The Impact of a High Sensitivity Troponin HEART Pathway Based Clinical Decision Protocol on Observation Visits.

BACKGROUND: Use of high-sensitivity troponin (hs-cTn) might lead to an increase in hospital observation visits due to higher number of abnormal troponin levels. STUDY OBJECTIVES: To determine the impact of incorporating hs-cTn into a chest pain clinical decision protocol (CDP) on observation visits in a large academic health system. METHODS: This is a retrospective observational cohort study of all chest pain observation patients in four hospitals in an academic health system over 24 months. All hospitals used the Beckman Coulter Unicel Dxi instrument, and all shared the same emergency department (ED) chest pain protocol, which used the HEART pathway and serial troponins and directed ED dispositions to either an observation stay, ED discharge, or inpatient admission. Outcomes studied before and after introduction of a hs-cTn protocol included daily chest pain observation census, cost, observation hours, and inpatient admit rate. Census was reported as the daily chest pain observation census and as a proportion of all observation visits. Data was retrieved from a health system data warehouse and a cost accounting program. RESULTS: There were 6,712 chest pain observation visits over 24-months, with 4,087 visits before and 2,634 visits after the hs-cTn protocol implementation. Comparison groups were similar in terms of age, gender, and type of insurance. There were 10.59 (95% CI: 10.24 - 10.95) daily chest pain observation visits before and 7.66 (95% CI: 7.34 - 7.97) visits after implementation, with a 28% (95% CI: 35% - 20%) decrease in the total daily census. As a portion of all observation visits, there was a 22% drop in the proportion that were observed for chest pain. The daily number of chest pain patients requiring inpatient admission was unchanged. The daily total direct cost for chest pain observation decreased with an effective daily cost savings of $4,313 USD (95% CI: $1,534 - $6,998). The total daily number of chest pain observation bed hours also decreased by 41.5 hours (95% CI 13.4 - 96.4 hr). CONCLUSION: Implementation of a hs-cTn chest pain protocol was associated with a significant decrease in the number and proportion of observation visits, a decrease in total daily cost and bed hours used, and no increase in inpatient admissions.

Survival of transfused red blood cells from a donor with alpha-thalassemia trait in a recipient with sickle cell disease.

BACKGROUND: Post-transfusion survival of donor red blood cells (RBCs) is important for effective chronic transfusion therapy in conditions including sickle cell disease (SCD). Biotin labeling RBCs allows direct in vivo measurement of multiple donor RBC units simultaneously post-transfusion. STUDY DESIGN AND METHODS: In an observational trial of patients with SCD receiving monthly chronic transfusion therapy, aliquots of RBCs from one transfusion episode were biotin-labeled and infused along with the unlabeled RBC units. Serial blood samples were obtained to measure RBC survival. Donor units were tested for RBC indices, hemoglobin fractionation, and glucose-6-phosphate dehydrogenase (G6PD) enzyme activity. For microcytic donor RBCs (MCV < 70 fL), HBA1 and HBA2 genetic testing was performed on whole blood. RESULTS: We present one recipient, a pediatric patient with SCD and splenectomy who received two RBC units with aliquots from each unit labeled at distinct biotin densities (2 and 18 µg/mL biotin). One donor unit was identified to have microcytosis (MCV 68.5 fL after biotinylation); whole blood sample obtained at a subsequent donation showed 2-gene deletion alpha-thalassemia trait (ɑ-3.7kb/ɑ-3.7kb) and normal serum ferritin. G6PD activity was >60% of normal mean for both. The RBCs with alpha-thalassemia RBC had accelerated clearance and increased surface phosphatidylserine post-transfusion, as compared with the normocytic RBC (half life 65 vs. 86 days, respectively). DISCUSSION: Post-transfusion RBC survival may be lower for units from donors with alpha-thalassemia trait, although the impact of thalassemia trait donors on transfusion efficacy requires further study.

Large-Scale Scientific Study Led by a Professional Organization during the COVID-19 Pandemic: Operations, Best Practices, and Lessons Learned.

In 2021, the Association for Diagnostics & Laboratory Medicine (ADLM) (formerly the American Association for Clinical Chemistry [AACC]) developed a scientific study that aimed to contribute to the understanding of SARS-CoV-2 immunity during the evolving course of the pandemic. This study was led by a group of expert member volunteers and resulted in survey data from 975 individuals and blood collection from 698 of those participants. This paper describes the formulation and execution of this large-scale scientific study, encompassing best practices and insights gained throughout the endeavor.

Rapid, high throughput, automated detection of SARS-CoV-2 neutralizing antibodies against Wuhan-WT, delta and omicron BA1, BA2 spike trimers.

Traditional cellular and live-virus methods for detection of SARS-CoV-2 neutralizing antibodies (nAbs) are labor- and time-intensive, and thus not suited for routine use in the clinical lab to predict vaccine efficacy and natural immune protection. Here, we report the development and validation of a rapid, high throughput method for measuring SARS-CoV-2 nAbs against native-like trimeric spike proteins. This assay uses a blockade of human angiotensin converting enzyme 2 (hACE-2) binding (BoAb) approach in an automated digital immunoassay on the Quanterix HD-X platform. BoAb assays using Wuhan-WT (vaccine strain), delta (B.1.167.2), omicron BA1 and BA2 variant viral strains showed strong correlation with cell-based pseudovirus neutralization activity (PNA) and live-virus neutralization activity. Importantly, we were able to detect similar patterns of delta and omicron variant resistance to neutralization in samples with paired vaccine strain and delta variant BoAb measurements. Finally, we screened clinical samples from patients with or without evidence of SARS-CoV-2 exposure by a single-dilution screening version of our assays, finding significant nAb activity only in exposed individuals. Importantly, this completely automated assay can be performed in 4 h to measure neutralizing antibody titers for 16 samples over 8 serial dilutions or, 128 samples at a single dilution with replicates. In principle, these assays offer a rapid, robust, and scalable alternative to time-, skill-, and cost-intensive standard methods for measuring SARS-CoV-2 nAb levels.

Race-free renal function estimation equations and potential impact on Black patients: Implications for cancer clinical trial enrollment.

BACKGROUND: Black patients face disparities in cancer outcomes. Additionally, Black patients are more likely to be undertreated and underrepresented in clinical trials. The recent recommendation to remove race from the estimated glomerular filtration rate (eGFR) results in lower eGFR values for Black patients. The ramifications of this decision, both intended and unintended, are still being elucidated in the medical community. Here, the authors analyze the removal of race from eGFR for Black patients with cancer, specifically with respect to clinical trial eligibility. METHODS: In a cohort of self-identified Black patients who underwent nephrectomy at a tertiary referral center from 2009 to 2021 (n = 459), eGFR was calculated with and without race in commonly used equations (Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] and Modification of Diet in Renal Disease [MDRD]). The distribution of patients and changes within chronic kidney disease stages with different equations was considered. Theoretical exclusion at commonly observed clinical trial eGFR points was then simulated on the basis of the utilization of the race coefficient. RESULTS: The median eGFR from CKD-EPI was significantly higher with race (76 ml/min/1.73 m2 ) than without race (66 ml/min/1.73 m2 ; p < .0001). The median eGFR from MDRD was significantly higher with race (71.0 ml/min/1.73 m2 ) than without race (58 ml/min/1.73 m2 ; p < .0001). Observing results in the context of common clinical trial cutoff points, the authors found that 13%-22%, 6%-12%, and 2%-3% more Black patients would fall under common clinical trial cutoffs of 60, 45, and 30 ml/min, respectively, depending on the equation used. A subanalysis of stage III-IV patients only was similar. CONCLUSIONS: Race-free renal function equations may inadvertently result in increased exclusion of Black patients from clinical trials. This is especially concerning because of the underrepresentation and undertreatment that Black patients already experience. PLAIN LANGUAGE SUMMARY: Black patients experience worse oncologic outcomes and are underrepresented in clinical trials. Kidney function, as estimated by glomerular filtration rate equations, is a factor in who can and cannot be in a clinical trial. Race is a variable in some of these equations. For Black patients, removing race from these equations leads to the calculation of lower kidney function. Lower estimated kidney function may result in more black patients being excluded from clinical trials. The inclusion of all races in clinical trials is important for offering best care to everyone and for making results from clinical trials applicable to everyone.

A Survey of Sigma Metrics across Three Academic Medical Centers.

BACKGROUND: Sigma metric calculations provide laboratories an objective means to assess analytical method performance. Methods with higher sigma values are desirable because they are more reliable and may use less frequent quality control in order to maintain optimal performance. Sigma metrics can also serve as a tool when comparing method performance across assay and manufacturer platforms. METHODS: Sigma values were calculated for 28 common chemistry and 24 immunoassay assays across 3 academic medical centers. Method imprecision and percent bias relative to peer group means was tabulated from Bio-Rad quality control (QC) data. Sigma values were calculated for each method using allowable total error (TEa) from either the CLIA evaluation limits or desirable biological variation. Average sigma values were generated for each site and graded as optimal: >6 sigma; good: 5-6 sigma; marginal: 3-5 sigma; or poor: <3 sigma. Analysis of NIST SRM1950 standards for a subset of analytes allowed an estimation of absolute bias. RESULTS: Clinical chemistry assays displayed similar method performance across all 3 study sites. Immunoassays showed significant differences between manufacturers, and a majority of assays failed to meet an optimal level of performance. Different TEa values produced different sigma metrics with more stringent TEa limits based on biological variation, resulting in poorer performance estimates than the wider CLIA limits. Analysis of NIST standards revealed similar performance. CONCLUSIONS: Sigma metrics are comparable for chemistry but not immunoassay platforms. The selection of total allowable error goals led to differences in sigma metrics.

Rapid Generation of Neutralizing Antibody Responses in COVID-19 Patients.

SARS-CoV-2, the virus responsible for COVID-19, is causing a devastating worldwide pandemic, and there is a pressing need to understand the development, specificity, and neutralizing potency of humoral immune responses during acute infection. We report a cross-sectional study of antibody responses to the receptor-binding domain (RBD) of the spike protein and virus neutralization activity in a cohort of 44 hospitalized COVID-19 patients. RBD-specific IgG responses are detectable in all patients 6 days after PCR confirmation. Isotype switching to IgG occurs rapidly, primarily to IgG1 and IgG3. Using a clinical SARS-CoV-2 isolate, neutralizing antibody titers are detectable in all patients by 6 days after PCR confirmation and correlate with RBD-specific binding IgG titers. The RBD-specific binding data were further validated in a clinical setting with 231 PCR-confirmed COVID-19 patient samples. These findings have implications for understanding protective immunity against SARS-CoV-2, therapeutic use of immune plasma, and development of much-needed vaccines.

Rapid generation of neutralizing antibody responses in COVID-19 patients.

SARS-CoV-2 is currently causing a devastating pandemic and there is a pressing need to understand the dynamics, specificity, and neutralizing potency of the humoral immune response during acute infection. Herein, we report the dynamics of antibody responses to the receptor-binding domain (RBD) of the spike protein and virus neutralization activity in 44 COVID-19 patients. RBD-specific IgG responses were detectable in all patients 6 days after PCR confirmation. Using a clinical isolate of SARS-CoV-2, neutralizing antibody titers were also detectable in all patients 6 days after PCR confirmation. The magnitude of RBD-specific IgG binding titers correlated strongly with viral neutralization. In a clinical setting, the initial analysis of the dynamics of RBD-specific IgG titers was corroborated in a larger cohort of PCR-confirmed patients (n=231). These findings have important implications for our understanding of protective immunity against SARS-CoV-2, the use of immune plasma as a therapy, and the development of much-needed vaccines.