Beneficial Effect of Ursodeoxycholic Acid in Patients with ACOX2 Deficiency-Associated Hypertransaminasemia

Background: A variant (p.Arg225Trp) of peroxisomal acyl-CoA oxidase 2 (ACOX2), involved in bile acid (BA) side-chain shortening, has been associated with unexplained persistent hypertransaminasemia and accumulation of C27-BAs, mainly trihydroxycholestanoic acid (THCA). Aims: To investigate the prevalence of ACOX2 deficiency-associated hypertransaminasemia (ADAH), its response to ursodeoxycholic acid (UDCA), elucidate its pathophysiological mechanism and identify other inborn errors that could cause this alteration. Methods & results: Among 33 patients with unexplained hypertransaminasemia from 11 hospitals, and 13 of their relatives, 7 individuals with abnormally high C27-BA levels (>50% of total BAs) were identified by HPLC-MS/MS. The p.Arg225Trp variant was found in homozygosity (exon amplification/sequencing) in 2 patients and 3 family members. Two additional non-related patients were heterozygous carriers of different alleles: c.673C>T (p.Arg225Trp) and c.456_459del (p.Thr154fs). In ADAH patients, impaired liver expression of ACOX2, but not ACOX3, was found (immunohistochemistry). Treatment with UDCA normalized transaminases levels. Incubation of HuH-7 liver cells with THCA, which was efficiently taken up, but not through BA transporters, increased ROS production (flow cytometry), ER stress biomarkers (GRP78, CHOP and XBP1-S/XBP1-U ratio), and BAX¿ expression (RT-qPCR and immunoblot), whereas cell viability was decreased (MTT). THCA-induced cell toxicity was higher than that of major C24-BAs and was not prevented by UDCA. Fourteen predicted ACOX2 variants were generated (site-directed mutagenesis) and expressed in HuH-7 cells. Functional tests to determine their ability to metabolize THCA identified six with the potential to cause ADAH. Conclusion: Dysfunctional ACOX2 has been found in several patients with unexplained hypertransaminasemia. This condition can be accurately identified by a non-invasive diagnostic strategy based on plasma BA profiling and ACOX2 sequencing. Moreover, UDCA treatment can efficiently attenuate liver damage in these patients.This study was supported by the following grants: CIBERehd (EHD15PI05/2016); Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III, Spain (PI19/00819 and PI20/00189), co-funded by European Regional Development Fund/European Social Fund, “Investing in your future”; “Junta de Castilla y León” (SA074P20); Fundació Marato TV3 (201916–31); AECC Scientific Foundation (2017/2020), Spain; and “Centro Internacional sobre el Envejecimiento” (OLD-HEPAMARKER, 0348_CIE_6_E), Spain. We also acknowledge support from grants PID2019-111669RBI- 100, PID2020-115055RB- I00 from Plan Nacional de I+D funded by the “Agencia Estatal de Investigación” (AEI) and the center grant P50AA011999 Southern California Research Center for ALPD and Cirrhosis funded by NIAAA/NIH, as well as support from AGAUR of the “Generalitat de Catalunya” SGR-2017- 1112, European Cooperation in Science & Technology (COST) ACTION CA17112 Prospective European Drug-Induced Liver Injury Network. Marta Alonso-Peña was the recipient of a predoctoral fellowship from “Ministerio de Educación, Cultura y Deporte” (BOE-A- 2015- 9456; FPU-14/ 00214) and a Mobility Grant for Short Stays from “Ministerio de Ciencia, Innovación y Universidades” (EST17/00186). Ricardo Espinosa-Escudero is the recipient of a predoctoral fellowship from “Junta de Castilla y León” and “Fondo Social Europeo” (EDU/574/2018). The funding sources were not involved in the research design or preparation of the articl

ESTRATIFICACIÓN DEL RIESGO EN EL SÍNDROME CORONARIO AGUDO CON ELEVACIÓN DEL SEGMENTO ST / Risk stratification in acute coronary syndrome with ST-segment elevation

Resumen Introducción y objetivos: El tamaño del infarto y la repercusión sobre la función ventricular constituyen problemas importantes para el pronóstico del paciente. El objetivo de este trabajo fue valorar los factores de mal pronóstico antes del egreso hospitalario mediante la realización de ergometría submaximal y ecocardiograma. Material y método: Se realizó una investigación descriptiva, prospectiva, con 85 pacientes con infarto que recibieron o no terapia trombolítica, en el Hospital Universitario “Celestino Hernández Robau” de Santa Clara, a los cuales se les realizó ergometría y ecocardiograma antes del egreso para detectar variables de mal pronóstico. Resultados: Predominó el sexo masculino (82,2 %), el grupo de edad de 55 años y más (47,1 %), la hipertensión arterial (80 %) y el tabaquismo (75,2 %). La localización más frecuente fue la póstero-inferior (78,8 %); la fracción de eyección del ventrículo izquierdo fue mejor en los tratados con trombolíticos, y se detectaron los que tenían una mala función ventricular (10,6 %). El 74,1 % presentó clase funcional I y se identificaron 21 pacientes (24,7 %) con mal pronóstico. No hubo diferencia significativa respecto a la terapia trombolítica, pero los pacientes que la recibieron presentaron un mejor comportamiento clínico. Conclusiones: Se encontraron 31 pacientes con prueba de esfuerzo positiva, de mal pronóstico, 5 de ellos con clase funcional III, los cuales presentaron también FEVI disminuida. La prueba de esfuerzo submáxima y el ecocardiograma bidimensional constituyeron herramientas de primera línea en la valoración pronóstica del paciente con IAM, por su existencia en casi todos los centros hospitalarios, bajo costo, poco o ningún riesgo y ser fácil de realizar, y reproducir. / Abstract Introduction and Objectives: Infarct size and the effect on ventricular function are significant problems for the patient's prognosis. The aim of this study was to assess poor prognostic factors prior to hospital discharge by performing submaximal ergometry and echocardiogram. Material and Methods: A descriptive, prospective study was performed on 85 patients with infarction who received or not thrombolytic therapy, in the University Hospital "Dr. Celestino Hernandez Robau" Santa Clara, and who underwent ergometry and echocardiography prior to hospital discharge in order to identify poor prognosis variables. Results: Males were predominant (82.2%), the group aged 55 years and over (47,1 %), hypertension (80%) and smoking (75,2 %). The most common location was the posterior-inferior (78.8 %) left ventricle ejection fraction was better in patients treated with thrombolysis, and those who had poor ventricular function were identified (10.6%), 74,1 % had functional class I and 21 patients (24,7 %) with poor prognosis were identified. There was no significant difference compared to thrombolytic therapy, but the patients who received it had a better clinical behavior. Conclusions: There were 31 patients with positive stress testing and poor prognosis, 5 of them with functional class III, which also showed decreased LVEF. Submaximal exercise testing and two-dimensional echocardiography are first-choice tools in the prognostic assessment of patients with AMI, due to its existence in almost all hospitals, low cost, little or no risk and easy to perform, and reproduce

Estratificación del riesgo en el síndrome coronario agudo con elevación del segmento st

Introduction and Objectives: Infarct size and the effect on ventricular function are significant problems for the patient's prognosis. The aim of this study was to assess poor prognostic factors prior to hospital discharge by performing submaximal ergometry and echocardiogram. Material and Methods: A descriptive, prospective study was performed on 85 patients with infarction who received or not thrombolytic therapy, in the University Hospital "Dr. Celestino Hernandez Robau" Santa Clara, and who underwent ergometry and echocardiography prior to hospital discharge in order to identify poor prognosis variables. Results: Males were predominant (82.2%), the group aged 55 years and over (47,1 %), hypertension (80%) and smoking (75,2 %). The most common location was the posterior-inferior (78.8 %) left ventricle ejection fraction was better in patients treated with thrombolysis, and those who had poor ventricular function were identified (10.6%), 74,1 % had functional class I and 21 patients (24,7 %) with poor prognosis were identified. There was no significant difference compared to thrombolytic therapy, but the patients who received it had a better clinical behavior. Conclusions: There were 31 patients with positive stress testing and poor prognosis, 5 of them with functional class III, which also showed decreased LVEF. Submaximal exercise testing and two-dimensional echocardiography are first-choice tools in the prognostic assessment of patients with AMI, due to its existence in almost all hospitals, low cost, little or no risk and easy to perform, and reproduceIntroducción y objetivos: El tamaño del infarto y la repercusión sobre la función ventricular constituyen problemas importantes para el pronóstico del paciente. El objetivo de este trabajo fue valorar los factores de mal pronóstico antes del egreso hospitalario mediante la realización de ergometría submaximal y ecocardiograma. Material y método: Se realizó una investigación descriptiva, prospectiva, con 85 pacientes con infarto que recibieron o no terapia trombolítica, en el Hospital Universitario �Celestino Hernández Robau� de Santa Clara, a los cuales se les realizó ergometría y ecocardiograma antes del egreso para detectar variables de mal pronóstico. Resultados: Predominó el sexo masculino (82,2 %), el grupo de edad de 55 años y más (47,1 %), la hipertensión arterial (80 %) y el tabaquismo (75,2 %). La localización más frecuente fue la póstero-inferior (78,8 %); la fracción de eyección del ventrículo izquierdo fue mejor en los tratados con trombolíticos y se detectaron los que tenían una mala función ventricular (10,6 %). El 74,1 % presentó clase funcional I y se identificaron 21 pacientes (24,7 %) con mal pronóstico. No hubo diferencia significativa respecto a la terapia trombolítica, pero los pacientes que la recibieron presentaron un mejor comportamiento clínico. Conclusiones: Se encontraron 31 pacientes con prueba de esfuerzo positiva, de mal pronóstico, 5 de ellos con clase funcional III, los cuales presentaron también FEVI disminuida. La prueba de esfuerzo submáxima y el ecocardiograma bidimensional constituyeron herramientas de primera línea en la valoración pronóstica del paciente con IAM, por su existencia en casi todos los centros hospitalarios, bajo costo, poco o ningún riesgo y ser fácil de realizar, y reproducir

Risk of recurrence after discontinuing anticoagulation in patients with COVID-19- associated venous thromboembolism: a prospective multicentre cohort studyResearch in context

Summary: Background: The clinical relevance of recurrent venous thromboembolism (VTE) after discontinuing anticoagulation in patients with COVID-19-associated VTE remains uncertain. We estimated the incidence rates and mortality of VTE recurrences developing after discontinuing anticoagulation in patients with COVID-19-associated VTE. Methods: A prospective, multicenter, non-interventional study was conducted between March 25, 2020, and July 26, 2023, including patients who had discontinued anticoagulation after at least 3 months of therapy. All patients from the registry were analyzed during the study period to verify inclusion criteria. Patients with superficial vein thrombosis, those who did not receive at least 3 months of anticoagulant therapy, and those who were followed for less than 15 days after discontinuing anticoagulation were excluded. Outcomes were: 1) Incidence rates of symptomatic VTE recurrences, and 2) fatal PE. The rate of VTE recurrences was defined as the number of patients with recurrent VTE divided by the patient-years at risk of recurrent VTE during the period when anticoagulation was discontinued. Findings: Among 1106 patients with COVID-19-associated VTE (age 62.3 ± 14.4 years; 62.9% male) followed-up for 12.5 months (p25-75, 6.3–20.1) after discontinuing anticoagulation, there were 38 VTE recurrences (3.5%, 95% confidence interval [CI]: 2.5–4.7%), with a rate of 3.1 per 100 patient-years (95% CI: 2.2–4.2). No patient died of recurrent PE (0%, 95% CI: 0–7.6%). Subgroup analyses showed that patients with diagnosis in 2021–2022 (vs. 2020) (Hazard ratio [HR] 2.86; 95% CI 1.45–5.68) or those with isolated deep vein thrombosis (vs. pulmonary embolism) (HR 2.31; 95% CI 1.19–4.49) had significantly higher rates of VTE recurrences. Interpretation: In patients with COVID-19-associated VTE who discontinued anticoagulation after at least 3 months of treatment, the incidence rate of recurrent VTE and the case-fatality rate was low. Therefore, it conceivable that long-term anticoagulation may not be required for many patients with COVID-19-associated VTE, although further research is needed to confirm these findings. Funding: Sanofi and Rovi, Sanofi Spain

Delayed colorectal cancer care during covid-19 pandemic (decor-19). Global perspective from an international survey

Background The widespread nature of coronavirus disease 2019 (COVID-19) has been unprecedented. We sought to analyze its global impact with a survey on colorectal cancer (CRC) care during the pandemic. Methods The impact of COVID-19 on preoperative assessment, elective surgery, and postoperative management of CRC patients was explored by a 35-item survey, which was distributed worldwide to members of surgical societies with an interest in CRC care. Respondents were divided into two comparator groups: 1) ‘delay’ group: CRC care affected by the pandemic; 2) ‘no delay’ group: unaltered CRC practice. Results A total of 1,051 respondents from 84 countries completed the survey. No substantial differences in demographics were found between the ‘delay’ (745, 70.9%) and ‘no delay’ (306, 29.1%) groups. Suspension of multidisciplinary team meetings, staff members quarantined or relocated to COVID-19 units, units fully dedicated to COVID-19 care, personal protective equipment not readily available were factors significantly associated to delays in endoscopy, radiology, surgery, histopathology and prolonged chemoradiation therapy-to-surgery intervals. In the ‘delay’ group, 48.9% of respondents reported a change in the initial surgical plan and 26.3% reported a shift from elective to urgent operations. Recovery of CRC care was associated with the status of the outbreak. Practicing in COVID-free units, no change in operative slots and staff members not relocated to COVID-19 units were statistically associated with unaltered CRC care in the ‘no delay’ group, while the geographical distribution was not. Conclusions Global changes in diagnostic and therapeutic CRC practices were evident. Changes were associated with differences in health-care delivery systems, hospital’s preparedness, resources availability, and local COVID-19 prevalence rather than geographical factors. Strategic planning is required to optimize CRC care