Generalized lymphatic anomaly (GLA) is a vascular disorder characterized by diffuse or multifocal lymphatic malformations (LMs). The etiology of GLA is poorly understood. We identified four distinct ...somatic
variants (Glu542Lys, Gln546Lys, His1047Arg, and His1047Leu) in tissue samples from five out of nine patients with GLA. These same
variants occur in
-related overgrowth spectrum and cause hyperactivation of the PI3K-AKT-mTOR pathway. We found that the mTOR inhibitor, rapamycin, prevented lymphatic hyperplasia and dysfunction in mice that expressed an active form of
(His1047Arg) in their lymphatics. We also found that rapamycin reduced pain in patients with GLA. In conclusion, we report that somatic activating
mutations can cause GLA, and we provide preclinical and clinical evidence to support the use of rapamycin for the treatment of this disabling and deadly disease.
Background & Aims There is an increasing discrepancy between the number of potential liver graft recipients and the number of organs available. Organ allocation should follow the concept of benefit ...of survival, avoiding human-innate subjectivity. The aim of this study is to use artificial-neural-networks (ANNs) for donor-recipient (D-R) matching in liver transplantation (LT) and to compare its accuracy with validated scores (MELD, D-MELD, DRI, P-SOFT, SOFT, and BAR) of graft survival. Methods 64 donor and recipient variables from a set of 1003 LTs from a multicenter study including 11 Spanish centres were included. For each D-R pair, common statistics (simple and multiple regression models) and ANN formulae for two non-complementary probability-models of 3-month graft-survival and -loss were calculated: a positive-survival (NN-CCR) and a negative-loss (NN-MS) model. The NN models were obtained by using the Neural Net Evolutionary Programming (NNEP) algorithm. Additionally, receiver-operating-curves (ROC) were performed to validate ANNs against other scores. Results Optimal results for NN-CCR and NN-MS models were obtained, with the best performance in predicting the probability of graft-survival (90.79%) and -loss (71.42%) for each D-R pair, significantly improving results from multiple regressions. ROC curves for 3-months graft-survival and –loss predictions were significantly more accurate for ANN than for other scores in both NN-CCR (AUROC-ANN = 0.80 vs. –MELD = 0.50; -D-MELD = 0.54; -P-SOFT = 0.54; -SOFT = 0.55; –BAR = 0.67 and -DRI = 0.42) and NN-MS (AUROC-ANN = 0.82 vs. –MELD = 0.41; -D-MELD = 0.47; -P-SOFT = 0.43; -SOFT = 0.57, -BAR = 0.61 and -DRI = 0.48). Conclusions ANNs may be considered a powerful decision-making technology for this dataset, optimizing the principles of justice, efficiency and equity. This may be a useful tool for predicting the 3-month outcome and a potential research area for future D-R matching models.
Enteral nutrition (EN) therapy in ICU patients requiring oxygen therapy with high-flow nasal cannula (HFNC) and/or noninvasive mechanical ventilation (NIMV) is controversial. A prospective, cohort, ...observational, and multicenter study was conducted in 10 ICUs in Spain to analyze the 90-day mortality, tolerance, side effects, and infectious complications of trophic EN in patients requiring HFNC therapy and/or NIVM. A total of 149 patients were enrolled. The mean age, severity scores, tracheobronchitis, bacteremia, and antimicrobial therapy were significantly higher in deceased than in living patients (
< 0.05), and the mortality rate was 14.8%. A total of 110 patients received oral trophic feedings, 36 patients received nasogastric tube feedings (NGFs), and 3 received mixed feedings. Trophic EN was discontinued in only ten (14.9%) patients because of feeding-related complications. The variables selected for the multivariate logistic regression on feeding discontinuation were SOFA upon admission (OR per unit = 1.461) and urea (OR per mg/dL = 1.029). There were no significant differences in the development of new infections according to the route of EN administration. Early trophic feeding administered to patients with acute respiratory failure requiring noninvasive ventilation is safe and feasible, and is associated with few dietary and infectious complications in a mortality, setting comparable to similar studies.
Aims: The purposes of this research were to study the convergent validity of the Mode and Frequency of Commuting To and From School Questionnaire using objectively assessed steps and time spent in ...different physical activity intensities and to compare the self-reported versus objective journey time in Spanish youths. Methods: Three hundred and eighty-nine Spanish youth aged 7–19 years were asked to complete the questionnaire and wore an accelerometer for five days. The objective commuting distance and time from home to school were estimated using Google MapsTM. Results: There were significant differences between passive and walking participants on step numbers, sedentary time and physical activity levels (except for vigorous physical activity in children). For children, a mean difference of −4.03 minutes between objective measured and self-reported journey time was found (95% limits of agreement were 13.55 and −21.60 minutes). For adolescents, the mean difference was −1.39 minutes (95% limits of agreement were 15.23 and −18.02 minutes). Conclusions: The findings indicated that the Mode of Commuting To and From School Questionnaire showed a convergent validity to assess this behaviour in Spanish youths. Self-reported journey time for walking is comparable to Google MapsTM in adolescents but not in children.
Chronic graft versus host disease (cGVHD) is a life-threatening complication of allogeneic hematopoietic stem cell transplantation that generates considerable morbidity and compromises the physical ...capacity of patients. We determined the effects of an exercise training program performed after allogeneic hematopoietic stem cell transplantation on clinical and biological variables in a minor histocompatibility antigen-driven murine model of cGVHD treated with cyclosporine A.
Recipient BALB/C female mice (age 8 wk) received bone marrow cells and splenocytes from donor B10.D2 male mice and were randomly assigned to an exercise (n = 11) or control group (n = 12). For approximately 11 wk after transplant, the exercise group completed a moderate-intensity treadmill program. Variables assessed were clinical severity scores, survival, physical fitness, cytokine profile, immune cell reconstitution, molecular markers of muscle exercise adaptations, and histological scores in affected tissues.
Exercise training increased survival (P = 0.011), diminished total clinical severity scores (P = 0.002), improved physical fitness (P = 0.030), and reduced blood IL-4 and tumor necrosis factor α levels (P = 0.03), while increasing circulating B220 (P = 0.008) and CD4 lymphocytes (P = 0.043).
A moderate-intensity exercise program that mimics widely accepted public health recommendations for physical activity in human adults was well tolerated and positive effects on survival as well as on clinical and biological indicators of cGVHD.
The Gender-Equity Model for liver Allocation corrected by serum sodium (GEMA-Na) and the Model for End-stage Liver Disease 3.0 (MELD 3.0) could amend sex disparities for accessing liver ...transplantation (LT). We aimed to assess these inequities in Spain and to compare the performance of GEMA-Na and MELD 3.0.
Nationwide cohort study including adult patients listed for a first elective LT (January 2016–December 2021). The primary outcome was mortality or delisting for sickness within the first 90 days. Independent predictors of the primary outcome were evaluated using multivariate Cox's regression with adjusted relative risks (RR) and 95% confidence intervals (95% CI). The discrimination of GEMA-Na and MELD 3.0was assessed using Harrell c-statistics (Hc).
The study included 6071 patients (4697 men and 1374 women). Mortality or delisting for clinical deterioration occurred in 286 patients at 90 days (4.7%). Women had reduced access to LT (83.7% vs. 85.9%; p = 0.037) and increased risk of mortality or delisting for sickness at 90 days (adjusted RR = 1.57 95% CI 1.09–2.28; p = 0.017). Female sex remained as an independent risk factor when using MELD or MELD-Na but lost its significance in the presence of GEMA-Na or MELD 3.0. Among patients included for reasons other than tumours (n = 3606; 59.4%), GEMA-Na had Hc = 0.753 (95% CI 0.715–0.792), which was higher than MELD 3.0 (Hc = 0.726 95% CI 0.686–0.767; p = 0.001), showing both models adequate calibration.
GEMA-Na and MELD 3.0 might correct sex disparities for accessing LT, but GEMA-Na provides more accurate predictions of waiting list outcomes and could be considered the standard of care for waiting list prioritization.
Instituto de Salud Carlos III, Agencia Estatal de Investigación (Spain), and European Union.
Graft-versus-host-disease (GVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT), which is associated with high morbimortality and decreased patients' ...physical capacity. We evaluated the effects of an 11-week moderate-intensity exercise (treadmill) training program performed after allo-HSCT in a murine acute (aGVHD) and chronic GVHD model (cGVHD). Female mice (aged 8–12 weeks) were randomly assigned to the exercise or the control group. They completed a maximal treadmill test before allo-HSCT (with donor bone marrow cells and splenocytes) and after the 11-week period, during which we evaluated clinical severity scores and survival (Kaplan–Meier method). Before allo-HSCT and at days +21, +52 and +83 (upon sacrifice), we collected blood samples for immune cell reconstitution and cytokine analysis. The main results were that (i) in aGVHD, exercise improved maximal physical capacity over the 11-week period compared with pre-allo-HSCT conditions (p < 0.001 for the between-group comparison) and benefited total clinical score evolution (p = 0.05 for the group×time interaction effect), without altering immune reconstitution; (ii) in cGVHD, exercise training resulted in a lesser deterioration of physical capacity after 11 weeks (p = 0.023). Our results highlight the potential beneficial effects of exercise as coadjuvant intervention against GVHD, especially in the acute form of the disease.
Despite administration of annual influenza vaccination, influenza-associated complications in transplant recipients continue to be an important cause of hospitalization and death. Although influenza ...vaccination has been proven to be the most effective measure to reduce influenza infection after transplantation, transplant recipients are still vulnerable to influenza infections, with lower serological responses to vaccination compared to the general population. In order to assess the efficacy and safety of an alternative immunization scheme for solid organ transplant recipients, the TRANSGRIPE1-2 Study Group aimed to test a booster dose administration 5 weeks after the standard vaccination. The primary objective of this trial was to compare short-term and long-term neutralizing antibody immunogenicity of a booster dose of influenza vaccination to the standard single-dose immunization scheme. Secondary objectives included the evaluation of the efficacy and/or safety, cellular immune response, incidence of influenza infection, graft rejection, retransplant and mortality rates.
This phase III, randomized, controlled, open-label clinical trial was conducted between October 2012 and December 2013 in 12 Spanish public referral hospitals. Solid organ transplant recipients (liver, kidney, heart or lung), older than 16 years of age more than 30 days after transplantation were eligible to participate. Patients (N = 514) were stratified 1:1 by center, type of organ and time after transplantation and who either received the standard single dose (n = 257) or were treated according to a novel influenza vaccination schedule comprising the administration of a booster dose 5 weeks after standard vaccination (n = 254). Seroconversion rates were measured as a determinant of protection against influenza (main outcome). Efficacy and safety outcomes were followed until 1 year after influenza vaccination with assessment of short-term (0, 5, 10 and 15 weeks) and long-term (12 months) results. Intention-to-treat, per-protocol and safety analyses will be performed.
This trial will increase knowledge about the safety and efficacy of a booster dose of influenza vaccine in solid organ transplant recipients. At the time the manuscript was submitted for publication, trial recruitment was closed with a total of 499 participants included during a 2-month period (within the seasonal influenza vaccination campaign).
ClinicalTrials.gov Identifier: NCT01761435 (registered 13 December 2012). EudraCT Identifier: 2011-003243-21 (registered 4 July 2011).
ResumenLa metodología docente “service-learning”, como su nombre indica, combina en un proyecto único, un servicio a la comunidad con un aprendizaje académico relacionado con el curriculum del ...estudiante. En esta comunicación se presentan los resultados obtenidos en dos proyectos docentes que han utilizado este método para facilitar a los estudiantes de Grado la adquisición de conocimientos significativos y el desarrollo de habilidades personales y sociales difíciles de conseguir con las metodologías tradicionales. Estos proyectos han sido desarrollados por un grupo de profesores que imparten docencia en la Facultad de Ciencias Biológicas y Ambientales de la Universidad de León, en los Grados en Biología, Biotecnología y Ciencias Ambientales, durante los cursos 2014-15 y 2015-16. Con la introducción de la metodología docente “service-learning” se consigue que la Universidad se abra a la sociedad y alcance una conexión real con su entorno, avanzando en lo que se ha denominado la tercera misión de la universidad. El fin último de estos proyectos, es que tanto los estudiantes como los profesores universitarios conozcan las potencialidades de esta metodología y se planteen incorporarla institucionalmente, como ya se hace en otras Universidades americanas y europeas. Abstract Service-learning is a teaching and learning methodology that integrates community service with academic coursework, enhancing the students’ learning experience. This communication summarizes the results obtained in two teaching projects in which students applied course contents to community-based activities, incorporating learning and community action goals. These projects were designed by a group of university professors from the Faculty of Biological and Environmental Sciences of the University of León, and were carried out by a selected group of students from the Degrees in Biology, Biotechnology and Environmental Sciences, in collaboration with different community partners. The purpose of these teaching experiences was to provide the students with a hand-on experience that linked personal and social development, helping them to develop new skills difficult to acquire with traditional teaching methods. Moreover, service-learning projects enhance community-university relations improving institutional commitment with the society. Our final goal is to publicize the benefits of community engagement pedagogies like service-learning among students and professors and to set the path to integrate them into the existing curriculum of the University of Leon.
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