DigitalUM :: Browsing by browse.metadata.contributordepartment "Medicina"

Browsing by browse.metadata.contributordepartment "Medicina"

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A contemporary picture of enterococcal endocarditis
(Elsevier, 2020-02-03) Pericàs, Juan M.; Llopis, Jaume; Muñoz, Patricia; Gálvez-Acebal, Juan; Kestler, Martha; Valerio, Maricela; Hernández-Meneses, Marta; Goenaga, Miguel Á.; Cobo-Belaustegui, Manuel; Montejo, Miguel; Ojeda-Burgos, Guillermo; Sousa-Regueiro, M. Dolores; Alarcón, Arístides de; Ramos-Martínez, Antonio; Miró, José M.; García-Vázquez, Elisa; GAMES Investigators; Medicina
BACKGROUND: Enterococcal endocarditis (EE) is a growing entity in Western countries. However, quality data from large studies is lacking. OBJECTIVES: The purpose of this study was to describe the characteristics and analyze the prognostic factors of EE in the GAMES cohort. METHODS: This was a post hoc analysis of a prospectively collected cohort of patients from 35 Spanish centers from 2008 to 2016. Characteristics and outcomes of 516 cases of EE were compared with those of 3,308 cases of nonenterococcal endocarditis (NEE). Logistic regression and Cox proportional hazards regression analysis were performed to investigate risk factors for in-hospital and 1-year mortality, as well as relapses. RESULTS: Patients with EE were significantly older; more frequently presented chronic lung disease, chronic heart failure, prior endocarditis, and degenerative valve disease; and had higher median age-adjusted Charlson score. EE more frequently involved the aortic valve and prosthesis (64.3% vs. 46.7%; p < 0.001; and 35.9% vs. 28.9%; p ¼ 0.002, respectively) but less frequently pacemakers/defibrillators (1.5% vs. 10.5%; p < 0.001), and showed higher rates of acute heart failure (45% vs. 38.3%; p ¼ 0.005). Cardiac surgery was less frequently performed in EE (40.7% vs.45.9%; p ¼ 0.024). No differences in in-hospital and 1-year mortality were found, whereas relapses were significantly higher in EE (3.5% vs. 1.7%; p ¼ 0.035). Increasing Charlson score, LogEuroSCORE, acute heart failure, septic shock, and paravalvular complications were risk factors for mortality, whereas prior endocarditis was protective and persistent bacteremia constituted the sole risk factor for relapse. CONCLUSIONS: Besides other baseline and clinical differences, EE more frequently affects prosthetic valves and less frequently pacemakers/defibrillators. EE presents higher rates of relapse than NEE.
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A human antithrombin isoform dampens inflammatory responses and protects from organ damage during bacterial infection
(Nature Research, 2019) Papareddy, Praveen; Rossnagel, Madlen; Hollwedel, Femke; Kilic, Gülcan; Veerla, Srinivas; Naudin, Clément; Smeds, Emanuel; Westman, Johannes; Martínez-Martínez, Irene; Egesten, Arne; Morena-Barrio, María Eugenia de la; Corral, Javier; Linder, Adam; Artoni, Andrea; Abbattista, Maria; Novembrino, Cristina; Brakebusch, Cord Hebert; Martinelli, Ida; Kasetty, Gopinath; Herwarld, Heiko; Medicina
Severe infectious diseases are often characterized by an overwhelming and unbalanced systemic immune response to microbial infections. Human antithrombin (hAT) is a crucial coagulation inhibitor with anti-inflammatory activities. Here we identify three hAT-binding proteins (CD13, CD300f and LRP-1) on human monocytes that are involved in blocking the activity of nuclear factor-κB. We found that the modulating effect is primarily restricted to the less abundant β-isoform (hβAT) of hAT that lacks N-glycosylation at position 135. Individuals with a mutation at this position have increased production of hβAT and analysis of their blood, which was stimulated ex vivo with lipopolysaccharide, showed a decreased inflammatory response. Similar findings were recorded when heterozygotic mice expressing hAT or hβAT were challenged with lipopolysaccharide or infected with Escherichia coli bacteria. Our results finally demonstrate that in a lethal E. coli infection model, survival rates increased when mice were treated with hβAT one hour and five hours after infection. The treatment also resulted in a reduction of the inflammatory response and less severe organ damage.
Open Access
A novel clinical risk prediction model for sudden cardiac death in hypertrophic cardiomyopathy (HCM Risk-SCD)
(Oxford University Press, European Society of Cardiology, 2013-10-14) O’Mahony, Constantinos; Jichi, Fatima; Pavlou, Menelaos; Monserrat, Lorenzo; Anastasakis, Aristides; Rapezzi, Claudio; Biagini, Elena; Gimeno Blanes, Juan Ramón; Elliott, Perry M.; Hypertrophic Cardiomyopathy Outcomes Investigators; Medicina; Facultad de Medicina
Aims: Hypertrophic cardiomyopathy (HCM) is a leading cause of sudden cardiac death (SCD) in young adults. Current risk algorithms provide only a crude estimate of risk and fail to account for the different effect size of individual risk factors. The aim of this study was to develop and validate a new SCD risk prediction model that provides individualized risk estimates. Methods and results: The prognostic model was derived from a retrospective, multi-centre longitudinal cohort study. The model was developed from the entire data set using the Cox proportional hazards model and internally validated using bootstrapping. The cohort consisted of 3675 consecutive patients from six centres. During a follow-up period of 24 313 patient-years (median 5.7 years), 198 patients (5%) died suddenly or had an appropriate implantable cardioverter defibrillator (ICD) shock. Of eight pre-specified predictors, age, maximal left ventricular wall thickness, left atrial diameter, left ventricular outflow tract gradient, family history of SCD, non-sustained ventricular tachycardia, and unexplained syncope were associated with SCD/appropriate ICD shock at the 15% significance level. These predictors were included in the final model to estimate individual probabilities of SCD at 5 years. The calibration slope was 0.91 (95% CI: 0.74, 1.08), C-index was 0.70 (95% CI: 0.68, 0.72), and D-statistic was 1.07 (95% CI: 0.81, 1.32). For every 16 ICDs implanted in patients with ≥4% 5-year SCD risk, potentially 1 patient will be saved from SCD at 5 years. A second model with the data set split into independent development and validation cohorts had very similar estimates of coefficients and performance when externally validated. Conclusion: This is the first validated SCD risk prediction model for patients with HCM and provides accurate individualized estimates for the probability of SCD using readily collected clinical parameters.
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A Phase I Dose Escalation and Cohort Expansion Study of CB307, a Trispecific Humabody against PSMA, CD137, and Albumin in Patients with PSMA-Positive Solid Tumors
(American Association for Cancer Research, 2025-08-15) de Bon, Johann S. ; Williams, Anja ; Melero, Ignacio ; Jayaram, Anuradha ; Hawley, Jessica E.; de Speville, Bernard Doger ; Moreno, Irene ; Castellano, Daniel ; Reig, Oscar; Knapen, Daan G.; Anguera, Georgia ; Martínez, Julia ; Gort, Eelke ; de Jonge, Maja ; Alonso Romero, José Luis; Boni, Valentina ; Pérez Gracia, Jose Luis ; Falcon, Alejandro ; de Groot, Derk Jan; Pierce, Andrew J.; Leishman, Andrew J.; Lloyd, Peter ; Bartlett, Phillip D.; Bland-Ward, Philip ; Chau, Albert ; Song, Minjung ; Duffy, Kevin ; Hashimoto, Kenji ; de Vries, Eisabeth ; Medicina; Facultades de la UMU::Facultad de Medicina
Purpose: CB307 is a trispecific variable heavy-chain antibody fragment against prostate-specific membrane antigen (PSMA), CD137, and human serum albumin. It is designed to mitigate hepatotoxicity by activating T cells only in PSMA-positive tumors and to increase drug half-life through albumin binding. This phase I study investigated the safety and tolerability of CB307 as monotherapy or in combination with pembrolizumab. Patients and Methods: Patients who were heavily pretreated with PSMA-positive solid tumors were enrolled in the dose-escalation phase of CB307 monotherapy. The additional safety and efficacy of CB307 were assessed in the CB307 monotherapy expansion cohort and in combination with pembrolizumab. Results: CB307 was administered to 75 patients. CB307 was given once every 7 days as monotherapy (N = 50) or in combination with pembrolizumab (N = 25). Two dose-limiting toxicities (grade 3 transient transaminitis) were observed. A total of three grade 3 transaminitis events (one in the monotherapy cohort and two in the combination cohort) were observed, and none involved bilirubin elevation. Durable RECIST responses were observed in two patients with metastatic castration-resistant prostate cancer enrolled in the 800 mg CB307 monotherapy and in one patient in the combination cohort (overall response rates: 11.1% and 7.1%, respectively). A disease control rate (DCR) of 50% was observed in patients enrolled in the 800 mg CB307 monotherapy cohort and 42.9% in the combination cohort. In a post hoc analysis, the response was numerically better in patients who had not received chemotherapy in the 6 months prior to starting CB307 (ORR = 20%, DCR = 60% vs. ORR = 0%, DCR = 37.5%). CB307 induces cytotoxic cell expansion in tumors and PD-L1 expression. Conclusions: CB307 was well tolerated as a monotherapy and in combination with pembrolizumab, and tumor responses were observed in patients with metastatic castration-resistant prostate cancer.
Open Access
Activating Killer-cell Immunoglobulin-like Receptors are associated with the severity of COVID-19
(Oxford University Press, 2021-04-30) Bernal, Enrique; Alcaraz, María J.; Quadee, Ahmed A.; Moreno, Marta; Martínez-Sánchez, María V.; Campillo, José A.; Gómez, Jose M.; Peláez, Ana; García-Vázquez, Elisa; Herranz, Maite; Hernández-Olivo, Marta; Martínez-Alfaro, Elisa; Alcaraz, Antonia; Muñoz, Ángeles; Cano, Alfredo; McKay, Matthew R.; Muro, Manuel; Minguela, Alfredo; Murcian COVID19 Study group; Gimeno Arias, Lourdes; Medicina
Background: Etiopathogenesis of the clinical variability of the coronavirus disease 2019 (COVID-19) remains mostly unknown. Here we investigate the role of Killer-cell Immunoglobulin-like receptor (KIR)/Human Leukocyte Antigen Class-I (HLA-I) interactions in the susceptibility and severity of COVID-19. Methods: KIR and HLA-I genotyping and NK cell (NKc) receptors immunophenotyping in 201 symptomatic patients and 210 non-infected controls. Results: NKcs with a distinctive immunophenotype, suggestive of recent activation (KIR2DS4low CD16low CD226low CD56high TIGIThigh NKG2Ahigh), expanded in patients with severe COVID-19. This was associated with a higher frequency of the functional A-telomeric activating KIR2DS4 in severe than mild/moderate patients and controls (83.7%, 55.7% and 36.2%, p<7.7x10-9). In mild/moderate patients HLA-B*15:01 was associated with higher frequencies of activating B-telomeric KIR3DS1 compared to patients with other HLA-B*15 subtypes and non-infected controls (90.9%, 42.9% and 47.3%, p<0.002, Pc=0.022). This strongly suggests that HLA-B*15:01 specifically presenting SARS-CoV-2 peptides could form a neo-ligand interacting with KIR3DS1. Similarly, a putative neo-ligand for KIR2DS4 could arise from other HLA-I molecules presenting SARS-CoV-2 peptides expressed on infected/activated lung antigen presenting cells. Conclusions: Our results support a crucial role of NKcs in the clinical variability of COVID-19 with specific KIR/Ligand interactions associated to disease severity.
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Addition of a macrolide to a b-Lactam–Based empirical antibiotic regimen Is associated with lower in-hospital mortality for patients with bacteremic pneumococcal pneumonia
(Oxford University Press, 2003-01-31) Martínez, José A.; Horcajada, Juan P.; Almela, Manuel; Marco, Francesc; Soriano, Alex; García-Vázquez, Elisa; Marco, Maria Ángeles; Torres, Antoni; Mensa, Josep; Medicina
To assess the association between inclusion of a macrolide in a b-lactam–based empirical antibiotic regimen and mortality among patients with bacteremic pneumococcal pneumonia, 10 years of data from a database were analyzed. The total available set of putative prognostic factors was subjected to stepwise logistic regression, with in-hospital death as the dependent variable. Of the 409 patients analyzed, 238 (58%) received a b-lactam plus a macrolide and 171 (42%) received a b-lactam without a macrolide. Multivariate analysis revealed 4 variables to be independently associated with death: shock ( ), age of 65 years ( ), infectionsP ! .0001 P .02 with pathogens that have resistance to both penicillin and erythromycin ( ), and no inclusion of aP p .04 macrolide in the initial antibiotic regimen ( ). For patients with bacteremic pneumococcal pneumonia,P p .03 not adding a macrolide to a b-lactam–based initial antibiotic regimen is an independent predictor of inhospital mortality. However, only a randomized study can definitively determine whether this association is due to a real effect of macrolides.
Open Access
Adjuvant trastuzumab in HER2-Positive breast cancer
(Massachusetts Medical Society, 2011-10-06) Slamon, Dennis; Eiermann, Wolfgang; Robert, Nicholas; Pienkowski, Tadeusz; Martin, Miguel; Press, Michael; Mackey, John; Glaspy, John; Chan, Arlene; Pawlicki, Marek; Pinter, Tamas; Valero, Vicente; Liu, Mei-Ching; Sauter, Guido; Minckwitz, Gunter von; Visco, Frances; Bee, Valerie; Buyse, Marc; Bendahmane, Belguendouz; Tabah-Fisch, Isabelle; Lindsay, Mary-Ann; Riva, Alessandro; Crown, John; Breast Cancer International Research Group; Medicina
Background: Trastuzumab improves survival in the adjuvant treatment of HER-positive breast cancer, although combined therapy with anthracycline-based regimens has been associated with cardiac toxicity. We wanted to evaluate the efficacy and safety of a new nonanthracycline regimen with trastuzumab. Methods: We randomly assigned 3222 women with HER2-positive early-stage breast cancer to receive doxorubicin and cyclophosphamide followed by docetaxel every 3 weeks (AC-T), the same regimen plus 52 weeks of trastuzumab (AC-T plus trastuzumab), or docetaxel and carboplatin plus 52 weeks of trastuzumab (TCH). The primary study end point was disease-free survival. Secondary end points were overall survival and safety. Results: At a median follow-up of 65 months, 656 events triggered this protocol-specified analysis. The estimated disease-free survival rates at 5 years were 75% among patients receiving AC-T, 84% among those receiving AC-T plus trastuzumab, and 81% among those receiving TCH. Estimated rates of overall survival were 87%, 92%, and 91%, respectively. No significant differences in efficacy (disease-free or overall survival) were found between the two trastuzumab regimens, whereas both were superior to AC-T. The rates of congestive heart failure and cardiac dysfunction were significantly higher in the group receiving AC-T plus trastuzumab than in the TCH group (P<0.001). Eight cases of acute leukemia were reported: seven in the groups receiving the anthracycline-based regimens and one in the TCH group subsequent to receiving an anthracycline outside the study. Conclusions: The addition of 1 year of adjuvant trastuzumab significantly improved disease-free and overall survival among women with HER2-positive breast cancer. The risk–benefit ratio favored the nonanthracycline TCH regimen over AC-T plus trastuzumab, given its similar efficacy, fewer acute toxic effects, and lower risks of cardiotoxicity and leukemia.
Open Access
AEOL-Induced NRF2 Activation and DWORF Overexpression Mitigate Myocardial I/R Injury
(2024-05-15) Lax Pérez, Antonio Manuel; Asensio López, María del Carmen; Ruiz Ballester, Miriam; Pascual Oliver, Silvia; Fernández del Palacio, María Josefa; Sassi, Yassine; Fuster, Jose Javier; Pascual Figal, Domingo; Soler Pardo, Fernando; Medicina
The causal relationship between the activation of NRF2 and the preservation of SERCA2a function in mitigating myocardial ischemia-reperfusion (mI/R) injury, along with the associated regulatory mechanisms, remains incompletely understood. The aim of this study was to characterize this relationship by testing the pharmacological repositioning of AEOL-10150 (AEOL) as a novel NRF2 activator. C57BL6/J, Nrf2 knockout (Nrf2−/−), and wild-type (Nrf2+/+) mice, as well as human induced pluripotent stem cell-derived cardiomyocytes (hiPSCMs) were subjected to I/R injury. Gain/loss of function techniques, RT-qPCR, western blotting, LC/MS/MS, and fluorescence spectroscopy were utilized. Cardiac dimensions and function were assessed by echocardiography. In the early stages of mI/R injury, AEOL administration reduced mitochondrial ROS production, decreased myocardial infarct size, and improved cardiac function. These effects were due to NRF2 activation, leading to the overexpression of the micro-peptide DWORF, consequently enhancing SERCA2a activity. The cardioprotective effect induced by AEOL was diminished in Nrf2−/− mice and in Nrf2/Dworf knockdown models in hiPSCMs subjected to simulated I/R injury. Our data show that AEOL-induced NRF2-mediated upregulation of DWORF disrupts the phospholamban-SERCA2a interaction, leading to enhanced SERCA2a activation and improved cardiac function. Taken together, our study reveals that AEOL-induced NRF2-mediated overexpression of DWORF enhances myocardial function through the activation of the SERCA2a offering promising therapeutic avenues for mI/R injury.
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Age‑dependent association of clonal hematopoiesis with COVID‑19 mortality in patients over 60 years
(Springer, 2022-10-03) Del Pozo‑Valero, Marta; Corton, Marta; López‑Rodríguez, Rosario; Mahillo‑Fernández, Ignacio; Ruiz‑Hornillos, Javier; Minguez, Pablo; Villaverde, Cristina; Pérez‑Tomás, María Elena; Barreda‑Sánchez, María; Mancebo, Esther; STOP_Coronavirus Study Group; Paz‑Artal, Estela; Guillén‑Navarro, Encarna; Almoguera, Berta; Ayuso, Carmen; García-Vázquez, Elisa; Medicina
Clonal hematopoiesis, especially that of indeterminate potential (CHIP), has been associated with age-related diseases, such as those contributing to a more severe COVID-19. Four studies have attempted to associate CHIP with COVID-19 severity without conclusive findings. In the present work, we explore the association between CHIP and COVID-19 mortality. Genomic DNA extracted from peripheral blood of COVID-19 patients (n = 241 deceased, n = 239 survivors) was sequenced with the Myeloid Solutions™ panel of SOPHiA Genetics. The association between clonality and age and clonality and mortality was studied using logistic regression models adjusted for sex, ethnicity, and comorbidities. The association with mortality was performed with patients stratified into four groups of age according to the quartiles of the distribution: 60–74 years, 75–84 years, 85–91 years, and 92–101 years. Clonality was found in 38% of the cohort. The presence of CHIP variants, but not the number, significantly increased with age in the entire cohort of COVID-19 patients, as well as in the group of survivors (p < 0.001). When patients were stratified by age and the analysis adjusted, CHIP classified as pathogenic/likely pathogenic was significantly more represented in deceased patients compared with survivors in the group of 75–84 years (34.6% vs 13.7%, p = 0.020). We confirmed the well-established linear relationship between age and clonality in the cohort of COVID-19 patients and found a significant association between pathogenic/likely pathogenic CHIP and mortality in patients from 75 to 84 years that needs to be further validated.
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Alpelisib for PIK3CA-mutated, hormone receptor–positive advanced breast cancer
(Massachusetts Medical Society, 2019-05-15) André, Fabrice; Ciruelos, Eva; Rubovszky, Gabor; Campone, Mario; Loibl, Sibylle; Rugo, Hope S.; Iwata, Hiroji; Conte, Pierfranco; Mayer, Ingrid A.; Kaufman, Bella; Yamashita, Toshinari; Lu, Yen-Shen; Inoue, Kenichi; Takahashi, Masato; Pápai, Zsuzsanna; Longin, Anne-Sophie; Mills, David; Wilke, Celine; Hirawat, Samit; Juric, Dejan; Alonso Romero, José Luis; Medicina
Background: PIK3CA mutations occur in approximately 40% of patients with hormone receptor (HR)–positive, human epidermal growth factor receptor 2 (HER2)–negative breast cancer. The PI3Kα-specific inhibitor alpelisib has shown antitumor activity in early studies. Methods: In a randomized, phase 3 trial, we compared alpelisib (at a dose of 300 mg per day) plus fulvestrant (at a dose of 500 mg every 28 days and once on day 15) with placebo plus fulvestrant in patients with HR-positive, HER2-negative advanced breast cancer who had received endocrine therapy previously. Patients were enrolled into two cohorts on the basis of tumor-tissue PIK3CA mutation status. The primary end point was progression-free survival, as assessed by the investigator, in the cohort with PIK3CA-mutated cancer; progression-free survival was also analyzed in the cohort without PIK3CA-mutated cancer. Secondary end points included overall response and safety. Results: A total of 572 patients underwent randomization, including 341 patients with confirmed tumor-tissue PIK3CA mutations. In the cohort of patients with PIK3CA-mutated cancer, progression-free survival at a median follow-up of 20 months was 11.0 months (95% confidence interval [CI], 7.5 to 14.5) in the alpelisib–fulvestrant group, as compared with 5.7 months (95% CI, 3.7 to 7.4) in the placebo–fulvestrant group (hazard ratio for progression or death, 0.65; 95% CI, 0.50 to 0.85; P<0.001); in the cohort without PIK3CA-mutated cancer, the hazard ratio was 0.85 (95% CI, 0.58 to 1.25; posterior probability of hazard ratio <1.00, 79.4%). Overall response among all the patients in the cohort with PIK3CA-mutated cancer was greater with alpelisib–fulvestrant than with placebo–fulvestrant (26.6% vs. 12.8%); among patients with measurable disease in this cohort, the percentages were 35.7% and 16.2%, respectively. In the overall population, the most frequent adverse events of grade 3 or 4 were hyperglycemia (36.6% in the alpelisib–fulvestrant group vs. 0.7% in the placebo–fulvestrant group) and rash (9.9% vs. 0.3%). Diarrhea of grade 3 occurred in 6.7% of patients in the alpelisib–fulvestrant group, as compared with 0.3% of those in the placebo–fulvestrant group; no diarrhea of grade 4 was reported. The percentages of patients who discontinued alpelisib and placebo owing to adverse events were 25.0% and 4.2%, respectively. Conclusions: Treatment with alpelisib–fulvestrant prolonged progression-free survival among patients with PIK3CA-mutated, HR-positive, HER2-negative advanced breast cancer who had received endocrine therapy previously. (Funded by Novartis Pharmaceuticals; SOLAR-1 ClinicalTrials.gov number, NCT02437318.)
Open Access
Amelioration of the severity of heparin-binding antithrombin mutations by posttranslational mosaicism
(American Society of Hematology, 2012-04-12) Martínez-Martínez, Irene; Navarro-Fernández, José; Ostergaad, Alice; Gutierrez-Gallego, Ricardo; Padilla, José; Miñano, Antonia; Pascual, Cristina; Martínez, Constantino; Morena-Barrio, María Eugenia de la; Pedersen, Shona; Kristensen, Soren Risom; Corral, Javier; Bohdan, Nataliya; Morena Barrio, María Eugenia de la; Águila Martínez, Sonia; Vicente García, Vicente; Corral de la Calle, Javier; Medicina
The balance between actions of procoagulant and anticoagulant factors protects organisms from bleeding and thrombosis. Thus, antithrombin deficiency increases the risk of thrombosis, and complete quantitative deficiency results in intrauterine lethality. However, patients homozygous for L99F or R47C antithrombin mutations are viable. These mutations do not modify the folding or secretion of the protein, but abolish the glycosaminoglycan-induced activation of antithrombin by affecting the heparin-binding domain. We speculated that the natural β-glycoform of antithrombin might compensate for the effect of heparin-binding mutations. We purified α- and β-antithrombin glycoforms from plasma of 2 homozygous L99F patients. Heparin affinity chromatography and intrinsic fluorescence kinetic analyses demonstrated that the reduced heparin affinity of the α-L99F glycoform (K(D), 107.9 ± 3nM) was restored in the β-L99F glycoform (K(D), 53.9 ± 5nM) to values close to the activity of α-wild type (K(D), 43.9 ± 0.4nM). Accordingly, the β-L99F glycoform was fully activated by heparin. Similar results were observed for recombinant R47C and P41L, other heparin-binding antithrombin mutants. In conclusion, we identified a new type of mosaicism associated with mutations causing heparin-binding defects in antithrombin. The presence of a fully functional β-glycoform together with the activity retained by these variants helps to explain the viability of homozygous and the milder thrombotic risk of heterozygous patients with these specific antithrombin
Open Access
Anabolic status and functional impairment in men with mild chronic heart failure
(2011-09) Pastor Perez, Francisco J.; Manzano Fernandez, Sergio; Garrido Bravo, Iris P.; Nicolás, Francisco; Tornel, Pedro L.; Lax Pérez, Antonio Manuel; de la Morena, Gonzalo; Valdés, Mariano; Pascual-Figal, Domingo A.; Medicina
The purpose of this study was to establish the role of hormonal anabolic deficiencies in exercise intolerance in patients with chronic heart failure One hundred four consecutive men (mean age 53.1 ± 10.6 years) with established diagnoses of chronic heart failure were included. At enrollment, blood samples were taken, and echocardiography and cardiopulmonary exercise testing were carried out. Exercise capacity was expressed as peak oxygen consumption (Vo₂), predicted peak Vo₂, and the ventilatory response to exercise (VE/Vco₂) slope. The mean left ventricular ejection fraction was 29.7 ± 11.9%, and most patients (86%) were in New York Heart Association class I or II, with a mean peak Vo₂ of 18 ml/min/kg. According to the age-adjusted reference values, hormonal deficiencies were present in 29% for total testosterone, 39% for estimated free testosterone, 34% for insulin-like growth factor-1, and 61% for dehydroepiandrosterone sulfate. Dehydroepiandrosterone sulfate showed a significant correlation with peak Vo₂ (r = 0.29, p = 0.007), predicted peak Vo₂ (r = 0.28, p = 0.006), and VE/Vco₂ slope (r = -0.39, p <0.001), whereas total testosterone, estimated free testosterone, and insulin-like growth factor-1 were not significantly correlated. After adjusting in a multivariable model, dehydroepiandrosterone sulfate remained an independent predictor of each exercise parameter. In conclusion, in a cohort of patients with mild chronic heart failure, exercise capacity objectively measured using cardiopulmonary exercise testing was related to anabolic impairment of the adrenal rather than the somatotropic or peripheral axis.
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Analysis of adolescent oncology cases from 2008 through 2018 in a tertiary-level hospital: an opportunity for improvement
(Taylor and Francis Group, 2021-02-25) Sánchez Martínez, Domingo A.; Cañadilla-Ferreira, Marta; Sánchez Henarejos, Pilar; Alonso-Romero, José Luis; Medicina
Purpose: The purpose of this study was to disclose the variability of pathways currently taken in the treatment of adolescent patients from diagnosis to final follow-up with a view to developing a more homogenous system. Patients & methods: A cross-sectional, observational and retrospective study of the cancer diagnosis and assignment to medical care teams in adolescent patients (12–20 years) from January 2008 to December 2018 was conducted. A total of 345 adolescent patients aged between 12 and 20 years, diagnosed with cancer and treated at Hospital Clinico Universitario Virgen de la Arrixaca were included. Results: CNS tumors, followed by leukemia were the most frequent tumors. At the time of diagnosis, the highest incidences of patients were assisted in the pediatrics service adult oncology service (21.7%) and hematology (11%). Conclusion: Our aim is to highlight the need for a better transition for patients from pediatric to adult oncology and hematology services.
Open Access
Anticipating the side effects of benznidazole: HLA-B*35 and patch test
(Elsevier, 2024-04-14) Vázquez, Cristina; García-Vázquez, Elisa; Carrilero, Bartolomé; Muro, Manuel; Sánchez-Guerrero, Inmaculada; González López, Rosana; Franco, Fuensanta; Segovia, Manuel; Medicina
ABSTRACT: Introduction: Treatment of Chagas disease frequently causes distress to patients due to a high incidence of adverse effects. Different preemptive tests have been researched to prevent these effects and to allow focus to be given to certain predisposed patients. Benznidazole is the most prescribed Chagas disease treatment in Spain. In this work, we analyzed the genetic markers HLA-B*35 allele group and HLA-B*35:05 allele specifically, as well as an allergy patch test, as benznidazole’s most frequent adverse effects are cutaneous. Methods: HLA-B intermediate-resolution genotyping was performed followed by a high-resolution level analysis. Cutaneous allergies were tested using strips impregnated with a mixture of benznidazole and placed on the upper back of patients before starting treatment. Results: In our sample of more than 400 patients, there was almost no relationship between any kind of side effect and either of the HLA-B alleles studied. The patch testing was quickly discarded as a preemptive test due to its low sensitivity (16.7%). Conclusion: In conclusion, we were unable to replicate and corroborate genetic markers identified by other groups and there is currently no test that can anticipate the adverse effects of benznidazole, therefore, more investigation should be carried out in this field.
Embargo
Antithrombin p.Thr147Ala: The First Founder Mutation in People of African Origin Responsible for Inherited Antithrombin Deficiency
(Thieme Gruppe, 2021) Orlando, Christelle; Morena-Barrio, Belén de la; Pareyn, Inge; Vanhoorelbeke, Karen; Martínez-Martínez, Irene; Vicente, Vicente; Corral, Javier; Jochmans, Kristin; Morena-Barrio, María Eugenia de la; Medicina
Background: Hereditary antithrombin deficiency is a rare autosomal-dominant disorder predisposing to recurrent venous thromboembolism (VTE). To date, only two founder mutations have been described. Objectives: We investigated the antithrombin p.Thr147Ala variant, found in 12 patients of African origin. This variant is known as rs2227606 with minor allele frequency of 0.5% in Africans and absent in Europeans. A possible founder effect was investigated. Methods: Phenotypical characterization was established through immunological and functional methods, both under basal and stress conditions. Recombinant antithrombin molecules were constructed by site-directed mutagenesis and expressed in HEK-293T cells. Secreted antithrombin was purified and functionally characterized. Structural modeling was performed to predict the impact of the mutation on protein structure. A novel nanopore sequencing approach was used for haplotype investigation. Results: Ten patients experienced VTE, stroke, or obstetric complications. Antithrombin antigen levels and anti-IIa activity were normal or slightly reduced while anti-Xa activity was reduced with only one commercial assay. On crossed immunoelectrophoresis, an increase of antithrombin fractions with reduced heparin affinity was observed under high ionic strength conditions but not under physiological conditions. The recombinant p.Thr147Ala protein displayed a reduced anti-Xa activity. Structural modeling revealed that residue Thr147 forms three hydrogen bonds that are abolished when mutated to alanine. The investigated patients shared a common haplotype involving 13 SERPINC1 intragenic single nucleotide polymorphisms. Conclusion: Antithrombin p.Thr147Ala, responsible for antithrombin type II heparin binding site deficiency, is the first founder mutation reported in people of African ancestry. This study further emphasizes the limitations of commercial methods to diagnose this specific subtype.
Open Access
Archeogenetics of F11 p.Cys38Arg: a 5400-year-old mutation identified in different southwestern European countries
(American Society of Hematology, 2019) Morena-Barrio, María Eugenia de la; Salloum-Asfar, Salam; Esteban, Julio; Morena-Barrio, Belén de la; Altisent, Carmen; Martín-Fernández, Laura; Gueguen, Paul; Padilla, José; Miñano, Antonia; Parra, Rafael; Vicente, Vicente; Vidal, Francisco; Bauduer, Frederic; Carbonell, Pablo; Corral, Javier; Medicina
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Assessment of a commercial rapid urinary antigen test to detect Streptococcus pneumoniae in patients who received 23-valent pneumococcal polysaccharide vaccine
(Springer, 2004-11-17) García Vázquez, E.; Marcos, M. A.; Vilella, A.; Yagüe, J; Bayas, J. M.; Mensa, J.; Medicina
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Assessment of the usefulness of sputum culture for diagnosis of community-acquired pneumonia using the PORT predictive scoring system
(American Medical Association, 2004) García-Vázquez, Elisa; Marcos, María Angeles; Mensa, José; Roux, Andrés de; Puig, Jordi; Font, Carmen; Francisco, Gloria; Torres, Antonio; Medicina
Background: The usefulness of sputum culture in guiding microbiological diagnosis of community-acquired pneumonia is controversial. We evaluate and assess it using the Patients Outcome Research Team (PORT) predictive scoring system. Methods: A cohort of 1669 patients with community-acquired pneumonia was studied. Before administering antibiotic therapy, sputum was collected and its quality evaluated. Samples were gram stained and those of good quality were assessed for a predominant morphotype (PM). Sputum cultures were processed according to standard protocols. Results: A sputum sample was obtained from 983 (59%) of the 1669 patients and 532 (54%) of the samples were of good quality. There was a PM in 240 (45%) of the latter samples (ie, for 14.4% of the 1669 patients) and there was no PM in 292 (55%). Culture yielded a microorganism in 207 (86%) of the 240 samples with PM and 57 (19.5%) of the 292 samples without PM (P .05). Rates of sputum obtained, good-quality sputum specimens, PM identification, and positive culture were not significantly different among the PORT-score groups of patients (P>.05). The sensitivity and specificity of the gram-positive diplococci identification in the sputum culture of Streptococcus pneumoniae were 60% and 97.6%, and the positive and negative predictive values were 91% and 85.3%, respectively. Conclusions: Good-quality sputum with PM could be obtained in only 14.4% of all patients. A PORT-score group in which sputum could be of greater usefulness in identifying the causative organism could not be iden- tified. The presence of gram-positive diplococci in gramstained sputum culture was highly specific for S pneumoniae
Open Access
Association of body mass index with clinical outcomes in patients with atrial fibrillation: a report from the FANTASIIA registry
Bertomeu-Gonzalez, Vicente; Moreno-Arribas, José; Esteve-Pastor, María Asunción; Roldan-Rabadán, Inmaculada; Muñiz, Javier; Raña-Miguez, Paula; Ruiz-Ortiz, Martín; Cequier, Ángel; Bertomeu-Martinez, Vicente; Badimón, Lina; Anguita, Manuel; Lip, Gregory Y.H.; Marin Ortuño, Francisco; Medicina
Background-—Obesity and atrial fibrillation (AF) frequently coexist and independently increase mortality. We sought to assess the association between obesity and adverse events in patients receiving oral anticoagulants for AF. Methods and Results-—Consecutive AF outpatients receiving anticoagulant agents (both vitamin K antagonists and direct oral anticoagulants) were recruited into the FANTASIIA (Atrial fibrillation: influence of the level and type of anticoagulation on the incidence of ischemic and hemorrhagic stroke) registry. This observational, multicenter, and prospective registry of AF patients analyzes the quality of anticoagulation, incidence of events, and differences between oral anticoagulant therapies. We analyzed baseline patient characteristics according to body mass index, normal: <25 kg/m2, overweight: 25–30 kg/m2, and obese: ≥30 kg/m2), assessing allcause mortality, stroke, major bleeding and major adverse cardiovascular events (a composite of ischemic stroke, myocardial infarction, and total mortality) at 3 years’ follow-up. In this secondary prespecified substudy, the association of weight on prognosis was evaluated. We recruited 1956 patients (56% men, mean age 73.8 9.4 years): 358 (18.3%) had normal body mass index, 871(44.5%) were overweight, and 727 (37.2%) were obese. Obese patients were younger (P<0.01) and had more comorbidities. Mean time in the therapeutic range was similar across body mass index categories (P=0.42). After a median follow-up of 1070 days, 255 patients died (13%), 45 had a stroke (2.3%), 146 a major bleeding episode (7.5%) and 168 a major adverse ardiovascular event (8.6%). Event rates were similar between groups for total mortality (P=0.29), stroke (P=0.90), major bleeding (P=0.31), and major adverse cardiovascular events (P=0.24). On multivariate Cox analysis, body mass index was not independently associated with all-cause mortality, cardiovascular mortality, stroke, major bleeding, or major adverse cardiovascular events. Conclusions-—In this prospective cohort of patients anticoagulated for AF, obesity was highly prevalent and was associated with more comorbidities, but not with poor prognosis.
Open Access
Atrial fibrillation management in older heart failure patients: a complex clinical problem
(Wichtig Publishing, 2016-09-22) Pulignano, Giovanni; Del Sindaco, Donatella; Tinti, Maria Denitza; Tolone, Stefano; Minardi, Giovanni; Lax Pérez, Antonio Manuel; Uguccioni, Massimo; Medicina
Background: Atrial fibrillation (AF) and heart failure (HF), two problems of growing prevalence as a consequence of the ageing population, are associated with high morbidity, mortality, and healthcare costs. AF and HF also share common risk factors and pathophysiologic processes such as hypertension, diabetes mellitus, ischemic heart disease, and valvular heart disease often occur together. Although elderly patients with both HF and AF are affected by worse symptoms and poorer prognosis, there is a paucity of data on appropriate management of these patients. Methods: PubMed was searched for studies on AF and older patients using the terms atrial fibrillation, elderly, heart failure, cognitive impairment, frailty, stroke, and anticoagulants.Results: The clinical picture of HF patients with AF is complex and heterogeneous with a higher prevalence of frailty, cognitive impairment, and disability. Because of the association of mental and physical impairment to non-administration of oral anticoagulants (OACs), screening for these simple variables in clinical practice may allow better strategies for intervention in this high-risk population. Since novel direct OACs (NOACs) have a more favorable risk-benefit profile, they may be preferable to vitamin K antagonists (VKAs) in many frail elderly patients, especially those at higher risk of falls. Moreover, NOACs are simple to administer and monitor and may be associated with better adherence and safety in patients with cognitive deficits and mobility impairments. Conclusions: Large multicenter longitudinal studies are needed to examine the effects of VKAs and NOACs on long-term cognitive function and frailty; future studies should include geriatric conditions.