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The necessity of individual tests within the most commonly used disease-oriented test panels has not been well established. We evaluated test-ordering practices for total calcium, both before and after implementation of American Medical Association (AMA)-approved panels (basic metabolic panel [BMP] and comprehensive metabolic panel [CMP]) in our electronic ordering system. We performed a retrospective review of all total calcium orders placed during April and June 2018, before and after implementation of the panels. Orders from inpatient, outpatient, and emergency department (ED) care units were totaled, and the percentage of abnormal test results was calculated. We then queried institutional databases to determine the number of unique patients with calcium-related diagnoses and compared the rates from a 5-month period both before and after implementation of the panels. Total test volumes and tests per unique patient increased by more than 3-fold after implementation of calcium-containing AMA-approved panels, with the majority of those orders coming from BMPs and CMPs. The rate of low calcium values increased because of the shift toward more inpatient testing; however, the percentage of abnormal results within each patient population (inpatient, outpatient, ED) decreased. The prevalence of hypo- and hypercalcemia-related diagnoses among patients in the 5 months after implementation did not change significantly (1.29% before implementation vs 1.27% after implementation). Implementation of BMPs and CMPs dramatically increased total calcium testing volumes without changing the rate of calcium-related diagnoses. The results suggest that the increase in total calcium orders associated with panel-based testing largely constitutes excess or unnecessary testing.

Abstract Objectives To evaluate the analytical and clinical performance characteristics of the fifth-generation troponin T reagent. Methods Troponin T was measured in 2,332 paired serum and plasma samples from emergency department and hospital patients using the fourth- and fifth-generation reagents. Testing was repeated after recentrifugation to determine the frequency of analytical outliers and percentage of patients with elevated values for each assay. We conducted separate experiments to determine the effects of biotin and hemolysis interference, as well as measure interinstrument variability, for fifth-generation troponin T. Results Analytic outliers occurred more frequently using the fifth-generation reagent (3.4%) compared with the fourth-generation reagent (1.0%). The frequency of elevated troponin T above the 99th percentile upper reference limit was 26% for the fourth-generation reagent and 52% for the fifth-generation reagent. Clinically significant assay interference by biotin was observed at 20 ng/mL, but hemolysis interference was not observed until an H index of 150. Instrument-to-instrument variability between e411 and e601/602 instrument platforms is predicted to confound clinical interpretation of troponin changes. Conclusions Analytical outliers and instrument-to-instrument variability are the two analytical variables most likely to confound interpretation of changes in fifth-generation troponin T results over time.

N-methyl-d-aspartate receptors (NMDARs) are an important receptor in the brain and have been implicated in multiple neurological disorders. Many non-selective NMDAR-targeting drugs are poorly tolerated, leading to efforts to target NMDAR subtypes to improve the therapeutic index. We describe here a series of negative allosteric NMDAR modulators with submaximal inhibition at saturating concentrations. Modest changes to the chemical structure interconvert negative and positive modulation. All modulators share the ability to enhance agonist potency and are use-dependent, requiring the binding of both agonists before modulators act with high potency. Data suggest that these modulators, including both enantiomers, bind to the same site on the receptor and share structural determinants of action. Due to the modulator properties, submaximal negative modulators in this series may spare NMDAR at the synapse, while augmenting the response of NMDAR in extrasynaptic spaces. These modulators could serve as useful tools to probe the role of extrasynaptic NMDARs. The neurons in the brain form networks that can change in response to experience, causing new connections to form between certain neurons and breaking the connections between others. This remodeling process underlies learning and memory. However, in certain neurological disorders, such as schizophrenia and epilepsy, these networks are disrupted and no longer work correctly. A receptor protein called the NMDA receptor plays an important role in reshaping the networks of neurons. Chemicals called neurotransmitters that are released by one neuron bind to and activate NMDA receptors on a neighbouring neuron to communicate with it. This activation encourages new connections to form between neurons. Drugs that alter the activity of the NMDA receptor could potentially act as treatments for neurological conditions that disrupt how the networks of neurons work. However, few have been approved for use in patients because most of the potential drug compounds investigated so far produce severe side effects. Perszyk et al. have now identified a new group of compounds that can potentially alter the activity of NMDA receptors without fully blocking the response, potentially eliminating the unwanted side effects. The compounds were tested on frog egg cells and human embryonic kidney cells that had been engineered to produce NMDA receptors. Small changes to the chemical structure of these compounds could switch their effect from increasing to decreasing the activity of the receptor. The compounds only interact with active receptors that have a neurotransmitter bound to them, and compete with each other to bind to the receptors. Perszyk et al. also found that some compounds behaved differently depending on how active the NMDA receptor was. These compounds could potentially be used to sense the activity in a network of neurons, which opens up new options for treating neurological conditions that affect the networks. Further experiments are now required to see how these compounds affect the activity of NMDA receptors in neurons and living animals. The range of effects produced by the compounds studied by Perszyk et al. suggests that other related compounds may have different effects on receptor activity. Future work could investigate the properties of these compounds to see if they could treat a different set of neurological disorders.

[...]HB2645 states that tests do not need to be covered by private insurance or abide by state cost-containment systems. If the solution to rising healthcare costs is to promote appropriate test utilization and conserve hospital resources for patients who need them most, it appears that the expansion of DAT may steer us in the wrong direction.

Abstract Hemolysis is a common preanalytical issue in the clinical laboratory, often causing a delay in test results and requiring patients to have blood re-collected to obtain acceptable specimens. Most specimen hemolysis occurs in vitro because of blood collection issues and/or handling/transport conditions. Special handling instructions (SHIs) were developed for hospitalized patients with two consecutive blood collections that are hemolyzed beyond the acceptable threshold for the physician-ordered tests. SHIs are managed by clinical chemistry fellows/residents and include specimen collection in a lithium heparin blood gas syringe followed by hand delivery to the laboratory. This process has been in place for several years, yet there have been no studies to quantitate how effectively SHIs reduce specimen hemolysis. The objective of this study was to determine if SHIs effectively reduce specimen hemolysis to allow reporting of laboratory test results. This study met criteria for a quality assurance/improvement initiative and did not require Mayo Clinic IRB review. Ninety-eight SHIs were reviewed between May and December 2017. Analytes (potassium [K], aspartate aminotransferase [AST], direct bilirubin [Dbil], lactate dehydrogenase [LDH], alkaline phosphatase [ALP], and total bilirubin [Tbil]) were measured in serum/plasma using Roche Cobas c701/c501/c502 analyzers and hemolysis was assessed using hemolysis index (H-index) (Roche Diagnostics, Indianapolis, IN). Analyte-specific H-index thresholds were used to prevent release of results and trigger specimen re-collection when H-index thresholds were exceeded. For each case, the time of collection, H-index, and analyte were obtained for the hemolyzed specimen that initiated SHI (pre-SHI) and the first sample collected after SHI implementation (post-SHI). The time between pre- and post-SHI collections (Δt), the percent difference in H-index (ΔH), and the percentage of results that were able to be reported after implementation of SHIs were calculated. The median Δt was 3.5 hours (interquartile range [IQR], 2.2–6.4). The median H-index pre-SHI and post-SHI was 215 (IQR: 150–400) and 18 (IQR: 6–55), respectively (P < .0001). The median ΔH between pre- and post-SHI was –93% (95% confidence interval [CI], –95 to –89%). Potassium was the analyte most likely to initiate SHI (n = 64, H-index threshold: 125), followed by AST (n = 20, concentration-dependent H-index: 50–500), Dbil (n = 8, concentration-dependent H-index: 50–70), LDH (n = 4, H-index: 50), ALP (n = 1, H-index: 200), and Tbil (n = 1, H-index: 400). Post-SHI, 89% (57/64) of K, 80% (16/20) of AST, 75% (6/8) of Dbil, 75% (3/4) of LDH, and 100% (1/1) of ALP and Tbil results were able to be reported because the H-index values were below the interference threshold. From this cohort of patients with repeatedly hemolyzed specimens, collecting blood using SHI significantly reduced specimen hemolysis and allowed the majority of results to be reported.

Abstract Introduction Analytical outliers occur with most troponin assays and can adversely affect patient management. We developed a system to detect analytical outliers for the Roche Troponin T (cTnT) Gen 5 assay using repeat analysis of samples manifesting changing values over 2 to 6 hours. Methods In our ED practice, troponins are collected at baseline, 2 hours, and at times at 6 hours in plasma separator tubes and processed on the Roche Cobas e411 (Indianapolis, IN). When troponin values change by ≥10 ng/L or ≤10 ng/L in the 2- or 6-hour sample compared to baseline, the sample that produced the result is repeated. If initial and repeat values differ by > ±5 ng/L (cTnT <100 ng/L) or ±5% (cTnT ≥100 ng/L), the initial value is deemed to be an analytical outlier. Outliers are confirmed by a third measurement. Results Since March 2018, 19 of 17,154 (0.11%) troponin samples analyzed have been labeled outliers. Outliers were falsely elevated in 14 cases and falsely decreased in 5. Mean (range) of initial cTnT values for outliers was 39 ng/L (18-621 ng/L), with only one initial value >100 ng/L. All changes could affect analysis of change over time. Eleven of 19 outliers were outside gender-specific reference interval on both samples and thus did not cause a change from abnormal to normal. Repeat measurements on 8 of 19 outliers were within the URL, which may have greater clinical consequences. Conclusions Repeat analysis upon observation of changing values allows detection of analytical outliers in real time, prior to reporting results. These outliers are almost always clinically significant in terms of interpretation of changing values and at times change patients from above to below the URL. If we tested more than just changing samples, we might detect still more outliers.

A perimenopausal woman presented with palpitations, hirsutism, and inability to lose weight. Laboratory tests revealed an unusual endocrine hormonal profile including pituitary hormones (TSH, ACTH, and prolactin) below reference intervals and gonadal (testosterone) and adrenal (cortisol) hormones above reference intervals. Ultimately, after a comprehensive workup including a scheduled surgical procedure, abnormal laboratories were determined due to biotin interference. Biotin (vitamin B7) is a water-soluble vitamin and essential cofactor for the metabolism of fatty acids, glucose, and amino acids. The recommended daily intake of biotin for adults is 30 µg/d. Many over-the-counter products, particularly those marketed for hair, skin, and nail growth, contain biotin 100-fold of recommended daily intake. This case is unique due to the abnormalities observed not only in the well-described TSH “sandwich” immunoassay, but also in tests for gonadal steroids, adrenal, and pituitary hormones. Falsely high as well as falsely low results can be ascribed to biotin. Competitive immunoassays (Fig. 1A)— in this case, tests used initially for serum cortisol and testosterone— can demonstrate falsely high results. Interference falsely lowers the immunometric “sandwich” immunoassay (Fig. 1B)—in this case, TSH. Biotin effect on our patient’s endocrine testing led to decidedly abnormal findings, unnecessary medical referrals and diagnostic studies, and comprehensible psychological distress. Interference with one immunoassay, TSH, persisted a full 2 weeks after discontinuation of biotin; indeed, some tests demonstrate sensitivity to lesser quantities of biotin. Improved communication between patients, health care providers, and laboratory professionals is required concerning the likelihood of biotin interference with immunoassays.We report a case of biotin interference with endocrine laboratory testing, which nearly resulted in an unnecessary surgical procedure.