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: ObjectivesSalivary analysis is a noninvasive alternative that may be more acceptable to patients, especially children. As such, it has the potential for incorporation into comprehensive, dynamic investigations of metabolic dysfunctions - a significant advancement over a single time point serum analysis. In this study, we wanted to determine if the serum cortisol assay on our routine immunoassay analyzer could reliably measure salivary cortisol concentrations. Because of potential fluctuations in salivary concentrations, we included a biologic variation study as a main facet of our preliminary method evaluation.: Design and methodsTwenty-eight healthy individuals (12 males, 16 females) volunteered to provide 5 nonconsecutive first morning saliva samples over a two-week period. Samples were stored frozen at home until the completion of the study. Following thawing and centrifugation, cortisol was measured in batch mode for each set of participant samples on the ROCHE Elecsys. Biologic variation was determined following removal of outliers. A method comparison was performed with the DPC Coat-A-Count Cortisol assay following the recommended modifications for salivary analysis, and with the Salimetrics HS-Cortisol two-site monoclonal assay optimized for salivary cortisol.: ResultsMean salivary cortisol concentration was 20.4 nmol/L. Analytical variation (CVA = 3.8%), within-subject variation (CVI = 6.3%), between-subject variation (CVG = 20.5%), index of individuality (II = 0.36) and reference change value (RCV = 20.4%) were determined. A negative 40% proportional bias was observed on the Elecsys compared to the two methods that have already been optimized for salivary analysis.: ConclusionsThis study demonstrated that salivary cortisol can be reliably measured on a routine automated immunoassay analyzer such as the ROCHE Elecsys. This particular assay needs to be optimized at the low end of the standard curve for routine use with salivary samples. Based on the relatively small intra-individual variation and low index of individuality, reference change values are preferable to the use of population reference intervals for this assay. [Copyright &y& Elsevier]

Objectives: Previous literature has approached proficiency testing (PT) performance by defining the minimum levels, and combinations of imprecision and bias, necessary to meet PT requirements. In this case report, current PT performance was assessed and modeling performed to prioritize our quality improvement efforts.Methods: A total of 1006 chemistry challenge results from Ontario’s Laboratory Proficiency Testing Program (LPTP, now QMPLS) performed on 69 tests during 1999 and 2000 were used for this retrospective analysis. Peer group means, all method means and results from reference labs were used for comparison. QMPLS flagging and recommended performance criteria were compiled, and modeling performed to predict different levels of performance.Results: Our internal imprecision is <5% for 72% of our 69 tests; however, only 20% of our tests had a CV/PT <25%. Of the 1006 challenges performed, 136 (13.5%) results were outside PT limits, 55 (5.5%) results were flagged, and 12 requests were received from QMPLS seeking clarification on 24 (2.4%) results. Follow-up identified 9 (38%) nonanalytical errors, 8 (33%) method bias errors, 4 (17%) random errors, 2 poor methods, and one with no error identified. Modeling predicted flagging rates of 2.4% using QMPLS recommended precision performance, 1.6% using our current internal imprecision, 2.2% or 7.0% if we included an overall 20% or 50% relative bias rate with our current imprecision levels, or 15.0% when an estimate of our actual bias for each analyte was considered along with our current imprecision levels.Conclusions: If imprecision were the only cause of PT errors, our flagging rate for this study period would be 1.6%, and we would need to formally investigate 8 results a year. In practice, strict application of the QMPLS PT criteria would result in 68 investigations annually; however, judicial review of the results before request for clarification significantly reduced this number to 12 investigations (of which 38% were nonanalytical errors). At the present time bias is a significant cause of poor PT performance in a variety of assays. Individual laboratories need to address the problem of bias, and ultimately so do manufacturers. It would be helpful if PT programs also acknowledged this necessary evolution in both their criteria and processes. [Copyright &y& Elsevier]

• Significant variability between PTH assays exists. • Manufacturer supplied reference ranges do not reflect this variability. • Discordance exists between manufacturers as to whether PTH values exceed their ULN. • The ULN is an important cut-point for CKD-BMD assessment and management. • Discordance is reduced but not eliminated using empirically derived ULN. Parathyroid hormone (PTH) is measured routinely as part of Chronic Kidney Disease Bone and Mineral Disorders (CKD-MBD) assessment. Multiple PTH assays exist with known differences resulting in CKD-MBD guidelines recommending treatment based on assay-specific thresholds. The study objectives are to assess between manufacturer and within manufacturer variability of PTH assays and the impact of assay variability on the assessment of CKD-BMD using both vendor defined and empirically derived thresholds. Data were collected from Ontario, Canada's Proficiency Testing Program (24 challenge vials, 115–133 laboratories all using secondary generation PTH assays. Mean PTH and precision by the coefficient of analytical variation (CV a) were calculated. For each vial, whether the manufacturer's mean value exceeded the vendor-defined and empirically-derived upper limit of normal (ULN) was recorded and the concordance between assays was determined. Across all laboratories, the mean PTH range was 12.0 ± 3.9 pmol/L and the mean CV a was 30%. The percent of vials with a mean PTH exceeding manufacturer's specific ULN varied substantially between manufacturers. Only 58% of vials had complete concordance as to whether mean PTH was above assay-specific ULNs. This increased to 83% using the empirically derived ULN. CKD-BMD assessment and management will depend on the PTH assay. The between-assay variability is reduced but not eliminated when empirically derived reference intervals are used. Improvements in PTH measurement are required in order to ensure consistent patient care. [ABSTRACT FROM AUTHOR]

Respiratory loads can cause respiratory pump failure but the underlying causes, often assumed to be asphyxia and inspiratory muscle fatigue, remain unresolved. In rat, we hypothesized that breathing at an increased end-expiratory lung volume would cause not just respiratory but cardiovascular failure. Rats breathed at an increased lung volume until inspiratory pressure generation decreased to half the loaded values (respiratory pump failure) or mean arterial pressure dropped below 60 mmHg (cardiovascular failure). Loading resulted in immediate arterial hypoxemia and hypercapnia, as well as a decrease in diaphragmatic contractility (ratio of transdiaphragmatic pressure to integrated phrenic activity). Contractility remained at this level during loading, despite arterial hypoxemia and hypercapnia/acidosis, until decreasing again at the time of respiratory pump failure. Respiratory drive was maintained and heart rate increased but blood pressure declined steadily. At termination of loading, cardiac troponin T was detected in the blood, indicating myocardial injury; moreover, the rats were hyperkalemic and hypoglycemic. Thus, in rats forced to breathe at an increased lung volume, cardiorespiratory, not just respiratory, failure occurs and factors other than fatigue, hypoxia and hypercapnia/ acidosis, such as hypoglycemia and hyperkalemia, may contribute. [ABSTRACT FROM AUTHOR]

Objectives: Measurement of the serum B-type natriuretic peptide (BNP) level and more recently its precursor, N-terminal proBNP (NT-proBNP), has been advocated to facilitate the diagnosis of heart failure in the emergency department (ED). We sought to determine the potential impact of adding NT-proBNP testing to the routine evaluation of emergency patients with acute dyspnea. Methods: This prospective cohort study enrolled a convenience sample of acutely dyspneic patients at a tertiary care ED. We excluded trauma patients and those under 30 years of age. Patients underwent standard evaluation, including radiography when indicated. At the point of final diagnosis and blinded to the NT-proBNP result, physicians documented the likelihood that heart failure accounted for the patient's acute dyspnea on a 7-point Likert scale, the data from which was subsequently collapsed to 3 categories for analysis purposes. The primary outcome was the agreement between clinical impression and the NT-proBNP assay classified using manufacturer-recommended, age-specific cut-offs. Newly proposed cut-offs from a recent study were also evaluated. Results: One hundred and twenty-nine patients making 139 ED visits were enrolled (median age 76 years; 59% admitted). The serum NT-proBNP assay was positive in 119 (86%, 95% confidence interval [CI] 80%–91%) cases, including 75% (43/57, 95% CI 62%–86%) of the cases that the treating physician felt were not caused by heart failure, and 86% (25/29, 95% CI 68%–96%) where the treating physician was unsure. The median NT-proBNP concentration was higher in patients clinically believed to have heart failure rather than pneumonia or chronic obstructive pulmonary disease; however, the ranges of these values overlapped extensively (median 4361 pg/mL; interquartile range [IQR] 2386–10877 v. 1651 pg/mL; IQR 370–4745, respectively). Conclusions: There is high discordance between the clinical impression of treating physicians and NT-proBNP concentrations, notably in patients who are believed not to have heart failure. Although the reference standard of ED diagnosis is imperfect, the broad overlap in NT-proBNP concentrations suggests poor specificity in this target patient population. The introduction of routine ED NT-proBNP testing using the current cut-offs would be expected to result in substantial indirect costs from further diagnostic testing. It remains unclear whether the introduction of this diagnostic test would have a positive impact on clinically relevant patient outcomes. [ABSTRACT FROM AUTHOR]

Recent years have seen a steady decline in the number of new physician-investigation (Association of American Medical Colleges, 2000). To encourage medical students to select research careers, the Queen's University Faculty of Health Sciences curriculum includes a mandatory Critical Enquiry elective in the 2nd year. An anonymous written survey was administered to medical students before and after the elective to determine their perceptions of the value of the elective and its impact on their decision to pursue a career in medical research. There was a significant increase in the number of students expressing an interest in pursuing a research career following the elective (35-42%, p = 0.029). Students recognized other benefits including the development of critical appraisal, information literacy, and critical thinking skills; and the opportunity to select an area of and form contacts for postgraduate training. Even students who choose not to pursue careers in medical research perceive benefits to a mandatory undergraduate research elective. [ABSTRACT FROM AUTHOR]

Abstract Background Diagnosis, prognostication and treatment in chronic kidney disease is often informed by an estimate of the glomerular filtration rate (GFR). Commonly used GFR estimation (eGFR) equations are based on serum creatinine (Cr) concentrations and display suboptimal precision and accuracy. Newer equations incorporating additional endogenous markers such as β-Trace Protein (BTP), β 2 -Microglobulin (B2M) and cystatin C (cysC) have been developed but require validation. Methods This prospective cohort study evaluated the performance of 6 eGFR equations developed by the chronic kidney disease - epidemiology collaboration group (CKD-EPI) against urinary inulin clearance GFR in patients recruited from outpatient nephrology clinics. Results Mean biases were negligible and similar between equations. The eGFR-EPI Cr/cysC had the best precision and accuracy of all the equations and the best agreement with inulin mGFR when classifying participants into GFR categories. The BTP and B2M equations displayed the worst precisions and accuracies and showed the least consistent performance across levels of GFR. Thus, the eGFR-EPI Cr/cysC is the least biased, most precise and has the highest accuracy as compared to other eGFR-EPI equations. Conclusions The BTP and B2M equations are the worst performing of the eGFR-EPI equations, and no benefit is observed with the addition of BTP or B2M to Cr/cysC. [ABSTRACT FROM AUTHOR]

Objective Reference intervals are widely used decision-making tools in laboratory medicine, serving as health-associated standards to interpret laboratory test results. Numerous studies have shown wide variation in reference intervals, even between laboratories using assays from the same manufacturer. Lack of consistency in either sample measurement or reference intervals across laboratories challenges the expectation of standardized patient care regardless of testing location. Here, we present data from a national survey conducted by the Canadian Society of Clinical Chemists (CSCC) Reference Interval Harmonization (hRI) Working Group that examines variation in laboratory reference sample measurements, as well as pediatric and adult reference intervals currently used in clinical practice across Canada. Design and Methods Data on reference intervals currently used by 37 laboratories were collected through a national survey to examine the variation in reference intervals for seven common laboratory tests. Additionally, 40 clinical laboratories participated in a baseline assessment by measuring six analytes in a reference sample. Results Of the seven analytes examined, alanine aminotransferase (ALT), alkaline phosphatase (ALP), and creatinine reference intervals were most variable. As expected, reference interval variation was more substantial in the pediatric population and varied between laboratories using the same instrumentation. Reference sample results differed between laboratories, particularly for ALT and free thyroxine (FT4). Reference interval variation was greater than test result variation for the majority of analytes. Conclusion It is evident that there is a critical lack of harmonization in laboratory reference intervals, particularly for the pediatric population. Furthermore, the observed variation in reference intervals across instruments cannot be explained by the bias between the results obtained on instruments by different manufacturers. [ABSTRACT FROM AUTHOR]

Background: During pregnancy, the demand for folic acid increases since the fetus requires this nutrient for its rapid growth and cell proliferation. The placenta concentrates folic acid into the fetal circulation; as a result the fetal levels are 2 to 4 times higher than the maternal level. Animal and in vitro studies have suggested that alcohol may impair transport of folic acid across the placenta by decreasing expression of transport proteins. We aim to determine if folate transfer to the fetus is altered in human pregnancies with chronic alcohol consumption. Methodology/Principal Findings: Serum folate was measured in maternal blood and umbilical cord blood at the time of delivery in pregnancies with chronic and heavy alcohol exposure (n = 23) and in non-drinking controls (n = 24). In the alcohol-exposed pairs, the fetal:maternal serum folate ratio was >1.0 in over half (n = 14), whereas all but one of the controls were >1.0. Mean folate in cord samples was lower in the alcohol-exposed group than in the controls (33.15±19.89 vs 45.91±20.73, p = 0.04). Conclusions/Significance: Our results demonstrate that chronic and heavy alcohol use in pregnancy impairs folate transport to the fetus. Altered folate concentrations within the placenta and in the fetus may in part contribute to the deficits observed in the fetal alcohol spectrum disorders. [ABSTRACT FROM AUTHOR]

Fibroblast growth factor 23 ( FGF-23) is elevated in patients with end-stage kidney disease and has been linked with mortality, vascular calcification, markers of bone turnover, and left ventricular hypertrophy. In this cohort study, we determined the correlates of FGF-23 (including cardiac troponin T [ cTNT]) and determined its association with mortality over 3.5 years of follow-up in 103 prevalent hemodialysis patients. Mean age was 61.2 (15.5) and the mean dialysis vintage was 4.19 years (4.6). The median (interquartile range) FGF-23 was 1259 (491, 2885) RU/ mL. Independent predictors (estimate standard error) of log-transformed FGF-23 concentrations included phosphorus (0.75 [0.237], P = 0.002) and cardiac troponin T (1.04 [0.41], P = 0.01). There were 57 deaths. In the fully adjusted model, the significant predictors of mortality included age and albumin. The independent association between FGF-23 and cTNT is a novel finding. Whether this relationship supports the possibility that a downstream effect of dysregulated phosphorous homeostasis may be enhanced cardiac remodeling requires further study. [ABSTRACT FROM AUTHOR]

Abstract: Chronic ethanol exposure (CEE) can produce developmental abnormalities in the CNS of the embryo and developing fetus. Folic acid (FA) is an important nutrient during pregnancy and low folate status exacerbates ethanol-induced teratogenicity. This study tested the hypotheses that (1) CEE depletes folate stores in the mother and fetus; and (2) maternal FA supplementation maintains folate stores. CEE decreased fetal body, brain, hippocampus weights, and brain to body weight ratio but not hippocampus to body weight ratio. These effects of CEE were not mitigated by maternal FA administration. The FA regimen prevented the CEE-induced decrease of term fetal liver folate. However, it did not affect maternal liver folate or fetal RBC folate at term, and did not mitigate the nutritional deficit-induced decrease of term fetal hippocampus folate. This study suggests that maternal FA supplementation may have differential effects on folate status in the mother and the fetus. [Copyright &y& Elsevier]

Background: Drug abuse is a frequent factor in emergency department (ED) visits. Although commonly performed, qualitative testing of urine for drugs of abuse (u-DOA) is inherently limited in its ability to establish the identity, timing or dose of substances used. Previous studies have demonstrated these limitations, but their designs cannot be used to determine whether the results of u-DOA tests affect physicians' patient care decisions. Our objective was to determine the impact of u-DOA testing on the care of patients who present to the ED. Methods: All adults 18 years of age or older who had u-DOA testing in 2 urban teaching EDs were eligible. Victims of vehicular trauma or sexual assault were excluded. Just prior to communicating the results of u-DOA testing for a patient, an investigator interviewed the ordering physician or consultant physician about the patient care plans for that patient. Test results were then revealed, and the questions immediately repeated. This design isolated the impact of knowledge of u-DOA test results on physicians' patient care decisions. Any intended changes in patient care plans reported by the interviewed physician were compared to a priori criteria for substantive change and then subsequently reviewed by an independent expert to determine whether that change was justified. Results: Of the 110 u-DOA test results studied and the resultant 133 opportunities to influence physician management plans, there were 4 reported changes in management. One management change was judged to be substantive, but none of the 4 reported changes were considered by the independent expert reviewer to be justified. Urine-DOA testing thus led to a justified change in management in 0/133 instances (95% confidence interval 0%-2.3%). Conclusions: Urine-DOA is rarely helpful in guiding patient care decisions in the ED. The results of this study call into question the need for this test in the ED setting. [ABSTRACT FROM AUTHOR]