External validation of models to predict hepatocellular carcinoma in Hepatitis C Virus cured F3-F4 patients.

BACKGROUND & AIMS: Several hepatocellular carcinoma (HCC) risk-models have been developed to individualise patient surveillance following sustained viral response (SVR) in Hepatitis C Virus patients. Validation of these models in different cohorts is an important step to incorporate a more personalised risk assessment in clinical practice. We aimed at applying these models to stratify the risk in our patients and potentially determine cost-saving associated with individualised HCC risk-stratification screening strategy. METHODS: Patients with baseline F3-4 fibrosis treated with new oral direct-acting antivirals who had reached a SVR were regularly followed as part of the HCC surveillance strategy. Six models were applied: Pons, aMAP, Ioannou, HCC risk, Alonso and Semmler. Validation of the models was performed based on sensitivity and the proportion of patients labelled as "high risk". RESULTS: After excluding 557 with less than 3 fibrosis, 12 without SVR, 18 with a follow up (FU) <1 year, 17 transplant recipients, 16 lost to FU and 31 with HCC at time of antiviral therapy, our cohort consisted of 349 F3-4 SVR patients. Twenty-three patients (6.6%) developed HCC after a median FU of 5.12 years. The sensitivity of the different models varied between 0.17 (Semmler7noalcohol) and 1 (Alonso A and aMAP). The lowest proportion of high-risk patients corresponded to the Semmler-noalcohol model (5%). Sixty-three and 90% of the Alonso A and aMAP patients, respectively were labelled as high risk. The most reliable HCC risk-model applied to our cohort to predict HCC development is the Alonso model (based on fibrosis stage assessed by liver stiffness measurements or Fibrosis-4 index (FIB-4) at baseline and after 1 year, and albumin levels at 1 year) with a-100% sensitivity in detecting HCC among those at high risk and 63% labelled as high risk. The application of the model would have saved the cost of 1290 ultrasound no longer being performed in the 37% low-risk group. CONCLUSION: In our cohort, the Alonso A model allows the most reliable reduction in HCC screening resulting in safely stopping life-long monitoring in about a third of F3-F4 patients achieving SVR with DAAs.

Multidrug-resistant bacterial infections after liver transplantation: Prevalence, impact, and risk factors.

BACKGROUND & AIMS: Infections by multidrug-resistant bacteria (MDRB) are an increasing healthcare problem worldwide. This study analyzes the incidence, burden, and risk factors associated with MDRB infections after liver transplant(ation) (LT). METHODS: This retrospective, multicenter cohort study included adult patients who underwent LT between January 2017 and January 2020. Risk factors related to pre-LT disease, surgical procedure, and postoperative stay were analyzed. Multivariate logistic regression analysis was performed to identify independent predictors of MDRB infections within the first 90 days after LT. RESULTS: We included 1,045 LT procedures (960 patients) performed at nine centers across Spain. The mean age of our cohort was 56.8 ± 9.3 years; 75.4% (n = 782) were male. Alcohol-related liver disease was the most prevalent underlying etiology (43.2.%, n = 451). Bacterial infections occurred in 432 patients (41.3%) who presented with a total of 679 episodes of infection (respiratory infections, 19.3%; urinary tract infections, 18.5%; bacteremia, 13.2% and cholangitis 11%, among others). MDRB were isolated in 227 LT cases (21.7%) (348 episodes). Enterococcus faecium (22.1%), Escherichia coli (18.4%), and Pseudomonas aeruginosa (15.2%) were the most frequently isolated microorganisms. In multivariate analysis, previous intensive care unit admission (0-3 months before LT), previous MDRB infections (0-3 months before LT), and an increasing number of packed red blood cell units transfused during surgery were identified as independent predictors of MDRB infections. Mortality at 30, 90, 180, and 365 days was significantly higher in patients with MDRB isolates. CONCLUSION: MDRB infections are highly prevalent after LT and have a significant impact on prognosis. Enterococcus faecium is the most frequently isolated multi-resistant microorganism. New pharmacological and surveillance strategies aimed at preventing MDRB infections after LT should be considered for patients with risk factors. IMPACT AND IMPLICATIONS: Multidrug-resistant bacterial infections have a deep impact on morbidity and mortality after liver transplantation. Strategies aimed at improving prophylaxis, early identification, and empirical treatment are paramount. Our study unveiled the prevalence and main risk factors associated with these infections, and demonstrated that gram-positive bacteria, particularly Enterococcus faecium, are frequent in this clinical scenario. These findings provide valuable insights for the development of prophylactic and empirical antibiotic treatment protocols after liver transplantation.

Serological response and breakthrough infection after COVID-19 vaccination in patients with cirrhosis and post-liver transplant.

BACKGROUND: Vaccine hesitancy and lack of access remain major issues in disseminating COVID-19 vaccination to liver patients globally. Factors predicting poor response to vaccination and risk of breakthrough infection are important data to target booster vaccine programs. The primary aim of the current study was to measure humoral responses to 2 doses of COVID-19 vaccine. Secondary aims included the determination of factors predicting breakthrough infection. METHODS: COVID-19 vaccination and Biomarkers in cirrhosis And post-Liver Transplantation is a prospective, multicenter, observational case-control study. Participants were recruited at 4-10 weeks following first and second vaccine doses in cirrhosis [n = 325; 94% messenger RNA (mRNA) and 6% viral vaccine], autoimmune liver disease (AILD) (n = 120; 77% mRNA and 23% viral vaccine), post-liver transplant (LT) (n = 146; 96% mRNA and 3% viral vaccine), and healthy controls (n = 51; 72% mRNA, 24% viral and 4% heterologous combination). Serological end points were measured, and data regarding breakthrough SARS-CoV-2 infection were collected. RESULTS: After adjusting by age, sex, and time of sample collection, anti-Spike IgG levels were the lowest in post-LT patients compared to cirrhosis (p < 0.0001), AILD (p < 0.0001), and control (p = 0.002). Factors predicting reduced responses included older age, Child-Turcotte-Pugh B/C, and elevated IL-6 in cirrhosis; non-mRNA vaccine in AILD; and coronary artery disease, use of mycophenolate and dysregulated B-call activating factor, and lymphotoxin-α levels in LT. Incident infection occurred in 6.6%, 10.6%, 7.4%, and 15.6% of cirrhosis, AILD, post-LT, and control, respectively. The only independent factor predicting infection in cirrhosis was low albumin level. CONCLUSIONS: LT patients present the lowest response to the SARS-CoV-2 vaccine. In cirrhosis, the reduced response is associated with older age, stage of liver disease and systemic inflammation, and breakthrough infection with low albumin level.

Overview of Cellular and Soluble Mediators in Systemic Inflammation Associated with Non-Alcoholic Fatty Liver Disease.

Non-alcoholic fatty liver disease (NAFLD) is currently the most prevalent chronic liver disease in Western countries, affecting approximately 25% of the adult population. This condition encompasses a spectrum of liver diseases characterized by abnormal accumulation of fat in liver tissue (non-alcoholic fatty liver, NAFL) that can progress to non-alcoholic steatohepatitis (NASH), characterized by the presence of liver inflammation and damage. The latter form often coexists with liver fibrosis which, in turn, may progress to a state of cirrhosis and, potentially, hepatocarcinoma, both irreversible processes that often lead to the patient's death and/or the need for liver transplantation. Along with the high associated economic burden, the high mortality rate among NAFLD patients raises interest, not only in the search for novel therapeutic approaches, but also in early diagnosis and prevention to reduce the incidence of NAFLD-related complications. In this line, an exhaustive characterization of the immune status of patients with NAFLD is mandatory. Herein, we attempted to gather and compare the current and relevant scientific evidence on this matter, mainly on human reports. We addressed the current knowledge related to circulating cellular and soluble mediators, particularly platelets, different leukocyte subsets and relevant inflammatory soluble mediators.

Análise do índice de vulnerabilidade, equilíbrio e depressão em idosos praticantes e não praticantes de atividade física após o período de isolamento social na pandemia da Covid-19 / Analysis of the index of vulnerability, balance and depression in elderly people who practice and non-practice of physical activity after the period of social isolation during the COVID-19 pandemic

Idosos são suscetíveis a formas graves da Covid-19, o que resultou em medidas de isolamento social que intensificaram o estilo de vida sedentário, com comprometimento emocional e funcional. A atenção primária deve preparar-se para lidar com as repercussões desse período. Risco de quedas, rastreio de sintomas depressivos e vulnerabilidade são preditores de redução da capacidade funcional em idosos. Objetivo: Comparar o índice de vulnerabilidade, equilíbrio, depressão em idosos praticantes e não praticantes de atividade física após o período de isolamento social na pandemia da Covid-19. Casuística e Métodos: Estudo analítico transversal comparativo, com amostragem não probabilística voluntária de 56 idosos vinculados a um programa comunitário de saúde de uma capital brasileira, sendo 28 participantes do Grupo Fisioterapia (GF) e 28 do Grupo Sedentários (GS), com período de coleta de dados entre agosto a novembro de 2022. Utilizou-se questionários sociodemográficos de autopercepção de saúde e do estado emocional pela Geriatric Depression Scale (GDS-30), de classificação do nível de vulnerabilidade pelo Índice de vulnerabilidade Clínico-Funcional-20 (IVCF-20) e de risco de quedas e avaliação do equilíbrio pelo Timed Up and Go Test (TUG). Resultados: Média de idade de 69,36 ± 6,97 anos com predominância feminina (76,8%). Significância estatística entre grupos para escores GDS-30 e TUG (p=0,03; p<0,01) que evidenciaram depressão moderada em ambos os grupos e risco para quedas no GS. A média do IVCF-20 dos grupos revelou baixo comprometimento quanto à vulnerabilidade. O GF apresentou menores índices em todos os casos. Conclusão: A atividade física mostrou-se um modelo de intervenção que impacta na autonomia e bem-estar dos idosos, com melhores escores de vulnerabilidade, mobilidade funcional e depressão

Elderly are susceptible to severe forms of Covid-19 and this led to social isolation measures that intensified a sedentary lifestyle, with emotional and functional impairment. Primary care must prepare to deal with the repercussions of this period. Risk of falls, screening for depressive symptoms and vulnerability are predictors of reduced functional capacity in the elderly. Objective: To compare the vulnerability index, balance, depression in elderly practitioners and non-practitioners of physical activity after the period of social isolation of the Covid-19 pandemic. Casuistic and Methods: Comparative cross-sectional analytical study, with voluntary nonprobabilistic sampling of 56 elderly people linked to a community health program in a Brazilian capital, with 28 participants in the Physical Therapy Group (GF) and 28 in the Sedentary Group (GS), with a collection period between August and November 2022. Socio-demographic questionnaires were used to assess self-perception of health and emotional state using the Geriatric Depression Scale (GDS-30), classification of vulnerability level using the Clinical-Functional Vulnerability Index-20 (IVCF-20) and risk of falls and assessment of balance by the Timed Up and Go Test (TUG). Results: Mean age of 69.36 ± 6.97 years, with female predominance (76.8%). Statistical significance between groups for GDS-30 and TUG scores (p=0.03; p<0.01), which showed moderate depression in both groups and risk for falls in the GS. The IVCF-20 average of the groups revealed low impairment in terms of vulnerability. The GF had lower rates in all cases. Conclusion: Physical activity proved to be an intervention model that impacts the autonomy and well-being of the elderly, with better vulnerability scores, functional mobility and depression

Virtual Screening and Molecular Docking: Discovering Novel c-KIT Inhibitors.

Gastrointestinal stromal tumors (GISTs) are unusual cancers, which are developed in specialized cells in the gastrointestinal tract wall. Various strategies involving single-agents, combinations, and rapid complementary inhibitor cycling are now being used to control such tumors. Based on promising early clinical trial experience, certain novel KIT and PDGFRA tyrosine kinase inhibitors have shown advanced clinical development. Resistance to tyrosine kinase inhibitors has brought immense difficulties, with patients now requiring additional therapeutic options. This review describes and discusses the last five years (2016-2020) in developing novel c-KIT kinase inhibitors using virtual screening and docking approaches. Computational techniques can be used to complement experimental studies to identify new candidate molecules for therapeutic use. Molecular modeling strategies allow the analysis of the required characteristics that compounds must have to effectively bind c-KIT. Through such analyses, it is possible to both discover and design novel inhibitors against cancer-related proteins that play a critical role in tumor development (including mutant strains). Docking showed potential in the detection of the key residues responsible for ligand recognition and is very helpful to understand the interactions in the active site that can be used to develop new compounds/classes of anticancer drugs and help millions of cancer patients.

Cytomegalovirus reactivation in liver transplant recipients due to hepatitis C cirrhosis is associated with higher cardiovascular risk - an observational, retrospective study.

The association between cytomegalovirus (CMV) reactivation and cardiovascular risk has been reported in solid organ transplant populations; however, it has yet to be assessed in liver transplantation (LT). We aim to evaluate whether CMV reactivation is associated with cardiovascular events (CVE) in HCV-LT patients. LT patients (2010 and 2014) due to HCV cirrhosis were included. Clinically significant CMV (CS-CMV) was defined as viral load (VL) >5000 copies/ml, need of therapy or CMV disease. Baseline variables and endpoint measures (CVE, survival, severe recurrent hepatitis C, de novo tumors, and diabetes) were collected. One hundred and forty patients were included. At LT, a history of AHT was present in 23%, diabetes 22%, tobacco use 45%, obesity 20%, and renal impairment (eGFR < 60 ml/min) in 26.5%. CS-CMV reactivation occurred in 25% of patients. Twenty-six patients (18.5%) developed a CVE. Cox regression analysis revealed two factors significantly associated with CVE: Pre-LT DM [HR = 4.6 95% CI (1.6, 13), P = 0.004] and CS-CMV [HR = 4.7 95% CI (1.8, 12.5), P = 0.002]. CS-CMV was not independently associated with the remaining endpoints except for survival (P = 0.03). In our series, CS-CMV reactivation was associated with a greater risk of developing CVE, thus confirming data from other solid organ transplant populations and emphasizing the need for adequate CMV control.

Reflections and collective production about being a municipal health counselor / Reflexiones y producción colectiva sobre "ser" consejero municipal de salud / Reflexões e produção coletiva sobre o "ser" conselheiro municipal de saúde

ABSTRACT Objective: to identify the participation dynamics of a municipal council and to develop a critical-reflexive process on "being a counselor", identifying weaknesses and possibilities of this council, in addition to collectively generating new knowledge and (re)elaborating the MHC Ordinary Law. Method: Convergent care research, including documentary analysis, non-participant observation and thematic workshops. The research was carried out in 2016, with municipal health counselors from a city in the Western Region of Santa Catarina. Results: this study made it possible to identify forms of social participation that should be strengthened in the performance of social power, to reflect and share individual experiences, to anchor them in the current legislation, and to build knowledge that enabled the elaboration/organization of a product - a new text for the Ordinary Law of the Council, adjusted to current legislation. Final considerations: There is a need to increase participation, considering the presence of the counselors in the meetings, the effective representation and a greater interaction in the discussions and deliberations of the council.

RESUMEN Objetivo: Identificar la dinámica participativa de un consejo municipal de salud mediante el desarrollo de un proceso crítico-reflexivo sobre "ser consejero", señalando las fragilidades y posibilidades de este colegiado, además de generar, colectivamente, nuevos saberes y la (re)elaboración de la Ley Ordinaria del CMS. Método: se trata de una investigación convergente asistencial, incluyendo análisis documental, observación no participante y talleres temáticos. La investigación se llevó a cabo en 2016, con consejeros municipales de salud de un municipio de la Región Oeste de Santa Catarina. Resultados: este estudio permitió compartir y reflexionar acerca de experiencias individuales e identificó diversas formas de participación social que deberían fortalecerse en el ejercicio del control social al insertarlas en la legislación vigente con el intuito de construir conocimientos, lo que posibilitó la elaboración/organización de un producto - readecuación de la Ley Ordinaria del consejo a la legislación vigente. Consideraciones finales: se hace necesario ampliar la participación, considerando la presencia de los consejeros en las reuniones con una representación eficaz y una intervención más amplia en las discusiones y deliberaciones del consejo.

RESUMO Objetivo: Identificar a dinâmica participativa de um conselho municipal de saúde, com o desenvolvimento de processo crítico-reflexivo sobre o "ser conselheiro", apontando fragilidades e possibilidades desse colegiado, além de gerar coletivamente novos saberes e a (re)elaboração da Lei Ordinária do CMS. Método: Pesquisa convergente assistencial, incluindo análise documental, observação não participante e oficinas temáticas. A pesquisa foi em 2016, com conselheiros municipais de saúde de um município da Região Oeste de Santa Catarina. Resultados: Este estudo possibilitou identificar formas de participação social a serem fortalecidas no exercício do controle social, compartilhar e refletir sobre as experiências individuais, ancorá-las na legislação vigente e construir conhecimentos que oportunizaram a elaboração/organização de um produto - readequação da Lei Ordinária do conselho à legislação vigente. Considerações finais: Pontua-se a necessidade de ampliar a participação, considerando a presença dos conselheiros nas reuniões, a representação efetiva e a sua maior interação nas discussões e deliberações do conselho.

Oxidative imbalance in low/intermediate-1-risk myelodysplastic syndrome patients: The influence of iron overload.

OBJECTIVE: To assess the generation of reactive oxygen species (ROS) and the involvement of the main antioxidant pathways in low/intermediate-1-risk myelodysplastic syndromes (MDS) with iron overload (IOL). METHODS: We examined the levels of superoxide anion (O2-), hydrogen peroxide (H2O2), antioxidants (glutathione, GSH; superoxide dismutase, SOD; catalase, CAT; and glutathione peroxidase, GPx), mitochondrial membrane potential (ΔΨm), and by-products of oxidative damage (8-isoprostanes and 8-oxo-7,8-dihydro-2'-deoxyguanosine, 8-oxo-dG) in 42 MDS patients (28 without IOL at diagnosis, and 14 who developed IOL) and 20 healthy subjects. RESULTS: Patients with IOL showed higher O2- levels (39.4 MFI) than normal controls (22.7 MFI, p=0.0356) and patients at diagnosis (19.4 MFI, p=0.0049). Antioxidant systems, except SOD activity, exhibited significant changes in IOL patients with respect to controls (CAT: 7.1 vs 2.7nmol/ml/min, p=0.0023; GPx: 50.9 vs 76.4nmol/ml/min, p=0.0291; GSH: 50.2 vs 24.1 MFI, p=0.0060). Furthermore, mitochondrial dysfunction was only detected in IOL cases compared to controls (ΔΨm: 3.6 vs 6.4 MFI, p=0.0225). Finally, increased levels of 8-oxo-dG were detected in both groups of patients. CONCLUSION: Oxidative stress is an important but non-static phenomenon in MDS disease, whose status is influenced by, among other factors, the presence of injurious iron.

Quem canta seus males espanta: um relato de experiência sobre o uso da música como ferramenta de atuação na promoção da saúde da criança / Sing away sorrow, cast away care: an experience report on the use of music as an instrument for child health promotion / Quién canta sus males espanta: un relato de experiencia sobre el uso de la música como herramienta de actuación en la promoción de la salud del nino

Considerando a importância da música na saúde das pessoas, em especial na infância, em 2014 foi criado o projeto de extensão "Promovendo a saúde da criança através da música e ações educativas", do curso de Enfermagem, da Universidade Federal Fronteira Sul. O objetivo foi promover a saúde da criança a partir da utilização da música, em busca de uma vida saudável, oportunizando a diminuição de tempo ocioso, bem como momentos de aprendizado mútuo, cultural e lazer por meio do canto coral. E após evidenciar resultados positivos no desenvolvimento das atividades, surgiu então esse relato de experiência, com o intuito de compartilhar a experiência do projeto de extensão "Promovendo a saúde da criança através da música e ações educativas". Discutiu-se a atuação da música na promoção da saúde, à luz da literatura já existente, desvelando as contribuições que o canto coral proporciona no desenvolvimento e na saúde das crianças em idade escolar. Constatou-se escassa produção científica sobre a temática na área da enfermagem, bem como a importância de sensibilizar enfermeiros e demais profissionais da saúde para o uso da música na sua prática de assistir o outro e a si próprio.

Considering the importance of music in people's health, especially in children, an extension project was created in 2014, called "Promoting the health of children through music and educational activities" in the nursing department of the Federal University of Fronteira Sul. The aim was to promote childrerís health by using music as a way of seeking a healthy life, providing opportunities to decrease idle time, and to enhance moments of mutual learning, culture and leisure through choral singing. After positive results were obtained in the development of activities, this experience report was developed, with the aim of sharing the experience of the extension project"Promoting the health of children through music and educational activities", discussing the role of music in promoting health, in light of the existing literature, revealing the contributions that the choir provides in the development and health of school children. There is scarce scientfic literature on this subject in the area of nursing, as well as the importance of sensitizing nurses and other healthcare professionals to the use of music in their practice of caring for others and for themselves.

Teniendo en cuenta la importancia de la música en la salud de las personas, especialmente en los ninos, en 2014 fue creado el proyecto de extensión "Promoción de la salud de los ninos a través de la música y las actividades educativas' del curso de Enfermería de la Universidad Federal Fronteira Sul. El proyecto se ha propuesto promover la salud de los ninos mediante el uso de la música en busca de una vida saludable, proporcionando oportunidades para disminuir el tiempo ocioso, así como momentos de aprendizaje mutuo, cultural y de entretenimiento a través del canto. Con este relato de experiencia se ha buscado compartir la experiencia del mencionado proyecto una vez que ha mostrado resultados positivos en el desarrollo de las actividades. Se discute el papel de la música en la promoción la salud, a la luz de la literatura existente, revelando las contribuciones del canto al desarrollo y salud de los ninos en edad escolar. Se ha constatado que hay escasa producción científica sobre el tema en el área de enfermería y se ha comprobado la importancia de sensibilizar a las enfermeras y otros profesionales de la salud para el uso de la música en la atención de los demás y para ellos mismos.

[Ovine abortion associated with toxoplasmosis: serological, anatomo-pathological and immunohistochemistry characterization]. / Aborto em ovinos associado à toxoplasmose: caracterização sorológica, anátomo-patológica e imunoistoquímica.

Ovine toxoplasmosis is a major cause of abortion and placentitis. Lambs with congenital infection are born with encephalitis. Abortions occurred between May and August 2006 in an estate in Três Palmeiras, southern Brazil. This study aimed to assess the frequency of abortion associated with toxoplasmosis among ewes in southern Brazil using indirect hemagglutination and pathoanatomical and immunohistochemical analyses. Blood samples were collected from nine animals for indirect hemagglutination. One fetus underwent necropsy and histopathological and immunohistochemical analyses. Three samples, one of which belonged to the necropsied animals mother, were positive on the serological test. The necropsy revealed pale foci in the liver, lungs with a marbled appearance, heart with severe pallor and brain and cerebellar congestion. Fragments of all organs were collected, fixed in 10% buffered formalin, processed, and stained with hematoxylin-eosin. Microscopically, there were cysts and tachyzoites in the brain in areas of malacia with microgliosis and lymphoplasmacytic infiltration, suggesting toxoplasmic encephalitis. There was also interstitial pneumonia, centrolobular necrosis with structures compatible with tachyzoites, focal lymphocytic myocarditis and acute tubular nephrosis. The immunohistochemical test was positive for Toxoplasma gondii. The results allowed diagnosing the ovine toxoplasmosis.