Outcomes after liver transplantation using deceased after circulatory death donors: A comparison of outcomes in the UK and the US.

BACKGROUND AND AIMS: Identifying international differences in utilization and outcomes of liver transplantation (LT) after donation after circulatory death (DCD) donation provides a unique opportunity for benchmarking and population-level insight. METHODS: Adult (≥18 years) LT data between 2008 and 2018 from the UK and US were used to assess mortality and graft failure after DCD LT. We used time-dependent Cox-regression methods to estimate hazard ratios (HR) for risk-adjusted short-term (0-90 days) and longer-term (90 days-5 years) outcomes. RESULTS: One-thousand five-hundred-and-sixty LT receipts from the UK and 3426 from the US were included. Over the study period, the use of DCD livers increased from 15.7% to 23.9% in the UK compared to 5.1% to 7.6% in the US. In the UK, DCD donors were older (UK:51 vs. US:33 years) with longer cold ischaemia time (UK: 437 vs. US: 333 min). Recipients in the US had higher Model for End-stage Liver Disease (MELD) scores, higher body mass index, higher proportions of ascites, encephalopathy, diabetes and previous abdominal surgeries. No difference in the risk-adjusted short-term mortality or graft failure was observed between the countries. In the longer-term (90 days-5 years), the UK had lower mortality and graft failure (adj.mortality HR:UK: 0.63 (95% CI: 0.49-0.80); graft failure HR: UK: 0.72, 95% CI: 0.58-0.91). The cumulative incidence of retransplantation was higher in the UK (5 years: UK: 11.9% vs. 4.6%; p < .001). CONCLUSIONS: For those receiving a DCD LT, longer-term post-transplant outcomes in the UK are superior to the US, however, significant differences in recipient illness, graft quality and access to retransplantation were seen between the two countries.

Use of allopathic and complementary medicine for preventing SARS-CoV-2 infection in Mexican adults: A national survey.

BACKGROUND: The aim of this study was to assess the frequency of allopathic and complementary medicine use for preventing the infection with SARS-CoV-2 in Mexico. A descriptive and cross-sectional study was conducted using an online questionnaire among general adult population (n = 16,724) of the 32 Mexican states from March to November 2020. METHODS: The factors associated with the use, self-medication practice, and adverse reactions due the consumption of allopathic and complementary medicine to prevent infection with SARS-CoV-2 virus were assessed using a structured questionnaire. The suspected adverse reactions associated with the use of drugs or complementary medicine were reported. RESULTS: The prevalence (42.9%) of allopathic and/or complementary medicine use for preventing SARS-CoV-2 infection was mainly associated with unemployment [OR:2.026 (1.722-2.283)]. Acetaminophen (n = 2272) and vitamin C (n = 3252) were the main allopathic and complementary medicine products used to prevent SARS-CoV-2 infection, respectively. The prevalence of self-medication and adverse reactions was 35.3% and 4.8%, respectively. Self-medication [OR:1.930 (1.633-2.282)] and adverse reactions [OR:2.603 (2.015-3.363)] were mainly associated with individuals of low socioeconomic status. Hydroxychloroquine (21.2%) and chloroquine (15.2%) showed the highest prevalence of adverse reactions, which were mainly related to gastrointestinal disorders. CONCLUSION: The use of medications and complementary medicine to prevent SARS-CoV-2 infection is prevalent (almost one-half of the respondents) among Mexican population, and it is mainly associated with unemployment. Self-medication and the adverse reactions derived from self-medication are also prevalent and seem to be influenced by low socioeconomic status.

Interaction between tacrolimus, MELD score and acute kidney injury after liver transplantation. Analysis on a large contemporary bicenter meld-era series.

BACKGROUND: Acute kidney injury (AKI) after liver transplantation (LT) is a common problem with complex management. The aims were to analyze the profile of AKI-RIFLE categories in the post-transplant setting of a wide multicentre cohort of patients in the MELD era and to specifically determine the effect of tacrolimus-based (TACRO) immunosuppressive regimes on the development of AKI. METHODS: A retrospective analysis of 550 (2007-2012) consecutive patients transplanted at Reina Sofia, Cordoba, and King's College Hospital, London, was performed. Inclusion criterion was to have CNI as part of initial immunosuppression immediately after LT. RESULTS: After exclusion criteria, a total of 477 patients were analyzed. Incidence of AKI within the first 2 weeks after LT was 65.8% (AKI-Risk), 41.3% (AKI-Injury), and 12.3% (AKI-Failure). The development of any type of AKI had no impact on short- and/or long-term survival up to 3 years after the transplant. Moreover, AKI was almost universal in the early post-transplant period and TACRO trough concentrations during the first 2 weeks after the transplant were not predictors of AKI in none of its categories in the multivariate analyses. CONCLUSIONS: Low-TACRO-based regimes were not as useful as expected in the prevention of AKI when analyzed in the context of a large contemporary LT series.

Is size the only determinant of delayed abdominal closure in pediatric liver transplant?

The aim was to determine the factors associated with the use of delayed abdominal closure in pediatric liver transplantation (LT) and whether this affected outcome. From a prospectively maintained database, transplants performed in children (≤18 years) were identified (October 2010 to March 2015). Primary abdominal closure was defined as mass closure performed at time of transplant. Delayed abdominal closure was defined as mass closure not initially performed at the same time as transplant; 230 children underwent LT. Of these, 176 (76.5%) had primary closure. Age was similar between the primary and delayed groups (5.0 ± 4.9 versus 3.9 ± 5.0 years; P = 0.13). There was no difference in the graft-to-recipient weight ratio (GRWR) in the primary and delayed groups (3.4 ± 2.8 versus 4.1 ± 2.1; P = 0.12). Children with acute liver failure (ALF) were more likely to experience delayed closure then those with chronic liver disease (CLD; P < 0.001). GRWR was similar between the ALF and CLD (3.4 ± 2.4 versus 3.6 ± 2.7; P = 0.68). Primary closure children had a shorter hospital stay (P < 0.001), spent fewer days in pediatric intensive care unit (PICU; P = 0.001), and required a shorter duration of ventilation (P < 0.001). Vascular complications (arterial and venous) were similar (primary 8.2% versus delayed 5.6%; P = 0.52). Graft (P = 0.42) and child survival (P = 0.65) in the primary and delayed groups were similar. Considering timing of mass closure after transplant, patients in the early delayed closure group (<6 weeks) were found to experience a shorter time of ventilation (P = 0.03) and in PICU (P = 0.003). In conclusion, ALF was the main determinant of delayed abdominal closure rather than GRWR. The optimal time for delayed closure is within 6 weeks. The use of delayed abdominal closure does not adversely affect graft/child survival. Liver Transplantation 23 352-360 2017 AASLD.

Fetal alpha 5-reductase Val89Leu mutation is associated with late miscarriage.

The present study was undertaken to determine the role of different polymorphisms affecting the testosterone/oestrogen pathway in miscarriage. Alpha 5-reductase (SRD5A2) rs523349 and rs9282858, cytochrome P450 aromatase (CYP19A1) rs4646, rs10046 and rs2236722 and oestrogen receptor (ESR1) rs9340799, rs2234693 and rs6932902 polymorphisms were selected. The case group consisted of 94 samples of formalin-fixed and paraffin-embedded fetal tissue from a miscarriage at ≤24 weeks. The control group comprised a population of 331 young healthy subjects. Only those single nucleotide polymorphisms (SNPs) fitting the Hardy-Weinberg equilibrium (n = 4) and euploid miscarriage samples (n = 67) were included for downstream analysis. Interestingly, SRD5A2 rs523349 (Val89Leu) was significantly associated with the risk of undergoing miscarriage after Bonferroni correction (odds ratio = 11.245, P < 2.2 × 10-9). Moreover, when Mantel-Cox regression analysis was performed, we observed that the effect was significantly constrained to the second trimester (P = 0.024, log rank). These results are compatible with an imbalance of testosterone/dihydrotestosterone, associated with a higher risk of miscarriage, especially in late pregnancy.

Centenarians and their hearts: A prospective registry with comprehensive geriatric assessment, electrocardiogram, echocardiography, and follow-up.

BACKGROUND: Data on the cardiac characteristics of centenarians are scarce. Our aim was to describe electrocardiogram (ECG) and echocardiography in a cohort of centenarians and to correlate them with clinical data. METHODS: We used prospective multicenter registry of 118 centenarians (28 men) with a mean age of 101.5±1.7 years. Electrocardiogram was performed in 103 subjects (87.3%) and echocardiography in 100 (84.7%). All subjects underwent a follow-up for at least 6 months. RESULTS: Centenarians with abnormal ECG were less frequently females (72% vs 93%), had higher rates of previous consumption of tobacco (14% vs 0) and alcohol (24% vs 12%), and scored lower in the perception of health status (6.8±2.0 vs 8.3±6.8). Centenarians with significant abnormalities in echocardiography were less frequently able to walk 6 m (33% vs 54%). Atrial fibrillation/flutter was found in 27 subjects (26%). Mean left ventricular (LV) ejection fraction was 60.0±10.5%. Moderate or severe aortic valve stenosis was found in 16%, mitral valve regurgitation in 15%, and aortic valve regurgitation in 13%. Diastolic dysfunction was assessed in 79 subjects and was present in 55 (69.6%). Katz index and LV dilation were independently associated with the ability to walk 6 m. Age, Charlson and Katz indexes, and the presence of significant abnormalities in echocardiography were associated with mortality. CONCLUSIONS: Centenarians have frequent ECG alterations and abnormalities in echocardiography. More than one fifth has atrial fibrillation, and most have diastolic dysfunction. Left ventricular dilation was associated with the ability to walk 6 m. Significant abnormalities in echocardiography were associated with mortality.

A score model for the continuous grading of early allograft dysfunction severity.

Early allograft dysfunction (EAD) dramatically influences graft and patient outcomes. A lack of consensus on an EAD definition hinders comparisons of liver transplant outcomes and management of recipients among and within centers. We sought to develop a model for the quantitative assessment of early allograft function [Model for Early Allograft Function Scoring (MEAF)] after transplantation. A retrospective study including 1026 consecutive liver transplants was performed for MEAF score development. Multivariate data analysis was used to select a small number of postoperative variables that adequately describe EAD. Then, the distribution of these variables was mathematically modeled to assign a score for each actual variable value. A model, based on easily obtainable clinical parameters (ie, alanine aminotransferase, international normalized ratio, and bilirubin) and scoring liver function from 0 to 10, was built. The MEAF score showed a significant association with patient and graft survival at 3-, 6- and 12-month follow-ups. Hepatic steatosis and age for donors; cold/warm ischemia times and postreperfusion syndrome for surgery; and intensive care unit and hospital stays, Model for End-Stage Liver Disease and Child-Pugh scores, body mass index, and fresh frozen plasma transfusions for recipients were factors associated significantly with EAD. The model was satisfactorily validated by its application to an independent set of 200 patients who underwent liver transplantation at a different center. In conclusion, a model for the quantitative assessment of EAD severity has been developed and validated for the first time. The MEAF provides a more accurate graft function assessment than current categorical classifications and may help clinicians to make early enough decisions on retransplantation benefits. Furthermore, the MEAF score is a predictor of recipient and graft survival. The standardization of the criteria used to define EAD may allow reliable comparisons of recipients' treatments and transplant outcomes among and within centers.

Metabolomics discloses donor liver biomarkers associated with early allograft dysfunction.

BACKGROUND & AIMS: Early allograft dysfunction (EAD) dramatically influences graft and patient outcome after orthotopic liver transplantation and its incidence is strongly determined by donor liver quality. Nevertheless, objective biomarkers, which can assess graft quality and anticipate organ function, are still lacking. This study aims to investigate whether there is a preoperative donor liver metabolomic biosignature associated with EAD. METHODS: A comprehensive metabolomic profiling of 124 donor liver biopsies collected before transplantation was performed by mass spectrometry coupled to liquid chromatography. Donor liver grafts were classified into two groups: showing EAD and immediate graft function (IGF). Multivariate data analysis was used to search for the relationship between the metabolomic profiles present in donor livers before transplantation and their function in recipients. RESULTS: A set of liver graft dysfunction-associated biomarkers was identified. Key changes include significantly increased levels of bile acids, lysophospholipids, phospholipids, sphingomyelins and histidine metabolism products, all suggestive of disrupted lipid homeostasis and altered histidine pathway. Based on these biomarkers, a predictive EAD model was built and further evaluated by assessing 24 independent donor livers, yielding 91% sensitivity and 82% specificity. The model was also successfully challenged by evaluating donor livers showing primary non-function (n=4). CONCLUSIONS: A metabolomic biosignature that accurately differentiates donor livers, which later showed EAD or IGF, has been deciphered. The remarkable metabolomic differences between donor livers before transplant can relate to their different quality. The proposed metabolomic approach may become a clinical tool for donor liver quality assessment and for anticipating graft function before transplant.

Diaphragmatic hernia after liver transplantation in children: case series and review of the literature.

A diaphragmatic hernia (DH) is a rare complication of pediatric liver transplantation (LT), with multiple factors implicated in the pathophysiology. It is a potentially life-threatening condition in the absence of early recognition and surgical treatment. A DH after LT has been reported in 16 patients in 7 case series. We report 10 cases from our institution and review the published literature to understand the underlying pathophysiology. The study sample included all children (<18 years of age) who underwent LT from October 1989 to August 2013 at our center and subsequently presented with a DH. Among 4433 LT procedures performed in this time period, 1032 were for children. Ten DH cases were recognized, and risk factors were assessed. The mean age at diagnosis was 4.9 years, all patients with a DH received left lateral segment split grafts, and the mean graft weight was 248 ± 41 g with a mean graft-to-recipient body weight ratio (GBWR) of 3% ± 1.22% (range = 1.7%-5.0%). The mean cold ischemia time was 510.7 ± 307.6 minutes (range = 60-900 minutes). Six patients had a primary abdominal muscle closure, 3 had a temporary Silastic mesh closure, and 1 had a skin closure only. Postoperative ascites and pleural effusion did not appear to be significant risk factors. All 10 children presented with a right posterolateral DH, with 1 also having a left DH. The small bowel was herniated in the majority. All patients underwent prompt surgical intervention without complications. An early age, a split graft, and a high GBWR may be risk factors for a DH. A high index of suspicion and prompt surgical intervention minimize complications.

[Current status and future perspectives of hepatocyte transplantation]. / Estado actual y perspectivas futuras del trasplante de hepatocitos.

The imbalance between the number of potential beneficiaries and available organs, originates the search for new therapeutic alternatives, such as Hepatocyte transplantation (HT).Even though this is a treatment option for these patients, the lack of unanimity of criteria regarding indications and technique, different cryopreservation protocols, as well as the different methodology to assess the response to this therapy, highlights the need of a Consensus Conference to standardize criteria and consider future strategies to improve the technique and optimize the results.Our aim is to review and update the current state of hepatocyte transplantation, emphasizing the future research attempting to solve the problems and improve the results of this treatment.

Self-treatment and adverse reactions with herbal products for treating symptoms associated with anxiety and depression in adults from the central-western region of Mexico during the Covid-19 pandemic.

ETHNOPHARMACOLOGICAL RELEVANCE: There are plant species used in the Mexican traditional medicine for the empirical treatment of anxiety and depression. AIM OF THE STUDY: This work assessed the prevalence of self-medication with medicinal plants and the prevalence of the concomitant use of prescribed psychiatric drugs and medicinal plants for treating symptoms associated with anxiety and depression during the Covid-19 lockdown in Mexico. MATERIALS AND METHODS: The suspected adverse reactions associated with drug-herb interactions were assessed. The factors associated with self-medication, the concomitant use of herb-drug combinations, and the presence of adverse reactions due their combined use is also reported. The study was descriptive and cross-sectional using an online questionnaire conducted among population with symptoms associated with anxiety and depression (n = 2100) from seven states of central-western Mexico. RESULTS: The prevalence of the use of herbs (61.9%) and the concomitant use of drug-herb combinations (25.3%) were associated with being diagnosed with mental illness [OR:2.195 (1.655-2.912)] and the use of psychiatric medications [OR:307.994 (178.609-531.107)], respectively. The presence of adverse reactions (n = 104) by the concomitant use of drug-herb combinations was associated with being unemployed [p = 0.004, OR: 3.017 (1.404-6.486)]. CONCLUSION: Health professionals should be aware if their patients concomitantly use medicinal plants and psychiatric drugs. Public health campaigns should promote the possible adverse reactions that might produce the concomitant use of drug-herb combinations for mental illnesses.

[Epithelioid hemangioendothelioma: an uncommon liver tumor]. / Hemangioendotelioma epitelioide: un tumor hepatico infrecuente.

We report the case of a female patient who was referred to our unit because of a solid liver tumor, suggestive of metastasis. After biopsy, the patient was diagnosed with epithelioid hemangioendothelioma of the liver. Epithelioid hemangioendothelioma is a rare entity with an unpredictable, potentially fatal, clinical course and outcome. Due to its rarity, this entity should be considered when a solitary hepatic lesion is detected and should be included in the differential diagnosis with liver metastases. We highlight the infrequency of this tumor, its presentation as a solitary hepatic lesion and the indication of surgical treatment. We describe the clinical and pathological characteristics of epithelioid hemangioendothelioma of the liver and report a new case of this entity. The distinct therapeutic options are discussed.

[Hepatic cell transplantation: a new therapy in liver diseases]. / Trasplante celular hepático: un nuevo tratamiento en las enfermedades hepáticas.

Liver transplantation has been remarkably effective in the treatment in patients with end-stage liver disease. However, disparity between solid-organ supply and increased demand is the greatest limitation, resulting in longer waiting times and increase in mortality of transplant recipients. This situation creates the need to seek alternatives to orthotopic liver transplantation.Hepatocyte transplantation or liver cell transplantation has been proposed as the best method to support patients. The procedure consists of transplanting individual cells to a recipient organ in sufficient quantity to survive and restore the function. The capacity of hepatic regeneration is the biological basis of hepatocyte transplantation. This therapeutic option is an experimental procedure in some patients with inborn errors of metabolism, fulminant hepatic failure and acute and chronic liver failure, as a bridge to orthotopic liver transplantation. In the Hospital La Fe of Valencia, we performed the first hepatocyte transplantation in Spain creating a new research work on transplant program.

Anaesthetic management of organ transplant patients.

In this paper we will describe anaesthetic management of solid organ and reconstructive transplantation (RT) patients. We will focus on similar underlying principles of reperfusion, ischaemic-reperfusion injury, preconditioning and extracorporeal donor organ preservation. Special concerns for anaesthetic management of these patients need to focus on pre-assessment, pre-operative optimisation, vascular access, fluid management, blood and products replacement, cardiovascular monitoring, use of inotropes and vasoconstrictors, maintaining electrolyte balance and regional anaesthesia. Despite the complexity and long duration of transplant procedures, fast-tracking to the surgical ward after transplantation is becoming more popular and its benefits are well recognised.

Liver transplantation in children: state of the art and future perspectives.

In this review, we provide a state of the art of liver transplantation in children, as the procedure is now carried out for more than 30 years and most of our paediatric colleagues are managing these patients jointly with liver transplant centres. Our goal for this article is to enhance the understanding of the liver transplant process that a child and his family goes through while explaining the surgical advances and the associated complications that could happen in the immediate or long-term follow-up. We have deliberately introduced the theme that 'liver transplant is a disease' and 'not a cure', to emphasise the need for adherence with immunosuppression, a healthy lifestyle and lifelong medical follow-up.

An in silico argument for mitochondrial microRNA as a determinant of primary non function in liver transplantation.

Mitochondria have their own genomic, transcriptomic and proteomic machinery but are unable to be autonomous, needing both nuclear and mitochondrial genomes. The aim of this work was to use computational biology to explore the involvement of Mitochondrial microRNAs (MitomiRs) and their interactions with the mitochondrial proteome in a clinical model of primary non function (PNF) of the donor after cardiac death (DCD) liver. Archival array data on the differential expression of miRNA in DCD PNF was re-analyzed using a number of publically available computational algorithms. 10 MitomiRs were identified of importance in DCD PNF, 7 with predicted interaction of their seed sequence with the mitochondrial transcriptome that included both coding, and non coding areas of the hypervariability region 1 (HVR1) and control region. Considering miRNA regulation of the nuclear encoded mitochondrial proteome, 7 hypothetical small proteins were identified with homolog function that ranged from co-factor for formation of ATP Synthase, REDOX balance and an importin/exportin protein. In silico, unconventional seed interactions, both non canonical and alternative seed sites, appear to be of greater importance in MitomiR regulation of the mitochondrial genome. Additionally, a number of novel small proteins of relevance in transplantation have been identified which need further characterization.

Hepatocyte transplantation program: Lessons learned and future strategies.

This review aims to share the lessons we learned over time during the setting of the hepatocyte transplantation (HT) program at the Hepatic Cell Therapy Unit at Hospital La Fe in Valencia. New sources of liver tissue for hepatocyte isolation have been explored. The hepatocyte isolation and cryopreservation procedures have been optimized and quality criteria for assessment of functionality of hepatocyte preparations and suitability for HT have been established. The results indicate that: (1) Only highly viable and functional hepatocytes allow to recover those functions lacking in the native liver; (2) Organs with steatosis (≥ 40%) and from elderly donors are declined since low hepatocyte yields, viability and cell survival after cryopreservation, are obtained; (3) Neonatal hepatocytes are cryopreserved without significant loss of viability or function representing high-quality cells to improve human HT; (4) Cryopreservation has the advantage of providing hepatocytes constantly available and of allowing the quality evaluation and suitability for transplantation; and (5) Our results from 5 adults with acute liver failure and 4 from children with inborn metabolic diseases, indicate that HT could be a very useful and safe cell therapy, as long as viable and metabolically functional human hepatocytes are used.

Does Donation After Cardiac Death Utilization Adversely Affect Hepatocellular Cancer Survival?

BACKGROUND: Hepatocellular cancer (HCC) is an established indication for liver transplantation. This group is often allocated a donor after cardiac death (DCD) liver as a solution for waiting times. There are concerns that this approach may oncologically disadvantage HCC recipients. The aim of this study was to determine whether DCD transplantation was associated with poorer cancer-related survival in HCC. METHODS: Study population was from a single institute (2001-2014) with an HCC listing diagnosis. Variables related to recipient, tumor, and graft were analyzed to determine association with HCC death. RESULTS: There were 347 recipients listed for HCC of which 91 received a DCD. Donor after cardiac death and donor after brain stem death (DBD) had equivalent 1-, 3-, and 5-year overall (P = 0.115) and cancer-specific survival (P = 0.7). On univariate analysis recipient age, sex, model for end stage liver disease, viral etiology had no bearing on the risk of HCC death. Neither did the graft variables of type (DCD vs DBD), donor age, steatosis, cold ischemic time, peak aspartate transaminase, day 5 bilirubin or international normalized ratio after transplant. Only tumor variables of alpha-fetoprotein, number, total diameter, microvascular invasion, and differentiation were predictors of HCC death. On multivariate analysis, predictors of HCC death remained tumor number (P = 0.002), total diameter of tumor(s) (P < 0.001), microvascular invasion (P = 0.025), and poor differentiation (P = 0.021). CONCLUSIONS: Donor liver quality in terms of graft type (DCD) has no influence on cancer related survival in transplant for HCC (hazards ratio, 1.143; 95% confidence interval, 0.528-2.423; P = 0.752).

Design, synthesis and biological evaluation of quinazoline derivatives as anti-trypanosomatid and anti-plasmodial agents.

In this paper, the design, synthesis and biological evaluation of a set of quinazoline-2,4,6-triamine derivatives (1-9) as trypanocidal, antileishmanial and antiplasmodial agents are explained. The compounds were rationalized basing on docking studies of the dihydrofolate reductase (DHFR from Trypanosoma cruzi, Leishmania major and Plasmodium vivax) and pteridin reductase (PTR from T. cruzi and L. major) structures. All compounds were in vitro screened against both bloodstream trypomastigotes of T. cruzi (NINOA and INC-5 strains) and promatigotes of Leishmania mexicana (MHOM/BZ/61/M379 strain), and also for cytotoxicity using Vero cell line. Against T. cruzi, three compounds (5, 6 and 8) were the most effective showing a better activity profile than nifurtimox and benznidazole (reference drugs). Against L. mexicana, four compounds (5, 6, 8, and 9) exhibited the highest activity, even than glucantime (reference drug). In the cytotoxicity assay, protozoa were more susceptible than Vero cells. In vivo Plasmodium berghei assay (ANKA strain), the compounds 1, 5, 6 and 8 showed a more comparable activity than chloroquine and pyrimethamine (reference drugs) when they were administrated by the oral route. The antiprotozoal activity of these substances, endowed with redox properties, represented a good starting point for a medicinal chemistry program aiming for chemotherapy of Chagas' disease, leishmaniosis and malaria.