Antiphospholipid syndrome, monoclonal gammopathy, and cryoglobulinemia overlap leading to recurrent cutaneous microvascular thrombosis: A case report and retrospective cohort study.

Antiphospholipid syndrome (APS), cryoglobulinemia, and monoclonal gammopathies are variably accompanied by thrombotic complications. We describe a patient with recurrent skin microvascular thrombosis, APS, cryoglobulinemia, marginal zone lymphoma, and IgMκ monoclonal gammopathy, responsive to chemoimmunotherapy. The cryoglobulin fraction contained the IgMκ paraprotein, while antiphospholipid antibodies (aPL) were predominantly in the cryosupernatant. A retrospective analysis of aPL-positive patients in our institution showed that 8.1% co-expressed monoclonal gammopathy. These overlap patients had thrombotic complications and most had recurrences. Patients with multiple gammopathies of thrombotic significance may have several autoantibodies and constitute a high-risk group.

Coming in Hot: A quality improvement approach to improving care of febrile infants.

Background and Objectives: Significant practice variation exists in managing young infants with fever. Quality improvement strategies can aid in risk stratification and standardization of best care practices, along with a reduction of unnecessary interventions. The aim of this initiative was to safely reduce unnecessary admissions, antibiotics, and lumbar punctures (LPs) by 10% in low-risk, febrile infants aged 29 to 90 days presenting to the emergency department (ED) over a 12-month period. Methods: Using the Model for Improvement, a multidisciplinary team developed a multipronged intervention: an updated clinical decision tool (CDT), procalcitonin (PCT) adoption, education, a feedback tool, and best practice advisory (BPA) banner. Outcome measures included the proportion of low-risk infants that were admitted, received antibiotics, and had LPs. Process measures were adherence to the CDT and percentage of PCT ordered. Missed bacterial infections and return visits were balancing measures. The analysis was completed using descriptive statistics and statistical process control methods. Results: Five hundred and sixteen patients less than 90 days of age were included in the study, with 403 patients in the 29- to 90-day old subset of primary interest. In the low-risk group, a reduction in hospital admissions from a mean of 24.1% to 12.0% and a reduction in antibiotics from a mean of 15.2% to 1.3% was achieved. The mean proportion of LPs performed decreased in the intervention period from 7.5% to 1.8%, but special cause variation was not detected. Adherence to the CDT increased from 70.4% to 90.9% and PCT was ordered in 92.3% of cases. The proportion of missed bacterial infections was 0.3% at baseline and 0.5% in the intervention period while return visits were 6.7% at baseline and 5.0% in the intervention period. Conclusions: The implementation of a quality improvement strategy, including an updated evidence-based CDT for young infant fever incorporating PCT, safely reduced unnecessary care in low-risk, febrile infants aged 29 to 90 days in the ED. Purpose: To develop and implement a multipronged improvement strategy including an evidence-based CDT utilizing PCT to maximize value of care delivered to well-appearing, febrile infants presenting to EDs.

Evaluation of hemolysis, lipemia, and icterus interference with common clinical immunoassays.

OBJECTIVES: Hemolysis, icterus, and lipemia (HIL) are common sources of endogenous interference in clinical laboratory testing. Defining the threshold of interference for immunoassays enables appropriate reporting of their results when they are affected by HIL. METHODS: Pools of residual patient serum samples were spiked with a known amount of interferent to create samples with varying concentrations of hemolysate, bilirubin, and Intralipid that mimicked the effects of endogenous HIL. Samples were analysed on the Alinity i analyser (Abbott Diagnostics) for more than 25 immunoassays. The average recovery relative to the non-spiked sample was calculated for each interference level and was compared to a predefined allowable bias. RESULTS: C-peptide, estradiol, serum folate, free T4, homocysteine, insulin, and vitamin B12 were found to be affected by hemolysis, at hemoglobin concentrations between 0.3 to 20 g/L. Immunoassays for BNP, estradiol, free T3, and homocysteine were affected by icterus at conjugated bilirubin concentrations between 50 to 1,044 µmol/L. BNP, serum folate, and homocysteine were affected by Intralipid with measured triglyceride concentrations between 0.8 to 10 mmol/L. Lastly, serological immunoassays for HIV and hepatitis A, B and C were also affected by interferences. CONCLUSIONS: Immunoassays are impacted by varying degrees of HIL interference. Some measurands, in the presence of interference, are affected in a manner not previously indicated. The data presented herein provide an independent evaluation of HIL thresholds and will be of aid to resource-limited clinical laboratories that are unable to internally verify endogenous interferences when implementing the Alinity i analyser.

Modification of proteins with azobenzene crosslinkers using reversible covalent bonds.

Thiol-reactive reagents designed for the chemical modification of proteins cannot, in general, be used directly for the modification of intracellular targets because the presence of millimolar concentrations of glutathione inside cells effectively outcompetes reaction with target thiols. Here we report an equilibrium, entropic strategy for achieving target selectivity using a cyanoacrylate-based thiol-reactive cross-linker (BCNA) with two reactive sites. This compound exhibits ≳200-fold selectivity for reaction with target peptides and proteins containing appropriately spaced pairs of thiols, versus reaction with mono-thiols. Photo-isomerization of the azobenzene moiety of the cross-linker can be used to affect the conformation of the target peptide or protein. This approach suggests a general strategy for the chemical modification of intracellular peptide and protein targets.

A Case of Clinical Confusion Due to Erroneous M-protein Quantifications: To Splice or Skim?

An M-protein identified on electrophoresis is conventionally quantified by integrating the M-spike from baseline (PD), invariably including some irrelevant/background proteins. The use of an alternative approach that skims the M-spike tangentially thereby excluding the background proteins (TS), however, has been scanty. We report herein a case in which PD overestimated the M-proteins inconsistently, leading to confusion over relapse in a multiple myeloma patient. At diagnosis, a 65-year old male had an IgG kappa M-spike of 44 g/L which decreased to 6 g/L (PD) following chemotherapy. Six weeks after autologous stem cell transplantation (ASCT), two M-spikes measuring respectively 10 and 5 g/L emerged. Together with decreases in hemoglobin and blood cell counts, a relapse was suspected. Bone marrow examinations, however, did not reveal any significant plasmacytosis or clonal restriction. Re-analyses by TS reduced the original M-protein estimations by 12% and 88% pre- and post-ASCT respectively, and corroborated the disease activity/status consistently.

Complex biological patterns of soluble cytokines and CD163 in childhood necessitating age-specific reference intervals for evidence-based clinical interpretation.

BACKGROUND: Cytokine measurements to support clinical laboratory and research investigations have become increasingly common in pediatrics. However, there is a paucity of accurate pediatric reference intervals (RIs) essential to the interpretation of cytokine results. To address this gap, here, we establish age- and sex-specific pediatric reference values for clinically relevant inflammatory markers including CD163, and the cytokines IL-1ß, IL-6, IL-10, IL-18, TNF-α, IFN-γ, and CXCL-9. METHODS: Healthy children and adolescents (n = 311, 1-19 years) were recruited as part of the Canadian Laboratory Initiative on Pediatric Reference Intervals (CALIPER) study. Multi-analyte measurements in plasma and analytical performance verification were conducted on the ProteinSimple® Ella™ automated immunoassay platform (Bio-Techne, MN, USA). Age- and sex-specific RIs were calculated based on Clinical and Laboratory Standards Institute guidelines. Additionally, 75th and 95th percentile cut-offs were determined. RESULTS: Three types of reference value distributions were observed: (a) consistent levels throughout age and sex: IL-6, and IFN-γ, (b) gradual decline in concentration with age: CD163, TNF-α, CXCL-9, and IL-10, (c) significantly higher concentrations during ages 4-14 years than earlier and later ages: IL-1ß and IL-18. Reference values for CXCL-9, IL-10, and TNF-α under 8 years of age differed significantly from older children. CD163, IL-18 and IL-1ß required three age partitions. CD163 demonstrated significant sex differences in ages 8-13 years. CONCLUSION: The circulating profile of cytokines in children is complex and can vary by age and sex. This necessitates careful interpretation of test results based on age and/or sex specific RIs facilitating more accurate clinical decision making.

Recurring Critical Results and Their Impact on the Volume of Critical Calls at a Tertiary Care Center.

BACKGROUND: When a test result is critically abnormal, laboratories notify the responsible caregivers immediately, usually with a phone call. If the same test was ordered repeatedly, our institution has a policy of not notifying the caregiver if the previous result was also critical and within 24 h. We compared our policy with those of several different laboratories in North America and estimated the impact of changing our current policy to calling for all critical results, regardless of the time interval. METHODS: Several North American laboratories (n = 15) were surveyed regarding their critical result notification policy. For our institution, we performed a retrospective analysis focusing on critical values in a 5-month period for common chemistry tests. We estimated the effect on volume of calls and the impact on workload with regard to changing the critical result notification policy and critical thresholds. RESULTS: A majority of surveyed laboratories had some form of restriction for calling about recurring critical results. In our institution, removing the restrictions would increase the average number of daily calls by 11%-155%, depending on the analyte. The choice of critical thresholds also has an effect on the number of calls, and the effect depends on the analyte and the threshold chosen. CONCLUSIONS: Guidelines do not specify how recurring critical results should be communicated. Depending on the institutional resources, some laboratories call only the first critical result for one or more tests if certain criteria are met. Modification of these policies can lead to significant changes in the volume of calls made by the laboratory and can have numerous impacts related to workload, logistics, and patient care.

Inaccuracy of Sodium Measurement in Patients with Severe Hypernatremia.

INTRODUCTION: We observed discordant sodium results from a patient with severe hypernatremia such that whole-blood analysis produced results up to 9.6 mmol/L higher than plasma sodium obtained on the same collection. We investigated this bias by comparing other patients' sodium results and performing comparisons of 3 blood gas and 2 chemistry analyzers. METHODS: First, the laboratory information system was queried for whole-blood sodium results >160 mmol/L, which were used for comparison against plasma results from the same collection. Second, whole blood was collected from a healthy donor, a portion of which was spiked with sodium chloride to generate 8 samples with target concentrations of 140 to 185 mmol/L. Whole-blood sodium was measured in duplicate on the ABL90, RAPIDPoint 500, and GEM 4000. Plasma sodium was then measured in duplicate on the Architect c8000 and Cobas c702. Finally, plasma was injected on the blood gas analyzers to measure sodium in singleton. RESULTS: Overall, 53 paired results from patients showed a significant positive bias on the ABL90 relative to Vitros when sodium was >160 mmol/L. The magnitude of difference was insignificant within the reference range but increased proportionately with concentration. The magnitude and pattern of positive bias in ABL90 sodium results were consistent with the observation in patient results. CONCLUSION: In severe hypernatremia, sodium results produced by blood gas and plasma analyzers can differ significantly.