Applying the concept of uncertainty to the sFlt-1/PlGF cut-offs for diagnosis and prognosis of preeclampsia.

OBJECTIVES: Placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) assays and the corresponding ratios (sFlt-1/PlGF) have been proposed to aid in the diagnosis by exclusion and/or prognosis of preeclampsia (PE). A method for evaluating ratio uncertainties (RUs), based on the theory of error propagation, was applied to the sFlt-1/PlGF ratio. METHODS: RUs were calculated using data derived from sFlt-1 and PlGF Internal Quality Control (IQC) results collected from four centers using Elecsys (Roche) or Kryptor (Thermo Fisher) sFlt-1 and PlGF assays. The corresponding ratio uncertainties were defined for each ratio value. RESULTS: The RUs increased linearly with the sFlt-1/PlGF ratio values. The Elecsys RUs were lower than the Kryptor RUs. Although RUs cannot eliminate differences in ratio values observed among various immunoassays, it can affect interpretation of the sFlt-1/PlGF ratio, especially when results are within the range of predefined PE diagnosis or prognosis cut-offs. CONCLUSIONS: Since RUs are only a function of PlGF and sFlt-1 precision, they can be calculated for each assay from each laboratory to adjust the interpretation of sFlt-1/PlGF ratio results in the context of PE.

A clinical risk score of myocardial fibrosis predicts adverse outcomes in aortic stenosis.

AIMS: Midwall myocardial fibrosis on cardiovascular magnetic resonance (CMR) is a marker of early ventricular decompensation and adverse outcomes in aortic stenosis (AS). We aimed to develop and validate a novel clinical score using variables associated with midwall fibrosis. METHODS AND RESULTS: One hundred forty-seven patients (peak aortic velocity (Vmax) 3.9 [3.2,4.4] m/s) underwent CMR to determine midwall fibrosis (CMR cohort). Routine clinical variables that demonstrated significant association with midwall fibrosis were included in a multivariate logistic score. We validated the prognostic value of the score in two separate outcome cohorts of asymptomatic patients (internal: n = 127, follow-up 10.3 [5.7,11.2] years; external: n = 289, follow-up 2.6 [1.6,4.5] years). Primary outcome was a composite of AS-related events (cardiovascular death, heart failure, and new angina, dyspnoea, or syncope). The final score consisted of age, sex, Vmax, high-sensitivity troponin I concentration, and electrocardiographic strain pattern [c-statistic 0.85 (95% confidence interval 0.78-0.91), P < 0.001; Hosmer-Lemeshow χ(2) = 7.33, P = 0.50]. Patients in the outcome cohorts were classified according to the sensitivity and specificity of this score (both at 98%): low risk (probability score <7%), intermediate risk (7-57%), and high risk (>57%). In the internal outcome cohort, AS-related event rates were >10-fold higher in high-risk patients compared with those at low risk (23.9 vs. 2.1 events/100 patient-years, respectively; log rank P < 0.001). Similar findings were observed in the external outcome cohort (31.6 vs. 4.6 events/100 patient-years, respectively; log rank P < 0.001). CONCLUSION: We propose a clinical score that predicts adverse outcomes in asymptomatic AS patients and potentially identifies high-risk patients who may benefit from early valve replacement.

Upper reference limits of high-sensitivity cardiac troponin T in a general population: comparison with those of sensitive cardiac troponin I.

BACKGROUND: Upper reference limits (97.5th, 99th percentiles) of high-sensitivity and sensitive cardiac troponins (hs-cTn and s-cTn) can be influenced by several factors. Our aim was to study: (1) the ability of hs-cTnT and s-cTnI to detect circulating cTn in a general community population, and (2) the effects of age, renal function, and gender on their 97.5th - 99th percentile values. METHODS: Hs-cTnT and s-cTnI values were measured in 177 subjects. RESULTS: Thirty-six subjects (20%) presented hs-cTnT values above the limit of detection (LoD), whereas no subjects presented detectable s-cTnI values. Men presented more frequently than women with detectable hs-cTnT levels (37% vs. 11%; p = 0.0001). Hs-cTnT was more frequently found in older (> or = 70 years) than in younger subjects (57 vs. 14%; p < 0.0001). Subjects with low estimated glomerular filtration rates (eGFR < 60 mL/min1/ 1.73m2) presented more frequently with detectable hs-cTnT levels than subjects with higher eGFR (71% vs. 17%; p < 0.0001). Hs-cTnT 97.5th - 99th percentiles varied according to selection by age, renal function, and gender; percentile values of s-cTnI were below the LoD of the assay. CONCLUSIONS: Hs-cTnT is more often quantified than s-cTnI in healthy subjects. Age, gender, and eGFR values influence 97.5th - 99th hs-cTnT percentile values.

Prognostic Value of Hyponatremia During Acute Painful Episodes in Sickle Cell Disease.

BACKGROUND: Low plasma sodium concentration has been recognized as a prognostic factor in several disorders but never evaluated in sickle cell disease. The present study evaluates its value at admission to predict a complication in adult patients with sickle cell disease hospitalized for an initially uncomplicated acute painful episode. METHODS: The primary outcome of this retrospective study, performed between 2010 and 2015 in a French referral center for sickle cell disease, was a composite criterion including acute chest syndrome, intensive care unit transfer, red blood cell transfusion or inpatient death. Analyses were adjusted for age, sex, hemoglobin genotype and concentration, lactate dehydrogenase (LDH) concentration, and white blood cell count. RESULTS: We included 1218 stays (406 patients). No inpatient death occurred during the study period. Hyponatremia (plasma sodium ≤135 mmol/L) at admission in the center was associated with the primary outcome (adjusted odds ratio [OR] 1.95, 95% confidence interval [CI] 1.3-2.91, P = 0.001), with acute chest syndrome (OR 1.95 [95% CI 1.2-3.17, P = 0.008]), and red blood cell transfusion (OR 2.71 [95% CI 1.58-4.65, P <0.001]) but not significantly with intensive care unit transfer (OR 1.83 [95% CI 0.94-3.79, P = 0.074]). Adjusted mean length of stay was longer by 1.1 days (95% CI 0.5-1.6, P <0.001) in patients with hyponatremia at admission. CONCLUSIONS: Hyponatremia at admission in the medical department for an acute painful episode is a strong and independent prognostic factor of unfavorable outcome and, notably, acute chest syndrome. It could help targeting patients who may benefit from closer monitoring.

[Potential value of placental angiogenic factors as biomarkers in preeclampsia for clinical physicians]. / Intérêts potentiels des facteurs angiogéniques placentaires comme biomarqueurs dans la pré-éclampsie pour le clinicien.

The role of angiogenic factors in the onset of clinical manifestations of preeclampsia was demonstrated in 2003 by the implication of sFlt-1, PlGF and VEGF, and in 2006 by the implication of soluble endoglin. Placental ischemia and inflammation observed in preeclampsia alter both the production and progression of angiogenic factors during pregnancy. During the first trimester, the combination of PlGF with clinical, biophysical and biological factors results in a better test than the conventional one. However, the clinical value of this method remains to be confirmed. During the second and third trimesters, the sFlt-1/PlGF ratio may be used, with or without pre-existing renal disease, for short-term prediction, diagnosis, and prognosis, and to evaluate the effectiveness of preeclampsia treatment. While a sFlt-1/PlGF ratio<38 and≤33, respectively, rules out the short-term onset and diagnosis of preeclampsia, a sFlt-1/PlGF ratio≥85 between 20 and 34 weeks of pregnancy and≥110 beyond 34 weeks of pregnancy confirms a diagnosis of preeclampsia. Angiogenic and non-angiogenic preeclampsia are identified by a sFlt-1PlGF≥85 and<85, respectively, with the risk of maternal and fetal complications at two weeks differing between the two. Similarly, a sFlt-1/PlGF ratio>665 and>205, respectively, is a good short-term predictor of adverse outcomes of early and late-onset preeclampsia. These values could be incorporated into future guidelines for better clinical management of preeclampsia.

Study of two comparison procedures applied to biochemical results from twin analyzers.

Two procedures for checking agreement between twin analyzers (Abbott Architect ci 8200) were tested in 23 blood and 7 urine parameters (10,160 paired results from 7,882 blood and 2,278 urine tests). Two protocols were compared. In protocol 1, acceptance criterion is based on standard-deviation originated either from French recommendations (Société française de biologie clinique) or from within subject biological variation. In protocol 2, acceptance criterion is based on values of expanded uncertainty of measurements calculated according to SH GTA 04. Percentages of comparisons refused were significantly different (p < 0.05) and varied from 0.0 to 18.6% (median: 0.45%) and from 0.0 to 8.75% (median: 1.2%). For 9 blood parameters (sodium, total CO2 , total proteins, calcium, urea, LDH, amylase, lipase and troponin I) and 4 urine parameters (sodium, protein, glucose, creatinine) a significant difference was observed between protocol 1 and 2. For the majority of tests, evaluation criterion based on within run standard deviation (protocol 1) is less stringent than protocol 2 based on expanded uncertainly of measurements. The use of expanded uncertainty as comparability criterion seems to be an interesting approach, especially for assays presenting wide theoretical physiopathology changes.

Importance of pre-analytical for urinalysis with urinary crystals.

Crystalluria is an imbalance between promoters and inhibitors; the first are the engine of the crystals and the second are made of substances. The biological assays make it possible to demonstrate one or more lithogenic factors observed during the lithiasis. The objective of our work was to study the impact of acidification or alkalization of the urine of lithiasic patients during a cristallurie assessment. All urine in the morning must be stored at room temperature and examined within two-three hours following voiding. 80 lithiasic patients (40 for urinary calcium and 40 for urinary uric acid) were selected from the results of cristalluria: more than 20 calcium-dependent crystals or uric acid crystal/mm3. For calcium and uric acid, concentration differences, after acidification and alkalization are observed: r2=0.43 (p<0.01) and r2=0.36 (p<0.01) respectively. In conclusion, in this lithiasic population with the presence of cystals, this pre-analytical stage is essential for urinary calcium and uric acid, making it possible to establish a diagnosis of certainly for the patient.