CIBERER: Spanish national network for research on rare diseases: A highly productive collaborative initiative

CIBER (Center for Biomedical Network Research; Centro de Investigacion Biomédica En Red) is a public national consortium created in 2006 under the umbrella of the Spanish National Institute of Health Carlos III (ISCIII). This innovative research structure comprises 11 different specific areas dedicated to the main public health priorities in the National Health System. CIBERER, the thematic area of CIBER focused on rare diseases (RDs) currently consists of 75 research groups belonging to universities, research centers, and hospitals of the entire country. CIBERER's mis sion is to be a center prioritizing and favoring collaboration and cooperation between biomedical and clinical research groups, with special emphasis on the aspects of genetic, molecular, biochemical, and cellular research of RDs. This research is the basis for providing new tools for the diagnosis and therapy of low prevalence diseases, in line with the International Rare Diseases Research Consor tium (IRDiRC) objectives, thus favoring translational research between the scientific environment of the laboratory and the clinical setting of health centers. In this arti cle, we intend to review CIBERER's 15-year journey and summarize the main results obtained in terms of internationalization, scientific production, contributions toward the discovery of new therapies and novel genes associated to diseases, cooperation with patients' associations and many other topics related to RD research

Stability of Ampicillin plus Ceftriaxone Combined in Elastomeric Infusion Devices for Outpatient Parenteral Antimicrobial Therapy

Ampicillin; Infective endocarditis; Outpatient parenteral antimicrobial therapyAmpicil·lina; Endocarditis infecciosa; Teràpia antimicrobiana parenteral ambulatòriaAmpicilina; Endocarditis infecciosa; Terapia antimicrobiana parenteral ambulatoriaCurrently, ampicillin plus ceftriaxone (AC) is one of the preferred treatments for Enterococcus faecalis infective endocarditis. However, there is a lack of stability data for the combination of both drugs in elastomeric devices, so the inclusion of AC in Outpatient Parenteral Antimicrobial Therapy (OPAT) programs is challenging. The objective of the study was to determine the stability of AC in elastomeric pumps when stored at 8 ± 2 °C, 25 ± 2 °C, 30 ± 2 °C and 37 ± 2 °C using LC-MS/MS. The combination was diluted in 0.9% sodium chloride and the final concentrations were ampicillin 24 g/L plus ceftriaxone 8 g/L. Physical and chemical stability were evaluated at 12, 20, 24, 36 and 48 h after preparation. Stability was met at each time point if the percentage of intact drug was ≥90% of its respective baseline concentration and color and clearness remained unchanged. The drug combination was stable for 48 h when it was kept at 8 ± 2 °C. At 25 ± 2 °C and 30 ± 2 °C, they were stable for 24 h of storage. At 37 ± 2 °C, the stability criterion was not met at any time point. These results prove that AC could be included in OPAT programs using elastomeric infusion devices for the treatment of E. faecalis infections.This work was supported by the Sociedad Española de Farmacia Hospitalaria and the AFinf Working Group for the project “Stability study of antimicrobials under conditions analogous to the outpatient parenteral antibiotic therapy program (OPAT)”. A.G.-V. was supported by the Instituto de Salud Carlos III, co-financed by the European Development Regional Fund (“A way to achieve Europe”), Subprograma Miguel Servet (grant CP19/00159). L.H.-H. was supported by the Instituto de Salud Carlos III, co-financed by the European Development Regional Fund (“A way to achieve Europe”), Subprograma Juan Rodés (grant JR22/00049)

Stability of Antimicrobials in Elastomeric Pumps: A Systematic Review

Antimicrobials; Elastomer; Systematic reviewAntimicrobianos; Elastómero; Revisión sistemáticaAntimicrobians; Elastòmer; Revisió sistemàticaOutpatient parenteral antimicrobial therapy (OPAThttp) programs have become an important healthcare tool around the world. Portable elastomeric infusion pumps are functional devices for ambulatory delivery of antimicrobial drugs, and their stability is an essential point to guarantee an appropriate infusion administration. We conducted a systematic review to provide a synthesis and a critical evaluation of the current evidence regarding antimicrobial stability in elastomeric pumps. Data sources were PubMed, EMBASE, and Web of Sciences. The review protocol was registered on the Center for Open Science, and it was carried out following the PRISMA guidelines. Studies were eligible if the aim was the evaluation of the physicochemical stability of an antimicrobial agent stored in an elastomeric device. Of the 613 papers identified, 33 met the inclusion criteria. The most studied group of antimicrobials was penicillins, followed by cephalosporins and carbapenems. In general, the stability results of the antimicrobials that have been studied in more than one article agree with each other, with the exception of ampicillin, flucloxacillin, and ceftazidime. The antibiotics that displayed a longer stability were glycopeptides and clindamycin. Regarding the stability of antifungals and antivirals, only caspofungin, voriconazole, and ganciclovir have been investigated. The information provided in this article should be considered in patient treatments within the OPAT setting. Further stability studies are needed to confirm the appropriate use of the antimicrobials included in this program to ensure optimal patient outcomes.This work was supported by the Sociedad Española de Farmacia Hospitalaria and the AFinf Working Group for the project “Stability study of antimicrobials under conditions analogous to the outpatient parenteral antibiotic therapy program (OPAT)”. A.G.-V. was supported by the Instituto de Salud Carlos III, co-financed by the European Development Regional Fund (“A way to achieve Europe”), Subprograma Miguel Servet (grant CP19/00159). L.H.-H. was supported by the Instituto de Salud Carlos III, Subprograma Rio Hortega (grant CM19/00152)

Differential molecular response of monodehydroascorbate reductase and glutathione reductase by nitration and S-nitrosylation

The ascorbate–glutathione cycle is a metabolic pathway that detoxifies hydrogen peroxide and involves enzymatic and non-enzymatic antioxidants. Proteomic studies have shown that some enzymes in this cycle such as ascorbate peroxidase (APX), monodehydroascorbate reductase (MDAR), and glutathione reductase (GR) are potential targets for post-translational modifications (PMTs) mediated by nitric oxide-derived molecules. Using purified recombinant pea peroxisomal MDAR and cytosolic and chloroplastic GR enzymes produced in Escherichia coli, the effects of peroxynitrite (ONOO–) and S-nitrosoglutathione (GSNO) which are known to mediate protein nitration and S-nitrosylation processes, respectively, were analysed. Although ONOO– and GSNO inhibit peroxisomal MDAR activity, chloroplastic and cytosolic GR were not affected by these molecules. Mass spectrometric analysis of the nitrated MDAR revealed that Tyr213, Try292, and Tyr345 were exclusively nitrated to 3-nitrotyrosine by ONOO–. The location of these residues in the structure of pea peroxisomal MDAR reveals that Tyr345 is found at 3.3 Å of His313 which is involved in the NADPbinding site. Site-directed mutagenesis confirmed Tyr345 as the primary site of nitration responsible for the inhibition of MDAR activity by ONOO–. These results provide new insights into the molecular regulation of MDAR which is deactivated by nitration and S-nitrosylation. However, GR was not affected by ONOO– or GSNO, suggesting the existence of a mechanism to conserve redox status by maintaining the level of reduced GSH. Under a nitro-oxidative stress induced by salinity (150 mM NaCl), MDAR expression (mRNA, protein, and enzyme activity levels) was increased, probably to compensate the inhibitory effects of S-nitrosylation and nitration on the enzyme. The present data show the modulation of the antioxidative response of key enzymes in the ascorbate–glutathione cycle by nitric oxide (NO)- PTMs, thus indicating the close involvement of NO and reactive oxygen species metabolism in antioxidant defence against nitro-oxidative stress situations in plants.Spanish GovernmentERDF - Ministry of Economy and Competitiveness BIO2012-33904Junta de Andalucía BIO286 BIO19

Tumour heterogeneity in glioblastoma assessed by MRI texture analysis: a potential marker of survival

Objective: The main objective of this retrospective work was the study of three-dimensional (3D) heterogeneity measures of post-contrast pre-operative MR images acquired with T1 weighted sequences of patients with glioblastoma (GBM) as predictors of clinical outcome. Methods: 79 patients from 3 hospitals were included in the study. 16 3D textural heterogeneity measures were computed including run-length matrix (RLM) features (regional heterogeneity) and co-occurrence matrix (CM) features (local heterogeneity). The significance of the results was studied using Kaplan?Meier curves and Cox proportional hazards analysis. Correlation between the variables of the study was assessed using the Spearman?s correlation coefficient. Results: Kaplan?Meyer survival analysis showed that 4 of the 11 RLM features and 4 of the 5 CM features considered were robust predictors of survival. The median survival differences in the most significant cases were of over 6 months. Conclusion: Heterogeneity measures computed on the post-contrast pre-operative T1 weighted MR images of patients with GBM are predictors of survival. Advances in knowledge: Texture analysis to assess tumour heterogeneity has been widely studied. However, most works develop a two-dimensional analysis, focusing only on one MRI slice to state tumour heterogeneity. The study of fully 3D heterogeneity textural features as predictors of clinical outcome is more robust and is not dependent on the selected slice of the tumour

Two-center experience comparing the use of the FLOT4 and CROSS schemes for patients with gastric, esophageal, and gastroesophageal junction adenocarcinoma

Introduction. Gastric (GAD), gastroesophageal junction (GEJA), and esophageal adenocarcinoma (EAD) share pathophysiological features. At localized stages, FLOT is used perioperatively for the treatment of GAD and GEJA and CROSS for EAD and some GEJA. Although both therapies have been compared with MAGIC, comparative randomized data on FLOT and CROSS are not yet available. Material andmethods. We retrospectively analyzed and compared 40 patients treated with FLOT and 16 patients treated with CROSS in terms of clinical features and neoadjuvant, surgical, adjuvant, and survival outcomes. Results. At the time of analysis, 65% of patients treated with FLOT4 and 56.3% with CROSS remained in complete remission. Those who progressed after FLOT4 did so mainly at the peritoneal level (25%) and after CROSS at the bone, lymph node, and peritoneal levels (12.5% respectively). Six patients (37.5%) died after CROSS (median OS of 17.5 months; 95% CI 2–41) and 10 (25%) after FLOT4 (median OS 16.5 months; 95% CI 11–22). For the living patients, the median numbers of months from diagnosis to the follow-up cutoff date were 47.5 (95% CI 11–67) and 27 (95% CI 14–44) for CROSS and FLOT4, respectively. There were no significant differences in median OS estimated by Kaplan Meier analysis [FLOT4: 50 ± 4.6 months (95% CI 40.9–59.2); CROSS: 51.2 ± 7 months (95% CI 37.4–65.0; p = 0.79)].  Conclusions. Although we obtained lower pCR rates; TNM downstaging after neoadjuvant therapy, R0 rates, tolerance, PFS, and OS were similar in both groups and comparable with trial results. The adjuvant compliance rate was high with FLOT4. CROSS allows sequencing with nivolumab in PD-L1+ tumors

News and updates in the treatment of localized stage triple-negative breast cancer

Compared to other breast cancer subtypes, triple-negative breast cancer presents a worse prognosis and higher mortality. Even in localized stages, the risk of relapse is high, especially in patients with ≥ cT2 and/or ≥ cN1. We know that those patients who achieve a complete pathologic response after neoadjuvant treatment have better disease-free survival. Therefore, many research efforts have been made to try to optimize neoadjuvant chemo/immunotherapy to increase pathologic complete response rates. The available evidence related to that subject matter is summarized in this article. In the field of adjuvant therapy, the challenge of improving disease-free survival in those patients who do not achieve pathologic complete response after neoadjuvant therapy stands out. The second part of this article will deal with the challenges inherent to this issue

Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers Withdrawal Is Associated with Higher Mortality in Hospitalized Patients with COVID-19

Our main aim was to describe the effect on the severity of ACEI (angiotensin-converting enzyme inhibitor) and ARB (angiotensin II receptor blocker) during COVID-19 hospitalization. A retrospective, observational, multicenter study evaluating hospitalized patients with COVID-19 treated with ACEI/ARB. The primary endpoint was the incidence of the composite outcome of prognosis (IMV (invasive mechanical ventilation), NIMV (non-invasive mechanical ventilation), ICU admission (intensive care unit), and/or all-cause mortality). We evaluated both outcomes in patients whose treatment with ACEI/ARB was continued or withdrawn. Between February and June 2020, 11,205 patients were included, mean age 67 years (SD = 16.3) and 43.1% female; 2162 patients received ACEI/ARB treatment. ACEI/ARB treatment showed lower all-cause mortality (p < 0.0001). Hypertensive patients in the ACEI/ARB group had better results in IMV, ICU admission, and the composite outcome of prognosis (p < 0.0001 for all). No differences were found in the incidence of major adverse cardiovascular events. Patients previously treated with ACEI/ARB continuing treatment during hospitalization had a lower incidence of the composite outcome of prognosis than those whose treatment was withdrawn (RR 0.67, 95%CI 0.63-0.76). ARB was associated with better survival than ACEI (HR 0.77, 95%CI 0.62-0.96). ACEI/ARB treatment during COVID-19 hospitalization was associated with protection on mortality. The benefits were greater in hypertensive, those who continue

Famílies botàniques de plantes medicinals

Facultat de Farmàcia, Universitat de Barcelona. Ensenyament: Grau de Farmàcia, Assignatura: Botànica Farmacèutica, Curs: 2013-2014, Coordinadors: Joan Simon, Cèsar Blanché i Maria Bosch.Els materials que aquí es presenten són els recull de 175 treballs d’una família botànica d’interès medicinal realitzats de manera individual. Els treballs han estat realitzat per la totalitat dels estudiants dels grups M-2 i M-3 de l’assignatura Botànica Farmacèutica durant els mesos d’abril i maig del curs 2013-14. Tots els treballs s’han dut a terme a través de la plataforma de GoogleDocs i han estat tutoritzats pel professor de l’assignatura i revisats i finalment co-avaluats entre els propis estudiants. L’objectiu principal de l’activitat ha estat fomentar l’aprenentatge autònom i col·laboratiu en Botànica farmacèutica