Perfil de citosinas durante la terapia con colchicina, interferon-alfa o pentoxifilina en pacientes con hepatitis C crónica

La hepatitis C crónica (HCC) es una enfermedad ocasionada por el virus de la hepatitis C (VHC), es un virus ARN que pertenece a la familia de los flavivirus. A nivel mundial es una enfermedad que afecta aproximadamente a 170 millones de personas, se considera el 3% de la población mundial, en México es alrededor del 1.2-1.8% de personas que padecen estas enfermedad. La hepatitis C crónica es una enfermedad que evoluciona a cirrosis hepática después de 20 años de haber adquirido la infección y por último a hepatocarcinoma celular, hasta el momento no existe tratamiento adecuado (cura) para esta enfermedad. Se conoce que el VHC dispara mecanismos intracelulares que producen inflamación y necrosis en el hígado, y además activan la respuesta inmune del huésped. Las moléculas que participan activamente en este proceso son las citocinas, ocasionando una cascada de activación de varias citocinas durante la infección por el VHC. Nos planteamos conocer que efecto tiene el IFN-α y otros fármacos como son la Pentoxifilina (PTX) y la Colchicina (COL) sobre la expresión y secreción en células mononucleares (CMNs) de IL-1β, el TNF-α, el IFN-γ y CXCL-8/IL8, además de su expresión en el tejido hepático, se conoce que participan en la respuesta del huésped contra el VHC. Cada uno de los medicamentos que decidimos estudiar tienen funciones diferentes, el IFN-α 2b actúa como inmunomodulador y antiviral, antifibrogénicos (COL) o anti-inflamatorias (PTX). Resultados: La IL-1β, el TNF-α, el IFN-γ son citocinas pro inflamatorias y CXCL-8 es una quimiocina que atrae neutrofilos a los sitios de daño. Encontramos que cada uno de los fármacos modificó de manera diferencial la expresión y secreción de estas proteínas. En CMNs de los pacientes con VHC, los 3 tratamientos después de un año disminuyeron mínimamente la expresión de estas citocinas. En cuanto a la secreción, la PTX fue el único fármaco que disminuyó las 4 moléculas que estudiamos al año de tratamiento mientras que el IFN-α y la COL no tuvieron efecto sobre CXCL-8. En la biopsia hepática, el IFN-α disminuyó la expresión del ARNm de TNF-α. En el grupo de COL la expresión de CXCL-8 se elevó de manera significativa al comparar con los valores basales, probablemente porque las proteínas virales inducen la producción de esta quimiocina. La PTX redujo el ARNm de IL-1β y TNF-α durante todo el año, comprobando el efecto anti-inflamatorio en HCC que se le ha atribuido en otras enfermedades hepáticas. A los 2 meses se cuantificó la carga viral en los 3 grupos de pacientes y encontramos que el único fármaco que tuvo acción antiviral fue el IFN−α ya que redujo la carga viral, mientras que en el grupo que recibió COL la carga viral fue alta durante todo el tiempo de tratamiento, lo que refleja que el VHC continua replicándose en las células de los pacientes. Conclusión: En la HCC existe un componente inflamatorio que contribuye a la cronicidad de esta infección. El IFN-α, la COL y la PTX modifican de manera diferencial a algunas citocinas pro-inflamatorias. La PTX fue el único medicamento que modificó a nivel periférico y en tejido el proceso inflamatorio que sucede en la HCC. Es necesario considerar la posibilidad de una terapia combinada que aumente la respuesta celular y complemente el efecto de los fármacos antivirales (IFN-α) para inhibir la replicación del virus.The hepatitis C virus (HCV) is a highly mutable, hepatotropic RNA virus that causes acute and chronic hepatitis. Chronic hepatitis C (CHC) is responsible for progressive liver disease leading to cirrhosis, end-stage liver disease, and hepatocellular carcinoma. The worldwide prevalence of CHC is about 170 million people (3%) and in México it is approximately of 1.2-18%. The mechanism of liver injury caused by HCV is thought to be mediated by the host’s cellular immune response. An effective host response against virus requires a coordinated effort of both nonspecific and specific antigen immune responses, including the production of various cytokines and chemokines. The imbalance of pro-inflammatory cytokines such as Interleukin-1 (IL-1), IL-2, IL-6, Interferon gamma (IFN-γ), Tumor Necrosis Factor-alpha (TNF-α), CXCL8/IL-8 and anti-inflammatory cytokines (IL-4, IL-10) in liver tissue and in peripheral blood may contribute to viral persistence and chronic liver disease. Colchicine (COL) has been used as antifibrogenic therapy in others diseases, IFNalpha 2b (IFN-α) is a molecule that has immuno-modulatory and antiviral activity and Pentoxifylline (PTX) ameliorates inflammatory response in CHC not only by inhibiting TNF-α but also suppressing others cytokines. The aim of the study is to analyze the expression and secretion of pro-inflammatory cytokines IL-1beta, TNF- α, IFN- γ and the chemokine CXCL8/IL-8 in peripheral blood mononuclear cells (PBMC) and their expression in liver tissue of patients with CHC, before and after to IFN- α, COL or PTX therapy. We studied twenty six patients with clinical and histological diagnosis of CHC. All were HCV-RNA (+), quantitative HCV-RNA ranged from 23,000 to 3,000 000 UI/ml; none had a concomitant systemic diseases or autoimmunity. All were naïve to antiviral treatment. All patients were genotype 1 and had fibrosis score was F1-F4 according to Metavir classification. The ALT and AST, viral load, and Metavir score were measured before and after treatment. Eight patients received COL, 7 IFN- α and 11 PTX. None of them had significant changes in the Metavir score following COL, IFN-a or PTX administration. IFN- α was the only to induce a significant decreased in viral load (p< 0.05). Aminotransferases were modified by PTX during treatment but histology was not modified. We found that COL, IFN- α and PTX minimal dimished the expression of cytokines in PBMC; the effects on cytokine secretion were more evident and significantly varied among treatments. PTX was the only therapy that diminished the secretion of IL-1, TNF- α, IFN- γ and CXCL-8/IL-8 whereas IFN- α and COL did not modified the later. In liver biopsy specimens COL significantly increased the CXCL-8 expression, IFN- α down regulated the expression of TNF- α and PTX reduced RNAm of IL-1β and TNF- α when compared with pretreatment values respectively. CONCLUSION: The inflammatory process seen in chronic hepatitis C seems to contribute to chronicity. Treatment with COL, IFN- α or PTX differentially modified the expression of pro-inflammatory cytokines. Locally (within the liver) and systemically (PBMC) produced cytokines may serve as biomarkers of inflammation on CHC. PTX inhibits the expression of several pro-inflammatory cytokines in the liver and in PBMC. Combined therapies using either COL or PTX along with IFN- α looking to modify the host´s inflammatory response and inhibit the viral replication seem promising and wroth to explore in large clinical trials

Cellular Senescence in Livers from Children with End Stage Liver Disease

Senescent cells occur in adults with cirrhotic livers independent of the etiology. Aim: Investigate the presence rate of cellular senescence and expression of cell cycle check points in livers from children with end stage disease. staining occurred in the areas of ductular transformation and in the interlobular bile ducts.Cellular senescence in livers of children with end stage disease is associated with damage rather than corresponding to an age dependent phenomenon. Further studies are needed to support the hypothesis that these senescence markers correlate with disease progression

Un examen actualizado de la percepción de las barreras para la implementación de la farmacogenómica y la utilidad de los pares fármaco/gen en América Latina y el Caribe

La farmacogenómica (PGx) se considera un campo emergente en los países en desarrollo. La investigación sobre PGx en la región de América Latina y el Caribe (ALC) sigue siendo escasa, con información limitada en algunas poblaciones. Por lo tanto, las extrapolaciones son complicadas, especialmente en poblaciones mixtas. En este trabajo, revisamos y analizamos el conocimiento farmacogenómico entre la comunidad científica y clínica de ALC y examinamos las barreras para la aplicación clínica. Realizamos una búsqueda de publicaciones y ensayos clínicos en este campo en todo el mundo y evaluamos la contribución de ALC. A continuación, realizamos una encuesta regional estructurada que evaluó una lista de 14 barreras potenciales para la aplicación clínica de biomarcadores en función de su importancia. Además, se analizó una lista emparejada de 54 genes/fármacos para determinar una asociación entre los biomarcadores y la respuesta a la medicina genómica. Esta encuesta se comparó con una encuesta anterior realizada en 2014 para evaluar el progreso en la región. Los resultados de la búsqueda indicaron que los países de América Latina y el Caribe han contribuido con el 3,44% del total de publicaciones y el 2,45% de los ensayos clínicos relacionados con PGx en todo el mundo hasta el momento. Un total de 106 profesionales de 17 países respondieron a la encuesta. Se identificaron seis grandes grupos de obstáculos. A pesar de los continuos esfuerzos de la región en la última década, la principal barrera para la implementación de PGx en ALC sigue siendo la misma, la "necesidad de directrices, procesos y protocolos para la aplicación clínica de la farmacogenética/farmacogenómica". Las cuestiones de coste-eficacia se consideran factores críticos en la región. Los puntos relacionados con la reticencia de los clínicos son actualmente menos relevantes. Según los resultados de la encuesta, los pares gen/fármaco mejor clasificados (96%-99%) y percibidos como importantes fueron CYP2D6/tamoxifeno, CYP3A5/tacrolimus, CYP2D6/opioides, DPYD/fluoropirimidinas, TMPT/tiopurinas, CYP2D6/antidepresivos tricíclicos, CYP2C19/antidepresivos tricíclicos, NUDT15/tiopurinas, CYP2B6/efavirenz y CYP2C19/clopidogrel. En conclusión, aunque la contribución global de los países de ALC sigue siendo baja en el campo del PGx, se ha observado una mejora relevante en la región. La percepción de la utilidad de las pruebas PGx en la comunidad biomédica ha cambiado drásticamente, aumentando la concienciación entre los médicos, lo que sugiere un futuro prometedor en las aplicaciones clínicas de PGx en ALC.Pharmacogenomics (PGx) is considered an emergent field in developing countries. Research on PGx in the Latin American and the Caribbean (LAC) region remains scarce, with limited information in some populations. Thus, extrapolations are complicated, especially in mixed populations. In this paper, we reviewed and analyzed pharmacogenomic knowledge among the LAC scientific and clinical community and examined barriers to clinical application. We performed a search for publications and clinical trials in the field worldwide and evaluated the contribution of LAC. Next, we conducted a regional structured survey that evaluated a list of 14 potential barriers to the clinical implementation of biomarkers based on their importance. In addition, a paired list of 54 genes/drugs was analyzed to determine an association between biomarkers and response to genomic medicine. This survey was compared to a previous survey performed in 2014 to assess progress in the region. The search results indicated that Latin American and Caribbean countries have contributed 3.44% of the total publications and 2.45% of the PGx-related clinical trials worldwide thus far. A total of 106 professionals from 17 countries answered the survey. Six major groups of barriers were identified. Despite the region’s continuous efforts in the last decade, the primary barrier to PGx implementation in LAC remains the same, the “need for guidelines, processes, and protocols for the clinical application of pharmacogenetics/pharmacogenomics”. Cost-effectiveness issues are considered critical factors in the region. Items related to the reluctance of clinicians are currently less relevant. Based on the survey results, the highest ranked (96%–99%) gene/drug pairs perceived as important were CYP2D6/tamoxifen, CYP3A5/tacrolimus, CYP2D6/opioids, DPYD/fluoropyrimidines, TMPT/thiopurines, CYP2D6/tricyclic antidepressants, CYP2C19/tricyclic antidepressants, NUDT15/thiopurines, CYP2B6/efavirenz, and CYP2C19/clopidogrel. In conclusion, although the global contribution of LAC countries remains low in the PGx field, a relevant improvement has been observed in the region. The perception of the usefulness of PGx tests in biomedical community has drastically changed, raising awareness among physicians, which suggests a promising future in the clinical applications of PGx in LAC

An Updated Examination of the Perception of Barriers for Pharmacogenomics Implementation and the Usefulness of Drug/Gene Pairs in Latin America and the Caribbean

Pharmacogenomics (PGx) is considered an emergent field in developing countries. Research on PGx in the Latin American and the Caribbean (LAC) region remains scarce, with limited information in some populations. Thus, extrapolations are complicated, especially in mixed populations. In this paper, we reviewed and analyzed pharmacogenomic knowledge among the LAC scientific and clinical community and examined barriers to clinical application. We performed a search for publications and clinical trials in the field worldwide and evaluated the contribution of LAC. Next, we conducted a regional structured survey that evaluated a list of 14 potential barriers to the clinical implementation of biomarkers based on their importance. In addition, a paired list of 54 genes/drugs was analyzed to determine an association between biomarkers and response to genomic medicine. This survey was compared to a previous survey performed in 2014 to assess progress in the region. The search results indicated that Latin American and Caribbean countries have contributed 3.44% of the total publications and 2.45% of the PGx-related clinical trials worldwide thus far. A total of 106 professionals from 17 countries answered the survey. Six major groups of barriers were identified. Despite the region’s continuous efforts in the last decade, the primary barrier to PGx implementation in LAC remains the same, the “need for guidelines, processes, and protocols for the clinical application of pharmacogenetics/pharmacogenomics”. Cost-effectiveness issues are considered critical factors in the region. Items related to the reluctance of clinicians are currently less relevant. Based on the survey results, the highest ranked (96%–99%) gene/drug pairs perceived as important were CYP2D6/tamoxifen, CYP3A5/tacrolimus, CYP2D6/opioids, DPYD/fluoropyrimidines, TMPT/thiopurines, CYP2D6/tricyclic antidepressants, CYP2C19/tricyclic antidepressants, NUDT15/thiopurines, CYP2B6/efavirenz, and CYP2C19/clopidogrel. In conclusion, although the global contribution of LAC countries remains low in the PGx field, a relevant improvement has been observed in the region. The perception of the usefulness of PGx tests in biomedical community has drastically changed, raising awareness among physicians, which suggests a promising future in the clinical applications of PGx in LAC

Evaluation of factors leading to poor outcomes for pediatric acute lymphoblastic leukemia in Mexico: a multi-institutional report of 2,116 patients

Background and aimsPediatric acute lymphoblastic leukemia (ALL) survival rates in low- and middle-income countries are lower due to deficiencies in multilevel factors, including access to timely diagnosis, risk-stratified therapy, and comprehensive supportive care. This retrospective study aimed to analyze outcomes for pediatric ALL at 16 centers in Mexico.MethodsPatients &lt;18 years of age with newly diagnosed B- and T-cell ALL treated between January 2011 and December 2019 were included. Clinical and biological characteristics and their association with outcomes were examined.ResultsOverall, 2,116 patients with a median age of 6.3 years were included. B-cell immunophenotype was identified in 1,889 (89.3%) patients. The median white blood cells at diagnosis were 11.2.5 × 103/mm3. CNS-1 status was reported in 1,810 (85.5%), CNS-2 in 67 (3.2%), and CNS-3 in 61 (2.9%). A total of 1,488 patients (70.4%) were classified as high-risk at diagnosis. However, in 52.5% (991/1,889) of patients with B-cell ALL, the reported risk group did not match the calculated risk group allocation based on National Cancer Institute (NCI) criteria. Fluorescence in situ hybridization (FISH) and PCR tests were performed for 407 (19.2%) and 736 (34.8%) patients, respectively. Minimal residual disease (MRD) during induction was performed in 1,158 patients (54.7%). The median follow-up was 3.7 years. During induction, 191 patients died (9.1%), and 45 patients (2.1%) experienced induction failure. A total of 365 deaths (17.3%) occurred, including 174 deaths after remission. Six percent (176) of patients abandoned treatment. The 5-year event-free survival (EFS) was 58.9% ± 1.7% for B-cell ALL and 47.4% ± 5.9% for T-cell ALL, while the 5-year overall survival (OS) was 67.5% ± 1.6% for B-cell ALL and 54.3% ± 0.6% for T-cell ALL. The 5-year cumulative incidence of central nervous system (CNS) relapse was 5.5% ± 0.6%. For the whole cohort, significantly higher outcomes were seen for patients aged 1–10 years, with DNA index &gt;0.9, with hyperdiploid ALL, and without substantial treatment modifications. In multivariable analyses, age and Day 15 MRD continued to have a significant effect on EFS.ConclusionOutcomes in this multi-institutional cohort describe poor outcomes, influenced by incomplete and inconsistent risk stratification, early toxic death, high on-treatment mortality, and high CNS relapse rate. Adopting comprehensive risk-stratification strategies, evidence-informed de-intensification for favorable-risk patients and optimized supportive care could improve outcomes

Annual Conference on Formative Research on EFL. Practices thar inspire change.

The conference papers of the Annual Conference on Formative Research on EFL. Practices thar inspire change collect pedagogical experiences, research reports, and reflections about social issues, language teaching, teaching training, interculturality under the panorama of the Covid-19 pandemic. Each paper invites the reader to implement changes in their teaching practice through disruptive pedagogies, reflect on the social and emotional consequences of the lockdown, new paths for teacher training and different approaches for teaching interculturality. We expect to inspire new ways to train pre-service teachers and teach languages in this changing times

Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

Funder: European Society of Intensive Care Medicine; doi: http://dx.doi.org/10.13039/501100013347Funder: Flemish Society for Critical Care NursesAbstract: Purpose: Intensive care unit (ICU) patients are particularly susceptible to developing pressure injuries. Epidemiologic data is however unavailable. We aimed to provide an international picture of the extent of pressure injuries and factors associated with ICU-acquired pressure injuries in adult ICU patients. Methods: International 1-day point-prevalence study; follow-up for outcome assessment until hospital discharge (maximum 12 weeks). Factors associated with ICU-acquired pressure injury and hospital mortality were assessed by generalised linear mixed-effects regression analysis. Results: Data from 13,254 patients in 1117 ICUs (90 countries) revealed 6747 pressure injuries; 3997 (59.2%) were ICU-acquired. Overall prevalence was 26.6% (95% confidence interval [CI] 25.9–27.3). ICU-acquired prevalence was 16.2% (95% CI 15.6–16.8). Sacrum (37%) and heels (19.5%) were most affected. Factors independently associated with ICU-acquired pressure injuries were older age, male sex, being underweight, emergency surgery, higher Simplified Acute Physiology Score II, Braden score 3 days, comorbidities (chronic obstructive pulmonary disease, immunodeficiency), organ support (renal replacement, mechanical ventilation on ICU admission), and being in a low or lower-middle income-economy. Gradually increasing associations with mortality were identified for increasing severity of pressure injury: stage I (odds ratio [OR] 1.5; 95% CI 1.2–1.8), stage II (OR 1.6; 95% CI 1.4–1.9), and stage III or worse (OR 2.8; 95% CI 2.3–3.3). Conclusion: Pressure injuries are common in adult ICU patients. ICU-acquired pressure injuries are associated with mainly intrinsic factors and mortality. Optimal care standards, increased awareness, appropriate resource allocation, and further research into optimal prevention are pivotal to tackle this important patient safety threat

Correction to: Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

The original version of this article unfortunately contained a mistake

Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

Funder: European Society of Intensive Care Medicine; doi: http://dx.doi.org/10.13039/501100013347Funder: Flemish Society for Critical Care NursesAbstract: Purpose: Intensive care unit (ICU) patients are particularly susceptible to developing pressure injuries. Epidemiologic data is however unavailable. We aimed to provide an international picture of the extent of pressure injuries and factors associated with ICU-acquired pressure injuries in adult ICU patients. Methods: International 1-day point-prevalence study; follow-up for outcome assessment until hospital discharge (maximum 12 weeks). Factors associated with ICU-acquired pressure injury and hospital mortality were assessed by generalised linear mixed-effects regression analysis. Results: Data from 13,254 patients in 1117 ICUs (90 countries) revealed 6747 pressure injuries; 3997 (59.2%) were ICU-acquired. Overall prevalence was 26.6% (95% confidence interval [CI] 25.9–27.3). ICU-acquired prevalence was 16.2% (95% CI 15.6–16.8). Sacrum (37%) and heels (19.5%) were most affected. Factors independently associated with ICU-acquired pressure injuries were older age, male sex, being underweight, emergency surgery, higher Simplified Acute Physiology Score II, Braden score 3 days, comorbidities (chronic obstructive pulmonary disease, immunodeficiency), organ support (renal replacement, mechanical ventilation on ICU admission), and being in a low or lower-middle income-economy. Gradually increasing associations with mortality were identified for increasing severity of pressure injury: stage I (odds ratio [OR] 1.5; 95% CI 1.2–1.8), stage II (OR 1.6; 95% CI 1.4–1.9), and stage III or worse (OR 2.8; 95% CI 2.3–3.3). Conclusion: Pressure injuries are common in adult ICU patients. ICU-acquired pressure injuries are associated with mainly intrinsic factors and mortality. Optimal care standards, increased awareness, appropriate resource allocation, and further research into optimal prevention are pivotal to tackle this important patient safety threat

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030