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Proton pump inhibitors and risk for recurrent ischemic events or death in outpatients with symptomatic artery disease

  • Munoz-Torrero, JFS
  • Zamorano, J
  • Rico-Martin, S
  • Rivas, MD
  • Bacaicoa, MA
  • Robles, R
  • Sanchez-Bacaicoa, C
  • Monreal, M
  • FRENA Investigators
Bagkground and aims: The influence of proton pump inhibitors (PPIs) on outcome in patients with symptomatic artery disease remains controversial. Methods: FRENA is a prospective registry of consecutive outpatients with symptomatic coronary (CAD), cerebrovascular (CVD) or peripheral artery disease (PAD). We compared the risk for subsequent ischemic events or death according to the use of PPIs. Results: As of December 2016, 5170 patients were recruited: 1793 (35%) had CAD, 1530 (30%) CVD and 1847 (35%) had PAD. Overall, 2289 patients (44%) were regularly using PPIs. During a median follow-up of 36 months, 172 patients suffered a recurrent myocardial infarction, 139 had ischemic stroke, 71 underwent limb amputation and 267 died (cardiovascular death, 109). On multivariable analysis, patients using PPIs were at a lower risk for subsequent limb amputation (hazard ratio [HR]: 0.53; 95%CI: 0.30-0.94), a similar risk for myocardial infarction (HR: 0.78; 95%CI: 0.55-1.10) or stroke (HR: 0.93; 95%CI: 0.64-1.35) and at a higher risk of death (HR: 1.37; 95%CI: 1.04-1.79). Conclusions: Among stable outpatients with symptomatic artery disease, the use of PPIs was associated with a lower risk for subsequent ischemic events but a higher risk for death.
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From Loops to Looks: Transcription Factors and Chromatin Organization Shaping Terminal B Cell Differentiation

  • Azagra, A
  • Marina-Zarate, E
  • Ramiro, AR
  • Javierre, BM
  • Parra, M
B lymphopoiesis is tightly regulated at the level of gene transcription. In recent years, investigators have shed light on the transcription factor networks and the epigenetic machinery involved at all differentiation steps of mammalian B cell development. During terminal differentiation, B cells undergo dramatic changes in gene transcriptional programs to generate germinal center E cells, plasma cells and memory B cells. Recent evidence indicates that mature B cell formation in volves an essential contribution from 3D chromatin conformations through its interplay with transcription factors and epigenetic machinery. Here, we provide an up-to-date overview of the coordination between transcription factors, epigenetic changes, and chromatin architecture during terminal B cell differentiation, focusing on recent discoveries and technical advances for studying 3D chromatin structures.
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Long-term outcome comparing histological grades of follicular lymphoma patients treated with immunochemotherapy as first-line therapy: A retrospective analysis from two institutions

  • Mercadal, S
  • Sancho, JM
  • Climent, F
  • Tapia, G
  • Pomares, H
  • Carro, I
  • Sorigue, M
  • Pane, M
  • Domingo-Domenech, E
  • Encuentra, M
  • Aguilera, C
  • Oliveira, AC
  • Andrade, M
  • de Sevilla, AF
  • Ribera, JM
  • Gonzalez-Barca, E
  • Sureda, A
Objectives To clarify the impact of histological grades in follicular lymphoma. Methods We retrospectively analysed 250 patients diagnosed with FL treated with chemoimmunotherapy: 188 patients were grades 1-2 and 62 grade 3A. Results In our series, grade 3A FL patients were older, higher proportion of localised disease and lower bone marrow infiltration at diagnosis comparing grades 1-2 FL patients. Estimated six-year progression-free survival and time to progression showed no differences between both groups [grade 3A: 56% (95%CI: 39%-73%) and 51% (95%CI: 41%-61%) vs grades 1-2:55% (95%CI: 46%-63%) and 57% (95%CI: 49%-65%), P = .782 and P = .521, respectively]. Estimated six-year overall survival was lower, 76% (95%CI: 64%-88%) for the grade 3A group than grades 1-2 83% (95%CI: 77%-89%); P = .044. In addition to that, cumulative incidence curves of death not related to lymphoma at 10 years between groups were as follows: [0.26 (95%CI: 0.25-0.27) and 0.05 (95%CI: 0.04-0.06) for G3AFL and G1-2FL, respectively], P = .010. Grade 3A FL showed in PFS curve no relapses after 6 years. These results were absolutely reproduced in 199 patients receiving R-CHOP regimen as induction. Conclusions Our results indicate similar long-term outcomes in terms of progression-free survival and time to progression in grades 1-2 and 3A. No relapses were observed in G3AFL group after 6 years.
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Segmentation of distal airways using structural analysis

  • Gil, D
  • Sanchez, C
  • Borras, A
  • Diez-Ferrer, M
  • Rosell, A
Segmentation of airways in Computed Tomography (CT) scans is a must for accurate support of diagnosis and intervention of many pulmonary disorders. In particular, lung cancer diagnosis would benefit from segmentations reaching most distal airways. We present a method that combines descriptors of bronchi local appearance and graph global structural analysis to fine-tune thresholds on the descriptors adapted for each bronchial level. We have compared our method to the top performers of the EXACT09 challenge and to a commercial software for biopsy planning evaluated in an own-collected data-base of high resolution CT scans acquired under different breathing conditions. Results on EXACT09 data show that our method provides a high leakage reduction with minimum loss in airway detection. Results on our data-base show the reliability across varying breathing conditions and a competitive performance for biopsy planning compared to a commercial solution.
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Quality of life of patients undergoing conventional vs leadless pacemaker implantation: A multicenter observational study

  • Cabanas-Grandio, P
  • Campo, EG
  • Bisbal, F
  • Garcia-Seara, J
  • Pachon, M
  • Juan-Salvadores, P
  • Paredes, E
  • Molinero, A
  • Martinez-Sande, JL
  • Arias, MA
  • Romo, AI
Background: Leadless pacemakers (L-PM) are an emerging effective and safe technology that offer an alternative to conventional pacemakers (C-PM) for right ventricular stimulation. However, there is little information about their potential benefits for quality of life (QoL) in patients with L-PM. We compared QoL between patients with L-PM and C-PM. Methods: The study population comprised patients undergoing single chamber pacemaker implantation from December 2016 to March 2018. The SF-36 questionnaire was used to evaluate QoL at baseline and at 6 months of followup. We also used a questionnaire consisted of 10 specific questions related to the implant procedure. Results: A total of 106 patients (64 C-PM; 42 L-PM) were included. There were no differences in baseline characteristics between the groups (C-PM vs L-PM), except for age (81.5 vs 77.3 years; P = .012) and diabetes (38% vs 17%; P = .021). Baseline SF-36 scores did not differ between the groups. At 6 months followup, patients in the L-PM group scored significantly higher on physical function (63 vs 42; P < .001), physical role (64 vs 36; P = .004), and mental health (75 vs 65; P = .017), even after adjusting for covariates. Pacemaker-related discomfort and physical restrictions were significantly lower for the L-PM group. Conclusion: L-PM is associated with better QoL than C-PM in both physical and mental health. Patients undergoing L-PM implantation reported less procedure-related discomfort, physical restriction, and preoccupation.
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The Chemical Optimization of Cerebral Embolectomy trial: Study protocol

  • Renu, A
  • Blasco, J
  • Millan, M
  • Marti-Fabregas, J
  • Cardona, P
  • Oleaga, L
  • Macho, J
  • Molina, C
  • Roquer, J
  • Amaro, S
  • Davalos, A
  • Zarco, F
  • Laredo, C
  • Tomasello, A
  • Guimaraens, L
  • Barranco, R
  • Castano, C
  • Vivas, E
  • Ramos, A
  • Lopez-Rueda, A
  • Urra, X
  • Muchada, M
  • Cuadrado-Godia, E
  • Camps-Renom, P
  • Roman, LS
  • Rios, J
  • Leira, EC
  • Jovin, T
  • Torres, F
  • Chamorro, A
  • CHOICE Investigators
Rationale The potential value of rescue intraarterial thrombolysis in patients with large vessel occlusion stroke treated with mechanical thrombectomy has not been assessed in randomized trials. Aim The CHemical OptImization of Cerebral Embolectomy trial aims to establish whether rescue intraarterial thrombolysis is more effective than placebo in improving suboptimal reperfusion scores in patients with large vessel occlusion stroke treated with mechanical thrombectomy. Sample size estimates A sample size of 200 patients allocated 1:1 to intraarterial thrombolysis or intraarterial placebo will have >95% statistical power for achieving the primary outcome (5% in the control versus 60% in the treatment group) for a two-sided (5% alpha, and 5% lost to follow-up). Methods and design We conducted a multicenter, randomized, placebo-controlled, double blind, phase 2b trial. Eligible patients are 18 or older with symptomatic large vessel occlusion treated with mechanical thrombectomy resulting in a modified treatment in cerebral ischemia score 2b at end of the procedure. Patients will receive 20-30 min intraarterial infusion of recombinant tissue plasminogen activator or placebo (0.5 mg/ml, maximum dose limit 22.5 mg). Study outcome(s) The primary outcome is the proportion of patients with an improved modified treatment in cerebral ischemia score 10 min after the end of the study treatment. Secondary outcomes include the shift analysis of the modified Rankin Scale, the infarct expansion ratio, the proportion of excellent outcome (modified Rankin Scale 0-1), the proportion of infarct expansion, and the infarction volume. Mortality and symptomatic intracerebral bleeding will be assessed. Discussion The study will provide evidence whether rescue intraarterial thrombolysis improves brain reperfusion in patients with large vessel occlusion stroke and incomplete reperfusion (modified treatment in cerebral ischemia 2b) at the end of mechanical thrombectomy.
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Effect of a Strategy of Comprehensive Vasodilation vs Usual Care on Mortality and Heart Failure Rehospitalization Among Patients With Acute Heart Failure The GALACTIC Randomized Clinical Trial

  • Kozhuharov, N
  • Goudev, A
  • Flores, D
  • Maeder, MT
  • Walter, J
  • Shrestha, S
  • Gualandro, DM
  • de Oliveira, MT
  • Sabti, Z
  • Muller, B
  • Noveanu, M
  • Socrates, T
  • Ziller, R
  • Bayes-Genis, A
  • Sionis, A
  • Simon, P
  • Michou, E
  • Gujer, S
  • Gori, T
  • Wenzel, P
  • Pfister, O
  • Conen, D
  • Kapos, I
  • Kobza, R
  • Rickli, H
  • Breidthardt, T
  • Munzel, T
  • Erne, P
  • Mueller, C
  • Dimov, B
  • Herr, N
  • Isenrich, R
  • Mosimann, T
  • Twerenbold, R
  • Boeddinghaus, J
  • Nestelberger, T
  • Puelacher, C
  • Freese, M
  • Vogele, J
  • Meissner, K
  • Martin, J
  • Strebel, I
  • Wussler, D
  • Schumacher, C
  • Osswald, S
  • Vogt, F
  • Hilti, J
  • Schwarz, J
  • Fitze, B
  • Hartwiger, S
  • Arenja, N
  • Glatz, B
  • Rentsch, K
  • Bossa, A
  • Jallad, S
  • Soeiro, A
  • Jansen, T
  • Gebel, G
  • Bossard, M
  • Christ, M
  • GALACTIC Investigators
IMPORTANCE Short-term infusions of single vasodilators, usually given in a fixed dose, have not improved outcomes in patients with acute heart failure (AHF). OBJECTIVE To evaluate the effect of a strategy that emphasized early intensive and sustained vasodilation using individualized up-titrated doses of established vasodilators in patients with AHF. DESIGN, SETTING, AND PARTICIPANTS Randomized, open-label blinded-end-point trial enrolling 788 patients hospitalized for AHF with dyspnea, increased plasma concentrations of natriuretic peptides, systolic blood pressure of at least 100mmHg, and plan for treatment in a general ward in 10 tertiary and secondary hospitals in Switzerland, Bulgaria, Germany, Brazil, and Spain. Enrollment began in December 2007 and follow-up was completed in February 2019. INTERVENTIONS Patients were randomized 1:1 to a strategy of early intensive and sustained vasodilation throughout the hospitalization (n = 386) or usual care (n = 402). Early intensive and sustained vasodilation was a comprehensive pragmatic approach of maximal and sustained vasodilation combining individualized doses of sublingual and transdermal nitrates, low-dose oral hydralazine for 48 hours, and rapid up-titration of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, or sacubitril-valsartan. MAIN OUTCOMES AND MEASURES The primary end pointwas a composite of all-cause mortality or rehospitalization for AHF at 180 days. RESULTS Among 788 patients randomized, 781 (99.1%; median age, 78 years; 36.9% women) completed the trial and were eligible for primary end point analysis. Follow-up at 180 days was completed for 779 patients (99.7%). The primary end point, a composite of all-cause mortality or rehospitalization for AHF at 180 days, occurred in 117 patients (30.6%) in the intervention group (including 55 deaths [14.4%]) and in 111 patients (27.8%) in the usual care group (including 61 deaths [15.3%]) (absolute difference for the primary end point, 2.8% [95% CI, -3.7% to 9.3%]; adjusted hazard ratio, 1.07 [95% CI, 0.83-1.39]; P =.59). The most common clinically significant adverse events with early intensive and sustained vasodilation vs usual care were hypokalemia (23% vs 25%), worsening renal function (21% vs 20%), headache (26% vs 10%), dizziness (15% vs 10%), and hypotension (8% vs 2%). CONCLUSIONS AND RELEVANCE Among patients with AHF, a strategy of early intensive and sustained vasodilation, compared with usual care, did not significantly improve a composite outcome of all-cause mortality and AHF rehospitalization at 180 days.
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Predicting the artificial immunity induced by RUTI (R) vaccine against tuberculosis using universal immune system simulator (UISS)

  • Pennisi, M
  • Russo, G
  • Sgroi, G
  • Bonaccorso, A
  • Palumbo, GAP
  • Fichera, E
  • Mitra, DK
  • Walker, KB
  • Cardona, PJ
  • Amat, M
  • Viceconti, M
  • Pappalardo, F
Background: Tuberculosis (TB) represents a worldwide cause of mortality (it infects one third of the world's population) affecting mostly developing countries, including India, and recently also developed ones due to the increased mobility of the world population and the evolution of different new bacterial strains capable to provoke multidrug resistance phenomena. Currently, antitubercular drugs are unable to eradicate subpopulations of Mycobacterium tuberculosis (MTB) bacilli and therapeutic vaccinations have been postulated to overcome some of the critical issues related to the increase of drug-resistant forms and the difficult clinical and public health management of tuberculosis patients. The Horizon 2020 EC funded project "In Silico Trial for Tuberculosis Vaccine Development" (STriTuVaD) to support the identification of new therapeutic interventions against tuberculosis through novel in silico modelling of human immune responses to disease and vaccines, thereby drastically reduce the cost of clinical trials in this critical sector of public healthcare. Results: We present the application of the Universal Immune System Simulator (UISS) computational modeling infrastructure as a disease model for TB. The model is capable to simulate the main features and dynamics of the immune system activities i.e., the artificial immunity induced by RUTI (R) vaccine, a polyantigenic liposomal therapeutic vaccine made of fragments of Mycobacterium tuberculosis cells (FCMtb). Based on the available data coming from phase II Clinical Trial in subjects with latent tuberculosis infection treated with RUTI (R) and isoniazid, we generated simulation scenarios through validated data in order to tune UISS accordingly to STriTuVaD objectives. The first case simulates the establishment of MTB latent chronic infection with some typical granuloma formation; the second scenario deals with a reactivation phase during latent chronic infection; the third represents the latent chronic disease infection scenario during RUTI (R) vaccine administration. Conclusions: The application of this computational modeling strategy helpfully contributes to simulate those mechanisms involved in the early stages and in the progression of tuberculosis infection and to predict how specific therapeutical strategies will act in this scenario. In view of these results, UISS owns the capacity to open the door for a prompt integration of in silico methods within the pipeline of clinical trials, supporting and guiding the testing of treatments in patients affected by tuberculosis.
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Baseline Risk Stratification of Patients Older Than 75 Years With Infarction and Cardiogenic Shock Undergoing Primary Angioplasty

  • Hernandez, JMDLT
  • Brugaletta, S
  • Hospital, JAG
  • Baz, JA
  • de Prado, AP
  • Palop, RL
  • Cid, B
  • Camarero, TG
  • Diego, A
  • Gutierrez, H
  • Diaz, JAF
  • Sanchis, J
  • Alfonso, F
  • Blanco, R
  • Botas, J
  • Cuartero, JN
  • Moreu, J
  • Bosa, F
  • Valle, JMV
  • Elizaga, J
  • Arrebola, AL
  • Arroyo, JRR
  • Hernandez, F
  • Salvatella, N
  • Monteagudo, M
  • Jaume, AG
  • Carrillo, X
  • Reyes, RM
  • Lozano, F
  • Rumoroso, JR
  • Andraka, L
  • Dominguez, AJ
Background and objectives: Patients older than 75 years with ST-segment elevation myocardial infarction undergoing primary angioplasty in cardiogenic shock have high mortality. Identification of preprocedural predictors of short- and long-term mortality could be useful to guide decision-making and further interventions. Methods: We analyzed a nationwide registry of primary angioplasty in the elderly (ESTROFA MI + 75) comprising 3576 patients. The characteristics and outcomes of the subgroup of patients in cardiogenic shock were analyzed to identify associated factors and prognostic predictors in order to derive a baseline risk prediction score for 1-year mortality. The score was validated in an independent cohort. Results: A total of 332 patients were included. Baseline independent predictors of mortality were anterior myocardial infarction (HR 2.8, 95%CI, 1.4-6.0 P= .005), ejection fraction < 40% (HR 2.3, 95%CI, 1.14-4.50 P = .018), and time from symptom onset to angioplasty > 6 hours (HR 3.2, 95%CI, 1.6-7.5; P= .001). A score was designed that included these predictive factors (score "6-ANT-40"). Survival at 1 year was 54.5% for patients with score 0, 32.3% for score 1, 27.4% for score 2 and 17% for score 3 (P = .004, c-statistic 0.70). The score was validated in an independent cohort of 124 patients, showing 1-year survival rates of 64.5%, 40.0%, 28.9%, and 22.2%, respectively (P = .008, c-statistic 0.68). Conclusion: A preprocedural score based on 3 simple clinical variables (anterior location, ejection fraction < 40%, and delay time > 6 hours) may be used to estimate survival after primary angioplasty in elderly patients with cardiogenic shock and to guide preinterventional decision-making. (C) 2018 Sociedad Espanola de Cardiologia. Published by Elsevier Espana, S.L.U. All rights reserved.
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