altered in CRC group (e.g., choline and DG 40:4) were identified. Notably, EOCRC exhibited distinct polar metabolomic and differential lipidomic profiles compared to LOCRC, with polar metabolites like aminoadipate and uridine contributing significantly to the difference, and originating from pathways such as lysine biosynthesis and nucleotide metabolism. Furthermore, gene set enrichment analysis (GSEA) using independent TCGA gene expression data identified pathways significantly enriched in either EOCRC or LOCRC. Integrating gene expression and metabolomics data revealed numerous associations differentiating EOCRC and LOCRC. Our multi-omics integration underscores critical molecular distinctions, offers insights into the EOCRC development mechanisms and potential plasma biomarkers for diagnosis.

Mindfulness meditation intervention improves the mindfulness awareness level of nurses' second victims to enhance their psychological support.

Introduction: The medical staff involved in adverse events, referred to as second victims, usually suffer second victim syndrome endangering their health. Still, there are few organizational support projects in this area in China. Objective: To explore the effect of mindfulness meditation on the level and needs of organizational support, and mindfulness awareness among nurses as second victims. Methods: Forty-six nurses from a comprehensive tertiary hospital in Wuhan, China were selected to participate in the study. This study was conducted using a convenience sampling method for eight weeks of mindfulness meditation intervention. The Second Victim Experience and Support Tool and Mindfulness Attention Awareness Scale were used to assessing the need for support and mindfulness awareness of nurses prior to intervention, during the fourth and eighth weeks of intervention, and at the conclusion of the intervention course. Results: The difference between the scores measured before the intervention, in the fourth week, and in the eighth week of intervention showed that the need for the second victim support from work-related organizations was significant (F = 34.513, p = .000); there was no significant difference in the scores related to the need for nonwork-related support of the second victim in the participating nurses (F = 1.373, p = .257); the scores of the level of mindfulness awareness were (64.85 ± 11.41), (68.63 ± 11.33), and (71.20 ± 8.41), a significant difference (F = 18.848; p = .000) was found in terms of before and after the intervention; nurses' second victim support needs gradually shifted from evasion to confronting problems appropriately. Conclusion: Mindfulness meditation intervention is applicable to the second victim population of nurses. It is an effective way to support second victim nurses and can effectively improve their level of mindfulness and awareness.

Relationship between TSH and free thyroxine in outpatient cancer patient population.

BACKGROUND: The inverse log-linear relationship between Thyroid-stimulating hormone (TSH) and free thyroxine (FT4) is well established and reliably used for evaluation of hypothalamus-pituitary-thyroid (HPT) axis function. However, there are limited data regarding oncologic states in the TSH-FT4 relationship. The purpose of this study was to evaluate thyroid pituitary hypothalamic feedback regulation by the inverse log TSH and FT4 relationship in the cancer patient population at the Ohio State University Comprehensive Cancer Center (OSUCCC-James). METHODS: This retrospective study analyzed the correlation between TSH and FT4 results from 18846 outpatient subjects collected in August 2019-November 2021 at the Department of Family Medicine (OSU Wexner Medical Center), Department of Oncology (OSUCCC-James). Patients with diagnoses related to cancers were included in the oncology group. Patients with diagnoses not related to cancers were included in the non-oncology group. Patients of the Department of Endocrinology, Department of Cardiology, Department of Obstetrics & Gynecology and Department of Hematology were excluded from this study. Time of collection for TSH and FT4 was from 7am to 7 pm. Data were analyzed by morning (7am-12pm) and afternoon (12pm-7pm). Spearman correlation and non-linear fit were used for data analysis. Sex differences were analyzed as well in each group. RESULTS: Overall, an inverse correlation was observed between TSH and FT4 in both groups (non-oncology and oncology) regardless of sample collection time and sex differences. Further analysis by linear model in log TSH and FT4 showed a significant inverse fit in males compared with females in the group of oncology, both in the afternoon (p < 0.05). Data were further analyzed by ranges of FT4, as lower or higher (pathophysiology) or within (physiology) the reference interval of FT4. There was no statistical significance between the non-oncology and oncology groups, but relatively good correlation in non-oncology group in either physiologic or pathophysiologic FT4 levels and sample collection time. Interestingly, the best correlation between TSH and FT4 was found in the non-oncology group at pathophysiologic FT4 concentrations (abnormally high). In addition, at pathophysiologic FT4 concentrations (abnormally low), the oncology group demonstrated a significant TSH response in the morning than in the afternoon (p < 0.05). CONCLUSIONS: Though overall the TSH-FT4 curves showed an inverse relationship, there are variations of TSH-FT4 relationship for collection times when considering FT4 in physiologic or pathophysiologic states. The results advance understanding of TSH response, which is beneficial for the interpretation of thyroid disease. We recommend re-evaluation for interpretation of pituitary hypothalamic axis by TSH results when FT4 is abnormally high in oncology patients or low in non-oncology patients, due to poor predictability and the potential for misdiagnosis. A better understanding of the complex nature of the TSH-FT4 relationship may need further study with better defining subclinical states of cancer patients.

Utility of Commercially Available Quantitative hCG Immunoassays as Tumor Markers in Trophoblastic and Non-Trophoblastic Disease.

BACKGROUND: The use of quantitative human chorionic gonadotropin (hCG) as a tumor marker is widely accepted despite lack of FDA-approval for oncology. Differences in iso- and glycoform recognition among hCG immunoassays is well established, exhibiting wide inter-method variability. Here, we assess the utility of 5 quantitative hCG immunoassays for use as tumor markers in trophoblastic and non-trophoblastic disease. METHODS: Remnant specimens were obtained from 150 patients with gestational trophoblastic disease (GTD), germ cell tumors (GCT), or other malignancies. Specimens were identified by review of results from physician-ordered hCG and tumor marker testing. Five analyzer platforms were used for split specimen analysis of hCG: Abbott Architect Total, Roche cobas STAT, Roche cobas Total, Siemens Dimension Vista Total, and Beckman Access Total. RESULTS: Frequency of elevated hCG concentrations (above reference cutoffs) was highest in GTD (100%), followed by GCT (55% to 57%), and other malignancies (8% to 23%). Overall, the Roche cobas Total detected elevated hCG in the greatest number of specimens (63/150). Detection of elevated hCG in trophoblastic disease was nearly equivalent among all immunoassays (range, 41 to 42/60). CONCLUSIONS: While no immunoassay is likely to be perfect in all clinical situations, results for the 5 hCG immunoassays evaluated suggest that all are adequate for use of hCG as a tumor marker in gestational trophoblastic disease and select germ cell tumors. Further harmonization of hCG methods is needed as serial testing for biochemical tumor monitoring must still be performed using a single method. Additional studies are needed to assess the utility of quantitative hCG as a tumor marker in other malignant disease.

Heparin Concentration in Evacuated Tubes and Its Effect on pH, Ionized Calcium, Lactate, and Potassium in Venous Blood Gas Analysis.

Arterial blood specimens collected in evacuated tubes are unacceptable for blood gas analysis. However, evacuated tubes are routinely used for venous blood-gas analysis. The impact of the blood to heparin ratio on venous blood in evacuated tubes is unclear. Venous blood was drawn into lithium and sodium heparin evacuated tubes that were 1/3 full, ½ full, 2/3 full, and fully filled. Specimens were analyzed for pH, ionized calcium (iCa), lactate, and potassium on a blood-gas analyzer. The results for specimens filled only 1/3 full for lithium and sodium heparin tubes revealed a significant increase in pH and a significant decrease in the iCa. Underfilling the lithium and sodium heparin evacuated tubes did not significantly impact the lactate or potassium results. Venous whole-blood specimens should be filled to at least 2/3 full for accurate pH and iCa results.

Morphometric analysis of the size-adjusted linear dimensions of the skull landmarks revealed craniofacial dysmorphology in Mid1-cKO mice.

BACKGROUND: The early craniofacial development is a highly coordinated process involving neural crest cell migration, proliferation, epithelial apoptosis, and epithelial-mesenchymal transition (EMT). Both genetic defects and environmental factors can affect these processes and result in orofacial clefts. Mutations in MID1 gene cause X-linked Opitz Syndrome (OS), which is a congenital malformation characterized by craniofacial defects including cleft lip/palate (CLP). Previous studies demonstrated impaired neurological structure and function in Mid1 knockout mice, while no CLP was observed. However, given the highly variable severities of the facial manifestations observed in OS patients within the same family carrying identical genetic defects, subtle craniofacial malformations in Mid1 knockout mice could be overlooked in these studies. Therefore, we propose that a detailed morphometric analysis should be necessary to reveal mild craniofacial dysmorphologies that reflect the similar developmental defects seen in OS patients. RESULTS: In this research, morphometric study of the P0 male Mid1-cKO mice were performed using Procrustes superimposition as well as EMDA analysis of the size-adjusted three-dimensional coordinates of 105 skull landmarks, which were collected on the bone surface reconstructed using microcomputed tomographic images. Our results revealed the craniofacial deformation such as the increased dimension of the frontal and nasal bone in Mid1-cKO mice, in line with the most prominent facial features such as hypertelorism, prominent forehead, broad and/or high nasal bridge seen in OS patients. CONCLUSION:  While been extensively used in evolutionary biology and anthropology in the last decades, geometric morphometric analysis was much less used in developmental biology. Given the high interspecies variances in facial anatomy, the work presented in this research suggested the advantages of morphometric analysis in characterizing animal models of craniofacial developmental defects to reveal phenotypic variations and the underlining pathogenesis.

Discordance of insulin-like growth factor-1 results and interpretation on four different platforms.

OBJECTIVE: Inconsistent Insulin-like Growth Factor 1 (IGF-1) measurements among different platforms have been observed. In this study, we compared the IGF-1 assay on four different platforms. METHODS: A total of 110 serum specimens were analyzed in this comparison study. IGF-1 was measured on the three different chemiluminescent automated immunoassay of Siemens Immulite 2000 XPi, DiaSorin Liaison XL, IDS iSYS and LC-MS/MS method. Results were compared with Weighted Deming regression. Bias was evaluated using the Bland-Altman method. RESULTS: Weighted Deming regression analysis showed approximately 36 % negative variation on Immulite, compared to Liaison (Immulite = 0.64 * DiaSorin + 2.95, r2 = 0.95); 8 % negative variation on iSYS, compared to Liaison (iSYS = 0.92 * DiaSorin + 0.51, r2 = 0.97); 17 % negative variation on LC-MS/MS, compared to Liaison (LC-MS/MS = 0.83 * DiaSorin-11.23, r2 = 0.93); 34 % positive variation on LC-MS/MS compared to Immulite (LC-MS/MS = 1.34 * Immulite-21.97, r2 = 0.96); 81 % positive variation on IDS iSYS compared to Immulite (IDS iSYS = 1.81 * Immulite-117.65, r2 = 0.83). The Bland-Altman plot showed a significant negative variation of Immulite versus DiaSorin and positive variation of IDS iSYS versus Immulite. Overall agreement between different platforms was poor, which reflected systematic difference. The variation between platforms increased as IGF-1 values increased. CONCLUSIONS: There are wide variations between different platforms for IGF-1 measurement. The lack of standardization in IGF-1 measurement creates a challenge for clinicians to monitor IGF-1 and treat patients with pituitary disorders, when switching from one platform to another. The potential impact of the variations in IGF-1 measurement between different platforms should be taken into consideration when managing patients.

Hybrid surgery for coexistence of cerebral arteriovenous malformation and primitive trigeminal artery: A case report and literature review.

The primitive trigeminal artery (PTA), an abnormal carotid-basilar anastomosis, forms the vascular anomaly connection between the internal carotid artery and vertebrobasilar system. Rarely, PTA can be complicated by several other cerebrovascular disease, including arteriovenous malformations (AVMs), intracranial aneurysms, moyamoya disease, and carotid-cavernous malformations. Herein, we reported a rare case of PTA combined with an AVM in a male patient. The patient was a 28-year-old male with epileptic seizures at the onset of symptoms. Magnetic resonance imaging showed abnormal signal foci and localized softening foci formation with gliosis in the right parietal temporal lobe. Furthermore, using a digital subtraction angiogram (DSA), it was found that an abnormal carotid-basilar anastomosis had developed through a PTA originating from the cavernous portion of the right internal carotid artery (ICA) and a large AVM on the surface of the right carotid artery. The lesion of AVM tightly developed and draining into superior sagittal sinus. A hybrid operating room was used for the surgery. The main feeding arteries of the AVM originating from three major arteries, including the right middle cerebral artery, the right anterior cerebral artery, and the right posterior cerebral artery, were clipped and subsequently, then the AVM was thoroughly removed. The intraoperative DSA showed that the AVM had been resected completely. Postoperative pathological examination of the resected specimen indicated the presence of an AVM. The patient recovered well after surgery and has been symptom-free for more than 3 months. In summary, the pathogenesis of the coexistence of PTA and AVM remains unknown. As highlighted in this case report, hybrid surgery can be used to remove AVMs and can improve the patients' prognosis. To our best knowledge, this is the first case in the literature of successful AVM treatment using hybrid surgery.

New Diagnostic Cutoffs for Adrenal Insufficiency After Cosyntropin Stimulation Using Abbott Architect Cortisol Immunoassay.

INTRODUCTION: The accurate interpretation of the cosyntropin (adrenocorticotropic hormone [ACTH]) stimulation test requires method- and assay-specific cutoffs of the level of cortisol. Compared with a historical cutoff (18 µg/dL) for polyclonal antibody-based immunoassays, lower thresholds were proposed for the Roche Elecsys II assay, which uses a monoclonal antibody. However, cutoffs for other commonly adopted, monoclonal antibody-based cortisol assays were not yet available. Here, we established the thresholds for the level of cortisol specific to the Abbott Architect immunoassay by comparing the measurements of the level of cortisol using 3 immunoassays. METHODS: The ACTH stimulation test was performed in patients with suspected adrenal insufficiency (n = 50). The serum cortisol level was measured using the Abbott Architect, Roche Elecsys II, and Siemens Centaur assays. The results of the Abbott assay were also compared with those of liquid chromatography-tandem mass spectrometry. The receiver operating characteristic analysis was performed to derive new diagnostic thresholds for the Abbott assay using the polyclonal antibody-based Siemens assay as the reference method. RESULTS: The concentrations of cortisol measured using the Abbott assay were similar to those measured using liquid chromatography-tandem mass spectrometry and the Roche Elecsys II assay but significantly lower than those measured using the Siemens assay. The optimized threshold for cortisol using the Abbott assay was 14.6 µg/dL at 60 minutes after stimulation (sensitivity, 92%; specificity, 96%) and 13.2 µg/dL at 30 minutes after stimulation (sensitivity, 100%; specificity, 89%). CONCLUSION: We recommend a threshold of 14.6 µg/dL for the level of cortisol at 60 minutes after ACTH stimulation for the Abbott assay. In comparison with the historical threshold of 18 µg/dL, the application of the new cutoff may significantly decrease false-positive results due to ACTH stimulation testing. The use of assay-specific cutoffs will be essential for reducing misclassification and overtreatment in patients with suspected adrenal insufficiency.

miR-203, fine-tunning neuroinflammation by juggling different components of NF-κB signaling.

BACKGROUND: miR-203 was first indicated in maintaining skin homeostasis and innate immunity. Aberrant expression of miR-203 was found associated with pathological progressions of immune disorders, cancers, as well as neurodegenerations. Recently, increasing data on miR-203 in regulating neuroinflammation and neuronal apoptosis has raised extensive concern about the biological function of this microRNA. METHODS: Mouse model with ectopic miR-203 expression in the hippocampus was constructed by stereotactic injection of lentiviral expression vector of pre-miR-203. Association of miR-203 and mRNA of Akirin2, as well as the competition for miR-203 targeting between Akirin2 3'UTR and another recently characterized miR-203 target, 14-3-3θ, was verified using Dual-Luciferase Reporter Gene Assay and western blot. Microglia activation and pro-inflammatory cytokines expression in the hippocampus of mice overexpressing miR-203 was evaluated using immunohistochemistry analysis and western blot. Neuronal cell death was monitored using anti-caspase 8 in immunohistochemistry as well as TUNEL assay. Cognition of mice was assessed with a behavior test battery consisting of nesting behavior test, Barnes maze and fear conditioning test. RESULTS: Akirin2, an activator of NF-κB signaling, was identified as a direct target of miR-203. By also targeting 14-3-3θ, a negative regulator of NF-κB signaling, miR-203 displayed an overall pro-inflammatory role both in vitro and in vivo. Promoted nuclear translocation of NF-κB and increased expression of proinflammatory cytokines were observed in cultured BV2 cells transfected with miR-203 mimics. Microglia activation and upregulation of NF-κB, IL-1ß and IL-6 were observed in mouse hippocampus with overexpression of miR-203. In addition, promoted neuronal cell death in the hippocampus and impaired neuronal activities resulted in cognitive dysfunction of mice with ectopic miR-203 expression in the hippocampus. CONCLUSION: A pro-inflammatory and neurodisruptive role of miR-203 was addressed based on our data in this study. Given the identification of Akirin2 as a direct target of miR-203 and the competition with 14-3-3θ for miR-203 targeting, together with the findings of other signaling molecules in NF-κB pathway as targets of miR-203, we proposed that miR-203 was a master modulator, fine-tunning neuroinflammation by juggling different components of NF-κB signaling.

Large inter-assay difference of serum creatinine in pediatric population: a threat to accurate staging of chronic kidney disease.

BACKGROUND: Serum creatinine concentration is a primary component of Bedside Schwartz equation for estimated glomerular filtration rate (eGFR) in children. To standardize creatinine measurement, most manufacturers have adopted calibration procedures traceable to isotope dilution mass spectrometry (IDMS) using National Institute of Standards and Technology reference material. However, reference material representing much lower creatinine concentrations seen in children is not available and it is unclear how well commercial assays perform at pediatric levels. METHODS: One thousand nine hundred seventy-one specimens from consecutive children <19 years, with creatinine ≤0.8 mg/dL by Abbott Jaffe method were included. Creatinine measurements were compared between Abbott-Jaffe and Abbott-enzymatic methods. Furthermore, we evaluated performance of six commercial creatinine assays at concentrations seen in pediatric patients utilizing IDMS traceable serum samples. RESULTS: Median difference (enzymatic-Jaffe) for prepubertal females was -0.18 mg/dL (2.5%tile, 97.5%tile: -0.30, -0.06), -0.12 mg/dL (-0.25, -0.00) for pubertal females, -0.17  mg/dL (-0.30, -0.04) for prepubertal males, -0.11 mg/dL (-0.24, 0.01) for pubertal males. Bias appeared proportional for each subgroup and decreased as creatinine concentrations increased. Using IDMS traceable samples, the greatest inter-assay variability was seen with the lowest creatinine levels (target 0.273 mg/dL), where 67% (4/6) of methods failed to reach minimal bias specification of 8% (range -7.5 to 86%). For samples with higher creatinine targets (0.440-0.634 mg/dL), two methods failed to meet minimal bias specification, whereas four showed bias <8%. CONCLUSION: Many commonly used creatinine assays remain inaccurate for pediatric populations after over a decade of nationwide efforts to standardize measurements. When creatinine-based eGFR is used for chronic kidney disease (CKD) staging in children, large inter-assay variability can lead to disease misclassification, inappropriate diagnostic and therapeutic interventions. A higher resolution version of the Graphical abstract is available as Supplementary information.

Evaluation of the Preanalytical Interference of Hemoglobin, Bilirubin, or Lipids in Therapeutic Drug Monitoring Assays on Beckman Coulter AU Analyzers.

OBJECTIVE: The aim of this study was to evaluate the influence of hemolysis, icterus, and lipemia (HIL) interferences on 8 therapeutic drug monitoring (TDM) assays. METHODS: Amikacin, carbamazepine, digoxin, lidocaine, lithium, methotrexate, phenobarbital, and theophylline were spiked in specimen pools at the clinical decision cutoff values. The interferents were spiked in vitro in specimen pools. All analytes were tested on Beckman Coulter AU analyzers. RESULTS: Hemolysis interference was detected in quantitative microsphere system (QMS) amikacin at 55.59 µg/mL at a concentration of 500 mg/dL hemoglobin. Icterus interference was detected in enzyme multiplied immunoassay technique amikacin at 43.62 µg/mL and in QMS amikacin at 55.59 µg/mL, at a concentration of 20 mg/dL bilirubin. CONCLUSION: Although the reference range value is recommended for clinical significance bias assessment for HIL interferences on most chemistry assays, an important investigation of the HIL interferences on TDM assays is to establish interferent thresholds at the clinical critical cutoff values.

Comparison of the Siemens Atellica BRAHMS and the Abbott Architect BRAHMS Procalcitonin Assays.

OBJECTIVE: In this study, we compared the Abbott Architect B.R.A.H.M.S procalcitonin (PCT) assay with the newly developed Siemens Atellica B.R.A.H.M.S PCT assay. METHODS: Residual 45 lithium heparin plasma/serum specimens were randomly selected from routine hospital orders, and PCT was measured on both systems and compared with Passing-Bablok regression. Bias was evaluated using the Bland-Altman method. Concordance correlation was used for agreement evaluation at the clinically diagnostic cutoff of 0.10, 0.25, 0.50, and 2.00 ng/mL. RESULTS: Weighted Deming regression analysis showed approximately 13% positive bias (Atellica PCT=1.13*Architect PCT+0.02, r=0.961). The Passing-Bablok regression analysis of the total sample range revealed approximately 12% positive bias of the Atellica PCT compared to the Architect PCT (Atellica PCT=1.12*Architect PCT+0.02, r=0.961). The Bland-Altman plot showed the agreement between Atellica and Architect PCT was on average 0.04±0.25 ng/mL in the clinically relevant range of 0.1-2.0 ng/mL. The concordance of both methods at the clinically diagnostic cutoff (0.1, 0.25, 0.5, 2.0 ng/mL) showed excellent overall agreement at each threshold (90-100%). CONCLUSIONS: The Siemens Atellica B.R.A.H.M.S PCT assay showed good correlation with the established Abbott Architect B.R.A.H.M.S PCT assay. Therefore, this technique can be used in clinical routine with the same clinical interpretation.

No increase in the incidence of cardiac troponin I concentration above the 99th percentile by Siemens Centaur high-sensitivity compared to the contemporary assay.

BACKGROUND: This study aimed to compare the incidence of cardiac troponin I (cTnI) concentrations above the limit of quantification (LOQ) and the sex-specific 99th percentile upper reference limits (URLs) between the Ultra contemporary cTnI assay and the high-sensitivity (hs-cTnI) assay on Siemens Centaur in patients evaluated in the emergency department (ED) and inpatient at a U.S. urban academic hospital. METHODS: A retrospective study was performed in an unselected patient cohort who presented to the hospital with symptoms suggestive of myocardial injury. All clinically ordered samples for cTnI assay (n = 1,056, LOQ 0.03 µg/L, URL 0.04 µg/L) were simultaneously tested on the hs-cTnI assay (LOQ 2.5 ng/L; URL 58 ng/L and 39 ng/L for male and female, respectively). RESULTS: The incidence of elevated cTnI above the 99th percentile URL in males measured by the hs-cTnI assay was significantly lower compared to the cTnI assay (31.4% vs. 38.7%, p = 0.016), whereas there was no difference in females (27.4% vs. 30.2%, p = 0.35) in all the patient samples. In ED patient samples (n = 718), the incidence of elevated cTnI above the sex-specific 99th percentile URL was not significantly different between the hs-cTnI and contemporary cTnI assays in either sex (male: hs-cTnI 16.6% vs. cTnI 21.5%, p = 0.13; female: hs-cTnI 19.6% vs. cTnI 21.1%, p = 0.66). The agreement between the two assays was 93.5% (kappa = 0.798). Results were confirmed in an independent patient cohort measured by the same instruments at another hospital. CONCLUSION: Our study suggests that implementation of the hs-cTnI assay would not lead to an increase in the proportion of elevated cTnI above the 99th percentile in the emergency department and other inpatient units.

Detection of subclinical cardiotoxicity in sarcoma patients receiving continuous doxorubicin infusion or pre-treatment with dexrazoxane before bolus doxorubicin.

BACKGROUND: Continuous infusion of doxorubicin or dexrazoxane pre-treatment prior to bolus doxorubicin are proven strategies to protect against doxorubicin-induced cardiotoxicity. Recently, global longitudinal peak systolic strain (GLS) measured with speckle tracking echocardiography (STE) and high-sensitivity troponin T (hs-TnT) have been validated as sensitive indicators of doxorubicin-induced cardiotoxicity. Here, we asked whether changes in hs-TnT and/or GLS can be detected in patients who were treated with continuous infusion of doxorubicin or pre-treated with dexrazoxane followed by bolus doxorubicin. METHODS: Twenty-nine patients with newly diagnosed sarcoma were assigned to receive either 72-h doxorubicin infusion or dexrazoxane pre-treatment before bolus doxorubicin. Eight patients received dexrazoxane pre-treatment; eleven patients received continuous doxorubicin infusion; ten patients crossed over from continuous infusion to dexrazoxane. Bloods were collected for hs-TnT at baseline, 24 h or 72 h after initiation of doxorubicin treatment in each chemotherapy cycle. All blood samples were assayed in batch using hs-TnT kit from Roche diagnostics. 2D Echo and STE were performed before doxorubicin, after cycle 3, and at the end of chemotherapy. RESULTS: Seven patients in the cross-over group have at least one hs-TnT measurement between 5 ng/L to 10 ng/L during and after chemotherapy. Ten patients have at least one hs-TnT measurement above 10 ng/ml during and after chemotherapy (six in dexrazoxane group, three in continuous infusion group, one in cross-over group). The average hs-TnT level increases with each additional cycle of doxorubicin treatment. Eight patients had a more than 5% reduction in LVEF at the end of chemotherapy (four in dexrazoxane group, three in continuous infusion group, and one in cross-over group). Four out of these eight patients had a change of GLS by more than 15% (three in the dexrazoxane group). CONCLUSION: Elevation in hs-TnT levels were observed in more than 59% of patients who had received either continuous doxorubicin infusion or dexrazoxane pre-treatment before bolus doxorubicin. However, changes in LVEF and GLS were less frequently observed. Thus, continuous doxorubicin infusion or dexrazoxane pre-treatment do not completely ameliorate subclinical doxorubicin-induced cardiotoxicity as detected by more sensitive techniques.

Cerebral Hyperperfusion Syndrome After Revascularization Surgery in Patients with Moyamoya Disease: Systematic Review and Meta-Analysis.

BACKGROUND: Cerebral hyperperfusion syndrome (CHS) after bypass surgery is known as a complication of moyamoya disease (MMD). However, the incidence of CHS has not been accurately reported, and there is no consensus on related risk factors. OBJECTIVE: To evaluate the incidence and characteristics of CHS in patients with MMD after revascularization surgery via meta-analysis. METHODS: Relevant cohort studies were retrieved through a literature search of PubMed, Embase, and Ovid until December 1, 2018. Eligible studies were identified per search criteria. A systematic review and meta-analysis were used to assess the CHS total incidence, incidence in pediatric patients with MMD and adult patients with MMD, incidence for direct and combined bypass surgery, progress rate, and proportion of each symptom (including transient neurologic deficits [TNDs], hemorrhage, and seizure). RESULTS: A total of 27 cohort studies with 2225 patients were included in this meta-analysis. The weighted proportions per random-effects model were 16.5% (range, 11.3%-22.3%) for CHS total incidence, 3.8% (range, 0.3%-9.6%) for pediatric patients with MMD, 19.9% (range, 11.7%-29.4%) for adult patients with MMD, 15.4% (range, 5.4%-28.8%) for direct bypass surgery, and 15.2% (range, 8.4%-23.2%) for combined bypass surgery. Progress rate was 39.5% (range, 28.7%-50.8%). The most common CHS-related symptom was TNDs (70.2%; range, 56.3%-82.7%), followed by hemorrhage (15.0%; range, 5.5%-26.9%) and seizure (5.3%; range, 0.6%-12.9%). CONCLUSIONS: CHS is a common complication after revascularization surgery in MMD. It is more frequently seen in adult patients. The most common CHS-related symptom was TNDs, followed by hemorrhage and seizure.

Efficacy of two vitamin D immunoassays to detect 25-OH vitamin D2 and D3.

OBJECTIVES: Assessment of Vitamin D status by measurement of 25-Hydroxyvitamin D (25-OH-D) is widely performed by immunoassay. Yet, the ability of these assays to detect Vitamin D2 (as 25-OH-D2) or Vitamin D3 (as 25-OH-D3) varies. It is important to recognize the ability of an assay to quantitate either form of 25-OH-D to evaluate Vitamin D status of supplemented patients. We evaluated detection of 25-OH-D2 and 25-OH-D3 by two assays in our medical center. DESIGN AND METHODS: The Abbott Architect i1000 SR 25-OH Vitamin D assay and Roche Cobas 8000 Vitamin D assay were compared for their recovery of 25-OH-D2 or D3 from spiked serum samples. Samples with known endogenous concentrations of 25-OH-D2 or D3 by LC-MS/MS were also measured to calculate bias between our assays and LC-MS/MS. RESULTS: Recovery of 25-OH-D3 in spiked samples was similar by Architect (84-87%) and Cobas (90%). Recovery of 25-OH-D2 was lower than 25-OH-D3, and was poorer by Architect (37-40%) than by Cobas (69-71%). In measurement of samples with known 25-OH-D concentrations, performance of Architect and Cobas assays was similar for 25-OH-D3. However, at concentrations >50 nmol/L 25-OH-D2, the Architect assay exhibited large average negative bias (-27%). CONCLUSIONS: While the Architect and Cobas assays performed similarly in detection of 25-OH-D3, the Architect assay was significantly poorer at detecting 25-OH-D2 than Cobas, with poorer recovery and significant negative bias at higher concentrations of 25-OH-D2. This agrees with other studies, and indicates that caution should be used in interpreting Architect 25-OH-D results in patients supplemented with Vitamin D2.