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This study systematically compared the performance and comparability of two medical laboratory analytical instruments, the conventional wet chemistry analyzer (cobas) and the dry slide technology (Vitros), across various clinical chemistry assays.

Mean platelet volume (MPV), platelet distribution width (PDW), and plateletcrit (PCT) possess diagnostic and prognostic capabilities in a variety of diseases. We aimed to establish reference intervals (RI) for platelet indices (PI) in seniors.

Phenobarbital serves as an antiepileptic drug (AED) and finds application in the treatment of epilepsy either as monotherapy or adjunctive therapy. This drug exhibits various pharmacodynamic properties that account for its beneficial effects as well as potential side effects. Accurate measurement of its concentration is critical for optimizing AED therapy through appropriate dose adjustments. Therefore, our objective was to develop and validate a new reference measurement procedure (RMP) for the accurate quantification of phenobarbital levels in human serum and plasma. A sample preparation protocol based on protein precipitation followed by a high dilution step was established in combination with a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method using a C8 column to separate target analytes from known and unknown interferences. Assay validation and determination of measurement uncertainty were performed based on current guidelines. Selectivity and Specificity were assessed using spiked serum and plasma samples; to investigate possible matrix effects (MEs) a post-column infusion experiment and a comparison of standard line slopes was performed. Precision and accuracy were determined within a multiday precision experiment. The RMP was shown to be highly selective and specific, with no evidence of matrix interferences. It can be used to quantify phenobarbital in the range of 1.92 to 72.0 μg/mL. Intermediate precision was less than 3.2 %, and repeatability coefficient of variation (CV) ranged from 1.3 to 2.0 % across all concentration levels. The relative mean bias ranged from −3.0 to −0.7 % for native serum levels, and from −2.8 to 0.8 % for Li-heparin plasma levels. The measurement uncertainties (k=1) for single measurements and target value assignment were 1.9 to 3.3 % and 0.9 to 1.6 %, respectively. A novel LC-MS/MS-based candidate RMP for the quantification of phenobarbital in human serum and plasma is presented which can be used for the standardization of routine assays and the evaluation of clinically relevant samples. [ABSTRACT FROM AUTHOR]

A reference measurement procedure (RMP) using isotope dilution liquid chromatography-tandem mass spectrometry (ID-LC-MS/MS) was developed and validated with the aim of accurately measuring carbamazepine-10,11-epoxide concentrations in human serum and plasma. To establish traceability to SI units, the absolute content of the reference material was determined using quantitative nuclear magnetic resonance (qNMR) spectroscopy. As sample preparation a protein precipitation protocol followed by a high dilution step was established. Chromatographic separation from carbamazepine and potential metabolites was achieved using a C18 stationary phase. Selectivity, specificity, matrix effects, precision and accuracy, inter-laboratory equivalence, and uncertainty of measurement were evaluated based on guidelines from the Clinical and Laboratory Standards Institute, the International Conference on Harmonization, and the Guide to the Expression of Uncertainty in Measurement. The RMP demonstrated very good selectivity and specificity, showing no evidence of a matrix effect. This enabled accurate quantification of carbamazepine-epoxide in the concentration range of 0.0400–12.0 μg/mL. The intermediate precision was found to be less than 2.1 %, and the repeatability coefficient of variation (CV) ranged from 1.2 to 1.8 % across all concentration levels. Regarding accuracy, the relative mean bias varied from 1.4 to 2.5 % for native serum levels and from 1.4 to 3.5 % for Li-heparin plasma levels. The measurement uncertainty for single measurements ranged from 1.6 to 2.1 %. In this study, we introduce a new LC-MS/MS-based candidate RMP for accurately measuring carbamazepine-10,11-epoxide in human serum and plasma. This novel method offers a traceable and dependable platform, making it suitable for standardizing routine assays and assessing clinically relevant samples. [ABSTRACT FROM AUTHOR]

An isotope dilution liquid chromatography-tandem mass spectrometry (ID-LC-MS/MS)-based candidate reference measurement procedure (RMP) was developed and validated to accurately measure serum and plasma concentrations of carbamazepine. Quantitative nuclear magnetic resonance (qNMR) spectroscopy was used to determine the absolute content of the reference material, ensuring its traceability to SI units. The separation of carbamazepine from potential interferences, whether known or unknown, was achieved using a C18 column. A protein precipitation protocol followed by a high dilution step was established for sample preparation. Assay validation and determination of measurement uncertainty were performed in accordance with the guidelines of the Clinical and Laboratory Standards Institute, the International Conference on Harmonization (ICH), and the Guide to the Expression of Uncertainty in Measurement (GUM). In order to demonstrate equivalence to the already existing RMP a method comparison study was performed. The RMP was proven to be highly selective and specific with no evidence of a matrix effect, allowing for quantification of carbamazepine within the range of 0.800–18.0 μg/mL. Intermediate precision and repeatability (n=60 measurements) was found to be <1.6 % and <1.3 % over all concentration levels and independent from the matrix. The relative mean bias ranged from −0.1 to 0.6 % for native serum and from −0.3 to −0.1 % for Li-heparin plasma levels. The measurement uncertainties for single measurements and target value assignment were found to be <1.8 % and <1.3 %, respectively. Method comparison showed a good agreement between the Joint Committee of Traceability in Laboratory Medicine (JCTLM) listed RMP and the candidate RMP resulting in a Passing–Bablok regression equation with a slope of 1.01 and an intercept of −0.01. The bias in the patient cohort was found to be 0.9 %. We present a novel LC-MS/MS-based candidate RMP for carbamazepine in human serum and plasma which provides a traceable and reliable platform for the standardization of routine assays and evaluation of clinically relevant samples. [ABSTRACT FROM AUTHOR]

To describe and validate an isotope dilution-liquid chromatograph-tandem mass spectrometry (ID-LC-MS/MS) based reference measurement procedure (RMP) for zonisamide to accurately measure serum and plasma concentrations. Quantitative nuclear magnetic resonance (qNMR) spectroscopy was employed to determine the absolute content of the reference material used in order to establish traceability to SI units. Separation of zonisamide from known or unknown interferences was performed on a C8 column. For sample preparation a protocol based on protein precipitation in combination with a high dilution step was established. Assay validation and determination of measurement uncertainty were performed based on guidelines from the Clinical and Laboratory Standards Institute, the International Conference on Harmonization, and the Guide to the expression of uncertainty in measurement. The RMP was proven to be highly selective and specific with no evidence of a matrix effect, allowing for quantification of zonisamide within the range of 1.50–60.0 μg/mL. Intermediate precision was <1.4 % and repeatability CV ranged from 0.7 to 1.2 % over all concentration levels. The relative mean bias ranged from 0.0 to 0.8 % for native serum levels and from 0.2 to 2.0 % for Li-heparin plasma levels. The measurement uncertainties for single measurements and target value assignment ranged from 1.1 to 1.4 % and 0.8–1.0 %, respectively. We present a novel LC-MS/MS-based candidate RMP for zonisamide in human serum and plasma which provides a traceable and reliable platform for the standardization of routine assays and evaluation of clinically relevant samples. [ABSTRACT FROM AUTHOR]

Topiramate is an antiepileptic drug (AED) used for the monotherapy or adjunctive treatment of epilepsy and for the prophylaxis of migraine. It has several pharmacodynamic properties that contribute to both its clinically useful properties and observed adverse effects. Accurate measurement of its concentration is therefore essential for dose adjustment/optimisation of AED therapy. Our aim was to develop and validate a novel reference measurement procedure (RMP) for the quantification of topiramate in human serum and plasma. An isotope dilution-liquid chromatography-tandem mass spectrometry (ID-LC-MS/MS) method in combination with a protein-precipitation-based sample preparation allows for quantification of topiramate in human serum and plasma. To assure traceability to SI units, quantitative nuclear magnetic resonance (qNMR) was applied to characterize the reference material used as primary calibrator for this RMP. Matrix effects were determined by performing a post-column infusion experiment and comparing standard line slopes. Accuracy and precision was evaluated performing an extensive five day precision experiment and measurement uncertainty was evaluated according Guide to the Expression of Uncertainty in Measurement (GUM). The method enabled topiramate quantification within the range of 1.20–36.0 μg/mL without interference from structurally related compounds and no evidence of a matrix effect. Intermediate precision was ≤3.2 % and repeatability was 1.4–2.5 % across all concentration levels. The relative mean bias was −0.3 to 3.5 %. Expanded measurement uncertainties for target value assignment (n=6) were found to be ≤2.9 % (k=2) independent of the concentration level and the nature of the sample. In human serum and plasma, the RMP demonstrated high analytical performance for topiramate quantification and fulfilled the requirements on measurement uncertainty. Traceability to SI units was established by qNMR content determination of the topiramate, which was used for direct calibration of the RMP. This RMP is, therefore, fit for purpose for routine assay standardization and clinical sample evaluation. [ABSTRACT FROM AUTHOR]

To develop an isotope dilution-liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based candidate reference measurement procedure (RMP) for levetiracetam quantification in human serum and plasma. Quantitative nuclear magnetic resonance spectroscopy (qNMR) was used to characterize the RMP material to ensure traceability to SI units. To quantify levetiracetam, an LC-MS/MS method was optimized using a C8 column for chromatographic separation following protein-precipitation-based sample preparation. Spiked matrix samples of serum and plasma were used to test selectivity and specificity. Matrix effects were determined by performing a post-column infusion experiment and comparing standard line slopes. Precision and accuracy were evaluated over 5 days. Measurement uncertainty was evaluated according to the Guide to the Expression of Uncertainty in Measurement (GUM). The RMP was proven to be highly selective and specific with no evidence of a matrix effect, allowing for quantification of levetiracetam within the range of 1.53–90.0 μg/mL. Intermediate precision was <2.2% and repeatability was 1.1–1.7% across all concentrations. The relative mean bias ranged from −2.5% to −0.3% across all levels and matrices within the measuring range. Diluted samples were found with a mean bias ranging from −0.1 to 2.9%. The predefined acceptance criterion for measurement uncertainty was met and determined for individual measurements independently of the concentration level and sample type to be ≤4.0% (k=2). We present a novel LC-MS/MS)-based candidate RMP for levetiracetam in human serum and plasma. Its expanded measurement uncertainty of ≤4.0% meets the clinical needs in levetiracetam monitoring. Utilizing qNMR to characterize levetiracetam reference materials allowed metrological traceability to SI units. [ABSTRACT FROM AUTHOR]

To describe and validate a reference measurement procedure (RMP) for gabapentin, employing quantitative nuclear magnetic resonance (qNMR) spectroscopy to determine the absolute content of the standard materials in combination with isotope dilution-liquid chromatograph-tandem mass spectrometry (ID-LC-MS/MS) to accurately measure serum and plasma concentrations. A sample preparation protocol based on protein precipitation in combination with LC-MS/MS analysis using a C8 column for chromatographic separation was established for the quantification of gabapentin. Assay validation and determination of measurement uncertainty were performed according to guidance from the Clinical and Laboratory Standards Institute, the International Conference on Harmonization, and the Guide to the expression of uncertainty in measurement. ID-LC-MS/MS parameters evaluated included selectivity, specificity, matrix effects, precision and accuracy, inter-laboratory equivalence, and uncertainty of measurement. The use of qNMR provided traceability to International System (SI) units. The chromatographic assay was highly selective, allowing baseline separation of gabapentin and the gabapentin-lactam impurity, without observable matrix effects. Variability between injections, preparations, calibrations, and days (intermediate precision) was <2.3%, independent of the matrix, while the coefficient of variation for repeatability was 0.9–2.0% across all concentration levels. The relative mean bias ranged from −0.8–1.0% for serum and plasma samples. Passing-Bablok regression analysis indicated very good inter-laboratory agreement; the slope was 1.00 (95% confidence interval [CI] 0.98 to 1.03) and the intercept was −0.05 (95% CI -0.14 to 0.03). Pearson's correlation coefficient was ≥0.996. Expanded measurement uncertainties for single measurements were found to be ≤5.0% (k=2). This analytical protocol for gabapentin, utilizing traceable and selective qNMR and ID-LC-MS/MS techniques, allows for the standardization of routine tests and the reliable evaluation of clinical samples. [ABSTRACT FROM AUTHOR]

We developed an isotope dilution (ID)-liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based candidate reference measurement procedure (RMP) for lamotrigine in human serum and plasma, using quantitative nuclear magnetic resonance-characterized reference standards to ensure traceability to the International System of Units. A sample preparation protocol based on protein precipitation combined with LC-MS/MS analysis using a C18 column for chromatographic separation was established for the quantification of lamotrigine in human serum and plasma. Assay validation was performed according to current guidelines. Spiked serum and plasma samples were used to assess selectivity and specificity; a post-column infusion experiment and comparison of standard line slopes were performed to ascertain possible matrix effects. Precision and accuracy were determined in a 5 days validation experiment. Measurement uncertainty was determined per the Guide to the Expression of Uncertainty in Measurement. The method allowed the quantification of lamotrigine in serum and plasma in a range of 0.600–24.0 μg/mL without any observable matrix effects. The relative mean bias (n=6) ranged from 1.7 to 3.7%; intermediate precision, including variances in between-day, -calibration, and -injection, was ≤2.4%, independent of the level and matrix. Total measurement uncertainty for a single measurement was ≤2.6%; expanded uncertainty was ≤5.2% (coverage factor k=2). This candidate RMP based on ID-LC-MS/MS provides a traceable and reliable platform for the standardization of routine assays and the evaluation of clinical samples. [ABSTRACT FROM AUTHOR]

Objectives: The use of kidney function and injury markers for early detection of drug-related glomerular or tubular kidney injury in infants, children and adolescents requires age-specific data on reference intervals in a pediatric healthy population. This study characterizes serum values for eight kidney function and injury markers in healthy infants, children and adolescents. Methods: A single center prospective observational study was conducted between December 2018 and June 2019. Serum samples from 142 healthy infants, children and adolescents aged between 0 and ≤15 years were collected. Statistical analyses for eight markers (albumin (ALB), β2-microglobulin (B2M), β-trace protein (BTP), creatinine (SCR), cystatin C (CYSC), kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), uromodulin (URO)) were performed to obtain reference intervals and associations with age, sex and weight were investigated (Pearson correlation, linear and piecewise regression). Results: ALB and SCR increased with age (p<0.01), whereas B2M, BTP and KIM-1 values decreased with advancing age (p<0.05) in this healthy pediatric study population. CYSC showed dependency on sex (lower concentration in females) and decreased with age until reaching approximately 1.8 years; thereafter an increase with age was seen. NGAL and URO did not show any age-dependency. Conclusions: This study provides age appropriate reference intervals for key serum kidney function and injury markers determined in healthy infants, children and adolescents. Such reference intervals facilitate the interpretation of changes in kidney function and injury markers in daily practice, and allow early detection of glomerular and tubular injury in infancy, childhood and adolescence. [ABSTRACT FROM AUTHOR]

Objectives: The sensitivity of molecular and serological methods for COVID-19 testing in an epidemiological setting is not well described. The aim of the study was to determine the frequency of negative RT-PCR results at first clinical presentation as well as negative serological results after a follow-up of at least 3 weeks. Methods: Among all patients seen for suspected COVID-19 in Liechtenstein (n=1921), we included initially RT-PCR positive index patients (n=85) as well as initially RT-PCR negative (n=66) for follow-up with SARS-CoV-2 antibody testing. Antibodies were detected with seven different commercially available immunoassays. Frequencies of negative RT-PCR and serology results in individuals with COVID-19 were determined and compared to those observed in a validation cohort of Swiss patients (n=211). Results: Among COVID-19 patients in Liechtenstein, false-negative RT-PCR at initial presentation was seen in 18% (12/66), whereas negative serology in COVID-19 patients was 4% (3/85). The validation cohort showed similar frequencies: 2/66 (3%) for negative serology, and 16/155 (10%) for false negative RT-PCR. COVID-19 patients with negative follow-up serology tended to have a longer disease duration (p=0.05) and more clinical symptoms than other patients with COVID-19 (p<0.05). The antibody titer from quantitative immunoassays was positively associated with the number of disease symptoms and disease duration (p<0.001). Conclusions: RT-PCR at initial presentation in patients with suspected COVID-19 can miss infected patients. Antibody titers of SARS-CoV-2 assays are linked to the number of disease symptoms and the duration of disease. One in 25 patients with RT-PCR-positive COVID-19 does not develop antibodies detectable with frequently employed and commercially available immunoassays. [ABSTRACT FROM AUTHOR]

Keywords: antibody; coronavirus; COVID-19; kinetics; SARS-CoV-2 EN antibody coronavirus COVID-19 kinetics SARS-CoV-2 e49 e51 3 01/21/21 20210201 NES 210201 To the Editor, Antibodies against the receptor-binding domain (RBD) of SARS-CoV-2 spike (S) protein are known to decay rapidly in patients with mild COVID-19 [[1]]. Table 1: Sensitivities of for SARS-CoV-2 N antigen total antibody, SARS-CoV-2 N-antigen IgG, SARS-CoV-2 S protein IgG, and SARS-CoV-2 S protein IgA at median 48 and 140 days after symptom onset is shown. IgA and IgG against the SARS-CoV-2 S-protein show a decrease; however, the total antibody levels directed against the SARS-CoV-2 N-antigen remain stable despite a decrease in SARS-CoV-2 N-antigen IgG. [Extracted from the article]

Background: The total testosterone (T) cutoffs clinically adopted to define late-onset hypogonadism (LOH) do not consider the differences that exist between different analytical platforms, nor do they consider the body mass index (BMI) or age of the patient. We aimed at providing method, age and BMI-specific normal values for total T in European healthy men. Methods: A total of 351 eugonadal healthy men were recruited, and total T was measured with four automated immunometric assays (IMAs): ARCHITECT i1000SR (Abbott), UniCel DxI800 (Beckman Coulter), Cobas e601 (Roche), IMMULITE 2000 (Siemens) and liquid chromatography-tandem mass spectrometry (LC-MS/MS). Reference ranges (RRs) were calculated for each method. Results: Passing and Bablok regression analysis and Bland-Altman plot showed an acceptable agreement between Abbott and LC-MS/MS, but a poor one between LC-MS/MS and the other IMAs. Age-specific T concentrations in non-obese (BMI <29.9 kg/m2) men were greater than in all men. The total T normal range, in non-obese men aged 18–39 years, measured with LC-MS/MS was 9.038–41.310 nmol/L. RRs calculated with LC-MS/MS statistically differed from the ones calculated with all individual IMAs, except Abbott and among all IMAs. Statistically significant differences for both upper and lower reference limits between our RRs and the ones provided by the manufacturers were also noticed. Conclusions: We calculated normal ranges in a non-obese cohort of European men, aged 18–39 years, with four commercially available IMAs and LC-MS/MS and found statistically significant differences according to the analytical method used. Method-specific reference values can increase the accuracy of LOH diagnosis and should be standardly used. [ABSTRACT FROM AUTHOR]

Background: Fibroblast growth factor 23 (FGF-23), an osteocyte hormone involved in the regulation of phosphate metabolism, is associated with incident and progressive chronic kidney disease. We aimed to assess the association of FGF-23 with renal parameters, vascular function and phosphate metabolism in a large cohort of young and healthy individuals. Methods: Healthy individuals aged 25-41 years were included in a prospective population-based study. Fasting venous blood and morning urinary samples were used to measure plasma creatinine, cystatin C, endothelin-1, phosphate and plasma FGF-23 as well as urinary creatinine and phosphate. Multivariable regression models were constructed to assess the relationship of FGF-23 with parameters of renal function, endothelin-1 and fractional phosphate excretion. Results: The median age of 2077 participants was 37 years, 46% were males. The mean estimated glomerular filtration rate (eGFR - CKD-EPI creatinine-cystatin C equation) and fractional phosphate excretion were 110 mL/min/1.73 m² and 8.7%, respectively. After multivariable adjustment, there was a significant inverse relationship of FGF-23 with eGFR (β per 1 log-unit increase -3.81; 95% CI [-5.42; -2.20]; p < 0.0001). Furthermore, we found a linear association between FGF-23 and endothelin-1 (β per 1 log-unit increase 0.06; [0.01, 0.11]; p = 0.01). In addition, we established a significant relationship of FGF-23 with fractional phosphate excretion (β per 1 log-unit increase 0.62; [0.08, 1.16]; p = 0.03). Conclusions: Increasing plasma FGF-23 levels are strongly associated with decreasing eGFR and increasing urinary phosphate excretion, suggesting an important role of FGF-23 in the regulation of kidney function in young and healthy adults. [ABSTRACT FROM AUTHOR]

Reference intervals (RIs) for laboratory analyses by and large, are provided by analytical platform providers – the provenience and preanalytics of materials for the calculation of intervals often remain arcane particularly relating to the age group of donors. In an observational, prospective cohort study on 1467 healthy uniracial Caucasian residents >60 years of age, 105 frequently used lab tests were done on one blood sample. With a nonrestrictive definition of health, several pathological lab results pointing to occult disease have been found and published from SENIORLAB so far. The RIs found for hemoglobin in women went from 117.9 to 152.4 g/L (80–84 years) and in men from 124.9 to 170.6 g/L (90% confidence interval [CI]). This article lists RIs computed with SENIORLAB data for such frequently ordered analyses as platelet counts, vitamin B12 and folate, ferritin and analytes measured to estimate metabolic performance in glucose turnover. In fact, 64.5% of the cohort showed prediabetic fasting plasma glucose (FPG) and/or glycated hemoglobin (HbA1c); total serum folate levels but not red blood cell folate decreased with progressing age. As much as 66% of evaluable study participants had insufficient levels of 25(OH) vitamin D. Published reports from SENIORLAB are referenced in this article. [ABSTRACT FROM AUTHOR]

Background: It has been demonstrated that vitamin B12 determinations fail, especially in patients with pernicious anemia with high titers of intrinsic factor antibody. Consistent with this finding, we observed a case of falsely normal holotranscobalamin (HoloTC) results in a patient with pernicious anemia and severe vitamin B12 deficiency. We aimed to investigate whether such a situation can also be seen in other individuals. Methods: Within the frameworks of the SENIORLAB study and routine samples from a mixed patient population referred to a laboratory for investigation of B12 status, we searched for study participants displaying a normal HoloTC level (≥50 pmol/L) together with a decreased total vitamin B12 level (<125 pmol/L). Thereafter, we determined whether samples with discrepant biochemical markers (i.e. low vitamin B12, normal HoloTC) also had increased functional markers of vitamin B12 deficiency (methyl malonic acid [MMA], homocysteine [Hcy]) and/or a low value of Fedosov’s combined indicator of vitamin B12 status (<−0.5). Results: The prevalence of a normal HoloTC level and low total vitamin B12 level among the group of healthy seniors (n=1451) was 0.21% (95% confidence interval [CI], CI, 0.08–0.6%). Among the 106,635 routine samples with concurrent HoloTC and total vitamin B12 determination, 176 (i.e. 0.17%, 95% CI, 0.14–0.19%) had discrepant biochemical markers. Among them, 24 who were identified as having discrepant biochemical markers and a diagnosis of vitamin B12 deficiency could be confirmed with functional markers. Conclusions: Initial and isolated screening for vitamin B12 deficiency using a HoloTC cut-off of ≥50 pmol/L in a small subset of patients may reveal false-negative (normal) results, meaning that patients with vitamin B12 deficiency may remain undetected. [ABSTRACT FROM AUTHOR]

Background: The circadian fluctuations in the blood levels of selected components of the complement system are ill-defined. Some authors found nadir serum levels of C4 and C3 components, together with C3a at nighttime, while others reported insomnia when pro-inflammatory components exhibited increased serum levels. In this study, we quantitatively estimate the morning and evening daytime serum levels of CH50, C4, C3, put into context with C-reactive protein (CRP), cortisol, parathyroid hormone (PTH) and 25(OH)vitamin D at 07:00 A.M. and at 07:00 P.M. Methods: Seven healthy adult women and 11 men who were voluntary participants agreed to a fasting venipuncture in the morning after having normally eaten through the day and in the evening. The C4 and C3 serum levels were measured on a Cobas (Roche Diagnostics, Switzerland) modular analyzer, CH50 was estimated using the COMPL300 enzyme-linked immunosorbent assay (ELISA) of Wieslab (Malmö, Sweden). CRP, 25(OH)vitamin D, PTH and cortisol concentrations were assessed with electro-chemiluminescence immunoassay (ECLIA) on the Roche Cobas 6000 platform; IgG was measured using nephelometry (Siemens, Germany). Results: With the exception of higher PTH levels in the evening [3.12-5.46, 95% confidence interval (CI)] compared to the morning (2.93-4.65, 95% CI), the mean and median values of C4, C3, CH50 as well as CRP, PTH and 25(OH) vitamin D fell within the established reference intervals. Cortisol levels were measured as an internal positive control for diurnal fluctuations (morning: 294-522 nmol/L, 95% CI; evening: 106-136 nmol/L, 95% CI). Conclusions: The concentrations of the assessed complement components C4 and C3 as well as CH50 surrogate assay did not yield significantly different values between early morning and evening. This does not exclude their participation in the circadian metabolome; this pilot study with healthy participants suggests that patients with an autoimmune disease in remission can give their blood samples independently during daytime with or without fasting. [ABSTRACT FROM AUTHOR]

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Background: Endothelin-1 (ET-1), a vasoconstrictive and pro-inflammatory peptide, is associated with several cardiovascular risk factors and outcomes. We aimed to investigate the association of plasma ET-1 levels and renal function among young and healthy adults. Methods: Individuals aged 25–41 years were enrolled in a population-based cohort study. Main exclusion criteria were established kidney disease, cardiovascular diseases, diabetes mellitus and a body mass index > 35 kg/m2. Fasting venous plasma samples were used to measure creatinine, cystatin C and ET-1. The estimated glomerular filtration rate (eGFR) was calculated using the creatinine based chronic kidney disease epidemiology collaboration (CKD-EPI) formula. Multivariable regression models were constructed to assess interrelationships of plasma ET-1 with parameters of renal function. Results: Median age of the 2139 participants was 37 years, 47% males. Median creatinine and eGFR were 67 μmol/L and 112 mL/min/1.73 m2, respectively. Using quartile one as the reference group, the β-coefficients (95% confidence intervals [CIs]) for eGFR were 0.06 (− 1.22 to 1.35), − 0.66 (− 1.95 to 0.62) and − 1.70 (− 3.01 to − 0.39) for quartiles 2–4 (p-for-trend = 0.0056), respectively and β-coefficients (95% CIs) for cystatin C were 0.002 (− 0.01 to 0.02), 0.02 (0.003–0.03) and 0.03 (0.01–0.04) for quartiles 2–4 (p-fortrend < 0.0001), respectively. Using ET-1 as a continuous variable, the β-coefficient (95% CI) for eGFR per 1-unit increase was − 1.82 (− 3.19 to − 0.44, p = 0.0095) and 0.02 (0.01–0.04, p = 0.0003) for cystatin C. Similar results were found between creatinine and ET-1 levels. Conclusions: ET-1 levels are strongly associated with parameters of renal function among young and healthy adults, suggesting an important role of ET-1 and endothelial function in the regulation of kidney function. [ABSTRACT FROM AUTHOR]

Background: In chronic kidney diseases of various etiologies, the urinary excretion of uromodulin is usually decreased in parallel with the glomerular filtration rate. This study aimed to investigate whether serum uromodulin is associated with kidney function. Methods: Within the framework of the Seniorlabor study, a subset of subjectively healthy individuals 60 years of age and older were included in the study. Serum uromodulin was measured with ELISA. The relationship between serum uromodulin and different stages of kidney function (i.e., cystatin C-based 2012-CKD-EPI eGFRCysC>90 mL/min/1.73 m2, 60-89 mL/min/1.73 m2, 45-59 mL/min/1.73 m2, and <45 mL/min/1.73 m2) was investigated. Furthermore, the relationship between serum uromodulin and other markers of kidney function (i.e., creatinine, cystatin C, and urea) was assessed. Results: In total, 289 participants (140 males/149 females; mean age 71±7 years) were included in the study. There were significant differences in serum uromodulin among the four groups according to different kidney function stages (p<0.001). Serum uromodulin displayed inverse relationships with creatinine (r=-0.39), cystatin C (r=-0.42), and urea (r=-0.30) and, correspondingly, a positive relationship with eGFRCysC (r=0.38, p<0.001 for all). These associations remained intact when fitting a regression model that incorporated age, gender, body mass index, and current smoking status as covariates. Conclusions: Serum uromodulin behaves in a manner opposite that of the different conventional renal retention markers by displaying lower concentrations with decreasing kidney function. As uromodulin is produced by the cells of the thick ascending limb of the loop of Henle, lower uromodulin serum levels may reflect a reduction in number or function of these cells in chronic kidney disease. [ABSTRACT FROM AUTHOR]

Circadian rhythms are synchronized by the light/dark (L/D) cycle over the 24-h day. A suprachiasmatic nucleus in the hypothalamus governs time keeping based on melanopsin messages from the retina in the eyes and transduces regulatory signals to tissues through an array of hormonal, metabolic and neural outputs. Currently, vague impressions on circadian regulation in health and disease are replaced by scientific facts: in addition to L/D cyling, oscillation is maintained by genetic ( Clock, Bmal1, Csnk1, CHRONO, Cry, Per) programs, autonomous feedback loops, including melatonin activities, aerobic glycolysis intensity and lipid signalling, among others. Such a multifaceted influential system on circadian rhythm is bound to be fragile and genomic clock acitvities can become disrupted by epigenetic modifications or such environmental factors as mistimed sleep and feeding schedules albeit leaving the centrally driven melatonin-dependent pacemakter more or less unaffected. [ABSTRACT FROM AUTHOR]

Background: An author is generally regarded as an individual 'who has made substantial intellectual academic contributions to a published study'. However, the extent of the contribution that laboratory medicine professionals have made as authors of research papers in high-impact medical journals remains unclear. Methods: From 1 January 2004 to 31 March 2009, 4837 original research articles appeared in the: New England Journal of Medicine, Lancet, Annals of Internal Medicine, JAMA and BMJ. Using authorship as an indicator of intellectual contribution, we analyzed articles that included laboratory medicine parameters in their titles in an observational cross-sectional study. We also extracted data regarding radiological topics that were published during the same time within the same journals. Results: Out of 481 articles concerning laboratory medicine topics, 380 provided information on the affiliations of the authors. At least one author from an institution within the field of laboratory medicine was listed in 212 articles (55.8%). Out of 3943 co-authors, only 756 (19.2%) were affiliated with laboratory medicine institutions. Authors from laboratory medicine institutions were listed as the first, last or corresponding authors in 99 articles (26.1%). The comparative proportions for author affiliation from 55 radiology articles were significantly higher, as 72.7% (p=0.026) of articles and 24.8% (p=0.001) of authors indicated an affiliation with a radiology institution. Radiology professionals from 72.7% of the articles were listed as either the first, last or corresponding authors (p<0.0001). The subgroup analysis revealed that laboratory medicine professionals from North America were significantly less frequently involved as co-authors than were their colleagues from Europe (p=0.04). Conclusions: Laboratory medicine professionals are underrepresented as co-authors in laboratory medicine studies appearing in high-impact general medicine journals. [ABSTRACT FROM AUTHOR]

Age appropriate reference intervals for eight kidney function and injury markers in infants, children and adolescents. The paper characterized eight kidney function and injury markers in healthy infants, children and adolescents. [Extracted from the article]