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Post-transplant lymphoproliferative disorders (PTLD) represent a broad spectrum of lymphoid proliferations, frequently associated with Epstein-Barr Virus (EBV) infection. The molecular profile of pediatric monomorphic PTLDs (mPTLD) has not been elucidated and it is unknown whether they display similar genetic features as their counterpart in adult and immunocompetent (IMC) pediatric patients. In this study, we investigated 31 pediatric mPTLD after solid organ transplantation, including 24 diffuse large B-cell lymphomas (DLBCL), mostly classified as activated B-cell, and seven Burkitt lymphoma (BL), 93% of which were EBV positive. We performed an integrated molecular approach, including fluorescence in situ hybridization, targeted gene sequencing and copy-number (CN) arrays. Overall, PTLD-BL carried mutations in MYC,ID3, DDX3X, ARID1A or CCND3 resembling IMC-BL, higher mutational burden than PTLD-DLBCL and less CN alterations than IMC-BL. PTLD-DLBCL showed a very heterogeneous genomic profile with fewer mutations and CN alterations than IMC-DLBCL. Epigenetic modifiers and genes of Notch pathway were the most recurrently mutated in PTLD-DLBCL (both 28%). Mutations in cell cycle and Notch pathways correlated with worse outcome. All seven PTLD-BL were alive after treatment with pediatric B-cell Non-Hodgkin Lymphoma protocols, whereas 54% of DLBCL patients were cured with immunosuppression reduction, rituximab and/or low-dose chemotherapy. These findings highlight the low complexity of pediatric PTLD-DLBCL, their good response to low intensity treatment and the shared pathogenesis between PTLD-BL and EBV+ IMC-BL. We also suggest new potential parameters that could help in the diagnosis and the design of better therapeutic strategies for these patients.

Treballs Finals de Grau d'Enginyeria Biomèdica. Facultat de Medicina i Ciències de la Salut. Universitat de Barcelona. Curs: 2021-2022. Tutora: Carme Junqué Plaja, [cat] bla bla bla, [spa] ble ble ble

Tacrolimus (Tac) is a pivotal immunosuppressant agent used to prevent graft-versus-host disease (GVHD) after allogeneic stem cell transplantation (alloHSCT). Tac is characterized by a narrow therapeutic window and a high inter-patient and intra-patient pharmacokinetic variability (IPV). Although high IPV of Tac concentrations has been associated with adverse post-transplant outcomes following solid organ transplantation, the effects of Tac IPV on alloHSCT recipients have not been determined. Tac IPV was therefore retrospectively evaluated in 128 alloHSCT recipients receiving high-dose post-transplant cyclophosphamide (PTCy) and the effects of Tac IPV on the occurrence of acute GVHD (aGVHD) were analyzed. Tac IPV was calculated from pre-dose concentrations (C0) measured during the first month after Tac initiation. The cumulative rates of grades II-IV and grades III-IV aGVHD at day +100 were 22.7% and 7%, respectively. Higher Tac IPV was associated with a greater risk of developing GVHD, with patients having IPV > 50th percentile having significantly higher rates of grades II-IV (34.9% vs. 10.8%; hazard ratio [HR] 3.858, p < 0.001) and grades III-IV (12.7% vs. 1.5%; HR 9.69, p = 0.033) aGVHD than patients having IPV ≤ 50th percentile. Similarly, patients with IPV > 75th percentile had higher rates of grades II-IV (41.9% vs. 16.5%; HR 3.30, p < 0.001) and grades III-IV (16.1% vs. 4.1%; HR 4.99, p = 0.012) aGVHD than patients with IPV ≤ 75th percentile. Multivariate analyses showed that high Tac IPV (>50th percentile) was an independent risk factor for grades II-IV (HR 2.99, p = 0.018) and grades III-IV (HR 9.12, p = 0.047) aGVHD. Determination of Tac IPV soon after alloHSCT could be useful in identifying patients at greater risk of aGVHD.

Several genetic polymorphisms of the innate immune system have been described to increase the risk of cytomegalovirus (CMV) infection in transplant patients. The aim of this study was to assess the impact of a polygenic score to predict CMV infection and disease in high risk CMV transplant recipients (heart, liver, kidney or pancreas). On hundred and sixteen CMV-seronegative recipients of grafts from CMV-seropositive donors undergoing heart, liver, and kidney or pancreas transplantation from 7 centres were prospectively included for this purpose during a 2-year period. All recipients received 100-day prophylaxis with valganciclovir. CMV infection occurred in 61 patients (53%) at 163 median days from transplant, 33 asymptomatic replication (28%) and 28 CMV disease (24%). Eleven patients (9%) had recurrent CMV infection. Clinically and/or functionally relevant single nucleotide polymorphisms (SNPs) from TLR2, TLR3, TLR4, TLR7, TLR9, AIM2, MBL2, IL28, IFI16, MYD88, IRAK2 and IRAK4 were assessed by real time polymerase chain reaction (RT-PCR) or sequence-based typing (PCR-SBT). A polygenic score including the TLR4 (rs4986790/rs4986791), TLR9 (rs3775291), TLR3 (rs3775296), AIM2 (rs855873), TLR7 (rs179008), MBL (OO/OA/XAO), IFNL3/IL28B (rs12979860) and IFI16 (rs6940) SNPs was built based on the risk of CMV infection and disease. The CMV score predicted the risk of CMV disease with an AUC of the model of 0.68, with sensitivity and specificity of 64.3 and 71.6%, respectively. Even though further studies are needed to validate this score, its use would represent an effective model to develop more robust scores predicting the risk of CMV disease in donor/recipient mismatch (D+/R-) transplant recipients., This work was supported by Spanish Ministerio de Sanidad y Consumo (FIS PI12/01743), Instituto de Salud Carlos III, Fondo Europeo de Desarrollo Regional (FEDER). Unión Europea. “Una manera de hacer Europa”; Network for the Research in Infectious Diseases (REIPI) from the Instituto de Salud Carlos III, Madrid, Spain; and Ministerio de Ciencia e Innovación (PID2019-106658RB-I00, funded by MCIN/AEI/10.13039/501100011033). MF-R holds a research contract “Miguel Servet” (CP18/00073) from the Instituto de Salud Carlos III, Spanish Ministerio de Ciencia e Innovación.

Due to the high vulnerability of the pancreas to ischemia-reperfusion injury, choices regarding preservation solution markedly affect pancreas transplant success. A retrospective single-center analysis of 380 pancreas transplants (2000–2019) was performed to correlate current preservation solutions with transplant outcomes. Early graft failure requiring transplantectomy within 30 days post-transplant occurred in 7.5% for University of Wisconsin (UW) group (n = 267), 10.8% of Celsior (CS) group (n = 83), 28.5% of Histidine-Tryptophan-Ketoglutarate (HTK) group (n = 7), and none for Institut Georges Lopez-1 (IGL-1) group (n = 23). The most common causes of technical failures in this cohort included abdominal hemorrhage (8.4%); graft pancreatitis (3.7%); fluid collections (2.6%); intestinal complications (6.6%); and vascular thrombosis (20.5%). Although IGL-1 solution provided lower surgical complication rates, no significant differences were found between studied groups. Nevertheless, HTK solution was associated with elevated pancreatitis rates. The best graft survival was achieved at 1 year using UW and IGL-1, and at 3 and 5 years using IGL-1 (p = 0.017). There were no significant differences in patient survival after a median follow-up of 118.4 months. In this setting therefore, IGL-1 solution appears promising for perfusion and organ preservation in clinical pancreas transplantation, compared to other commonly used solutions., This work was supported by grant from Ministerio de Ciencia, Innovación y Universidades, reference PID2019-104130RB-I00 awarded to EF-P.

Macrophages have mechanisms for eliminating cholesterol from cells. If excess cholesterol is not eliminated from the macrophages, then transformation into a foam cell may occur. Foam cells are a hallmark of the atherosclerotic lesions that contribute to the development and rupture of atherosclerotic plaques. Several in vitro and in vivo studies have shown changes in the macrophage phenotype and improved phagocytosis after the acquisition of functional mitochondria. However, the effect of mitochondrial transplantation on promoting phagocytosis and phenotypic changes in lipid-loaded macrophages leading to foam cells has not been studied. We aimed to prove that the transplantation of healthy mitochondria to highly cholesterol-loaded macrophages induces macrophage phagocytosis and reduces the macrophage shift towards foam cells. For this purpose, using a murine macrophage cell line, RAW264.7, we determined if mitochondria transplantation to 7-ketocholesterol (7-KC)-loaded macrophages reduced lipid accumulation and modified their phagocytic function. We evidenced that mitochondrial transplantation to 7-KC-loaded macrophages reestablished phagocytosis and reduced lipid content. In addition, CPT1a expression and antiinflammatory cytokines were restored after mitochondrial transplantation. We have developed a potential therapeutic approach to restore foam cell functionality., This study was funded by grant from the Fondo de Investigación Sanitaria (FIS), reference PI20/00900, awarded to G.H.

Simple Summary We present the long-term results of patients receiving allogeneic stem cell transplantation (allo-SCT) for relapsed/refractory mantle cell lymphoma (R/R MCL) in the last 25 years in Spain. We conclude that allo-SCT may be a curative option in R/R MCL with a low cumulative incidence (CI) of relapse, although non-relapse mortality (NRM) is still high, which is mainly secondary to acute graft-versus-host disease (aGVHD). Results are better for fit patients, using HLA-identical (related or unrelated) or haploidentical related donors and without previous ASCT. However, the arrival of new highly effective and low toxic immunotherapeutic or targeted therapies inevitably will relegate allo-SCT to those fit patients who fail these therapies, being administered far away from the optimal timing. Allo-SCT is a curative option for selected patients with relapsed/refractory (R/R) MCL, but with significant NRM. We present the long-term results of patients receiving allo-SCT in Spain from March 1995 to February 2020. The primary endpoints were EFS, OS, and cumulative incidence (CI) of NRM, relapse, and GVHD. We included 135 patients, most (85%) receiving RIC. After a median follow-up of 68 months, 5-year EFS and OS were 47 and 50%, respectively. Overall and CR rates were 86 and 80%. The CI of relapse at 1 and 3 years were 7 and 12%. NRM at day 100 and 1 year were 17 and 32%. Previous ASCT and Grade 3-4 aGVHD were associated with a higher NRM. Grade 3-4 aGVHD, donor type (mismatch non-related), and the time-period 2006-2020 were independently related to worse EFS. Patients from 1995-2005 were younger, most from HLA-identical sibling donors, and were pretreated less. Our data confirmed that allo-SCT may be a curative option in R/R MCL with low a CI of relapse, although NRM is still high, being mainly secondary to aGVHD. The arrival of new, highly effective and low toxic immunotherapeutic or targeted therapies inevitably will relegate allo-SCT to those fit patients who fail these therapies, far away from the optimal timing of treatment.

Post-transplantation cyclophosphamide (PTCY) effectively prevents graft-versus-host disease (GVHD) after unmanipulated HLA-haploidentical hematopoietic stem cell transplantation (HSCT) and achieves low rates of GVHD in HLA-identical transplantation. To compare the outcomes of haploidentical versus HLA identical HSCT in patients undergoing HSCT for acute myeloid leukemia (AML) using PTCY. We conducted a retrospective study of 229 patients undergoing first HSCT for AML using PTCY with additional immunosuppression, 99 from matched sibling or unrelated donor (MSD/MUD) performed in 3 hospitals and 130 from haploidentical donors (haplo group) performed in 20 hospitals within the Spanish Group of Hematopoietic Stem Cell Transplantation and Cellular Therapy. Peripheral blood stem cells were used as graft in 89% of patients; myeloablative conditioning was used in 56%. There were significantly more patients with active disease (5% versus 20%, P = .001), high/very high disease risk index (DRI) (32% versus 67%, P = .000) and prior auto-HSCT (2% versus 11%, P = .010) in the haplo group. Median follow-up was 27 and 62.5 months for MSD/MUD and haplo, respectively. At 2 years, no significant differences were observed in overall survival (OS) (72% versus 62%, P = .07), event-free survival (EFS) (70% versus 54%, P = .055), cumulative incidence of relapse (19% versus 25%, P = .13), non-relapse mortality (14% versus 19%, P = .145), and the composite endpoint of GVHD and relapse-free survival (49% versus 42%, P = .249). Multivariate analysis identified only age and active disease as significant risk factors for OS and EFS; reduced-intensity conditioning, high/very high DRI, and haplo donor were nearly statistically significant for these outcomes. Grade II-IV acute GVHD was lower in MSD/MUD (14% versus 47%, P = .000). Cumulative incidences of grade III-IV acute GVHD (4% versus 9%, P = .14) and moderate-severe chronic GVHD (22% versus 19%, P = .28) were similar. Limitations of our study include limited sample size, differences between haplo and MSD/MUD groups and heterogeneous additional immunosuppression and PTCY timing in MSD/MUD. The use of an HLA-identical donor with PTCY in patients with AML showed lower incidence of clinically significant grade II-IV acute GVHD compared to haplo donors. Further studies with larger sample sizes should be performed to establish a possible benefit of HLA-identical donor on survival. (c) 2022 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Treballs Finals de Grau de Química, Facultat de Química, Universitat de Barcelona, Any: 2022, Tutors: Rafael Franco Fernandez, Mercè Brunet Serra, Liver transplanted patients receive strong immunosuppressive drugs with the aim of preventing allograft rejection. Although nowadays new drugs and surgical techniques and technologies are being used, the diagnose of allograft rejection is still a concern. This is due to the conventional biomarkers that are used in order to diagnose allograft rejection. Their values are often abnormal, or they are not able to discriminate this disease from others, and thus it is needed to perform a biopsy which is related with complications. It is though needed new sensitive and specific biomarkers for screening and monitoring liver transplanted patients. miRNAs are a subtype of noncoding RNAs which have been studied the past decades and appear to be biomarkers related with several diseases. In this study, we are going to evaluate different miRNAs (miRNA-155-5p, miRNA-181a-5p and miRNA-122-5p), in order to predict allograft rejection. Their analysis will be performed via quantitative real-time polymerase chain reaction, and we will obtain their expression in plasma. Rejector patients will be compared to non-rejector patients through statistical treatment of the miRNAs expression.

Mature T-cell lymphomas constitute the most common indication for allogeneic hematopoietic cell transplantation (allo-HCT) of all lymphomas. Large studies evaluating contemporary outcomes of allo-HCT in mature T-cell lymphomas relative to commonly used donor sources are not available. Included in this registry study were adult patients who had undergone allo-HCT for anaplastic large cell lymphoma, angioimmunoblastic T-cell lymphoma (AITL), or peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) between 2008 and 2018. Hematopoietic cell transplantation (HCT) platforms compared were posttransplant cyclophosphamide-based haploidentical (haplo-)HCT, matched sibling donor (MSD) HCT, matched unrelated donor HCT with in vivo T-cell depletion (MUD TCD+), and matched unrelated donor HCT without in vivo T-cell depletion (MUD TCD−). Coprimary end points were overall survival (OS) and progression-free survival (PFS); secondary end points included nonrelapse mortality (NRM), and relapse/progression incidence (RI). A total of 1942 patients were eligible (237 haplo-HCT; 911 MSD; 468 MUD TCD+; 326 MUD TCD−). Cohorts were comparable for baseline characteristics with the exception of higher proportions of patients with decreased performance status (PS) and marrow graft recipients in the haplo-HCT group. Using univariate and multivariate comparisons, OS, PFS, RI, and NRM were not significantly different among the haplo-HCT, MSD, MUD TCD+, and MUD TCD− cohorts, with 3-year OS and PFS of 60%, 63%, 59%, and 64%, respectively, and 50%, 50%, 48%, and 52%, respectively. Significant predictors of inferior OS and PFS on multivariate analysis were active disease status at HCT and decreased PS. AITL was associated with significantly reduced relapse risk and better PFS compared with PTCL-NOS. Allo-HCT can provide durable PFS in patients with mature T-cell lymphoma (TCL). Outcomes of haplo-HCT were comparable to those of matched donor allo-HCT.

Modelo animal; Medicina regenerativa; Retina Model animal; Medicina regenerativa; Retina Animal model; Regenerative medicine; Retina Background: The aim of this study was to test the feasibility and safety of subretinal transplantation of human induced pluripotent stem cell (hiPSC)-derived retinal pigment epithelium (RPE) cells into the healthy margins and within areas of degenerative retina in a swine model of geographic atrophy (GA). Methods: Well-delimited selective outer retinal damage was induced by subretinal injection of NaIO3 into one eye in minipigs (n = 10). Thirty days later, a suspension of hiPSC-derived RPE cells expressing green fluorescent protein was injected into the subretinal space, into the healthy margins, and within areas of degenerative retina. In vivo follow-up was performed by multimodal imaging. Post-mortem retinas were analyzed by immunohistochemistry and histology. Results: In vitro differentiated hiPSC-RPE cells showed a typical epithelial morphology, expressed RPE-related genes, and had phagocytic ability. Engrafted hiPSC-RPE cells were detected in 60% of the eyes, forming mature epithelium in healthy retina extending towards the border of the atrophy. Histological analysis revealed RPE interaction with host photoreceptors in the healthy retina. Engrafted cells in the atrophic zone were found in a patchy distribution but failed to form an epithelial-like layer. Conclusions: These results might support the use of hiPSC-RPE cells to treat atrophic GA by providing a housekeeping function to aid the overwhelmed remnant RPE, which might improve its survival and therefore slow down the progression of GA. This work was supported by Spanish Ministry of Science and Innovation (MICINN, RTI2018-095377-B-100), Instituto de Salud Carlos III ISCIII/FEDER (PRB2 PT13/0001/0041; TerCel RD16/0011/0024 and Oftared-RETICS RD16/0008), ERA-NET EuroNanoMed III/ISCIII (AC19/00080), the Catalan Government, AGAUR (2017-SGR-899), CERCA Programme/Generalitat de Catalunya, and by Fundació Carmen i Mª José Godó (Fundació CMJ Godó 2017).

The Endothelial Activation and Stress Index (EASIX) is a laboratory-based prognosis index defined as creatinine × lactate dehydrogenase/platelets. When measured at pretransplantation evaluation (EASIX-PRE), it predicts allogeneic hematopoietic cell transplantation (alloHCT) mortality. This study explores its ability to predict intensive care unit (ICU) admission and validates EASIX-PRE predictive power for overall survival (OS) and nonrelapse mortality (NRM) in 167 consecutive patients undergoing alloHCT. EASIX-PRE was calculated retrospectively in all patients and transformed into log2 values (log2-EASIX-PRE). Log2-EASIX-PRE predicted ICU admission (hazard ratio [HR], 1.41; P < .001), OS (HR, 1.19; P = .011), and NRM (HR, 1.28; P = .004). The most discriminating EASIX-PRE cutoff value for risk of ICU admission was the 75th percentile (2.795); for OS and NRM, it was the median value (1.703). Patients with EASIX-PRE >2.795 had higher incidence of ICU admission in comparison with patients with lower EASIX-PRE values (day +180, 35.8% vs 12.8%; HR, 2.28; P = .010). Additionally, patients with EASIX-PRE >1.073 had lower OS (2 years, 57.7% vs 68.7%; HR, 1.98; P = .006) and higher NRM (2 years, 38.7% vs 18.5%; HR, 2.92; P = .001) than patients with lower EASIX-PRE results. Log2-EASIX-PRE was not associated with incidence of transplantation-associated microangiopathy, sinusoidal obstruction syndrome, or acute graft-versus-host disease. This study proposes EASIX-PRE as a prognostic tool to identify patients undergoing alloHCT at increased risk of severe organ dysfunction and who would therefore require ICU admission. Early identification of patients at high risk of severe events could contribute to personalized intervention design. Additionally, it validates the association between EASIX-PRE and OS and NRM in those undergoing alloHCT.

Autologous (auto-) and allogeneic (allo-) hematopoietic cell transplantation (HCT) are accepted treatment modalities in contemporary treatment algorithms for mantle cell lymphoma (MCL). Chimeric antigen receptor (CAR) T cell therapy recently received approval for MCL; however, its exact place and sequence in relation to HCT remain unclear. The American Society of Transplantation and Cellular Therapy, Center of International Blood and Marrow Transplant Research, and the European Society for Blood and Marrow Transplantation jointly convened an expert panel to formulate consensus recommendations for role, timing, and sequencing of auto-HCT, allo-HCT, and CAR T cell therapy for patients with newly diagnosed and relapsed/refractory (R/R) MCL. The RAND-modified Delphi method was used to generate consensus statements. Seventeen consensus statements were generated, with a few key statements as follows: in the first line setting, auto-HCT consolidation represents standard of care in eligible patients, whereas there is no clear role of allo-HCT or CAR T cell therapy outside of clinical trials. In the R/R setting, the preferential option is CAR T cell therapy, especially in patients with MCL failing or intolerant to at least one Bruton’s tyrosine kinase inhibitor, while allo-HCT is recommended if CAR T cell therapy fails or is infeasible. Several recommendations were based on expert opinion, where the panel developed consensus statements for important real-world clinical scenarios to guide clinical practice. In the absence of contemporary evidence-based data, the panel found RAND-modified Delphi methodology effective in providing a formal framework for developing consensus recommendations for the timing and sequence of cellular therapies for MCL.

Tafasitamab; B-cell lymphoma Tafasitamab; Linfoma de células B Tafasitamab; Limfoma de cèl·lules B Tafasitamab (MOR208), an Fc-modified, humanized, anti-CD19 monoclonal antibody, combined with the immunomodulatory drug lenalidomide was clinically active with a good tolerability profile in the open-label, single-arm, phase II L-MIND study of patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) ineligible for autologous stem-cell transplantation. To assess long-term outcomes, we report an updated analysis with ≥35 months’ follow-up. Patients were aged >18 years, had received one to three prior systemic therapies (including ≥1 CD20-targeting regimen) and Eastern Cooperative Oncology Group performance status 0-2. Patients received 28-day cycles of tafasitamab (12 mg/kg intravenously), once weekly during cycles 1-3, then every 2 weeks during cycles 4-12. Lenalidomide (25 mg orally) was administered on days 1-21 of cycles 1-12. After cycle 12, progression-free patients received tafasitamab every 2 weeks until disease progression. The primary endpoint was best objective response rate. After ≥35 months’ follow-up (data cut-off: October 30, 2020), the objective response rate was 57.5% (n=46/80), including a complete response in 40.0% of patients (n=32/80) and a partial response in 17.5% of patients (n=14/80). The median duration of response was 43.9 months (95% confidence interval [95% CI]: 26.1-not reached), the median overall survival was 33.5 months (95% CI: 18.3-not reached) and the median progression-free survival was 11.6 months (95% CI: 6.3-45.7). There were no unexpected toxicities. Subgroup analyses revealed consistent long-term efficacy results across most subgroups of patients. This extended follow-up of L-MIND confirms the long duration of response, meaningful overall survival, and well-defined safety profile of tafasitamab plus lenalidomide followed by tafasitamab monotherapy in patients with relapsed/refractory diffuse large B-cell lymphoma ineligible for autologous stem cell transplantation. ClinicalTrials.gov identifier: NCT02399085.

Trasplante de pulmón; Fibrosis pulmonar; Trastornos de los telómeros Trasplantament pulmonar; Fibrosi pulmonar; Trastorns dels telòmers Lung transplantation; Pulmonary fibrosis; Telomere disorders Introduction: Fibrotic interstitial lung diseases (ILDs) are the first indication for lung transplantation (LT). Telomere dysfunction has been associated with poor post-transplant outcomes. The aim of the study was to evaluate the morbi-mortality and quality of life in fibrotic ILDs after lung transplant depending on telomere biology. Methods: Fibrotic ILD patients that underwent lung transplant were allocated to two arms; with or without telomere dysfunction at diagnosis based on the telomere length and telomerase related gene mutations revealed by whole-exome sequencing. Post-transplant evaluation included: (1) short and long-term mortality and complications and (2) quality of life. Results: Fifty-five percent of patients that underwent LT carried rare coding mutations in telomerase-related genes. Patients with telomere shortening more frequently needed extracorporeal circulation and presented a higher rate of early post-transplant hematological complications, longer stay in the intensive care unit (ICU), and a higher number of long-term hospital admissions. However, post-transplant 1-year survival was higher than 80% regardless of telomere dysfunction, with improvement in the quality of life and oxygen therapy withdrawal. Conclusions: Post-transplant morbidity is higher in patients with telomere dysfunction and differs according to elapsed time from transplantation. However, lung transplant improves survival and quality of life and the associated complications are manageable. This study was funded by Instituto de Salud Carlos III through project PI18/00367 (Co-funded by European Regional Development Fund, ERDF, a way to build Europe), Spanish Society of Respiratory (SEPAR), Barcelona Respiratory Network (BRN), and Fundació Ramón Pla Armengol. RP laboratory was funded by grants PI20-00335 (Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III, Spain supported by FEDER funds). MM-M was funded by grants PI18/00367 (Fondo de Investigaciones Sanitarias, ISCIII, Spain, supported by FEDER funds), AC19/00006 (Projects of International Programs, ISCIII, Spain, supported by FEDER funds), Cohorte FPI CIBERES-ISCIII, Barcelona Respiratory Network-Fundation Ramon Pla Armengol, Spanish Society of Respiratory (SEPAR), and Catalan Society of Respiratory (SOCAP-FUCAP). CF was funded by Ministerio de Ciencia e Innovación (grant RTC-2017-6471-1; AEI/FEDER, UE), and by Cabildo Insular de Tenerife (CGIEU0000219140).

This prospective study reports the design and results obtained after the EMPODaT project implementation. This project was funded by the Tempus programme of the European Commission with the objective to implement a common postgraduate programme on organ donation and transplantation (ODT) in six selected universities from Middle East/North Africa (MENA) countries (Egypt, Lebanon and Morocco). The consortium, coordinated by the University of Barcelona, included universities from Spain, Germany, Sweden and France. The first phase of the project was to perform an analysis of the current situation in the beneficiary countries, including existing training programmes on ODT, Internet connection, digital facilities and competences, training needs, and ODT activity and accreditation requirements. A total of 90 healthcare postgraduate students participated in the 1-year training programme (30 ECTS academic credits). The methodology was based on e-learning modules and face-to-face courses in English and French. Training activities were evaluated through pre- and post-tests, self-assessment activities and evaluation charts. Quality was assessed through questionnaires and semi-structured interviews. The project results on a reproducible and innovative international postgraduate programme, improvement of knowledge, satisfaction of the participants and confirms the need on professionalizing the activity as the cornerstone to ensure organ transplantation self-sufficiency in MENA countries.

[spa] 1.1 INTRODUCCIÓN: Una parte importante de la práctica diaria de un anestesiólogo incluye la prevención y tratamiento del dolor que acontece durante el acto quirúrgico. Factores moduladores del dolor inherentes en la cirugía cardiotorácica como la hipotermia, la administración de corticoides o el uso de la circulación extracorpórea pueden impactar en los requerimientos analgésicos de nuestros pacientes. Escasas son las evidencias científicas sobre los requerimientos analgésicos para el control del dolor agudo durante el acto quirúrgico y el postoperatorio inmediato en procedimientos de cirugía torácica como la endarterectomía pulmonar y el trasplante de pulmón. 1.2 HIPÓTESIS: 1.-Los pacientes con hipertensión tromboembólica crónica sometidos a endarterectomía pulmonar con parada circulatoria hipotérmica requieren una menor analgesia en el postoperatorio inmediato que los pacientes sometidos a cirugía cardíaca valvular. 2.- El acceso quirúrgico empleado en el trasplante pulmonar impacta en la intensidad del dolor postoperatorio inmediato, y en otras variables clínicas como la hemorragia en el postoperatorio, la duración de ventilación mecánica postoperatoria y la estancia en unidad de cuidados críticos. 1.3 RESULTADOS Y DISCUSIÓN: 1. Los pacientes con hipertensión tromboembólica crónica sometidos a endarterectomía pulmonar con parada circulatoria hipotérmica requieren una menor cantidad de opioides durante el acto quirúrgico y una menor cantidad de analgesia en el postoperatorio inmediato en comparación a los pacientes sometidos a cirugía cardíaca valvular. Ambos grupos de pacientes presentaron un buen control del dolor agudo en el postoperatorio inmediato. 2. Entre las distintas técnicas quirúrgicas estudiadas en el trasplante pulmonar, los pacientes a los que se les practicó una toracotomía presentaron un mayor dolor postoperatorio inmediato, una menor hemorragia postoperatoria, una menor duración de ventilación mecánica y una menor estancia hospitalaria en la unidad de cuidados de críticos en comparación a los pacientes que se les practicó esternotomía o clamshell. 3. Existen aparte de la escala categórica usada en los estudios 1 y 3 otras herramientas de medición de la intensidad de dolor cómo EVA y NPRS útil en otros escenarios clínicos. 1.4 CONCLUSIONES: 1- Los requerimientos analgésicos en pacientes intervenidos de tromboendarterectomía pulmonar con parada circulatoria hipotérmica son menores que en cirugía cardíaca valvular. 2- Los pacientes intervenidos de una tromboendarterectomía pulmonar recibieron corticoides intraoperatorios, cuya influencia pudo ser determinante en la reducción de los requerimientos analgésicos. 3- La vía de acceso quirúrgica en el trasplante de pulmón por toracotomía presenta un mayor dolor agudo en el postoperatorio inmediato. 4- La vía de acceso quirúrgica en el trasplante de pulmón por toracotomía se acompaña de mejores resultados respecto a la hemorragia postoperatoria, la duración de la ventilación mecánica y la estancia hospitalaria en la UCI. 5. El trasplante unipulmonar se asoció con estancias en UCI más cortas. 6. La técnica analgésica no mostró ser un factor relacionado con la estancia en la UCI. 7- La analgesia epidural favorece un control del dolor en casos en que la administración de opioides sea insuficiente, no siendo necesario su colocación sistemática en todos los pacientes sometidos a trasplante de pulmón. 8- La escala categórica verbal de 0 a 3 de medición de la intensidad de dolor, utilizada en las cirugías de tromboendarterectomía pulmonar y trasplante pulmonar, permite una valoración rápida y continua del dolor agudo postoperatorio inmediato en este tipo de cirugías., [eng] An important role of modern anaesthesiologist is to prevent pain that occurs during surgical act. In cardiothoracic surgery, known factors that modify pain are hypothermia, corticosteroids administration and cardiopulmonary bypass. There are scarce evidences regarding analgesic requirements in specific cardiothoracic procedures such as pulmonary thromboendarterectomy and lung transplantation. HYPOTHESIS: Patients with thromboembolic pulmonary hypertension undergoing pulmonary thromboendarterectomy with deep hypothermic circulatory arrest have less analgesic requirements compared with patients undergoing valvular heart surgery The surgical access in lung transplant impact on postoperative pain intensity and other clinical variables such as postoperative haemorrhage, duration of mechanical ventilation and length of stay in intensive care unit. RESULTS AND DISCUSSION: Patients with thromboembolic pulmonary hypertension undergoing pulmonary thromboendarterectomy require less opioids during surgical act and less analgesic drugs during postoperative period compared with patients undergoing valvular heart surgery Among different surgical accesses in lung transplantation, thoracotomy presented with higher postoperative pain scores, less postoperative haemorrhage, less duration of mechanical ventilation and shorter length of stay in critical care unit when compared with patients having sternotomy and clamshell. CONCLUSIONS: Analgesic requirements of patients undergoing pulmonary thromboendarterectomy with deep hypothermic circulatory arrest are less than patients having valvular heart surgery. Patients undergoing pulmonary thromboendarterectomy received corticosteroids intraoperatively which could impact on analgesic requirements. In lung transplantation, thoracotomy is the surgical access that induces more postoperative pain. Thoracotomy is associated with better outcomes in terms of postoperative haemorrhage, duration of mechanical ventilation and length of stay in ICU. Analgesic technique did not influence length of stay in ICU while single lung transplant is associated with shorter length of stay in ICU.

La mejora en el control del daño mediado por anticuerpos constituye un aspecto crucial para extender la sobrevida del injerto renal. Actualmente, se desconoce de manera completa el grado de respuesta del rechazo mediado por anticuerpos a los tratamientos aceptados como habituales (recambios plasmáticos, IVIG y rituximab). Los resultados de dichas estrategias terapéuticas son controvertidos, especialmente en el caso del rechazo crónico activo medido por anticuerpos. Por otro lado, la población en terapia renal sustitutiva ha mejorado progresivamente su sobrevida, lo que conlleva envejecimiento y aumento de los segundos trasplantes. Esto, condiciona una creciente sensibilización y fragilidad de los receptores, que hacen necesarias nuevas estrategias no basadas en un incremento de la inmunosupresión para el control del daño humoral. El trasplante hepatorrenal simultáneo, en comparación con el trasplante renal aislado, se asocia en series históricas a un menor riesgo de daño crónico mediado por anticuerpos. Sin embargo, actualmente, la mayoría de las series publicadas, describen una mayor mortalidad en los pacientes con sensibilización contra el donante. Es pertinente estudiar el impacto del daño mediado por anticuerpos en la sobrevida del injerto y el paciente con trasplante hepatorrenal simultáneo, dado que el mismo o variantes basadas en su fisiopatología inmune, podrían constituir en un futuro, una alternativa terapéutica en el manejo del rechazo mediado por anticuerpos. La fotoaféresis extracorpórea ha demostrado, con un grado variable de evidencia, su efectividad en el manejo del rechazo del injerto de pulmón y corazón. La misma no se asocia a mayor inmunosupresión o a un incremento del riesgo de infecciones o tumores, lo cual la hace, una terapia atractiva a valorar en el trasplante renal. Sin embargo, hasta el momento, no hay datos sobre su efectividad en el contexto del daño mediado por anticuerpos en el injerto renal.

[spa] El consumo de riesgo o el trastorno por uso de alcohol y sustancias, y los factores psicosociales asociados, influyen negativamente en la patología mental y orgánica avanzada como es el caso de pacientes ingresados en psiquiatría o en candidatos a trasplante. Se precisan instrumentos validados, traducidos y adaptados, de detección del consumo de riesgo en pacientes con patología mental y de detección del riesgo psicosocial en candidatos a trasplante. El tabaco es uno de los factores de riesgo que pueden influir en la supervivencia y en los resultados del trasplante hepático. El primer estudio analiza las propiedades psicométricas de la “Prueba de detección de consumo de alcohol, tabaco y sustancias” (ASSIST) en 202 pacientes ingresados en psiquiatría. Se encontró excelente consistencia interna en puntuaciones de riesgo total (TSI) (α = 0,92 y ω = 0,93) y de cada sustancia (SSI) (α = 0,88 - .96 y ω = 0,89 - .95). La estructura interna de tabaco, alcohol y cannabis resultó en modelos unidimensionales con índices de bondad de ajuste adecuados. Las puntuaciones del ASSIST correlacionaron significativamente con: ASI (r = 0,795 a r = 0,953), AUDIT (r = 0,864), FTND (r = 0,808), DAST (r = 0,831), SDS (r = 0,519) y “número de diagnósticos de abuso/dependencia” en MINI-Plus (TSI: r = 0,857 - 0,862; SSI: r = 0,646 - 0,834). El análisis de la curva de ROC y U de Mann-Whitney mostraron evidencias de validez discriminativa. El segundo estudio pretende traducir y adaptar a nuestro contexto, la entrevista semiestructurada “Stanford Integrated Psychosocial Assessment for Transplantation” (SIPAT), y analizar la fiabilidad en una muestra de 150 candidatos a trasplante de hígado, corazón y trasplante de progenitores hematopoyéticos. La fiabilidad interjueces fue excelente para la puntuación general SIPAT (ICC = 0,93) y de cada dominio (ICC de 0,77 a 0,94) y se obtuvo buena consistencia interna, (α = 0.84). El tercer trabajo es un estudio longitudinal de seguimiento a 10 años de una cohorte de 314 pacientes trasplantados de hígado por cirrosis alcohólica que evalúa el impacto del tabaquismo en la supervivencia a través del análisis de Kaplan-Meier y el riesgo de mortalidad a través del análisis de regresión de riesgos proporcionales de Cox. Se evalúa el impacto del tabaquismo en resultados clínicos y se analizan los factores de riesgo asociados a fumar antes y después del trasplante a través de una regresión logística binomial. La probabilidad de supervivencia de los “no fumadores y ex fumadores” fue del 95,2%, 91,5%, 85,2% y 81,0% a 1, 3, 5 y 10 años de seguimiento, significativamente mayor (log-rank p = 0,033) que la probabilidad de supervivencia de los “fumadores activos” 96.0%, 85.6%, 80.0% y 70.4%. La diferencia siguió siendo significativa (log-rank p = 0,019) al comparar solo “exfumadores” frente a “fumadores” antes del trasplante. Ser fumador (OR 1,79, IC del 95%: 1,06-3,03, p = 0,03) se asoció con un mayor riesgo de mortalidad. Los fumadores tuvieron un riesgo de mortalidad significativamente mayor (modelo de Cox 1: HR = 1,63, IC del 95%: 1,04-2,56, p = 0,034) en comparación al resto de la muestra y en comparación con exfumadores (modelo de Cox 3: HR = 1,84, IC 95%: 1,10-3,09, p = 0,02). Los fumadores antes del trasplante que tenían una pobre conciencia de toxicidad del alcohol, tenían más del doble de riesgo de mortalidad (modelo 4 de Cox: HR = 2,20, IC del 95%: 1,05–4,58, p =0,04). El tabaquismo antes del trasplante se asoció con mayor riesgo de recaída en el consumo de sustancias (p = 0,02) y con mayor riesgo de cáncer no de piel (p = 0,04). Seis meses o menos de abstinencia de alcohol antes del trasplante, con una OR de 3,2 (IC 95%: 1,19–8,78; p = 0,021) y tener un trastorno por consumo de sustancias con una OR de 4,9 (IC del 95%: 2,17-10,96; p =0,001) fueron predictores independientes de fumar tras el trasplante. La conciencia de la dependencia del alcohol fue un factor protector frente al tabaquismo tras el trasplante, con una OR de 0,43 (IC 95%: 0,19-0,97; p = 0,042)., [eng] Hazardous alcohol and substance use consumption and alcohol and substance use disorder (SUD), and associated psychosocial factors, negatively influence mental and organic pathology, as is the case of patients admitted to psychiatry or transplant candidates. Validated, translated and adapted instruments are needed to detect hazardous substance use in patients with mental illness and to detect psychosocial risk in transplant candidates. Tobacco is one of the risk factors that can influence survival and liver transplant outcomes. The first study analyzes the psychometric properties of the “Alcohol, Smoking and Substance Involvement Screening Test” (ASSIST) in 202 patients admitted to a psychiatric ward. Excellent internal consistency was found in total substance involvement score (TSI) (α = 0.92 and ω = 0.93) and for specific substance involvement scores (SSI) (α = 0.88 - 0.96 and ω = 0.89 - 0.95). The internal structure of tobacco, alcohol, and cannabis resulted in unidimensional models with adequate goodness-of-fit indices. ASSIST scores correlated significantly with: ASI (r = 0.795 and r = 0.953), AUDIT (r = 0.864), FTND (r = 0.808), DAST (r = 0.831), SDS (r = 0.519 ) and “number of abuse / dependence diagnoses” in MINI-Plus (TSI: r = 0.857 - 0.862; SSI: r = 0.646 – 0.834). The analysis of the ROC curve and the Mann-Whitney U test showed evidence of discriminative validity. The second study aims to translate and adapt the semi-structured interview "Stanford Integrated Psychosocial Assessment for Transplantation" (SIPAT) to our context, and analyze the reliability in a sample of 150 candidates for liver, heart and hematopoietic stem cell transplantation. Inter- rater reliability was excellent for the general SIPAT score (ICC = 0.93) and for each domain (ICC from 0.77 to 0.94) and good internal consistency was obtained (α = 0.84). The third work is a 10-year longitudinal follow-up study of a cohort of 314 liver transplant patients with alcoholic cirrhosis, that assesses the impact of smoking on survival through Kaplan-Meier analysis and the risk of mortality through Cox proportional hazards regression analysis The impact of smoking on clinical outcomes and the risk factors associated with smoking before and after transplantation are analyzed through binomial logistic regression. The probability of survival of the “non-smokers and ex-smokers” was 95.2%, 91.5%, 85.2% and 81.0% at 1, 3, 5 and 10 years of follow-up, significantly higher (log -rank p = 0.033) than the survival probability of “active smokers” 96.0%, 85.6%, 80.0% and 70.4%. The difference remained significant (log-rank p = 0.019) when comparing only “ex-smokers” versus “smokers” before transplantation. Being a smoker (OR 1.79, 95% CI: 1.06-3.03, p = 0.03) was associated with an increased risk of mortality. Smokers had a significantly higher risk of mortality (Cox model 1: HR = 1.63, 95% CI: 1.04-2.56, p = 0.034) compared to the rest of the sample and compared to ex-smokers (Cox 3 model: HR = 1.84, 95% CI: 1.10-3.09, p = 0.02). Smokers before transplantation who had poor alcohol toxicity awareness, had more than twice the risk of mortality (Cox model 4: HR = 2.20, 95% CI: 1.05-4.58, p = 0.04). Smoking before transplantation was associated with a higher risk of relapse in substance use (p = 0.02) and with a higher risk of non-skin cancer (p = 0.04). Six months or less of alcohol abstinence before transplantation, with an OR of 3.2 (95% CI: 1.19–8.78; p = 0.021) and having a substance use disorder with an OR of 4, 9 (95% CI: 2.17-10.96; p = 0.001) were independent predictors of smoking after transplantation. Awareness of alcohol dependence was a protective factor against smoking after transplantation, with an OR of 0.43 (95% CI: 0.19-0.97; p = 0.042).

The aim was to analyze the characteristics and predictors of unfavorable outcomes in solid organ transplant recipients (SOTRs) with COVID-19. We conducted a prospective observational cohort study of 210 consecutive SOTRs hospitalized with COVID-19 in 12 Spanish centers from 21 February to 6 May 2020. Data pertaining to demographics, chronic underlying diseases, transplantation features, clinical, therapeutics, and complications were collected. The primary endpoint was a composite of intensive care unit (ICU) admission and/or death. Logistic regression analyses were performed to identify the factors associated with these unfavorable outcomes. Males accounted for 148 (70.5%) patients, the median age was 63 years, and 189 (90.0%) patients had pneumonia. Common symptoms were fever, cough, gastrointestinal disturbances, and dyspnea. The most used antiviral or host-targeted therapies included hydroxychloroquine 193/200 (96.5%), lopinavir/ritonavir 91/200 (45.5%), and tocilizumab 49/200 (24.5%). Thirty-seven (17.6%) patients required ICU admission, 12 (5.7%) suffered graft dysfunction, and 45 (21.4%) died. A shorter interval between transplantation and COVID-19 diagnosis had a negative impact on clinical prognosis. Four baseline features were identified as independent predictors of intensive care need or death: advanced age, high respiratory rate, lymphopenia, and elevated level of lactate dehydrogenase. In summary, this study presents comprehensive information on characteristics and complications of COVID-19 in hospitalized SOTRs and provides indicators available upon hospital admission for the identification of SOTRs at risk of critical disease or death, underlining the need for stringent preventative measures in the early post-transplant period., This study was supported by Plan Nacional de I+D+i 2013-2016 and Instituto de Salud Carlos III, Subdireccio´n General de Redes y Centros de Investigacio´n Cooperativa, Ministerio de Ciencia, Innovacio´n y Universidades, Spanish Network for Research in Infectious Diseases (REIPI RD16/0016); co-financed by European Development Regional Fund “A way to achieve Europe”, Operative Program Intelligence Growth 2014-2020. EC and JSC received grants from the Instituto de Salud Carlos III, Ministerio de Ciencia e Innovacio´n, Proyectos de Investigacio´n sobre el SARSCoV-2 y la enfermedad COVID-19 (COV20/ 00370; COV20/00580). JSC is a researcher belonging to the program “Nicola´s Monardes”(C0059–2018), Servicio Andaluz de Salud, Junta de Andalucı´a, Spain. SS-A is supported by a grant from the Instituto de Salud Carlos III, Ministerio de Ciencia e Innovacio´n, Proyectos de Investigacio´n sobre el SARS-CoV-2 y la enfermedad COVID-19 (COV20/00370).

[spa] Cada año, miles de personas fallecen a causa de enfermedades hepáticas en estado terminal, siendo la falta de injertos hepáticos un problema sin resolver en la práctica clínica. Para tratar de resolver esta grave situación clínica y social, se está explorando la utilización de hígados de criterio extendido como son los donantes procedentes de pacientes fallecidos por asistolia o parada cardiaca. Desafortunadamente, la alta incidencia de disfunción hepática y complicaciones biliares causadas por la interrupción del suministro de sangre durante el tiempo de isquemia caliente de este tipo de donantes tras la declaración del fallecimiento por criterios cardiorrespiratorios dificulta la utilización de los injertos hepáticos para el trasplante. Adicionalmente, la mayoría de los injertos presentan cierto grado de esteatosis, debido a la alta prevalencia de obesidad presente en la población a nivel mundial. Desgraciadamente, la esteatosis hepática es uno de los factores de riesgo más graves ya que afectan negativamente los resultados postoperatorios, exacerbando la lesión inducida por isquemia/reperfusión y afectando negativamente la regeneración hepática. Investigaciones recientes en pacientes con cirrosis y otras enfermedades asociadas con inflamación intestinal, han establecido una implicación de estas patologías con alteraciones en moléculas intestinales como el FGF15/19, así como también se han mostrado resultados prometedores debido al tratamiento con GLP-1 en modelos experimentales en isquemia caliente, evidenciando la importancia de moléculas intestinales en el tratamiento de patologías hepáticas. Es así donde surge la presente tesis doctoral; de la necesidad de evaluar el efecto de la muerte por parada cardiocirculatoria en el donante sobre el eje intestinal-hepático y evaluar su posible implicación sobre la lesión y regeneración en modelos experimentales de trasplante hepático con injertos esteatóticos y no esteatóticos. En este contexto, investigaciones dirigidas a establecer los mecanismos fisiopatológicos implicados en trasplante hepático procedente de donantes con parada cardiaca (los cuales cada vez se utilizan más debido a la falta de injertos hepáticos para trasplantar) es de vital importancia para esclarecer las bases moleculares que agravan los resultados postrasplante y en consecuencia buscar dianas de posible acción terapéutica que al modularlas farmacológicamente permitan mejorar los resultados postoperatorios, la calidad de vida de los pacientes que han sido sometidos a trasplante procedentes de donantes con parada cardiaca, y en última instancia, reducir las listas de espera en el trasplante hepático.

Introduction The impact of preformed donor-specific anti–human leukocyte antigen (HLA) antibodies (pDSAs) after combined liver-kidney transplantation (CLKT) is still uncertain. Methods We conducted a retrospective study in 8 European high-volume transplant centers and investigated the outcome of 166 consecutive CLKTs, including 46 patients with pDSAs. Results Patient survival was lower in those with pDSAs (5-year patient survival rate of 63% and 78% with or without pDSA, respectively; P = 0.04). The presence of pDSAs with a mean fluorescence intensity (MFI) ≥ 5000 (hazard ratio 4.96; 95% confidence interval: 2.3–10.9; P < 0.001) and the presence of 3 or more pDSAs (hazard ratio 6.5; 95% confidence interval: 2.5–18.8; P = 0.05) were independently associated with death. The death-censored liver graft survival was similar in patients with or without pDSAs. Kidney graft survival was comparable in both groups. (The 1- and 5-year death-censored graft survival rates were 91.6% and 79.5%, respectively, in patients with pDSAs and 93% and 88%, respectively, in the donor-specific antibody [DSA]-negative group, P = not significant). Despite a higher rate of kidney graft rejection in patients with pDSAs (5-year kidney graft survival rate without rejection of 87% and 97% with or without pDSAs, respectively; P = 0.04), kidney function did not statistically differ between both groups at 5 years post-transplantation (estimated glomerular filtration rate 45 ± 17 vs. 57 ± 29 ml/min per 1.73 m2, respectively, in patients with and without pDSAs). Five recipients with pDSAs (11.0%) experienced an antibody-mediated kidney rejection that led to graft loss in 1 patient. Conclusion Our results suggest that CLKT with pDSAs is associated with a lower patients’ survival despite good recipients’, liver and kidney grafts’ outcome., Graphical abstract

Summary Livers from donation after circulatory death (DCD) donors are an increasingly more common source of organs for transplantation. While there are few high‐level studies in the field of DCD liver transplantation, clinical practice has undergone progressive changes during the past decade, in particular due to mounting use of postmortem normothermic regional perfusion (NRP). In Spain, uncontrolled DCD has been performed since the late 1980s/early 1990s, while controlled DCD was implemented nationally in 2012. Since 2012, the rise in DCD liver transplant activity in Spain has been considerable, and the great majority of DCD livers transplanted in Spain today are recovered with NRP. A panel of the Spanish Liver Transplantation Society was convened in 2018 to evaluate current evidence and accumulated experience in DCD liver transplantation, in particular addressing issues related to DCD liver evaluation, acceptance criteria, and recovery as well as recipient selection and postoperative management. This panel has created a series of consensus statements for the standard of practice in Spain and has published these statements with the hope they might help guide other groups interested in implementing new forms of DCD liver transplantation and/or introducing NRP into their clinical practices.

Background and Aims: Prognosis after liver transplantation differs between hepatocellular carcinoma (HCC) arising in cirrhotic and non-cirrhotic livers and aetiology is poorly understood. The aim was to investigate differences in mortality after liver transplantation between these patients. Methods: We included patients from the European Liver Transplant Registry transplanted due to HCC from 1990 to November 2016 and compared cirrhotic and non-cirrhotic patients using propensity score (PS) calibration of Cox regression estimates to adjust for unmeasured confounding. Results: We included 22,787 patients, of whom 96.5% had cirrhosis. In the unadjusted analysis, non-cirrhotic patients had an increased risk of overall mortality with a hazard ratio (HR) of 1.37 (95% confidence interval [CI] 1.23–1.52). However, the HR approached unity with increasing adjustment and was 1.11 (95% CI 0.99–1.25) when adjusted for unmeasured confounding. Unadjusted, non-cirrhotic patients had an increased risk of HCC-specific mortality (HR 2.62, 95% CI 2.21–3.12). After adjustment for unmeasured confounding, the risk remained significantly increased (HR 1.62, 95% CI 1.31–2.00). Conclusions: Using PS calibration, we showed that HCC in non-cirrhotic liver has similar overall mortality, but higher HCC-specific mortality. This may be a result of a more aggressive cancer form in the non-cirrhotic liver as higher mortality could not be explained by tumour characteristics or other prognostic variables.

Organ transplantation is a multifactorial process in which proper graft preservation is a mandatory step for the success of the transplantation. Hypothermic preservation of abdominal organs is mostly based on the use of several commercial solutions, including UW, Celsior, HTK and IGL-1. The presence of the oncotic agents HES (in UW) and PEG35 (in IGL-1) characterize both solution compositions, while HTK and Celsior do not contain any type of oncotic agent. Polyethylene glycols (PEGs) are non-immunogenic, non-toxic and water-soluble polymers, which present a combination of properties of particular interest in the clinical context of ischemia-reperfusion injury (IRI): they limit edema and nitric oxide induction and modulate immunogenicity. Besides static cold storage (SCS), there are other strategies to preserve the organ, such as the use of machine perfusion (MP) in dynamic preservation strategies, which increase graft function and survival as compared to the conventional static hypothermic preservation. Here we report some considerations about using PEG35 as a component of perfusates for MP strategies (such as hypothermic oxygenated perfusion, HOPE) and its benefits for liver graft preservation. Improved liver preservation is closely related to mitochondria integrity, making this organelle a good target to increase graft viability, especially in marginal organs (e.g., steatotic livers). The final goal is to increase the pool of suitable organs, and thereby shorten patient waiting lists, a crucial problem in liver transplantation., This study was supported by grant from Ministerio de Ciencia e Innovación, reference PID2019-104130R B-I00 awarded to E.F.-P., the European Comission H2020-MSCA-ITN-ETN-2016 “FOIE GRAS – Metabolism and the Liver-Gut Axis in Non-Alcoholic Fatty Liver Disease” and the Marie Curie Fellow to Rui Teixeira da Silva. The authors thank Veronica Raker for revising the manuscript.

Treballs Finals de Grau d'Infermeria, Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona, Curs: 2019-2020, Tutor: Marta Raurell Torredà, Introducción: La donación es la liberalidad de alguien que transmite gratuitamente algo que le pertenece a favor de otra persona que lo acepta. Es considerado uno de los gestos más altruistas y caritativos de nuestra sociedad. Existen principalmente dos métodos para la realización de la donación: la donación tras muerte encefálica (DME) y la donación en asistolia (DA) que se divide en la Clasificación de Maastricht: cuatro categorías (I, II, III y IV) y dos grupos. La función de la enfermera dentro de una unidad de cuidados críticos (UCI) en relación a la donación de órganos, se ha de realizar desde una perspectiva holística del individuo, velando por su calidad de vida y respeto de las decisiones propias o familiares. No obstante, es difícil, pero necesario, delimitar las actuaciones enfermeras dentro de este entorno. Objetivos: Determinar las intervenciones enfermeras en el mantenimiento del paciente crítico para la posterior donación de órganos. Metodología: Revisión de la literatura en la que se utilizaron las siguientes bases de datos: PubMed, CINHAL, Dialnet y SciELO. Así como, la búsqueda específica en revistas relacionadas con la temática: Medicina intensiva, Metas de Enfermería y Enfermería intensiva. Resultados: Se incluyeron un total de 16 estudios que fueron seleccionados de acuerdo a los criterios preestablecidos: cuatro revisiones bibliográficas, cinco artículos de divulgación, tres artículos originales, tres artículos especiales y una revisión sistemática. Conclusiones: El papel de la enfermería es de suma importancia en la donación de órganos debido al contacto exhaustivo con el paciente y su entorno. Sus cuidados repercutirán directamente en el estado de conservación del órgano del futuro receptor. Por estos motivos, se precisa de una excelente coordinación y organización del equipo multidisciplinar, protocolos estandarizados y regulados por un marco legal, y un aprendizaje continuo mediante programas educativos para reforzar todos los conocimientos, aptitudes y pensamientos acerca de la donación y trasplante de órganos.

There is paucity of data on the impact of surgical incision and analgesia on relevant outcomes. A retrospective STROBE-compliant cohort study was performed between July 2007 and August 2017 of patients undergoing lung transplantation. Gender, age, indication for lung transplantation, and the 3 types of surgical access (Thoracotomy (T), Sternotomy (S), and Clamshell (C)) were used, as well as 2 analgesic techniques: epidural and intravenous opioids. Outcome variables were: pain scores; postoperative hemorrhage in the first 24 hours, duration of mechanical ventilation, and length of stay at intensive care unit (ICU). Three hundred forty-one patients were identified. Thoracotomy was associated with higher pain scores than Sternotomy (OR 1.66, 95% CI: 1.01; 2.74, P: .045) and no differences were found between Clamshell and Sternotomy incision. The median blood loss was 800 mL [interquartile range (IQR): 500; 1238], thoracotomy patients had 500 mL [325; 818] (P

Introducing post-transplant, cyclophosphamide (PT-Cy) graft-versus-host disease (GVHD) prophylaxis in the setting of haploidentical donor transplantation has marked the most important advance in allogeneic hematopoietic cell transplantation (alloHCT) within the past 15 years. The efficacy of this procedure and its simple features have allowed for the significantly widespread application of alloHCT worldwide. Indeed, the procedure’s effectiveness in reducing immunological complications in the haploidentical setting has even challenged the status quo use of calcineurin-inhibitor, methotrexate-based GVHD prophylaxis in the setting of HLA-identical donors. Currently, however, prospective clinical trials in support of PT-Cy-based GVHD prophylaxis in the HLA-matched setting are striving to resolve the matter of its potential role. This review will briefly report the overall outcomes of PT-Cy-based GVHD prophylaxis in the haploidentical setting and summarize results obtained in the HLA-identical field. We will present future perspectives at the end of the manuscript.

[eng] Crohn’s disease [CD] is a chronic inflammatory disease of the intestinal tract with considerable heterogeneity among affected patients in terms of disease phenotype and therapeutic responses. Despite the increase in the number of drugs approved for the management of CD, a significant percentage of patients remain unresponsive or lose response over time to treatments, and eventually require surgery to control disease activity and/or complications. Nonetheless, in a fraction of these refractory patients, intestinal resection may not be possible due to disease location, extension or previous surgeries. For such patients, autologous hematopoietic stem cell transplantation [HSCT] represents a potential salvage therapy despite the risks associated with this procedure. Stem cell transplantation is an accepted therapy for hematological disorders, aplastic anemia and immunodeficiencies. In the context of autoimmune diseases, the serendipitous benefits of transplantation were initially reported in patients suffering from both immune-mediated diseases and hematological disorders. This led to trials that have shown the efficacy of autologous HSCT in treating an array of autoimmune diseases including refractory severe multiple sclerosis, systemic lupus erythematosus, juvenile idiopathic arthritis, rheumatoid arthritis and, more recently, CD. The benefit of HSCT in autoimmunity is thought to originate from the ability of intense immune depletion to eliminate auto-reactive cells regardless of their specificity. This would lead to de novo generation of immune cells that could re-establish tolerance, although no objective evidence of this ‘resetting’ has been reported thus far. To explore this hypothesis, we group of CD patients [n = 18] receiving autologous HSCT, with 50% of them achieving endoscopic drug-free remission. To elucidate the mechanisms driving efficacy, we monitored changes after HSCT in blood and intestine immune-cell composition. CD patients [n = 22] receiving anti-tumor necrosis factor [TNF]-α were included for comparison. Severe immune ablation followed by HSCT induced dramatic changes in both peripheral blood T and B cells in all patients regardless of the efficacy of the treatment. Endoscopic remission at week 52 following HSCT was associated with significant intestinal transcriptional changes. A comparison of the remission signature with that of anti-TNFα identified both common and unique genes in the HSCT-induced response. Based on deconvolution analysis of intestinal biopsy transcriptome data, we show that response to HSCT, but not to anti-TNFα, is associated with an expansion of naïve B-cells, as seen in blood, and a decrease in the memory resting T- cell content. As expected, endoscopic remission, in response to both HSCT and anti-TNFα, led to a significant reduction in intestinal neutrophil and M1 macrophage content. HSCT dramatically renewed the pre-existing T-cell receptor [TCR] repertoire; however, persistent high-frequency TCR clones were detected in all patients in both blood and biopsy throughout the first year of follow-up. The number of persistent resident T cell clonotypes in tissue after treatment decreased in patients that achieve endoscopic remission. Furthermore, we found that low TCR peripheral diversity at baseline, and up to 1 year after HSCT, were associated with a lack of response to the immunoablative protocol. Peripheral blood immune remodeling after HSCT does not predict efficacy. In contrast, a profound intestinal T-cell depletion that is maintained long after transplant is associated with mucosal healing following HSCT, but not anti-TNFα., [spa] Se ha demostrado la eficacia del trasplante hematopoyético de células madre (THCM) en pacientes con enfermedad de Crohn severamente refractaria. La hipótesis aceptada es que el proceso de THCM elimina células auto-reactivas, devolviendo así la tolerancia. No obstante, no existen estudios específicos y exhaustivos sobre la reconstitución inmune en pacientes con enfermedad de Crohn tratados con THCM. En esta tesis, monitorizamos una cohorte de 18 pacientes con enfermedad de Crohn refractaria que recibieron trasplante autólogo de células madre hematopoyéticas, de los cuales el 50% consiguieron la remisión endoscópica sin tratamiento de mantenimiento. Para elucidar los mecanismos que determinan la eficacia, monitorizamos los cambios después de THCM en la composición de células inmunes tanto en sangre como en tejido intestinal. Como resultado, observamos que la ablación inmune producida durante el TCMH induce cambios dramáticos en las células T y B en sangre en todos los pacientes, independientemente de la eficacia del tratamiento. La remisión endoscópica en la semana 52 posterior al TCMH se asoció con cambios transcripcionales intestinales significativos. Una comparación de la transcripción en remisión con la de la remisión inducida por fármaco identificó genes comunes y únicos en la respuesta inducida por el TCMH. A través de un análisis de deconvolución de los datos del transcriptoma de la biopsia intestinal, mostramos que la respuesta al TCMH, pero no a fármaco inmuno- modulador, se asocia con una expansión de las células B naïve y una disminución en el contenido de células T memoria. Como se esperaba, la remisión endoscópica, en respuesta a tanto a TCMH como a fármaco, condujo a una reducción significativa en el contenido de neutrófilos intestinales y macrófagos M1 La remodelación inmune de la sangre periférica después del TCMH no predice la eficacia. No obstante, la depleción de las células T intestinales mantenida un año después del trasplante se asocia con la curación mucosa después del TCMH.

Solid organ transplant (SOT) recipients are especially at risk of developing infections by multidrug resistant bacteria (MDR). In this study, the biofilm-forming capability of 209 MDR strains (Escherichia coli n = 106, Klebsiella pneumoniae n = 78, and Enterobacter spp. n = 25) isolated from rectal swabs in the first 48 hours before or after kidney (93 patients), liver (60 patients) or kidney/pancreas transplants (5 patients) were evaluated by using a microplate assay. Thirty-nine strains were isolated before transplant and 170 strains were isolated post-transplant. Overall, 16% of E. coli strains, 73% of K. pneumoniae strains and 4% Enterobacter strains showed moderate or strong biofilm production. Nine strains isolated from infection sites after transplantation were responsible of infections in the first month. Of these, 4 K. pneumoniae, 1 E. coli and 1 Enterobacter spp. strains isolated pre-transplant or post-transplant as colonizers caused infections in the post-transplant period. Our results suggest that in vitro biofilm formation could be an important factor for adhesion to intestine and colonization in MDR K. pneumoniae strains in SOT recipients, but this factor appears to be less important for MDR E. coli and Enterobacter spp. Acknowledgements: The authors thank Dr. Fidel Madrazo (Electron Microscopy Unit, Technology Support Services, IDIVAL) for helping with confocal microscopy. This research was supported by ‘Plan Nacional de I + D + i and Instituto de Salud Carlos III (Fondo de Investigaciones Sanitarias PI 13/01191 to MCF and PI 16/01103 to JRV), Subdirección General de Redes y Centros de Investigación Cooperativa, Spanish Ministry of Economy and Competitiveness, Spanish Network for Research in Infectious Diseases (REIPI RD12/0015) and (REIPI RD16/0016) co-financed by the European Development Regional Fund “A way to achieve Europe” ERDF.

Allograft infiltration has been described in up to 20% of all patients with posttransplant lymphoproliferative disorder (PTLD), most representing EBV-positive B-cell lymphomas. Plasma cells are often observed in humoral rejection biopsies, but graft infiltration by plasmacytoma-like PTLD is rare. We report the case of a 54-year-old simultaneous pancreas-kidney transplant recipient (immunosuppression: OKT3, methylprednisolone, cyclosporine, and azathioprine), diagnosed with an IgG-kappa monoclonal gammopathy of undetermined significance eighteen years after transplant. Nine months later, pancreas allograft biopsy performed due to new-onset hyperglycemia (HgA1C 8.6%, C-peptide 6.15ng/mL and anti-GAD 0.9UI/mL) revealed a monotypic plasma cell infiltrate, CD19, CD79a, CD138 positive, with IgG-kappa light chain restriction, and EBV negative. PET-scan FDG uptake was limited to pancreas allograft. Tumor origin could not be established (using DNA microsatellite analysis). Despite treatment with bortezomib and dexamethasone, patient eventually died one month later. This is the first report of a late onset extramedullary plasmacytoma involving a pancreas allograft.

[spa] La hepatectomía parcial bajo isquemia-reperfusión (PH + I/R) es una estrategia que se utiliza comúnmente en la práctica clínica para reducir la hemorragia durante la resección del parénquima hepático. Más del 20% de los pacientes que se someten a una resección hepática presentan algún grado de esteatosis, un factor de riesgo importante en la cirugía de las resecciones hepáticas, ya que se asocia a un mayor índice de complicaciones y mortalidad postoperatoria. A pesar de los avances en los tratamientos farmacológicos, los resultados no han sido concluyentes y pocos son los estudios que se han realizado con modelos que mimeticen a máximo las condiciones clínicas de las resecciones hepáticas, por lo que la lesión por isquemia – reperfusión sigue siendo un problema sin resolver. Teniendo en cuenta tal problemática clínica, la presente tesis plantea posibles terapias farmacológicas con el cortisol y el factor de crecimiento endotelial vascular tipo A (VEGFA) que protejan los hígados frente a la lesión inducida por la isquemia-reperfusión y fallo en la regeneración hepática, utilizando animales de experimentación en presencia o ausencia de esteatosis hepática (ratas de la cepa Zucker y ratas de la cepa Sprague-Dawley alimentadas con una dieta deficiente en colina) sometidas a 70% de hepatectomía parcial bajo isquemia- reperfusión. Los resultados de la presente tesis indicaron la activación solo en hígados no esteatósicos de los mecanismos enzimáticos del metabolismo del cortisol encargados de mantener niveles bajos de cortisol para evitar en consecuencia sus efectos nocivos sobre la lesión y regeneración. En presencia de esteatosis, el cortisol exacerba el daño y el fallo en la regeneración asociado a la cirugía hepática, debido a una descompensación de los mecanismos hepáticos productores de cortisol y las estrategias para reducir sus niveles hepáticos. Estos efectos se asociaron a niveles hepáticos elevados de acetilcolina. La administración de un antagonista del receptor muscarínico M3 (pero no el receptor alfa 7 nicotínico) protegió a los hígados frente a la lesión, mejoró la regeneración del parénquima y la tasa de supervivencia tras la cirugía. Los resultados de la presente tesis también indicaron que el VEGFA reduce la incidencia de complicaciones postoperatorias en hígados no esteatósicos después de la cirugía a través de la activación de la vía VEGFR2-Wnt2, y de forma independiente de Id1. Inesperadamente, la administración de VEGFA redujo notablemente los niveles de VEGFA en hígados esteatósicos, exacerbando el daño y el fallo regenerativo asociado a la cirugía, ya que el VEGFA circulante fue secuestrado por los altos niveles de circulación de sFlt1 liberado por el tejido adiposo. En consecuencia, se requirió la administración concomitante de VEGFA y un anticuerpo anti-sFlt1 para bloquear el sFlt1 y evitar la unión de sFlt1 a VEGFA, aumentado la biodisponibilidad de VEGFA. Este efecto se asoció con altos niveles de VEGFA en hígados esteatósicos y protección frente al daño y fallo en la regeneración a través de la activación de la vía de señalización PI3K/Akt, independientemente de la vía Id1-Wnt2. La presente tesis proporciona por primera vez el papel del cortisol en hígados esteatósicos y no esteatósicos en condiciones de PH bajo oclusión vascular y establece el potencial terapéutico de la vía cortisol-acetilcolina-receptores muscarínicos M3 en la cirugía con hígados esteatósicos y no esteatósicos. Así mismo, establece los diferentes efectos y vías de señalización de VEGFA en la cirugía del hígado que requieren PH bajo oclusión vascular según el tipo de hígado y sugiere el potencial de estrategias terapéuticas basadas en VEGFA junto a un anticuerpo anti-sFlt1 para hígados sometidos a hepatectomía bajo isquemia- reperfusión en presencia de esteatosis., [eng] Partial hepatectomy under ischemia-reperfusion (PH+I/R) is commonly used in clinical practice to reduce bleeding during hepatic resection. More than 20% of patients that undergo liver resection have some degree of steatosis, an important risk factor in liver surgery, associated with more complications and postoperative mortality. The present thesis proposes possible pharmacological therapies with cortisol and VEGFA to protect livers against I/R injury and regenerative failure, using experimental animals with or without hepatic steatosis subjected to 70% PH under I/R. Our results indicated the activation of mechanisms responsible for maintaining low levels of cortisol only in non-steatotic livers to avoid consequently its harmful effects on injury and regeneration. In the presence of steatosis, cortisol exacerbates damage and regenerative failure after surgery, associated with elevated hepatic acetylcholine levels. The administration of an M3 muscarinic receptor antagonist protected livers against injury, improved regeneration and survival rate after surgery. Our results also indicated that VEGFA reduces the incidence of postoperative complications in non-steatotic livers after surgery through the VEGFR2-Wnt2 pathway, independently of Id1. Unexpectedly, administration of VEGFA markedly reduced VEGFA levels in steatotic livers, exacerbating damage and regenerative failure, since circulating VEGFA was sequestered by the high levels of plasmatic sFlt1 released by adipose tissue. Accordingly, administration of VEGFA and an anti-sFlt1 antibody was required to block sFlt1, to prevent this sequestration. This was associated with high VEGFA levels in steatotic livers and protection against damage and regenerative failure through the activation of the PI3K / Akt pathway. This thesis provides, for the first time, the role of cortisol in steatotic and non-steatotic livers under PH+I/R conditions and establishes the therapeutic potential of the cortisol- acetylcholine-M3 muscarinic receptors pathway in liver surgery. Likewise, it establishes the different effects and signalling pathways of VEGFA in liver surgery requiring PH under vascular occlusion according to the type of liver.

Background: We analyzed the prevalence, etiology, and risk factors of culture-positive preservation fluid and their impact on the management of solid organ transplant recipients. Methods: From July 2015 to March 2017, 622 episodes of adult solid organ transplants at 7 university hospitals in Spain were prospectively included in the study. Results: The prevalence of culture-positive preservation fluid was 62.5% (389/622). Nevertheless, in only 25.2% (98/389) of the cases were the isolates considered "high risk" for pathogenicity. After applying a multivariate regression analysis, advanced donor age was the main associated factor for having culture-positive preservation fluid for high-risk microorganisms. Preemptive antibiotic therapy was given to 19.8% (77/389) of the cases. The incidence rate of preservation fluid-related infection was 1.3% (5 recipients); none of these patients had received preemptive therapy. Solid organ transplant (SOT) recipients with high-risk culture-positive preservation fluid receiving preemptive antibiotic therapy presented both a lower cumulative incidence of infection and a lower rate of acute rejection and graft loss compared with those who did not have high-risk culture-positive preservation fluid. After adjusting for age, sex, type of transplant, and prior graft rejection, preemptive antibiotic therapy remained a significant protective factor for 90-day infection. Conclusions: The routine culture of preservation fluid may be considered a tool that provides information about the contamination of the transplanted organ. Preemptive therapy for SOT recipients with high-risk culture-positive preservation fluid may be useful to avoid preservation fluid-related infections and improve the outcomes of infection, graft loss, and graft rejection in transplant patients.

[spa] Actualmente, el 80% de los injertos hepático proceden de donantes con muerte cerebral. Sin embargo, la muerte cerebral reduce la tolerancia de los injertos hepáticos a la lesión por isquemia/reperfusión y contrarresta los efectos beneficiosos derivados del precondicionamiento isquémico, la única estrategia quirúrgica que se está aplicando hasta el momento en la práctica clínica aunque con resultados contradictorios. Ante la creciente demanda de órganos y el drástico aumento de la mortalidad de los pacientes en lista de espera, los centros hospitalarios decidieron ampliar los criterios de aceptación de un órgano. Esta es la razón por la que se emplean hígados esteatósicos, aún cuando presentan poca tolerancia a la lesión por isquemia-reperfusión y un mayor riesgo de disfunción o fallo primario del injerto. Se estima que la esteatosis se encuentra presente en más del 30% de los hígados de donantes con muerte cerebral y se considera un factor de riego y de pronóstico en los resultados post-trasplante. Por lo anteriormente expuesto, es evidente la necesidad de desarrollar estrategias protectoras para minimizar los efectos adversos de la muerte cerebral y la lesión por isquemia/reperfusión tanto en hígados esteatósicos como no esteatósicos. En la presente tesis se investigó el papel de la proteína del grupo de alta movilidad Box 1, el efecto del cortisol y sus enzimas implicadas, así como la relevancia de los cambios de los niveles de la hormona del crecimiento y su posible regulación por el factor de crecimiento epidérmico tras la muerte cerebral. La presente tesis proporciona nuevos avances sobre la fisiopatología de la lesión inducida por isquemia/reperfusión en injertos hepáticos esteatósicos y no esteatósicos procedentes de donante con muerte cerebral y contribuye al desarrollo de nuevas estrategias farmacológicas y quirúrgicas novedosas y eficaces para mejorar en última instancia la calidad del injerto hepático y los resultados post-trasplante., [eng] Currently, 80% of grafts are taken from brain-dead (BD) donors. However, BD markedly reduces the tolerance of liver grafts to ischemia/reperfusion (I/R) injury and may counteract the protection conferred by ischemic preconditioning (IP). This is the only surgical strategy that has been applied in clinical liver transplantation (LT), but with controversial results. The shortage of organs has led centers to expand their criteria for the acceptance of steatotic grafts that exhibit poor tolerance to I/R. Some of these include the use of steatotic livers. However, I/R injury is the underlying cause of graft dysfunction in marginal organs. Indeed, the use of steatotic livers for transplantation is associated with an increased risk of primary non-function or dysfunction after surgery. In addition, steatosis is currently estimated to be present in up to 30% of deceased donor livers and is recognized as a key donor variable predicting post-transplant outcome. Thus, further investigations are required for the establishment of protective strategies in steatotic and non-steatotic liver transplantation from BD donors. There are few experimental studies, mainly focused in non-steatotic livers that explain how BD affects liver grafts. In the present study, we examined the role of high-mobility group box 1 (HMGB1), the effects of cortisol and their involved enzymes, as well as the relevance of changes in the levels of growth hormone and epidermal growth factor after brain death. This thesis provides, for the first time, new mechanistic insights into the pathophysiology of BD with may help to reduce its adverse effects in both steatotic and non-steatotic liver grafts and contributes to the development of novel and efficient pharmacological and surgical strategies to ultimately improve liver graft quality.

A 51-year-old man who had undergone liver transplantation developed a symptomatic anastomotic biliary stricture 23 months after surgery. Endoscopic biliary therapy via endoscopic retrograde cholangiopancreatography (ERCP) was planned. Progressive biliary balloon dilation of the stenosis was performed, with placement of three coaxial plastic stents (8.5-Fr × 12 cm, 8.5-Fr × 9 cm, and 10-Fr × 12 cm; Advanix, Boston Scientific, Natick, Massachusetts, USA). During an endoscopy to replace the stents, fluoroscopy revealed proximal migration of an 8.5-Fr plastic stent at the level of the cystic insertion ([Fig. 1]). Several failed extraction attempts were made using the standard ERCP techniques (i. e. extractor balloon, Lasso technique, and others) [1] [2]. Single-operator peroral intraductal cholangioscopy (SpyGlass DS direct visualization system, Boston Scientific) confirmed impaction of the distal end of the proximally migrated stent, located 3 cm proximally to the duodenal papilla. An attempt to mobilize the migrated stent was made using biopsy forceps (SpyBite, Boston Scientific), without success.

ObjectiveImprovement in insulin alternatives is leading to a delayed presentation of microvascular and macrovascular complications of diabetes. The objective of this study was to evaluate the long-term outcomes of older (≥50 years) diabetic patients who receive a pancreas transplantation (PT).Research design and methodsWe retrospectively evaluated all 338 PTs performed at our center between 2000 and 2016 (mean follow-up 9.4±4.9 years). Recipient and graft survivals were estimated for up to 10 years after PT. Major adverse cardiovascular events (MACEs) before and after PT were included in the analysis.ResultsThirty-nine patients (12%) were ≥50 years old (52.7±2.3 years) at the day of PT, of which 29 received a simultaneous pancreas–kidney transplantation (SPK) and 10 a pancreas after kidney transplantation (PAK). SPK recipients were first transplants, whereas in the PAK up to 50% were pancreas re-transplantations. Recipient and pancreas graft survivals at 10 years were similar between the group 0.05). The prevalence of MACE prior to PT was similar between both groups (31% vs 29%). Following PT, older recipients presented inferior post-transplant MACE-free survival. In a multivariate regression model, diabetes vintage (HR 1.054, p=0.03) and pre-transplantation MACE (HR 1.98, p=0.011), but not recipient age (HR 1.45, p=0.339), were associated with post-transplant MACE.ConclusionsLong-term survival of older pancreas transplant recipients are similar to younger counterparts. Diabetes vintage, but not age, increased the risk of post-transplantation MACE. These results suggest pancreas transplantation is a valuable treatment alternative to older diabetic patients.

Background Strongyloides stercoralis is a worldwide disseminated parasitic disease that can be transmitted from solid organ transplant (SOT) donors to recipients. We determined the serological prevalence of S. stercoralis among deceased individuals from endemic areas considered for SOT donation, using our institution’s serum bank. Methodology Retrospective study including all deceased potential donors from endemic areas of strongyloidiasis considered for SOT between January 2004 and December 2014 in a tertiary care hospital. The commercial serological test IVD-Elisa was used to determine the serological prevalence of S. stercoralis. Principal findings Among 1025 deceased individuals during the study period, 90 were from endemic areas of strongyloidiasis. There were available serum samples for 65 patients and 6 of them tested positive for S. stercoralis (9.23%). Only one of the deceased candidates was finally a donor, without transmitting the infection. Conclusions Among deceased individuals from endemic areas considered for SOT donation, seroprevalence of strongyloidiasis was high. This highlights the importance of adhering to current recommendations on screening for S. stercoralis among potential SOT donors at high risk of the infection, together with the need of developing a rapid diagnostic test to fully implement these screening strategies., Author summary Strongyloidiasis is a neglected tropical disease caused by a parasite which is endemic in most parts of the world. It can cause a life-threatening disease among immunosuppressed individuals and can be transmitted from solid organ transplant donors to recipients. We retrospectively investigated the prevalence of strongyloidiasis among deceased individuals from endemic areas who were considered for solid organ transplant donation in our center, by performing a serological assay using our institution’s serum bank. We found a high prevalence of strongyloidiasis among these deceased candidates to donation, but only one of the six who tested positive was finally a donor, without transmitting the disease to recipients. Our results should encourage physicians to adhere to current guidelines which recommend active screening of strongyloidiasis in potential solid organ transplant donors from endemic areas who may be infected. There is a clear need for a rapid diagnostic test to fully implement systematic screening among these individuals.

Brown adipose tissue (BAT) is raising high expectations as a potential target in the fight against metabolic disorders such as obesity and type 2 diabetes. BAT utilizes fuels such as fatty acids to maintain body temperature by uncoupling mitochondrial electron transport to produce heat instead of ATP. This process is called thermogenesis. BAT was considered to be exclusive to rodents and human neonates. However, in the last decade several studies have demonstrated that BAT is not only present but also active in adult humans and that its activity is reduced in several pathological conditions, such as aging, obesity, and diabetes. Thus, tremendous efforts are being made by the scientific community to enhance either BAT mass or activity. Several activators of thermogenesis have been described, such as natriuretic peptides, bone morphogenic proteins, or fibroblast growth factor 21. Furthermore, recent studies have tested a therapeutic approach to directly increase BAT mass by the implantation of either adipocytes or fat tissue. This approach might have an important future in regenerative medicine and in the fight against metabolic disorders. Here, we review the emerging field of BAT transplantation including the various sources of mesenchymal stem cell isolation in rodents and humans and the described metabolic outcomes of adipocyte cell transplantation and BAT transplantation in obesity. KEYWORDS: Brown adipose tissue; Obesity; Transplantation

Objective: Chronic kidney disease is characterized by progressive and irreversible loss of kidney function. The impact of this disease on oral health also presents controversial results. The aim of the study was to determine oral health conditions and oral symptoms of patients with Chronic kidney disease undergoing hemodialysis. Methods: A cross-sectional study on a population with chronic renal failure was performed. Anamnesis and oral examination, decayed, miss and filled teeth (DMFT) index, community periodontal index, simplified oral hygiene index (OHI-S) and gingival index were conducted. Data were processed using SPSS v.s. 20.0 using descriptive statistics and Fischer’s exact test and ANOVA test (p

[spa] INTRODUCCIÓN Y OBJETIVOS El uso de injertos provenientes de donantes en asistolia (DA) como estrategia para reducir la mortalidad en lista de espera presenta como menoscabo una mayor incidencia de estenosis biliares no anastomóticas. Esto se debe a la mayor susceptibilidad del epitelio biliar a la isquemia caliente que se da durante la fase de asistolia. La activación del endotelio del plexo peribiliar y la consecuente formación de microtrombos exacerbaría la hipoxia colangiocelular. Ante dicha hipótesis, el uso de fibrinolíticos se postuló como una prometedora estrategia para mejorar la viabilidad de los órganos, al lisar los trombos y permitir el paso de sangre. Sin embargo, estudios realizados en pacientes que han sufrido una parada cardiorespiratoria recuperada muestran un estado de hiperfibrinolisis mediante tromboelastometría. Para valorar la efectividad del tratamiento con fibrinolíticos en los DA no controlados, por un lado analizamos el patrón de coagulación de éstos a su llegada a nuestro hospital; y paralelamente, mediante un estudio experimental, analizamos la efectividad del uso de fibrinolíticos sobre los injertos hepáticos. MATERIAL, MÉTODOS Y RESULTADOS En el estudio clínico se describen las alteraciones en la coagulación de los DA tipo 2 de la clasificación de Maastricht. De los 33 potenciales donantes llegados al hospital durante 18 meses, se trasplantaron 22 riñones y 5 hígados. El análisis tromboelastométrico muestra un patrón de hipocoagulabilidad e hiperfibrinolisis en todos ellos. Se vio una correlación inversa entre el grado de lisis a los 30 minutos y el pico de transaminasas. En el estudio experimental porcino, se reproduce la situación clínica del DA. Se analizó el efecto de la heparina pre-PCR, de 60 minutos de duración; o fibrinolítico (tPA) tras PCR y durante la perfusión regional abdominal normotérmica (PRAN), que se mantuvo 60 minutos. El injerto hepático se implantó en un receptor, seguido durante 5 días. Se observó una mejoría en los flujos durante la PRAN en aquellos animales que recibieron heparina pre-parada frente a aquellos animales que no la recibieron. Así mismo, la supervivencia fue superior en este grupo, con un menor pico de transaminasas y mayor recuperación de la función hepática medida por el tiempo de protrombina. No se observaron diferencias en el grupo en el que se administró tPA en comparación con el grupo control. En cuanto al análisis histológico, en ninguno de los grupos se observaron depósitos de fibrina significativos. La lesión por isquemia-reperfusión y la expresión de los marcadores de activación endotelial e inflamación fue menor en aquellos animales pre-tratados con heparina. DISCUSIÓN Y CONCLUSIONES En el estudio clínico, el patrón de hiperfibrinolisis en todos los potenciales DA es similar a los resultados de los estudios en pacientes que sufrieron PCR recuperadas. Dicha hiperfibrinolisis podría atribuirse a un mecanismo de protección mediado por la vía de la proteína C. En el estudio experimental, el hecho de que no hubiera diferencias en cuanto a la calidad del injerto hepático y la viabilidad del mismo en aquellos animales que habían recibido tPA en comparación con los controles; así como la ausencia de depósitos significativos de fibrina tras 60 minutos de parada cardíaca, no justifica la administración de fibrinolítico. Por otro lado, la heparina administrada pre-PCR la viabilidad del injerto. En conclusión, el patrón de hiperfibrinolisis en los DA tipo 2 de la clasificación de Maastricht, la ausencia de depósitos de fibrina en el tejido hepático después de la PRC en el modelo animal, y el hecho de que el tratamiento con un agente fibrinolítico fuera inefectivo para mejorar la viabilidad del injerto hepático, ponen en entredicho la utilidad de este tratamiento. Por otro lado, la administración de heparina pre-PCR ha demostrado su utilidad para mejorar tanto la calidad del injerto durante la PRAN como su viabilidad postoperatoria., [eng] INTRODUCTION AND GOAL The use of organs obtained from donation after cardiocirculatory death (DCD) is limited by the appearance of ischemic-type biliary strictures. These are due to a greater susceptibility of the biliary epithelium to warm ischemia. Some studies suggest the use of fibrinolytics to dissolve microthrombi formed during this period to improve graft function; however, other studies describe a hiperfibrinolytic thromboelastometry pattern in patients who suffer cardiac arrest (CA). To evaluate the adequacy of fibrinolytic treatment in the Maastricht type II donor, we performed a clinical and an experimental study. MATERIAL AND METHODS In the clinical study, lab analysis and viscoelastic assays were performed in all potential DCD type II donors arriving at our hospital during an 18-month period. In the experimental study performed in a previously validated porcine model, we analyzed the usefulness of fibrinolysis in liver outcomes by either administering tPA after a 60 minute CA and during normothermic abdominal perfusion, or the use of heparin prior to CA. RESULTS 33 potential donors arrived in our hospital during the period of study, from which 22 kidneys and 5 livers were transplanted. Viscoelastic assays in all cases found a pattern of hyperfibrinolysis. There was an inverse correlation between clot stability as measured by Ly30 and transaminase levels. In the experimental study, there were no differences in pump flows, liver graft function or histologic parameters in those animals treated with tPA as compared to the control group. Moreover, fibrin deposition was not detected in any group after one hour of cardiac arrest. On the other hand, the use of pre-arrest heparin did improve pump flow and liver graft quality. CONCLUSIONS Both results in the clinical and experimental studies indicate no additional role for fibrinolytic therapy in the Maastricht type II setting. Heparin does offer anti-inflammatory and other cytoprotective effects that help improve DCD liver graft quality.

ESPAÑOL La enfermedad hepática alcohólica (EHA) es una de las causas más frecuentes de trasplante hepático en enfermedad hepática terminal. No hay evidencia de impacto de la detección regular de sustancias en orina (DRSO) sobre la supervivencia de los pacientes con EHA. Los objetivos de este estudio fueron comparar la sensibilidad de la DRSO, evaluar su impacto en la supervivencia y en el trasplante de hígado, y evaluar el impacto de la adherencia a la DRSO. Realizamos un estudio retrospectivo (N = 84) con candidatos para trasplante de hígado por EHA. Registramos las variables demográficas, bioquímicas y clínicas al inicio del estudio. Evaluamos la adherencia a la DRSO durante el seguimiento. Calculamos la sensibilidad tanto de la DRSO como de las declaraciones de los pacientes para todas las sustancias. Realizamos análisis multivariables (regresión logística) y de supervivencia para explorar los factores asociados y el impacto de la adherencia a la DRSO, y de los resultados positivos en la DRSO sobre la supervivencia. La DRSO tuvo una alta sensibilidad para identificar bebedores activos (76,9%), fumadores (78,9%) y consumidores de cannabis (83,3%). Alta adherencia a la DRSO tuvo una asociación inversa con mortalidad durante el seguimiento. La presencia de trastornos de la personalidad tuvo un impacto negativo (RM ,29, IC 95% ,08-,97) sobre la adherencia a la DRSO. Tanto la DRSO como las declaraciones deben llevarse a cabo en este perfil de pacientes. Los profesionales que participan en programas de trasplante hepático deben promover el cumplimiento de la DRSO, principalmente en pacientes con trastornos de la personalidad. ENGLISH. Alcohol Liver Disease (ALD) is one of the most prevalent conditions leading to liver transplantation for end-stage liver disease. There is lacking evidence of regular urine screening testing (RUST) impact on survival or liver transplantation of ALD patients. The aims of this study were to compare the sensitivity of RUST, to assess its impact on survival and liver transplantation, and to evaluate factors associated with adherence to RUST. We performed a single-centered retrospective study (N = 84) with ALD candidates for liver transplantation. Demographic, biochemical and clinical variables were recorded at baseline. Adherence to RUST was evaluated during follow-up. The sensitivity of both RUST and self-reports were calculated for all drugs. Multivariable logistic and survival regression analyses were performed to explore associated factors and the impact of adherence to RUST, and positive results on survival. RUST had high sensitivity for identifying active drinkers (76.9%), smokers (78.9%) and cannabis users (83.3%). High adherence to RUST was inversely associated with mortality during follow-up. Presence of personality disorders negatively impacted (OR 0.29, CI 95% 0.08-0.97) adherence to RUST. Both RUST and self-reports should be carried out in this setting. Professionals involved in liver transplantation programs must promote adherence to RUST, primarily in patients with personality disorders.

To the editor: the comprehensive review article by Loupy and Lefaucheur (Sept. 20 issue)1 on antibody-mediated rejection describes major advances in understanding the pathophysiological process and diagnosis of antibody-mediated rejection, but successful treatment is still limited to the acute forms of antibody-mediated rejection.2 Allograft loss eventually occurs in the majority of patients in whom true pathogenic donor-specific anti-HLA antibodies develop.3 This is frustrating for both clinicians and patients because even treatments administered at early stages of the disease are not effective. It is quite obvious that the best strategy to minimize the risk of donor-specific antibodies is to improve the level of HLA matching between the donor and recipient.4 This point was omitted in the article.

[eng] Islet transplantation is considered a potentially curative treatment for type 1 diabetes, Despite the key important advances achieved by the establishment of the Edmonton protocol, islet transplantation remains clinically limited due to several challenges, which lead to massive islet loss or failure of the grafts. Therefore searching for new targets to facilitate islet revascularization may lead to improved future results in cell transplantation.Islets native architecture is characterized by a dense vessel network that, delivers oxygen, hormones, glucose, and nutrients to islet’s cells allowing them to function correctly. After transplantation, the survival and function of islet grafts must depend on the reestablishment of new vessels within the grafts to derive blood flow from the host vascular system. This vascular network is severed when islets are isolated for transplantation, and even though islets freely revascularize, they do not reach the levels of vascularization present in endogenous pancreatic islets, which results in the impairment of grafts function and survival. Altogether, the lack of a proper vascular network account as the primary responsible for early graft loss. Although the molecular mechanisms underlying islet revascularization remain elusive, a number of factors have been implicated, such as the vascular endothelial growth factor A (VEGFA), a key angiogenic molecule that acts to stimulate new vessel formation. VEGFA expression in transplanted islets is significantly impaired, which is further pronounced in prevailing hyperglycemia, and coincides with delayed and insufficient islet revascularization in diabetic mice In this thesis we identify for the first time, tyrosine phosphatase PTP-1B as a target for improving graft revascularization. We targeted PTP-1B, either by its inhibition, following a sodium tungstate treatment after transplantation, or by transplanting islets lacking PTP-1B, using a genetic model of PTP-1B knock-out, or following genetic silencing, using siRNA and shRNA Lentivirus particles. Following transplantation into the anterior chamber of the eye in diabetic mice, islet-grafts showed increased revascularization by inducing the expression of VEGF-A by ß-cells in the graft. This improved revascularization was followed by an improvement of islet-graft survival and function, as transplanted mice recovered normoglycemia and glucose tolerance. Furthermore, we demonstrated that PTP-1B induces VEGF-A expression and secretion in islets by upregulating HIF1A-independent PGC1α/ERRα signaling. Finally, we demonstrated that this regulatory mechanism is conserved in human islets. Together, these findings unravel the potential role of PTP-1B as a target for improving islet transplantation outcomes., [spa] El trasplante de islotes ha sido reconocido como una prometedora opción de tratamiento de la diabetes tipo 1 (DT1) tras la introducción del protocolo de Edmonton, el cual enfatiza el requerimiento de un adecuado número de islotes donantes así como el uso de regímenes de inmunosupresores libres de esteroides. Además es un procedimiento quirúrgico menos invasivo y que conlleva menos complicaciones comparado con el trasplante de páncreas. A pesar de los importantes avances establecidos por el protocolo de Edmonton, el uso clínico del trasplante de islotes para el tratamiento de pacientes DT1 continúa siendo limitado, debido en gran parte a los retos post-trasplante. Tras el trasplante, los islotes son separados de su red vascular nativa, por lo que la funcionalidad y supervivencia del injerto dependerá del restablecimiento de nuevos vasos en el injerto para derivar el flujo sanguíneo al sistema vascular del huésped. Sin embargo, los estudios han demostrado que el grado de revascularización de los islotes trasplantados es considerablemente menor que el de la microvasculatura nativa de los islotes pancreáticos, incluso a los 9 meses del injerto . Ésta retrasada y insuficiente revascularización priva los nuevos islotes injertados de oxígeno y nutrientes, pudiendo provocar su muerte celular y el fallo temprano del injerto. En el estudio realizado, identificamos, por primera vez, la proteína tirosina fosfatasa 1B (PTP-1B) como una diana terapéutica, capaz de mejorar la revascularización de los injerto pancreáticos sin comprometer la masa ß-celular del injerto y la principal mediadora de la acción del tratamiento del tungstato sódico en la revascularización de islotes. Además hemos identificado el mecanismo por lo cual la PTP-1B induce la revascularización. Nuestros datos apuntan que en la ausencia de PTP-1B, los islotes pancreáticos expresan y secretan el factor de crecimiento del endotelio vascular A (VEGFA), una citoquina pro-angiogénica, mediante la activación de la PGC1 alpha y ERR-alpha de forma independiente de hipoxia. Finalmente hemos comprobado que éste mecanismo de inducción de VEGFA se conserva en islotes humanos. De ésta forma concluimos que PTP-1B es una diana prometedora en el desarrollo de nuevas terapias para la mejora de la revascularización de injertos de islotes.

Solid organ transplant (SOT) recipients are especially at risk of developing infections by multidrug resistant (MDR) Gram-negative bacilli (GNB), as they are frequently exposed to antibiotics and the healthcare setting, and are regulary subject to invasive procedures. Nevertheless, no recommendations concerning prevention and treatment are available. A panel of experts revised the available evidence; this document summarizes their recommendations: (1) it is important to characterize the isolate´s phenotypic and genotypic resistance profile; (2) overall, donor colonization should not constitute a contraindication to transplantation, although active infected kidney and lung grafts should be avoided; (3) recipient colonization is associated with an increased risk of infection, but is not a contraindication to transplantation; (4) different surgical prophylaxis regimens are not recommended for patients colonized with carbapenem-resistant GNB; (5) timely detection of carriers, contact isolation precautions, hand hygiene compliance and antibiotic control policies are important preventive measures; (6) there is not sufficient data to recommend intestinal decolonization; (7) colonized lung transplant recipients could benefit from prophylactic inhaled antibiotics, specially for Pseudomonas aeruginosa; (8) colonized SOT recipients should receive an empirical treatment which includes active antibiotics, and directed therapy should be adjusted according to susceptibility study results and the severity of the infection. J.T.S. holds a research contract from the Fundación para la Formación e Investigación de los Profesionales de la Salud de Extremadura (FundeSalud), Instituto de Salud Carlos III. M.F.R. holds a clinical research contract “Juan Rodés” (JR14/00036) from the Spanish Ministry of Economy and Competitiveness, Instituto de Salud Carlos III.

We investigated the involvement of glycogen synthase kinase-3β (GSK3β) and the voltage-dependent anion channel (VDAC) in livers subjected to cold ischemia–reperfusion injury (I/R) associated with orthotopic liver transplantation (OLT). Rat livers were preserved in University of Wisconsin (UW) and Institute Georges Lopez (IGL-1) solution, the latter enriched or not with trimetazidine, and then subjected to OLT. Transaminase (ALT) and HMGB1 protein levels, glutamate dehydrogenase (GLDH), and oxidative stress (MDA) were measured. The AKT protein kinase and its direct substrates, GSK3β and VDAC, as well as caspases 3, 9, and cytochrome C and reticulum endoplasmic stress-related proteins (GRP78, pPERK, ATF4, and CHOP), were determined by Western blot. IGL-1+TMZ significantly reduced liver injury. We also observed a significant phosphorylation of AKT, which in turn induced the phosphorylation and inhibition of GSK3β. In addition, TMZ protected the mitochondria since, in comparison with IGL-1 alone, we found reductions in VDAC phosphorylation, apoptosis, and GLDH release. All these results were correlated with decreased ER stress. Addition of TMZ to IGL-1 solution increased the tolerance of the liver graft to I/R injury through inhibition of GSK3β and VDAC, contributing to ER stress reduction and cell death prevention., The authors would like to thank Michael Maudsley at the Language Advisory Service of the University of Barcelona for revising the English text. This work was supported by Instituto de Salud Carlos III (ISCIII) through the FIS project PI12/0056 co-funded by FEDER from Regional Development European Funds (European Union)., We acknowledge support by the CSIC Open Access Publication Initiative through its Unit of Information Resources for Research (URICI).

Sistema Nerviós Autònom; Risc de malalties cardiovasculars; Procediments mèdics quirúrgics i invasius Sistema nervioso autónomo; Riesgo de enfermedad cardiovascular; Procedimientos médicos quirúrgicos e invasivos Autonomic Nervous System; Cardiovascular disease risk; Surgical and invasive medical procedures Background Neurological complications after lung transplantation are common. The full spectrum of neurological complications and their impact on clinical outcomes has not been extensively studied. Methods We investigated the neurological incidence of complications, categorized according to whether they affected the central, peripheral or autonomic nervous systems, in a series of 109 patients undergoing lung transplantation at our center between January 1 2013 and December 31 2014. Results Fifty-one patients (46.8%) presented at least one neurological complication. Critical illness polyneuropathy-myopathy (31 cases) and phrenic nerve injury (26 cases) were the two most prevalent complications. These two neuromuscular complications lengthened hospital stays by a median period of 35.5 and 32.5 days respectively. However, neurological complications did not affect patients’ survival. Conclusions The real incidence of neurological complications among lung transplant recipients is probably underestimated. They usually appear in the first two months after surgery. Despite not affecting mortality, they do affect the mean length of hospital stay, and especially the time spent in the Intensive Care Unit. We found no risk factor for neurological complications except for long operating times, ischemic time and need for transfusion. It is necessary to develop programs for the prevention and early recognition of these complications, and the prevention of their precipitant and risk factors. JG is the recipient of a grant from the Spanish Fondo de Investigaciones Sanitarias (FIS PI13-01272-FEDER).

BACKGROUND: Current guidelines recommend that treatment of resistant cytomegalovirus (CMV) in solid organ transplant (SOT) recipients must be based on genotypic analysis. However, this recommendation is not systematically followed. OBJECTIVES: To assess the presence of mutations associated with CMV resistance in SOT recipients with suspected resistance, their associated risk factors and the clinical impact of resistance. STUDY DESIGN: Using Sanger sequencing we prospectively assessed the presence of resistance mutations in a nation-wide prospective study between September 2013-August 2015. RESULTS: Of 39 patients studied, 9 (23%) showed resistance mutations. All had one mutation in the UL 97 gene and two also had one mutation in the UL54 gene. Resistance mutations were more frequent in lung transplant recipients (44% p=0.0068) and in patients receiving prophylaxis >/=6 months (57% vs. 17%, p=0.0180). The mean time between transplantation and suspicion of resistance was longer in patients with mutations (239 vs. 100days, respectively, p=0.0046) as was the median treatment duration before suspicion (45 vs. 16days, p=0.0081). There were no significant differences according to the treatment strategies or the mean CMV load at the time of suspicion. Of note, resistance-associated mutations appeared in one patient during CMV prophylaxis and also in a seropositive organ recipient. Incomplete suppression of CMV was more frequent in patients with confirmed resistance. CONCLUSIONS: Our study confirms the need to assess CMV resistance mutations in any patient with criteria of suspected clinical resistance. Early confirmation of the presence of resistance mutations is essential to optimize the management of these patients.

International audience; BACKGROUND: The two common sialic acids (Sias) in mammals are N-acetylneuraminic acid (Neu5Ac) and its hydroxylated form N-glycolylneuraminic acid (Neu5Gc). Unlike most mammals, humans cannot synthesize Neu5Gc that is considered foreign and recognized by circulating antibodies. Thus, Neu5Gc is a potential xenogenic carbohydrate antigen in bioprosthetic heart valves (BHV) that tend to deteriorate in time within human patients.METHODS: We investigated Neu5Gc expression in non-engineered animal-derived cardiac tissues and in clinically used commercial BHV, and evaluated Neu5Gc immunogenicity on BHV through recognition by human anti-Neu5Gc IgG.RESULTS: Neu5Gc was detected by immunohistochemistry in porcine aortic valves and in porcine and bovine pericardium. Qualitative analysis of Sia linkages revealed Siaα2-3>Siaα2-6 on porcine/bovine pericardium while the opposite in porcine aortic/pulmonary valve cusps. Similarly, six commercial BHV containing either porcine aortic valve or porcine/bovine/equine pericardium revealed Siaα2-3>Siaα2-6 expression. Quantitative analysis of Sia by HPLC showed porcine/bovine pericardium express 4-fold higher Neu5Gc levels compared to the porcine aortic/pulmonary valves, with Neu5Ac at 6-fold over Neu5Gc. Likewise, Neu5Gc was expressed on commercial BHV (186.3±16.9 pmol Sia/μg protein), with Neu5Ac at 8-fold over Neu5Gc. Affinity-purified human anti-Neu5Gc IgG showing high specificity toward Neu5Gc-glycans (with no binding to Neu5Ac-glycans) on a glycan microarray, strongly bound to all tested commercial BHV, demonstrating Neu5Gc immune recognition in cardiac xenografts.CONCLUSIONS: We conclusively demonstrated Neu5Gc expression in native cardiac tissues, as well as in six commercial BHV. These Neu5Gc xeno-antigens were recognized by human anti-Neu5Gc IgG, supporting their immunogenicity. Altogether, these findings suggest BHV-Neu5Gc/anti-Neu5Gc may play a role in valve deterioration warranting further investigation.