How Donor and Surgical Factors Affect the Viability and Functionality of Human Hepatocytes Isolated From Liver Resections.

Liver resections are a significant source of primary human hepatocytes used mainly in artificial liver devices and pharmacological and biomedical studies. However, it is not well known how patient-donor and surgery-dependent factors influence isolated hepatocytes' yield, viability, and function. Hence, we aimed to analyze the impact of all these elements on the outcome of human hepatocyte isolation. Patients and methods: Hepatocytes were isolated from liver tissue from patients undergoing partial hepatectomy using a two-step collagenase method. Hepatocyte viability, cell yield, adhesion, and functionality were measured. In addition, clinical and analytical patient variables were collected and the use or absence of vascular clamping and its type (continuous or intermittent) plus the ischemia times during surgery. Results: Malignant disease, previous chemotherapy, and male gender were associated with lower hepatocyte viability and isolation cell yields. The previous increase in transaminases was also associated with lower yields on isolation and lower albumin production. Furthermore, ischemia secondary to vascular clamping during surgery was inversely correlated with the isolated hepatocyte viability. An ischemia time higher than 15 min was related to adverse effects on viability. Conclusion: Several factors correlated with the patient and the surgery directly influence the success of human hepatocyte isolation from patients undergoing liver resection.

Mortality and Causes of Death After Liver Transplantation: Analysis of Sex Differences in a Large Nationwide Cohort.

In the last few years, several studies have analyzed sex and gender differences in liver transplantation (LT), but none have performed a disaggregated analysis of both mortality and causes of death. Data from 15,998 patients, 11,914 (74.5%) males and 4,069 (25.5%) females, transplanted between 2000 and 2016 were obtained from the Liver Transplantation Spanish Registry. Survival analysis was applied to explore recipient sex as a risk factor for death. The causes of death at different follow-up duration were disaggregated by recipient sex for analysis. Short-term survival was higher in males, whereas long-term survival was higher in females. Survival at 1, 5 and 10 years post-transplant was 87.43%, 73.83%, and 61.23%, respectively, in males and 86.28%, 74.19%, and 65.10%, respectively, in females (p = 0.05). Post-LT mortality related to previous liver disease also presented sex differences. Males had 37% increased overall mortality from acute liver failure (p = 0.035) and 37% from HCV-negative cirrhosis (p < 0.001). Females had approximately 16% increased mortality when the liver disease was HCV-positive cirrhosis (p = 0.003). Regarding causes of death, non-malignancy HCV+ recurrence (6.3% vs. 3.9% of patients; p < 0.001), was more frequently reported in females. By contrast, death because of malignancy recurrence (3.9% vs. 2.2% of patients; p = 0.003) and de novo malignancy (4.8% vs. 2.5% of patients; p < 0.001) were significantly more frequent in male recipients. Cardiovascular disease, renal failure, and surgical complications were similar in both. In summary, male patients have lower short-term mortality than females but higher long-term and overall mortality. In addition, the post-LT mortality risk related to previous liver disease and the causes of mortality differ between males and females.

Prevention and Management of Donor-transmitted Cancer After Liver Transplantation: Guidelines From the ILTS-SETH Consensus Conference.

As with any other intervention in health, liver transplantation (LT) entails a variety of risks, including donor-transmitted cancers (DTCs). At present, 2%-4% of used deceased organ donors are known to have a current or past history of malignancy. The frequency of DTCs is consistently reported at 3-6 cases per 10 000 solid organ transplants, with a similar frequency in the LT setting. A majority of DTCs are occult cancers unknown in the donor at the time of transplantation. Most DTCs are diagnosed within 2 y after LT and are associated with a 51% probability of survival at 2 y following diagnosis. The probability of death is greatest for DTCs that have already metastasized at the time of diagnosis. The International Liver Transplantation Society-Sociedad Española de Trasplante Hepático working group on DTC has provided guidance on how to minimize the occurrence of DTCs while avoiding the unnecessary loss of livers for transplantation both in deceased and living donor LT. The group endorses the Council of Europe classification of risk of transmission of cancer from donor to recipient (minimal, low to intermediate, high, and unacceptable), classifies a range of malignancies in the liver donor into these 4 categories, and recommends when to consider LT, mindful of the risk of DTCs, and the clinical condition of patients on the waiting list. We further provide recommendations to professionals who identify DTC events, stressing the need to immediately alert all stakeholders concerned, so a coordinated investigation and management can be initiated; decisions on retransplantation should be made on a case-by-case basis with a multidisciplinary approach.

Changes in severity, mortality, and virus genome among a Spanish cohort of patients hospitalized with SARS-CoV-2.

Comparing pandemic waves could aid in understanding the evolution of COVID-19. The objective of the present study was to compare the characteristics and outcomes of patients hospitalized for COVID-19 in different pandemic waves in terms of severity and mortality. We performed an observational retrospective cohort study of 5,220 patients hospitalized with SARS-CoV-2 infection from February to September 2020 in Aragon, Spain. We compared ICU admissions and 30-day mortality, clinical characteristics, and risk factors of the first and second waves of COVID-19. The SARS-CoV-2 genome was also analyzed in 236 samples. Patients in the first wave (n = 2,547) were older (median age 74 years [IQR 60-86] vs. 70 years [53-85]; p < 0.001) and had worse clinical and analytical parameters related to severe COVID-19 than patients in the second wave (n = 2,673). The probability of ICU admission at 30 days was 16% and 10% (p < 0.001) and the cumulative 30-day mortality rates 38% and 32% in the first and second wave, respectively (p = 0.007). Survival differences were observed among patients aged 60 to 80 years. We also found some variability among death risk factors and the viral genome between waves. Therefore, the two analyzed COVID-19 pandemic waves were different in terms of disease severity and mortality.

A Clinical Decision Web to Predict ICU Admission or Death for Patients Hospitalised with COVID-19 Using Machine Learning Algorithms.

The purpose of the study was to build a predictive model for estimating the risk of ICU admission or mortality among patients hospitalized with COVID-19 and provide a user-friendly tool to assist clinicians in the decision-making process. The study cohort comprised 3623 patients with confirmed COVID-19 who were hospitalized in the SALUD hospital network of Aragon (Spain), which includes 23 hospitals, between February 2020 and January 2021, a period that includes several pandemic waves. Up to 165 variables were analysed, including demographics, comorbidity, chronic drugs, vital signs, and laboratory data. To build the predictive models, different techniques and machine learning (ML) algorithms were explored: multilayer perceptron, random forest, and extreme gradient boosting (XGBoost). A reduction dimensionality procedure was used to minimize the features to 20, ensuring feasible use of the tool in practice. Our model was validated both internally and externally. We also assessed its calibration and provide an analysis of the optimal cut-off points depending on the metric to be optimized. The best performing algorithm was XGBoost. The final model achieved good discrimination for the external validation set (AUC = 0.821, 95% CI 0.787-0.854) and accurate calibration (slope = 1, intercept = -0.12). A cut-off of 0.4 provides a sensitivity and specificity of 0.71 and 0.78, respectively. In conclusion, we built a risk prediction model from a large amount of data from several pandemic waves, which had good calibration and discrimination ability. We also created a user-friendly web application that can aid rapid decision-making in clinical practice.

Estudio de la prevalencia del riesgo de desnutrición en la población mayor de 65 años no institucionalizada atendida en un centro de salud de Barcelona / Study of the prevalence of the risk of malnutrition in the non-institutionalized population over 65 years old attended in a health center in Barcelona

Objetivo: Conocer la prevalencia del riesgo de desnutrición de la población mayor de 65años no institucionalizada, atendida en un centro de salud, y evaluar la versión corta frente a la versión larga del test Mini Nutritional Assessment (MNA) y conocer los factores relacionados con el riesgo de desnutrición. Método: Estudio descriptivo transversal en un equipo de atención primaria de salud en ámbito urbano. Participaron 337 pacientes mayores de 65años atendidos en el centro. La recogida de datos se hizo mediante entrevista personalizada y revisión de la historia clínica. Se administró el MNA (versión corta [MNA-SF] +texto completo [MNA-FT]) y se recogieron variables sociodemográficas y de evaluación funcional (test cognitivos de Pfeiffer y de Lawton y Brody sobre actividades instrumentales de la vida diaria (AIVD) y antecedentes clínicos. Utilizando MNA-FT como gold standard se evaluó la sensibilidad, la especificidad y los valores predictivos de MNA-SF. Los participantes fueron informados de los objetivos del estudio y firmaron el consentimiento informado. El estudio obtuvo el visto bueno del Comité de Ética de referencia. Resultados: Según el MNA-FT la prevalencia fue del 0,6% de desnutrición y del 7,7% de riesgo, sin diferencias según el sexo. La media de edad era superior en los pacientes con desnutrición o riesgo de ella (p=0,016). Se relacionaba con desnutrición tener cuidador (p<0,0001) o mayor grado de dependencia (p<0,0001). El MNA-SF mostró aceptable sensibilidad (67,9%) y buena especificidad (92,6%). Conclusiones: Se observó una baja prevalencia de riesgo de desnutrición entre los pacientes ambulatorios mediante el test MNA. Se recomienda el uso del MNA-FT dada la mejorable sensibilidad mostrada por el MNA-SF, evitando así el consecuente infradiagnóstico. Pacientes con cuidador, mayor dependencia y edad tienen más probabilidad de peor estado nutricional.(AU)

Objective: To know the prevalence of risk of malnutrition in community-dwelling elderly (defined as aged >65) attended in a Primary Care Center, to find the main factors associated to malnutrition risk and to evaluate the Mini Nutritional Assessment Questionnaire (MNA) MNA Short Form vs. MNA Full Test. Method: Design: Cross-Sectional study. Setting: Primary Care Center. Subjects: 337 participants visited in the Community Care Center. Mini Nutritional Assessment Questionnaire (MNA) was applied; sociodemographic and Health variables were collected as well as functional evaluation tests (Short Portable Mental Status Questionnaire and Lawton & Brody Instrumental Activities of Daily Living Scale). Clinical history information was taken from the Medical Records. Using MNA Full Test (MNA-FT) as the gold standard, sensitivity, specificity and predictive values of MNA Short Form (MNA-SF) were evaluated. Results: prevalence according MNA-FT was 0.6% for malnutrition and 7.7% for malnutrition risk. No gender differences were found. The average age was higher in the population with malnutrition or at risk for malnutrition (p=0.016). Significant association of malnutrition with having carer (p<0.0001) or being more dependent (p<0.0001) was found. MNA-SF showed an acceptable sensitivity (67.9%) and good specificity (92.6%). Conclusions: Compared with other studies this data showed a low prevalence of malnutrition risk in community-living elderly using the MNA test. It is recommended to use the MNA-FT in order to avoid under diagnosing malnutrition with MNA-SF.(AU)

Study of the prevalence of the risk of malnutrition in the non-institutionalized population over 65 years old attended in a health center in Barcelona. / Estudio de la prevalencia del riesgo de desnutrición en la población mayor de 65 años no institucionalizada atendida en un centro de salud de Barcelona.

OBJECTIVE: To know the prevalence of risk of malnutrition in community-dwelling elderly (defined as aged >65) attended in a Primary Care Center, to find the main factors associated to malnutrition risk and to evaluate the Mini Nutritional Assessment Questionnaire (MNA) MNA Short Form vs. MNA Full Test. METHOD: Design: Cross-Sectional study. SETTING: Primary Care Center. SUBJECTS: 337 participants visited in the Community Care Center. Mini Nutritional Assessment Questionnaire (MNA) was applied; sociodemographic and Health variables were collected as well as functional evaluation tests (Short Portable Mental Status Questionnaire and Lawton & Brody Instrumental Activities of Daily Living Scale). Clinical history information was taken from the Medical Records. Using MNA Full Test (MNA-FT) as the gold standard, sensitivity, specificity and predictive values of MNA Short Form (MNA-SF) were evaluated. RESULTS: prevalence according MNA-FT was 0.6% for malnutrition and 7.7% for malnutrition risk. No gender differences were found. The average age was higher in the population with malnutrition or at risk for malnutrition (p=0.016). Significant association of malnutrition with having carer (p<0.0001) or being more dependent (p<0.0001) was found. MNA-SF showed an acceptable sensitivity (67.9%) and good specificity (92.6%). CONCLUSIONS: Compared with other studies this data showed a low prevalence of malnutrition risk in community-living elderly using the MNA test. It is recommended to use the MNA-FT in order to avoid under diagnosing malnutrition with MNA-SF.

Cardiovascular morbidity and mortality after liver transplantation: The protective role of mycophenolate mofetil.

Cardiovascular (CV) diseases are recognized longterm causes of death after liver transplantation (LT). The objective of this multicenter study was to analyze the prevalence and the evolution of CV risk factors and CV morbidity and mortality in 1819 LT recipients along 5 years after LT. The influence of baseline variables on survival, morbidity, and mortality was studied. There was a continuous and significant increase of the prevalence of all the CV risk factors (except smoking) after LT. CV diseases were the fourth cause of mortality in the 5 years after LT, causing 12% of deaths during the follow-up. Most CV events (39%) occurred in the first year after LT. Preexisting CV risk factors such as age, pre-LT CV events, diabetes, metabolic syndrome, and hyperuricemia, and mycophenolate-free immunosuppressive therapy, increased post-LT CV morbidity and mortality. The development of new-onset CV risk factors after LT, such as dyslipidemia and obesity, independently affected late CV morbidity and mortality. Tacrolimus and steroids increased the risk of posttransplant diabetes, whereas cyclosporine increased the risk of arterial hypertension, dyslipidemia, and metabolic syndrome. In conclusion, CV complications and CV mortality are frequent in LT recipients. Preexisting CV risk factors, immunosuppressive drugs, but also the early new onset of obesity and dyslipidemia after LT play an important role on late CV complications. A strict metabolic control in the immediate post-LT period is advisable for improving CV risk of LT recipients. Liver Transplantation 23 498-509 2017 AASLD.

How important is donor age in liver transplantation?

The age of liver donors has been increasing in the past several years because of a donor shortage. In the United States, 33% of donors are age 50 years or older, as are more than 50% in some European countries. The impact of donor age on liver transplantation (LT) has been analyzed in several studies with contradictory conclusions. Nevertheless, recent analyses of the largest databases demonstrate that having an older donor is a risk factor for graft failure. Donor age is included as a risk factor in the more relevant graft survival scores, such as the Donor Risk Index, donor age and Model for End-stage Liver Disease, Survival Outcomes Following Liver Transplantation, and the Balance of Risk. The use of old donors is related to an increased rate of biliary complications and hepatitis C virus-related graft failure. Although liver function does not seem to be significantly affected by age, the incidence of several liver diseases increases with age, and the capacity of the liver to manage or overcome liver diseases or external injuries decreases. In this paper, the importance of age in LT outcomes, the role of donor age as a risk factor, and the influence of aging on liver regeneration are reviewed.

Intention-to-treat survival analysis of hepatitis C virus/human immunodeficiency virus coinfected liver transplant: Is it the waiting list?

In human immunodeficiency virus (HIV)/hepatitis C virus (HCV) coinfected patients, the accelerated severity of liver disease, associated comorbidities, and mortality on the waiting list could change the possibility and results of liver transplantation (LT). Intention-to-treat survival analysis (ITTA) can accurately estimate the applicability and efficacy of LT. The primary objective of this study was to compare the survival of patients with HCV with and without HIV infection. We analyzed a cohort of 199 patients with HCV infection enrolled for LT between 1998 and 2015; 17 were also infected with HIV. The patients with HCV/HIV coinfection had higher mortality on the waiting list than those with HCV monoinfection (35.3% versus 4.6%; P < 0.001). ITTA at 1, 3, and 4 years was 75%, 64%, and 57% for HCV monoinfection and 52%, 47%, and 39% for HCV/HIV coinfection, respectively (Wilcoxon test P < 0.05). The ITTA at 1, 3, 6, and 12 months was 96%, 91%, 87%, and 75% for HCV monoinfection and 76%, 70%, 64%, and 52% for HCV/HIV coinfection, respectively (log-rank P < 0.05; Wilcoxon test P < 0.01). A Cox regression analysis was carried out including all variables with predictive value in the univariate analysis, showing that only donor age > 70 years (hazard ratio [HR] = 3.12; P < 0.05), United Network for Organ Sharing status 1 (HR = 10.1; P < 0.01), Model for End-Stage Liver Disease (HR = 1.13; P < 0.001), and HIV coinfection (HR = 2.65; P < 0.05) had independent negative predictive value for survival. In conclusion, our study indicates that HIV coinfection is a factor in mortality prior to transplantation and associated with higher mortality on the waiting list. Liver Transplantation 22 1186-1196 2016 AASLD.

Incubation with dimethyl sulfoxide prior to cryopreservation improves functionality of thawed human primary hepatocytes.

BACKGROUND: Efficient cryopreservation of human hepatocytes is essential for their use in cell therapy. This study investigated the effects of adding melatonin and/or dimethyl sulfoxide (DMSO) to pre-incubation and/or freezing solutions on the viability and function of thawed human hepatocytes. METHODS: Isolated human hepatocytes were pre-incubated for 90 min at 4°C in Williams' Medium E (WEM), WEM containing 5 mM melatonin dissolved in DMSO, or WEM containing the equivalent amount of DMSO (1%). The hepatocytes were frozen in University of Wisconsin solution (UW) and 10% DMSO, with or without 5 mM melatonin. After thawing, viability, plating efficiency, mitochondrial dehydrogenase activity (MTT), and albumin and urea production were analyzed. RESULTS: Viability and plating efficiency were not affected by melatonin or DMSO in pre-incubation media. Unexpectedly, hepatocytes pre-incubated with DMSO had significantly higher MTT (29.7% vs. control, p<0.01), albumin (82.8% vs. control, p<0.05), and urea amounts (26.2% vs. control, p=0.06) than those incubated only with WEM. Hepatocytes pre-incubated in media containing melatonin had amounts between those of cells incubated with DMSO or only with WEM (p<0.05 for MTT and p>0.05 for albumin and urea values). Also, the addition of melatonin to the freezing media did not significantly improve any of the studied parameters (p>0.05). DISCUSSION: Adding 1% DMSO to pre-incubation media prior to the cryopreservation of human hepatocytes preserves hepatocyte function after thawing. These findings could be considered in current hepatocyte cryopreservation protocols.