Progression of valve heart disease in a cohort of patients undergoing renal replacement therapy / Progressão da doença cardíaca valvar em coorte de doentes em terapia renal substitutiva

Abstract Introduction: Cardiovascular disease is an important cause of death among patients with chronic kidney disease (CKD). Valve calcification is a predictor of cardiovascular mortality and coronary artery disease. Objective: To assess heart valve disease frequency, associated factors, and progression in CKD patients. Methods: We conducted a retrospective study on 291 CKD patients at Hospital das Clínicas de Pernambuco. Inclusion criteria were age ≥ 18 with CKD and valve disease, while those on conservative management or with missing data were excluded. Clinical and laboratory variables were compared, and patients were categorized by dialysis duration (<5 years; 5-10 years; >10 years). Statistical tests, including chi-square, Fisher's exact, ANOVA, and Kruskal-Wallis, were employed as needed. Simple and multivariate binary regression models were used to analyze valve disease associations with dialysis duration. Significance was defined as p < 0.05. Results: Mitral valve disease was present in 82.5% (240) of patients, followed by aortic valve disease (65.6%; 86). Over time, 106 (36.4%) patients developed valve disease. No significant association was found between aortic, pulmonary, mitral, or tricuspid valve disease and dialysis duration. Secondary hyperparathyroidism was the sole statistically significant factor for mitral valve disease in the regression model (OR 2.59 [95% CI: 1.09-6.18]; p = 0.031). Conclusion: CKD patients on renal replacement therapy exhibit a high frequency of valve disease, particularly mitral and aortic valve disease. However, no link was established between dialysis duration and valve disease occurrence or progression.

Resumo Introdução: Doenças cardiovasculares são uma causa significativa de morte em pacientes com Doença Renal Crônica (DRC). A calcificação valvar é preditor de mortalidade cardiovascular e doença arterial coronariana. Objetivo: Avaliar a frequência, fatores associados e progressão de valvopatias em pacientes com DRC. Métodos: Coorte retrospectiva com 291 pacientes ambulatoriais no Hospital das Clínicas de Pernambuco. Inclusão: ≥18 anos com DRC e valvopatia; exclusão: tratamento conservador ou dados incompletos. Variáveis clínicas e laboratoriais foram comparadas e categorizadas por tempo de terapia dialítica (TTD): <5 anos, 5-10 anos, >10 anos. Foram aplicados os testes Qui-quadrado, exato de Fisher, ANOVA, Kruskal-Wallis. Associação entre valvopatia e TTD foi avaliada por regressão binária. Significância foi definida como p < 0,05. Resultados: A valvopatia mitral foi encontrada em 82,5% (240) dos casos, seguida da aórtica (65,6%; 86). Houve progressão da doença valvar em 106 (36,4%) pacientes. Não houve associação entre valvopatias aórtica, pulmonar, mitral ou tricúspide e TTD. Hiperparatireoidismo secundário foi a única variável explicativa significativa na regressão para valvopatia mitral (OR 2,59 [IC95%: 1,09-6,18]; p = 0,031). Conclusão: Encontramos alta frequência de valvopatias, especialmente mitral e aórtica, aem pacientes com DRC. Não houve associação entre TTD e valvopatia.

Controversy on the CONVINCE study findings: the PRO take / Controvérsia sobre os achados do estudo CONVINCE: a perspectiva PRO

ABSTRACT The CONVINCE study, recently published in the New England Journal of Medicine, reveals a groundbreaking 23% reduction in the relative risk of all-cause mortality among end-stage kidney patients undergoing high convective volume hemodiafiltration. This significant finding challenges the conventional use of high-flux hemodialysis and offers hope for improving outcomes in chronic kidney disease patients. While some controversies surround the study's findings, including concerns about generalizability and the causes of death, it is essential to acknowledge the study's design and its main outcomes. The CONVINCE study, part of the HORIZON 2020 project, enrolled 1360 patients and demonstrated the superiority of hemodiafiltration in reducing all-cause mortality overall, as well as in specific patient subgroups (elderly, short vintage, non-diabetic, and those without cardiac issues). Interestingly, it was shown that hemodiafiltration had a protective effect against infection, including COVID-19. Future research will address sustainability, dose scaling effects, identification of subgroups especially likely to benefit and cost-effectiveness. However, for now, the findings strongly support a broader adoption of hemodiafiltration in renal replacement therapy, marking a significant advancement in the field.

RESUMO O estudo CONVINCE, publicado recentemente no New England Journal of Medicine, revela uma redução inovadora de 23% no risco relativo de mortalidade por todas as causas entre pacientes renais em estágio terminal submetidos à hemodiafiltração de alto volume de convecção. Esse achado significativo desafia o uso convencional da hemodiálise de alto fluxo e oferece esperança de melhoria dos desfechos em pacientes com doença renal crônica. Embora algumas controvérsias cerquem os achados do estudo, incluindo preocupações sobre a generalização e as causas de óbito, é essencial reconhecer o desenho do estudo e seus principais desfechos. O estudo CONVINCE, parte do projeto HORIZON 2020, inscreveu 1.360 pacientes e demonstrou a superioridade da hemodiafiltração na redução da mortalidade por todas as causas em geral, bem como em subgrupos específicos de pacientes (idosos, HD de curta duração, não diabéticos e aqueles sem problemas cardíacos). Curiosamente, demonstrou-se que a hemodiafiltração teve um efeito protetor contra infecções, incluindo a COVID-19. Pesquisas futuras abordarão sustentabilidade, efeitos de escalonamento da dose, identificação de subgrupos especialmente propensos a se beneficiar e a relação custo-benefício. No entanto, por ora, os achados apoiam fortemente uma adoção mais ampla da hemodiafiltração na terapia renal substitutiva, marcando um avanço significativo na área.

High volume online hemodiafiltration: a global perspective and the Brazilian experience / Hemodiafiltração on-line de alto volume: uma perspectiva global e a experiência brasileira

ABSTRACT Online hemodiafiltration (HDF) is a rapidly growing dialysis modality worldwide. In Brazil, the number of patients with private health insurance undergoing HDF has exceeded the number of patients on peritoneal dialysis. The achievement of a high convection volume was associated with better clinical imprand patient - reported outcomes confirming the benefits of HDF. The HDFit trial provided relevant practical information on the implementation of online HDF in dialysis centers in Brazil. This article aims to disseminate technical information to improve the quality and safety of this new dialysis modality.

RESUMO A hemodiafiltração (HDF) on-line é uma modalidade dialítica em rápido crescimento no mundo. No Brasil, o número de pacientes com planos de saúde privados tratados por HDF já ultrapassa aquele de pacientes em diálise peritoneal. O alcance de um alto volume convectivo associado à redução de desfechos clínicos e do risco de morte confirmam os benefícios da HDF. Dados nacionais do estudo HDFit forneceram informações práticas relevantes sobre a implementação da HDF on-line em clínicas de diálise no Brasil. O objetivo desta publicação é a disseminação de informações técnicas que possam auxiliar na utilização, com qualidade e segurança, dessa nova modalidade dialítica.

Dying with end stage kidney disease: factors associated with place of death on a palliative care program / Fim de vida na doença renal terminal: fatores associados ao local de óbito num programa de cuidados paliativos

Abstract Introduction: End of life care of patients with end-stage kidney disease (ESKD) may be particularly challenging and requires the intervention of a specialized palliative care team (PCT). Objective: To characterize the population of ESKD patients referred to a PCT and evaluate the determinants of planned dying at home. Methods: We performed a retrospective observational cohort study of all patients with ESKD referred to our PCT between January 2014 and December 2021 (n = 60) and further characterized those with previously known ESKD regarding place of death (n = 53). Results: The majority of the patients were female and the median age was 84 years. Half of the patients were on conservative treatment, 43% were on chronic hemodialysis, and the remainder underwent hemodialysis on a trial basis and were subsequently suspended. Of those with previously known ESKD, 18% died at home and neither gender, age, cognition, performance status, comorbidities, CKD etiology, or treatment modality were associated with place of death. Anuria was significantly associated with dying at the hospital as was shorter time from dialysis suspension and death. Although not reaching statistical significance, we found a tendency towards a longer duration of palliative care follow-up in those dying at home. Conclusion: Dying at home is possible in a palliative domiciliary program regardless of age, gender, etiology of CKD, major comorbidities, and treatment modality. Anuria and shorter survival from RRT withdrawal may be limiting factors for planned dying at home. A longer follow-up by palliative care may favor dying at home.

Resumo Introdução: Os cuidados de fim de vida em doentescom doença renal terminal (DRT) podem ser desafiantes e necessitar do apoio de uma equipa especializada em cuidados paliativos (ECP). Objetivo: Caracterizar a população de doentes com DRT encaminhada à ECP e avaliar os determinantes para um fim de vida planeado no domicílio. Métodos: Realizámos um estudo de coorte observacional retrospectivo dos doentes com DRT encaminhados à ECP entre janeiro/2014 e dezembro/2021 (n = 60) e caracterizámos aqueles com DRT previamente conhecida relativamente ao local de fim de vida (n = 53). Resultados: A maioria dos pacientes eram mulheres comidade mediana de 84 anos. Metade dos doentes encontrava-se em tratamento conservador, 43% em hemodiálise crónica e os restantes suspenderam diálise iniciada agudamente. Daqueles com DRT previamente conhecida, 18% morreram em casa. Não foi objetivada associação entre género, idade, cognição, status funcional, comorbilidades, etiologia da DRC ou modalidade de tratamento da DRT e o local de óbito. A anúria e a menor sobrevida após suspensão de diálise associaram-se a um fim de vida no hospital e verificámos uma tendência para o fim de vida em casa nos doentes com mais tempo de acompanhamento pela ECP. Conclusão: O fim de vida no domicílio é possível num programa domiciliário de cuidados paliativos, independentemente de idade, sexo, etiologia da DRC, principais comorbilidades e modalidade de tratamento. A anúria e o menor tempo de sobrevida após suspensão da TRS podem ser fatores limitantes. Um acompanhamento mais longo em cuidados paliativos pode favorecer o fim de vida no domicílio.

Plant-based diets and their effects on the metabolism and survival of chronic renal patients undergoing conservative treatment

Diet therapy in conservative treatment of chronic kidney disease involves protein restriction, but there is not enough evidence to recommend a particular type of protein, whether animal or plant based. However, studies suggest that plant-based diets help reduce the consumption of total and animal protein, reduce the need for nephroprotective drugs, improve complications and bring advantages in terms of disease progression and patient survival. The article considers up-to-date data on the effects of this diet and observed that when low in protein, primarily vegetable and in some cases supplemented with ketoanalogues, it can result in positive clinical outcomes, such as: delay in the decrease in the glomerular filtration rate, lower concentrations of urea, reduction of serum creatinine and phosphorus concentrations, lower metabolic acidosis, higher insulin sensitivity and lower systemic inflammation. As a whole, this dietary pattern may be able to postpone the start of dialysis with less progression of renal insufficiency. Additional research is needed to better characterize this dietary pattern.

La dietoterapia en el tratamiento conservador de la enfermedad renal crónica implica la restricción de proteínas, pero aún no hay pruebas suficientes para recomendar un tipo concreto de proteínas, ya sean animales o vegetales. Sin embargo, los estudios sugieren que las dietas basadas en plantas ayudan a reducir la ingesta de proteínas totales y animales, disminuyen la necesidad de fármacos nefroprotectores, mejoran las complicaciones y presentan ventajas con respecto a la progresión de la enfermedad y la supervivencia de los pacientes. En este artículo se consideran datos actualizados sobre los efectos de esta dieta y se observa que, cuando es hipoproteica, principalmente vegetal y en algunos casos se complementa con cetoanálogos, puede dar lugar a resultados clínicos positivos, como una disminución retardada de la tasa de filtración glomerular, concentraciones más bajas de urea, concentraciones reducidas de creatinina y fósforo séricos, menor acidosis metabólica, mayor sensibilidad a la insulina y menor inflamación sistémica. En conjunto, este patrón dietético tiene el potencial de retrasar el inicio de la diálisis con una menor progresión de la insuficiencia renal. Es necesario seguir investigando para caracterizar mejor este patrón dietético.

Albúmina en cirrosis: perspectiva inflamatoria / Albumin in cirrhosis: inflammatory perspective

La albúmina sérica humana es la proteína más abundante en el plasma, su estructura molecular le confiere estabilidad, pero también flexibilidad para ligar y transportar un amplio rango de moléculas. Su función oncótica es la propiedad más reconocida que la lleva a introducirse en la terapéutica médica como un expansor de volumen. Sin embargo, en los últimos años se le han adicionado funciones con carácter antioxidante, inmunomodulador y de estabilización endotelial, que hacen presumir que su impacto terapéutico está más allá de sus funciones volumétricas. En los últimos años, específicamente en la cirrosis y la falla hepática aguda sobre crónica, se ha tenido un cambio en el paradigma fisiológico, desde una perspectiva netamente hemodinámica hacia una perspectiva inflamatoria, en donde las funciones oncóticas y no oncóticas de la albúmina están alteradas y tienen un carácter pronóstico en estas entidades. Este conocimiento creciente, desde una perspectiva inflamatoria, hace que se fortalezca el uso terapéutico de la albúmina sérica humana desde las indicaciones tradicionales como prevención de la disfunción circulatoria posparacentesis, prevención y tratamiento de lesión renal aguda, hasta las discusiones para administración a largo plazo en pacientes cirróticos con ascitis.

Human serum albumin is the most abundant protein in plasma, with a molecular structure that provides stability while also allowing flexibility to bind and transport a wide range of molecules. Its oncotic function is the most recognized property, leading to its introduction in medical therapy as a volume expander. However, in recent years, additional functions with antioxidant, immunomodulatory, and endothelial stabilization properties have been identified, suggesting that its therapeutic impact extends beyond its volumetric functions. Specifically, in cirrhosis and acute-on-chronic liver failure, there has been a shift in the pathophysiological paradigm from a purely hemodynamic perspective to an inflammatory perspective, where both oncotic and non-oncotic functions of albumin are altered and have prognostic significance in these conditions. This growing understanding from an inflammatory perspective strengthens the therapeutic use of human serum albumin, not only for traditional indications such as the prevention of post-paracentesis circulatory disfunction, prevention and treatment of acute kidney injury, but also for discussions regarding long-term administration in cirrhotic patients with ascites.

Ablação por Cateter para Fibrilação Atrial em Pacientes com Fração de Ejeção do Ventrículo Esquerdo ≤ 45%: Uma Metanálise de Ensaios Clínicos Randomizados / Catheter Ablation for Atrial Fibrillation in Patients with Left Ventricular Ejection Fraction ≤ 45%: A Meta-Analysis of Randomized Controlled Trials

Resumo Fundamento A fibrilação atrial (FA) e a insuficiência cardíaca (IC) coexistem frequentemente, resultando em desfechos adversos. No entanto, permanecem controvérsias quanto à eficácia da ablação por cateter (AC) em pacientes com FA com disfunção ventricular esquerda grave. Objetivos O objetivo deste estudo foi realizar uma metanálise de ensaios prospectivos randomizados e controlados para avaliar a eficácia da AC versus terapia médica (TM) em pacientes com FA com fração de ejeção do ventrículo esquerdo (FEVE) ≤45%. Métodos Procuramos na literatura estudos que comparassem AC com TM em pacientes com FA com FEVE ≤45%. Foi realizada uma metanálise de 7 ensaios clínicos, incluindo 1.163 pacientes com FA e IC. A análise de subgrupo foi realizada com base na FEVE basal. Todos os testes foram bilaterais; apenas o valor p <0,05 foi considerado estatisticamente significativo. Resultados Descobrimos que a AC estava associada a menor mortalidade por todas as causas (taxa de risco: 0,52, IC 95%: 0,37 a 0,72; p<0,01) e maiores melhorias na FEVE (diferença média: 4,80%, IC 95%: 2,29% a 7,31%; p<0,01) em comparação com TM. Os pacientes do grupo AC apresentaram menor risco de hospitalização por IC e recorrência de FA e qualidade de vida significativamente melhor do que aqueles do grupo TM. Os resultados da análise de subgrupo indicaram que pacientes com disfunção ventricular esquerda mais leve melhoraram a FEVE após a ablação de FA (diferença média: 6,53%, IC 95%: 6,18% a 6,88%; p<0,01) em comparação com pacientes com doença mais grave (diferença média : 2,02%, IC 95%: 0,87% a 3,16%; p<0,01). Conclusões Nossa metanálise demonstrou que a AC foi associada a melhorias significativas nos resultados de pacientes com FA com FEVE ≤45%. Além disso, pacientes com FA com disfunção ventricular esquerda mais leve poderiam se beneficiar mais com a AC.

Abstract Background Atrial fibrillation (AF) and heart failure (HF) frequently coexist, resulting in adverse outcomes. However, controversies remain regarding the efficacy of catheter ablation (CA) in AF patients with severe left ventricular dysfunction. Objectives The purpose of this study was to perform a meta-analysis of prospective randomized controlled trials to evaluate the efficacy of CA versus medical therapy (MT) in AF patients with left ventricular ejection fraction (LVEF) ≤45%. Methods We searched the literature for studies that compared CA to MT in AF patients with LVEF ≤45%. A meta-analysis of 7 clinical trials was performed, including 1163 patients with AF and HF. Subgroup analysis was performed based on baseline LVEF. All tests were 2-sided; only the p-value <0.05 was considered statistically significant. Results We found that CA was associated with lower all-cause mortality (risk ratio: 0.52, 95% CI: 0.37 to 0.72; p<0.01) and greater improvements in LVEF (mean difference: 4.80%, 95% CI: 2.29% to 7.31%; p<0.01) compared to MT. Patients in the CA group had a lower risk of HF hospitalization and AF recurrence and a significantly better quality of life than those in the MT group. The results of subgroup analysis indicated that patients with milder left ventricular dysfunction improved LVEF after AF ablation (mean difference: 6.53%, 95% CI: 6.18% to 6.88%; p<0.01) compared to patients with more severe disease (mean difference: 2.02%, 95% CI: 0.87% to 3.16%; p<0.01). Conclusions Our meta-analysis demonstrated that CA was associated with significant improvements in outcomes of AF patients with LVEF ≤45%. Additionally, AF patients with milder left ventricular dysfunction could benefit more from CA.

Research progress on the mechanism of -lactam resistance in group A Streptococci in vivo / 中国当代儿科杂志

-lactams, including penicillin, have been used for over 80 years in the treatment of group A Streptococcus (GAS) infections. Although -lactam-resistant GAS strains have not been identified in vitro tests, clinical treatment failures have been reported since the 1950s. The mechanism underlying the clinical failure of -lactam treatment in GAS infections remains unclear. Previous research has suggested that -lactam resistance in GAS in vivo is associated with reduced drug susceptibility of strains, bacterial inoculation effects, biofilm formation, the effect of coexisting bacteria, bacterial persistence, and bacterial internalization into host cells. This article reviews the main reports on -lactam treatment failure in GAS infections and analyzes the possible mechanisms of -lactam resistance in vivo. The findings aim to contribute to future research and clinical approaches in the field.

Research Progress in the Effect of His-Purkinje Conduction System Pacing on Cardiac Function / 中山大学学报(医学科学版)

Cardiac pacing is an effective treatment for cardiac pacing and conduction dysfunction and severe heart failure. However， the conventional right ventricular pacing may increase the incidences of heart failure and atrial fibrillation， and biventricular pacing has a relatively high non-response rate. As a new technique of physiological pacing， a number of studies in recent years have been conducted to show the stability of pacing parameters and good cardiac synchronization of his-purkinje system pacing. This article reviews the current status of research and progress in the effects of his-purkinje conduction system pacing on cardiac function， so as to provide a theoretical basis for promoting the development of this technology.

Value of serum creatinine-to-cystatin C ratio in assessing the prognosis of hepatitis B virus-related acute-on-chronic liver failure / 临床肝胆病杂志

ObjectiveTo investigate the clinical value of serum creatinine-to-cystatin C ratio （CCR） in evaluating the prognosis of hepatitis B virus-related acute-on-chronic liver failure （HBV-ACLF）. MethodsA retrospective analysis was performed for the clinical data of 130 patients with HBV-ACLF （treatment group） who were hospitalized in Department of Infectious Diseases， The First Affiliated Hospital of Soochow University， from January 2021 to November 2022. According to the treatment outcome， they were divided into survival group with 87 patients and death group with 43 patients； according to the presence or absence of infection， they were divided into infection group with 37 patients and non-infection group with 93 patients. A total of 30 individuals who underwent physical examination during the same period of time were enrolled as control group. Routine blood test results were collected on the day of admission， including white blood cell count， platelet count， neutrophil count， and lymphocyte count； serum creatinine， cystatin C， serum albumin （Alb）， and prothrombin time （PT） were observed on the day of admission and on days 5， 10， and 15 of hospitalization， and related indicators were calculated， including CCR， neutrophil-to-lymphocyte ratio （NLR）， platelet-to-lymphocyte ratio （PLR）， prognostic nutritional index （PNI）， CCR5 （CCR on day 5 after admission）， ΔCCR5 （CCR on day 5 after admission minus CCR on the day of admission）， CCR10 （CCR on day 10 after admission）， ΔCCR10 （CCR on day 10 after admission minus CCR on day 5 after admission）， CCR15 （CCR on day 15 after admission）， and ΔCCR15 （CCR on day 15 after admission minus CCR on day 10 after admission）. The above indicators were compared between the survival group and the death group and between the infection group and the non-infection group. The Mann-Whitney U test was used for comparison of continuous data between two groups， and the Kruskal-Wallis H test was used for comparison between multiple groups. The univariate and multivariate logistic regression analyses were used to investigate the influencing factors for disease prognosis； the receiver operating characteristic （ROC） curve was used to assess the value of CCR in predicting HBV-ACLF death events， and the DeLong test was used for comparison of the area under the ROC curve （AUC）. ResultsThere were significant differences in CCR， NLR， PNI， PT， and Alb at baseline between the treatment group and the healthy control group （all P<0.001）， and there were significant differences in CCR， NLR， and PT between the survival group and the death group on the day of admission （all P<0.05）. Among the 130 patients with HBV-ACLF， there were 25 in the precancerous stage， 48 in the early stage， 32 in the intermediate stage， and 25 in the advanced stage， and there were significant differences in baseline CCR， PLR， and PT between the patients in different stages of HBV-ACLF （all P<0.05）. There were significant differences in ΔCCR5 and NLR between the infection group and the non-infection group （P<0.05）， and there were significant differences in ΔCCR5， CCR10， and CCR15 between the survival group and the death group （all P<0.05）. The multivariate logistic regression analysis showed that ΔCCR5 （odds ratio ［OR］=1.175， 95% confidence interval ［CI］： 1.098‍ — ‍1.256， P<0.001）， NLR （OR=0.921， 95%CI： 0.880‍ — ‍0.964， P<0.001）， and PT （OR=0.921， 95%CI： 0.873‍ — ‍0.973， P=0.003） were independent influencing factors for the prognosis of HBV-ACLF patients. ΔCCR5 had an AUC of 0.774， a sensitivity of 0.687， and a specificity of 0.757， and the AUC of ΔCCR5+PT+NLR was 0.824， which was significantly higher than the AUC of ΔCCR5， NLR， or PT alone （all P<0.05）. ConclusionΔCCR5， NLR， and PT can reflect the condition and prognosis of patients with HBV-ACLF and are independent predictive indicators for death events in patients with HBV-ACLF. The combination ofΔCCR5， PT， and NLR has the best predictive efficiency.

Optimization of non-bioartificial liver technology and research advances in biological artificial liver / 临床肝胆病杂志

Liver failure is a common clinical syndrome with rapid progression and poor prognosis. Currently， there are still limited internal medical treatment methods for liver failure， and artificial liver support therapy is an effective treatment method. Non-bioartificial liver technology is widely used in clinical practice， and clinicians should determine the starting time， mode， and specific parameters of treatment according to the pathophysiological mechanism and dynamic evolution process of the disease， as well as the specific conditions of patients. Compared with non-bioartificial liver， biological artificial liver can better simulate the biological function of liver cells. At present， substantial progress has been made in its core technology， and related clinical studies are being conducted actively， suggesting a vast potential for future development. This article summarizes and discusses the optimization of non-bioartificial liver technology and the advances in biological artificial liver， in order to provide a reference for the clinical application and research of artificial liver technology.

Artificial liver support therapy for patients with pre-liver failure / 临床肝胆病杂志

Liver failure is a common clinical syndrome of severe liver disease with rapid progression and high mortality. Therefore， early intervention in pre-liver failure or “golden window” is of great significance in improving the prognosis of patients. Hepatitis B virus-related acute-on-chronic liver failure and alcohol-related acute-on-chronic liver failure are the main topics of studies on pre-liver failure. This article discusses the pathogenesis of pre-liver failure and artificial liver support therapy， so as to guide the reasonable and affective applications of artificial liver technology in clinical practice， promote related studies， and thereby reduce the mortality rate of patients with liver failure.

Clinical practice and research advances in artificial liver support therapy / 临床肝胆病杂志

Artificial liver support system is one of the important therapies for liver failure， and in recent years， the role of non-bioartificial liver support system in the treatment of liver failure has been gradually recognized， with wide application in non-liver failure diseases. In clinical practice， various factors should be considered to reasonably select the timing and mode of non-bioartificial liver support therapy， and standardized， individualized， and precise treatment and optimal combination of different modes are the trend of the clinical application of artificial liver support therapy. There have been constant improvements in the key techniques of bioartificial liver support system such as seed cell source and bioreactor， and some of them have entered the stage of clinical trial. Although remarkable progress has been made in the clinical practice and research of artificial liver support therapy， there are still many challenges， and it is urgently needed to solve the problems of how to further improve its efficacy and safety through technological innovation and combination optimization and how to obtain higher-level evidence-based medical evidence through high-quality clinical trials.

Mechanism of Cuscutae Semen to Control Premature Ovarian Failure Based on Lipid and Atherosclerosis Pathways / 中国实验方剂学杂志

ObjectiveThe active ingredients， action targets， and signaling pathways of Cuscutae Semen to control premature ovarian failure were initially predicted by network pharmacology and molecular docking techniques， and an animal model of premature ovarian failure was constructed to explore the mechanism of Cuscutae Semen based on lipid and atherosclerosis signaling pathways. MethodThe effective components and corresponding targets of drugs were obtained from Traditional Chinese Medicines Systems Pharmacology Platform （TCMSP）， Swiss Target Prediction， Pharmmapper， and other databases. GeneCards database was used to collect disease-related targets. Venny2.1.0 online tool was used to screen out the intersection targets of drugs and diseases， and STRING database and Cytoscape v3.7.2 software were used to construct the network diagram of "drug-component-target" and protein-protein interaction （PPI）. The gene ontology （GO） and the Kyoto encyclopedia of genes and genomes （KEGG） enrichment analyses of the intersection targets were performed by running the R language script. The molecular docking technology was utilized to dock drug components with targets and visualize some of the docking results. The mice were randomly divided into a blank group， a model group， a Cuscutae Semen group， and an estradiol valerate group， and the ovarian premature failure model was prepared by chronic stress. The blank group and the model group were gavaged with the same amount of normal saline， and the Cuscutae Semen group was given a Cuscutae Semen decoction of 2.6 g·kg-1·d-1. The estradiol valerate group was given an estradiol valerate solution of 0.13 mg·kg-1·d-1. After four weeks， samples were collected， and hematoxylin-eosin （HE） staining was performed to observe the histopathological changes in the ovary. Serum levels of follicle-stimulating hormone （FSH）， luteinizing hormone （LH）， estradiol （E2）， Muller's tube inhibitor/anti-Muller's tube hormone （AMH）， total cholesterol （TC）， high-density lipoprotein cholesterol （HDL-C）， and low-density lipoprotein cholesterol （LDL-C） were determined by enzyme-linked immunosorbent assay （ELISA）. The expression levels of extracellular regulatory protein kinase （ERK）， nuclear transcription factor-κB p65 （NF-κB p65）， nuclear transcription factor-κB suppressor α （IκBα）， interleukin-1β （IL-1β）， IL-6， and tumor necrosis factor-α （TNF-α） were measured by Western blot. ResultA total of 171 targets of Cuscutae Semen for the prevention and treatment of premature ovarian failure were screened， mainly including tumor protein p53 （TP53）， protein kinase B1 （Akt1）， sarcoma （SRC）， tumor necrosis factor （TNF）， epidermal growth factor receptor （EGFR）， etc. KEGG pathway enrichment analysis predicts that Cuscutae Semen is mainly involved in lipid and atherosclerosis， TNF signaling pathway， and TP53 signaling pathway to control premature ovarian failure. The animal experiments show that compared with the premature ovarian failure model group， the Cuscutae Semen group can significantly upregulate AMH， E2， and HDL-C （P<0.05， P<0.01）， significantly downregulate LH， TC， and LDL-C （P<0.01）， greatly reduce IL-1β， IL-6， and TNF-α protein levels， as well as ERK， NF-κB p65， and their phosphorylation levels （P<0.01）. ConclusionCuscutae Semen can regulate hormone levels and improve ovarian function through a multi-component， multi-target， and multi-pathway approach， and the mechanism may be related to the regulation of lipid and atherosclerosis signaling pathways.

Current research status of animal models for acute-on-chronic liver failure / 临床肝胆病杂志

Acute-on-chronic liver failure has complex conditions， rapid progression， and a high mortality rate， and further studies are still needed to clarify its pathogenesis and etiology. The establishment of animal models for acute-on-chronic liver failure can not only provide a good basis for exploring the pathogenesis of acute-on-chronic liver failure， but also provide an experimental basis for clinical treatment. Through a literature review， this article summarizes the methods commonly used to establish the animal models of acute-on-chronic liver failure， including carbon tetrachloride combined with LPS/GaIN， thioacetamide combined with LPS， serum albumin， and bile duct ligation. This article analyzes the characteristics of various animal models， so as to provide documentary and experimental bases for further exploration of more ideal animal models.

Menaquinone-4 exerts a protective effect against carbon tetrachloride-induced acute liver injury in mice by alleviating ferroptosis / 临床肝胆病杂志

ObjectiveTo investigate whether menaquinone-4 （MK-4） can exert a protective effect against carbon tetrachloride （CCl4）-induced acute liver injury （ALI） in mice by alleviating ferroptosis. MethodsAfter adaptive feeding， adult male ICR mice， aged 8 weeks， were divided into Control group， MK-4 group， CCl4 model group （6-hour， 12-hour， and 24-hour）， and MK-4+CCl4 group （6-hour， 12-hour， and 24-hour）， with 6 mice in each group. The mice in the Control group were given intraperitoneal injection of an equal dose of corn oil； the mice in the MK-4 group were given intraperitoneal injection of 40 mg/kg MK-4 solution， followed by an equal dose of corn oil after 1 hour； the mice in the MK-4+CCl4 group （6-hour， 12-hour， and 24-hour） were given intraperitoneal injection of 40 mg/kg MK-4 solution， and after 1 hour， the mice in this group and the CCl4 model group （6-hour， 12-hour， and 24-hour） were given intraperitoneal injection of 0.3 mL/kg CCl4 solution， with samples collected at 6， 12， and 24 hours. HE staining was used to observe the pathological changes of mouse liver； Prussian blue staining was used to observe iron accumulation in liver tissue； a biochemical analyzer was used to measure the serum levels of aspartate aminotransferase （AST） and alanine aminotransferase （ALT）； related kits were used to measure the levels of tissue iron content and the oxidative stress indices malondialdehyde （MDA） and glutathione （GSH） in liver homogenate； RT-PCR was used to measure the expression levels of ferroptosis marker genes （acyl-CoA synthetase long-chain family member 4 ［ACSL4］， prostaglandin-endoperoxide synthase 2 ［PTGS2］， and glutathione peroxidase 4 ［GPX4］） and iron metabolism-related genes （hemojuvelin ［HJV］， transferrin receptor 1 ［TFR1］， and ferroportin ［FPN］）， and Western blot was used to measure the protein expression level of GPX4. A one-way analysis of variance was used for comparison of continuous data between multiple groups， and the least significant difference t-test was used for further comparison between two groups. ResultsIn the aging study， compared with the Control group， the CCl4 model group （6-hour， 12-hour， and 24-hour） had significant increases in liver weight coefficient and the serum levels of ALT and AST （all P<0.05）， and HE staining also showed that liver injury gradually aggravated over time. Meanwhile， compared with the CCl4 model group （6-hour， 12-hour， and 24-hour）， the MK-4+CCl4 （12-hour） group had significant reductions in liver weight coefficient and the serum levels of ALT and AST （all P<0.05）， with a reduction in the necrotic area of liver tissue， and therefore， 12-hour mouse tissue samples were used for detection in the following study. Compared with the Control group， the CCl4 group had a significant increase in MDA and a significant reduction in GSH （both P<0.05）， and compared with the CCl4 group， the MK-4+CCl4 group had a significant reduction in MDA and a significant increase in GSH （both P<0.05）. Compared with the Control group， the CCl4 group had significant increases in the key ferroptosis indices ASCL4 and PTGS2 and a significant reduction in GPX4 （all P<0.05）； compared with the CCl4 group， the MK-4+CCl4 group had significant reductions in the mRNA expression levels of ASCL4 and PTGS2 and a significant increase in the mRNA expression level of GPX4 （all P<0.05）. Western blotting showed that compared with the Control group， the CCl4 group had a significant reduction in the protein expression level of GPX4 （P<0.05）， and compared with the CCl4 group， the MK-4+CCl4 group had a significant increase in the protein expression level of GPX4 （P<0.05）. Prussian blue staining showed that compared with the Control group， the CCl4 group had a significant increase in iron accumulation； after MK-4 intervention， compared with the CCl4 group， the MK-4+CCl4 group had a significant reduction in iron accumulation. As for the measurement of iron metabolism genes in mouse liver， compared with the Control group， the CCl4 group had a significant increase in iron content， significant reductions in the mRNA expression levels of FPN and HJV， and a significant increase in the mRNA expression level of TFR1 （all P<0.05）； after protection with MK-4， there was a significant reduction in iron content， significant increases in the mRNA expression levels of FPN and HJV， and a significant reduction in the mRNA expression level of TFR1 （all P<0.05）. ConclusionMK-4 intervention in advance can alleviate CCl4-induced ALI in mice， possibly by inhibiting ferroptosis and improving the expression of iron metabolism-related genes in mouse liver.

Clinical effect of double plasma molecular adsorption system in treatment of patients with chronic liver failure in high-altitude areas / 临床肝胆病杂志

ObjectiveTo investigate the differences in clinical features and mortality rate between native patients with chronic liver failure （CHF） and migrated patients with CHF after treatment with double plasma molecular adsorption system （DPMAS） in high-altitude areas. MethodsA total of 63 patients with CHF who received DPMAS treatment in the intensive care unit of General Hospital of Tibet Military Command from January 2016 to December 2021 were enrolled， and according to their history of residence in high-altitude areas， they were divided into native group with 29 patients and migrated group with 34 patients. The two groups were compared in terms of baseline data and clinical features before and after DPMAS treatment. The independent-samples t test was used for comparison of normally distributed continuous data between groups， and the paired t-test was used for comparison before and after treatment within each group； the Mann-Whitney U test was used for comparison of non-normally distributed continuous data between groups， and the Wilcoxon signed rank sum test was used for comparison before and after treatment within each group； the chi-square test was used for comparison of categorical data between groups. The Kaplan-Meier method was used to plot survival curves， and the Log-rank test was used for comparison of the risk of death. ResultsCompared with the native group， the migrated group had a significantly higher proportion of Chinese Han patients （χ2=41.729， P<0.001）， and compared with the migrated group， the native group had a significantly longer duration of the most recent continuous residence in high-altitude areas （Z=3.364， P<0.001）. Compared with the native group， the migrated group had significantly higher MELD score and incidence rates of hepatic encephalopathy， hepatorenal syndrome， and gastrointestinal bleeding （Z=2.318， χ2=6.903， 5.154， and 6.262， all P<0.05）. Both groups had significant changes in platelet count （PLT）， hemoglobin count （HGB）， alanine aminotransferase （ALT）， aspartate aminotransferase （AST）， albumin， total bilirubin （TBil）， direct bilirubin （DBil）， lactate dehydrogenase （LDH）， creatinine （Cr）， and international normalized ratio （INR） after DPMAS treatment （all P<0.05）. Before DPMAS treatment， compared with the native group， the migrated group had significantly higher levels of ALT， AST， TBil， DBil， LDH， Cr， BUN， and INR （all P<0.05） and a significantly lower level of HGB （P<0.05）； after DPMAS treatment， compared with the native group， the migrated group had significantly greater reductions in PLT and HGB （both P<0.05） and still significantly higher levels of ALT， AST， TBil， DBil， LDH， BUN， and INR （all P<0.05）. The 60-day mortality rate of patients after DPMAS treatment was 52.5% （95% confidence interval ［CI］： 41.7 — 63.8） in the native group and 81.3% （95%CI： 77.9 — 85.6） in the migrated group. Compared with the native group （hazard ratio ［HR］=0.47， 95%CI： 0.23 — 0.95）， the migrated group had a significant increase in the risk of death on day 60 （HR=2.14， 95%CI： 1.06 — 4.32， P=0.039）. ConclusionCompared with the native patients with CHF in high-altitude areas， migrated patients have a higher degree of liver impairment， a lower degree of improvement in liver function after DPMAS treatment， and a higher mortality rate. Clinical medical staff need to pay more attention to migrated patients with CHF， so as to improve their survival rates.

Application of FMEA model and 6S management method in reducing dispensing errors in PIVAS of children’s hospitals / 中国药房

OBJECTIVE To reduce dispensing errors in pharmacy intravenous admixture service （PIVAS） of children’s hospitals. METHODS The risk of dispensing procedures in our PIVAS was identified by applying failure mode and effect analysis （FMEA） model. Potential failure modes that might lead to dispensing errors in each link were determined， and failure causes were analyzed. The severity， incidence and detection degree of potential failure modes were quantitatively scored， and their risk priority number （RPN） was calculated to screen failure modes that needed to be improved in priority； the corresponding improvement measures were developed by 6S management method from six aspects， namely， finishing （seiri）， rectifying （seiton）， sweeping （seiso）， sanitation （seiketsu）， literacy （shitsuke） and safety. The effect of intervention before and after rectification was evaluated. RESULTS Based on the RPN， 32 potential failure modes were selected， of which a total of 18 critical failure modes that needed to be improved in priority. After implementing corresponding measures according to 6S management method， the RPN of 18 critical failure modes decreased. The total RPN decreased from 497 to 142 with a decrease rate of 71.43%. The error rates of 15 critical failure modes were significantly lower than before implementation （P＜0.05）. CONCLUSIONS Applying FMEA model and 6S management method to the risk control of all aspects of PIVAS workflow can effectively reduce the risk of PIVAS dispensing errors and ensure the safety of children’s intravenous medication.

Effect of Yixintai on Mitochondrial Fission Proteins Fis1 and Mff in Rat Model of Chronic Heart Failure / 中国实验方剂学杂志

ObjectiveTo study the effect and mechanism of Yixintai on mitochondrial fission proteins in the rat model of chronic heart failure. MethodTen of 60 SD rats were randomly selected as the sham operation group， and the remaining 50 rats were subjected to ligation of the left anterior descending coronary artery for the modeling of heart failure post myocardial infarction. The successfully modeled rats were randomized into model， low-， medium-， and high-dose （1.4， 2.8， and 5.6 g·kg-1， respectively） Yixintai， and trimetazidine （10 mg·kg-1） groups. The rats were administrated with corresponding doses of drugs by gavage， and the rats in the model group and sham operation group were given an equal volume of normal saline by gavage for 28 consecutive days. Enzyme-linked immunosorbent assay （ELISA） was then employed to measure the levels of amino-terminal pro-B-type natriuretic peptide （NT-pro BNP）， B-type natriuretic peptide （BNP）， and adenosine triphosphate （ATP） in the serum. Color Doppler ultrasound imaging was conducted to examine the cardiac function indicators. Hematoxylin-eosin staining and Masson staining were conducted to observe the pathological changes in the heart， and Image J was used to calculate collagen volume fraction （CVF）. Transmission electron microscopy was employed to observe the ultrastructural changes of myocardial cells. Terminal-deoxynucleoitidyl transferase-mediated nick-end labeling （TUNEL） was employed to measure the apoptosis rate of myocardial cells. Western blot was employed to determine the protein levels of mitochondrial fission protein 1 （Fis1） and mitochondrial fission factor （Mff） in the outer mitochondrial membrane of the myocardial tissue. ResultCompared with the sham operation group， the model group showed elevated levels of NT-pro BNP and BNP in the serum， decreased ATP content， left ventricular ejection fraction （LVEF）， and left ventricular fraction shortening （LVFS）， increased left ventricular end-diastolic diameter （LVIDd） and left ventricular end-systolic diameter （LVIDs）， disarrangement of myocardial cells， inflammatory cell infiltration， increased collagen fibers and CVF， damaged myocardium and mitochondria， and increased apoptosis rate of myocardial cells， and up-regulated expression of Fis1 and Mff in the cardiac tissue （P<0.01）. Compared with the model group， different doses of Yixintai and trimetazidine lowered the serum levels of NT-pro BNP and BNP （P<0.05）， increased the ATP content （P<0.05）， increased LVEF and LVFS （P<0.01）， decreased LVIDd and LVIDs （P<0.01）. Moreover， the drugs alleviated the myocardial inflammatory damage and fibrosis， reduced CVF （P<0.01）， repaired the myocardial mitochondrial structure， and decreased the apoptosis rate of myocardial cells （P<0.01）. Medium- and high-dose Yixintai and trimetazidine down-regulated the expression of Fis1 and Mff in the myocardial tissue （P<0.05）. ConclusionYixintai can improve mitochondrial structure， reduce myocardial cell apoptosis， and improve cardiac function by inhibiting the expression of Fis1 and Mff in the myocardial tissue.