Harmonized D-dimer levels upon admission for prognosis of COVID-19 severity: Results from a Spanish multicenter registry (BIOCOVID-Spain study).

Coagulopathy is a key feature of COVID-19 and D-dimer has been reported as a predictor of severity. However, because D-dimer test results vary considerably among assays, resolving harmonization issues is fundamental to translate findings into clinical practice. In this retrospective multicenter study (BIOCOVID study), we aimed to analyze the value of harmonized D-dimer levels upon admission for the prediction of in-hospital mortality in COVID-19 patients. All-cause in-hospital mortality was defined as endpoint. For harmonization of D-dimer levels, we designed a model based on the transformation of method-specific regression lines to a reference regression line. The ability of D-dimer for prediction of death was explored by receiver operating characteristic curves analysis and the association with the endpoint by Cox regression analysis. Study population included 2663 patients. In-hospital mortality rate was 14.3%. Harmonized D-dimer upon admission yielded an area under the curve of 0.66, with an optimal cut-off value of 0.945 mg/L FEU. Patients with harmonized D-dimer ≥ 0.945 mg/L FEU had a higher mortality rate (22.4% vs. 9.2%; p < 0.001). D-dimer was an independent predictor of in-hospital mortality, with an adjusted hazard ratio of 1.709. This is the first study in which a harmonization approach was performed to assure comparability of D-dimer levels measured by different assays. Elevated D-dimer levels upon admission were associated with a greater risk of in-hospital mortality among COVID-19 patients, but had limited performance as prognostic test.

Cardiac troponin and COVID-19 severity: Results from BIOCOVID study.

BACKGROUND: Myocardial injury is a common finding in COVID-19 strongly associated with severity. We analysed the prevalence and prognostic utility of myocardial injury, characterized by elevated cardiac troponin, in a large population of COVID-19 patients, and further evaluated separately the role of troponin T and I. METHODS: This is a multicentre, retrospective observational study enrolling patients with laboratory-confirmed COVID-19 who were hospitalized in 32 Spanish hospitals. Elevated troponin levels were defined as values above the sex-specific 99th percentile upper reference limit, as recommended by international guidelines. Thirty-day mortality was defined as endpoint. RESULTS: A total of 1280 COVID-19 patients were included in this study, of whom 187 (14.6%) died during the hospitalization. Using a nonspecific sex cut-off, elevated troponin levels were found in 344 patients (26.9%), increasing to 384 (30.0%) when a sex-specific cut-off was used. This prevalence was significantly higher (42.9% vs 21.9%; P < .001) in patients in whom troponin T was measured in comparison with troponin I. Sex-specific elevated troponin levels were significantly associated with 30-day mortality, with adjusted odds ratios (ORs) of 3.00 for total population, 3.20 for cardiac troponin T and 3.69 for cardiac troponin I. CONCLUSION: In this multicentre study, myocardial injury was a common finding in COVID-19 patients. Its prevalence increased when a sex-specific cut-off and cardiac troponin T were used. Elevated troponin was an independent predictor of 30-day mortality, irrespective of cardiac troponin assay and cut-offs to detect myocardial injury. Hence, the early measurement of cardiac troponin may be useful for risk stratification in COVID-19.

Characteristics and laboratory findings on admission to the emergency department among 2873 hospitalized patients with COVID-19: the impact of adjusted laboratory tests in multicenter studies. A multicenter study in Spain (BIOCOVID-Spain study).

Identification of predictors for severe disease progression is key for risk stratification in COVID-19 patients. We aimed to describe the main characteristics and identify the early predictors for severe outcomes among hospitalized patients with COVID-19 in Spain. This was an observational, retrospective cohort study (BIOCOVID-Spain study) including COVID-19 patients admitted to 32 Spanish hospitals. Demographics, comorbidities and laboratory tests were collected. Outcome was in-hospital mortality. For analysis, laboratory tests values were previously adjusted to assure the comparability of results among participants. Cox regression was performed to identify predictors. Study population included 2873 hospitalized COVID-19 patients. Nine variables were independent predictors for in-hospital mortality, including creatinine (Hazard ratio [HR]:1.327; 95% Confidence Interval [CI]: 1.040-1.695, p = .023), troponin (HR: 2.150; 95% CI: 1.155-4.001; p = .016), platelet count (HR: 0.994; 95% CI: 0.989-0.998; p = .004) and C-reactive protein (HR: 1.037; 95% CI: 1.006-1.068; p = .019). This is the first multicenter study in which an effort was carried out to adjust the results of laboratory tests measured with different methodologies to guarantee their comparability. We reported a comprehensive information about characteristics in a large cohort of hospitalized COVID-19 patients, focusing on the analytical features. Our findings may help to identify patients early at a higher risk for an adverse outcome.

D-dimer during pregnancy: establishing trimester-specific reference intervals.

Pregnancy is associated with an increased risk of venous thromboembolism (VTE). D-dimer is a biomarker used as an exclusion criterion of VTE disease, but its usefulness during pregnancy shows limitations because D-dimer levels physiologically increase through pregnancy. The aim of our study was to follow the changes of D-dimer levels and to establish trimester-specific reference intervals during normal pregnancy. This is a longitudinal prospective study in which the reference population finally included 102 healthy pregnant women. Plasma D-dimer levels were measured during the three trimesters of pregnancy, using a latex-based immunoturbidimetric assay. Reference intervals were calculated according to the Clinical and Laboratory Standards Institute recommendations. D-dimer levels increased progressively and significantly through pregnancy and peaked in the third trimester, in which D-dimer levels were above the conventional cut-off point (500 µg/L) in 99% of pregnant women. The following reference intervals were defined: first trimester: 169-1202 µg/L, second trimester: 393-3258 µg/L and third trimester: 551-3333 µg/L. The study provides reference intervals of D-dimer during the pregnancy using latex-based immunoturbidimetry on the ACL 300 TOP automated coagulation analyser. Further prospective studies of pregnant women with clinical suspicion of VTE are needed to validate these results.

Epigenetic silencers and Notch collaborate to promote malignant tumours by Rb silencing.

Cancer is both a genetic and an epigenetic disease. Inactivation of tumour-suppressor genes by epigenetic changes is frequently observed in human cancers, particularly as a result of the modifications of histones and DNA methylation. It is therefore important to understand how these damaging changes might come about. By studying tumorigenesis in the Drosophila eye, here we identify two Polycomb group epigenetic silencers, Pipsqueak and Lola, that participate in this process. When coupled with overexpression of Delta, deregulation of the expression of Pipsqueak and Lola induces the formation of metastatic tumours. This phenotype depends on the histone-modifying enzymes Rpd3 (a histone deacetylase), Su(var)3-9 and E(z), as well as on the chromodomain protein Polycomb. Expression of the gene Retinoblastoma-family protein (Rbf) is downregulated in these tumours and, indeed, this downregulation is associated with DNA hypermethylation. Together, these results establish a mechanism that links the Notch-Delta pathway, epigenetic silencing pathways and cell-cycle control in the process of tumorigenesis.

MiR-215-5p is a tumor suppressor in colorectal cancer targeting EGFR ligand epiregulin and its transcriptional inducer HOXB9.

Growing evidence suggests that microRNAs are involved in the development and progression of colorectal cancer (CRC). In the present study, deregulation and functioning of tumor-suppressive miR-215-5p was evaluated in CRC. In total, 448 tumor tissues and 325 paired adjacent healthy tissues collected from Czech and Spain cohorts of CRC patients have been used for miR-215-5p expression analyses. A series of in vitro experiments have been performed using transient transfection of miR-215-5p mimics into four CRC cell lines to identify specific cellular processes affected by miR-215-5p. Further, the effects of miR-215-5p on tumor growth were evaluated in vivo using NSG mice and stable cell line overexpressing miR-215-5p. Target mRNAs of miR-215-5p were tested using luciferase assay and western blot analyses. We found that miR-215-5p is significantly downregulated in tumor tissues compared with non-tumor adjacent tissues and its decreased levels correlate with the presence of lymph node metastases, tumor stage, and shorter overall survival in CRC patients. Overexpression of miR-215-5p significantly reduced proliferation, clonogenicity, and migration of CRC cells, lead to cell cycle arrest in G2/M phase and p53-dependent induction of apoptosis. The ability of miR-215-5p to inhibit tumor growth was confirmed in vivo. Finally, we confirmed epiregulin and HOXB9 to be the direct targets of miR-215-5p. As epiregulin is EGFR ligand and HOXB9 is its transcriptional inducer, we suggest that the main molecular link between miR-215-5p and CRC cells phenotypes presents the EGFR signaling pathway, which is one of the canonical pathogenic pathways in CRC.

Intervalos de referencia de ácido úrico en suero durante la gestación / Reference intervals for serum uric acid during pregnancy

Introducción. La interpretación de las magnitudes bioquímicas durante la gestación requiere de intervalos de referencia específicos para dicha etapa, dados los cambios fisiológicos que se producen durante el embarazo. El objetivo de este estudio fue obtener el intervalo de referencia de la concentración sérica de ácido úrico, biomarcador asociado a un incremento del riesgo de desarrollo de preeclampsia en gestantes residentes en el Área 2 de Salud de la Región de Murcia (España). Material y métodos. Estudio prospectivo, longitudinal y consecutivo en el que la población de referencia estuvo finalmente formada por 270 gestantes sanas en las que se midió la uricemia durante los tres trimestres de gestación. Las recomendaciones del Clinical and Laboratory Standards Institute se utilizaron para la obtención de los intervalos de referencia. Resultados. La uricemia aumentó de forma significativa durante la gestación, alcanzando una concentración marcadamente superior durante el tercer trimestre. Se definieron los siguientes intervalos de referencia: primer trimestre: 2,0-4,6 mg/dl, segundo trimestre: 2,0-4,7 mg/dl y tercer trimestre: 2,6-5,7 mg/dl. Conclusión. La interpretación de la uricemia durante la gestación requiere de intervalos de referencia específicos para este estado fisiológico, estratificados por trimestres. Los intervalos obtenidos en nuestro estudio son una herramienta útil en la interpretación de la uricemia durante la gestación para la identificación de aquellas gestantes con un riesgo incrementado de preeclampsia (AU)

Introduction. Interpretation of biochemical variables during pregnancy requires reference intervals specific to that state, due to the physiological changes that occur during pregnancy. The objective of this study was to obtain the reference range of serum uric acid, biomarker associated with an increase in the risk of developing preeclampsia, in pregnant women of the Area 2 of the Region of Murcia (Spain). Material and methods. This is a consecutive longitudinal prospective study in which the reference population finally included 270 healthy pregnant women, in which serum uric acid was measured during the three trimesters of pregnancy. Recommendations of the Clinical and Laboratory Standards Institute were used to obtain reference intervals. Results. Serum uric acid levels increased significantly during pregnancy, reaching a concentration notably higher during the third trimester. The following reference intervals were defined: first trimester: 2,0-4,6 mg/dl, second trimester: 2,0-4,7 mg/dl and third trimester: 2,6-5,7 mg/dl. Conclusion. Interpretation of serum uric acid levels during pregnancy requires reference intervals specific to this physiological state, stratified by trimesters. The ranges obtained in our study are a useful tool to identificate those pregnant women with an increased risk of preeclampsia (AU)