Comparison of abdominal adipose tissue versus Body Mass Index (BMI) as a predictor of complications and survival in liver transplantation.

INTRODUCTION: Because of the obesity epidemic, more obese patients are on liver transplant (LT) waiting lists. The diseases associated with obesity may increase complications and limit survival after LT. However, there is no established measure or cut-off point to determine this impact and aid decision making. The aim of the present study is to evaluate obesity in patients undergoing LT via BMI and CT-based measurement of adipose tissue (AAT). These parameters will be used to predict the risk of postoperative complications and 5-year survival. METHODS: A retrospective, single-center study was carried out at a tertiary Spanish hospital, including all patients who received LT between January 2012 and July 2019 (n = 164). The patients were adults who underwent LT using the 'piggyback' technique, preserving the recipient vena cava. Visceral adipose tissue (VAT) and BMI were calculated to examine correlations with postoperative complications and 5-year survival. RESULTS: No significant association was found between postoperative complications by Comprehensive Complication Index, BMI, AAT/height, subcutaneous fat/height and VAT/height. Kaplan-Meier curves for 5-year survival compared LT recipients with BMI < 30.45 vs ≥30.45, with an estimated survival of 58.97 months versus 43.11 months, respectively (P < .001) (Fig. 3) and for LT recipients with an AAT/height <27.35 mm versus ≥27.35 mm, with an estimated survival of 57.69 months versus 46.34 months (P = .001). CONCLUSIONS: This study does not show a higher rate of postoperative complications in obese patients. There is a significantly lower long-term survival in patients with AAT/height ≥27.35 mm and BMI ≥ 30.45. BMI is a valid estimate of obesity and is predictive of survival.

Risk of Recurrence of Hepatocarcinoma after Liver Transplantation: Performance of Recurrence Predictive Models in a Cohort of Transplant Patients.

Liver transplantation (LT) is a curative treatment for early-stage hepatocellular carcinoma (HCC) unsuitable for surgical resection. However, tumor recurrence (TR) rates range from 8% to 20% despite strict selection criteria. The validation of new prognostic tools, such as pre-MORAL or RETREAT risks, is necessary to improve recurrence prediction. A retrospective study was conducted at Marqués de Valdecilla University Hospital in Cantabria, Spain, between 2010 and 2019 to determine the rate of TR in LT patients and identify associated factors. Patients with liver-kidney transplantation, re-transplantation, HIV infection, survival less than 90 days, or incidental HCC were excluded. Data on demographic, liver disease-related, LT, and tumor-related variables, as well as follow-up records, including TR and death, were collected. TR was analyzed using the Log-Rank test, and a multivariate Cox regression analysis was performed. The study was approved by the IRB of Cantabria. TR occurred in 13.6% of LT patients (95% CI = 7.3-23.9), primarily as extrahepatic recurrence (67%) within the first 5 years (75%). Increased TR was significantly associated with higher Body Mass Index (BMI) (HR = 1.3 [95% CI = 1.1-1.5]), vascular micro-invasion (HR = 8.8 [1.6-48.0]), and medium (HR = 20.4 [3.0-140.4]) and high pre-MORAL risk (HR = 30.2 [1.6-568.6]). TR also showed a significant correlation with increased mortality. Conclusions: LT for HCC results in a 13.6% rate of tumor recurrence. Factors such as BMI, vascular micro-invasion, and medium/high pre-MORAL risk are strongly associated with TR following LT.

Hepatocyte mARC1 promotes fatty liver disease.

Background & Aims: Non-alcoholic fatty liver disease (NAFLD) has a prevalence of ∼25% worldwide, with significant public health consequences yet few effective treatments. Human genetics can help elucidate novel biology and identify targets for new therapeutics. Genetic variants in mitochondrial amidoxime-reducing component 1 (MTARC1) have been associated with NAFLD and liver-related mortality; however, its pathophysiological role and the cell type(s) mediating these effects remain unclear. We aimed to investigate how MTARC1 exerts its effects on NAFLD by integrating human genetics with in vitro and in vivo studies of mARC1 knockdown. Methods: Analyses including multi-trait colocalisation and Mendelian randomisation were used to assess the genetic associations of MTARC1. In addition, we established an in vitro long-term primary human hepatocyte model with metabolic readouts and used the Gubra Amylin NASH (GAN)-diet non-alcoholic steatohepatitis mouse model treated with hepatocyte-specific N-acetylgalactosamine (GalNAc)-siRNA to understand the in vivo impacts of MTARC1. Results: We showed that genetic variants within the MTARC1 locus are associated with liver enzymes, liver fat, plasma lipids, and body composition, and these associations are attributable to the same causal variant (p.A165T, rs2642438 G>A), suggesting a shared mechanism. We demonstrated that increased MTARC1 mRNA had an adverse effect on these traits using Mendelian randomisation, implying therapeutic inhibition of mARC1 could be beneficial. In vitro mARC1 knockdown decreased lipid accumulation and increased triglyceride secretion, and in vivo GalNAc-siRNA-mediated knockdown of mARC1 lowered hepatic but increased plasma triglycerides. We found alterations in pathways regulating lipid metabolism and decreased secretion of 3-hydroxybutyrate upon mARC1 knockdown in vitro and in vivo. Conclusions: Collectively, our findings from human genetics, and in vitro and in vivo hepatocyte-specific mARC1 knockdown support the potential efficacy of hepatocyte-specific targeting of mARC1 for treatment of NAFLD. Impact and implications: We report that genetically predicted increases in MTARC1 mRNA associate with poor liver health. Furthermore, knockdown of mARC1 reduces hepatic steatosis in primary human hepatocytes and a murine NASH model. Together, these findings further underscore the therapeutic potential of targeting hepatocyte MTARC1 for NAFLD.

Results from the Uruguay's 2022 report card on physical activity for children and adolescents.

Background/objective: Uruguay was enrolled in the fourth edition of the Global Matrix on physical activity-related indicators in children and adolescents with the aim of producing its second Report Card and analyses on the ten core indicators. Methods: A harmonized development process proposed by the Active Healthy Kids Global Alliance was followed. The best available scientific and grey literature was systematically searched for all the indicators included in the Report Card (Overall Physical Activity, Organized Sport Participation, Active Play, Active Transportation, Sedentary Behavior, Physical Fitness, Family and Peers, School, Community and Environment, and Government). A grading scale ranging from A to F was used. A new approach was used to grade the Government indicator according to the Active Healthy Kids Global Alliance guidance. Results: New information was identified and 7 out of 10 indicators were graded, while there were 3 out of 10 indicators with incomplete information to be graded. An gender-based analysis was included in this second Report Card, providing separate grades for 5 of the indicators [girls/boys]: Overall Physical Activity [F/F], Organized Sport Participation [F/D], Active Transportation [C/C], Sedentary Behavior [D+/D+], and Community and Environment [D+/C-]. The comparison between 2018 and 2022 analysis showed a decrease in Overall Physical Activity and Organized Sport Participation, while the sources of influence School and Government obtained a higher grade in comparison with the previous Report Card. Conclusion: Uruguay has developed its second version of the Report Card on physical activity-related indicators in children and adolescents. The gender analysis showed inequalities between girls and boys. In summary, behavioral indicators have decreased while sources of influence have risen along the time.

Physical activity-related indicators in children and adolescents in Uruguay: A scoping review based on the Global Matrix initiative.

Background: The first Uruguay's Report Card in 2018 based on the Global Matrix initiative showed the lack of information on physical activity in children and adolescents. This study mapped and examined the available evidence on physical activity-related indicators based on Uruguay's 2022 Report Card. Methods: The scoping review was reported using the Joanna Briggs Institute and the Preferred Reporting Items for Systematic Reviews extension for Scoping Reviews guidelines. A comprehensive literature search was performed for the period between 2018 and 2021, including electronic databases (PubMed, Web of Science, LILACS, Scielo, and Latindex), gray literature (Google Scholar, open access thesis, relevant websites of State-agencies and International Organizations), national and regional relevant journals, and reference lists of key texts. Two researchers independently conducted both the selection and data-charting process. Data items from each paper were charted based on the Population, Concept, and Context elements reflected in the objective of the review. A narrative synthesis and network plots were conducted to summarize the evidence. Results: A total of 20 papers were included in this review, consisting of four peer-reviewed scientific papers, three bachelor's theses, four official documents of State-agencies, four Government reports, of which three included national surveys, and five laws. Strengths, weaknesses, and knowledge gaps were identified from the available evidence. We synthesized main challenges such as publishing scientific studies, establishing cross-national and cross-sectoral collaborations in research projects, generating high-quality data, reporting information on social inequality indicators that influence equitable distribution, or increasing access to public information. Our results support early emerging and growth research on this topic. However, despite existing papers on physical activity-related indicators in Uruguayan youths, the lack of high-quality evidence remains clear. Conclusion: The findings of this scoping review provide the best available evidence for identifying and overcoming the challenges of physical activity-related indicators research in Uruguay. The methodological framework used could be useful for countries involved in future editions of the Global Matrix initiative. Systematic review registration: Open Science Framework, https://osf.io/hstbd/.

TCF7L2 plays a complex role in human adipose progenitor biology, which might contribute to genetic susceptibility to type 2 diabetes.

INTRODUCTION: Non-coding genetic variation at TCF7L2 is the strongest genetic determinant of type 2 diabetes (T2D) risk in humans. TCF7L2 encodes a transcription factor mediating the nuclear effects of WNT signaling in adipose tissue (AT). In vivo studies in transgenic mice have highlighted important roles for TCF7L2 in adipose tissue biology and systemic metabolism. OBJECTIVE: To map the expression of TCF7L2 in human AT, examine its role in human adipose cell biology in vitro, and investigate the effects of the fine-mapped T2D-risk allele at rs7903146 on AT morphology and TCF7L2 expression. METHODS: Ex vivo gene expression studies of TCF7L2 in whole and fractionated human AT. In vitro TCF7L2 gain- and/or loss-of-function studies in primary and immortalized human adipose progenitor cells (APCs) and mature adipocytes (mADs). AT phenotyping of rs7903146 T2D-risk variant carriers and matched controls. RESULTS: Adipose progenitors (APs) exhibited the highest TCF7L2 mRNA abundance compared to mature adipocytes and adipose-derived endothelial cells. Obesity was associated with reduced TCF7L2 transcript levels in whole subcutaneous abdominal AT but paradoxically increased expression in APs. In functional studies, TCF7L2 knockdown (KD) in abdominal APs led to dose-dependent activation of WNT/ß-catenin signaling, impaired proliferation and dose-dependent effects on adipogenesis. Whilst partial KD enhanced adipocyte differentiation, near-total KD impaired lipid accumulation and adipogenic gene expression. Over-expression of TCF7L2 accelerated adipogenesis. In contrast, TCF7L2-KD in gluteal APs dose-dependently enhanced lipid accumulation. Transcriptome-wide profiling revealed that TCF7L2 might modulate multiple aspects of AP biology including extracellular matrix secretion, immune signaling and apoptosis. The T2D-risk allele at rs7903146 was associated with reduced AP TCF7L2 expression and enhanced AT insulin sensitivity. CONCLUSIONS: TCF7L2 plays a complex role in AP biology and has both dose- and depot-dependent effects on adipogenesis. In addition to regulating pancreatic insulin secretion, genetic variation at TCF7L2 might also influence T2D risk by modulating AP function.

Actividad física basada en dispositivos versus autorreporte en estudiantes universitarios uruguayos / Device-based monitoring in physical activity versus self-report in Uruguayan university students / Atividade física baseada em dispositivos versus atividade física autorreferida em estudantes universitários uruguaios

Resumen: Introducción: la medición precisa de la actividad física (AF) es clave para analizar su asociación con resultados de salud. Sin embargo, en Uruguay no existen estudios que comparen diferentes métodos para determinar la AF en adultos. El objetivo de este estudio fue analizar la confiabilidad del Cuestionario Internacional de Actividad Física (IPAQ) en estudiantes universitarios uruguayos y evaluar su validez concurrente en comparación con la AF basada en dispositivos. Método: 54 estudiantes universitarios de educación física completaron el IPAQ (versión larga) en dos ocasiones con 7 días de diferencia y utilizaron acelerómetros GeneActiv durante ese período. La confiabilidad se evaluó a través del Coeficiente de Correlación Intraclase (ICC) y se utilizó el análisis de Bland-Altman para determinar la validez concurrente. Resultados: todos los dominios de AF mostraron niveles moderados de ICC. El transporte (ICC = 0,64), el tiempo libre (ICC = 0,58), y la AF total (ICC = 0,53) fueron los dominios con niveles moderados más altos. El total de minutos de AF evaluados a través del IPAQ en las dos ocasiones reportó un promedio de 773 minutos de diferencia (IC 95% 362,88-1.184,01). La diferencia de minutos de AF entre la evaluación con el IPAQ y con los acelerómetros es de 752 minutos (IC 95% 418,05-1.087.16). Conclusiones: el IPAQ sobreestima la AF respecto al acelerómetro en estudiantes universitarios uruguayos, sin embargo fue más confiable al considerar dominios de transporte y tiempo libre para los participantes que reportaron realizar un promedio menor a 400 minutos de AF semanal.

Summary: Introduction: precise measurement of physical activity (PA) is key to analyze its association with health results. However, there are no studies in Uruguay comparing the different methods to determine PA in adults. The study aims to analyze the reliability of the International Physical Activity Questionnaire (IPAQ) in Uruguayan university students and to assess its validity by comparing it to device-based monitoring PA. Method: 54 Physical Education university students completed the IPAQ (long version) on 2 occasions with a 7 day difference using GeneActive accelerometers during that period. Reliability was assessed with the Intraclass Correlation Coefficient (ICC) and the Bland-Altman analysis was used to determine concurrent validity. Results: all PA domains evidenced moderate ICC levels. Transport (ICC= 0.64), free time (ICC= 0.58) and total PA (ICC= 0.53) were the domains with the highest moderate levels. The total number of minutes of PA assessed by IPAQ reported an average of a 773 minutes difference (CI 95%: 362.88; 1184.01). Difference of PA in minutes, considering the assessment with the IPAQ and the accelerometers is 752 minutes (CI 95%: 418.05; 1087.16). Conclusions: the IPAQ overestimates the PA when compared to the accelerometer in Uruguayan university students. However, it was more reliable when considering the transport and free time domains for participants who reported an average physical activity under 400 minutes per week.

Resumo: Introdução: a mensuração precisa da atividade física (AF) é fundamental para analisar sua associação com desfechos de saúde. No entanto, no Uruguai não existem estudos que comparem diferentes métodos para determinar a AF em adultos. Objetivo: analisar a confiabilidade do Questionário Internacional de Atividade Física (IPAQ) em estudantes universitários uruguaios e avaliar sua validade concorrente em comparação com a AF baseada em dispositivos. Método: 54 estudantes universitários de Educação Física preencheram o IPAQ (versão longa) em 2 ocasiões com 7 dias de intervalo e usaram acelerômetros GeneActiv durante esse período. A confiabilidade foi avaliada por meio do Coeficiente de Correlação Intraclasse (ICC) e a análise de Bland-Altman foi utilizada para determinar a validade concorrente. Resultados: todos os domínios da AF apresentaram níveis moderados de ICC. Transporte (ICC = 0,64), tempo livre (ICC = 0,58) e AF total (ICC = 0,53) foram os domínios com os níveis moderados mais altos. O total de minutos de AF avaliados pelo IPAQ em ambas as ocasiões apresentou diferença média de 773 minutos (IC 95%: 362,88; 1184,01). A diferença em minutos de AF entre a avaliação com o IPAQ e com os acelerômetros é de 752 minutos (IC 95%: 418,05; 1087,16). Conclusões: o IPAQ superestima a AF em relação ao acelerômetro em universitários uruguaios, porém, foi mais confiável ao considerar os domínios transporte e tempo livre para participantes que relataram realizar em média menos de 400 minutos de AF por semana.

NMDA Receptor Antagonists Increase the Release of GLP-1 From Gut Endocrine Cells.

Type 2 diabetes mellitus (T2DM) remains one of the most pressing health issues facing modern society. Several antidiabetic drugs are currently in clinical use to treat hyperglycaemia, but there is a need for new treatments that effectively restore pancreatic islet function in patients. Recent studies reported that both murine and human pancreatic islets exhibit enhanced insulin release and ß-cell viability in response to N-methyl-D-aspartate (NMDA) receptor antagonists. Furthermore, oral administration of dextromethorphan, an over-the-counter NMDA receptor antagonist, to diabetic patients in a small clinical trial showed improved glucose tolerance and increased insulin release. However, the effects of NMDA receptor antagonists on the secretion of the incretin hormone GLP-1 was not tested, and nothing is known regarding how NMDA receptor antagonists may alter the secretion of gut hormones. This study demonstrates for the first time that, similar to ß-cells, the NMDA receptor antagonist MK-801 increases the release of GLP-1 from a murine L-cell enteroendocrine model cell line, GLUTag cells. Furthermore, we report the 3' mRNA expression profiling of GLUTag cells, with a specific focus on glutamate-activated receptors. We conclude that if NMDA receptor antagonists are to be pursued as an alternative, orally administered treatment for T2DM, it is essential that the effects of these drugs on the release of gut hormones, and specifically the incretin hormones, are fully investigated.

Combinatorial ECM Arrays Identify Cooperative Roles for Matricellular Proteins in Enhancing the Generation of TH+ Neurons From Human Pluripotent Cells.

The development of efficient cell culture strategies for the generation of dopaminergic neurons is an important goal for transplantation-based approaches to treat Parkinson's disease. To identify extracellular matrix molecules that enhance differentiation and might be used in these cell cultures we have used micro-contact printed arrays on glass slides presenting 190 combinations of 19 extracellular matrix molecules selected on the basis of their expression during embryonic development of the ventral midbrain. Using long-term neuroepithelial stem cells (Lt-NES), this approach identified a number of matricellular proteins that enhanced differentiation, with the combination of Sparc, Sparc-like (Sparc-l1) and Nell2 increasing the number of tyrosine hydroxylase+ neurons derived from Lt-NES cells and, critically for further translation, human pluripotent stem cells.

Dimethyl fumarate reduces hepatocyte senescence following paracetamol exposure.

Liver disease is a major cause of premature death. Oxidative stress in the liver represents a key disease driver. Compounds, such as dimethyl fumarate (DMF), can activate the antioxidant response and are used clinically to treat disease. In this study, we tested the protective properties of DMF before or after paracetamol exposure. Following DMF administration, Nrf2 nuclear translocation was tracked at the single-cell level and target gene transactivation confirmed. Next, the protective properties of DMF were examined following paracetamol exposure. Transcriptomic and biochemical analysis revealed that DMF rescue was underpinned by reduced Nf-kB and TGF-ß signaling and cell senescence. Following on from these studies, we employed a Zebrafish model to study paracetamol exposure in vivo. We combined a genetically modified Zebrafish model, expressing green fluorescent protein exclusively in the liver, with automated microscopy. Pre-treatment with DMF, prior to paracetamol exposure, led to reduced liver damage in Zebrafish demonstrating protective properties.

Incidental mesonephric remnant hyperplasia of the jejunal mesentery: A diagnostic challenge.

Mesonephric remnants are embryonic vestiges of the mesonephric (Wolffian) ducts which regress during normal development. These remnants have been uncommonly reported in the female and male reproductive tract as a spectrum of morphologic lesions that can be misdiagnosed as carcinoma. One case of mesonephric remnant hyperplasia of the jejunal mesentery incidentally found in a 47-year-old man is herein reported. This is the first description of mesonephric hyperplasia arisen in the mesentery. The presence of ducts, tubules, and cysts lined by bland, epithelial, cuboidal cells with scant cytoplasm, and diffuse pseudoinfiltrative growth pattern can raise the possibility of neoplasia. Immunohistochemically, mesonephric epithelia have a characteristic staining. CD10 highlights the apical-luminal aspect of the cells. Besides, intense reactivity is showed for high-molecular-weight cytokeratin (CK), CK7, bcl2, and vimentin. The main differential diagnosis includes mesothelial hyperplasia, epithelial mesothelioma, well-differentiated neuroendocrine tumor, and infiltration due to acinar adenocarcinoma of the prostate. However, a detailed microscopic study with the aid of immunohistochemistry helps separate mesonephric remnants from malignant processes. The mesonephric hyperplasia of the mesentery we have reported adds to the spectrum of mesonephric remnants a new location. Familiarity with this lesion is indispensable to avoid overdiagnosis.

Beneficios de los videojuegos activos sobre parámetros de aptitud física relacionada con la salud: un comentario en tiempos de cuarentena / Benefits of active videogames on health-related physical fitness parameters: Commentary in the times of quarantine / Benefícios dos videogames ativos nos parâmetros de condicionamento físico relacionados à saúde: um comentário em tempos de quarentena

Resumen: En la actualidad estamos viviendo una pandemia provocada por el virus del SARS-CoV-2, el COVID-19, siendo lo más recomendado quedarse en casa para disminuir el contagio y que éste se reduzca al mínimo posible. En el siglo XXI la tecnología está más presente que nunca y forma parte de nuestra vida cotidiana. Dado que existe un importante abuso de aquélla, especialmente por parte de los adolescentes, desde nuestra perspectiva promotora del movimiento y de la reducción del comportamiento sedentario, proponemos el uso de los videojuegos activos como sustitución de los videojuegos convencionales. Para ello, se han revisado los principales beneficios que éstos pueden aportar, tanto a la población más joven como a los adultos mayores. Este último grupo de edad es uno de los más afectados por la pandemia y por tanto hay una fuerte recomendación para que permanezcan en sus hogares. No obstante, se recomienda hacer un uso responsable y no invertir un tiempo excesivo que pueda conllevar perjuicios.

Summary: We are currently living the SARS CoV2, COVID-19 pandemic, the highest recommendation being to stay at home to reduce the risk of contagion and thus disease transmission to the minimum. More than ever, technology is part of our daily life in this 21st century. Given the significant abuse of technology, in particular by adolescents, and considering our perspective that is grounded on promoting movement and reducing a sedentary lifestyle, we suggest using active videogames to substitute conventional ones. To that end, we have conducted a review of the main benefits of videogames on the younger population, as well as on older adults, who constitute one of the most affected sectors by the pandemic and were consequently strongly encouraged to stay at home. However, a recommendation is made to make a responsible use of active videogames and avoid investing excessive time, what may result in a negative impact.

Resumo: No momento vivemos uma pandemia causada pelo vírus SARS-CoV-2, COVID-19, sendo o mais recomendado ficar em casa para reduzir o contágio e que este seja reduzido ao mínimo possível. No século 21, a tecnologia está mais presente do que nunca e faz parte do nosso dia a dia. Tendo em vista que há significativo abuso da mesma, principalmente por adolescentes, na nossa perspectiva que promove o movimento e a redução do comportamento sedentário, propomos o uso de videogames ativos em substituição aos videogames convencionais. Para isso, fizemos uma revisão dos principais benefícios que estas podem trazer, tanto para a população mais jovem como para os idosos. Esta última faixa etária é uma das mais afetadas pela pandemia e, portanto, há uma forte recomendação para que fiquem em casa. No entanto, é recomendável usá-lo com responsabilidade e não investir tempo excessivo que possa causar danos.

Functional module detection through integration of single-cell RNA sequencing data with protein-protein interaction networks.

BACKGROUND: Recent advances in single-cell RNA sequencing have allowed researchers to explore transcriptional function at a cellular level. In particular, single-cell RNA sequencing reveals that there exist clusters of cells with similar gene expression profiles, representing different transcriptional states. RESULTS: In this study, we present SCPPIN, a method for integrating single-cell RNA sequencing data with protein-protein interaction networks that detects active modules in cells of different transcriptional states. We achieve this by clustering RNA-sequencing data, identifying differentially expressed genes, constructing node-weighted protein-protein interaction networks, and finding the maximum-weight connected subgraphs with an exact Steiner-tree approach. As case studies, we investigate two RNA-sequencing data sets from human liver spheroids and human adipose tissue, respectively. With SCPPIN we expand the output of differential expressed genes analysis with information from protein interactions. We find that different transcriptional states have different subnetworks of the protein-protein interaction networks significantly enriched which represent biological pathways. In these pathways, SCPPIN identifies proteins that are not differentially expressed but have a crucial biological function (e.g., as receptors) and therefore reveals biology beyond a standard differential expressed gene analysis. CONCLUSIONS: The introduced SCPPIN method can be used to systematically analyse differentially expressed genes in single-cell RNA sequencing data by integrating it with protein interaction data. The detected modules that characterise each cluster help to identify and hypothesise a biological function associated to those cells. Our analysis suggests the participation of unexpected proteins in these pathways that are undetectable from the single-cell RNA sequencing data alone. The techniques described here are applicable to other organisms and tissues.

Influence of postoperative complications on long-term survival in liver transplant patients.

BACKGROUND: Liver transplant (LT) is a complex procedure with frequent postoperative complications. In other surgical procedures such as gastrectomy, esophagectomy or resection of liver metastases, these complications are associated with poorer long-term survival. It is possible this happens in LT but there are not enough data to establish this relationship. AIM: To analyze the possible influence of postoperative complications on long-term survival and the ability of the comprehensive complication index (CCI) to predict this. METHODS: Retrospective study in a tertiary-level university hospital. The 164 participants were all patients who received a LT from January 2012 to July 2019. The follow-up was done in the hospital until the end of the study or death. Comorbidity and risk after transplantation were calculated using the Charlson and balance of risk (BAR) scores, respectively. Postoperative complications were graded according to the Clavien-Dindo classification and the CCI. To assess the CCI cut-off value with greater prognostic accuracy a receiver operating characteristic (ROC) curve was built, with calculation of the area under the curve (AUC). Overall survival was estimated according to the Kaplan-Meier test and log-rank test. Groups were compared by the Mann-Whitney test. For the multivariable analysis the Cox regression was used. RESULTS: The mean follow-up time of the cohort was 37.76 (SD = 24.5) mo. A ROC curve of CCI with 5-year survival was built. The AUC was 0.826 (0.730-0.922), P < 0.001. The cut-off was calculated by means of the Youden index with a result of 35.95. The sensitivity was 84.6% and the specificity 61.3%. Survival curves for comparison of patients with CCI score < 36 vs ≥ 36 were calculated. The estimated 5-year survival was 57.65 and 43.95 months, respectively (log-rank < 0.001). This suggests that patients with more severe complications exhibit worse long-term survival. Other cut-off values were analysed. Comparison between patients with CCI < 33.5 vs > 33.5 (33.5 = median CCI value) showed estimated 5-year survival was 57.4 and 45.71 months, respectively (log-rank < 0.0001). Dividing patients according to the mode CCI value (20.9) showed an estimated 5-year survival of 60 mo for a CCI below 20.9 vs 57 mo for a CCI above 20.9 (log-rank = 0.147). The univariate analysis did not show any association between individual complications and long-term survival. A multivariate analysis was carried out to analyse the possible influence of CCI, Charlson comorbidity index, BAR and hepatocellular carcinoma on survival. Only the CCI score showed significant influence on long-term survival. CONCLUSION: A complicated postoperative period - well-defined by means of the CCI score - can influence not only short-term survival, but also long-term survival.

Srebf1 Controls Midbrain Dopaminergic Neurogenesis.

Liver X receptors (LXRs) and their ligands are potent regulators of midbrain dopaminergic (mDA) neurogenesis and differentiation. However, the molecular mechanisms by which LXRs control these functions remain to be elucidated. Here, we perform a combined transcriptome and chromatin immunoprecipitation sequencing (ChIP-seq) analysis of midbrain cells after LXR activation, followed by bioinformatic analysis to elucidate the transcriptional networks controlling mDA neurogenesis. Our results identify the basic helix-loop-helix transcription factor sterol regulatory element binding protein 1 (SREBP1) as part of a cluster of proneural transcription factors in radial glia and as a regulator of transcription factors controlling mDA neurogenesis, such as Foxa2. Moreover, loss- and gain-of-function experiments in vitro and in vivo demonstrate that Srebf1 is both required and sufficient for mDA neurogenesis. Our data, thus, identify Srebf1 as a central player in mDA neurogenesis.

Desarrollo y validación de una herramienta para la evaluación de la anastomosis intestinal laparoscópica en simulación / Development and Validation of a Tool for the Evaluation of Laparoscopic Intestinal Anastomosis in Simulation

INTRODUCCIÓN: La anastomosis intestinal laterolateral laparoscópica es una práctica habitual en la clínica y entrenada en simulación. El objetivo del estudio es el diseño y posterior validación de una herramienta fiable y reproducible para su evaluación. MÉTODOS: Se utilizó un método Delphi modificado para desarrollar los elementos de evaluación al que finalmente incluyeron 5 apartados (separación entre puntos, eversión, tensión, estanqueidad y iatrogenia). Se incluyeron 21 participantes, 10 residentes quirúrgicos de primer año y 11 expertos. Realizaron anastomosis enteroentéricas laterolateral laparoscópica en víscera ex-vivo porcina de 5 cm. Las evaluaciones fueron ciegas y realizadas por 2 evaluadores de forma independiente. RESULTADOS: Las medias obtenidas por noveles y expertos fueron respectivamente: separación entre puntos 3,2 vs.5,7 (p < 0,001), eversión 3,3 vs.5,9 (p = 0,004), tensión 2,9 vs.5,9 (p = 0,001), estanqueidad 3,2 vs.5,7 (p = 0,005), iatrogenia 6,9 vs.7 (p = 0,47). El parámetro iatrogenia no es discriminatorio, por lo que fue eliminado de la herramienta. Los resultados totales fueron 12,5 los noveles y 23,2 los expertos (p = 0,001). La correlación entre observadores presenta un coeficiente de correlación intraclase de 0,99 para la separación entre puntos, 0,94 la eversión, 0,98 la tensión y 0,99 la estanqueidad. La relación entre la puntuación y la fuga anastomótica sin presión: presenta una R de Rosenthal de -0,71 (p < 0,001); con presión se obtiene una R = 0,55 (p = 0,01). CONCLUSIONES: La herramienta diseñada es válida para discriminar entre participantes noveles y expertos, presenta muy alta concordancia entre observadores y se correlaciona con el riesgo de fuga

INTRODUCTION: Laparoscopic side-to-side intestinal anastomosis is a common in clinic practice and training simulation. The aim of this study is to design and validate a reliable and reproducible tool for its evaluation. METHODS: A modified Delphi method was used to design a tool with elements that determine quality, including 5 items: separation between stiches, eversion, tension, leak and iatrogenesis. The study included 21 participants (10 first-year residents and 11 experts) who performed a 5 cm laparoscopic intestinal side-to-side anastomosis with porcine viscera. The evaluations were blinded and done independently by 2 evaluators. RESULTS: The means obtained by novice and expert participants were, respectively: separation between stiches 3.2 vs.5.7 (P < .001), eversion 3.3 vs.5.9 (P = .004), tension 2.9 vs.5.9 (P = .001), leak tightness 3.2 vs.5.7 (P = .005), iatrogenesis 6.9 vs.7 (P = .47). The iatrogenesis parameter was not discriminatory, so it was removed from the tool. The total results were 12.5 for novices and 23.2 for experts (P = .001). The correlation between observers presented an intraclass correlation coefficient of 0.99 for the separation between stiches, 0.94 for eversion, 0.98 for tension and 0.99 for leak. The correlation between the score and the leak without pressure presented a Rosenthal's R of -0.71 (P < .001); with pressure R = -0.55 (P = .01). CONCLUSIONS: The designed tool is valid to discriminate between novice and expert participants, presents very high concordance between observers and correlates with the risk of leak

Validation of the Balance of Risk as a Predictor of Liver Transplant Survival in a Spanish Population.

BACKGROUND: The Balance of Risk (BAR) score is a simple test that combines donor and recipient variables to predict liver transplant success. It has been validated in different publications, with cut-off points of between 15 and 18 points proposed depending on the region. The aim of this study is to test the validity of the BAR score and to find the optimal cut-off point for our population. MATERIALS AND METHODS: A retrospective cohort of 164 liver transplant patients was selected between January 2012 and July 2019. All were older than 18 years and were treated in a Spanish tertiary-level hospital. RESULTS: The receiver operating characteristic curve between BAR and 5-year survival yields a result of 0.622 (P = .046), placing the cut-off point at ≥7 (sensitivity 61.5%, specificity 61.6%). Patients with a BAR score <7 and a BAR score ≥7 have an estimated 5-year survival of 53.91 vs 47.51 months, respectively (log rank = .032). The only 2 variables associated with increased survival were a BAR score of <7 (hazard ratio = 2.566; P < .001) and a body mass index <30 (hazard ratio = 6.667; P < .001). CONCLUSIONS: A low BAR score correlates well with liver transplant survival at 5 years. The BAR is a simple tool that should be used for donor-recipient matching. Due to the characteristics, resources, and population in our environment, a BAR score of 7 would be the optimum cut-off point for a liver transplant.

Development and Validation of a Tool for the Evaluation of Laparoscopic Intestinal Anastomosis in Simulation. / Desarrollo y validación de una herramienta para la evaluación de la anastomosis intestinal laparoscópica en simulación.

INTRODUCTION: Laparoscopic side-to-side intestinal anastomosis is a common in clinic practice and training simulation. The aim of this study is to design and validate a reliable and reproducible tool for its evaluation. METHODS: A modified Delphi method was used to design a tool with elements that determine quality, including 5 items: separation between stiches, eversion, tension, leak and iatrogenesis. The study included 21 participants (10 first-year residents and 11 experts) who performed a 5cm laparoscopic intestinal side-to-side anastomosis with porcine viscera. The evaluations were blinded and done independently by 2 evaluators. RESULTS: The means obtained by novice and expert participants were, respectively: separation between stiches 3.2 vs. 5.7 (P < .001), eversion 3.3 vs. 5.9 (P = .004), tension 2.9 vs. 5.9 (P = .001), leak tightness 3.2 vs. 5.7 (P = .005), iatrogenesis 6.9 vs. 7 (P = .47). The iatrogenesis parameter was not discriminatory, so it was removed from the tool. The total results were 12.5 for novices and 23.2 for experts (P = .001). The correlation between observers presented an intraclass correlation coefficient of 0.99 for the separation between stiches, 0.94 for eversion, 0.98 for tension and 0.99 for leak. The correlation between the score and the leak without pressure presented a Rosenthal's R of -0.71 (P < .001); with pressure R = -0.55 (P = .01). CONCLUSIONS: The designed tool is valid to discriminate between novice and expert participants, presents very high concordance between observers and correlates with the risk of leak.

A Zeb2-miR-200c loop controls midbrain dopaminergic neuron neurogenesis and migration.

Zeb2 is a homeodomain transcription factor that plays pleiotropic functions during embryogenesis, but its role for midbrain dopaminergic (mDA) neuron development is unknown. Here we report that Zeb2 is highly expressed in progenitor cells in the ventricular zone of the midbrain floor plate and downregulated in postmitotic neuroblasts. Functional experiments show that Zeb2 expression in the embryonic ventral midbrain is dynamically regulated by a negative feedback loop that involves miR-200c. We also find that Zeb2 overexpression reduces the levels of CXCR4, NR4A2, and PITX3 in the developing ventral midbrain in vivo, resulting in migration and mDA differentiation defects. This phenotype was recapitulated by miR-200c knockdown, suggesting that the Zeb2-miR-200c loop prevents the premature differentiation of mDA progenitors into postmitotic cells and their migration. Together, our study establishes Zeb2 and miR-200c as critical regulators that maintain the balance between mDA progenitor proliferation and neurogenesis.

The Matricellular Protein R-Spondin 2 Promotes Midbrain Dopaminergic Neurogenesis and Differentiation.

The development of midbrain dopaminergic (mDA) neurons is controlled by multiple morphogens and transcription factors. However, little is known about the role of extracellular matrix proteins in this process. Here we examined the function of roof plate-specific spondins (RSPO1-4) and the floor plate-specific, spondin 1 (SPON1). Only RSPO2 and SPON1 were expressed at high levels during mDA neurogenesis, and the receptor LGR5 was expressed by midbrain floor plate progenitors. Surprisingly, RSPO2, but not SPON1, specifically promoted the differentiation of mDA neuroblasts into mDA neurons in mouse primary cultures and embryonic stem cells (ESCs). In addition, RSPO2 was found to promote not only mDA differentiation, but also mDA neurogenesis in human ESCs. Our results thus uncover an unexpected function of the matricellular protein RSPO2 and suggest an application to improve mDA neurogenesis and differentiation in human stem cell preparations destined to cell replacement therapy or drug discovery for Parkinson disease.