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Andrea Fabbri,1 Alberto M Borobia,2 Agnes Ricard-Hibon,3 Frank Coffey,4 Aurore Caumont-Prim,5 François Montestruc,5 Amedeo Soldi,6 Susana Traseira Lugilde,7 Sara Dickerson8 1Department of Emergency Medicine, Morgagni-Pierantoni Hospital, Forli, Italy; 2Clinical Pharmacology Department, La Paz University Hospital, School of Medicine, Universidad Autónoma de Madrid, IdiPAZ, Madrid, Spain; 3Emergency Department SAMU-SMUR 95, CHG Pontoise-Beaumont/Oise, Pontoise, France; 4DREEAM: Department of Research and Education in Emergency Medicine, Acute Medicine and Major Trauma, Nottingham University Hospitals NHS Trust, Nottingham, UK; 5eXYSTAT, Malakoff, France; 6Mundipharma Pharmaceuticals Srl, Milan, Italy; 7Mundipharma Pharmaceuticals S.L., Madrid, Spain; 8Mundibiopharma Limited, Cambridge, UKCorrespondence: Sara DickersonMundibiopharma Limited, Cambridge Science Park, Milton Road, Cambridge CB4 0AB, UKTel +44 1223 397684Email Sara.Dickerson@mundipharma.comPurpose: Undertreatment of trauma-related pain is common in the pre-hospital and hospital settings owing to barriers to the use of traditional standard of care analgesics. Low-dose methoxyflurane is an inhaled non-opioid analgesic with a rapid onset of pain relief that is approved for emergency relief of moderate-to-severe trauma-related pain in adults. This analysis was performed to compare the efficacy and safety of low-dose methoxyflurane with standard of care analgesics in adults with trauma-related pain.Methods: A meta-analysis was performed on pooled data from randomized controlled trials identified via a systematic review. The primary endpoint was the pain intensity difference between baseline and various time intervals (5, 10, 15, 20, and 30 minutes) after initiation of treatment.Results: The pain intensity difference was statistically superior with low-dose methoxyflurane compared with standard of care analgesics (overall estimated treatment effect=11.88, 95% CI=9.75– 14.00; P< 0.0001). The superiority of low-dose methoxyflurane was demonstrated at 5 minutes after treatment initiation and was maintained across all timepoints. Significantly more patients treated with methoxyflurane achieved response criteria of pain intensity ≤ 30 mm on a visual analog scale, and relative reductions in pain intensity of ≥ 30% and ≥ 50%, compared with patients who received standard of care analgesics. The median time to pain relief was shorter with methoxyflurane than with standard of care analgesics. The findings were consistent in a subgroup of elderly patients (aged ≥ 65 years).Conclusion: Methoxyflurane can be considered as an alternative to standard of care analgesics in pre-hospital and hospital settings for treatment of adult patients with acute trauma-related pain.Keywords: acute pain, inhaled analgesic, emergency service, wounds and injury, pain management, analgesia

The severity of COVID 19 symptoms has a direct correlation with lymphopenia, affecting natural killer (NK) cells. SARS-CoV-2 specific "memory" NK cells obtained from convalescent donors can be used as cell immunotherapy. In 2022 a phase I, dose-escalation, single center clinical trial was conducted to evaluate the safety and feasibility of the infusion of CD3 - /CD56 + NK cells against moderate/severe cases of COVID-19 (NCT04578210). Six participants with pneumonia and/or lymphopenia were infused. Four patients received a single-dose infusion of NK cells of 1×10 6 /kg, and the following two patients a dose of 2×10 6 /kg of NK cells. All participants' clinical status and inflammation markers were monitored. No serious adverse events were reported after infusion. Exploratory outcomes included the donor chimerism, NK-cell immunophenotype evolution, and immune lymphocyte reconstitution. This study provides preliminary evidence supporting the idea that treatment of COVID-19 patients with moderate/severe symptoms using NK from COVID-19 convalescent donors is feasible and safe., Competing Interests: The authors have no conflicts of interest to declare., (© 2024 Published by Elsevier Inc.)

Introduction: Genetic variations impact drug response, driving the need for personalised medicine through pre-emptive pharmacogenetic testing. However, the adoption of pre-emptive pharmacogenetic testing for commonly prescribed drugs, such as statins, outside of tertiary hospitals is limited due to a lack of pharmacoeconomic evidence to support widespread implementation by healthcare policy-makers. The Spanish Consortium for the Implementation of Pharmacogenetics (iPHARMGx Consortium) addresses this by developing a clinical trial master protocol that will govern multiple nested adaptive clinical trials that compare genotype-guided treatments to standard care in specific drug-gene-population triads, asses their cost-efficacy and identify novel biomarkers through advanced sequencing techniques. The first of these studies aims to assess whether a pre-emptive statin therapy genotyping scheme reduces the incidence of statin-associated muscle symptoms (SAMS) in a population at risk of cardiovascular disease susceptible of receiving high-intensity or moderate-intensity doses of statins: The PREVESTATGx trial., Methods and Analysis: the PREVESTATGX trial is a multicentre, adaptive randomised controlled pragmatic phase IV clinical trial nested to the iPHARMGx master protocol with two parallel arms, aiming for superiority. Randomisation will be conducted on an individual basis with a centralised approach and stratification by centre. After inclusion in the trial and genotyping has been performed, subjects will be randomly allocated to experimental group (pharmacogenetic genotype-guided statin prescription) or standard-of-care statin prescription (as deemed by attending physician). The main objective is to assess the efficacy of a statin pre-emptive genotyping strategy in reducing the incidence of SAMS. A total of 225 subjects will be recruited among the 10 participating centres if no futility/efficacy boundary is reached in the prespecified interim analyses. Recruitment will be carried out during a 12-month period and subjects will be followed for a 9-month period., Ethics and Dissemination: The PREVESTATGx trial received ethical approval on 24 April 2024. Results will be disseminated via publication in peer-reviewed journals as well as presentation at international conferences. Trial results will be submitted for publication in an open-access peer-reviewed medical speciality-specific publication., Trial Registration Number: EU CT number: 2023-509418-12-00/Clinical trial Identifier (ClinicalTrials.gov): NCT06262685. Protocol version 1.2 12 April 2024 (includes non-substantial modification number 14 June 2024). Trial registration of this study can be located at both the EU Clinical Trials Register available from https:// euclinicaltrials.eu/search-for-clinical-trials/?lang=en and https://clinicaltrials.gov. Registration on both websites was done before the enrolment of the first patient complying with European regulations. EU Clinical Trials Register is a primary registry according to the WHO., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Helping people recover from aphasia is among the top 10 research priorities relating to life after stroke., Objective: We aimed to evaluate the feasibility of dubbing techniques (using newly developed software) for post-stroke aphasia therapy and explore its potential efficacy., Methods: Randomised, crossover, interventional, feasibility trial that included patients with chronic post-stroke non-fluent aphasia. The intervention consisted of an individualised programme (16 sessions; 8 weeks) based on dubbing words and sentences progressively adapted to the severity of the aphasia. Patients were allocated to groups that underwent therapy within the first 3 months, or between 3 and 6 months from inclusion, each group serving as the control during the non-therapy periods. Outcomes were the pre-post differences in the Communicative Activity Log, the Boston Diagnostic Aphasia Examination, the General Health Questionnaire-12, the Stroke Aphasia Quality of Life Scale, and the Western Aphasia Battery Revised, administered by psychologists blinded to the patients' allocation., Results: Recruitment was limited due to COVID-19 and prematurely stopped because of funding coming to an end. A total of 23 patients were randomised, 20 of whom completed the study (1 withdrew consent, and 2 dropped out). The adherence rate to the allocated group was 95.3%. No statistically significant differences were found in any of the outcomes; however, 17 (85%) patients reported subjective improvements in communication skills., Conclusions: This trial shows the feasibility of dubbing therapy (using dedicated software) for patients with post-stroke non-fluent aphasia. Although it lacks statistical power, certain effects on language and communication cannot be ignored., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

CombiVacS study has demonstrated a strong immune response of the heterologous ChAdOx1-S/BNT162b2 vaccine combination. The primary outcomes of the study were to assess the humoral immune response against SARS-CoV-2, 28 days after a third dose of a mRNA vaccine, in subjects that received a previous prime-boost scheme with ChAdOx1-S/BNT162b2. Secondary outcomes extended the study to 3 and 6 months. The third vaccine dose of mRNA-1273 in naive participants previously vaccinated with ChAdOx1-S/BNT162b2 regimen reached higher neutralizing antibodies titers against the variants of concern Delta and BA.1 lineage of Omicron compared with those receiving a third dose of BNT162b2 at day 28. These differences between BNT162b2 and mRNA-1273 arms were observed against the ancestral variant G614 at day 90. Suboptimal neutralizing response was observed against BQ.1.1, XBB.1.5/XBB.1.9, and JN.1 in a relevant proportion of individuals 180 days after the third dose, even after asymptomatic Omicron breakthrough infections. EudraCT (2021-001978-37); ClinicalTrials.gov (NCT04860739)., Competing Interests: J.A. has received fees for educational programs from Gilead, MSD, GSK and Janssen outside of the submitted work. M.C.-A. has participated in advisory boards and has received research funding from GSK, Sanofi Pasteur, Pfizer, Novavax, and Janssen. C.B.-I. is the deputy general manager of the Instituto de Salud Carlos III. J.R.A. has received fees from Janssen, outside of the submitted work. A.M.B. is principal investigator of clinical trials sponsored by GlaxoSmithKline, Daiichi-Sankyo, Janssen, and Farmalider, outside of the submitted work., (© 2024 The Authors.)

Background: The drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome represents a severe form of drug hypersensitivity reaction characterized by significant morbidity, mortality, and long-term sequelae, coupled with limited therapeutic avenues. Accurate identification of the causative drug(s) is paramount for acute management, exploration of safe therapeutic alternatives, and prevention of future occurrences. However, the absence of a standardized diagnostic test and a specific causality algorithm tailored to DRESS poses a significant challenge in its clinical management. Methods: We conducted a retrospective case-control study involving 37 DRESS patients to validate a novel causality algorithm, the ALDRESS, designed explicitly for this syndrome, comparing it against the current standard algorithm, SEFV. Results: The ALDRESS algorithm showcased superior performance, exhibiting an 85.7% sensitivity and 93% specificity with comparable negative predictive values (80.6% vs. 97%). Notably, the ALDRESS algorithm yielded a substantially higher positive predictive value (75%) compared to SEFV (51.40%), achieving an overall accuracy rate of 92%. Conclusions: Our findings underscore the efficacy of the ALDRESS algorithm in accurately attributing causality to drugs implicated in DRESS syndrome. However, further validation studies involving larger, diverse cohorts are warranted to consolidate its clinical utility and broaden its applicability. This study lays the groundwork for a refined causality assessment tool, promising advancements in the diagnosis and management of DRESS syndrome.

The development of Pharmacogenetics and Pharmacogenomics in Western Europe is highly relevant in the worldwide scenario. Despite the usually low institutional support, many research groups, composed of basic and clinical researchers, have been actively working for decades in this field. Their contributions made an international impact and paved the way for further studies and pharmacogenomics implementation in clinical practice. In this manuscript, that makes part of the Special Issue entitled Spanish Pharmacology, we present an analysis of the state of the art of Pharmacogenetics and Pharmacogenomics research in Europe, we compare it with the developments in Spain, and we summarize the most salient contributions since 1988 to the present, as well as recent developments in the clinical application of pharmacogenomics knowledge. Finally, we present some considerations on how we could improve translation to clinical practice in this specific scenario., Competing Interests: Declaration of Competing Interest All authors declare that no financial or personal relationships with other people or organizations that could inappropriately influence (bias) this work exists., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background Aims: There are currently no effective anti-viral treatments for coronavirus disease 2019 (COVID-19)-hospitalized patients with hypoxemia. Lymphopenia is a biomarker of disease severity usually present in patients who are hospitalized. Approaches to increasing lymphocytes exerting an anti-viral effect must be considered to treat these patients. Following our phase 1 study, we performed a phase 2 randomized multicenter clinical trial in which we evaluated the efficacy of the infusion of allogeneic off-the-shelf CD45RA - memory T cells containing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific T cells from convalescent donors plus the standard of care (SoC) versus just the SoC treatment., Methods: Eighty-four patients were enrolled in three Spanish centers. The patients were randomized into the infusion of 1 × 10 6 /kg CD45RA - memory T cells or the SoC. We selected four unvaccinated donors based on the expression of interferon gamma SARS-CoV-2-specific response within the CD45RA - memory T cells and the most frequent human leukocyte antigen typing in the Spanish population., Results: We analyzed data from 81 patients. The primary outcome for recovery, defined as the proportion of participants in each group with normalization of fever, oxygen saturation sustained for at least 24 hours and lymphopenia recovery through day 14 or at discharge, was met for the experimental arm. We also observed faster lymphocyte recovery in the experimental group. We did not observe any treatment-related adverse events., Conclusions: Adoptive cell therapy with off-the-shelf CD45RA - memory T cells containing SAR-CoV-2-specific T cells is safe, effective and accelerates lymphocyte recovery of patients with COVID-19 pneumonia and/or lymphopenia., Trial Registration: NCT04578210., Competing Interests: Declaration of Competing Interest CF, AP-M and BS filed patent PCT/EP2021/076516 on Memory T cells as adoptive cell therapy for viral diseases. All other authors have no commercial, proprietary or financial interest in the products or companies described in this article., (Copyright © 2023 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.)

A candidate AS01-adjuvanted vaccine containing four surface proteins from non-typable Haemophilus influenzae and Moraxella catarrhalis (NTHi-Mcat) has been developed to help prevent exacerbations of chronic obstructive pulmonary disease (COPD). Sequential administration of different vaccines containing the same AS01-adjuvant system could lead to immune interference. We compared administration of NTHi-Mcat following AS01-adjuvanted recombinant zoster vaccine (RZV) versus NTHi-Mcat alone. This phase 2a, open-label trial (NCT03894969) randomized healthy current or former smokers (50-80 years) without COPD to administration of NTHi-Mcat at 1, 3 or 6 months after RZV or to NTHi-Mcat alone (2-dose for both vaccines). Primary outcome was non-inferiority of the humoral immune response to NTHi-Mcat administered 1 month after RZV versus NTHi-Mcat alone, evaluated by specific antibody geometric mean concentration (GMC) ratio with 95% confidence intervals (CIs). The per-protocol set included 411 participants. Primary objective was met; lower limit of the 95%CI for the GMC ratio above 0.667 for all four vaccine antigens, 1 month after the second NTHi-Mcat dose. NTHi-Mcat induced similar immune response regardless of whether administered alone or 1, 3 or 6 months following RZV. Safety and reactogenicity profiles were acceptable; adverse event frequency was similar among study groups. Injection site pain was the most common symptom. No new safety concerns were identified. The study demonstrated non-inferiority of the immune response elicited by NTHi-Mcat administered sequentially to RZV versus NTHi-Mcat alone, indicating no immune interference. Starting from 1 month, no specific interval is required between RZV and NTHi-Mcat containing the same AS01-adjuvant system components in different quantities.

Effective participant recruitment is a critical challenge in clinical trials. Inadequate enrollment of participants can precipitate delays, escalated costs, and compromise scientific integrity. Despite its relevance, particularly during the early phases, it persists as an obstacle in the field of clinical research. The primary aim of this study was to analyze the recruitment rates of early-phase clinical trials and evaluate their potential associations with key trial characteristics. Using a descriptive and statistical analysis, a research study was conducted based on the early-phase trials registered at the European Clinical Trials Register (EU-CTR), spanning the timeframe from January 2017 to December 2021. Among the 194 trials examined, we found median recruitment rates of 68%. A more detailed exploration revealed a greater level of success in terms of recruitment achievement in pediatric trials when compared to trials involving adults, non-oncologic trials, or those also developed in non-European countries. It is important to underscore that only 69 trials out of the total managed to conclude recruitment, with the most prevalent reason for premature cessation being the presence of efficacy and safety issues or sponsor's strategy. This number can be greatly improved. Despite certain disparities observed in the information within EU-CTR, we have successfully determined the recruitment rates of the studies and established associations with some of the clinical trial characteristics analyzed. Owing to the inherent constraints of this study, further research is warranted to gain a comprehensive understanding of the intricate interplay between trial characteristics and their impact on recruitment rates in early-phase studies., (© 2023 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

First-time-in-human (FTIH) trials are designed to generate information on the safety, tolerability, as well as the pharmacokinetic and pharmacodynamics profile of new drugs. To ensure the safety of participants, these trials need to be conducted at specifically equipped phase I clinical trial units (CTUs). In accordance with the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Guideline for Good Clinical Practice (GCP) and the European Union (EU) regulatory guidelines, one of the aims of the European Regime Accelerator for Tuberculosis (ERA4TB) project is to collaboratively create a feasibility tool, through a partnership between public and private entities, for the validation of CTUs selected to conduct FTIH trials. A feasibility form, encompassing nine sections, was created to gather information on the unit in relation to key attributes of FTIH trials. Collaboratively, industry and academic partners defined the minimal criteria to ensure the adherence of CTUs to the principles of ICH GCP and regulations outlined by the European Medicines Agency (EMA) for the execution of FTIH trials. Subsequently, all CTUs available for the project were assessed for FTIH trial eligibility. The introduction of the certification procedure through the feasibility tool within ERA4TB resulted in the accreditation of the five academic CTUs, which are now prepared to carry out FTIH trials as part of the Consortium. The developed feasibility tool aims to establish open and widely used minimum requirements for the validation of academic CTUs as FTIH units, marking it as the inaugural tool for CTU validation resulting from the collaboration between industry and academia within the ERA4TB project. The established partnership has enabled an innovative and novel way of working., (© 2023 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

The field of pharmacogenetics (PGx) holds great promise in advancing personalized medicine by adapting treatments based on individual genetic profiles. Despite its benefits, there are still economic, ethical and institutional barriers that hinder its implementation in our healthcare environment. A retrospective analysis approach of anonymized data sourced from electronic health records was performed, encompassing a diverse patient population and evaluating key parameters such as prescribing patterns and test results, to assess the impact of pharmacogenetic testing. A head-to-head comparison with previously published activity results within the same pharmacogenetic laboratory was also conducted to contrast the progress made after 10 years. The analysis revealed significant utilization of pharmacogenetic testing in daily clinical practice, with 1,145 pharmacogenetic tests performed over a 1-year period and showing a 35% growth rate increase over time. Of the 17 different medical departments that sought PGx tests, the Oncology department accounted for the highest number, representing 58.47% of all genotyped patients. A total of 1,000 PGx tests were requested for individuals susceptible to receive a dose modification based on genotype, and 76 individuals received a genotype-guided dose adjustment. This study presents a comprehensive descriptive analysis of real-world data obtained from a public tertiary hospital laboratory specialized in pharmacogenetic testing, and presents data that strongly endorse the integration of pharmacogenetic testing into everyday clinical practice., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Stewart, Dodero-Anillo, Guijarro-Eguinoa, Arias, Gómez López De Las Huertas, Seco-Meseguer, García-García, Ramírez García, Rodríguez-Antolín, Carcas, Rodriguez-Novoa, Rosas-Alonso and Borobia.)

To evaluate KL-6 levels in medium-term post-COVID and to compare them in three groups categorised by the severity of COVID-19, we conducted a real-world, retrospective, cohort study. Data from the COVID-19 episode and follow-up during the post-COVID phase were extracted from the COVID@HULP and POSTCOVID@HULP databases, respectively. For the post-COVID period we included demographics, medical history, symptoms, quality of life, physical activity, anxiety and depression status and laboratory results. Patients were categorised into three groups based on the severity of COVID-19: Group 1 (inpatient critical), Group 2 (inpatient non-critical) and Group 3 (hospitalised at home). KL-6 was measured during the follow-up of the three groups. In all, 802 patients were included (Group 1 = 59; Group 2 = 296; Group 3 = 447 patients). The median age was 59 years (48-70), and 362 (45.2%) were males. At admission, fibrinogen and ferritin levels were lower in Group 3 than in the other groups ( p < 0.001). Follow-up data were obtained 124 days (97-149) after the diagnosis of COVID-19. The median levels of fibrinogen, ferritin and KL-6 at follow-up were 336 mg/dL (276-413), 80.5 ng/mL (36-174.3) and 326 U/mL (240.3-440.3), respectively. KL-6 levels were lower in Group 3 than in the other groups (298 U/mL (231.5-398) vs. 381.5 U/mL (304-511.8) (Group 1) and 372 U/mL (249-483) (Group 2) ( p < 0.001)). KL-6 was associated with ferritin ( p < 0.001), fibrinogen ( p < 0.001), D-dimer ( p < 0.001) and gamma-glutamyl transferase ( p < 0.001). KL-6 levels are less elevated at medium-term post-COVID follow-up in patients with mild COVID-19 than in those with moderate or severe disease. KL-6 is associated with systemic inflammatory, hepatic enzyme and thrombosis biomarkers.

Introduction: There is a need to optimise the management of atopic dermatitis (AD), improving the efficacy of treatments and reducing the toxicity associated with them. Although the efficacy of ciclosporine (CsA) in the treatment of AD has been thoroughly documented in the literature, the optimal dose has not been yet established. The use of multiomic predictive models of treatment response could optimise CsA therapy in AD., Methods and Analysis: The study is a low-intervention phase 4 trial to optimise the treatment of patients with moderate-severe AD requiring systemic treatment. The primary objectives are to identify biomarkers that could allow for the selection of responders and non-responders to first-line treatment with CsA and to develop a response prediction model to optimise the CsA dose and treatment regimen in responding patients based on these biomarkers. The study is divided into two cohorts: the first comprised of patients starting treatment with CsA (cohort 1), and the second, of patients already receiving or who have received CsA therapy (cohort 2)., Ethics and Dissemination: The study activities began following authorisation by the Spanish Regulatory Agency (AEMPS) and the Clinical Research Ethics Committee of La Paz University Hospital approval. Trial results will be submitted for publication in an open access peer-reviewed medical speciality-specific publication.Trial registration of this study can be located at the EU Clinical Trials Register, available from https://euclinicaltrials.eu/search-for-clinical-trials/?lang=en. Our clinical trial was registered in the website before the enrolment of the first patient complying with European regulations. EU Clinical Trials Register is a primary registry according the WHO. Once our trial was included in a primary and official registry, in order to extend the accessibility to our research, we also registered it retrospectively in clinicaltrials.gov; however, this is not mandatory as per our regulation., Trial Registration Number: NCT05692843., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Platin-based chemotherapy is the standard treatment for patients with non-small cell lung cancer (NSCLC). However, resistance to this therapy is a major obstacle in successful treatment. In this study, we aimed to investigate the impact of several pharmacogenetic variants in patients with unresectable NSCLC treated with platin-based chemotherapy. Our results showed that DPYD variant carriers had significantly shorter progression-free survival and overall survival compared to DPYD wild-type patients, whereas DPD deficiency was not associated with a higher incidence of high-grade toxicity. For the first time, our study provides evidence that DPYD gene variants are associated with resistance to platin-based chemotherapy in NSCLC patients. Although further studies are needed to confirm these findings and explore the underlying mechanisms of this association, our results suggest that genetic testing of DPYD variants may be useful for identifying patients at a higher risk of platin-based chemotherapy resistance and might be helpful in guiding future personalized treatment strategies in NSCLC patients.

Background: A SARS-CoV-2 protein-based heterodimer vaccine, PHH-1V, has been shown to be safe and well-tolerated in healthy young adults in a first-in-human, Phase I/IIa study dose-escalation trial. Here, we report the interim results of the Phase IIb HH-2, where the immunogenicity and safety of a heterologous booster with PHH-1V is assessed versus a homologous booster with BNT162b2 at 14, 28 and 98 days after vaccine administration., Methods: The HH-2 study is an ongoing multicentre, randomised, active-controlled, double-blind, non-inferiority Phase IIb trial, where participants 18 years or older who had received two doses of BNT162b2 were randomly assigned in a 2:1 ratio to receive a booster dose of vaccine-either heterologous (PHH-1V group) or homologous (BNT162b2 group)-in 10 centres in Spain. Eligible subjects were allocated to treatment stratified by age group (18-64 versus ≥65 years) with approximately 10% of the sample enrolled in the older age group. The primary endpoints were humoral immunogenicity measured by changes in levels of neutralizing antibodies (PBNA) against the ancestral Wuhan-Hu-1 strain after the PHH-1V or the BNT162b2 boost, and the safety and tolerability of PHH-1V as a boost. The secondary endpoints were to compare changes in levels of neutralizing antibodies against different variants of SARS-CoV-2 and the T-cell responses towards the SARS-CoV-2 spike glycoprotein peptides. The exploratory endpoint was to assess the number of subjects with SARS-CoV-2 infections ≥14 days after PHH-1V booster. This study is ongoing and is registered with ClinicalTrials.gov, NCT05142553., Findings: From 15 November 2021, 782 adults were randomly assigned to PHH-1V (n = 522) or BNT162b2 (n = 260) boost vaccine groups. The geometric mean titre (GMT) ratio of neutralizing antibodies on days 14, 28 and 98, shown as BNT162b2 active control versus PHH-1V, was, respectively, 1.68 (p < 0.0001), 1.31 (p = 0.0007) and 0.86 (p = 0.40) for the ancestral Wuhan-Hu-1 strain; 0.62 (p < 0.0001), 0.65 (p < 0.0001) and 0.56 (p = 0.003) for the Beta variant; 1.01 (p = 0.92), 0.88 (p = 0.11) and 0.52 (p = 0.0003) for the Delta variant; and 0.59 (p ≤ 0.0001), 0.66 (p < 0.0001) and 0.57 (p = 0.0028) for the Omicron BA.1 variant. Additionally, PHH-1V as a booster dose induced a significant increase of CD4 + and CD8 + T-cells expressing IFN-γ on day 14. There were 458 participants who experienced at least one adverse event (89.3%) in the PHH-1V and 238 (94.4%) in the BNT162b2 group. The most frequent adverse events were injection site pain (79.7% and 89.3%), fatigue (27.5% and 42.1%) and headache (31.2 and 40.1%) for the PHH-1V and the BNT162b2 groups, respectively. A total of 52 COVID-19 cases occurred from day 14 post-vaccination (10.14%) for the PHH-1V group and 30 (11.90%) for the BNT162b2 group (p = 0.45), and none of the subjects developed severe COVID-19., Interpretation: Our interim results from the Phase IIb HH-2 trial show that PHH-1V as a heterologous booster vaccine, when compared to BNT162b2, although it does not reach a non-inferior neutralizing antibody response against the Wuhan-Hu-1 strain at days 14 and 28 after vaccination, it does so at day 98. PHH-1V as a heterologous booster elicits a superior neutralizing antibody response against the previous circulating Beta and the currently circulating Omicron BA.1 SARS-CoV-2 variants in all time points assessed, and for the Delta variant on day 98 as well. Moreover, the PHH-1V boost also induces a strong and balanced T-cell response. Concerning the safety profile, subjects in the PHH-1V group report significantly fewer adverse events than those in the BNT162b2 group, most of mild intensity, and both vaccine groups present comparable COVID-19 breakthrough cases, none of them severe., Funding: HIPRA SCIENTIFIC, S.L.U., Competing Interests: The authors of this manuscript declare: J Blanco has received institutional grants from HIPRA, 10.13039/501100016387Grifols, and MSD, royalties for licensed patent from AlbaJuna, honoraria for lectures from FLS Science and CIBER, supporting for meeting and/or travel from 10.13039/100016016Gilead Sciences, and unpaid independent COVID-19 monitoring from GMCSC (Multidisciplinary Collaborative Group for the Scientific Monitoring of COVID-19) and unpaid participation in COVID-19 advisory group for CCAC (Comitè Científic Assessor de la COVID-19). Outside of this work, J Blanco is the CEO, founder and shareholder of AlbaJuna Therapeutics, S.L. J Corominas, C Garriga, A Barreiro, L González-González, L Madrenas, I Güell, D Raïch-Regué, J G Prado, T Prat, E Torroella, B Trinité, L Ferrer, M Cañete and A Prenafeta have received funding from HIPRA. The funding from HIPRA to R Ramos was paid to his institution. A Soriano has received grants from 10.13039/100004319Pfizer and 10.13039/100005564Gilead Sciences, consulting fees from 10.13039/100004319Pfizer, MSD and 10.13039/501100005612Shionogi, and honoraria for lectures for 10.13039/100004319Pfizer, MSD, 10.13039/100005564Gilead Sciences, 10.13039/501100005612Shionogi, 10.13039/501100006546Angelini, and Menarini. B Trinité declares royalties by an institutional agreement and consulting fees for HIPRA, and is an unpaid member in advisory board for the Health Department of the 10.13039/501100002809Generalitat de Catalunya. N Izquierdo-Useros, D Raïch-Regué and M Gallemí declare institutional grants from HIPRA, Pharma Mar, 10.13039/501100016387Grifols, Dentaid, Palobiofarma, Mynorix and Amassence. N Izquierdo-Useros and M Gallemí have received speaking honoraria from FLS Science. JR Arribas has received consulting fees and payment for participating in advisory board from 10.13039/100005564Gilead Sciences, MSD, GSK, Eli Lilly, 10.13039/100004337Roche, 10.13039/100004319Pfizer and Sobi, honoraria for lectures and support for meetings and/or travel from MSD. A Borobia has received grants from GSK, Moderna and Janssen, speaking honoraria for Janssen, 10.13039/100005564Gilead Sciences and 10.13039/100004319Pfizer, and payment for participating in advisory board for 10.13039/100004319Pfizer, Janssen and MDI. PM García has received consulting fees and speaking honoraria from 10.13039/100005564Gilead Sciences, Mundipharma and 10.13039/100004319Pfizer, payment for expert testimony and participated in advisory board for 10.13039/100005564Gilead Sciences and received support for meeting and/or travel from 10.13039/100004319Pfizer. S Otero-Romero has received speaking honoraria from Genzyme, Biogen-Idec, Novartis, Roche, and MSD. Julia G Prado declares institutional grants from 10.13039/501100016387Grifols. J Corominas, C Garriga, A Prenafeta, A Moros, M Cañete, A Barreiro, L González-González, L Madrenas, I Güell, T Prat, E Torroella and L Ferrer are employees of HIPRA. Some of these authors may have stocks of HIPRA. Several patent applications have been filed by HIPRA SCIENTIFIC S.L.U. and Laboratorios HIPRA, S.A. on different SARS-CoV-2 vaccine candidates and SARS-CoV-2 subunit vaccines, including the novel recombinant RBD fusion heterodimer PHH-1V. A Barreiro, J Corominas, A Prenafeta, L González-González, L Madrenas, L Ferrer, E Torroella, T Prat and C Garriga are the inventors of these patent applications. N Izquierdo-Useros is a patent inventor with no economical compensation for Pharma Mar and Mynorix. The other authors have no relevant conflicts of interest to declare., (© 2023 The Author(s).)

Background and Objective: The COVID-19 pandemic has posed a threat to hospital capacity due to the high number of admissions, which has led to the development of various strategies to release and create new hospital beds. Due to the importance of systemic corticosteroids in this disease, we assessed their efficacy in reducing the length of stay (LOS) in hospitals and compared the effect of 3 different corticosteroids on this outcome., Methods: We conducted a real-world, controlled, retrospective cohort study that analysed data from a hospital database that included 3934 hospitalised patients diagnosed with COVID-19 in a tertiary hospital from April to May 2020. Hospitalised patients who received systemic corticosteroids (CG) were compared with a propensity score control group matched by age, sex and severity of disease who did not receive systemic corticosteroids (NCG). The decision to prescribe CG was at the discretion of the primary medical team., Results: A total of 199 hospitalized patients in the CG were compared with 199 in the NCG. The LOS was shorter for the CG than for the NCG (median = 3 [interquartile range = 0-10] vs. 5 [2-8.5]; p = 0.005, respectively), showing a 43% greater probability of being hospitalised ≤ 4 days than > 4 days when corticosteroids were used. Moreover, this difference was only noticed in those treated with dexamethasone (76.3% hospitalised ≤ 4 days vs. 23.7% hospitalised > 4 days [p < 0.001]). Serum ferritin levels, white blood cells and platelet counts were higher in the CG. No differences in mortality or intensive care unit admission were observed., Conclusions: Treatment with systemic corticosteroids is associated with reduced LOS in hospitalised patients diagnosed with COVID-19. This association is significant in those treated with dexamethasone, but no for methylprednisolone and prednisone., Competing Interests: Declaration of Competing Interest The authors declare that they do not have conflict of interest., (Copyright © 2022 Sociedad Española de Farmacia Hospitalaria (S.E.F.H). Publicado por Elsevier España, S.L.U. All rights reserved.)

Objective: The COVID-19 pandemic has posed a threat to hospital capacity due to the high number of admissions, which has led to the development of various strategies to release and create new hospital beds. Due to the importance of systemic corticosteroids in this disease, we assessed their efficacy in reducing the length of stay (LOS) in hospitals and compared the effect of 3 different corticosteroids on this outcome. MéTHOD: We conducted a real-world, controlled, retrospective cohort study that analysed data from a hospital database that included 3934 hospitalised patients diagnosed with COVID-19 in a tertiary hospital from April to May 2020. Hospitalised patients who received systemic corticosteroids (CG) were compared with a propensity score control group matched by age, sex and severity of disease who did not receive systemic corticosteroids (NCG). The decision to prescribe CG was at the discretion of the primary medical team., Results: A total of 199 hospitalized patients in the CG were compared with 199 in the NCG. The LOS was shorter for the CG than for the NCG (median=3 [interquartile range=0-10] vs. 5 [2-8.5]; p=0.005, respectively), showing a 43% greater probability of being hospitalised ≤4 days than >4 days when corticosteroids were used. Moreover, this difference was only noticed in those treated with dexamethasone (76.3% hospitalised ≤4 days vs. 23.7% hospitalised >4 days [p<0.001]). Serum ferritin levels, white blood cells and platelet counts were higher in the CG. No differences in mortality or intensive care unit admission were observed., Conclusions: Treatment with systemic corticosteroids is associated with reduced LOS in hospitalised patients diagnosed with COVID-19. This association is significant in those treated with dexamethasone, but no for methylprednisolone and prednisone., (Copyright © 2022 Sociedad Española de Farmacia Hospitalaria (S.E.F.H). Publicado por Elsevier España, S.L.U. All rights reserved.)

Background: Several cases of unusual thrombotic events and thrombocytopenia were described after vaccination with recombinant adenoviral vectors encoding the spike protein antigen of SARS-CoV-2., Objectives: The objective of this study was to elucidate the impact of a COVID-19 heterologous vaccination schedule, including priming with adenovirus vaccine, on hemostasis profiles., Methods: The present study is a subanalysis of the CombiVacS clinical trial initiated in April 2021 that included adult participants previously vaccinated with a single dose of ChAdOx1-S. Between 8 and 12 weeks after vaccination, they were randomly assigned (2:1) to receive either BNT162b2 vaccine (intervention group, n  = 99) or continue observation (control group, n  = 50). Samples drawn before and 28 days after a vaccination with BNT162b2 were analyzed for platelet count and markers of hemostasis (D-dimer, anti-PF4 antibodies, cfDNA, PAI-1, thrombin generation, and serum capacity to activate platelets)., Results: Platelet count from all participants after receiving BNT162b2 was within the normal range. Anti-PF4 antibodies were present in 26% and 18% of the subjects from the control and intervention groups, respectively, at day 28. In most cases, the levels of anti-PF4 antibodies were high before receiving BNT162b2. Serum from these participants did not activate platelets from healthy controls. There were no differences between the groups in PAI-1 and cfDNA plasma levels. According to the D-dimer plasma concentration, the thrombin generation test showed that none of the participants had a procoagulant profile., Conclusion: Our data suggest that the heterologous vaccination against COVID-19 with ChAdOx1-S and a second dose with BNT162b2 might be safe in terms of haemostasis., (© 2023 The Authors.)

Fast, high-throughput methods for measuring the level and duration of protective immune responses to SARS-CoV-2 are needed to anticipate the risk of breakthrough infections. Here we report the development of two quantitative PCR assays for SARS-CoV-2-specific T cell activation. The assays are rapid, internally normalized and probe-based: qTACT requires RNA extraction and dqTACT avoids sample preparation steps. Both assays rely on the quantification of CXCL10 messenger RNA, a chemokine whose expression is strongly correlated with activation of antigen-specific T cells. On restimulation of whole-blood cells with SARS-CoV-2 viral antigens, viral-specific T cells secrete IFN-γ, which stimulates monocytes to produce CXCL10. CXCL10 mRNA can thus serve as a proxy to quantify cellular immunity. Our assays may allow large-scale monitoring of the magnitude and duration of functional T cell immunity to SARS-CoV-2, thus helping to prioritize revaccination strategies in vulnerable populations., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: The Roussel Uclaf Causality Assessment Method (RUCAM) is a validated tool for assessing causality in cases of suspected drug-induced liver injury (DILI). However, RUCAM cannot discriminate between concomitant hepatotoxic drugs with the same temporal sequence. Objective: To analyse the utility of the lymphocyte transformation test (LTT) for assisting updated RUCAM in 45 patients and 40 controls with a clinical diagnosis of DILI. Methods: Suspected DILI cases were detected through the Prospective Pharmacovigilance Program from Laboratory Signals in Hospital (PPLSH) or by consultations. The controls completed the drug therapy with no adverse reactions during the study period. A receiver operating characteristics (ROC) curve analysis was performed to calculate the optimal cut-off value for the stimulation index (SI), corresponding to the largest sum for the specificity and sensitivity values of LTT for true DILI cases. Results: Out of 45 patients diagnosed with DILI, 42 cases were detected by the PPLSH, two cases by consultation and one case by both methods. Most DILI cases (64.4%) arose during hospitalization. According to the biochemical parameters, 24 cases (53.3%) had the hepatocellular phenotype, 14 (31.1%) had the cholestatic phenotype, and 7 cases (15.6%) had the mixed phenotype. Considering the severity criteria, 7 (15.5%) cases were classified as moderate DILI, and 4 (8.9%) were severe DILI; there were no fatal cases. A total of 149 drugs (median/case, 3; IQR, 2-5) were suspected to be involved in the DILI cases (RUCAM score ≥3). In 8 cases, only one drug was suspected, and polypharmacy (≥5 drugs) was identified in 29% of the cases. Of all DILI cases, 46 (30.9%) of the 149 suspected drugs produced positive LTT results, and the LTT was positive in 34 (75.5%) of the 45 patients. No exposed controls produced positive LTT results. The optimal cut-off of 1.95 for the SI was obtained with a sensitivity of 77% and specificity of 100% (area under the curve, 0.91; 95% asymptotic confidence interval 0.84-0.97; p < 0.001). The sensitivity of the hepatocellular phenotype was 92%. Conclusion: Our results demonstrate that LTT is an add on strengthening causality in cases of suspected idiosyncratic DILI, especially for patients with several suspected drugs and a hepatocellular phenotype., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Rodríguez, García-García, Martínez de Soto, Gómez López De Las Huertas, Borobia, González-Torbay, Akatbach-Bousaid, González-Muñoz and Ramírez.)

We evaluated in this randomised, double-blind clinical trial the efficacy of melatonin as a prophylactic treatment for prevention of SARS-CoV-2 infection among healthcare workers at high risk of SARS-CoV-2 exposure. Healthcare workers fulfilling inclusion criteria were recruited in five hospitals in Spain and were randomised 1:1 to receive melatonin 2 mg administered orally for 12 weeks or placebo. The main outcome was the number of SARS-CoV-2 infections. A total of 344 volunteers were screened, and 314 were randomised: 151 to placebo and 163 to melatonin; 308 received the study treatment (148 placebo; 160 melatonin). We detected 13 SARS-CoV-2 infections, 2.6% in the placebo arm and 5.5% in the melatonin arm ( p = 0.200). A total of 294 adverse events were detected in 127 participants (139 in placebo; 155 in melatonin). We found a statistically significant difference in the incidence of adverse events related to treatment: 43 in the placebo arm and 67 in the melatonin arm ( p = 0.040), and in the number of participants suffering from somnolence related to treatment: 8.8% ( n = 14) in the melatonin versus 1.4% ( n = 2) in the placebo arm ( p = 0.008). No severe adverse events related to treatment were reported. We cannot confirm our hypothesis that administration of melatonin prevents the development of SARS-CoV-2 infection in healthcare workers.

Data from several cohorts of coronavirus disease 2019 (COVID-19) suggest that the most common comorbidities for severe COVID-19 disease are the elderly, high blood pressure, and diabetes; however, it is not currently known whether the previous use of certain drugs help or hinder recovery. This study aims to explore the association of previous hospitalisation use of medication on the mortality of COVID-19 disease. A retrospective case-control from two hospitals in Madrid, Spain, included all patients aged 18 years or above hospitalised with a diagnosis of COVID-19. A Propensity Score matching (PSM) analysis was performed. Confounding variables were considered to be age, sex, and the number of comorbidities. Finally, 3712 patients were included. Of these, 687 (18.5%) patients died (cases). The 22,446 medicine trademarks used previous to admission were classified according to the ATC, obtaining 689 final drugs; all of them were included in PSM analysis. Eleven drugs displayed a reduction in mortality: azithromycin, bemiparine, budesonide-formoterol fumarate, cefuroxime, colchicine, enoxaparin, ipratropium bromide, loratadine, mepyramine theophylline acetate, oral rehydration salts, and salbutamol sulphate. Eight final drugs displayed an increase in mortality: acetylsalicylic acid, digoxin, folic acid, mirtazapine, linagliptin, enalapril, atorvastatin, and allopurinol. Medication associated with survival (anticoagulants, antihistamines, azithromycin, bronchodilators, cefuroxime, colchicine, and inhaled corticosteroids) may be candidates for future clinical trials. Drugs associated with mortality show an interaction with the underlying conditions.

Background: Communication is one of the most important predictors of social reintegration after stroke. Approximately 15-42% of stroke survivors experience post-stroke aphasia. Helping people recover from aphasia is one of the research priorities after a stroke. Our aim is to develop and validate a new therapy integrating dubbing techniques to improve functional communication., Methods: The research project is structured as three work packages (WP). WP1: development of the dubbed language cinema-based therapy: Two research assistants (a speech therapist and a dubbing actor) will select the clips, mute specific words/sentences in progressive speech difficulty, and guide patients to dub them across sessions. Words to be dubbed will be those considered to be functionally meaningful by a representative sample of aphasic patients and relatives through an online survey. WP2: a randomized, crossover, interventional pilot study with the inclusion of 54 patients with post-stroke non-fluent aphasia. Patients will be treated individually in 40-min sessions twice per week for 8 weeks. Primary outcomes will be significant pre/post differences in scores in the Communicative Activity Log (CAL) questionnaire and Boston Diagnostic Aphasia Examination (BDAE) administered by a psychologist blinded to the patients' clinical characteristics., Secondary Outcomes: General Health Questionnaire (GHQ)-12, Stroke Aphasia Quality of Life Scale (SAQOL-39), Western Aphasia Battery Revised (WAB-R), and the Stroke Aphasic Depression Questionnaire (SADQ10). WP3: educational activities and dissemination of results. WP3 includes educational activities to improve public knowledge of aphasia and dissemination of the results, with the participation of the Spanish patients' association Afasia Activa., Discussion: This pilot clinical trial will explore the efficacy of a new therapeutic tool based on dubbing techniques and computer technology to improve functional communication of patients suffering from post-stroke aphasia with the use of standardized test assessment., Trial Registration: ClinicalTrials.gov NCT04289493 . Registered on 28 February 2020., (© 2022. The Author(s).)

Acute ischemic stroke is currently a major cause of disability despite improvement in recanalization therapies. Stem cells represent a promising innovative strategy focused on reduction of neurologic sequelae by enhancement of brain plasticity. We performed a phase IIa, randomized, double-blind, placebo-controlled, single-center, pilot clinical trial. Patients aged ≥60 years with moderate to severe stroke (National Institutes of Health Stroke Scale [NIHSS] 8-20) were randomized (1:1) to receive intravenous adipose tissue-derived mesenchymal stem cells (AD-MSCs) or placebo within the first 2 weeks of stroke onset. The primary outcome was safety, evaluating adverse events (AEs), neurologic and systemic complications, and tumor development. The secondary outcome evaluated treatment efficacy by measuring modified Rankin Scale (mRS), NIHSS, infarct size, and blood biomarkers. We report the final trial results after 24 months of follow-up. Recruitment began in December 2014 and stopped in December 2017 after 19 of 20 planned patients were included. Six patients did not receive study treatment: two due to technical issues and four for acquiring exclusion criteria after randomization. The final study sample was composed of 13 patients (4 receiving AD-MSCs and 9 placebo). One patient in the placebo group died within the first week after study treatment delivery due to sepsis. Two non-treatment-related serious AEs occurred in the AD-MSC group and nine in the placebo group. The total number of AEs and systemic or neurologic complications was similar between the study groups. No injection-related AEs were registered, nor tumor development. At 24 months of follow-up, patients in the AD-MSC group showed a nonsignificantly lower median NIHSS score (interquartile range, 3 [3-5.5] vs 7 [0-8]). Neither treatment group had differences in mRS scores throughout follow-up visits up to month 24. Therefore, intravenous treatment with AD-MSCs within the first 2 weeks from ischemic stroke was safe at 24 months of follow-up.

Many factors have been described to contribute to voriconazole (VCZ) interpatient variability in plasma concentrations, especially CYP2C19 genetic variability. In 2014, Hicks et al. presented data describing the correlation between VCZ plasma concentrations and CYP2C19 diplotypes in immunocompromised pediatric patients and utilized pharmacokinetic modeling to extrapolate a more suitable VCZ dose for each CYP2C19 diplotype. In 2017, in our hospital, a clinical protocol was developed for individualization of VCZ in immunocompromised patients based on preemptive genotyping of CYP2C19 and dosing proposed by Hicks et al., Clinical Pharmacogenetics Implementation Consortium (CPIC) clinical guidelines, and routine therapeutic drug monitoring (TDM). We made a retrospective review of a cohort of 28 immunocompromised pediatric patients receiving VCZ according to our protocol. CYP2C19 gene molecular analysis was preemptively performed using PharmArray ® . Plasma trough concentrations were measured by immunoassay analysis until target concentrations (1-5.5 μg/ml) were reached. Sixteen patients (57.14%) achieved VCZ trough target concentrations in the first measure after the initial dose based on PGx. This figure is similar to estimations made by Hicks et al. in their simulation (60%). Subdividing by phenotype, our genotyping and TDM-combined strategy allow us to achieve target concentrations during treatment/prophylaxis in 90% of the CYP2C19 Normal Metabolizers (NM)/Intermediate Metabolizers (IM) and 100% of the Rapid Metabolizers (RM) and Ultrarapid Metabolizers (UM) of our cohort. We recommended modifications of the initial dose in 29% ( n = 8) of the patients. In RM ≥12 years old, an increase of the initial dose resulted in 50% of these patients achieving target concentrations in the first measure after initial dose adjustment based only on PGx information. Our experience highlights the need to improve VCZ dose predictions in children and the potential of preemptive genotyping and TDM to this aim. We are conducting a multicenter, randomized clinical trial in patients with risk of aspergillosis in order to evaluate the effectiveness and efficiency of VCZ individualization: VORIGENIPHARM (EudraCT: 2019-000376-41)., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 García-García, Dapía, Montserrat, Martinez de Soto, Bueno, Díaz, Queiruga, Rodriguez Mariblanca, Guerra-García, Ramirez, Frías, Pérez Martínez, Carcas-Sansuan and Borobia.)

Background: Moderate/severe cases of COVID-19 present a dysregulated immune system with T cell lymphopenia and a hyper-inflammatory state. This is a study protocol of an open-label, multi-center, double-arm, randomized, dose-finding phase I/II clinical trial to evaluate the safety, tolerability, alloreactivity, and efficacy of the administration of allogeneic memory T cells and natural killer (NK) cells in COVID-19 patients with lymphopenia and/or pneumonia. The aim of the study is to determine the safety and the efficacy of the recommended phase 2 dose (RP2D) of this treatment for patients with moderate/severe COVID-19., Methods: In the phase I trial, 18 patients with COVID-19-related pneumonia and/or lymphopenia with no oxygen requirement or with an oxygen need of ≤ 2.5 liters per minute (lpm) in nasal cannula will be assigned to two arms, based on the biology of the donor and the patient. Treatment of arm A consists of the administration of escalating doses of memory T cells, plus standard of care (SoC). Treatment of arm B consists of the administration of escalating doses of NK cells, plus SoC. In the phase II trial, a total of 182 patients with COVID-19-related pneumonia and/or lymphopenia requiring or not oxygen supplementation but without mechanical ventilation will be allocated to arm A or B, considering HLA typing. Within each arm, they will be randomized in a 1:1 ratio. In arm A, patients will receive SoC or RP2D for memory T cells plus the SoC. In arm B, patients will receive SoC or RP2D for NK cells plus the SoC., Discussion: We hypothesized that SARS-CoV-2-specific memory T-lymphocytes obtained from convalescent donors recovered from COVID-19 can be used as a passive cell immunotherapy to treat pneumonia and lymphopenia in moderate/severe patients. The lymphopenia induced by COVID-19 constitutes a therapeutic window that may facilitate donor engraftment and viral protection until recovery., Trial Registration: ClinicalTrials.gov NCT04578210 . First Posted : October 8, 2020., (© 2021. The Author(s).)

Coronavirus disease 2019 (COVID-19) has a wide spectrum of clinical manifestations. An elevation of liver damage markers has been observed in numerous cases, which could be related to the empirical use of potentially hepatotoxic drugs. The aim of this study was to describe the clinical and analytical characteristics and perform a causality analysis from laboratory signals available of drug-induced liver injury (DILI) detected by a proactive pharmacovigilance program in patients hospitalised for COVID-19 at La Paz University Hospital in Madrid (Spain) from 1 March 2020 to 31 December 2020. The updated Roussel Uclaf Causality Assessment Method (RUCAM) was employed to assess DILI causality. A lymphocyte transformation test (LTT) was performed on 10 patients. Ultimately, 160 patients were included. The incidence of DILI (alanine aminotransferase >5, upper limit of normal) was 4.9%; of these, 60% had previous COVID-19 hepatitis, the stay was 8.1 days longer and 98.1% were being treated with more than 5 drugs. The most frequent mechanism was hepatocellular (57.5%), with mild severity (87.5%) and subsequent recovery (88.1%). The most commonly associated drugs were hydroxychloroquine, azithromycin, tocilizumab and ceftriaxone. The highest incidence rate of DILI per 10,000 defined daily doses (DDD) was with remdesivir (992.7/10,000 DDD). Some 80% of the LTTs performed were positive, with a RUCAM score of ≥4. The presence of DILI after COVID-19 was associated with longer hospital stays. An immune mechanism has been demonstrated in a small subset of DILI cases.

Background: Effective treatments are still needed to reduce the severity of symptoms, time of hospitalization, and mortality of COVID-19. SARS-CoV-2 specific memory T-lymphocytes obtained from convalescent donors recovered can be used as passive cell immunotherapy., Methods: Between September and November 2020 a phase 1, dose-escalation, single centre clinical trial was conducted to evaluate the safety and feasibility of the infusion of CD45RA - memory T cells containing SARS-CoV-2 specific T cells as adoptive cell therapy against moderate/severe cases of COVID-19. Nine participants with pneumonia and/or lymphopenia and with at least one human leukocyte antigen (HLA) match with the donor were infused. The first three subjects received the lowest dose (1 × 10 5 cells/kg), the next three received the intermediate dose (5 × 10 5 cells/kg) and the last three received the highest dose (1 × 10 6 cells/kg) of CD45RA - memory T cells. Clinicaltrials.gov registration: NCT04578210., Findings: All participants' clinical status measured by National Early Warning Score (NEWS) and 7-category point ordinal scales showed improvement six days after infusion. No serious adverse events were reported. Inflammatory parameters were stabilised post-infusion and the participants showed lymphocyte recovery two weeks after the procedure. Donor microchimerism was observed at least for three weeks after infusion in all patients., Interpretation: This study provides preliminary evidence supporting the idea that treatment of COVID-19 patients with moderate/severe symptoms using convalescent CD45RA - memory T cells is feasible and safe., Funding: Clinical Trial supported by Spanish Clinical Research Network PT17/0017/0013. Co-funded by European Regional Development Fund/European Social Fund. CRIS CANCER Foundation Grant to AP-M and Agencia Valenciana de Innovación Grant AVI-GVA COVID-19-68 to BS., Competing Interests: AP-M filed patent EP20382850 on Memory T cells as adoptive cell therapy for viral diseases. CF filed patent EP20382850 on Memory T cells as adoptive cell therapy for viral diseases. BS received salary from University Miguel Hernandez, a grant from Agencia Valenciana de Innovacion, support from Al-Andalus Biopharma and medical writing from Comunidad de Madrid, since the initial planning of the work. He received grant AVI-GVA CO19–068 and consulting fees from Gilead-Weber. BS is on the board at Institut de Bioengineria de Catalunya and Laminar Pharmaceuticals. BS filed patent EP20382850 on Memory T cells as adoptive cell therapy for viral diseases. BS reports an unpaid role with FAID. BS reports the receipt of equipment, materials, drugs, medical writing, gifts or other services from Al-Andalus BioPharmaSL. CS received fees from MSD, Pfizer and Gilead not related to this topic, and reports payments made by Gilead, MSD, Janssen and Therakos to suppliers for support for attending meetings and/or travel. IG reports a “Rio Hortega” Grant (Plan Estatal de I + D + I 2013–2016. Plan Estatal de Investigación Científica y Técnica y de Innovación (2017–2020). Co-funded by European Regional Development Fund/European Social Fund "A way to make Europe"/"Investing in your future"). All other authors have nothing to declare., (© 2021 The Author(s).)

Introduction: Stroke is a serious public health problem, given it is a major cause of disability worldwide despite the spread of recanalisation therapies. Enhancement of brain plasticity with stem cell administration is a promising innovative therapy to reduce sequelae in these patients., Methods and Analysis: We have developed a phase IIb, multicentre, randomised, double-blind, placebo-controlled clinical trial protocol to evaluate the safety and efficacy of intravenous administration of allogeneic adipose tissue-derived mesenchymal stem cells (AD-MSCs) in patients with acute ischaemic stroke, concurrently with conventional stroke treatment. Thirty patients will be randomised on a 1:1 basis to receive either intravenous placebo or allogeneic AD-MSCs as soon as possible within the first 4 days from stroke symptom onset. Patients will be followed up to 24 months after randomisation. The primary objective is the safety assessment of early intravenous administration of allogeneic AD-MSCs by reporting all adverse events and neurological or systemic complications in both treatment groups. Secondary objectives assess efficacy of early intravenous AD-MSC treatment in acute ischaemic stroke by evaluating changes in the modified Rankin Scale and the National Institutes of Health Stroke Scale throughout the follow-up period. In addition, brain repair biomarkers will be measured at various visits., Ethics and Dissemination: This clinical trial has been approved by the Clinical Research Ethics Committee of La Paz University Hospital (Madrid, Spain) and by the Spanish Agency of Medication and Health Products and has been registered in Eudra CT (2019-001724-35) and ClinicalTrials.gov (NCT04280003). Study results will be disseminated through peer-reviewed publications in Open Access format and at conference presentations., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Patients with venous thromboembolism (VTE) require immediate treatment with anticoagulants such as acenocoumarol. This multicentre randomised clinical trial evaluated the effectiveness of a dosing pharmacogenetic algorithm versus a standard-of-care dose adjustment at the beginning of acenocoumarol treatment. We included 144 patients with VTE. On the day of recruitment, a blood sample was obtained for genotyping ( CYP2C9*2 , CYP2C9*3 , VKORC1 , CYP4F2 , APOE ). Dose adjustment was performed on day 3 or 4 after the start of treatment according to the assigned group and the follow-up was at 12 weeks. The principal variable was the percentage of patients with an international normalised ratio (INR) within the therapeutic range on day 7. Thirty-four (47.2%) patients had an INR within the therapeutic range at day 7 after the start of treatment in the genotype-guided group compared with 14 (21.9%) in the control group ( p = 0.0023). There were no significant differences in the time to achieve a stable INR, the number of INRs within the range in the first 6 weeks and at the end of study. Our results suggest the use of a pharmacogenetic algorithm for patients with VTE could be useful in achieving target INR control in the first days of treatment.

Introduction: Valproic acid (VPA) is an antiepileptic drug extensively used for treating partial and generalised seizures, acute mania and as prophylaxis for bipolar disorder. Drug-induced liver injury (DILI) persists as a significant issue related to fatal outcomes by VPA. The aim of this study was to increase our knowledge about this condition and to better identify patients affected., Methods: We conducted an observational retrospective case-control study that identified cases of DILI by VPA from the Pharmacovigilance Programme from our Laboratory Signals at La Paz University Hospital from January 2007 to December 2019. From the Therapeutic VPA Monitoring program, two control groups were assigned, VPA-tolerant patients and the other with patients who developed mild VPA-related liver injury but who did not meet the DILI criteria, matched for date, age and sex., Results: A total of 60 patients were included in the study: 15 cases of DILI, 30 VPA-tolerant controls and 15 controls with mild liver injury. Mean age for the cases was 45.7 years, 4 (26.7%) were women and 5 (33.34%) were children under 18 years, of them 3 (20%) were fatal. Polytherapy with other antiepileptic drugs ( p = 0.047) and alcohol consumption ( p < 0.001) were associated with a greater risk of developing DILI by VPA. A diagnosis of epileptic seizure was more frequently related to DILI when compared with the VPA-tolerant controls ( p < 0.001). The cases developed hepatocellular liver injury ( p < 0.001), while the mild hepatic damage controls had a higher rate of cholestatic liver injury ( p < 0.001). The laboratory lactate dehydrogenase values were statistically higher (even at baseline) in patients with DILI than in both control groups ( p = 0.033 and p = 0.039)., Conclusions: VPA hepatotoxicity remains a considerable problem. This study offers interesting findings for characterising VPA-induced liver injury and at-risk patients.

Background: In April 2020, two independent clinical trials to assess SARS-CoV-2 prophylaxis strategies among health care workers were initiated at our hospital: MeCOVID (melatonin vs placebo) and EPICOS (tenofovir disoproxil/emtricitabine vs hydroxychloroquine vs combination therapy vs placebo)., Objective: This study aimed to evaluate the reasons why health care workers chose to participate in the MeCOVID and EPICOS trials, as well as why they chose one over the other., Methods: Both trials were offered to health care workers through an internal news bulletin. After an initial screening visit, all subjects were asked to respond to a web-based survey., Results: In the first month, 206 health care workers were screened and 160 were randomized. The survey participation was high at 73.3%. Health care workers cited "to contribute to scientific knowledge" (n=80, 53.0%), followed by "to avoid SARS-CoV-2 infection" (n=33, 21.9%) and "the interest to be tested for SARS-CoV-2" (n=28, 18.5%), as their primary reasons to participate in the trials. We observed significant differences in the expected personal benefits across physicians and nurses (P=.01). The vast majority of volunteers (n=202, 98.0%) selected the MeCOVID trial, their primary reason being their concern regarding adverse reactions to treatments in the EPICOS trial (n=102, 69.4%)., Conclusions: Health care workers' reasons to participate in prophylaxis trials in an acute pandemic context appear to be driven largely by their desire to contribute to science and to gain health benefits. Safety outweighed efficacy when choosing between the two clinical trials., (©Alberto M Borobia, Irene García-García, Lucía Díaz-García, Amelia Rodríguez-Mariblanca, Lucía Martínez de Soto, Jaime Monserrat Villatoro, Enrique Seco Meseguer, Juan J González, Jesús Frías Iniesta, Elena Ramírez García, Jose Ramón Arribas, Antonio J Carcas-Sansuán. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 25.02.2021.)

BACKGROUND: From March to April 2020, Spain was the center of the SARS-CoV-2 pandemic, particularly Madrid with approximately 30% of the cases in Spain. The aim of this study is to report the suspected serious adverse drug reactions (SADRs) in COVID-19 patients vs. non-COVID-19 patients detected by the prospective pharmacovigilance program based on automatic laboratory signals (ALSs) in the hospital (PPLSH) during that period. We also compared the results with the suspected SADRs detected during the same period for 2019. METHODS: All ALSs that reflected potential SADRs including neutropenia, pancytopenia, thrombocytopenia, anemia, eosinophilia, leukocytes in cerebrospinal fluid, hepatitis, pancreatitis, acute kidney injury, rhabdomyolysis, and hyponatremia were prospectively monitored in hospitalized patients during the study periods. We analyzed the incidence and the distribution of causative drugs for the COVID-19 patients. RESULTS: The incidence rate of SADRs detected in the COVID-19 patients was 760.63 (95% CI 707.89-816.01) per 10,000 patients, 4.75-fold higher than the SADR rate for non-COVID-19 patients (160.15 per 10,000 patients, 95% CI 137.09-186.80), and 5.84-fold higher than the SADR rate detected for the same period in 2019 (130.19 per 10,000 patients, 95% CI 109.53-154.36). The most frequently related drugs were tocilizumab (59.84%), dexketoprofen (13.93%), azithromycin (8.43%), lopinavir-ritonavir (7.35%), dexamethasone (7.62%), and chloroquine/hydroxychloroquine (6.91%). CONCLUSIONS: The incidence rate of SADRs detected by the PPSLH in patients with COVID-19 was 4.75-fold higher than that of the non-COVID-19 patients. Caution is recommended when using medications for COVID-19 patients, especially drugs that are hepatotoxic, myotoxic, and those that induce thromboembolic events., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Ramírez, Urroz, Rodríguez, González‐Muñoz, Martín­Vega, Villán, Seco, Monserrat, Frías, Carcas and Borobia.)

Introduction: Paediatric transplantation is the only curative therapeutic procedure for several end-stage rare diseases affecting different organs and body systems, causing altogether great impact in European children's health and quality of life. Transplanted children shift their primary disease to a chronic condition of immunosuppression to avoid rejection. Longer life expectancy in children poses a greater risk of prolonged and severe side effects related to long-term immunosuppressive (IS) disabilities and secondary cancer susceptibility. The goal remains to find the best combination of IS agents that optimises allograft survival by preventing acute rejection while limiting drug toxicities. This systematic review will aim to determine the optimal IS strategy within the so-called minimisation, conversion or withdrawal strategies., Methods and Analysis: We will search the following databases with no language restrictions: Cochrane Central Register of Controlled Trials in the Cochrane Library, OvidSP Medline and Epub Ahead of Print, In-Process & Other Non-Indexed Citations and Daily; OvidSP Embase Classic+Embase; Ebsco CINAHL Plus, complete database; WHO International Clinical Trials Registry Platform search portal. We will include controlled and uncontrolled clinical trials along with any prospective or retrospective study that includes a universal cohort (all participants from a centre/region/city over a certain period). Cases series and cross-sectional studies are excluded. Two review authors will independently assess the trial eligibility, risk of bias and extract appropriate data points. The outcomes included in this review are: patient survival, acute graft rejection, chronic graft rejection, diabetes, graft function, graft loss, chronic graft versus host disease, acute graft versus host disease, surgical complications, infusion complications, post-transplant lymphoproliferative disease, liver function, renal function, cognition, depression, health-related quality of life, hospitalisation, high blood pressure, low blood pressure, cancer-other, cancer-skin, cardiovascular disease, bacterial infection, Epstein-Barr infection, cytomegalovirus infection, other viral infections and growth., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Recessive dystrophic epidermolysis bullosa (RDEB) is an incurable inherited mucocutaneous fragility disorder characterized by recurrent blisters, erosions, and wounds. Continuous blistering triggers overlapping cycles of never-ending healing and scarring commonly evolving to chronic systemic inflammation and fibrosis. The systemic treatment with allogeneic mesenchymal cells (MSC) from bone marrow has previously shown benefits in RDEB. MSC from adipose tissue (ADMSC) are easier to isolate. This is the first report on the use of systemic allogeneic ADMSC, correlating the clinical, inflammatory, and immunologic outcomes in RDEB indicating long-lasting benefits. We present the case of an RDEB patient harboring heterozygous biallelic COL7A1 gene mutations and with a diminished expression of C7. The patient presented with long-lasting refractory and painful oral ulcers distressing her quality of life. Histamine receptor antagonists, opioid analgesics, proton-pump inhibitors, and low-dose tricyclic antidepressants barely improved gastric symptoms, pain, and pruritus. Concomitantly, allogeneic ADMSC were provided as three separate intravenous injections of 10 6 cells/kg every 21 days. ADMSC treatment was well-tolerated. Improvements in wound healing, itch, pain and quality of life were observed, maximally at 6-9 months post-treatment, with the relief of symptoms still noticeable for up to 2 years. Remarkably, significant modifications in PBL participating in both the innate and adaptive responses, alongside regulation of levels of profibrotic factors, MCP-1/CCL2 and TGF-β, correlated with the health improvement. This treatment might represent an alternative for non-responding patients to conventional management. It seems critical to elucidate the paracrine modulation of the immune system by MSC for their rational use in regenerative/immunoregulatory therapies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Maseda, Martínez-Santamaría, Sacedón, Butta, Arriba, García-Barcenilla, García, Illera, Pérez-Conde, Carretero, Jiménez, Melen, Borobia, Jiménez-Yuste, Vicente, del Río, de Lucas and Escámez.)

Introduction: Invasive aspergillosis is the most important cause of morbidity and mortality in patients with haematological diseases. At present, voriconazole is the first-line treatment for invasive fungal disease. The pharmacokinetic interindividual variability of voriconazole depends on genetic factors. CYP450 is involved in 70%-75% of total metabolism of voriconazole, mainly CYP3A4 and CYP2C19, with the remaining 25%-30% of metabolism conducted by monooxygenase flavins. CYP2C19 single nucleotide polymorphisms could explain 50%-55% of variability in voriconazole metabolism., Materials and Methods: The main objective is to compare efficiency of pre-emptive voriconazole genotyping with routine practice. The primary outcome is serum voriconazole on the fifth day within the therapeutic range. The secondary outcome is the combined variables of therapeutic failure and adverse events within 90 days of first administration, associated with voriconazole. A total of 146 patients at risk of invasive aspergillosis who will potentially receive voriconazole will be recruited, and CYP2C19 will be genotyped. If the patient ultimately receives voriconazole, they will be randomised (1:1 experimental/control). In the experimental arm, patients will receive a dose according to a pharmacogenetic algorithm, including CYP2C19 genotype and clinical and demographic information. In the control arm, patients will receive a dose according to clinical practice guidelines. In addition, a Spanish National Healthcare System (NHS) point-of-view cost-effectiveness evaluation will be performed. Direct cost calculations for each arm will be performed., Conclusion: This trial will provide information about the viability and cost-effectiveness of the implementation of a pre-emptive voriconazole genotyping strategy in the Spanish NHS., Ethics and Dissemination: A Spanish version of this protocol has been evaluated and approved by the La Paz University Hospital Ethics Committee and the Spanish Agency of Medicines and Medical Devices. Trial results will be submitted for publication in an open peer-reviewed medical speciality-specific publication., Trial Registration Number: Eudra-CT: 2019-000376-41 and NCT04238884; Pre-results., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Since the confirmation of the first patient infected with SARS-CoV-2 in Spain in January 2020, the epidemic has grown rapidly, with the greatest impact on the region of Madrid. This article describes the first 2226 adult patients with COVID-19, consecutively admitted to La Paz University Hospital in Madrid., Methods: Our cohort included all patients consecutively hospitalized who had a final outcome (death or discharge) in a 1286-bed hospital of Madrid (Spain) from 25 February (first case admitted) to 19 April 2020. The data were manually entered into an electronic case report form, which was monitored prior to the analysis., Results: We consecutively included 2226 adult patients admitted to the hospital who either died (460) or were discharged (1766). The patients' median age was 61 years, and 51.8% were women. The most common comorbidity was arterial hypertension (41.3%), and the most common symptom on admission was fever (71.2%). The median time from disease onset to hospital admission was 6 days. The overall mortality was 20.7% and was higher in men (26.6% vs. 15.1%). Seventy-five patients with a final outcome were transferred to the intensive care unit (ICU) (3.4%). Most patients admitted to the ICU were men, and the median age was 64 years. Baseline laboratory values on admission were consistent with an impaired immune-inflammatory profile., Conclusions: We provide a description of the first large cohort of hospitalized patients with COVID-19 in Europe. Advanced age, male sex, the presence of comorbidities and abnormal laboratory values were more common among the patients with fatal outcomes.

Several cytochrome P450 (CYP) CYP3A polymorphisms were associated with reduced enzyme function. We aimed to evaluate the influence of these alleles on the pharmacokinetic parameters (PK) of several CYP3A substrates. We included 251 healthy volunteers who received a single dose of ambrisentan, atorvastatin, imatinib, aripiprazole, fentanyl, amlodipine, donepezil, olanzapine, fesoterodine, or quetiapine. The volunteers were genotyped for CYP3A4 and CYP3A5 polymorphisms by qPCR. To compare the PK across studies, measurements were corrected by the mean of each parameter for every drug and were logarithmically transformed. Neither CYP3A phenotype nor individual CYP3A4 or CYP3A5 polymorphisms were significantly associated with differences in PK. However, regarding the substrates that are exclusively metabolized by CYP3A, we observed a higher normalized AUC ( p = 0.099) and a tendency of lower normalized Cl ( p = 0.069) in CYP3A4 mutated allele carriers what was associated with diminished drug metabolism capacity. CYP3A4 polymorphisms did not show a pronounced influence on PK of the analysed drugs. If so, their impact could be detectable in a very small percentage of subjects. Although there are few subjects carrying CYP3A4 double mutations, the effect in those might be relevant, especially due to the majority of subjects lacking the CYP3A5 enzyme. In heterozygous subjects, the consequence might be less noticeable due to the high inducible potential of the CYP3A4 enzyme.

Background: The major reservoir of carbapenemase-producing Enterobacteriaceae (CPE) is the gastrointestinal tract of colonized patients. Colonization is silent and may last for months, but the risk of infection by CPE in colonized patients is significant., Methods: Eight long-term intestinal carriers of OXA-48-producing Enterobacteriaceae (OXA-PE) were treated during 3 weeks with daily oral lactitol (Emportal ® ), Bifidobacterium bifidum and Lactobacillus acidophilus (Infloran ® ). Weekly stool samples were collected during the treatment period and 6 weeks later. The presence of OXA-PE was investigated by microbiological cultures and qPCR., Results: At the end of treatment (EoT, secondary endpoint 1), four of the subjects had negative OXA-PE cultures. Three weeks later (secondary endpoint 2), six subjects were negative. Six weeks after the EoT (primary endpoint), three subjects had negative OXA-PE cultures. The relative intestinal load of OXA-PE decreased in all the patients during treatment., Conclusions: The combination of prebiotics and probiotics was well tolerated. A rapid reduction on the OXA-PE intestinal loads was observed. At the EoT, decolonization was achieved in three patients. Clinical Trials Registration: NCT02307383. EudraCT Number: 2014-000449-65., Competing Interests: Competing interestsThe authors report no conflict of interest., (© The Author(s) 2020.)

The low prevalence of European paediatric transplanted patients and scarcity of resources and expertise led to the need for a multidisciplinary network able to improve the quality of life of paediatric patients and families requiring a solid organ or haematopoietic stem cell transplantation. The European Reference Network (ERN) TransplantChild is one of the 24 ERNs established in a European legal framework to improve the care of patients with rare diseases. ERN TransplantChild is the only ERN focused on both solid organ and haematopoietic stem cell paediatric transplantation, based on the understanding of paediatric transplantation as a complex and highly specialised process where specific complications appear regardless the organ involved, thus linking the skills and knowledge of different organ disciplines. Gathering European centres of expertise in paediatric transplantation will give access to a correct and timely diagnosis, share expertise and knowledge and collect a critical mass of patients and data that increases the speed and value of clinical research outcomes. Therefore, the ERN TransplantChild aims for a paediatric Pan-European, Pan-transplant approach.