Effects of IFIH1 rs1990760 variants on systemic inflammation and outcome in critically ill COVID-19 patients in an observational translational study.

Background: Variants in IFIH1, a gene coding the cytoplasmatic RNA sensor MDA5, regulate the response to viral infections. We hypothesized that IFIH1 rs199076 variants would modulate host response and outcome after severe COVID-19. Methods: Patients admitted to an intensive care unit (ICU) with confirmed COVID-19 were prospectively studied and rs1990760 variants determined. Peripheral blood gene expression, cell populations, and immune mediators were measured. Peripheral blood mononuclear cells from healthy volunteers were exposed to an MDA5 agonist and dexamethasone ex-vivo, and changes in gene expression assessed. ICU discharge and hospital death were modeled using rs1990760 variants and dexamethasone as factors in this cohort and in-silico clinical trials. Results: About 227 patients were studied. Patients with the IFIH1 rs1990760 TT variant showed a lower expression of inflammation-related pathways, an anti-inflammatory cell profile, and lower concentrations of pro-inflammatory mediators. Cells with TT variant exposed to an MDA5 agonist showed an increase in IL6 expression after dexamethasone treatment. All patients with the TT variant not treated with steroids survived their ICU stay (hazard ratio [HR]: 2.49, 95% confidence interval [CI]: 1.29-4.79). Patients with a TT variant treated with dexamethasone showed an increased hospital mortality (HR: 2.19, 95% CI: 1.01-4.87) and serum IL-6. In-silico clinical trials supported these findings. Conclusions: COVID-19 patients with the IFIH1 rs1990760 TT variant show an attenuated inflammatory response and better outcomes. Dexamethasone may reverse this anti-inflammatory phenotype. Funding: Centro de Investigación Biomédica en Red (CB17/06/00021), Instituto de Salud Carlos III (PI19/00184 and PI20/01360), and Fundació La Marató de TV3 (413/C/2021).

Patients with severe COVID-19 often need mechanical ventilation to help them breathe and other types of intensive care. The outcome for many of these patients depends on how their immune system reacts to the infection. If the inflammatory response triggered by the immune system is too strong, this can cause further harm to the patient. One gene that plays an important role in inflammation is IFIH1 which encodes a protein that helps the body to recognize viruses. There are multiple versions of this gene which each produce a slightly different protein. It is possible that this variation impacts how the immune system responds to the virus that causes COVID-19. To investigate, Amado-Rodríguez, Salgado del Riego et al. analyzed the IFIH1 gene in 227 patients admitted to an intensive care unit in Spain for severe COVID-19 between March and December 2020. They found that patients with a specific version of the gene called TT experienced less inflammation and were more likely to survive the infection. Physicians typically treat patients with moderate to severe COVID-19 with corticosteroid drugs that reduce the inflammatory response. However, Amado-Rodríguez, Salgado del Riego et al. found that patients with the TT version of the IFIH1 gene were at greater risk of dying if they received corticosteroids. The team then applied the distribution of IFIH1 variants among different ethnic ancestries to data from a previous clinical trial, and simulated the effects of corticosteroid treatment. This 'mock' clinical trial supported their findings from the patient-derived data, which were also validated by laboratory experiments on immune cells from individuals with the TT gene. The work by Amado-Rodríguez, Salgado del Riego et al. suggests that while corticosteroids benefit some patients, they may cause harm to others. However, a real-world clinical trial is needed to determine whether patients with the TT version of the IFIH1 gene would do better without steroids.

Prenatal screening and diagnosis of genetic abnormalities: SEGO, SEQCML, AEDP consensus recommendations.

In this paper, the scientific societies SEGO, SEQCML and AEDP provide a series of consensus-based recommendations for prenatal screening and diagnosis of genetic abnormalities. A set of evaluation indicators are also proposed as a means to improve the quality of the biochemical, ultrasound, and genetic processes involved in prenatal screening and diagnosis of genetic anomalies. Some recommendations are also proposed in relation to invasive prenatal diagnostic procedures, more specifically regarding sample collection and genetic testing. The purpose of this proposal is to unify performance criteria and quality indicators at national level, with audits performed on a regular basis. It is strongly recommended that a national prenatal screening strategy be established and provided with the resources necessary to evaluate the performance of quality indicators and diagnostic procedures under the supervision of health authorities. Protocols should be revised on a regular basis to consider the incorporation of new cost-effective technologies.

The subset of patients with acute heart failure able to secrete relaxin-2 at pregnancy concentrations could have a longer survival: a pilot study.

OBJECTIVE: To investigate how many patients with acute heart failure (AHF) hypersecrete relaxin-2 concentrations similar to those of pregnant women and determine their long-term outcome. METHODS: In consecutive AHF patients relaxin-2 was quantified by ELISA sandwich method. Patients were divided into pregnancy-like group (PLG, relaxin-2 ≥ 500 pg/mL) and control group (CG, relaxin-2 < 500 pg/mL). The primary outcome was all-cause death during follow-up. Secondary endpoints were prolonged hospitalisation (>10 days), combined endpoint (death, rehospitalisation, ED revisit) 30 days after discharge, and 30-day, one-year and three-year death rates. RESULTS: We included 814 patients [81 (SD = 9) years; 53.0% women] followed during 1.9 (SD 2.8) years; 517 (63.5%) died. Twenty patients (2.5%) formed the PLG (median relaxin-2 = 1459 pg/mL; IQR = 1722) and 794 the CG (median = 26; IQR = 44). There was no interaction with variables included on adjustment (age, sex, ischaemic cardiomyopathy, NT-proBNP, glycaemia, and sodium). PLG patients did not have better short-term secondary endpoints, but did show a significantly lower three-year mortality [ORadjusted = 0.17 (0.05-0.5), p = 0.003]. CONCLUSIONS: The small proportion of AHF patients achieving relaxin-2 concentrations similar to those observed in pregnancy may survive longer.

N-terminal pro B-type natriuretic peptide and angiogenic biomarkers in the prognosis of adverse outcomes in women with suspected preeclampsia.

BACKGROUND: This study compares the performance of the soluble fms-like tyrosine kinase 1 to placental growth factor (sFlt-1/PlGF) ratio and the cardiac biomarker N-terminal pro-B type natriuretic peptide (NT-proBNP) in the prediction of adverse outcomes in women with suspicion of PE. METHODS: A retrospective cohort study was conducted on women admitted at triage with signs and/or symptoms of PE (n=340). Serum levels of sFlt-1, PlGF and NT-proBNP were determined by an electrochemiluminescence immunoassay (Roche Diagnostics). The main outcomes were early- or late-onset PE and development of adverse outcome, defined as delivery within the first week since clinical presentation or fetal/early neonatal death. RESULTS: NT-proBNP concentrations (ng/L) were significantly increased in PE versus non-PE women, both at <34 (169 versus 34) and ≥34weeks of gestation (101 versus 49) (p<0.001). A cut-point of 70 showed sensitivities/specificities of 78/74% for early-, and 70/62% for late-onset PE; slightly lower than those offered by the sFlt-1/PlGF ratio or uric acid. The respective cut-points of 178 and 219 for sFlt-1/PlGF ratio and NT-proBNP, demonstrated similar performance in the prediction of adverse outcome, with sensitivity/specificity of 95/84% and 94/76%, respectively. CONCLUSION: NT-proBNP and sFlt-1/PlGF ratio can be used to predict the development of an adverse outcome.

Interleukin-6 in cerebrospinal fluid as a biomarker of acute meningitis.

BACKGROUND: Microbiological culture of cerebrospinal fluid is the gold standard to differentiate between aseptic and bacterial meningitis, but this method has low sensitivity. A fast and reliable new marker would be of interest in clinical practice. OBJECTIVE: Interleukin-6, secreted by T cells in response to meningeal pathogens and quickly delivered into cerebrospinal fluid, was evaluated as a marker of acute meningitis. DESIGN AND METHODS: A total of 150 cerebrospinal fluid samples were analysed by an electrochemiluminescence method, selected according to patient diagnosis: (a) bacterial meningitis confirmed by positive culture (n = 26); (b) bacterial meningitis with negative culture or not performed (n = 15); (c) viral meningitis confirmed by polymerase chain reaction or immunoglobulin G determination (n = 23); (d) viral meningitis with polymerase chain reaction negative or not performed (n = 42); and (e) controls (n = 44). RESULTS: Cerebrospinal fluid interleukin-6 concentration showed significant differences between all pathologic groups and the control group (P < 0.001). As a diagnostic tool for bacterial meningitis, interleukin-6 showed an area under the curve of 0.937 (95% confidence intervals: 0.895-0.978), significantly higher than those of classical biomarkers. An interleukin-6 cutoff of 1418 pg/mL showed 95.5% sensitivity and 77.5% specificity, whereas a value of 15,060 pg/mL showed 63.6% sensitivity and 96.7% specificity, for diagnosis of bacterial meningitis. CONCLUSION: Interleukin-6 measured by electrochemiluminescence method is a promising marker for early differentiation between aseptic and bacterial meningitis. More studies are needed to validate clinical implications for future practice in an emergency laboratory.

Role of vitamin D and sFlt-1/PlGF ratio in the development of early- and late-onset preeclampsia.

BACKGROUND: The imbalanced production of placental biomarkers and vitamin D deficiency have been proposed as risk factors for the development of preeclampsia (PE). However, little is known about the relationship between them and their role in early- versus late-onset PE. The objectives were to assess the role of 25-hydroxyvitamin D [25(OH)D] concentrations and the soluble fms-like tyrosine kinase 1 (sFlt-1) to placental growth factor (PlGF) ratio in the development of early- and late-onset PE; and to evaluate the relationship between 25(OH)D and the biomarkers. METHODS: A retrospective, full-blinded cohort study was conducted at the Obstetric Emergency Service of a tertiary care hospital. Pregnant women (n=257) attending obstetric triage with suspicion of PE were included. sFlt-1, PlGF and 25(OH)D concentrations were measured by electrochemoluminescence (ECLIA) immunoassay and pregnancy outcome (development of PE) was registered from patients records. RESULTS: PE women showed lower 25(OH)D concentrations at clinical presentation than non-PE women (median: 35.0 nmol/L and 39.6 nmol/L, respectively; p=0.027). Women with 25(OH)D levels <50 nmol/L experienced an increased risk of developing late-onset PE [odds ratio (OR) 4.6, 95% confidence interval (CI) 1.4-15], but no association was found for early-onset PE. However, a sFlt-1/PlGF ratio above the corresponding cutpoints increased the risk of developing both early- and late-onset PE [ORs 58 (95% CI 11-312) and 12 (95% CI 5.0-27), respectively]. No association was found between 25(OH)D levels and sFlt-1/PlGF ratio. CONCLUSIONS: Low vitamin D status in women with suspected late-onset PE increases the risk of imminent development of the disease.

Diagnosis of infection in critical care.

Sepsis is the primary cause of death in the intensive care unit. The prevention of sepsis complications requires an early and accurate diagnosis as well as the appropriate mon itoring. A deep knowledge of the immunologic basis of sepsis is essential to better understand the scope of incorporating a new marker into clinical practice. Besides revising this theoretical aspect, the current available tools for bacterial iden tification have been briefly reviewed as well as a variety of new markers showing either well-recognized or potential usefulness for diagnosis and prognosis of infections in crit ically ill patients. Particular conditions such as community acquired pneumonia, pedi atric sepsis, or liver transplantation, among others, have been separately treated, since the optimal approaches and markers might be different in these special cases.

Vitamin D deficiency at pediatric intensive care admission / Deficiência de vitamina D em internações na unidade de terapia intensiva pediátrica

OBJECTIVE: to assess whether 25hydroxivitaminD or 25(OH)vitD deficiency has a high prevalence at pediatric intensive care unit (PICU) admission, and whether it is associated with increased prediction of mortality risk scores. METHOD: prospective observational study comparing 25(OH)vitD levels measured in 156 patients during the 12 hours after critical care admission with the 25(OH)vitD levels of 289 healthy children. 25(OH)vitD levels were also compared between PICU patients with pediatric risk of mortality III (PRISM III) or pediatric index of mortality 2 (PIM 2) > p75 [(group A; n = 33) vs. the others (group B; n = 123)]. Vitamin D deficiency was defined as < 20 ng/mL levels. RESULTS: median (p25-p75) 25(OH)vitD level was 26.0 ng/mL (19.2-35.8) in PICU patients vs. 30.5 ng/mL (23.2-38.6) in healthy children (p = 0.007). The prevalence of 25(OH)vitD < 20 ng/mL was 29.5% (95% CI: 22.0-37.0) vs. 15.6% (95% CI: 12.2-20.0) (p = 0.01). Pediatric intensive care patients presented an odds ratio (OR) for hypovitaminosis D of 2.26 (CI 95%: 1.41-3.61). 25(OH)vitD levels were 25.4 ng/mL (CI 95%: 15.5-36.0) in group A vs. 26.6 ng/mL (CI 95%: 19.3-35.5) in group B (p = 0.800). CONCLUSIONS: hypovitaminosis D incidence was high in PICU patients. Hypovitaminosis D was not associated with higher prediction of risk mortality scores. .

OBJETIVO: avaliar se a deficiência da 25-hidroxivitamina D, ou 25 (OH) vitD, tem prevalência elevada em internações na unidade de terapia intensiva pediátrica, e se estaria relacionada à previsão de escores de risco de mortalidade. MÉTODO: estudo observacional prospectivo comparando níveis de 25 (OH) vitD de 156 pacientes, mensurados nas primeiras 12 horas da internação em terapia intensiva, com níveis de 25 (OH) vitD de 289 crianças saudáveis. Os níveis de 25 (OH) vitD também foram comparados entre pacientes na UTIP com escore PRISM III ou PIM 2 > p75 (Grupo A; n = 33), e o restante, (Grupo B; n = 123). A deficiência de vitamina D foi definida como níveis < 20 ng/mL. RESULTADOS: o nível médio (p25-p75) de 25 (OH) vitD foi 26,0 ng/mL (19,2-35,8) em pacientes internados na UTIP, em comparação a 30,5 ng/mL (23,2-38,6) em crianças saudáveis (p = 0,007). A prevalência de 25 (OH) vitD < 20 ng/mL foi de 29,5% (IC 95%, 22,0-37,0), em comparação a 15,6% (IC 95%,12,2-20,0) (p = 0,01). Os pacientes em terapia intensiva pediátrica apresentaram uma razão de chance (RC) para hipovitaminose D de 2,26 (IC 95%, 1,41-3,61). Os níveis de 25 (OH) vitD foram 25,4 ng/mL (IC 95%, 15,5-36,0) no grupo A, em comparação a 26,6 ng/mL (IC 95%, 19,3-35,5) no grupo B (p = 0,800). CONCLUSÕES: a incidência de hipovitaminose D foi elevada em pacientes em terapia intensiva pediátrica, mas não foi associada à maior previsão de escores de risco de mortalidade. .

New biomarkers in diagnosis of early onset preeclampsia and imminent delivery prognosis.

BACKGROUND: Several studies have revealed a high soluble fms-like tyrosine kinase 1 (sFlt-1) to placental growth factor (PlGF) ratio in preeclamptic women. However, its role in patients with suspected preeclampsia (PE) at triage in the emergency department remains an issue and a controversial unique cutpoint of 85 has been proposed regardless of gestational age. A new cutpoint for sFlt-1/PlGF ratio was investigated to rule out PE at obstetric triage, and to assess its prognostic value for risk of imminent delivery. METHODS: Blood samples from 257 pregnant women with suspected PE were obtained at obstetric triage admission. Serum PlGF and sFlt-1 were measured by an electrochemoluminiscence immunoassay (ECLIA) on the immunoanalyzer Cobas e601 (Roche Diagnostics) and the corresponding ratio was calculated. Final outcomes (mainly development of PE) were reviewed and time between clinical presentation and delivery was calculated. RESULTS: The best ratio cutpoint to diagnose PE changed according to gestational age: 23 (92.0% sensitivity, 81.1% specificity) and 45 (83.7% sensitivity, 72.6% specificity) for women <34 and ≥ 34 weeks' gestation, respectively. Furthermore, sFlt-1/PlGF ratio inversely correlated with time elapsed between clinical presentation and delivery, and a cutpoint of 178 could predict complications such as imminent delivery or fetal/neonatal death with a sensitivity of 70.6% and a specificity of 97.8%. CONCLUSIONS: The new cut-off values for the sFlt-1/PlGF ratio adjusted by the gestational age at clinical presentation can be used to rule out PE at obstetric triage and to predict imminent delivery with better accuracy than the cutpoint currently accepted.

Vitamin D deficiency at pediatric intensive care admission.

OBJECTIVE: to assess whether 25hydroxivitaminD or 25(OH)vitD deficiency has a high prevalence at pediatric intensive care unit (PICU) admission, and whether it is associated with increased prediction of mortality risk scores. METHOD: prospective observational study comparing 25(OH)vitD levels measured in 156 patients during the 12 hours after critical care admission with the 25(OH)vitD levels of 289 healthy children. 25(OH)vitD levels were also compared between PICU patients with pediatric risk of mortality III (PRISM III) or pediatric index of mortality 2 (PIM 2) > p75 [(group A; n = 33) vs. the others (group B; n = 123)]. Vitamin D deficiency was defined as < 20 ng/mL levels. RESULTS: median (p25-p75) 25(OH)vitD level was 26.0 ng/mL (19.2-35.8) in PICU patients vs. 30.5 ng/mL (23.2-38.6) in healthy children (p = 0.007). The prevalence of 25(OH)vitD < 20 ng/mL was 29.5% (95% CI: 22.0-37.0) vs. 15.6% (95% CI: 12.2-20.0) (p = 0.01). Pediatric intensive care patients presented an odds ratio (OR) for hypovitaminosis D of 2.26 (CI 95%: 1.41-3.61). 25(OH)vitD levels were 25.4 ng/mL (CI 95%: 15.5-36.0) in group A vs. 26.6 ng/mL (CI 95%: 19.3-35.5) in group B (p = 0.800). CONCLUSIONS: hypovitaminosis D incidence was high in PICU patients. Hypovitaminosis D was not associated with higher prediction of risk mortality scores.

Pro-adrenomedullin, pro-endothelin-1, procalcitonin, C-reactive protein and mortality risk in critically ill children: a prospective study.

INTRODUCTION: We tested the hypothesis that higher mid-regional pro-adrenomedullin (MR-proADM), carboxy-terminal pro-endothelin-1 (CT-proET-1), procalcitonin (PCT) and C-reactive protein (CRP) plasma concentrations would be associated with increased prediction of mortality risk scores. METHODS: Prospective observational study set in two pediatric intensive care units (PICUs). Two-hundred-thirty-eight patients were included. MR-proADM, CT-proET-1, PCT and CRP levels were compared between children with PRISM III and PIM 2 > p75 (Group A; n = 33) and the rest (Group B; n = 205). RESULTS: Median (range) MR-proADM levels were 1.39 nmol/L (0.52-12.67) in group A versus 0.54 (0.15-3.85) in group B (P < 0.001). CT-proET-1 levels were 172 pmol/L (27-500) versus 58 (4-447) (P < 0.001). PCT levels were 7.77 ng/mL (0.34-552.00) versus 0.28 (0.02-107.00) (P < 0.001). CRP levels were 6.23 mg/dL (0.08-28.25) versus 1.30 mg/dL (0.00-42.09) (P = 0.210). The area under the ROC curve (AUC) for the differentiation of group A and B was 0.87 (95% CI:0.81-0.821) for MR-proADM, 0.86 (95% CI:0.79-0.92) for CT-proET-1 and 0.84 (95% CI:0.74-0.94) for PCT. A MR-proADM > 0.79 nmol/L had 93% sensitivity and 76% specificity to differentiate groups, whereas a CT-proET-1 > 123 pmol/L had 77% sensitivity and 84% specificity, and a PCT concentration > 2.05 ng/mL had 80% sensitivity and specificity. CONCLUSIONS: In critically ill children, high levels of MR-proADM, CT-proET-1 and PCT were associated with increased prediction of mortality risk scores. MR-proADM, CT-proET-1 and PCT concentrations higher than 0.80 nmol/L, 123 pmol/L and 2 ng/mL, respectively, could be used by clinicians to identify critically ill children at higher prediction of risk death scores.

Biological variation and prognosis usefulness of new biomarkers in liver transplantation.

BACKGROUND: An observational retrospective study has been conducted, including 52 patients (37 male and 15 female), ranging from 22 to 65 years old, who underwent an orthotopic liver transplantation (OLT) at the Hospital Universitario Central de Asturias (HUCA) between 2007 and 2010. METHODS: The main objective was to evaluate the post-OLT critical complication prognosis usefulness of the precursors of three new biomarkers: mid-regional proadrenomedullin (MR-proADM), carboxy-terminal-proendothelin-1 (CT-ProET-1) and mid-regional proatrial natriuretic peptide (MR-ProANP). As all of them are blood pressure mediators, stress-associated physiological phenomena are expected to affect their expression and secretion, mainly those related to blood circulation. Therefore, as a second goal, the biological variability of the biomarkers has been studied in a set of OLT patients without complications during the first postoperative week. The knowledge of the reference change value of the new biomarkers will be interesting for their correct interpretation in future investigations. The prognostic value of the new biomarkers was also compared to that of procalcitonin (PCT). RESULTS: It has been shown that the basal concentration of the biomarkers is higher in patients that undergo OLT than in the normal population, correlating with the severity of the pathology. The intra-individual biological variation of these biomarkers is similar to other biochemical parameters, the reference change value for OLT patients being 90% for CT-proET-1, 112% for MR-proADM and 127% for MR-proANP. CONCLUSIONS: Multivariate analysis showed that MR-proADM was the best biomarker for the prognosis of severe complications.

Improvement of a prenatal screening program for trisomy 18 in the first trimester of gestation.

BACKGROUND: The aim of this study was to evaluate population parameters (medians, standard deviations and coefficients of correlation) different from those used by the commercial software Elipse(®) v3.0 (Perkin Elmer) in the calculation of prenatal risk of trisomy 18. Moreover, the truncation limits used for extreme values of free ß-human chorionic gonadotropin (fß-hCG), pregnancy associated plasma protein-A (PAPP-A) and nuchal translucency (NT) were revised. METHODS: A calculation engine for the prenatal risk of trisomy 18 was developed [called FMF (Fetal Medicine Foundation) calculator]. Recently, published population parameters for fß-hCG and PAPP-A as well as new truncation limits were included in this calculator. The patient-specific risks obtained by Elipse(®) v3.0 and FMF calculators, were compared in 18,801 pregnant women, including 13 cases of trisomy 18, four cases of trisomy 13 and one case of triploidy. RESULTS: Using a cut-off point of 1:250, FMF calculator increased the detection rate of trisomy 18 from 62% to 100% with a 0.31% increase in the false-positive rate (FPR). When the detection rate was fixed at 100%, the FPR generated by Elipse v3.0 (1.52%) was significantly higher (p<0.0001) than that generated by the FMF calculator (0.36%). Moreover, an improved detection in cases of trisomy 13 and triploidy was observed. CONCLUSIONS: It is recommended that each laboratory reviews the population parameters and truncation limits used in the risk calculation of trisomy 18, in order to obtain an adequate performance in the screening.

Prognostic value of proadrenomedullin in severe sepsis and septic shock patients with community-acquired pneumonia.

PRINCIPLES: Midregional proadrenomedullin (proADM) is a novel biomarker with potential prognostic utility in patients with community-acquired pneumonia. The aim of this study was to investigate the value of proADM levels for severity assessment and outcome prediction in severe sepsis and septic shock due to CAP. METHODS: Prospective observational study including 49 patients admitted to ICU with both a clinical and radiologic diagnosis of pneumonia and fulfilling criteria for severe sepsis or septic shock. The prognostic accuracy of proADM levels was compared with those of pneumonia severity index and of procalcitonin (PCT) and C-reactive protein (CRP). RESULTS: 49 patients with severe sepsis or septic shock due to CAP were included in the study. Mortality was 24.5% for ICU and 34.7% for hospital mortality. In all cases proADM values at ICU admission were pathological (considering normal proADM levels <4 nmol/L). ProADM consistently rose as PSI class advanced from II to V (p = 0.02). Median proADM levels were higher (p <0.01) in hospital non-survivors 5.0 (1.9-10.1) nmol/L vs. survivors 1.7 (1.3-3.1) nmol/L. These differences were also significant with respect to ICU mortality. The receiver-operating characteristic curve for proADM yielded an AUC of 0.72; better than the AUC for PCT and CRP (0.40 and 0.44 respectively) and similar to PSI (0.74). CONCLUSIONS: In our study MR-proADM levels correlate with increasing severity of illness and death. High MR-proADM levels offer additional risk stratification in high-risk CAP patients.

Cord blood plasma reference intervals for potential sepsis markers: pro-adrenomedullin, pro-endothelin, and pro-atrial natriuretic peptide.

OBJECTIVES: To establish reference values in cord blood of the following new sepsis markers: pro-adrenomedullin (MR-proADM), pro-endothelin (CT-proET-1), and pro-atrial natriuretic peptide (MR-proANP). METHODS: MR-proADM, CT-proET-1, MR-proANP, and procalcitonin (PCT) were measured in cord blood of newborn infants by Time Resolved Amplified Cryptate Emission (TRACE) technology. The inclusion criteria in the control group (n=194) was the absence of any clinical sign or risk factor of sepsis. A group of 73 newborn infants presenting with risk factors of sepsis at delivery was also studied. RESULTS: The median values (reference interval) of CT-proET-1, MR-pro-ADM, and MR-proANP measured in cord blood plasma were 72 pmol/L (39-115), 0.84 nmol/L (0.5-1.38), and 163 pmol/L (76-389), respectively. The PCT reference interval was not significantly different from that previously described in cord blood serum. CONCLUSIONS: The reference intervals established will serve as a starting point for further clinical investigations aimed to elucidate the potential prognostic/diagnostic value of these markers in neonatal sepsis management.