Implementation of High-Sensitivity and Point-of-Care Cardiac Troponin Assays into Practice: Some Different Thoughts.

BACKGROUND: The primary role of the International Federation of Clinical Chemistry (IFCC) Committee on Clinical Application of Cardiac Bio-Markers (C-CB) is to provide educational materials about cardiac biomarker use, emphasizing high-sensitivity cardiac troponin assays. CONTENT: This mini-review, regarding high-sensitivity cardiac and point-of-care troponin assays, addresses 1) new IFCC C-CB/AACC Academy laboratory practice recommendations; 2) new and updated concepts from the Fourth Universal Definition of Myocardial Infarction; 3) the role of point-of-care assays in practice and research; 4) regulatory challenges concerning point-of-care assays; e) testing in the COVID-19 world. SUMMARY: Implementation of high-sensitivity cardiac troponin assays makes a difference now and into the future in clinical practice and research. Providing point-of-care high-sensitivity cardiac troponin assays and optimizing studies to allow clearance of these assays by regulatory agencies, in a timely fashion, may provide improved patient management and outcomes.

Current evidence and future perspectives on the effective practice of patient-centered laboratory medicine.

BACKGROUND: Systematic evidence of the contribution made by laboratory medicine to patient outcomes and the overall process of healthcare is difficult to find. An understanding of the value of laboratory medicine, how it can be determined, and the various factors that influence it is vital to ensuring that the service is provided and used optimally. CONTENT: This review summarizes existing evidence supporting the impact of laboratory medicine in healthcare and indicates the gaps in our understanding. It also identifies deficiencies in current utilization, suggests potential solutions, and offers a vision of a future in which laboratory medicine is used optimally to support patient care. SUMMARY: To maximize the value of laboratory medicine, work is required in 5 areas: (a) improved utilization of existing and new tests; (b) definition of new roles for laboratory professionals that are focused on optimizing patient outcomes by adding value at all points of the diagnostic brain-to-brain cycle; (c) development of standardized protocols for prospective patient-centered studies of biomarker clinical effectiveness or extraanalytical process effectiveness; (d) benchmarking of existing and new tests in specified situations with commonly accepted measures of effectiveness; (e) agreed definition and validation of effectiveness measures and use of checklists for articles submitted for publication. Progress in these areas is essential if we are to demonstrate and enhance the value of laboratory medicine and prevent valuable information being lost in meaningless data. This requires effective collaboration with clinicians, and a determination to accept patient outcome and patient experience as the primary measure of laboratory effectiveness.

Real evidence to assess clinical testing interference risk (REACTIR): A strategy using real world data to assess the prevalence of interfering substances in patients undergoing clinical laboratory testing.

INTRODUCTION: Laboratory test interferences can cause spurious test results and patient harm. Knowing the frequency of various interfering substances in patient populations likely to be tested with a particular laboratory assay may inform test development, test utilization and strategies to mitigate interference risk. METHODS: We developed REACTIR (Real Evidence to Assess Clinical Testing Interference Risk), an approach using real world data to assess the prevalence of various interfering substances in patients tested with a particular type of assay. REACTIR uses administrative real world data to identify and subgroup patient cohorts tested with a particular laboratory test and evaluate interference risk. RESULTS: We demonstrate the application REACTIR to point of care (POC) blood glucose testing. We found that exposure to several substances with the potential to interfere in POC blood glucose tests, including N-acetyl cysteine (NAC) and high dose vitamin C was uncommon in most patients undergoing POC glucose tests with several key exceptions, such as burn patients receiving high dose IV-vitamin C or acetaminophen overdose patients receiving NAC. CONCLUSIONS: Findings from REACTIR may support risk mitigation strategies including targeted clinician education and clinical decision support. Likewise, adaptations of REACTIR to premarket assay development may inform optimal assay design and assessment.

A Multicenter Evaluation of a Point-of-Care Blood Glucose Meter System in Critically Ill Patients.

BACKGROUND: Our purpose was to evaluate the performance of the ACCU-CHEK® Inform II blood glucose monitoring system (Roche Diagnostics GmbH) compared with the perchloric acid hexokinase (PCA-HK) comparator method on the cobas® 6000 analyzer (Roche Diagnostics International Ltd) in critically ill patients. METHODS: Overall, 476 arterial (376 pediatric/adult, 100 neonate), 375 venous, and 100 neonatal heel-stick whole-blood samples were collected and evaluated from critical care settings at 10 US hospitals, including the emergency department, medical and surgical intensive care units (ICUs), and neonatal and pediatric ICUs. The ACCU-CHEK Inform II system was evaluated at 2 cutoff boundaries: boundary 1 was ≥95% of results within ±12 mg/dL of the reference (samples with blood glucose <75 mg/dL) or ±12% of the reference (glucose ≥75 mg/dL), and boundary 2 was ≥98% of results within ±15 mg/dL or ±15% of the reference. Clinical performance was assessed by evaluating sample data using Parkes error grid, Monte Carlo simulation, and sensitivity and specificity analyses to estimate clinical accuracy and implications for insulin dosing when using the ACCU-CHEK Inform II system. RESULTS: Proportions of results within evaluation boundaries 1 and 2, respectively, were 96% and 98% for venous samples, 94% and 97% for pediatric and adult arterial samples, 84% and 98% for neonatal arterial samples, and 96% and 100% for neonatal heel-stick samples. Clinical evaluation demonstrated high specificity and sensitivity, with low risk of potential insulin-dosing errors. CONCLUSIONS: The ACCU-CHEK Inform II system demonstrated clinically acceptable performance against the PCA-HK reference method for blood glucose monitoring in a diverse population of critically ill patients in US care settings.

Patient misidentifications caused by errors in standard bar code technology.

BACKGROUND: Bar code technology has decreased transcription errors in many healthcare applications. However, we have found that linear bar code identification methods are not failsafe. In this study, we sought to identify the sources of bar code decoding errors that generated incorrect patient identifiers when bar codes were scanned for point-of-care glucose testing and to develop solutions to prevent their occurrence. METHODS: We identified misread wristband bar codes, removed them from service, and rescanned them by using 5 different scanner models. Bar codes were reprinted in pristine condition for use as controls. We determined error rates for each bar code-scanner pair and manually calculated internal bar code data integrity checks. RESULTS: As many as 3 incorrect patient identifiers were generated from a single bar code. Minor bar code imperfections, failure to control for bar code scanner resolution requirements, and less than optimal printed bar code orientation were confirmed as sources of these errors. Of the scanner models tested, the Roche ACCU-CHEK® glucometer had the highest error rate. The internal data integrity check system did not detect these errors. CONCLUSIONS: Bar code-related patient misidentifications can occur. In the worst case, misidentified patient results could have been transmitted to the incorrect patient medical record. This report has profound implications not only for point-of-care testing but also for bar coded medication administration, transfusion recipient certification systems, and other areas where patient misidentifications can be life-threatening. Careful control of bar code scanning and printing equipment specifications will minimize this threat to patient safety. Ultimately, healthcare device manufacturers should adopt more robust and higher fidelity alternatives to linear bar code symbologies.

Falsely decreased human chorionic gonadotropin (hCG) results due to increased concentrations of the free beta subunit and the beta core fragment in quantitative hCG assays.

BACKGROUND: Earlier studies have shown that increased concentrations of certain human chorionic gonadotropin (hCG) variants can cause false-negative results in some qualitative hCG devices. The objective of this study was to determine if increased concentrations of hCGß and hCGß core fragment (hCGßcf) cause falsely decreased results on 9 commercially available quantitative hCG assays. METHODS: Several concentrations of purified hCGß and hCGßcf were added to 2 sets of 6 serum samples with and without a fixed concentration of intact hCG. We examined 9 widely used immunoassays to measure immunoreactive hCG. Falsely decreased results were defined as those in which the measured hCG concentration was ≤50% of expected. RESULTS: High concentrations of hCGß (≥240 000 pmol/L) produced falsely decreased hCG measurements in 2 assays known to detect this variant. Similarly, high concentrations of hCGßcf (≥63 000 pmol/L) produced falsely decreased hCG measurements in 3 assays that do not detect purified hCGßcf. Two assays were identified that detected both hCGß and hCGßcf, and neither produced falsely decreased results in the presence of high concentrations of these variants. CONCLUSIONS: Extremely high concentrations of hCG variants can cause falsely decreased results in certain quantitative hCG assays. Of the 9 assays examined, none exhibited falsely decreased results in the presence of hCGß concentrations typically associated with hCGß-producing malignancies. Two assays exhibited decreased (>50%) hCG results in the presence of hCGßcf concentrations found during normal pregnancy.

Diffusion tensor imaging detects axonal injury and demyelination in the spinal cord and cranial nerves of a murine model of globoid cell leukodystrophy.

Globoid cell leukodystrophy is an inherited neurodegenerative disorder caused by a deficiency of the lysosomal enzyme galactosylceramidase. In both human patients and the authentic murine Twitcher model, pathological findings include demyelination as well as axonal damage in both the central and peripheral nervous system. Diffusion tensor imaging (DTI) has emerged as a powerful noninvasive technique that is sensitive to these white matter disease processes. Increases in radial diffusivity (lambda perpendicular) and decreases in axial diffusivity (lambda parallel) correlate with histopathological evidence of demyelination and axonal damage, respectively. Compared to age-matched, normal littermates, DTI of optic nerve and trigeminal nerve in end-stage Twitcher mice displayed a statistically significant increase in lambda perpendicular and decrease in lambda parallel, consistent with previously characterized demyelination and axonal damage in these regions. In the Twitcher spinal cord, a statistically significant decrease in lambda parallel was identified in both the dorsal and ventrolateral white matter, relative to normal controls. These results were consistent with immunofluorescence evidence of axonal damage in these areas as detected by staining for nonphosphorylated neurofilaments (SMI32). Increase in lambda perpendicular in Twitcher spinal cord white matter relative to normal controls reached statistical significance in the dorsal columns and approached statistical significance in the ventrolateral region. Correlative reduced levels of myelin basic protein were detected by immunofluorescent staining in both these white matter regions in the Twitcher spinal cord. Fractional anisotropy, a nonspecific but sensitive indicator of white matter disease, was significantly reduced in the optic nerve, trigeminal nerve, and throughout the spinal cord white matter of Twitcher mice, relative to normal controls. This first reported application of spinal cord DTI in the setting of GLD holds potential as a noninvasive, quantitative assay of therapeutic efficacy in future treatment studies.

Assay Integrity of a PCR Influenza Point-of-Care Test Remains Following Artificial System Contamination.

BACKGROUND: Healthcare providers who have access to tests at the point of care (POC) are increasingly requesting the same performance from the POC test as they expect from the laboratory. With the introduction of the cobas® Liat instrument, highly sensitive molecular diagnostic testing can be performed closer to the patient in CLIA-waived, POC settings. As more sensitive tests become available, there is concern regarding contamination of instrumentation owing to improper handling, mistakes made when processing, or environmental contamination. Recent concerns were raised when a nurse performed environmental surveillance for flu A/B by inserting a dry swab into the cobas Liat instrument and then ran it as a sample on the instrument, generating a positive result. This finding stimulated questions about the possibility of system contamination contributing to false-positive results, ultimately leading to the possibility of providing incorrect treatment to patients. METHODS: To assess the likelihood of system contamination contributing to the generation of false-positive results, in this study we contaminated a cobas Liat System with flu A/B-positive control material. The system contamination was then assessed by swabbing exposed surfaces. Following confirmed system contamination, negative control samples were processed to determine whether system contamination had an impact on the expected negative results. RESULTS: Instrument contamination was confirmed, and no detectable flu A/B signal was observed for any of the negative control tubes run immediately following confirmation of system contamination. CONCLUSION: Environmental contamination of the Liat instrument does not have an impact on the integrity of the result.

Barriers to quality health care for the transgender population.

The transgender community is arguably the most marginalized and underserved population in medicine. A special issue focusing on men's health would be incomplete without mention of this vulnerable population, which includes those transitioning to and from the male gender. Transgender patients face many barriers in their access to healthcare including historical stigmatization, both structural and financial barriers, and even a lack of healthcare provider experience in treating this unique population. Historical stigmatization fosters a reluctance to disclose gender identity, which can have dire consequences for long-term outcomes due to a lack of appropriate medical history including transition-related care. Even if a patient is willing to disclose their gender identity and transition history, structural barriers in current healthcare settings lack the mechanisms necessary to collect and track this information. Moreover, healthcare providers acknowledge that information is lacking regarding the unique needs and long-term outcomes for transgender patients, which contributes to the inability to provide appropriate care. All of these barriers must be recognized and addressed in order to elevate the quality of healthcare delivered to the transgender community to a level commensurate with the general population. Overcoming these barriers will require redefinition of our current system such that the care a patient receives is not exclusively linked to their sex but also considers gender identity.

Pathology consultation on prostate-specific antigen testing.

OBJECTIVES: To provide clarity on the pros and cons of using prostate-specific antigen (PSA) as a screening tool for prostate cancer. METHODS: Case scenarios and a literature review of recently published clinical trial data are presented to provide evidence of the controversy. RESULTS: PSA is a sensitive biomarker for detecting diseases of the prostate, but it is limited in its ability to distinguish cancerous from noncancerous conditions or aggressive from indolent cancers and has resulted in a considerable amount of overdiagnosis and overtreatment. CONCLUSIONS: The analytical methodology for total PSA testing is both reliable and cost-effective, but patients should be encouraged to talk to their providers to understand the benefits and harms associated with this testing.

Dermal exposure to a compounded pain cream resulting in severely elevated clonidine concentration.

INTRODUCTION: Clonidine is an imidazoline derivative antihypertensive medication that is also used as adjunctive therapy for neuropathic pain disorders via topical administration. Clonidine overdose can manifest both central and peripheral alpha-adrenergic agonist effects. CASE REPORT: A 23-year-old man presented to an emergency department with altered mental status, bradycardia, and hypertension after suspected overdose. He had rubbed a specially compounded medicinal cream over his entire body containing clonidine 0.2 % (w/w), gabapentin 6 %, imipramine 3 %, ketamine 10 %, lidocaine 2 %, and mefenamic acid 1 %. The patient presented with severe hypertension, bradycardia, and altered mental status. He was found to have a subarachnoid hemorrhage and was treated for hypertensive emergency. Toxicological analysis of initial blood samples revealed a serum clonidine concentration of 5,200 ng/ml. At 6-month follow-up, the patient had made a full recovery. DISCUSSION: There are limited reports of topical clonidine toxicity, and to our knowledge, this case involves the highest concentration yet reported following clonidine overdose by any route of exposure. The severely elevated serum clonidine concentration found in our patient demonstrates the possibility of toxicity resulting from inappropriate use of such a product. At high serum concentrations, the pharmacodynamic effects of clonidine appear to cause significant peripheral alpha-1 adrenergic stimulation. Toxicologists should be aware of the increasing use of topical clonidine preparations for the treatment of neuropathic pain and the potential for toxicity.

Interpreting laboratory results in transgender patients on hormone therapy.

BACKGROUND: Clinical guidelines recommend laboratory monitoring of transgender persons on cross-sex hormone therapy, but gender-specific reference intervals leave clinicians with the dilemma of deciding what is "normal" for each patient. The goal of this study was to identify consistent changes in measurands with hormone therapy and determine which reference interval is appropriate. METHODS: Laboratory data were abstracted from the medical records of 55 male-to-female patients on hormone therapy and compared with 20 male and 20 female nontransgender subjects. RESULTS: Hemoglobin, hematocrit, and low-density lipoprotein resembled female values (P < .005), while alkaline phosphatase, potassium, and creatinine resembled male values (P < .05). Triglycerides were higher (P < .005) than either the male or female groups. The remainder of the measurands showed no differences. CONCLUSIONS: Use of correct reference intervals in interpreting laboratory results reduces the risk of testing-related diagnostic error. Preliminary data suggest that new reference intervals need to be established for transgender patients.

A prospective tool for risk assessment of sendout testing.

OBJECTIVE: Errors associated with laboratory testing can cause significant patient harm. Sendout testing refers to tests sent by a primary lab to a reference lab when testing is unavailable at the primary lab. Sendout testing is particularly high risk for patient harm, due to many factors including increased hand-offs, manual processes, and complexity associated with rare, low-volume tests. No published prospective tools exist for sendout risk assessment. METHODS: A novel prospective tool was developed to assess risk of diagnostic errors involving laboratory sendout testing. This tool was successfully piloted at nine sites. RESULTS: Marked diversity was noted among survey respondents, particularly in the sections on quality metrics and utilization management. Of note, most sites had committees who managed rules for test ordering, but few places reported enforcing these rules. Only one site claimed to routinely measure the frequency clinicians failed to retrieve test results. An evaluation of the tool indicated that it was both useful and easy to use. CONCLUSIONS: This tool could be used by other laboratories to identify the areas of highest risk to patients, which in turn may guide them in focusing their quality improvement efforts and resources.