Estimation of the measurement uncertainty and practical suggestion for the description of the metrological traceability in clinical laboratories

Clinicians request a large part of measurements of biological quantities that clinical laboratories perform for diagnostic, prognostic or diseases monitoring purposes. Thus, laboratories need to provide patient's results as reliable as possible. Metrological concepts like measurement uncertainty and metrological traceability allow to know the accuracy of these results and guarantee their comparability over time and space. Such is the importance of these two parameters that the estimation of measurement uncertainty and the knowledge of metrological traceability is required for clinical laboratories accredited by ISO 15189:2012. Despite there are many publications or guidelines to estimate the measurement uncertainty in clinical laboratories, it is not entirely clear what information and which formulae they should use to calculate it. On the other hand, unfortunately, there are a small number of clinical laboratories that know and describe the metrological traceability of their results, even though they are aware of the lack of comparability that currently exists for patient's results. Thus, to try to facilitate the task of clinical laboratories, this review aims to provide a proposal to estimate the measurement uncertainty. Also, different suggestions are shown to describe the metrological traceability. Measurement uncertainty estimation is partially based on the ISO/TS 20914:2019 guideline, and the metrological traceability described using the ISO 17511:2020. Different biological quantities routinely measured in clinical laboratories are used to exemplify the proposal and suggestions

Measurement uncertainty of β-lactam antibiotics results: estimation and clinical impact on therapeutic drug monitoring

Background: Despite that measurement uncertainty data should facilitate an appropriate interpretation of measured values, there are actually few reported by clinical laboratories. We aimed to estimate the measurement uncertainty of some β-lactam antibiotics (β-LA), and to evaluate the impact of reporting the measurement uncertainty on clinicians' decisions while guiding antibiotic therapy. Methods: Measurement uncertainty of β-LA (aztreonam [ATM], cefepime [FEP], ceftazidime [CAZ], and piperacillin [PIP]) values, obtained by an UHPLC-MS/MS based-method, was estimated using the top-down approach called the single laboratory validation approach (EUROLAB guidelines). Main uncertainty sources considered were related to calibrators' assigned values, the intermediate precision, and the bias. As part of an institutional program, patients with osteoarticular infections are treated with β-LA in continuous infusion and monitored to assure values at least 4 times over the minimal inhibitory concentration (4×MIC). We retrospectively evaluated the impact of two scenarios of laboratory reports on clinicians' expected decisions while monitoring the treatment: reports containing only the β-LA values, or including the β-LA coverage intervals (β-LA values and their expanded measurement uncertainties). Results The relative expanded uncertainties for ATM, FEP, CAZ and PIP were lower than 26.7%, 26.4%, 28.8%, and 25.5%, respectively. Reporting the measurement uncertainty, we identified that clinicians may modify their decision especially in cases where 4×MIC values were within the β-LA coverage intervals. Conclusions: This study provides a simple method to estimate the measurement uncertainty of β-LA values that can be easily applied in clinical laboratories. Further studies should confirm the potential impact of reporting measurement uncertainty on clinicians' decision-making while guiding antibiotic therapy

Contribution of Dynamic and Genetic Tests for Short Stature Diagnosing: A Case Report

Genetics; Macimorelin; Short statureGenètica; Macimorelina; Baixa estaturaGenética; Macimorelina; Baja estaturaGenetic tests have led to the discovery of many novel genetic variants related to growth failure, but the clinical significance of some results is not always easy to establish. The aim of this report is to describe both clinical phenotype and genetic characteristics in an adult patient with short stature associated with a homozygous variant in disintegrin and metalloproteinase with thrombospondin motifs type 17 gene (ADAMTS17) combined with a homozygous variant in the GH secretagogue receptor (GHS-R). The index case had severe short stature (SS) (−3.0 SD), small hands and feet, associated with eye disturbances. Genetic tests revealed homozygous compounds for ADAMTS17 responsible for Weill–Marchesani-like syndrome but a homozygous variant in GHS-R was also detected. Dynamic stimulation with an insulin tolerance test showed a normal elevation of GH, while the GH response to macimorelin stimulus was totally flattened. We show the implication of the GHS-R variant and review the molecular mechanisms of both entities. These results allowed us to better interpret the phenotypic spectrum, associated co-morbidities, its implications in dynamic tests, genetic counselling and treatment options not only to the index case but also for her relatives

Patient with adrenal insufficiency due to a de novo mutation in the NR0B1 gene

Adrenal insufficiency; Congenital adrenal hypoplasiaInsuficiència suprarenal; Hipoplàsia suprarenal congènitaInsuficiencia suprarrenal; Hipoplasia suprarrenal congénitaObjectives Congenital X-linked adrenal hypoplasia is a rare disease with a known genetic basis characterized by adrenal insufficiency, hypogonadotropic hypogonadism, and a wide variety of clinical manifestations. Case presentation We present the case of a 26-day old male newborn with symptoms consistent with adrenal insufficiency, hyponatremia, and hyperkalemia. Following NaCl and fludrocortisone supplementation, the patient remained clinically stable. 17-OH-progesterone testing excluded congenital adrenal hyperplasia. The rest of hormones were within normal limits, except for adrenocorticotropic hormone (ACTH), which was significantly elevated, and aldosterone, which was below the reference value. Further testing included very long chain fatty acids to exclude adrenoleukodystrophy, the CYP11B2 gene (aldosterone synthase), and an MRI to screen for other morphological abnormalities. All tests yielded normal results. Finally, after cortisol deficiency was detected, expanded genetic testing revealed a mutation in the NR0B1 gene, which led to a diagnosis of congenital adrenal hypoplasia. Conclusions Diagnosis of congenital adrenal hypoplasia is challenging due to the heterogeneity of both clinical manifestations and laboratory abnormalities. As a result, diagnosis requires close monitoring and genetic testing

Dynamic profiles and predictive values of some biochemical and haematological quantities in COVID-19 inpatients

Introduction: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection in some hospitalized patients has shown some important alterations in laboratory tests. The aim of this study was to establish the most relevant quantities associated with the worst prognosis related to COVID-19. Materials and methods: This was a descriptive, longitudinal, observational and retrospective study, in a cohort of 845 adult inpatients from Bellvitge University Hospital (L'Hospitalet de Llobregat, Barcelona, Spain). A multivariate regression analysis was carried out in demographic, clinical and laboratory data, comparing survivors (SURV) and non-survivors (no-SURV). A receiver operating characteristic analysis was also carried out to establish the cut-off point for poor prognostic with better specificity and sensibility. Dynamic changes in clinical laboratory measurements were tracked from day 1 to day 28 after the onset of symptoms. Results: During their hospital stay, 18% of the patients died. Age, kidney disease, creatinine (CREA), lactate-dehydrogenase (LD), C-reactive-protein (CRP) and lymphocyte (LYM) concentration showed the strongest independent associations with the risk of death in the multivariate regression analysis. Established cut-off values for poor prognosis for CREA, LD, CRP and LYM concentrations were 75.0 mu mol/L, 320 U/L, 80.9 mg/L and 0.69 x10(9)/L. Dynamic profile of laboratory findings, were in agreement with the consequences of organ damage and tissue destruction. Conclusions: Age, kidney disease, CREA, LD, CRP and LYM concentrations in COVID-19 patients from the southern region of Catalonia provide important information for their prognosis. Measurement of LD has demonstrated to be very good indicator of poor prognosis at initial evaluation because of its stability over time

Patient with adrenal insufficiency due to a de novo mutation in the NR0B1 gene

Congenital X-linked adrenal hypoplasia is a rare disease with a known genetic basis characterized by adrenal insufficiency, hypogonadotropic hypogonadism, and a wide variety of clinical manifestations

Soluble Angiotensin-Converting Enzyme 2 as a Prognostic Biomarker for Disease Progression in Patients Infected with SARS-CoV-2

Predicting disease severity in patients infected with SARS-CoV-2 is difficult. Soluble angiotensin-converting enzyme 2 (sACE2) arises from the shedding of membrane ACE2 (mACE2), which is a receptor for SARS-CoV-2 spike protein. We evaluated the predictive value of sACE2 compared with known biomarkers of inflammation and tissue damage (CRP, GDF-15, IL-6, and sFlt-1) in 850 patients with and without SARS-CoV-2 with different clinical outcomes. For univariate analyses, median differences between biomarker levels were calculated for the following patient groups (classified by clinical outcome): RT-PCR-confirmed SARS-CoV-2 positive (Groups 1–4); RT-PCR-confirmed SARS-CoV-2 negative following previous SARS-CoV-2 infection (Groups 5 and 6); and ‘SARS-CoV-2 unexposed’ patients (Group 7). Median levels of CRP, GDF-15, IL-6, and sFlt-1 were significantly higher in hospitalized patients with SARS-CoV-2 compared with discharged patients (all p < 0.001), whereas levels of sACE2 were significantly lower (p < 0.001). ROC curve analysis of sACE2 provided cut-offs for predicting hospital admission (≤0.05 ng/mL (positive predictive value: 89.1%) and ≥0.42 ng/mL (negative predictive value: 84.0%)). These findings support further investigation of sACE2, as a single biomarker or as part of a panel, to predict hospitalization risk and disease severity in patients with SARS-CoV-2 infection

Recovery of serum testosterone levels is an accurate predictor of survival from COVID-19 in male patients

SARS-CoV-2 infection portends a broad range of outcomes, from a majority of asymptomatic cases to a lethal disease. Robust correlates of severe COVID-19 include old age, male sex, poverty, and co-morbidities such as obesity, diabetes, and cardiovascular disease. A precise knowledge of the molecular and biological mechanisms that may explain the association of severe disease with male sex is still lacking. Here, we analyzed the relationship of serum testosterone levels and the immune cell skewing with disease severity in male COVID-19 patients. Biochemical and hematological parameters of admission samples in 497 hospitalized male and female COVID-19 patients, analyzed for associations with outcome and sex. Longitudinal (in-hospital course) analyses of a subcohort of 114 male patients were analyzed for associations with outcome. Longitudinal analyses of immune populations by flow cytometry in 24 male patients were studied for associations with outcome. We have found quantitative differences in biochemical predictors of disease outcome in male vs. female patients. Longitudinal analyses in a subcohort of male COVID-19 patients identified serum testosterone trajectories as the strongest predictor of survival (AUC of ROC = 92.8%, p < 0.0001) in these patients among all biochemical parameters studied, including single-point admission serum testosterone values. In lethal cases, longitudinal determinations of serum luteinizing hormone (LH) and androstenedione levels did not follow physiological feedback patterns. Failure to reinstate physiological testosterone levels was associated with evidence of impaired T helper differentiation and augmented circulating classical monocytes. Recovery or failure to reinstate testosterone levels is strongly associated with survival or death, respectively, from COVID-19 in male patients. Our data suggest an early inhibition of the central LH-androgen biosynthesis axis in a majority of patients, followed by full recovery in survivors or a peripheral failure in lethal cases. These observations are suggestive of a significant role of testosterone status in the immune responses to COVID-19 and warrant future experimental explorations of mechanistic relationships between testosterone status and SARS-CoV-2 infection outcomes, with potential prophylactic or therapeutic implications. The online version contains supplementary material available at 10.1186/s12916-022-02345-