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Aims Levels of growth differentiation factor 15 (GDF-15), a cytokine secreted in response to cellular stress and inflammation, have been associated with multiple types of cardiovascular (CV) events. However, its comparative prognostic performance across different presentations of atherosclerotic cardiovascular disease (ASCVD) remains unknown. Methods and results An individual patient meta-analysis was performed using data pooled from eight trials including 53 486 patients. Baseline GDF-15 concentration was analyzed as a continuous variable and using established cutpoints (<1200 ng/L, 1200–1800 ng/L, > 1800 ng/L) to evaluate its prognostic performance for CV death/hospitalization for heart failure (HHF), major adverse cardiovascular events (MACE), and their components using Cox models adjusted for clinical variables and established CV biomarkers. Analyses were further stratified on ASCVD status: acute coronary syndrome (ACS), stabilized after recent ACS, and stable ASCVD. Overall, higher GDF-15 concentration was significantly and independently associated with an increased rate of CV death/HHF and MACE (P < 0.001 for each). However, while GDF-15 showed a robust and consistent independent association with CV death and HHF across all presentations of ASCVD, its prognostic association with future myocardial infarction (MI) and stroke only remained significant in patients stabilized after recent ACS or with stable ASCVD [hazard ratio (HR): 1.24, 95% confidence interval (CI): 1.17–1.31 and HR: 1.16, 95% CI: 1.05–1.28 for MI and stroke, respectively] and not in ACS (HR: 0.98, 95% CI: 0.90–1.06 and HR: 0.87, 95% CI: 0.39–1.92, respectively). Conclusion Growth differentiation factor 15 consistently adds prognostic information for CV death and HHF across the spectrum of ASCVD. GDF-15 also adds prognostic information for MI and stroke beyond clinical risk factors and cardiac biomarkers but not in the setting of ACS. [ABSTRACT FROM AUTHOR]

Aims Interest in targeted screening programmes for atrial fibrillation (AF) has increased, yet the role of genetics in identifying patients at highest risk of developing AF is unclear. Methods and results A total of 36,662 subjects without prior AF were analyzed from four TIMI trials. Subjects were divided into quintiles using a validated polygenic risk score (PRS) for AF. Clinical risk for AF was calculated using the CHARGE-AF model. Kaplan–Meier event rates, adjusted hazard ratios (HRs), C -indices, and net reclassification improvement were used to determine if the addition of the PRS improved prediction compared with clinical risk and N-terminal pro-B-type natriuretic peptide (NT-proBNP). Over 2.3 years, 1018 new AF cases developed. AF PRS predicted a significant risk gradient for AF with a 40% increased risk per 1-SD increase in PRS [HR: 1.40 (1.32–1.49); P < 0.001]. Those with high AF PRS (top 20%) were more than two-fold more likely to develop AF [HR 2.45 (1.99–3.03), P < 0.001] compared with low PRS (bottom 20%). Furthermore, PRS provided an additional gradient of risk stratification on top of the CHARGE-AF clinical risk score, ranging from a 3-year incidence of 1.3% in patients with low clinical and genetic risk to 8.7% in patients with high clinical and genetic risk. The subgroup of patients with high clinical risk, high PRS, and elevated NT-proBNP had an AF risk of 16.7% over 3 years. The C -index with the CHARGE-AF clinical risk score alone was 0.65, which improved to 0.67 (P < 0.001) with the addition of NT-proBNP, and increased further to 0.70 (P < 0.001) with the addition of the PRS. Conclusion In patients with cardiovascular conditions, AF PRS is a strong independent predictor of incident AF that provides complementary predictive value when added to a validated clinical risk score and NT-proBNP. [ABSTRACT FROM AUTHOR]

Objectives: In vitro hemolysis generates a spurious increase in potassium. Roche Diagnostics recently revised its recommended guidelines for potassium reporting on cobas analyzers. By dramatically reducing the allowable degree of hemolysis, these guidelines would increase specimen rejection rates. We attempted to balance the desire to avoid inaccurate results with the clinical implications of increased specimen rejection rates.Methods: We downloaded hemolytic indices (HI) for 80,795 specimens tested at our institution on cobas chemistry analyzers in 1 month and evaluated potential specimen rejection rates based on the new criteria. We also spiked nonhemolyzed samples with hemolyzed blood to assess the influence of HI values on potassium measurements.Results: The new recommendations would lead to specimen rejection rates of 76% in the neonatal intensive care unit (NICU), 41% in the emergency department (ED), 16% in inpatient specimens, and 9% in outpatient samples. Our current criteria of reporting potassium concentrations in inpatient and outpatient specimens with HI ≤100 and in NICU and ED specimens with HI ≤300 and additional interpretive guidance for HI values between 100 and 300 reduce unnecessary specimen rejections to 3% in NICU, 2% in ED and inpatients, and less than 1% in outpatients without significantly increasing the number of clinically consequential incorrect results.Conclusions: The new recommendations would lead to unacceptably high specimen rejection rates. Laboratories should develop context-specific, evidence-based reporting criteria that minimize reporting of inaccurate results without disrupting delivery of care. [ABSTRACT FROM AUTHOR]

Objectives: Poor phlebotomy technique can introduce pseudohyperkalemia without hemolysis, requiring additional workup and placing a significant burden on patients, clinical teams, and laboratories. Such preanalytical biases can be detected through systematic evaluation of potassium concentrations on a per-phlebotomist basis. We report our long-term experience with a potassium-based quality-of-service phlebotomy metric and its effects on resource utilization.Methods: Potassium monitoring and retraining of 26 full-time phlebotomists were piloted as a quality-of-service intervention. Changes in potassium concentrations and impact on resource utilization were assessed. An algorithm for data monitoring and phlebotomist feedback was developed, followed by institution-wide implementation.Results: Systematic intervention and retraining normalized K+ concentrations and lowered the percentage of venipunctures with K+ above 5.2 mmol/L, leading to a marked increase in phlebotomist compliance. This change resulted in resources savings of 13% to 100% for individual phlebotomists, reducing the total extra laboratory time required for repeat phlebotomies to determine hyperkalemia, mostly in the high-volume phlebotomist group.Conclusions: A quality-of-service algorithm that involved monitoring potassium concentrations on a per-phlebotomist basis with feedback and retraining contributed to a concrete, data-based quality improvement plan. The institution-wide implementation of this metric allowed for significant cost savings and a reduction in critical value alerts, directly affecting the quality of patient care. [ABSTRACT FROM AUTHOR]

Background: Serological testing provides a record of prior infection with SARS-CoV-2, but assay performance requires independent assessment. Methods: We evaluated 3 commercial (Roche Diagnostics pan-IG, and Epitope Diagnostics IgM and IgG) and 2 non-commercial (Simoa and Ragon/MGH IgG) immunoassays against 1083 unique samples that included 251 PCR-positive and 832 prepandemic samples. Results: The Roche assay registered the highest specificity 99.6% (3/832 false positives), the Ragon/MGH assay 99.5% (4/832), the primary Simoa assay model 99.0% (8/832), and the Epitope IgG and IgM 99.0% (8/830) and 99.5% (4/830), respectively. Overall sensitivities for the Simoa, Roche pan-IG, Epitope IgG, Ragon/MGH IgG, and Epitope IgM were 92.0%, 82.9%, 82.5%, 64.5% and 47.0%, respectively. The Simoa immunoassay demonstrated the highest sensitivity among samples stratified by days postsymptom onset (PSO), <8 days PSO (57.69%) 8–14 days PSO (93.51%), 15–21 days PSO (100%), and > 21 days PSO (95.18%). Conclusions: All assays demonstrated high to very high specificities while sensitivities were variable across assays. [ABSTRACT FROM AUTHOR]

Aims We investigated whether patients with atrial fibrillation (AF) demonstrate detectable changes in biomarkers including high-sensitivity troponin T (hsTnT), N-terminal B-type natriuretic peptide (NT-proBNP), and growth differentiation factor-15 (GDF-15) over 12 months and whether such changes from baseline to 12 months are associated with the subsequent risk of stroke or systemic embolic events (S/SEE) and bleeding. Methods and results ENGAGE AF-TIMI 48 was a randomized trial of the oral factor Xa inhibitor edoxaban in patients with AF and a CHADS2 score of ≥2. We performed a nested prospective biomarker study in 6308 patients, analysing hsTnT, NT-proBNP, and GDF-15 at baseline and 12 months. hsTnT was dynamic in 46.9% (≥2 ng/L change), NT-proBNP in 51.9% (≥200 pg/mL change), GDF-15 in 45.6% (≥300 pg/mL change) during 12 months. In a Cox regression model, upward changes in log2-transformed hsTnT and NT-proBNP were associated with increased risk of S/SEE [adjusted hazard ratio (adj-HR) 1.74; 95% confidence interval (CI) 1.36–2.23 and adj-HR 1.27; 95% CI 1.07–1.50, respectively] and log2-transformed GDF-15 with bleeding (adj-HR 1.40; 95% CI 1.02–1.92). Reassessment of ABC-stroke (age, prior stroke/transient ischaemic attack, hsTnT, and NT-proBNP) and ABC-bleeding (age, prior bleeding, haemoglobin, hsTnT, and GDF-15) risk scores at 12 months accurately reclassified a significant proportion of patients compared with their baseline risk [net reclassification improvement (NRI) 0.50; 95% CI 0.36–0.65; NRI 0.42; 95% CI 0.33–0.51, respectively]. Conclusion Serial assessment of hsTnT, NT-proBNP, and GDF-15 revealed that a substantial proportion of patients with AF had dynamic values. Greater increases in these biomarkers measured over 1 year are associated with important clinical outcomes in anticoagulated patients with AF. [ABSTRACT FROM AUTHOR]

Aims Pulmonary hypertension (PH) represents an important phenotype among the broader spectrum of patients with heart failure with preserved ejection fraction (HFpEF), but its mechanistic basis remains unclear. We hypothesized that activation of endothelin and adrenomedullin, two counterregulatory pathways important in the pathophysiology of PH, would be greater in HFpEF patients with worsening PH, and would correlate with the severity of haemodynamic derangements and limitations in aerobic capacity and cardiopulmonary reserve. Methods and results Plasma levels of C-terminal pro-endothelin-1 (CT-proET-1) and mid-regional pro-adrenomedullin (MR-proADM), central haemodynamics, echocardiography, and oxygen consumption (VO2) were measured at rest and during exercise in subjects with invasively-verified HFpEF (n  = 38) and controls free of HF (n  = 20) as part of a prospective study. Plasma levels of CT-proET-1 and MR-proADM were highly correlated with one another (r  = 0.89, P  < 0.0001), and compared to controls, subjects with HFpEF displayed higher levels of each neurohormone at rest and during exercise. C-terminal pro-endothelin-1 and MR-proADM levels were strongly correlated with mean pulmonary artery (PA) pressure (r  = 0.73 and 0.65, both P  < 0.0001) and pulmonary capillary wedge pressure (r  = 0.67 and r  = 0.62, both P  < 0.0001) and inversely correlated with PA compliance (r = −0.52 and −0.43, both P  < 0.001). As compared to controls, subjects with HFpEF displayed right ventricular (RV) reserve limitation, evidenced by less increases in RV s ′ and e ′ tissue velocities, during exercise. Baseline CT-proET-1 and MR-proADM levels were correlated with worse RV diastolic reserve (ΔRV e ′, r = −0.59 and −0.67, both P  < 0.001), reduced cardiac output responses to exercise (r = −0.59 and −0.61, both P  < 0.0001), and more severely impaired peak VO2 (r = −0.60 and −0.67, both P  < 0.0001). Conclusion Subjects with HFpEF display activation of the endothelin and adrenomedullin neurohormonal pathways, the magnitude of which is associated with pulmonary haemodynamic derangements, limitations in RV functional reserve, reduced cardiac output, and more profoundly impaired exercise capacity in HFpEF. Further study is required to evaluate for causal relationships and determine if therapies targeting these counterregulatory pathways can improve outcomes in patients with the HFpEF-PH phenotype. Clinical trial registration NCT01418248; https://clinicaltrials.gov/ct2/results? term=NCT01418248&Search=Search Open in new tab Download slide Open in new tab Download slide [ABSTRACT FROM AUTHOR]

Objectives: To control the cost of reference laboratory testing, to ensure that its usage is medically appropriate, and to review the contribution of reference testing to patient care at our institution. Methods: A multidisciplinary institutional committee was convened to manage the utilization of reference testing. A subset of tests was designated to be reviewed in real time by a team of clinical pathologists in consultation with clinical subject matter experts. Results: Twelve percent of testing requests, accounting for approximately 18% of send-out costs, were determined to be clinically unnecessary or would not produce actionable results at that point during that patient's care and were therefore not performed. This intervention, combined with insourcing of frequently requested tests, resulted in a reduction in the costs of reference testing to less than half of that predicted by the rate of growth from 2005 to 2009. Molecular diagnostic tests displayed a higher cost per test than other forms of testing but had a similar degree of clinical impact. Conclusions: Formal prospective review of reference laboratory testing requests resulted in substantial cost containment and improved the efficiency of patient care. [ABSTRACT FROM AUTHOR]

Buprenorphine (BUP), a semi-synthetic opioid analgesic, is increasingly prescribed for the treatment of chronic pain and opioid dependence. Urine immunoassay screening methods are available for monitoring BUP compliance and misuse; however, these screens may have poor sensitivity or specificity. We evaluated whether the pretreatment of urine with β-glucuronidase (BG) improves the sensitivity and overall accuracy of three BUP enzyme immunoassays when compared with liquid chromatography–tandem mass spectrometry (LC–MS-MS). Urine samples sent to our laboratories for BUP testing (n = 114) were analyzed before and after BG pretreatment by cloned enzyme donor immunoassay (CEDIA), enzyme immunoassay (EIA) and homogenous EIA (HEIA) immunoassays using a common 5 ng/mL cutoff. Total BUP and norbuprenorphine (NBUP) concentrations were measured by LC–MS-MS as the reference method. Urine BG pretreatment improved EIA, HEIA and CEDIA sensitivities from 70, 82 and 94%, respectively, to 97% for each of the three methods, when compared with LC–MS-MS. While the specificity of the EIA and HEIA remained 100% after BG pretreatment, the specificity of the CEDIA decreased from 74 to 67%. Urine pretreatment with BG is recommended to improve sensitivity of the EIA and HEIA BUP screening methods. [ABSTRACT FROM PUBLISHER]

The article informs on a research that utilizes the technique of Lin-Zhi urine buprenorphine enzyme immunoassay (EIA) technique for the screening of urine buprenorphine and compares it with the technique of Microgenics cloned enzyme donor immunoassay (CEDIA). It is mentioned that urine buprenorphine screening helps in detecting the illegal use of buprenorphine, however, it often presents cross reactivity with other opioids. Also, EIA methods presents specificity for buprenorphine use.

Aims The aim of this study is to simultaneously evaluate the incremental prognostic value of multiple cardiac biomarkers reflecting different underlying pathophysiological processes in a well-characterized population of patients with non-ST-segment acute coronary syndrome (NSTE-ACS). Methods and results We measured cardiac troponin I (cTnI), N-terminal pro B-type natriuretic peptide (NT-proBNP), C-reactive protein, and myeloperodixase (MPO) among 4352 patients with NSTE-ACS in the MERLIN-TIMI 36 (Metabolic Efficiency With Ranolazine for Less Ischaemia in Non-ST Elevation Acute Coronary-Thrombolysis In Myocardial Infarction 36) trial and followed them for a mean of 343 days. When added individually to a multivariable model adjusted for clinical characteristics, the risk of cardiovascular (CV) death rose in a stepwise fashion with increasing quartiles of each biomarker, and when using their pre-defined cut-points [HRadj 2.71 (P < 0.001) for cTnI ≥0.03 ng/mL; HRadj 3.01 (P < 0.001) for NT-proBNP ≥400 pg/mL; HRadj 1.45 (P = 0.019) for high-sensitivity (hs) C-reactive protein ≥15 mg/L; and HRadj 1.49 (P = 0.006) for MPO ≥670 pmol/L]. After including all biomarkers, only NT-proBNP and cTnI were independently associated with CV death, and only cTnI with myocardial infarction (MI). The addition of NT-proBNP to a model adjusted for TIMI risk score incorporating cTnI significantly improved both the discrimination and re-classification of the model for CV death and heart failure (HF) while there was no such improvement after the addition of either MPO or hs-C-reactive protein. Conclusion In this study of over 4300 patients presenting with NSTEACS, we found that both cTnI and NT-proBNP offer prognostic information beyond that achieved with clinical risk variables for CV death, MI, and HF. Myeloperoxidase and hs-C-reactive protein, while independently associated with some adverse CV outcomes, did not provide substantial incremental prognostic information when evaluated together with cTnI and NT-proBNP. [ABSTRACT FROM PUBLISHER]

Background The autosomal recessive chromosomal instability disorder Nijmegen breakage syndrome (NBS) is associated with increased risk of lymphoid malignancies and other cancers. Cells from NBS patients contain many double-stranded DNA breaks. More than 90% of NBS patients are homozygous for a founder mutation, 657del5, in the NBN gene. We investigated the 657del5 carrier status of cancer patients among blood relatives (i.e., first-, through fourth-degree relatives) of NBS patients in the Czech Republic and Slovakia to test the hypothesis that NBN heterozygotes have an increased cancer risk. Methods Medical information was compiled from 344 blood relatives of NBS patients in 24 different NBS families from January 1, 1998, through December 31, 2003. The 657del5 carrier status of subjects was unknown at the time of their recruitment but was later determined from blood samples collected at the time of the interview. Medical records and death certificates were used to confirm a diagnosis of cancer. For the relatives with cancer who are not obligate heterozygotes (such as parents and two grandparents in consanguineous families), the observed and expected number of mutation carriers were compared by use of the index-test method, which estimated the risk of cancer associated with carrying the mutation. All P values were two-sided. Results Thirteen of the 344 blood relatives had confirmed cases of any type of cancer;11 of these 13 cancer patients carried the NBN 657del5 mutation, compared with 6.0 expected (P= .005). Among the 56 grandparents with complete data from 14 NBS families, 10 of the 28 carriers of 657del5, but only one of the 28 noncarriers, developed cancer (odds ratio = 10.7, 95% CI = 1.4 to 81.5; P<.004). Conclusions The NBN 657del5 mutation appears to be associated with an elevated risk of cancer in heterozygotes. [ABSTRACT FROM AUTHOR]

Background: Worldwide, approximately 50 million people live with epilepsy, a quarter of which are treated with antiepileptic drugs (AEDs). Therapeutic drug monitoring (TDM) of AEDs is often necessary to assess therapeutic compliance, potential drug-drug interactions, and pharmacokinetic inter- and intravariability secondary to significant differences in excretion and metabolism. TDM is necessary to minimize the destructive toxicities of AEDs including hematopoietic dysfunction, pruritus, rash, Steven-Johnson syndrome, anxiety, agitation, suicidal ideation, liver failure, gastrointestinal issues, and neurologic dysfunction. Tandem mass spectrometry with stable isotope internal standards is the gold standard for the measurement of AEDs. Here, we present a rapid ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for the simultaneous measurement of gabapentin, lamotrigine, levetiracetam, monohydroxy derivative (MHD) of oxcarbazepine (the main, active oxcarbazepine metabolite, also known as licarbazepine), and zonisamide in serum. Methods: For analysis, 20 µL serum samples were added to acetonitrile in the presence of deuterated internal standards for protein precipitation. After centrifugation, 10 µL of supernatant was added to 90 µL of water. Ten µL of this solution was injected into a C18 column for reversed phase UPLC chromatographic separation. Quantification of analytes was accomplished using positive-mode electrospray ionization and collision-induced dissociation MS. Total run time was 3 minutes. Assay parameters were evaluated according to Food and Drug Administration (FDA) bioanalytical guidelines. Results: To guide our assay development, we evaluated the range of AED levels for our patient population from lab results assayed at a reference laboratory. Over the course of one year, 1,825 total samples were assayed. One levetiracetam drug level was greater than 100 ug/mL, and the lower limit of quantification (LLOQ) for all drugs analyzed ranged between 2 ug/mL and 0.2 ug/mL. Therefore, an assay range of 0.1 ug/mL to 100 ig/mL was chosen for all analytes and was linear (r2 >.999) from 0.1 ug/mL to 100 ug/mL. This assay demonstrated acceptable accuracy and precision (%DEV <20% and %CV <20% for the LLOQ, %DEV <15% and %CV <15% at all other levels tested), linearity across the reportable range (r2 >.999, slopes ranging 0.968–1.062), carryover, stability under relevant storage conditions, matrix effects, recovery, and extraction and processing efficiency in accordance with FDA guidelines. Additionally, a cross-comparison with a reference laboratory using a similar methodology was performed. Conclusions: A rapid, high-throughput, and robust UPLC-MS/MS method for monitoring multiple antiepileptics was developed and validated to address the clinical needs of our patient population. [ABSTRACT FROM AUTHOR]