Cell-specific Extracellular Vesicles and Their miRNA Cargo Released Into the Organ Preservation Solution During Cold Ischemia Storage as Biomarkers for Liver Transplant Outcomes.

BACKGROUND: Liver transplantation (LT) is crucial for end-stage liver disease patients, but organ shortages persist. Donation after circulatory death (DCD) aims to broaden the donor pool but presents challenges. Complications like acute rejection, hepatic artery thrombosis, and biliary issues still impact posttransplant prognosis. Biomarkers, including extracellular vesicles (EVs) and microRNAs (miRNAs), show promise in understanding and monitoring posttransplant events. This study explores the role of EVs and their miRNA cargo in LT, including their potential as diagnostic tools. METHODS: EVs from intrahepatic end-ischemic organ preservation solution (eiOPS) in 79 donated livers were detected using different techniques (nanosight tracking analysis, transmission electron microscopy, and flow cytometry). EV-derived miRNAs were identified by quantitative real time-polymerase chain reaction. Bioinformatics analysis was performed using the R platform. RESULTS: Different-sized and origin-specific EVs were found in eiOPS, with significantly higher concentrations in DCD compared with donation after brain death organs. Additionally, several EV-associated miRNAs, including let-7d-5p, miR-28-5p, miR-200a-3p, miR-200b-3p, miR-200c-3p, and miR-429, were overexpressed in DCD-derived eiOPS. These miRNAs also exhibited differential expression patterns in liver tissue biopsies. Pathway analysis revealed enrichment in signaling pathways involved in extracellular matrix organization and various cellular processes. Moreover, specific EVs and miRNAs correlated with clinical outcomes, including survival and early allograft dysfunction. A predictive model combining biomarkers and clinical variables showed promise in acute rejection detection after LT. CONCLUSIONS: These findings provide new insights into the use of EVs and miRNAs as biomarkers and their possible influence on posttransplantation outcomes, potentially contributing to improved diagnostic approaches and personalized treatment strategies in LT.

Factors associated with poor adherence to medication in patients with diabetes and hypertension in Peru: findings from a pooled analysis of six years of population-based surveys.

OBJECTIVE: To evaluate the factors associated with poor medication adherence in patients with DM and HTN in Peru. STUDY DESIGN: A cross-sectional study. METHODS: We analyzed data from the Peruvian Demographic and Family Health Survey from 2014 to 2019. Adjusted prevalence ratios (aPR) and their respective 95% confidence intervals (CI) were estimated to determine the factors associated with poor medication adherence. RESULTS: We included 15,184 participants with a known diagnosis of DM and HTN. The frequency of poor medication adherence was 37.1%, with 36.7% among individuals with HTN and 29.2% among individuals with DM. Those belonging to age groups above 30 years (aPR: 0.77; 95% CI: 0.74-0.80, for the group ≥ 60 years) had a lower frequency of poor medication adherence. Meanwhile, being male (aPR: 1.03; 95% CI: 1.01-1.05), lacking health insurance (aPR: 1.08; 95% CI: 1.05-1.10), belonging to lower wealth quintiles (aPR: 1.12; 95% CI: 1.08-1.17, for the first quintile), and living in the mountain region (aPR: 1.09; 95% CI: 1.06-1.12) were associated with a higher frequency of poor medication adherence. These findings were consistent when stratifying by the type of disease. CONCLUSION: This study showed that poor medication adherence is common in patients with HTN and DM in Peru and is associated with sociodemographic factors, highlighting the importance of public health approaches to improve adherence.

Operational tolerance research in liver transplantation: a bibliometric analysis using a new web resource.

Background: Operational tolerance in liver transplantation (OT-LT), defined as the graft survival with normal function in absence of immunosuppression, has been a field of intense research since the 1980s. Thereafter, tens of clinical trials and hundreds of articles have been published, making it challenging for researchers to assimilate all the information, more so outside of their disciplines. The aim of the present study was to analyze the research in OT-LT through a new web tool (https://tolerance.imib.es). Methods: We have developed a web resource that allowed the identification of the present trends and potential research avenues in OL-LT, an overview biomedical terms that were most often cited, including which journals published the most articles, and an advanced search engine that exploited all the information in these publications. Results: A total of 734 studies were analyzed until November 2023, with a mean of 15 articles published per year, a total sum of 3,751 impact factor points and a total of 26,542 citations. The analysis of citations allowed us to establish a ranking of the most prolific countries, authors, journals and institutions, in addition to the most influential publications in OT-LT. Likewise, keyword and co-occurrence analyses answered which themes involving OT-LT are the most popular, whereas cooperation analysis showed that principal authors in OT-LT form a network, although the lack of international cooperation, especially with regard to clinical trials, appears to be one of the main challenges. Conclusion: Despite its limitations, our web tool will allow both OT-LT expert and novel researchers to be able to draw a comprehensive picture of the past, present and future of OT-LT research.

Association between frailty and in-hospital outcomes in patients undergoing leadless pacemaker implantation: A nationwide analysis.

Background: Leadless pacing has recently emerged as a promising therapy. The impact of frailty on the prognosis of these patients is currently unknown. Objective: The purpose of this study was to assess the association between frailty and clinical outcomes in patients undergoing leadless pacemaker implantation. Methods: We included adult patients who underwent leadless pacemaker implantation using the National Inpatient Sample from 2017 to 2019. Frailty was evaluated using the Hospital Frailty Risk Score and stratified into low, intermediate, and high risk. Primary outcomes were in-hospital mortality and any complication (vascular, pericardial, pneumothorax, infectious, or device related), and secondary outcomes were the length of hospital stay and total charges. Results: A total of 16,825 patients were included in the final analysis, with 62% at intermediate or high risk of frailty. There was a higher risk of in-hospital mortality in patients at high (adjusted risk ratio [aRR] 6.37, 95% confidence interval [CI] 3.31-12.26) or intermediate (aRR 5.15, 95% CI 3.04-8.72) risk of frailty compared with those at low risk. Similarly, those at high or intermediate risk of frailty had higher total expenses and stayed in the hospital longer. Patients with a high (aRR 1.14, 95% CI 0.71-1.81) or intermediate (aRR 1.19, 95% CI 0.94-1.51) risk of frailty had a similar risk of any complication as patients with a low risk. Conclusion: Frailty was common in patients undergoing leadless pacemaker implantation. Higher levels of frailty were a strong predictor of in-hospital mortality, length of hospital stay, and hospital charges, except for any complication.

Textbook outcome in patients with biliary duct injury during cholecystectomy.

BACKGROUND: Iatrogenic bile duct injury (BDI) during cholecystectomy is associated with a complex and heterogeneous management owing to the burden of morbidity until their definitive treatment. This study aimed to define the textbook outcomes (TOs) after BDI with the purpose to indicate the ideal treatment and to improve it management. METHODS: We collected data from patients with an BDI between 1990 and 2022 from 27 hospitals. TO was defined as a successful conservative treatment of the iatrogenic BDI or only minor complications after BDI or patients in whom the first repair resolves the iatrogenic BDI without complications or with minor complications. RESULTS: We included 808 patients and a total of 394 patients (46.9%) achieved TO. Overall complications in TO and non-TO groups were 11.9% and 86%, respectively (P < .001). Major complications and mortality in the non-TO group were 57.4% and 9.2%, respectively. The use of end-to-end bile duct anastomosis repair was higher in the non-TO group (23.1 vs 7.8, P < .001). Factors associated with achieving a TO were injury in a specialized center (adjusted odds ratio [aOR], 4.01; 95% CI, 2.68-5.99; P < .001), transfer for a first repair (aOR, 5.72; 95% CI, 3.51-9.34; P < .001), conservative management (aOR, 5.00; 95% CI, 1.63-15.36; P = .005), or surgical management (aOR, 2.45; 95% CI, 1.50-4.00; P < .001). CONCLUSION: TO largely depends on where the BDI is managed and the type of injury. It allows hepatobiliary centers to identify domains of improvement of perioperative management of patients with BDI.

Restrictive diets are unnecessary for colonoscopy: Non-inferiority randomized trial.

Background and study aims In colonoscopy, preparation is often regarded as the most burdensome part of the intervention. Traditionally, specific diets have been recommended, but the evidence to support this policy is insufficient. The aim of this study was to evaluate the impact of the decision not to follow a restrictive diet on bowel preparation and colonoscopy outcomes. Patients and methods This was a multicenter, controlled, non-inferiority randomized trial with FIT-positive screening colonoscopy. The subjects were assigned to follow the current standard (1-day low residue diet [LRD]) or a liberal diet. The allocation was balanced for the risk of inadequate cleansing using the Dik et al. score. All participants received the same instructions for morning colonoscopy preparation. The primary outcome was the rate of adequate preparations as defined by the Boston Bowel Preparation Scale. Secondary outcomes included tolerability and measures of colonoscopy performance and quality. Results A total of 582 subjects were randomized. Of these, 278 who received the liberal diet and 275 who received the 1-day LRD were included in the intent-to-treat analysis. Non-inferiority was demonstrated with adequate preparation rates of 97.8% in the 1-day LRD and 96.4% in the liberal diet group. Tolerability was higher with the liberal diet (94.7% vs. 83.2%). No differences were found with respect to cecal intubation time, aspirated volume, or length of the examination. Global and right colon average adenoma detection rates per colonoscopy were similar. Conclusions The liberal diet was non-inferior to the 1-day LRD, and increased tolerability. Colonoscopy performance and quality were not affected. (NCT05032794).

American Society for Transplantation and Cellular Therapy International Affairs Committee: Report of the 4th Workshop on Quality as a Development Tool for Hematopoietic Cell Transplantation Programs at the 2023 Tandem BMT Meetings.

We provide a summary of the 4th ASTCT International Workshop with presentations from experts from Chile ("Setting Up a Transplantation Program in Chile," by Dr Pablo Ramirez), Saudi Arabia ("Developing Quality Programs in North Africa," by Dr Amal Alseraihy), and Japan ("The Japanese Transplant Registry Unified Management Program [TRUMP]: Current Issues and the Future," by Dr Yoshiko Atsuta). Workshop objectives included: (1) recognizing the benefits and importance for low- and middle-income countries of developing quality criteria and programs beyond existing accreditation programs, such as the Foundation for the Accreditation of Cellular Therapy (FACT) and the Joint Accreditation Committee ISCT-Europe and EBMT (JACIE); (2) describing the relationships among monitoring outcomes, including mortality, improvement of care, data reporting, and associated costs; and (3) reviewing how quality structures have been implemented and are improving care worldwide.

Explainable artificial intelligence prediction-based model in laparoscopic liver surgery for segments 7 and 8: an international multicenter study.

BACKGROUND: Artificial intelligence (AI) is becoming more useful as a decision-making and outcomes predictor tool. We have developed AI models to predict surgical complexity and the postoperative course in laparoscopic liver surgery for segments 7 and 8. METHODS: We included patients with lesions located in segments 7 and 8 operated by minimally invasive liver surgery from an international multi-institutional database. We have employed AI models to predict surgical complexity and postoperative outcomes. Furthermore, we have applied SHapley Additive exPlanations (SHAP) to make the AI models interpretable. Finally, we analyzed the surgeries not converted to open versus those converted to open. RESULTS: Overall, 585 patients and 22 variables were included. Multi-layer Perceptron (MLP) showed the highest performance for predicting surgery complexity and Random Forest (RF) for predicting postoperative outcomes. SHAP detected that MLP and RF gave the highest relevance to the variables "resection type" and "largest tumor size" for predicting surgery complexity and postoperative outcomes. In addition, we explored between surgeries converted to open and non-converted, finding statistically significant differences in the variables "tumor location," "blood loss," "complications," and "operation time." CONCLUSION: We have observed how the application of SHAP allows us to understand the predictions of AI models in surgical complexity and the postoperative outcomes of laparoscopic liver surgery in segments 7 and 8.

Tratamiento con TRIAC en pacientes pediátricos con deficiencia de MCT8 / Treatment with TRIAC in pediatric patients with MCT8

Los transportadores de monocarboxilatos (MCT) permiten el ingreso celular de hormonas tiroideas, especialmente en el sistema nervioso central (SNC), donde son indispensables para el neurodesarrollo. La deficiencia de MCT8 produce la combinación de hipotiroidismo en SNC e hipertiroidismo periférico, caracterizada por T3 elevada. El único tratamiento actualmente disponible es el ácido 3,3',5-triyodotiroacético (TRIAC), un análogo de hormonas tiroideas que tiene como objetivo mejorar la tirotoxicosis periférica y prevenir la progresión del deterioro neurológico. En el presente artículo, se evalúan las características clínicas, imagenológicas, bioquímicas y genéticas de 4 pacientes con deficiencia de MCT8 tratados con TRIAC hasta la fecha, las dosis utilizadas y la respuesta al tratamiento.

Monocarboxylate transporters (MCTs) allow the cellular entry of thyroid hormones, especially into the central nervous system (CNS), where they are crucial for neurodevelopment. MCT8 deficiency results in the combination of hypothyroidism in the CNS and peripheral hyperthyroidism, characterized by elevated T3 levels. The only treatment currently available is 3,3',5-triiodothyroacetic acid (TRIAC), a thyroid hormone analogue aimed at improving peripheral thyrotoxicosis and preventing the progression of neurological impairment. Here we assess the clinical, imaging, biochemical, and genetic characteristics of 4 patients with MCT8 deficiency who have received TRIAC to date, the doses used, and the response to treatment.

Registro multicéntrico Impella CP para shock cardiogénico o angioplastía de alto riesgo protegida en Chile

Antecedentes: El Shock Cardiogénico (SC) y las Angioplastías de Alto Riesgo (AAR) están asociadas con altas tasas de mortalidad. El uso del dispositivo Impella CP podría reducir el riesgo de muerte en estos escenarios. En Chile no existen reportes evaluando el uso del dispositivo Impella CP. Objetivo: Analizar los desenlaces clínicos en pacientes que fueron sometidos al uso del dispositivo Impella CP por SC o por AAR. Métodos: Se realizó un estudio retrospectivo en 17 pacientes, los cuales representan el total de implantes realizados en el país, entre octubre 2021 y agosto 2023. Se describió las características, demográficas, procedimentales y después del implante. Se estimó la mortalidad general y se identificaron factores asociados. Resultados: La edad de los pacientes fue 69± 3,7 años y 88,2% fueron hombres. El 64,7% recibió el dispositivo por SC y 35,3% por AAR. Dentro de las comorbilidades estudiadas, la hipertensión arterial fue la más frecuente, 94,1%. Un 58,8% de los pacientes fueron revascularizados a través de la arteria radial. El 29,4% recibió el dispositivo previo a la angioplastía y 70,6% lo recibió después. El 47,1% de las angioplastías fue guiada por imágenes. En 11,8% de ellos se realizó litotricia intracoronaria y 5,9% por ablación intracoronaria. Los pacientes estuvieron 13 ±3,4 días con el soporte. La mortalidad global fue de 41,2%. Conclusiones: El uso del dispositivo Impella presentó pocas complicaciones vasculares. La mortalidad asociada con su colocación en Chile fue relativamente similar con la reportada en la literatura.

Background: Cardiogenic shock and high-risk Angioplasty are associated with a high mortality rate. Using the Impella CP device could reduce the risk of death in these scenarios. In Chile, there are no studies evaluating the use of the Impella CP device. Objective: To analyse the clinical outcomes in patients who have undergone placement of the Impella CP device for cardiogenic shock and high-risk angioplasties. Methods: A retrospective study was carried out on 17 patients, which represent the total number of implants performed in the country, between October 2021 and August 2023. The demographic, procedural and post-implant characteristics were described. Overall mortality and associated factors were identified. Results: The age was 69± 3.7 years, where 88.2% were men. 64.7% of patients received the device by SC and 35.3% by AAR. Among the comorbidities studied, arterial hypertension was the most frequent with 94.1%. 58.8% of patients were revascularized through the radial artery. 29.4% of patients received the device before angioplasty and 70.6% received it afterwards. 47.1% of angioplasties were image-guided, 11.8% had intracoronary lithotripsy, and 5.9% had intracoronary ablation. The patients spent 13 ±3.4 days with the support. Overall mortality was 41.2%. Conclusion: use of the Impella device was associated with few vascular complications. Mortality associated with use of the Impella device in Chile was similar to that previously reported in other studies.

5 years DKMS Chile: approach, results and impact of the first unrelated stem cell donor center in Chile.

Introduction: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is performed worldwide to treat blood cancer and other life-threatening blood disorders. As successful transplantation requires an HLA-compatible donor, unrelated donor centers and registries have been established worldwide to identify donors for patients without a family match. Ethnic minorities are underrepresented in large donor registries. Matching probabilities are higher when donors and patients share the same ethnic background, making it desirable to increase the diversity of the global donor pool by recruiting donors in new regions. Here, we report the establishment and the first 5 years of operation of the first unrelated stem cell donor center in Chile, a high-income country in South America with a population of over 19 million. Methods: We used online and in-person donor recruitment practices through patient appeals and donor drives in companies, universities, the armed forces, and public services. After confirmatory typing donors were subjected to medical work-up and cleared for donation. Results: We recruited almost 170,000 donors in 5 years. There were 1,488 requests received for confirmatory typing and donor availability checks, of which 333 resulted in medical work-up, leading to 194 stem cell collections. Products were shipped to Chile (48.5%) and abroad. Even when the COVID-19 pandemic challenged our activities, the number of donors recruited and shipped stem cell products remained steady. In Chile there was an almost 8-fold increase in unrelated donor transplantation activity from 16 procedures in 2016-2018 to 124 procedures in 2019-2021, mainly for pediatric patients following the center's establishment. We estimate that 49.6% of Chilean patients would find at least one matched unrelated donor in the global DKMS donor pool. Discussion: Establishing a DKMS donor center in Chile has significantly increased donor availability for Chilean patients and contributed to an increase of unrelated donor stem cell transplant activity.

Diagnosing and monitoring pancreatic cancer through cell-free DNA methylation: progress and prospects.

Pancreatic cancer is one of the most challenging cancers due to its high mortality rates. Considering the late diagnosis and the limited survival benefit with current treatment options, it becomes imperative to optimize early detection, prognosis and prediction of treatment response. To address these challenges, significant research efforts have been undertaken in recent years to develop liquid-biopsy-based biomarkers for pancreatic cancer. In particular, an increasing number of studies point to cell-free DNA (cfDNA) methylation analysis as a promising non-invasive approach for the discovery and validation of epigenetic biomarkers with diagnostic or prognostic potential. In this review we provide an update on recent advancements in the field of cfDNA methylation analysis in pancreatic cancer. We discuss the relevance of DNA methylation in the context of pancreatic cancer, recent cfDNA methylation research, its clinical utility, and future directions for integrating cfDNA methylation analysis into routine clinical practice.

Exercise-based training programs for patients with chronic Chagas cardiomyopathy: A systematic review and meta-analysis.

Background: We assessed the effects of exercise-based training programs (EBTP) in patients with chronic Chagas cardiomyopathy (CCC) through a systematic review and meta-analysis. Methods: We conducted a search in Pubmed/Medline, Embase, Scopus, Web of Science, Cochrane Library, Virtual Health Library, and SciELO until January 2023. Randomized controlled trials (RCTs) and non-randomized intervention studies (NRIS) investigating the effects of EBTP in CCC patients were included. The primary outcomes were all-cause mortality, cardiovascular mortality, and health-related quality of life (HRQoL), and the secondary outcomes were exercise capacity by peak VO2, heart failure-related hospital admissions (HFRHA), and left ventricular ejection fraction (LVEF). Results: The search strategy yielded 3617 studies. After removing duplicates and screening, eight studies (3 RCTs and 5 NRIS) involving 222 patients were included. Seven studies were conducted in Brazil. The age range was from 30 to 71 years, and 47.1% were male. Data on mortality, HRQoL, LVEF, and HFRHA were scarcely reported. The meta-analysis pooling four studies showed that the peak VO2 was significantly higher (mean difference 4.45, 95% confidence interval 3.50 to 5.39 mL/kg/min, I2 = 0%) in the EBTP group compared to the control group. Conclusion: The evidence available was limited and heterogeneous. While EBTP has shown to improve HRQoL and exercise capacity, there is no conclusive information about the other proposed outcomes. These positive effects present an opportunity to provide treatment to CCC patients in low- and middle-income countries. Further studies are needed to ascertain the effects of EBTP on hard outcomes in this population.Registration number: CRD42022334060.

Organ xenotransplantation acceptance in veterinary students: A multicentric opinion study in Spain.

BACKGROUND: The shortage of available transplant organs has made it necessary to search for alternatives, one of which is xenotransplantation. However, the use of animal organs could face rejection from society and the personnel involved in its implementation. OBJECTIVES: (a) to analyze the attitudes of Veterinary Degree students in six Spanish Universities towards xenotransplantation; and (b) to determine the factors that affect its acceptance. METHODS: Of the 2815 students surveyed in the degree program, 2683 valid surveys were obtained. Attitudes towards organ xenotransplantation were evaluated using a validated questionnaire of organ donation. RESULTS: If xenotransplantation was confirmed as a clinical reality, 93% (n = 2493) of those surveyed would accept a xenotransplanted organ, whilst 7% would not. If the results of xenotransplantation were worse than those obtained with human donors and it entailed more risk, 12% (n = 318) would be in favor. 56% (n = 1497) of the students would accept a xenotransplantation provisionally pending the arrival of a human organ. Attitudes towards xenotransplantation were affected by the academic year in which a student was studying, with more favorable attitudes among students in the last year (88% in first year vs. 95% in fifth year; p < .001). More favorable attitudes are also observed depending on the attitude they have towards organ transplantation, with those students being more in favor of donating their organs when they die (94% vs. 88%; p < .001). CONCLUSION: Veterinary students would have a very favorable attitude toward xenotransplantation if these animal organs functioned as well as human organs. Therefore, these students could play an important role in the future promotion of this technique.

Endothelial cell activation mediated by cold ischemia-released mitochondria is partially inhibited by defibrotide and impacts on early allograft function following liver transplantation.

DAMPs (danger-associated molecular patterns) are self-molecules of the organism that appear after damage. The endothelium plays several roles in organ rejection, such as presenting alloantigens to T cells and contributing to the development of inflammation and thrombosis. This study aimed to assess whether DAMPs present in the organ preservation solution (OPS) after cold ischemic storage (CIS) contribute to exacerbating the endothelial response to an inflammatory challenge and whether defibrotide treatment could counteract this effect. The activation of cultured human umbilical vein endothelial cells (HUVECs) was analyzed after challenging with end-ischemic OPS (eiOPS) obtained after CIS. Additionally, transwell assays were performed to study the ability of eiOPS to attract lymphocytes across the endothelium. The study revealed that eiOPS upregulated the expression of MCP-1 and IL-6 in HUVECs. Moreover, eiOPS increased the membrane expression of ICAM-1and HLA-DR, which facilitated leukocyte migration toward a chemokine gradient. Furthermore, eiOPS demonstrated its chemoattractant ability. This activation was mediated by free mitochondria. Defibrotide was found to partially inhibit the eiOPS-mediated activation. Moreover, the eiOPS-mediated activation of endothelial cells (ECs) correlated with early allograft dysfunction in liver transplant patients. Our finding provide support for the hypothesis that mitochondria released during cold ischemia could trigger EC activation, leading to complications in graft outcomes. Therefore, the analysis and quantification of free mitochondria in the eiOPS samples obtained after CIS could provide a predictive value for monitoring the progression of transplantation. Moreover, defibrotide emerges as a promising therapeutic agent to mitigate the damage induced by ischemia in donated organs.