Resultados de investigación

Purpose To evaluate the disease biomarker response of venglustat in patients with Fabry disease (FD), utilizing data from a single-arm phase 2 study of venglustat and a placebo-controlled phase 3 study of agalsidase beta through historical control and case-matched analyses. Methods Eleven venglustat-treated male patients with classic FD in the phase 2 study were matched with placebo- or agalsidase beta–treated patients from the phase 3 study based on propensity scores at baseline. Changes from baseline in plasma globotriaosylceramide (GL-3 or Gb3) concentrations were analyzed at approximately 6–36 months. Results Venglustat treatment resulted in greater significant reductions in plasma GL-3 concentrations at 6 months from baseline vs. placebo (mean difference −2.56 μg/mL, p < 0.001), and at 24 and 36 months from baseline vs. agalsidase beta (mean difference −1.8 μg/mL, p < 0.05 and −2.35 μg/mL, p < 0.01, respectively). GL-3 concentrations continued to decline with venglustat for up to 3 years without plateauing. Conclusions Venglustat showed significantly greater reductions in plasma GL-3 concentrations than placebo after 6 months and agalsidase beta after 24 and 36 months. These findings support the potential of long-term venglustat treatment to reduce GL-3 accumulation in patients with classic FD. Further studies are needed to confirm clinical benefit, The studies were funded by Sanofi

Trial registration number NCT06540677, Introduction Although most cochlear implant (CI) users achieve good speech understanding in quiet without visual cues, they may have limited speech understanding in noise and often have poor music perception. The present study was designed to investigate the degree to which the use of Meludia training can improve music perception, music enjoyment and speech understanding in paediatric and postlingually deafened adult CI users. The study also aims to assess the participants’ changes in cognitive skills (attention and memory) and quality of life. Methods and analysis This randomised controlled trial will randomise new CI users and experienced CI users older than 6 years who meet the inclusion criteria in a 1:1 ratio to either a musical training (MT) group or a non-MT (NMT) group. The NMT group will receive standard care that does not include MT. Participants in the MT group will practise with Meludia software for 4 weeks and later for 12 additional weeks. Outcomes will include scores in: ‘Listening Up’ exercises, the -Music-Related Quality of Life questionnaire, the Music Questionnaire for Paediatric Population, Disyllables in silence, Matrix test, Mini Mental State Examination, Performance IQ and the Wechsler intelligence scale for children and the Assessment of Quality of Life—8 Dimensions questionnaire. The NMT group will receive standard care that does not include MT

Marstacimab targets the tissue factor pathway inhibitor to rebalance hemostasis. Previous phase 1 and 2 trials established marstacimab safety and efficacy in adults with severe hemophilia A (HA) or B (HB). BASIS is an open-label, marstacimab phase 3 trial in males aged 12 to 74 years with severe HA (factor VIII <1%) or moderately severe to severe HB (factor IX ≤2%). Participants without inhibitors received on-demand (OD) or routine prophylaxis (RP) therapy during a 6-month observational phase (OP) before receiving once-weekly subcutaneous 150 mg marstacimab during a 12-month active treatment phase (ATP). Primary end points were annualized bleeding rate (ABR) for treated bleeds vs previous OD or RP during the OP, and safety. Of 128 participants enrolled in the OP, 116 received marstacimab in the ATP. In the OD group (n = 33), mean ABR decreased from 39.86 (95% confidence interval [CI], 33.05-48.07) in the OP to 3.20 (95% CI, 2.10-4.88) in the ATP, demonstrating superiority of marstacimab (estimated ABR ratio, 0.080 [95% CI, 0.057-0.113]; P < .0001). In the RP group (n = 83), mean ABR decreased from 7.90 (95% CI, 5.14-10.66) in the OP to 5.09 (95% CI, 3.40-6.78) in the ATP, demonstrating noninferiority and superiority of marstacimab (estimated ABR difference, –2.81 [95% CI, –5.42 to –0.20]; P = .0349). There were no deaths or thromboembolic events. Weekly subcutaneous marstacimab reduced ABR vs OD or RP therapy in the OP in individuals with severe HA or moderately severe to severe HB without inhibitors. Marstacimab was safe and well tolerated with no unanticipated side effects. This trial was registered at www.clinicaltrials.gov as #NCT03938792., This study was sponsored by Pfizer

Trial registration number NCT05871502, Introduction Poststroke hyperglycaemia is an independent risk factor for poorer outcomes in patients treated with mechanical thrombectomy (MT) and is associated with a lower probability of functional recovery and higher mortality at 3 months. This study aims to evaluate the association between glucose levels during cerebral reperfusion with MT and functional recovery at 3 months, measured by subcutaneous continuous glucose monitoring (CGM) devices. Methods This prospective observational study aims to recruit 100 patients with ischaemic stroke and large anterior circulation vessel occlusion, in whom MT is indicated. CGM will be performed using a Freestyle Libre ProIQ device (FSL-CGM, Abbott Diabetes Care, Alameda, California, USA), which will be implanted on admission to the emergency department, to monitor glucose levels before, during and after reperfusion. The study’s primary endpoint will be the functional status at 3 months, as measured by the dichotomised modified Rankin Scale (0–2 indicating good recovery and 3–6 indicating dependency or death). We will analyse expression profiles of microRNA (miRNA) at the time of reperfusion and 24 hours later, as potential biomarkers of ischaemic-reperfusion injury. The most promising miRNAs include miR-100, miR-29b, miR-339, miR-15a and miR-424. All patients will undergo treatment according to current international recommendations and local protocols for the treatment of stroke, including intravenous thrombolysis if indicated. Ethics and dissemination This study (protocol V.1.1, dated 29 October 2021, code 6017) has been approved by the Clinical Research Ethics Committee of La Paz University Hospital (Madrid, Spain) and has been registered in ClinicalTrials.gov (NCT 05871502). Study results will be disseminated through peer-reviewed publications in Open Access format and at conference presentation, This work is funded by ISCIII and cofunded by the European Union under grant PI21/00962, INT 22/00039 to CHT and FI22/00187 to JPN; and RICORS network under grant RD21/0006/0012

Rationale Cognitive decline and dementia have been reportedly linked to atherosclerosis, the main cause of cardiovascular disease. Cohort studies identifying early brain alterations associated with subclinical atherosclerosis are warranted to understand the potential of prevention strategies before cerebral damage becomes symptomatic and irreversible. Methods & design The Progression of Early Subclinical Atherosclerosis (PESA) study is a longitudinal observational cohort study that recruited 4,184 asymptomatic middle-aged individuals (40-54 years) in 2010 in Madrid (Spain) to thoroughly characterize subclinical atherosclerosis development over time. In this framework, the PESA-Brain study has been designed to identify early structural, functional and vascular brain changes associated with midlife atherosclerosis and cardiovascular risk factors. The PESA-Brain study targets 1,000 participants at the 10-year follow-up PESA visit and consists of thorough neuropsychological testing, advanced multimodal neuroimaging, and quantification of blood-based neuropathological biomarkers. Primary hypothesis We hypothesize that, in middle-age, the presence of cardiovascular risk factors and a high burden of subclinical atherosclerosis will be associated with structural, functional and vascular brain alterations, greater amyloid burden and subtle cognitive impairment. We further hypothesize that the link between subclinical atherosclerosis and poor brain health in midlife will be mediated by cerebrovascular pathology and intracranial atherosclerosis. Enrollment dates The PESA-Brain study started in October 2020 and is estimated to be completed by December 2024. Conclusion This study is in a unique position to unveil novel relationships between cardiovascular and brain alterations in the health-to-disease transition, which may have important implications for interventional and therapeutic approaches., The PESA study is funded by CNIC and Santander Bank, Madrid, Spain and also receives funding from the European Regional Development Fund (ERDF–A Way to Build Europe), and the European Social Fund (ESF–Investing in Your Future). CNIC is a Severo Ochoa Center of Ex- cellence (CEX2020-001041-S) and is supported by the ISCIII, the Spanish Ministry for Science and Innovation and the Pro-CNIC Foundation

Endometrial cancer (EC) is the 4th most common neoplasm of the female genital tract, with 15–20% of patients being of high risk of recurrence which leads to a significant decrease in patient survival. Current therapeutic options for patients with EC are poor, being the combined therapy of carboplatin and paclitaxel the standard of care, with limited efficacy. Therefore, new therapeutic options and better monitoring tools are needed to improve the management of the disease. In the current case report, we showcase the value of liquid biopsy analyses in a microsatellite instability EC patient with initially good prognosis that however underwent rapid progression disease within 6 months post-surgery; through the study of plasma cfDNA/ctDNA dynamics to assess the tumour evolution during treatment, as well as the study of the uterine aspirate as a valuable sample that captures the intra-tumour heterogeneity that allows a comprehensive genomic profiling of the disease to identify potential therapeutic options. Furthermore, preclinical models were generated at the time of tumour progression to assess the efficacy of the identified targeted therapies

Background While nutritional interventions with prebiotics and probiotics seem to exert immunological effects, their clinical implications in human immunodeficiency virus (HIV)–infected subjects initiating antiretroviral therapy (ART) at advanced HIV disease remain unclear. Methods This was a pilot multicenter randomized, placebo-controlled, double-blind study in which 78 HIV-infected, ART-naive subjects with <350 CD4 T cells/μL or AIDS were randomized to either daily PMT25341 (a mixture of synbiotics, omega-3/6 fatty acids and amino acids) or placebo for 48 weeks, each in combination with first-line ART. Primary endpoints were changes in CD4 T-cell counts and CD4/CD8 ratio from baseline to week 48 and safety. Secondary endpoints were changes in markers of T-cell activation, bacterial translocation, inflammation, and α and β microbiota diversity. Results Fifty-nine participants completed the follow-up with a mean CD4+ T-cell count of 221 ± 108 cells/μL and mean CD4/CD8 ratio of 0.26 ± 0.19. PMT25341 was well tolerated, without grade 3–4 adverse effects attributable to the intervention. While most of the assessed biomarkers improved during the follow-up in both arms, PMT25341-treated subjects did not experience any significant change, compared to placebo-treated subjects, in mean CD4+ T-cell count change (278 vs 250 cells/μL, P = .474) or CD4/CD8 ratio change (0.30 vs 0.32, P = .854). Similarly, we did not detect differences between treatment arms in secondary endpoints. Conclusions In HIV-infected patients initiating ART at advanced disease, the clear immunological benefits of ART were not enhanced by this nutritional intervention targeting the gut-associated lymphoid tissue and microbiota, This work was supported by the Instituto de Salud Carlos III (Plan Estatal de I+D+i 2013–2016, projects PI13/00438, AC15/00022, and PI15/00345, and the Spanish AIDS Research Network RD16/0025/0001project), the Spanish Ministry of Science and Competitiveness (project SAF2015-65878-R), and co-financed by the European Development Regional Fund “A Way to Achieve Europe.” The present investigation was also funded by the Instituto de Salud Carlos III and the Fundación Asociación Española contra el Cáncer within the ERA (European Research Area)-NET aligning national/regional translational cancer research programmes and activities (TRANSCAN)-2 program (grant number AC17/00022). S. S.-V. was supported by a grant from the Spanish Ministry of Science and Competitiveness (Contratos Juan Rodés, ECC/1051/2013)

Artículo escrito por un elevado número de autores, solo se referencian el que aparece en primer lugar, el nombre del grupo de colaboración, si le hubiere, y los autores pertenecientes a la UAM, Clinical trial registration: https://www.clinicaltrialsregister.eu/ctr-search/search?query=2014-001620-29 EudraCT, ID:2014-001620-29, Background: Diffuse large B cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma worldwide. DLBCL is an aggressive disease that can be cured with upfront standard chemoimmunotherapy schedules. However, in approximately 35-40% of the patients DLBCL relapses, and therefore, especially in this setting, the search for new prognostic and predictive biomarkers is an urgent need. Natural killer (NK) are effector cells characterized by playing an important role in antitumor immunity due to their cytotoxic capacity and a subset of circulating NK that express CD8 have a higher cytotoxic function. In this substudy of the R2-GDP-GOTEL trial, we have evaluated blood CD8+ NK cells as a predictor of treatment response and survival in relapsed/refractory (R/R) DLBCL patients.Methods: 78 patients received the R2-GDP schedule in the phase II trial. Blood samples were analyzed by flow cytometry. Statistical analyses were carried out in order to identify the prognostic potential of CD8+ NKs at baseline in R/R DLBCL patients.Results: Our results showed that the number of circulating CD8+ NKs in R/R DLBCL patients were lower than in healthy donors, and it did not change during and after treatment. Nevertheless, the level of blood CD8+ NKs at baseline was associated with complete responses in patients with R/R DLBCL. In addition, we also demonstrated that CD8+ NKs levels have potential prognostic value in terms of overall survival in R/R DLBCL patients.Conclusion: CD8+ NKs represent a new biomarker with prediction and prognosis potential to be considered in the clinical management of patients with R/R DLBCL, The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This research was funded by the Spanish Lymphoma Oncology Group (GOTEL) with the financial support of Celgene (Investigator Initiated Trials Program); no grant numbers applicable. LH-P is supported by the Consejerı́a de Salud y Familias, Junta de Andalucı́a (RH-0047-2021) and Miguel Servet Researcher Fellow from the Instituto de Salud Carlos III. DG-D is supported by the VII Plan Propio de Investigacion y Transferencia of Universidad de Sevilla [Contrato de Acceso (II.4)/VII PPIT-US]. CJ-C is supported by the Margarita Salas fellowship, granted by the University of Seville (Seville, Spain)

Hay una corrección posterior a este artículo disponible en https://hdl.handle.net/10486/756620. Artículo escrito por un elevado número de autores, solo se referencian el que aparece en primer lugar, el nombre del grupo de colaboración, si le hubiere, y los autores pertenecientes a la UAM. Trial Registration: ClinicalTrials.gov identifier: NCT02328131, Background The influence of indications for Helicobacter pylori investigation on prescriptions and effectiveness is unknown. The aim of the study was to assess the impact of indications for H. pylori investigation on prescriptions, effectiveness, compliance, and tolerance. Methods International, prospective, non-interventional registry of the management of H. pylori infection by European gastroenterologists (Hp-EuReg). Treatment-näive patients registered from 2013 to 2023 at e-CRF AEG-REDCap were analyzed. The effectiveness was assessed by modified intention-to-treat analysis. Results Overall, 53,636 treatment-naïve cases from 34 countries were included. Most frequent indications were: dyspepsia with normal endoscopy (49%), non-investigated dyspepsia (20%), duodenal ulcer (11%), gastric ulcer (7.7%), and gastroesophageal reflux disease (GERD) (2.6%). Therapy effectiveness varied by indication: duodenal ulcer (91%), gastric ulcer (90%), preneoplastic lesions (90%), dyspepsia with normal endoscopy (89%), GERD (88%), and non-investigated dyspepsia (87%). Bismuth-metronidazole-tetracycline and clarithromycin-amoxicillin-bismuth quadruple therapies achieved 90% effectiveness in all indications except GERD. Concomitant clarithromycin-amoxicillin-tinidazole/metronidazole reached 90% cure rates except in patients with non-investigated dyspepsia; whereas sequential clarithromycin-amoxicillin-tinidazole/metronidazole proved optimal (≥90%) in patients with gastric ulcer only. Adverse events were higher in patients treated for dyspepsia with normal endoscopy and duodenal ulcer compared with the remaining indications (23% and 28%, p < 0.001). Therapeutic compliance was higher in patients with duodenal ulcer and preneoplastic lesions (98% and 99%, p < 0.001). Conclusion In Europe, patients with gastric or duodenal ulcers and preneoplastic lesions showed higher H. pylori treatment effectiveness. Bismuth and non-bismuth quadruple therapies achieved optimal results in almost all indications, This project was promoted and funded by the European Helicobacter and Microbiota Study Group (EHMSG) and received support from the Spanish Association of Gastroenterology (AEG) and the Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd). The Hp-EuReg was co-funded by the European Union Programme HORIZON (grant agreement number 101095359) and supported by the UK Research and Innovation (grant agreement number 10058099). The Hp-EuReg was co-funded by the European Union Programme EU4Health (grant agreement number 101101252). This study was funded by Diasorin. And funded by the Group of Translational Research in Digestive Diseases of Aragón Health Research Institute and the CIBERehd

Abstract Background Pacemaker lead septal perforation is an uncommon but potentially serious complication. Early identification remains crucial to prevent potential life-threatening events. Case Summary A 30-year-old man was admitted with an acute ischemic stroke. Past medical history included a premature pacemaker implantation because of a paroxysmal atrioventricular block, followed by multiple pacemaker-related failures and complications. Nine months before the present admission, a dual-chamber pacemaker with left bundle branch pacing was implanted. At admission, abnormal findings were noted during cardiac rhythm monitoring, and pacemaker interrogation revealed ventricular capture failure. Two-dimensional echocardiography disclosed a septal perforation, with a striking migration of the ventricular lead into the left ventricle. Given the thromboembolic complication, lead removal was indicated. Interestingly, a new tubular “ghost” image was observed on echocardiography after lead removal, with uncertain implications. Discussion Pacemaker septal perforation is very rare but may entail serious risks. Optimal management remains controversial and depends on associated symptoms and complications. Take-Home Messages In patients with progressive pacemaker threshold increase, early imaging is key. Lead septal perforation requires careful evaluation given potential associated complications, including thromboembolic risk