Direct and indirect reference intervals of 25-hydroxyvitamin D: it is not a real vitamin D deficiency pandemic.

Introduction: Many studies report vitamin D (25-OH-D) deficiency, although there is no consensus among scientific societies on cut-offs and reference intervals (RI). The aim of this study is to establish and compare RI for serum 25-OH-D by direct and indirect methods. Materials and methods: Two studies were performed in Zaragoza (Spain). A retrospective study (N = 7222) between January 2017 and April 2019 was used for RI calculation by indirect method and a prospective study (N = 312) with healthy volunteers recruited in August 2019 and February 2020 for direct method. Seasonal differences were investigated. Measurements were performed on Cobas C8000 (Roche-Diagnostics, Basel, Switzerland) using electrochemiluminescence immunoassay technology. Results: Reference intervals (2.5-97.5 percentile and corresponding 95% confidence intervals, CIs) were as follows: by indirect method 5.6 ng/mL (5.4 to 5.8) - 57.2 ng/mL (55.2 to 59.8), in winter 5.4 ng/mL (5.2 to 5.7) - 55.7 ng/mL (53.6 to 58.4), while in summer 5.9 ng/mL (5.4 to 6.2) - 59.9 ng/mL (56.3 to 62.9). By direct method 9.0 ng/mL (5.7 to 9.5) - 41.4 ng/mL (37.6 to 48.0), in winter 7.4 ng/mL (3.9 to 8.6) - 34.6 ng/mL (30.6 to 51.5), while in summer 13.3 ng/mL (10.1 to 14.1) - 44.1 ng/mL (38.9 to 66.0). In both methods, RIs were higher in summer. A significant difference was observed in 25-OH-D median values between the two methods (P < 0.001). Conclusions: Reference interval calculation according to the studied area may be a useful tool to adapt the deficiency cut-offs for 25-OH-D. Our data support 25-OH-D values over 12.0 ng/mL for healthy population as sufficient, therefore current recommendations should be updated. In addition, differences in seasonality should be taken into account.

Endocrine Evaluation and Homeostatic Model Assessment in Patients with Cornelia de Lange Syndrome.

Objective: The aim of this study was to expand knowledge about endocrine disorders in individuals with Cornelia de Lange syndrome (CdLS), a rare developmental genetic disorder with anomalies in multiple organs and systems. Methods: Hormone levels, clinical scores, anthropometric measurements, and molecular analysis were assessed in 24 individuals with CdLS. Results: Hyperprolactinemia was the most common endocrine disorder. Three patients showed subclinical hypothyroidism. In the gonadotropic axis, mildly delayed puberty was observed, as well as genital anomalies, such as cryptorchidism. Despite short stature, levels of insulin-like growth factor 1 and insulin-like growth factor-binding protein 3 were normal, on average. Three prepubertal individuals without risk factors had higher than normal values for the homeostatic model assessment of insulin resistance (HOMA-IR) and for insulinemia, suggesting insulin resistance. Furthermore, two adults had elevated BMIs associated with HOMA-IR values over the cut-off values. Conclusion: CdLS can lead to dysregulation of the endocrine system, particularly in patients with high HOMA-IR values and insulinemia who are at risk of insulin resistance. Therefore, clinical follow-ups with hormonal assessments are proposed for individuals with CdLS.

Reducing the Cut-Off Value of the Fecal Immunochemical Test for Symptomatic Patients Does Not Improve Diagnostic Performance.

Introduction: The fecal immunochemical test (FIT) has been established as a cost-effective test in colon cancer screening programmes. This test could also be helpful in symptomatic patients prior to colonoscopy, but data about diagnostic performance, and accurate cut-off values for these patients are still scarce. Materials and Methods: Prospective study that included consecutive unselected patients with gastrointestinal symptoms referred for colonoscopy between November 2016 and June 2018. We performed a FIT (FOB Gold® test, cut-off 20 micrograms of Hb/gram of feces) prior to colonoscopy and determined the accuracy of FIT in terms of sensitivity, specificity, positive and negative predictive value for clinically significant pathology, advanced neoplasia, and colorectal cancer in symptomatic patients, using two different cut-off values. Results: A total of 727 patients (44.3% men, aged 58.5 ± 14.9 years) was included in the study. The main symptom was history of previous (non-active) rectal bleeding (34.7%), followed by diarrhea (15.0%). Over one quarter of the patients (25.9%) had a positive FIT result. The caecal intubation rate was 95.5%. Clinically significant pathology was identified in 142 colonoscopies (19.5%), advanced neoplasia in 115 (15.8%) and colorectal cancer in 36 colonoscopies (5.0%). FIT performed very well for clinically significant pathology, advanced neoplasia and cancer, with a high negative predictive value (NPV). Reducing the cut-off value to 10 µg/g yielded similar NPV results, with a decrease in specificity. Using a combination of symptoms with a positive FIT result did not improve FIT performance. Only specificity was slightly higher compared to FIT alone, but this was paralleled by a decrease in sensitivity and NPV for cancer and clinically significant pathology. The odds of presenting clinically significant pathology, advanced neoplasia, or cancer increased with FIT concentration. Conclusions: The specificity and NPV of FIT for clinically significant pathology, advanced neoplasia, and cancer are high in symptomatic patients. FIT is a helpful test for determining the need to perform further studies. It may not be necessary to reduce the cut-off value for symptomatic patients, since FIT performance with the current standard cut-off value used in colorectal cancer screening was accurate. FIT can be used to avoid or prioritize colonoscopy procedures.

Cardiac Troponin T Release after Football 7 in Healthy Children and Adults.

The objective of this study was to compare the release of cardiac troponin T (cTnT) after a football 7 match between two cohorts of children and adult players. Thirty-six male football players (children = 24, adult = 12) played a football 7 match, and cTnT was measured before, and 3 h after exercise. Concentrations of cTnT were compared between groups and time, and correlated with participants' characteristics, as well as internal and external exercise load. Cardiac troponin T was elevated in all participants (p < 0.001), and exceeded the upper reference limit for myocardial infarction in 25 (~70%) of them. Baseline concentrations were higher in adults (p < 0.001), but the elevation of cTnT was comparable between the groups (p = 0.37). Age (p < 0.001), body mass (p = 0.001) and height (p < 0.001), and training experience (p = 0.001) were associated to baseline cTnT values, while distance (p < 0.001), mean speed (p < 0.001), and peak (p = 0.013) and mean (p = 0.016) heart rate were associated to the elevation of cTnT. The present study suggests that a football 7 match evoked elevations of cTnT during the subsequent hours in healthy players regardless of their age. However, adults might present higher resting values of cTnT than children. In addition, results suggest that the exercise-induced elevations of cTnT might be mediated by exercise load but not participant characteristics.

Effect of Surface Chemistry and Associated Protein Corona on the Long-Term Biodegradation of Iron Oxide Nanoparticles In Vivo.

The protein corona formed on the surface of a nanoparticle in a biological medium determines its behavior in vivo. Herein, iron oxide nanoparticles containing the same core and shell, but bearing two different surface coatings, either glucose or poly(ethylene glycol), were evaluated. The nanoparticles' protein adsorption, in vitro degradation, and in vivo biodistribution and biotransformation over four months were investigated. Although both types of nanoparticles bound similar amounts of proteins in vitro, the differences in the protein corona composition correlated to the nanoparticles biodistribution in vivo. Interestingly, in vitro degradation studies demonstrated faster degradation for nanoparticles functionalized with glucose, whereas the in vivo results were opposite with accelerated biodegradation and clearance of the nanoparticles functionalized with poly(ethylene glycol). Therefore, the variation in the degradation rate observed in vivo could be related not only to the molecules attached to the surface, but also with the associated protein corona, as the key role of the adsorbed proteins on the magnetic core degradation has been demonstrated in vitro.

Usefulness of the Hepatocyte Growth Factor as a Predictor of Mortality in Patients Hospitalized With Acute Heart Failure Regardless of Ejection Fraction.

Hepatocyte growth factor (HGF) plays a role in the improvement of cardiac function and remodeling. Their serum levels are strongly related with mortality in chronic systolic heart failure (HF). The aim of this study was to study prognostic value of HGF in acute HF, interaction with ejection fraction, renal function, and natriuretic peptides. We included 373 patients (age 76 ± 10 years, left ventricular ejection fraction [LVEF] 46 ± 14%, 48% men) consecutively admitted for acute HF. Blood samples were obtained at admission. All patients were followed up until death or close of study (>1 year, median 371 days). HGF concentrations were determined using a commercial enzyme-linked immunosorbent assay (human HGF immunoassay). The predictive power of HGF was estimated by Cox regression with calculation of Harrell C-statistic. HGF had a median of 1,942 pg/ml (interquartile rank 1,354). According to HGF quartiles, mortality rates (per 1,000 patients/year) were 98, 183, 375, and 393, respectively (p <0.001). In Cox regression analysis, HGF (hazard ratio1SD = 1.5, 95% confidence interval 1.1 to 2.1, p = 0.002) and N-terminal pro b-type natriuretic peptide (NT-proBNP; hazard ratio1SD = 1.8, 95% confidence interval 1.2 to 2.6, p = 0.002) were independent predictors of mortality. Interaction between HGF and LVEF, origin, and renal function was nonsignificant. The addition of HGF improved the predictive ability of the models (C-statistic 0.768 vs 0.741, p = 0.016). HGF showed a complementary value over NT-proBNP (p = 0.001): mortality rate was 490 with both above the median versus 72 with both below. In conclusion, in patients with acute HF, serum HGF concentrations are elevated and identify patients at higher risk of mortality, regardless of LVEF, ischemic origin, or renal function. HGF had independent and additive information over NT-proBNP.

Multiple approaches to assess fourteen non-invasive serum indexes for the diagnosis of liver fibrosis in chronic hepatitis C patients.

BACKGROUND: The aim of this study was to compare fourteen non-invasive indexes/scores: AAR, APRI, Fibroindex, MODEL3, Forns index, FIB4, GUCI, FI, FCI, Pohl score, AP index, CDS, HGM-1 and HGM-2, in order to diagnose the hepatic fibrosis stage in a survey of patients with chronic hepatitis C. METHODS: 84 patients with chronic hepatitis C were studied. Liver fibrosis was staged according to the Scheuer scoring system. The diagnostic accuracy of these indexes/scores was evaluated by AUROC, contingency tables and logistic regression analysis. RESULTS: The best AUROCs (>0.9) to discriminate cirrhosis (F=4), were observed for CDS, FI, AAR, MODEL3, FIB4, HGM-2 and FCI. To discriminate at least advance fibrosis (F≥3), the best AUROCs (>0.89) were for CDS, FI, FIB4, HGM2-2, MODEL3 and FCI. To discriminate at least significant fibrosis (F≥2), the best AUROCs (>0.8) were for FIB4, GUCI, APRI, FI, Forns index, HGM-2 and FCI. Contingency tables and logistic regression analysis supported the results obtained by AUROC. CONCLUSIONS: This study compares the diagnostic performance of fourteen indexes for the diagnosis of liver fibrosis stage in the same group of CHC patients. These results allow the selection of the best indexes for further studies in larger populations, in order to build diagnostic algorithms as an alternative to liver biopsy for fibrosis staging in patients with chronic HCV infection. These algorithms would allow to take therapeutical decisions and the continuous follow-up of hepatic fibrosis in these patients.

Individual variability in cardiac biomarker release after 30 min of high-intensity rowing in elite and amateur athletes.

This study had two objectives: (i) to examine individual variation in the pattern of cardiac troponin I (cTnI) and N-terminal pro-brain natriuretic peptide (NT-proBNP) release in response to high-intensity rowing exercise, and (ii) to establish whether individual heterogeneity in biomarker appearance was influenced by athletic status (elite vs. amateur). We examined cTnI and NT-proBNP in 18 elite and 14 amateur rowers before and 5 min, 1, 3, 6, 12, and 24 h after a 30-min maximal rowing test. Compared with pre-exercise levels, peak postexercise cTnI (pre: 0.014 ± 0.030 µg·L(-1); peak post: 0.058 ± 0.091 µg·L(-1); p = 0.000) and NT-proBNP (pre: 15 ± 11 ng·L(-1); peak post: 31 ± 19 ng·L(-1); p = 0.000) were elevated. Substantial individual heterogeneity in peak and time-course data was noted for cTnI. Peak cTnI exceeded the upper reference limit (URL) in 9 elite and 3 amateur rowers. No rower exceeded the URL for NT-proBNP. Elite rowers had higher baseline (0.019 ± 0.038 vs. 0.008 ± 0.015 µg·L(-1); p = 0.003) and peak postexercise cTnI (0.080 ± 0.115 vs. 0.030 ± 0.029 µg·L(-1); p = 0.022) than amateur rowers, but the change with exercise was similar between groups. There were no significant differences in baseline and peak postexercise NT-proBNP between groups. In summary, marked individuality in the cTnI response to a short but high-intensity rowing bout was observed. Athletic status did not seem to affect the change in cardiac biomarkers in response to high-intensity exercise.

Impact of an endurance training program on exercise-induced cardiac biomarker release.

We evaluated the influence of a 14-wk endurance running program on the exercise-induced release of high-sensitivity cardiac troponin T (hs-cTnT) and NH2-terminal pro-brain natriuretic peptide (NT-proBNP). Fifty-eight untrained participants were randomized to supervised endurance exercise (14 wk, 3-4 days/wk, 120-240 min/wk, 65-85% of maximum heart rate) or a control group. At baseline and after the training program, hs-cTnT and NT-proBNP were assessed before and 5 min, 1 h, 3 h, 6 h, 12 h, and 24 h after a 60-min maximal running test. Before training, hs-cTnT was significantly elevated in both groups with acute exercise (P < 0.0001) with no between-group differences. There was considerable heterogeneity in peak hs-cTnT concentration with the upper reference limit exceeded in 71% of the exercise tests. After training, both baseline and postexercise hs-cTnT were significantly higher compared with pretraining and the response of the control group (P = 0.008). Acute exercise led to a small but significant increase in NT-proBNP, but this was not mediated by training (P = 0.121). In summary, a controlled endurance training intervention resulted in higher pre- and postexercise values of hs-cTnT with no changes in NT-proBNP.