Non-invasive assessment of severe liver fibrosis in patients with Fontan-associated liver disease: The VALDIG-EASL FONLIVER cohort.

BACKGROUND & AIMS: Fontan-type surgery is used as a palliation for congenital heart disease with univentricular physiology but may, in the long term, lead to advanced chronic liver disease. This study assessed the accuracy of conventional non-invasive models in assessing liver fibrosis and introduces a new risk score employing non-invasive tools. METHODS: A prospective, cross-sectional, observational study was conducted across five European centers and encompassing all consecutive adult patients with Fontan circulation, liver biopsy and non-invasive tests (elastography, APRI, FIB-4, Fibrosis score, Doha, GUCI, and AAR). The primary outcome was the identification of severe liver fibrosis on biopsy. Multivariable logistic regression identified non-invasive predictors of severe fibrosis, leading to the development and internal validation of a new scoring model named the FonLiver risk score. RESULTS: In total, 217 patients (mean [standard deviation] age, 27.9 [8.9] years; 50.7% males) were included. Severe liver fibrosis was present in 47.9% (95% CI 41.2%-54.5%) and correlated with a lower functional class, protein-losing enteropathy, and compromised cardiopulmonary and systemic hemodynamics. The final FonLiver risk score incorporated liver stiffness measurement using transient elastography and platelet count and demonstrated strong discrimination and calibration (area under the receiver operating curve [AUROC] of 0.81). The FonLiver risk score outperformed conventional prediction models (APRI, FIB-4, Fibrosis score, Doha, GUCI, and AAR), which all exhibited worse performance in our cohort (AUROC < 0.70 for all). CONCLUSION: Severe liver fibrosis is prevalent in adults following Fontan-type palliation and can be effectively estimated using with the novel FonLiver risk score. This scoring system can be easily incorporated into the routine assessment of patients with Fontan circulation.

Prevalence, features and predictive factors of liver nodules in Fontan surgery patients: The VALDIG Fonliver prospective cohort.

BACKGROUND & AIMS: Fontan surgery is used to treat a variety of congenital heart malformations, and may lead to advanced chronic liver disease in the long-term. This study examines the prevalence, characteristics and predictors of liver nodules in patients following Fontan surgery. METHODS: This was a prospective, cross-sectional, observational study conducted at 8 European centres. Consecutive patients who had undergone Fontan surgery underwent blood tests, abdominal ultrasonography (US), transient elastography (Fibroscan®), echocardiography, haemodynamic assessments, and abdominal MRI/CT scan. The primary outcome measure was liver nodules detected in the MRI/CT scan. Predictors of liver nodules were identified by multivariate logistic regression. RESULTS: One hundred and fifty-two patients were enrolled (mean age 27.3 years). The mean time elapsed from surgery to inclusion was 18.3 years. Liver nodule prevalences were 29.6% (95% CI 23-37%) on US and 47.7% (95% CI 39-56%) on MRI/CT. Nodules were usually hyperechoic (76.5%), round-shaped (>80%), hyperenhancing in the arterial phase (92%) and located in the liver periphery (75%). The sensitivity and specificity of US were 50% (95% CI 38-62%) and 85.3% (95% CI 75-92%), respectively. Inter-imaging test agreement was low (adjusted kappa: 0.34). In the multivariate analysis, time since surgery >10 years was the single independent predictor of liver nodules (odds ratio 4.18; p = 0.040). Hepatocellular carcinoma was histologically diagnosed in 2 of the 8 patients with hypervascular liver nodules displaying washout. CONCLUSION: While liver nodules are frequent in Fontan patients, they may go unnoticed in US. Liver nodules are usually hyperechoic, hypervascular and predominantly peripheral. This population is at risk of hepatocellular carcinoma, the diagnosis of which requires confirmatory biopsy. LAY SUMMARY: Fontan surgery is the standard of care for many patients with univentricular congenital cardiopathies. Recent advances have improved the survival of Fontan patients, and nowadays most of them reach adulthood. In this setting, Fontan-associated liver disease (FALD) is increasingly recognised, and has become a significant prognostic factor. Liver nodules are considered a component of FALD yet their prevalence, imaging features and predictors have hardly been evaluated. In this study, we observed that liver nodules are frequent, typically hyperechoic, hypervascular and predominantly peripheral in patients with FALD. This population is at risk of hepatocellular carcinoma, the diagnosis of which must be confirmed by biopsy.

Natural History and Clinical Predictors of Atrial Tachycardia in Adults With Congenital Heart Disease.

BACKGROUND: Atrial tachycardias (ATs) are a significant source of morbidity in adults with congenital heart disease (CHD). This study evaluates the incidence and clinical predictors of AT in a cohort of patients with CHD. METHODS AND RESULTS: We included 3311 adults (median age at entry 22.6 years, 50.6% males) with CHD (49% simple, 39% moderate, and 12% complex) prospectively followed up in a tertiary center for 37 607 person-years. Predictors of AT were identified by multivariable Cox regression analysis accounting for left truncation. An external validation was performed in a contemporary cohort of 1432 patients. Overall, 153 (4.6%) patients presented AT. AT burden was highest in complex CHD, such as single ventricle (22.8%) and d-transposition of the great arteries (22.1%). Hazard rates of AT across lifetime, age at presentation, and the time lapse between surgery and the first AT episode varied among the most common CHD. Independent risk factors for developing AT were univentricular physiology, previous intracardiac repair, systemic right ventricle, pulmonary hypertension, pulmonary regurgitation, pulmonary atrioventricular valve regurgitation, pulmonary and systemic ventricular dysfunction. At the age of 40 years, AT-free survival in patients with 0, 1, 2, and ≥3 risk factors was 100%, 94%, 76%, and 50%, respectively. These findings were confirmed in the validation cohort. CONCLUSIONS: Natural history of AT differed among the most common forms of CHD. Simple clinical parameters, easily obtained by noninvasive means, were independent predictors of AT in adults with CHD. Although risk was negligible in patients without any of these factors, their addition progressively increased AT burden.

Adenosine monophosphate is elevated in the bronchoalveolar lavage fluid of mice with acute respiratory toxicity induced by nanoparticles with high surface hydrophobicity.

Inhaled nanomaterials present a challenge to traditional methods and understanding of respiratory toxicology. In this study, a non-targeted metabolomics approach was used to investigate relationships between nanoparticle hydrophobicity, inflammatory outcomes and the metabolic fingerprint in bronchoalveolar fluid. Measures of acute lung toxicity were assessed following single-dose intratracheal administration of nanoparticles with varying surface hydrophobicity (i.e. pegylated lipid nanocapsules, polyvinyl acetate nanoparticles and polystyrene beads; listed in order of increasing hydrophobicity). Broncho-alveolar lavage (BAL) fluid was collected from mice exposed to nanoparticles at a surface area dose of 220 cm(2) and metabolite fingerprints were acquired via ultra pressure liquid chromatography-mass spectrometry-based metabolomics. Particles with high surface hydrophobicity were pro-inflammatory. Multivariate analysis of the resultant small molecule fingerprints revealed clear discrimination between the vehicle control and polystyrene beads (p < 0.05), as well as between nanoparticles of different surface hydrophobicity (p < 0.0001). Further investigation of the metabolic fingerprints revealed that adenosine monophosphate (AMP) concentration in BAL correlated with neutrophilia (p < 0.01), CXCL1 levels (p < 0.05) and nanoparticle surface hydrophobicity (p < 0.001). Our results suggest that extracellular AMP is an intermediary metabolite involved in adenine nucleotide-regulated neutrophilic inflammation as well as tissue damage, and could potentially be used to monitor nanoparticle-induced responses in the lung following pulmonary administration.

Protecting the melatonin rhythm through circadian healthy light exposure.

Currently, in developed countries, nights are excessively illuminated (light at night), whereas daytime is mainly spent indoors, and thus people are exposed to much lower light intensities than under natural conditions. In spite of the positive impact of artificial light, we pay a price for the easy access to light during the night: disorganization of our circadian system or chronodisruption (CD), including perturbations in melatonin rhythm. Epidemiological studies show that CD is associated with an increased incidence of diabetes, obesity, heart disease, cognitive and affective impairment, premature aging and some types of cancer. Knowledge of retinal photoreceptors and the discovery of melanopsin in some ganglion cells demonstrate that light intensity, timing and spectrum must be considered to keep the biological clock properly entrained. Importantly, not all wavelengths of light are equally chronodisrupting. Blue light, which is particularly beneficial during the daytime, seems to be more disruptive at night, and induces the strongest melatonin inhibition. Nocturnal blue light exposure is currently increasing, due to the proliferation of energy-efficient lighting (LEDs) and electronic devices. Thus, the development of lighting systems that preserve the melatonin rhythm could reduce the health risks induced by chronodisruption. This review addresses the state of the art regarding the crosstalk between light and the circadian system.

Capillary electrophoresis-mass spectrometry for direct determination of urinary modified nucleosides. Evaluation of synthetic urine as a surrogate matrix for quantitative analysis.

This work describes the development of a fast and reliable method based on capillary zone electrophoresis coupled with electrospray ionization-mass spectrometry (CZE-ESI-MS) for the determination of modified nucleosides in untreated human urine. The target compounds were guanine, 1-methyl-guanine, 7-methyl-guanine, 9-methyl-guanine, adenosine, 1-methyl-adenosine, cytidine, guanosine, 7-methyl-guanosine. As internal standards, ribose-2-(13)C-adenosine and 8-(13)C-guanine were used. The CZE separation was carried out in acidic medium (pH 2.5). MS detection with a single quadrupole, with ESI operating in positive-ion mode, was optimized. For the analysis of urine samples, owing to the endogenous character of these analytes different quantification strategies were explored. The standard additions method, matrix-matched calibration in synthetic urine and calibration in pure aqueous medium were compared in order to evaluate the endogenous levels of these compounds in human urine. The results obtained showed that calibration in synthetic urine as a surrogate matrix was an appropriate alternative to the method of standard additions for the accurate quantitation of compounds such as guanine, 1-methyl-guanine, 7-methyl-guanine, adenosine, 1-methyl-adenosine and cytidine by CE-ESI-MS directly in the urine matrix; values in the range 0.1µg/mL for cytidine and 6.4µg/mL for 7mGua, as the lowest and the highest level, were found in untreated urine from healthy volunteers. These results were confirmed by LC-MS/MS detection. It can be concluded that the electrophoretic CZE-ESI-MS methodology offers a valid and reliable alternative for the determination of urinary nucleosides at naturally occurring levels in healthy individuals.

Frecuencias genotípicas del gen Kappa-Caseína en bovinos de un hato lechero y su correlación fenotípica / Genotype frequencies of kappa-casein gene in cattle from a dairy herd and their phenotypic correlation

El genotipo BB de la kappa-caseína, está asociado a un mayor contenido de proteína en la leche y sus propiedades de procesamiento, incluyendo la producción de queso. El diseño del estudio fue observacional, analítico de corte transversal. Este estudio tuvo como objetivo determinar las frecuencias genotípicas del gen kappa-caseína en bovinos de un hato lechero y su asociación con el contenido y volumen de la leche producida. La población estuvo constituida por 72 bovinos de la raza Holstein y 57 bovinos mestizos Holstein-Jersey. Se determinó la frecuencia genotípica del gen κ- caseína de ambos grupos por medio de técnicas moleculares y además se analizaron el contenido de proteína y el volumen de leche producida a los 305 días. Las frecuencias genotípicas para las vacas Holstein fueron AA 59,7%; AB 37,5 y BB, 2,8% y para las mestizas Holstein-Jersey AA 17,5; AB 72% y BB 10,5% empleando chi-cuadrado, estadístico T y ANOVA como análisis estadísticos. Se observó una diferencia significativa en las frecuencias genotípicas entre las dos razas estudiadas (p < 0,001). No hubo diferencias estadísticamente significativas entre los genotipos, el contenido de proteína y el volumen de leche a los 305 días (p > 0,05). Este es el primer trabajo en el país en utilizar herramientas moleculares para identificar los genotipos de las proteínas lácteas. Estas herramientas permitirían al productor identificar los animales por sus frecuencias genotípicas para mejorar su producto en calidad, aumentando no solo el valor nutritivo sino también el valor económico del mismo.

Essential thrombocytemia and acute coronary syndrome: clinical profile and association with other thromboembolic events.

BACKGROUND: The existence of a relationship between essential thrombocytemia (ET) and acute coronary syndromes (ACS) has been suggested. METHOD: Data from eleven consecutive patients admitted with ET in the cardiology department were reviewed. RESULTS: Nine patients (82%) presented with ACS and two with bradycardia. Patients with ACS had a mean age of 67+/-11 years. Risk factors, especially hypertension (6, 66.7%), and smoking (6, 66.7%) were frequent. Average platelet count was 509 778+/-282 126/mm3. Significant coronary lesions were found in five of six patients studied with coronary angiography. During hospitalization, a patient suffered a thrombotic stroke, a massive pulmonary embolism, and partial aortic thrombosis. Another patient had a transient ischemic attack. Discharge treatments were aspirin (78%), clopidogrel (56%), acenocumarol (33%), hydroxyurea (56%) and anagrelide (44%). Three patients (27%) had thromboembolic events during follow-up (median 1.6 years), 2 patients had coronary events and 1 patient had venous thrombosis. There were neither significant haemorrhages nor deaths. CONCLUSIONS: Patients with ET and ACS have similar profiles to those of traditional ACS with frequent risk factors and significant coronary artery disease. Association with other thrombotic events can be seen during admission and follow-up while haemorrhagic complications seem to be rare.

Infección del tracto urinario: comportamiento clínico y de laboratorio / Infection of the urinary treatment: clinical and laboratory behavior

Se realizó una investigación retrospectiva en 60 pacientes ingresados en la sala de misceláneas del Hospital Pediátrico Docente “Marfán”, en el período de enero a diciembre del año 2002, con el diagnóstico de infección del tracto urinario. Los grupos de edades que predominaron en nuestro universo de trabajo fueron los niños de 1 a 5 años en el 43,3 por ciento. El sexo más afectado fue el femenino en el 65 por ciento. La mayor incidencia de sexo masculino ocurrió en los lactantes. La forma clínica en las infecciones del tracto urinario (ITU) más encontrada fue la febril con el 50 por ciento de los pacientes predominando los lactantes; y la sepsis baja en los mayores de 5 años. En los análisis de laboratorio los hallazgos más encontrados fueron la leucocituria en el 85 por ciento y seguido por la microhematuria; la eritrosedimentación estuvo acelerada en las infecciones altas y normal en las infecciones bajas. El gérmen más aislado en los urocultivos fue la E. coli , seguido del Proteus mirabilis y Proteus rettgeri y el antimicrobiano más utilizado fue la amikacina, con buenos resultados de curación

Factores de inciden en la sobrevida de los pacientes reanimados fuera del hospital / Factors that influence in survive of patients reanimated out of hospital

La edad promedio de nuestro universo es de 62.7 años. Si no hubiese existido un niño de 8 años el promedio sería de 64.6 años. En nuestro universo predomina en más de 50 por ciento el sexo masculino. Los pacientes con cardiopatía isquémica son un grupo de alto riesgo de presentar PCR. Para mejorar su probabilidad de sobrevida, es necesario implementar un programa educativo dirigido a los familiares de estos pacientes en relación a maniobras de RCP. El PCR se asocia a un alto número de individuos con cardiopatía coronaria. En el 80 por ciento de nuestro universo el PCR ocurrió en el domicilio, lo que justifica el programa educativo dirigido a familiares de pacientes de alto riesgo. La recuperación de los pacientes que presentan PCR depende de la precocidad del inicio de las maniobras. Más del 80 por ciento fue atendido por personal especializado pero en forma tardía. Esto se debe a que en la mayoría de las situaciónes frente a un episodio de PCR la familia no interviene, sino espera la ayuda de personal especializado, lo que hace perder los primeros minutos críticos para comenzar con maniobras de RCP. Más de 50 por ciento de la muestra presentó 2 o 3 factores de riesgo cardiovascular, lo que indica que el paciente y su familia debe ser educada en relación a prevención de factores de riesgo, pesquisa precoz de complicaciones e importancia de un tratamiento oportuno