Plasma ammonia levels predict hospitalisation with liver-related complications and mortality in clinically stable outpatients with cirrhosis

BACKGROUND AND AIMS: Hyperammonaemia is central in the pathogenesis of hepatic encephalopathy, but also has pleiotropic deleterious effects on several organ systems, impacting on immune function, sarcopenia, energy metabolism and portal hypertension. This study was performed to test the hypothesis that severity of hyperammonaemia is a risk factor for liver-related complications in clinically stable outpatients with cirrhosis. METHODS: We collected data from 754 clinically stable outpatients with cirrhosis from 3 independent liver units. Baseline ammonia levels were corrected to the upper limit of normal (AMM-ULN) for the reference laboratory. The primary endpoint was hospitalisation with liver-related complications (a composite endpoint of bacterial infection, variceal bleeding, overt hepatic encephalopathy, or new onset or worsening of ascites). Multivariable competing risk frailty analysis and fast unified random forest were performed to predict complications and mortality. External validation was carried out using prospective data from 130 cirrhotic patients in an independent tertiary liver centre. RESULTS: Overall, 260 (35%) patients were hospitalised with liver-related complications. On multivariable analysis, AMM-ULN was an independent predictor of both liver-related complications (HR=2.13; 95%CI=1.89-2.40; p<0.001) and mortality (HR=1.45; 95%CI=1.20-1.76; p<0.001). AUROC of AMM-ULN was 77.9% for 1-year complications, higher than traditional severity scores. Statistical differences in survival were found between high and low levels of AMM-ULN both for complications and mortality (p<0.001) using 1.4 as the optimal cut-off from the training set. AMM-ULN remained a key variable for the prediction of complications within the random forests model in the derivation cohort and upon external validation. CONCLUSION: Ammonia is an independent predictor of hospitalisation with liver-related complications and mortality in clinically stable outpatients with cirrhosis and performs better than traditional prognostic scores in predicting complications. LAY SUMMARY: We conducted a prospective cohort study evaluating the association of blood ammonia levels with the risk of adverse outcomes in 754 patients with stable cirrhosis across 3 independent liver units. We found that ammonia is a key determinant that helps to predict which patients will be hospitalised, develop liver-related complications and die; this was confirmed in an independent cohort of patients

Estudio del efecto protector del ejercicio físico en marcadores dopaminérgicos medidos en el núcleo accumbens

Treball Final de Grau en Medicina. Codi: MD1158. Curs acadèmic: 2016-2017La dopamina liberada en el Núcleo Accumbens regula procesos relacionados con el esfuerzo y el componente activacional de la conducta motivada. El ejercicio físico ha demostrado tener efectos neuroprotectores en animales con depleción dopaminérgica en la vía nigroestriatal, implicada en el control motor voluntario, pero no hay datos sobre su efecto en el Núcleo Accumbens. Existen dos tipos de receptores de dopamina en el Núcleo Accumbens cuya activación produce aumento o disminución de fosforilación de la proteína DARPP-32 en diferentes neuronas, siendo ésto marcador indirecto de dopamina liberada. La tetrabenazina es un inhibidor de VMAT-2 que reduce los niveles extracelulares de dopamina alterando parámetros de DARPP-32 y se utiliza para inducir anergia. Nuestro objetivo es evaluar a través de la expresión de DARPP-32 si la realización de ejercicio físico prolongado produce efectos protectores sobre el sistema dopaminérgico que se vean reflejados en un test conductual que mide anergia inducida por tetrabenazina. Se emplearon ratones macho CD1 divididos en dos condiciones de entrenamiento en ruedas de actividad: ejercicio bloqueado y forzado, recibiendo sustancia vehículo o tetrabenazina. Estos experimentos demuestran que el ejercicio físico no altera niveles basales de dopamina pero en animales con anergia inducida por tetrabenazina tiene una tendencia protectora.Dopamine (DA) released in Nucleus Accumbens regulates processes related to effort and the activational component of motivated behaviours. Physical exercise has been shown to have neuroprotective effects in animals with a dopaminergic depletion in the Nigrostriatal pathway, which is involved in voluntary motor control. However, there is no data on its effect in the Nucleus Accumbens. There are two types of DA receptors, localized in different neurons in Nucleus Accumbens. DA receptor activation produces an increase or decrease in the phosphorylation of the DARPP-32 protein, which is an indirect marker of the released DA. Tetrabenazine is a VMAT-2 inhibitor that reduces extracelular DA levels inducing anergia and changing also phosphorilation of DARPP-32. Thus, our aim is to assess via the evaluation of DARPP-32 expression, if the performance of regular physical exercise produces protective effects on a behavioral test that measures tetrabenazine-induced anergia. Mice were divided into two training conditions: blocked and forced exercise on a running wheel, receiving either vehicle substance or tetrabenazine. These experiments demonstrate that physical exercise does not alter the basal levels of DA, although, in animals with tetrabenazine-induced anergia, exercise shows a protective tendency

Prevalence and Risk Factors for Colonization by Multidrug-Resistant Microorganisms among Long-Term Travelers and Recently Arrived Migrants

Multidrug-resistant (MDR) bacteria have become one of the most important health problems. We aimed to assess whether international travel may facilitate their spread through the colonization of asymptomatic travelers. A cross-sectional study was conducted (November 2018 to February 2022). Pharyngeal and rectal swabs were obtained from long-term travelers and recently arrived migrants from non-European countries, and an epidemiological survey was performed. Colonization by Gram-negative bacteria and methicillin-resistant Staphylococcus aureus (MRSA) was determined by chromogenic media and MALDI-TOF-MS. Resistance mechanisms were determined by the biochip-based molecular biology technique. Risk factors for colonization were assessed by logistic regression. In total, 122 participants were included: 59 (48.4%) recently arrived migrants and 63 (51.6%) long-term travelers. After their trip, 14 (11.5%) participants-5 (8.5%) migrants and 9 (14.3%) travelers-had rectal colonization by one MDR bacterium. Escherichia coli carrying the extended-spectrum beta-lactamase (ESBL) CTX-M-15 was the most frequent. No participants were colonized by MRSA or carbapenemase-producing Enterobacteriaceae. The only risk factor independently associated with MDR bacterial colonization was previous hospital attention [OR, 95% CI: 10.16 (2.06-50.06)]. The risk of colonization by MDR bacteria among recently arrived migrants and long-term travelers is similar in both groups and independently associated with previous hospital attention

Evolution over Time of Ventilatory Management and Outcome of Patients with Neurologic Disease∗

OBJECTIVES: To describe the changes in ventilator management over time in patients with neurologic disease at ICU admission and to estimate factors associated with 28-day hospital mortality. DESIGN: Secondary analysis of three prospective, observational, multicenter studies. SETTING: Cohort studies conducted in 2004, 2010, and 2016. PATIENTS: Adult patients who received mechanical ventilation for more than 12 hours. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Among the 20,929 patients enrolled, we included 4,152 (20%) mechanically ventilated patients due to different neurologic diseases. Hemorrhagic stroke and brain trauma were the most common pathologies associated with the need for mechanical ventilation. Although volume-cycled ventilation remained the preferred ventilation mode, there was a significant (p &lt; 0.001) increment in the use of pressure support ventilation. The proportion of patients receiving a protective lung ventilation strategy was increased over time: 47% in 2004, 63% in 2010, and 65% in 2016 (p &lt; 0.001), as well as the duration of protective ventilation strategies: 406 days per 1,000 mechanical ventilation days in 2004, 523 days per 1,000 mechanical ventilation days in 2010, and 585 days per 1,000 mechanical ventilation days in 2016 (p &lt; 0.001). There were no differences in the length of stay in the ICU, mortality in the ICU, and mortality in hospital from 2004 to 2016. Independent risk factors for 28-day mortality were age greater than 75 years, Simplified Acute Physiology Score II greater than 50, the occurrence of organ dysfunction within first 48 hours after brain injury, and specific neurologic diseases such as hemorrhagic stroke, ischemic stroke, and brain trauma. CONCLUSIONS: More lung-protective ventilatory strategies have been implemented over years in neurologic patients with no effect on pulmonary complications or on survival. We found several prognostic factors on mortality such as advanced age, the severity of the disease, organ dysfunctions, and the etiology of neurologic disease