David Navarro

University of Valencia, Valenza, Valencia, Spain

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Publications (101)305.66 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: The functional profile of cytomegalovirus (CMV)-specific CD8(+) T cells that associate with protection from and control of CMV DNAemia in allogeneic stem cell transplant (allo-SCT) recipients remains incompletely characterized. We enumerated pp65 and immediate early (IE)-1-specific CD8(+) T cells expressing interferon-gamma, tumor necrosis factor-alpha, and CD107a, by flow cytometry in 94 patients at days +30 and +60 after allo-SCT. Fifty out of 94 patients had CMV DNAemia within the first 100 days after transplant. CMV-specific CD8(+) T-cell responses (of any functional type) were more likely to be detected in patients who did not display CMV DNAemia than in those who did (P = 0.04). Qualitatively, no major differences in the functional signature of CMV-specific CD8(+) T cells were noted between patients who had or did not have CMV DNAemia. Patients displaying levels of polyfunctional CD8(+) T cells at day +30 >0.30 cell/μL had a lower risk of CMV DNAemia (positive predictive value 76%, and negative predictive value 43%). The presence of polyfunctional CD8(+) T cells (either expressing CD107a or not) was associated with lower levels of CMV replication, and higher frequency of self-resolved episodes. The data reported further clarify the role of polyfunctional CD8(+) T cells in control of CMV DNAemia in allo-SCT recipients. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Transplant Infectious Disease 04/2015; DOI:10.1111/tid.12391 · 1.98 Impact Factor
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    ABSTRACT: The role of Natural killer (NK) cells in the control of cytomegalovirus (CMV) infection in allogeneic stem cell transplant recipients has not been precisely characterized. The current study is aimed at investigating the potential role of NK cells expressing the activating receptor NKG2C in affording protection against the development of CMV DNAemia in patients exhibiting detectable CMV-specific CD8(+) T-cell responses early following transplantation. A total of 61 nonconsecutive patients were included in the study. Peripheral levels of CD56(bright) CD16(-/low) and CD56(dim) CD16(+) NKG2C(+) NK cells and CMV pp65/IE-1-specific IFN-γ-producing CD8(+) T-cells were enumerated by flow cytometry at days +30 and +60 after transplant. Neither the absolute number of NKG2C(+) NK cells, nor that of CD56(bright) CD16(-/low) and CD56(dim) CD16(+) NKG2C(+) NK-cell subsets at day 30 differed significantly between patients with or without subsequent CMV DNAemia. No significant correlation was found between levels of both NKG2C(+) NK-cell populations and the peak CMV DNA load within subsequent episodes of CMV DNAemia. The data indicate that enumeration of NKG2C(+) NK cells early after transplant is unlikely to be helpful in identifying those patients at highest risk of developing CMV DNAemia. Moreover, the data do not support a direct implication of NKG2C(+) NK cells in preventing the development of CMV DNAemia. J. Med. Virol. 2015. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    Journal of Medical Virology 03/2015; DOI:10.1002/jmv.24198 · 2.22 Impact Factor
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    ABSTRACT: In this study, we assessed the association between single-nucleotide polymorphisms (SNPs) in seven candidate genes involved in orchestrating the immune response against cytomegalovirus (CMV) and the 12-month incidence of CMV infection in 315 CMV-seropositive kidney transplant (KT) recipients. Patients were managed either by antiviral prophylaxis or preemptive therapy. CMV infection occurred in 140 patients (44.4%), including 13 episodes of disease. After adjusting for various clinical covariates, patients harboring T-allele genotypes of interleukin-28B (IL28B) (rs12979860) SNP had lower incidence of CMV infection (adjusted hazard ratio [aHR]: 0.66; 95% confidence interval [CI]: 0.46-0.96; p-value = 0.029). In the analysis restricted to patients not receiving prophylaxis, carriers of the TT genotype of toll-like receptor 9 (TLR9) (rs5743836) SNP had lower incidence of infection (aHR: 0.61; 95% CI: 0.38-0.96; p-value = 0.035), whereas the GG genotype of dendritic cell-specific ICAM 3-grabbing nonintegrin (DC-SIGN) (rs735240) SNP exerted the opposite effect (aHR: 1.86; 95% CI: 1.18-2.94; p-value = 0.008). An independent association was found between the number of unfavorable SNP genotypes carried by the patient and the incidence of CMV infection. In conclusion, specific SNPs in IL28B, TLR9 and DC-SIGN genes may play a role in modulating the susceptibility to CMV infection in CMV-seropositive KT recipients. © Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.
    American Journal of Transplantation 03/2015; DOI:10.1111/ajt.13107 · 6.19 Impact Factor
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    ABSTRACT: The performance of the CLART® PneumoVir system with that of the Luminex xTAG RVP Fast v1 assay for detection of most common respiratory viruses in upper and lower tract respiratory specimens (n=183) from unique patients with influenza-like syndrome or lower tract respiratory infection. Nested PCR coupled to automated sequencing was used for resolution of discrepancies. Fully concordant results were obtained for a total of 122 specimens, whereas 56 specimens gave partially (n=21) or fully discordant (n=35) results (Kappa coefficient, 0.62). The overall specificity of the Luminex xTAG RVP Fast v1 assay was slightly higher than that of the CLART® PneumoVir assay for human bocavirus, influenza A virus/H3N2, influenza B virus, human metapneumovirus, and parainfluenza virus, whereas the sensitivity of the latter was higher for most targeted viruses except, notably, for picornaviruses. This was irrespective of either the origin of the respiratory specimen or the age group to which the patients belonged. Copyright © 2015 Elsevier Inc. All rights reserved.
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    ABSTRACT: Single nucleotide polymorphisms (SNPs) in genes involved in the activation or regulation of innate and adaptive immune responses may modulate the susceptibility to and the natural history of certain chronic viral infections. The current study aimed to investigate whether donor and recipient SNPs in the chemokine receptor 5 (rs1800023), monocyte chemoattractant protein 1 (rs13900), interleukin-10 (rs1878672), and Toll-like receptor 9 (rs352140) genes would exert any influence on the rate of incidence and features of CMV DNAemia in the allogeneic stem cell transplantation setting. This was a retrospective observational multicenter study. The cohort consisted of 102 non-consecutive allogeneic stem cell transplant recipients. SNP genotyping was performed by allele-specific real-time PCR. CMV surveillance was performed by the pp65 antigenemia assay/and or by real-time PCR. Seventy-three patients developed CMV DNAemia within the first 100 days after transplantation (71.5%). Neither donor nor recipient SNPs were associated significantly with the rate of incidence of active CMV infection, nor with the need for pre-emptive antiviral therapy. Both the duration of CMV DNAemia and the plasma CMV DNA peak load during episodes were significantly higher in patients harboring the donor (but not the recipient) chemokine receptor 5 A/A genotype, than in their A/G and G/G counterparts (P = 0.022 and P = 0.045, respectively). The data reported suggest that SNPs in chemokine receptor 5 may influence the dynamics of CMV infection in the Allo-SCT setting. J. Med. Virol. 9999: XX–XX, 2014. © 2014 Wiley Periodicals, Inc.
    Journal of Medical Virology 02/2015; 87(2). DOI:10.1002/jmv.24050 · 2.22 Impact Factor
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    Future Virology 02/2015; 10(2):113-134. DOI:10.2217/fvl.14.102 · 1.00 Impact Factor
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    ABSTRACT: Microbiological documentation of peritoneal candidiasis (PC) is hampered by the low numbers of yeasts observable by direct microscopic examination and recoverable by culture methods. The performance of a polymerase chain reaction (PCR) DNA Low-Density Microarray System (CLART STIs B) was compared to that of BACTEC FX automated culture method for the detection of Candida spp. in 161 peritoneal fluids (PF) from patients with peritonitis. The clinical utility of (1-3)-β-d-glucan (BDG) antigenemia in the diagnosis of PC was evaluated in 42 of these patients. The overall agreement between the PCR assay and the culture method was good (κ = 0.790), and their sensitivities were 93.5% and 74.19%, respectively. Serum BDG levels in patients with Candida spp. in PFs (median, 200.3 pg/mL; Range, 22.0-523.4 pg/mL) was significantly higher (P = 0.002) than those found in patients without the yeast (median, 25.3 pg/mL; Range, 0-523.4 pg/mL). Our study demonstrates the potential clinical utility of molecular methods and the measurement of serum BDG levels for the diagnosis of PC. © The Author 2014. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
    Medical Mycology 12/2014; DOI:10.1093/mmy/myu075 · 2.26 Impact Factor
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    ABSTRACT: It is uncertain whether monitoring of plasma Ganciclovir (GCV) levels is useful in predicting CMV DNAemia clearance in preemptively treated allogeneic stem cell transplant recipients. In this observational study, including 13 episodes of CMV DNAemia treated with i.v. GCV or oral valganciclovir, we showed that monitoring of trough plasma GCV levels does not reliably predict response to therapy. Rather, immunological monitoring (pp65 and IE-1-specific IFN-γ-producing CD8(+) T cells) appeared to perform better for this purpose.
    Antimicrobial Agents and Chemotherapy 06/2014; 58(9). DOI:10.1128/AAC.02953-14 · 4.45 Impact Factor
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    ABSTRACT: The identification of non-immunosuppressed critically ill patients most at risk for developing cytomegalovirus (CMV) reactivation is potentially of great clinical relevance. The current study was aimed at determining (i) whether single nucleotide polymorphisms in the genes coding for chemokine receptor 5 (CCR5), interleukin-10 IL-10), and monocyte chemoattractant protein-1 (MCP-1) have an impact on the incidence rate of active CMV infection, (ii) whether serum levels of CMV-specific IgGs are associated with the risk of CMV reactivation, and (iii) whether detection of CMV DNA in saliva precedes that in the lower respiratory tract or the blood compartment. A total of 36 out of 78 patients (46%) developed an episode of active CMV infection. The incidence rate of active CMV infection was not significantly associated with any single nucleotide polymorphisms. A trend towards a lower incidence of active CMV infection (P = 0.06) was noted in patients harboring the IL10 C/C genotype. Patients carrying the CCR5 A/A genotype had high CMV DNA loads in tracheal aspirates. The serum levels of CMV IgGs did not differ significantly between patients with a subsequent episode of active CMV infection (median, 217 IU/mL) or without one (median, 494 IU/mL). Detection of CMV DNA in saliva did not usually precede that in plasma and/or tracheal aspirates. In summary, the analysis of single nucleotide polymorphisms in the IL10 and CCR5 genes might help to determine the risk of active CMV infection or the level of CMV replication within episodes, respectively, in non-immunosuppressed critically ill patients. J. Med. Virol. © 2013 Wiley Periodicals, Inc.
    Journal of Medical Virology 05/2014; 86(5). DOI:10.1002/jmv.23838 · 2.22 Impact Factor
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    ABSTRACT: The role of natural killer (NK) cells in affording protection against human cytomegalovirus (CMV) in allogeneic stem cell transplant recipients is largely unknown. The current study was aimed at determining whether NKG2C(+) NK cells confer protection from CMV DNAemia early following transplantation in patients lacking mono and polyfunctional CMV pp65 and IE-1-specific CD4(+) and CD8(+) T-cell responses, as measured by flow cytometry for intracellular cytokine staining. Fourteen out of the 36 patients included in this study developed CMV DNAemia between days +30 and +60 after transplant. Three patients did so after day +60. Peripheral blood levels of CD56(bright) CD16(-/low) and CD56(dim) CD16(+) NKG2C(+) NK cells measured at day +30 and at day +60 in patients who had or had not subsequent CMV DNAemia did not differ significantly. In addition, no significant correlation was found between CD56(bright) CD16(-/low) (σ = -0.229; P = 0.39) and CD56(dim) CD16(+) (σ = -0.285; P = 0.28) NKG2C(+) NK-cell levels and initial plasma CMV DNA loads. In summary, the data presented do not support a direct implication of NKG2C(+) NK cells in preventing the development of CMV DNAemia or modulating the magnitude of CMV replication at early stages during episodes of CMV DNAemia in allogeneic stem cell transplant patients with unreconstituted CMV-specific T-cell responses. J. Med. Virol. © 2013 Wiley Periodicals, Inc.
    Journal of Medical Virology 05/2014; 86(5). DOI:10.1002/jmv.23742 · 2.22 Impact Factor
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    ABSTRACT: The current study was aimed at investigating whether the single nucleotide polymorphism (SNP) (rs12979860), upstream of the IL28B gene, had any effect on the incidence rate and the features of active CMV infection in the Allogeneic stem cell transplantation setting. This was a retrospective observational study including 151 patients undergoing T cell-replete Allo-SCT. Donor and recipient IL28 SNP genotype was determined by allele-specific real-time PCR. The incidence rate of active CMV infection was not significantly associated with either the donor or the recipient IL28B SNP genotype. Nevertheless, a trend towards a lower incidence of active CMV infection was noted in the donor T/T population with respect to the donor C/T and C/C population. The duration of first episodes of CMV DNAemia was significantly shorter in patients carrying the donor T/T genotype with respect to their C/C or C/T counterparts (P = 0.038). Peak CMV DNAmeia levels tended to be lower in patients carrying the T/T genotype (donor or recipient) than in C/C or C/T patients, although statistical significance was not reached. In conclusion the data presented pointed to a protective effect of the T allele (recessive genetic model) against CMV infection in the Allo-SCT setting. J. Med. Virol. © 2013 Wiley Periodicals, Inc.
    Journal of Medical Virology 05/2014; 86(5). DOI:10.1002/jmv.23865 · 2.22 Impact Factor
  • Clinical Transplantation 04/2014; 28(4). DOI:10.1111/ctr.12332 · 1.49 Impact Factor
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    ABSTRACT: Cytomegalovirus (CMV) infection might increase the risk of fungal superinfection in allogeneic stem cell transplant patients. The potential association between the occurrence of CMV DNAemia and the development of invasive aspergillosis in this clinical setting was investigated. The current retrospective observational study included 167 patients undergoing T cell-replete allogeneic stem cell transplantation. Virological monitoring of active CMV infection was performed by the pp65 antigenemia assay and/or by a plasma real-time PCR assay. A total of 109 out of 167 patients developed CMV DNAemia. Twenty-three patients had proven (n = 4) or probable (n = 19) invasive aspergillosis. The occurrence of CMV DNAemia was not significantly associated with the subsequent development of invasive aspergillosis (P = 0.38). Overall, the duration of the episodes of active CMV infection and the peak level of CMV DNAemia within the episodes were comparable, irrespective of whether invasive aspergillosis developed subsequently or not (P = 0.99; P = 0.70, respectively). Peak CMV DNA load in patients with proven or probable invasive aspergillosis who died was higher (median, 5,461 copies/ml) than that in those who survived (median 1,179 copies/ml) (P = 0.41). The data argue against the existence of an association between the occurrence of CMV DNAemia and the development of invasive aspergillosis, however, CMV replication, particularly at high levels, might aggravate the prognosis of this disease. J. Med. Virol. © 2013 Wiley Periodicals, Inc.
    Journal of Medical Virology 04/2014; 86(4). DOI:10.1002/jmv.23735 · 2.22 Impact Factor
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    Critical Care 03/2014; 18(18):422. DOI:10.1186/cc13805 · 5.04 Impact Factor
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    ABSTRACT: Commercial immunoassays for detecting IgG and IgM antibodies against Epstein-Barr virus (EBV), viral capsid antigens (VCA), and IgGs towards EBV nuclear antigen-1 (EBNA-1) are routinely used in combination to categorize the EBV infection status. In this study we evaluated the performance of the ARCHITECT EBV VCA IgG, VCA IgM, and EBNA-1 IgG chemiluminescent microparticle assays (CMIA) in EBV serological analyses using indirect immunofluorescence assays and anti-complement immunofluorescence assays as the reference methods for VCA IgG, IgM, and EBNA antibodies detection respectively. A total of 365 sera representing different EBV-serological profiles were included in this study. The concordance between the results obtained in the ARCHITECT CMIA and those in the reference assay was κ, 0.905; P = < 0.0001 for VCA IgM; κ, 0.889; P = < 0.0001 for VCA IgG; κ, 0.961; P = < 0.0001, for EBNA-1 IgG. The sensitivities and specificities were as follows: 91.08% and 99.48%, respectively, for VCA IgM, 99.23% and 86.27% for VCA IgG, and 96.77% and 99.16%, for EBNA-1 IgG. The sensitivity and specificity of the ARCHITECT CMIA panel for diagnosing a primary infection were 99.15% and 98.6% respectively, for diagnosing a past EBV infection they were 97.62% and 93.39%, and 92.42% and 97.82% respectively for diagnosing the absence of an EBV infection. In summary, we demonstrated that the ARCHITECT EBV antibody panel performs very well for EBV antibody detection and correctly categorizes clinically relevant EBV infection states.
    Clinical and vaccine Immunology: CVI 03/2014; DOI:10.1128/CVI.00104-14 · 2.37 Impact Factor
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    ABSTRACT: Anidulafungin is indicated as a first-line treatment for invasive candidiasis in critically ill patients. In the intensive care unit, sepsis is the main cause of acute renal failure, and treatment with continuous renal replacement therapy (CRRT) has increased in recent years. Antimicrobial pharmacokinetics is affected by CRRT, but few studies have addressed the optimal dosage for anidulafungin during CRRT. We included 12 critically ill patients who received continuous venovenous haemodiafiltration to treat acute renal failure. Anidulafungin was infused on 3 consecutive days, starting with a loading dose (200 mg) on Day 1, and doses of 100 mg on Days 2 and 3. Blood and ultradiafiltrate samples were collected on Day 3 (during steady-state) before, and at regular intervals after, the infusion had started. Anidulafungin concentrations were determined with HPLC. On Day 3, peak plasma concentrations with the 100 mg dose were 6.2 ± 1.7 mg/L and 7.1 ± 1.9 mg/L in the arterial and venous samples, respectively. The mean, pre-filter trough concentration was 3.0 ± 0.6 mg/L. The mean AUC0-24 values for plasma anidulafungin were 93.9 ± 19.4 and 104.1 ± 20.3mg·h/L in the arterial and venous samples, respectively. There was no adsorption to synthetic surfaces, and the anidulafungin concentration in the ultradiafiltrate was below the limit of detection. The influence of CRRT on anidulafungin elimination appeared to be negligible. Therefore, we recommend no adjustments to the anidulafungin dose for patients receiving CRRT.
    Journal of Antimicrobial Chemotherapy 01/2014; 69(6). DOI:10.1093/jac/dkt542 · 5.44 Impact Factor
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    ABSTRACT: We report that in a population of allogeneic stem cell transplant recipients, determination of the viral doubling time (dt) of the cytomegalovirus (CMV) DNA plasma load predicted the eventual need for inception of pre-emptive antiviral therapy, whereas the level of the initial plasma CMV DNA load did not. The data thus indicated that determination of the dt of CMV DNA may be useful in the therapeutic management of CMV infection in this clinical setting.
    Journal of clinical microbiology 11/2013; 52(2). DOI:10.1128/JCM.02571-13 · 4.23 Impact Factor
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    ABSTRACT: The current study was designed to assess the predictive value of the evaluation of cytomegalovirus (CMV)-specific T-cell immunity early following admission to the intensive care unit for inferring the risk of active CMV infection in non-immunosuppressed surgical and trauma patients. A total of 31 CMV-seropositive patients were included. Patients were screened for the presence of CMV DNA in plasma and in tracheal aspirates by real-time PCR. Enumeration of CMV pp65 and IE-1-specific IFN-γ CD8(+) and CD4(+) T cells was performed by flow cytometry for intracellular cytokine staining. Virological and immunological monitoring was conducted once or twice a week. Active CMV infection occurred in 17 out of 31 patients. Undetectable levels of pp65 and IE-1-specific IFN-γ CD8(+) and CD4(+) T-cell subsets cells were observed in 10 patients who developed active CMV infection and in one who did not (at a median of 2 days following ICU admission). Peak CMV DNA loads in both tracheal aspirates and plasma were substantially higher (P = 0.018 and P = 0.091, respectively) in patients with undetectable IFN-γ T-cell responses than in patients with detectable responses. The expansion of both CMV-specific T-cell subsets following detection of active CMV infection was demonstrated in 9 out of 14 patients with active CMV infection. In conclusion, the evaluation of CMV pp65 and IE-1-specific IFN-γ-producing CD8(+) and CD4(+) T cells early following ICU admission may allow the identification of patients most at risk of either having or developing an episode of active CMV infection, particularly those associated with high-level virus replication. J Med. Virol. © 2013 Wiley Periodicals, Inc.
    Journal of Medical Virology 10/2013; 85(10). DOI:10.1002/jmv.23621 · 2.22 Impact Factor
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    ABSTRACT: Cytomegalovirus (CMV) may be a relevant cause of morbidity in patients displaying various inflammatory diseases. In this study, it was investigated whether CMV DNA is detected in the lower respiratory tract and the systemic compartment in pediatric patients with chronic or recurrent bronchopulmonary diseases. A total of 42 lower respiratory tract specimens and 11 paired plasma samples from 42 patients were analyzed for the presence of CMV DNA by real-time PCR. The respiratory specimens were also screened for the presence of respiratory viruses and human herpesvirus 6 (HHV-6) and 7 (HHV-7) by PCR methods. Quantitative bacterial and fungal cultures were performed. IL-6 levels in the respiratory specimens were quantified using ELISA. CMV DNA was detected either in the lower respiratory airways, in plasma, or both in 54.5% of CMV-seropositive patients. The levels of IL-6 were significantly higher in these patients than in those with no detectable levels of CMV DNA. HHV-6 and HHV-7 DNA were detected in three and one patients, respectively. Respiratory viruses were detected in 13 of the 42 patients. Significant growth of one or more bacterial species was observed in 17 patients. No significant association was found between the presence of CMV DNA and the detection of other microorganisms. The data indicated that the presence of CMV DNA in the lower respiratory tract is a frequent finding in children with chronic or recurrent bronchopulmonary diseases. Further, prospective observational studies are needed to assess the impact of this phenomenon, if any, on the clinical course of these patients. J. Med. Virol. © 2013 Wiley Periodicals, Inc.
    Journal of Medical Virology 05/2013; 85(5). DOI:10.1002/jmv.23499 · 2.22 Impact Factor
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    Bone marrow transplantation 01/2013; DOI:10.1038/bmt.2012.286 · 3.47 Impact Factor

Publication Stats

1k Citations
305.66 Total Impact Points

Institutions

  • 1998–2015
    • University of Valencia
      • Department of Microbiology and Ecology
      Valenza, Valencia, Spain
  • 2010–2014
    • Fundación de Investigación del Hospital Clínico Universitario de Valencia INCLIVA
      Valenza, Valencia, Spain
  • 1996–2013
    • Hospital Clínico Universitario de Valencia
      Valenza, Valencia, Spain
  • 2012
    • Polytechnical University of Valencia
      • Centre of Biomaterial and Tissue Engineering (CBIT)
      Valenza, Valencia, Spain
  • 1990–1997
    • University of California, San Francisco
      • • School of Dentistry
      • • Division of Hospital Medicine
      San Francisco, California, United States