IiSGM - Instituto de Investigación Sanitaria Gregorio Marañón (Madrid)

Permanent URI for this collectionhttps://hdl.handle.net/20.500.12105/16978

El Instituto está constituido por el Servicio Madrileño de Salud (SERMAS), a través del Hospital Universitario Gregorio Marañón, que representa el núcleo básico del Instituto, y grupos del ámbito de Atención Primaria del área de influencia del Hospital, por la Universidad Complutense de Madrid (UCM), la Universidad Carlos III de Madrid (UCIII MADRID), la Fundación para la investigación biomédica del Hospital Gregorio Marañón (FIBHGM) y la Dirección General de Investigación, Formación e Infraestructuras Sanitarias de la Consejería de Sanidad de la Comunidad de Madrid. Acreditado por el Instituto de Salud Carlos III como Instituto de Investigación Sanitaria en 2012, y renovando esta acreditación cada 5 años, forma parte así del total de 34 Institutos de Investigación Sanitaria acreditados existentes en la actualidad.

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Effectiveness of an Early Intervention in Mild Hyponatremia to Prevent Accidental Falls in Hospitalized Older Adults-A Crossover Ecological Clinical Trial
(Multidisciplinary Digital Publishing Institute (MDPI), 2025-04-10) Lobo-Rodríguez, Carmen; Pedraz-Marcos, Azucena; Velarde-García, Juan Francisco; Calderari Fernández, Elena; Gadea-Cedenilla, Carmen; Medina-Torres, Margarita; Moro-Tejedor, Mª Nieves; Sánchez García, Leonor; García-Pozo, Ana Mª; Fundación Mutua Madrileña
Background: Falls in hospitalized patients cause injuries of varying severity and even death. There is a link between falls and low blood sodium levels in older patients. Identifying and treating hyponatremia could help prevent falls and reduce hospital stays. The purpose of this study was to evaluate the effectiveness of the correction of hyponatremia on reducing the incidence of falls and the mean stay of hospitalized patients aged more than 65 years. Methods: A crossover ecological clinical trial was conducted in adult hospitalization units of a hospital in Madrid (Spain) over 12 months. Patients meeting inclusion criteria were divided into two randomized groups. The intervention was applied in two six-month phases, alternating between groups with a 15-day washout period. Early diagnosis and treatment of hyponatremia were implemented in the intervention group, while the control group received standard care. Primary outcomes included fall incidence and length of hospital stay. Data were collected using REDCap and analyzed with SPSS v.21. Statistical significance was set at p < 0.05 (ClinicalTrials identifier of the manuscript: NCT03265691). Results: A total of 1925 patients were included (408 intervention, 1517 control). Fall incidence was significantly lower in the intervention group (6.7 vs. 9.8, p = 0.000). Hyponatremia was corrected in 72% of cases. No significant differences were found in functional scores. The intervention effectively reduced falls compared to standard care. Conclusions: Early hyponatremia treatment reduces falls and hospital stay in older patients, supporting its inclusion in fall prevention strategies.
Prevalence of HCV Infection Among People Experiencing Homelessness in Madrid, Spain
(JAMA Network, 2024-10-01) Ryan, Pablo; Valencia, Jorge; Sepulveda-Crespo, Daniel; Amigot-Sánchez, Rafael; Cuevas, Guillermo; Lazarus, Jeffrey V; Pérez-García, Felipe; Martinez, Isidoro; Resino, Salvador; Gilead Sciences (Spain); Instituto de Salud Carlos III; AbbVie; Asociación Española para el Estudio del Hígado; Ministerio de Ciencia e Innovación (España); Unión Europea. Comisión Europea. NextGenerationEU; Centro de Investigación Biomédica en Red - CIBERINFEC (Enfermedades Infecciosas); Madrid Positivo Association
Importance: Hepatitis C virus (HCV) microelimination aims to detect and treat hidden infections, especially in at-risk groups, like people experiencing homelessness (PEH) with alcohol or drug use disorders. Point-of-care HCV RNA testing and peer support workers are crucial for identifying and preventing HCV infection among marginalized populations, contributing to overall elimination goals. Objective: To assess risk factors, prevalence, and trends of active HCV infection among PEH in Madrid, Spain (2019-2023). Design, setting, and participants: This cross-sectional study was conducted between 2019 and 2023 in PEH, defined as people who lacked a fixed, regular, and adequate night residence, screened on the street or in homeless shelters via mobile unit using rapid HCV antibody testing, followed by HCV-RNA testing in Madrid, Spain. Data were analyzed from January to June 2024. Main outcomes and measures: Active HCV infection among PEH was the main outcome. Risk factors analyzed included being born outside of Spain, alcohol misuse, lacking financial income, benzodiazepine use, injection drug use (IDU; including nonactive IDU and active IDU within the last year), opioid substitution therapy participation, and sexual behavior patterns. Data were analyzed using logistic regression. P values were adjusted for multiple testing using the false discovery rate (q-values). Results: A total of 4741 individuals were screened for HCV infection, of whom 2709 (mean [SD] age, 42.2 [12.7]; 1953 [72.2%] men) were PEH and included in analysis. A total of 363 PEH (13.4%) had test results positive for HCV antibodies, of whom 172 (47.4%) had test results positive for HCV-RNA, and 148 of these (91.9%) started HCV treatment. Overall, active HCV infection prevalence was 6.3%, and the main risk factors associated with active HCV infection included IDU, encompassing both nonactive IDU (adjusted odds ratio [aOR], 10.9; 95% CI, 6.1-19.4; q < .001) and active IDU in the last year (aOR, 27.0; 95% CI, 15.2-48.0; q < .001); a lack of financial income (aOR, 1.8; 95% CI, 1.1-2.9; q = .03); and alcohol misuse (aOR, 1.8; 95% CI, 1.3-2.6; q = .008). There was a significant decrease between 2019 and 2023 in active HCV infection prevalence across the entire population, from 7.2% to 3.4% (P = .04). Conclusions and relevance: In this cross-sectional study of PEH in Madrid, IDU, lack of income, and alcohol misuse were primary risk factors associated with HCV infection. The significant decline in HCV rates observed across all risk groups during the study period suggests preventive policies were effective in reducing HCV prevalence among the homeless population.
Phase IV adaptive randomised clinical trials evaluating efficacy and cost-efficacy of pre-emptive pharmacogenetic genotyping strategies in the Spanish National Health System: iPHARMGx Master Protocol and PREVESTATGx nested clinical trial
(BMJ Publishing Group, 2024-11-07) Stewart, Stefan; Seco-Meseguer, Enrique; Diago-Sempere, Elena; Marín-Candón, Alicia; Carmona, Montserrat; Estébanez, Miriam; López-Fernández, Luis A; Imaz-Iglesia, Iñaki; Del Mar García Saiz, María; Laserna-Mendieta, Emilio J; Peiró, Ana M; Farré, Magí; Rodriguez-Jimenez, Consuelo; Saiz-Rodriguez, Miriam; Sanabria-Cabrera, Judith; Rosas-Alonso, Rocío; Abad-Santos, Francisco; Pedrosa-Pérez, Lucía; Carcas, Antonio J; García García, Irene; Borobia, Alberto M; iPHARMGx study group; Instituto de Salud Carlos III; Unión Europea. Comisión Europea. NextGenerationEU
Introduction: Genetic variations impact drug response, driving the need for personalised medicine through pre-emptive pharmacogenetic testing. However, the adoption of pre-emptive pharmacogenetic testing for commonly prescribed drugs, such as statins, outside of tertiary hospitals is limited due to a lack of pharmacoeconomic evidence to support widespread implementation by healthcare policy-makers. The Spanish Consortium for the Implementation of Pharmacogenetics (iPHARMGx Consortium) addresses this by developing a clinical trial master protocol that will govern multiple nested adaptive clinical trials that compare genotype-guided treatments to standard care in specific drug-gene-population triads, asses their cost-efficacy and identify novel biomarkers through advanced sequencing techniques. The first of these studies aims to assess whether a pre-emptive statin therapy genotyping scheme reduces the incidence of statin-associated muscle symptoms (SAMS) in a population at risk of cardiovascular disease susceptible of receiving high-intensity or moderate-intensity doses of statins: The PREVESTATGx trial. Methods and analysis: the PREVESTATGX trial is a multicentre, adaptive randomised controlled pragmatic phase IV clinical trial nested to the iPHARMGx master protocol with two parallel arms, aiming for superiority. Randomisation will be conducted on an individual basis with a centralised approach and stratification by centre. After inclusion in the trial and genotyping has been performed, subjects will be randomly allocated to experimental group (pharmacogenetic genotype-guided statin prescription) or standard-of-care statin prescription (as deemed by attending physician). The main objective is to assess the efficacy of a statin pre-emptive genotyping strategy in reducing the incidence of SAMS. A total of 225 subjects will be recruited among the 10 participating centres if no futility/efficacy boundary is reached in the prespecified interim analyses. Recruitment will be carried out during a 12-month period and subjects will be followed for a 9-month period. Ethics and dissemination: The PREVESTATGx trial received ethical approval on 24 April 2024. Results will be disseminated via publication in peer-reviewed journals as well as presentation at international conferences. Trial results will be submitted for publication in an open-access peer-reviewed medical speciality-specific publication. Trial registration number: EU CT number: 2023-509418-12-00/Clinical trial Identifier (ClinicalTrials.gov): NCT06262685. Protocol version 1.2 12 April 2024 (includes non-substantial modification number 14 June 2024). Trial registration of this study can be located at both the EU Clinical Trials Register available from https:// euclinicaltrials.eu/search-for-clinical-trials/?lang=en and https://clinicaltrials.gov. Registration on both websites was done before the enrolment of the first patient complying with European regulations. EU Clinical Trials Register is a primary registry according to the WHO.
Diagnostic performance of hepatitis C virus core antigen testing for detecting hepatitis C in people living with hepatitis B: a systematic review and meta-analysis
(BioMed Central (BMC), 2024-12-02) Treviño-Nakoura, Ana; Sepulveda-Crespo, Daniel; Bellon, José M; Codina Márquez, Helena; Quero-Delgado, Marta; Ryan, Pablo; Martinez, Isidoro; Resino, Salvador; Instituto de Salud Carlos III; Gilead Sciences (Spain); Ministerio de Ciencia e Innovación (España); Unión Europea. Comisión Europea. NextGenerationEU; Centro de Investigación Biomédica en Red - CIBERINFEC (Enfermedades Infecciosas)
Background: The current diagnostic strategy for hepatitis C virus (HCV) infection involves a two-step approach: antibody HCV screening followed by confirmatory nucleic acid testing. This study aimed to evaluate the diagnostic performance of the Abbott ARCHITECT HCV Ag assay in serum/plasma samples as a potential one-step alternative for diagnosing active HCV infection in people living with hepatitis B virus (PLWHB) through a systematic review and meta-analysis. Methods: A systematic review and meta-analysis were conducted following PRISMA-DTA guidelines. This protocol was registered on PROSPERO (CRD42023402093). A comprehensive search of electronic databases identified studies published up to 1 November 2024, comparing the ARCHITECT HCV Ag assay to an HCV-RNA reference standard. Sensitivity, specificity, and likelihood ratios were pooled using a random-effects model within the MIDAS module of Stata software. Study quality was assessed using QUADAS-2. Heterogeneity was evaluated using the Q statistic, quantified using the I², and further explored through meta-regression. Results: Ten studies (n = 494 participants) met inclusion criteria. The Abbott ARCHITECT HCV Ag assay demonstrated high sensitivity [91%, 95% confidence interval (CI): 76-97%] and specificity (99%, 95% CI: 99-100%). The positive likelihood ratio (PLR) was 81.20 (95% CI: 12.34-534.36), and the negative likelihood ratio (NLR) was 0.09 (95% CI: 0.03-0.27). The area under the summary receiver operating characteristic curve (AUC-SROC) was 99% (95% CI 98-100%). In regions with high HCV prevalence (≥ 10%), the test accurately confirmed active HCV infection in over 90% of cases. However, confirmatory testing remains necessary in low-prevalence settings (≤ 5%). The assay demonstrated an excellent ability to identify individuals without HCV infection, with a low false-negative rate (≤ 2%) regardless of HCV prevalence. Heterogeneity analysis revealed moderate to substantial variation in test performance (I² = 72.09% for sensitivity, 35.47% for PLR, and 78.33% for NLR). QUADAS-2 applicability concerns predicted heterogeneity, but differences were likely insignificant due to minimal variations and limited studies. Conclusions: The Abbott ARCHITECT HCV Ag assay exhibited promising accuracy in detecting active HCV infection among PLWHB. This test might help diagnose active HCV infection in high-prevalence scenarios (≥ 10%) but needs further confirmation in low-prevalence settings (≤ 5%).
Plasma metabolomic profile is near-normal in people with HIV on long-term suppressive antiretroviral therapy
(Frontiers Media, 2024) Virseda-Berdices, Ana; Martín-Escolano, Rubén; Berenguer, Juan; González-García, Juan; Brochado-Kith, Oscar; Rojo, David; Fernandez-Rodriguez, Amanda; Pérez-Latorre, Leire; Hontañón, Víctor; Barbas, Coral; Resino, Salvador; Jimenez-Sousa, Maria Angeles; Instituto de Salud Carlos III; Ministerio de Ciencia e Innovación (España); Agencia Estatal de Investigación (España); Unión Europea. Comisión Europea. NextGenerationEU; Centro de Investigación Biomédica en Red - CIBERINFEC (Enfermedades Infecciosas); Comunidad de Madrid (España)
Background: Combination antiretroviral therapy (ART) has transformed human immunodeficiency virus (HIV) infection in people with HIV (PWH). However, a chronic state of immune activation and inflammation is maintained despite achieving HIV suppression and satisfactory immunological recovery. We aimed to determine whether the plasma metabolomic profile of PWH on long-term suppressive ART and immunologically recovered approximates the normality by comparison with healthy controls with similar age and gender. Methods: We carried out a cross-sectional study in 17 PWH on long-term ART (HIV-RNA <50 copies/mL, CD4+ ≥500 cells/mm3, and CD4+/CD8+ ≥1) and 19 healthy controls with similar age and gender. Metabolomics analysis was performed by gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-mass spectrometry (LC-MS). The statistical association analysis was performed by principal component analysis (PCA), partial least squares discriminant analysis (PLS-DA), and Generalized Linear Models (GLM) with a gamma distribution (log-link). Significance levels (p-value) were corrected for multiple testing (q-value). Results: PCA and PLS-DA analyses found no relevant differences between groups. Adjusted GLM showed 14 significant features (q-value<0.20), of which only three could be identified: lysophosphatidylcholine (LysoPC) (22:6) (q-value=0.148), lysophosphatidylethanolamine (LysoPE) (22:6) (q-value=0.050) and hydroperoxy-octadecatrienoic acid (HpOTrE)/dihydroperoxy-octadecatrienoic acid (DiHOTrE)/epoxy-octadecadienoic acid (EpODE) (q-value=0.136). These significant identified metabolites were directly correlated to plasma inflammatory biomarkers in PWH and negatively correlated in healthy controls. Conclusion: PWH on long-term ART have a metabolomic profile that is almost normal compared to healthy controls. Nevertheless, residual metabolic alterations linked to inflammatory biomarkers persist, which could favor the development of age-related comorbidities among this population.
Immunogenicity of the Conjugate Meningococcal ACWY-TT Vaccine in Children and Adolescents Living with HIV
(Multidisciplinary Digital Publishing Institute (MDPI), 2024) Berzosa, Arantxa; Guillen, Sara; Epalza, Cristina; Escosa, Luis; Navarro, Maria Luisa; Prieto, Luis M; Sainz, Talia; Jimenez de Ory, Santiago; Montes Mota, Marina; Abad, Raquel; Vazquez-Moreno, Julio Alberto; Serrano García, Irene; Ramos-Amador, José Tomás; Fundación Familia Alonso; RETICS-Sida (RIS-ISCIII) (España); Instituto de Salud Carlos III; Centro de Investigación Biomédica en Red - CIBERINFEC (Enfermedades Infecciosas); European Society for Paediatric Infectious Diseases
Background: Children and adolescents living with HIV (CALHIV) are at high risk of meningococcal infections and may present lower immune responses to vaccines. The objectives of this study were to assess the immunogenicity of the quadrivalent Men ACWY-TT vaccine (Nimenrix®) in CALHIV after a two-dose schedule and to describe possible HIV-related factors that may affect the immunogenic response. Methods: A multicenter prospective study was designed, including CALHIV followed in five hospitals in Madrid, between 2019 and 2021. Two doses of the Men ACWY-TT vaccine were administered. Serum bactericidal antibody (SBA) assays using rabbit complement (rSBA) against serogroups C, W, and Y were used to determine seroprotection and vaccine response (the proportion achieving a putative protective titer of ≥eight or a ≥four-fold rise in titer from baseline). Serum was collected at baseline, and at 3 and 12 months after vaccination. Results: There were 29 CALHIV included, 76% of whom were perinatally infected. All were receiving TAR and presented a good immunovirological and clinical status overall. At baseline, 45% of CALHIV had seroprotective titers to at least one serogroup, with individual seroprotection rates of 24%, 28%, and 32% against C, W, and Y, respectively. After a two-dose schedule, vaccine response was 83% for each serogroup, eliciting a vaccine response to all serogroups in 69% of them. One year after vaccination, 75% of CALHIV maintained seroprotective titers against the C serogroup, and 96% against W and Y. None of the HIV-related characteristics analyzed could predict vaccine response or antibody duration. Conclusions: CALHIV who received effective TAR and presented a good immuno-virological situation achieved an appropriate vaccine response after two doses of the Men ACWY-TT vaccine, and antibody-mediated protection against serogroups C, W, and Y was maintained in more than 70% of the patients one year after vaccination.
Sustained Long-Term Decline in Anti-HCV Neutralizing Antibodies in HIV/HCV-Coinfected Patients Five Years after HCV Therapy: A Retrospective Study
(Multidisciplinary Digital Publishing Institute (MDPI), 2024-08-30) Sepulveda-Crespo, Daniel; Volpi, Camilla; Amigot-Sánchez, Rafael; Yélamos, María Belén; Díez, Cristina; Gómez, Julián; Hontañón, Víctor; Berenguer, Juan; González-García, Juan; Martín-Escolano, Rubén; Resino, Salvador; Martinez, Isidoro; Instituto de Salud Carlos III; Ministerio de Ciencia e Innovación (España); Unión Europea. Comisión Europea. NextGenerationEU; Centro de Investigación Biomédica en Red - CIBERINFEC (Enfermedades Infecciosas)
Background: This study evaluated titers and amplitudes of anti-E2 antibodies (anti-E2-Abs) and neutralizing antibodies against hepatitis C virus (HCV; anti-HCV-nAbs) in HIV/HCV-coinfected individuals over five years after successful HCV treatment completion. Methods: We retrospectively analyzed 76 HIV/HCV-coinfected patients achieving sustained virologic response post-HCV treatment. Plasma levels of anti-E2-Abs and anti-HCV-nAbs against five HCV genotypes (Gt1a, Gt1b, Gt2a, Gt3a, and Gt4a) were determined using ELISA and microneutralization assays, respectively. Statistical analyses comparing the three follow-up time points (baseline, one year, and five years post-HCV treatment) were performed using generalized linear mixed models, adjusting p-values with the false discovery rate (q-value). Results: Compared to baseline, anti-E2-Abs titers decreased at one year (1.9- to 2.3-fold, q-value < 0.001) and five years (3.4- to 9.1-fold, q-value < 0.001) post-HCV treatment. Anti-HCV-nAbs decreased 2.9- to 8.4-fold (q-value < 0.002) at one year and 17.8- to 90.4-fold (q-value < 0.001) at five years post-HCV treatment. Anti-HCV-nAbs titers against Gt3a were consistently the lowest. Nonresponse rates for anti-E2-Abs remained low throughout the follow-up, while anti-HCV-nAbs nonresponse rates increased 1.8- to 13.5-fold (q-value < 0.05) at five years post-HCV treatment, with Gt3a showing the highest nonresponse rate. Conclusions: Humoral immune responses against HCV decreased consistently one and five years post-HCV treatment, regardless of HCV genotype and previous HCV therapy or type of treatment (IFN- or DAA-based therapy). This decline was more pronounced for anti-HCV-nAbs, particularly against Gt3.
Diagnostic potential of combining plasma biomarkers of tissue damage and inflammation in pediatric TB
(Elsevier, 2024-12) López-Suárez, Andrea; Santos-Sebastián, Mar; Hernanz-Lobo, Alicia; Rincón-López, Elena; Aguilera-Alonso, David; Saavedra-Lozano, Jesús; Ruiz Serrano, María Jesús; Hernández-Bartolomé, Ángel; Medrano, Luz Maria; Jiménez Fuentes, José Luis; Navarro, María Luisa; Tebruegge, Marc; Santiago-García, Begoña; Instituto de Salud Carlos III; Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); European Society for Paediatric Infectious Diseases
Introduction: Immune-based diagnostic tests for tuberculosis (TB) have suboptimal sensitivity in children and cannot differentiate between latent infection (LTBI) and active disease. This study evaluated the diagnostic potential of a broad range of biomarkers of tissue damage and inflammation in unstimulated plasma in children. Methods: We analyzed 17 biomarkers in 15 non-M. tuberculosis (MTB)-infected controls and 33 children with TB infection (LTBI, n = 8; probable TB, n = 19; confirmed TB, n = 6). Biomarker concentrations were measured using a Luminex magnetic bead-based platform and multiplex sandwich immunoassays. Concentrations, correlations and diagnostic accuracy assessments were conducted among patient groups. Results: Confirmed TB cases had significantly higher concentrations of IFN-γ and IL-2 and higher IFN-γ/MCP-1 and IL-2/MCP-1 ratios compared to LTBI and non-MTB-infected children. Among children with confirmed TB, there was a strong correlation between IFN-γ and IL-10 (r = 0.95; p < 0.001) and a significant correlation between IL-2 and IL-1ra (r = 0.92), IL-21 (r = 0.91), MCP-3 (r = 0.84), and MMP-1 (r = 0.85). The IFN-γ/MCP-1 ratio was the most accurate biomarker combination for differentiating between MTB-infected and non-MTB-infected children (AUC, 0.82; sensitivity, 87.9%; specificity, 66.6%; p < 0.001) and between active TB and non-MTB-infected children (AUC 0.82; sensitivity 88.0%; specificity 60.0%; p < 0.001). None of the biomarkers investigated were able to discriminate between LTBI and active TB. Conclusion: Our data suggest that combining the analyses of multiple biomarkers in plasma has the potential to enhance diagnosis of TB in children and, thus, warrants additional investigation. In particular, the diagnostic potential of IFN-γ/MCP-1 ratios should be further explored in larger pediatric cohorts.
Decrease in active hepatitis C infection among people who use drugs in Madrid, Spain, 2017 to 2023: a retrospective study
(European Centre for Disease Prevention and Control (ECDC), 2024-07) Ryan, Pablo; Valencia, Jorge; Cuevas, Guillermo; Amigot-Sánchez, Rafael; Martinez, Isidoro; Lazarus, Jeffrey V; Perez-Garcia, Felipe; Resino, Salvador; Gilead Sciences (Spain); Instituto de Salud Carlos III; AbbVie; Ministerio de Ciencia e Innovación (España); Unión Europea. Comisión Europea. NextGenerationEU; Centro de Investigación Biomédica en Red - CIBERINFEC (Enfermedades Infecciosas); Asociación Española para el Estudio del Hígado; Madrid Positivo Association
Background: People who use drugs (PWUD) are a key target population to reduce the burden of hepatitis C virus (HCV) infection. Aim: To assess risk factors and temporal trends of active HCV infection in PWUD in Madrid, Spain. Methods: We conducted a retrospective study between 2017 and 2023, including 2,264 PWUD visiting a mobile screening unit. Data about epidemiology, substance use and sexual risk behaviour were obtained through a 92-item questionnaire. HCV was detected by antibody test, followed by RNA test. The primary outcome variable was active HCV infection prevalence, calculated considering all individuals who underwent RNA testing and analysed by logistic regression adjusted by the main risk factors. Results: Of all participants, 685 tested positive for anti-HCV antibodies, and 605 underwent RNA testing; 314 had active HCV infection, and 218 initiated treatment. People who inject drugs (PWID) were identified as the main risk group. The active HCV infection rate showed a significant downward trend between 2017 and 2023 in the entire study population (23.4% to 6.0%), among PWID (41.0% to 15.0%) and PWUD without injecting drug use (7.0% to 1.3%) (p < 0.001 for all). These downward trends were confirmed by adjusted logistic regression for the entire study population (adjusted odds ratio (aOR): 0.78), PWID (aOR: 0.78), and PWUD non-IDU (aOR: 0.78). Conclusions: Our study demonstrates a significant reduction in active HCV infection prevalence among PWUD, particularly in PWID, which suggests that efforts in the prevention and treatment of HCV in Madrid, Spain, have had an impact on the control of HCV infection.
Impact of the COVID-19 pandemic on the self-care and health condition of the older adults. CUIDAMOS+75. A mixed methods study protocol
(Frontiers Media, 2024) Rico-Blazquez, Milagros; Esteban-Sepúlveda, Silvia; Sánchez-Ruano, Raquel; Aritztegui-Echenique, Ana María; Artigues-Barbera, Eva María; Brito-Brito, Pedro-Ruymán; Casado-Ramirez, Elvira; Cidoncha-Moreno, María Ángeles; Fabregat-Julve, María Inmaculada; Feria-Raposo, Isabel; Hernandez-Pascual, Montserrat; Lozano-Hernández, Cristina; Moreno-Casbas, Teresa; Otones-Reyes, Pedro; Palmar-Santos, Ana María; Pedraz-Marcos, Azucena; Romero-Rodriguez, Esperanza María; Solé-Agustí, María Cristina; Taltavull-Aparicio, Joana María; Vidal-Thomàs, María Clara; González-Chordá, Víctor M; Cuidamos+75 Group; Instituto de Salud Carlos III; Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF)
Aims: To assess the impact of the COVID-19 pandemic on the health condition of people ≥75 years of age and on their family caregivers in Spain. Design: Multicentric, mixed method concurrent study. Methods: This work, which will be conducted within the primary care setting in 11 administrative regions of Spain, will include three coordinated studies with different methodologies. The first is a population-based cohort study that will use real-life data to analyze the rates and evolution of health needs, care provision, and services utilization before, during, and after the pandemic. The second is a prospective cohort study with 18 months of follow-up that will evaluate the impact of COVID-19 disease on mortality, frailty, functional and cognitive capacity, and quality of life of the participants. Finally, the third will be a qualitative study with a critical social approach to understand and interpret the social, political, and economic dimensions associated with the use of health services during the pandemic. We have followed the SPIRIT Checklist to address trial protocol and related documents. This research is being funded by the Instituto de Salud Carlos III since 2021 and was approved by its ethics committee (June 2022). Discussion: The study findings will reveal the long-term impact of the COVID-19 pandemic on the older adults and their caregivers. This information will serve policymakers to adapt health policies to the needs of this population in situations of maximum stress, such as that produced by the COVID-19 pandemic. Trial registration: Identifier: NCT05249868 [ClinicalTrials.gov].
Gestational breast cancer: distinctive molecular and clinico-epidemiological features
(Springer, 2024-11-08) de la Haba-Rodríguez, J R; Mínguez, P; Rojo, F; Martín, M; Alba, E; Servitja, S; Prat, A; Pérez-Fidalgo, Jose Alejandro; Gavilá, J; Morales, C; Rodriguez-Lescure, A; Herrero, C; Peña-Enriquez, R; Herranz, J; Hernando, C; Hernández-Blanquisett, A; Guil-Luna, S; Martinez, M T; Blanch, S; Caballero, R; Martín, N; Pollan-Santamaria, Marina; Guerrero-Zotano, Ángel; Bermejo, B; Instituto de Salud Carlos III; University of Córdoba (España); Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF)
Gestational breast cancer (GBC), defined as breast cancer (BC) diagnosed during pregnancy or the first-year post-partum, accounts for 6-15% of BC cases in women aged 20-44 years. GBC has worse prognosis than non-GBC, but reasons behind are not clear. The GEICAM/2012-03 Study (Molecular Characterization of Gestational Breast Cancer) is a multicenter prospective/retrospective observational registry of patients diagnosed with GBC. From November 2014 to June 2015 seventy patients diagnosed with GBC were included in the study, 30 diagnosed during pregnancy and 40 after delivery. Our current study was aimed to explore differences in epidemiological, clinico-pathological and gene expression features of GBC tumors, from the GEICAM/2012-03 Study, compared to non-GBC tumors from patients of similar age (< 43 years) from six different GEICAM studies, used as non- GBC control population. As per the main objective, the study found multiple differences showing GBC tumors as a different biological entity. GBC showed a more aggressive biology, with higher Ki67 levels, higher incidence of breast and/or ovarian cancer family history, and germline deleterious BRCA1/2 mutations, and are enriched in basal-like intrinsic subtype. GBC patients showed a lower number of tumor infiltrating lymphocytes, while specific genetic signatures highlight differences in GBC´s distinctive transcriptome. Our study shows that GBC is potentially a clinically and molecularly different entity, with specific epidemiological, clinical, and histological features, as well as a distinctive altered immune state and genetic signature. Nevertheless, further studies are needed to better understand the biology of GBC and to identify new targets against which develop new, more effective, targeted therapies.
Toll-like receptor 8 (TLR8) polymorphisms are associated with non-progression of chronic hepatitis C in HIV/HCV coinfected patients
(Elsevier, 2015-12) Fernandez-Rodriguez, Amanda; Berenguer, Juan; Jimenez-Sousa, Maria Angeles; Garcia-Alvarez, Monica; Aldámiz-Echevarria, Teresa; Pineda-Tenor, Daniel; Díez, Cristina; De la Barrera, Jorge; Bellón, José María; Briz, Veronica; Resino, Salvador; Fundación para la Investigación y la Prevención del Sida en España; Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); Instituto de Salud Carlos III
Toll-like receptor 8 (TLR8) polymorphisms have been related to hepatitis C virus (HCV) infection. The aim was to estimate the association of TLR8 polymorphisms with HCV-related outcomes in HIV/HCV coinfected patients. We performed a cross-sectional study of 220 patients who underwent a liver biopsy. TLR8 polymorphisms were genotyped using GoldenGate® assay. The outcome variables were non-fibrosis (F0), mild-inflammation (A0/A1), and non-steatosis [fatty hepatocytes (FH) <10%]. Logistic regression analysis was used to compare the outcome variables according to TLR8 polymorphisms. Four polymorphisms were analyzed (rs1013151, rs5744069, rs17256081 and rs3764880rs1013151). Female patients had higher frequency of TLR8 major alleles at rs17256081 and rs101315, and minor alleles at rs3764880 and rs5744069. Male patients had higher frequency of TLR8 minor alleles except for rs3764880, where major alleles were higher (p<0.01). Two TLR8 polymorphisms (rs1013151 and rs5744069) were significantly associated with non-fibrosis (F0) [adjusted odds ratio (aOR)=4.42 (95% of confidence interval (95%CI)=1.54; 12.68) (p=0.006) and aOR=4.76 (95%CI=1.69; 13.37) (p=0.003); respectively]. When data were stratified by gender, rs1013151 and rs5744069 polymorphisms remained significant for male patients [adjusted odds ratio (aOR)=4.49 (95%CI=1.08; 18.62) (p=0.039) and aOR=6.17 (95%CI=1.45; 26.20) (p=0.014); respectively]. When data were stratified by major HCV genotypes, patients infected with HCV genotype 1 (GT1) had significant values for both rs1013151 and rs5744069 polymorphisms [aOR=5.79 (95%CI=1.44; 23.32) (p=0.013) and aOR=8.01 (95%CI=2.16; 35.65) (p=0.005); respectively]. Finally, none of the TLR8 polymorphisms were significantly associated with mild-inflammation or non-steatosis. In conclusion, TLR8 polymorphisms seem to be related to non-progression of liver fibrosis in HIV/HCV coinfected patients, particularly in males and those patients infected with GT1.
BK virus infection in human immunodeficiency virus-infected patients.
(Springer, 2012-07) Ledesma, Juan; Muñoz, P; García de Viedma, D; Cabrero, I; Loeches, B; Montilla, P; Gijon, P; Rodriguez-Sanchez, B; Bouza, Emilio; BKV Study Group; Instituto de Salud Carlos III; Ministerio de Sanidad y Consumo (España); Fundación Mutua Madrileña; Centro de Investigación Biomédica en Red - CIBERES (Enfermedades Respiratorias)
The aim of this study is to evaluate the prevalence of BK virus (BKV) infection in HIV-positive patients receiving highly active antiretroviral therapy (HAART) in our hospital. The presence of BKV was analysed in urine and plasma samples from 78 non-selected HIV-infected patients. Clinical data were recorded using a pre-established protocol. We used a nested PCR to amplify a specific region of the BKV T-large antigen. Positive samples were quantified using real-time PCR. Mean CD4 count in HIV-infected patients was 472 cells/mm3 and median HIV viral load was <50 copies/mL. BKV viraemia was detected in only 1 HIV-positive patient, but 57.7% (45 out of 78) had BKV viruria, which was more common in patients with CD4 counts>500 cells/mm3 (74.3% vs 25.7%; p=0.007). Viruria was present in 21.7% of healthy controls (5 out of 23 samples, p=0.02). All viral loads were low (<100 copies/mL), and we could not find any association between BKV infection and renal or neurological manifestations. We provide an update on the prevalence of BKV in HIV-infected patients treated with HAART. BKV viruria was more common in HIV-infected patients; however, no role for BKV has been demonstrated in this population.
BK polyomavirus genotyping at inter- and intra-patient level in Spain
(Wiley, 2013-08) Ledesma, Juan; Bouza, Emilio; González-Nicolás, M A; García de Viedma, D; Rodríguez-Sánchez, B; Muñoz, P; Instituto de Salud Carlos III; Ministerio de Sanidad y Consumo (España); Fundación Mutua Madrileña; Centro de Investigación Biomédica en Red - CIBERES (Enfermedades Respiratorias)
BK polyomavirus (BKV) is classified into four subtypes based on nucleotide variation of a 287 bp typing region in the VP1 protein. Most studies show that subtype I is predominant in different geographic settings, followed by subtype IV. However, BKV subtypes II and III are detected at low rates. In Spain, the prevalence of each subtype is not well known. The aim of this study was to identify the BKV subtypes from a selection of different types of patients and to determine whether different subtypes could be infecting the same patient. A hundred and twenty nine BKV-positive urine samples were selected to amplify and sequence the typing region. Plasma specimens collected at the same time as the urine samples were also studied in 34 patients. A phylogenetic analysis and a study of substitutions in the VP1 protein were carried out with the sequences obtained. Subtype I was the predominant subtype detected in urine (61.2%) and plasma (38.2%) samples followed by subtype II. The analysis of paired samples showed that the subtype found in urine was different from that found in plasma in 10 patients. Fourteen BKV variants based on substitutions in VP1 were identified. The finding of compartmentalized infections involving different subtypes at different sites in some patients might mean specific and different selective pressure in each tissue. The potential involvement in the viral cycle of the different BKV variants found should be analyzed.
Low plasma levels of BTLA and LAG-3 before HCV therapy are associated with metabolic disorders after HCV eradication in persons with HIV/HCV coinfection: a retrospective study
(Frontiers Media, 2024-10) Martín-Escolano, Rubén; Virseda-Berdices, Ana; Berenguer, Juan; González-García, Juan; Brochado-Kith, Oscar; Fernandez-Rodriguez, Amanda; Díez, Cristina; Hontañón, Víctor; Marathon Study Group; Resino, Salvador; Jimenez-Sousa, Maria Angeles; Instituto de Salud Carlos III; Ministerio de Ciencia e Innovación (España); Agencia Estatal de Investigación (España); Centro de Investigación Biomédica en Red - CIBERINFEC (Enfermedades Infecciosas); Unión Europea. Comisión Europea. NextGenerationEU; Comunidad de Madrid (España)
Background: Understanding the predictors of metabolic disorders in persons with HIV/HCV coinfection post-HCV therapy is crucial for improving patient outcomes. Since immune checkpoint proteins are usually upregulated in these persons with HIV/HCV coinfection, we aimed to evaluate the association between plasma immune checkpoint proteins at baseline (before HCV therapy) and metabolic disturbances during the follow-up (about 5 years after successful HCV treatment) in persons with HIV/HCV coinfection. Methods: We performed a retrospective study on 80 persons with HIV/HCV coinfection with advanced fibrosis or cirrhosis who cleared HCV infection after successful HCV therapy and were followed for about 5 years after completion of HCV treatment. Plasma samples were collected at baseline. Immune checkpoint proteins were analyzed using a Luminex 200™ analyzer. Outcomes were the development of a metabolic event (type 2 diabetes mellitus and/or dyslipidemia) and the change in Triglycerides and glucose (TyG) index. Results: During follow-up, 21 (26%) patients developed metabolic events (type 2 diabetes mellitus/dyslipidemia), and 29 (46.0%) patients had an increase in TyG during the follow-up. Low baseline values of BTLA and LAG-3, two immune checkpoint proteins, were associated with the development of metabolic events (aAMR = 0.69 and aAMR = 0.71, respectively) and with increases in TyG values (aAMR = 0.72 and aAMR = 0.70, respectively). In addition, other immune checkpoint proteins were also inversely associated with increases in TyG. Conclusion: We discovered that low plasma levels of BTLA and LAG-3 before HCV therapy significantly correlate with an increased risk of developing metabolic disorders after treatment.
Immune checkpoint proteins are associated with persistently high liver stiffness after successful HCV treatment in people with HIV: a retrospective study
(Frontiers Media, 2024) Martín-Escolano, Rubén; Virseda-Berdices, Ana; Berenguer, Juan; Resino, Salvador; González-García, Juan; Brochado-Kith, Oscar; Fernandez-Rodriguez, Amanda; Díez, Cristina; Hontañón, Víctor; Resino, Salvador; Jimenez-Sousa, Maria Angeles; Instituto de Salud Carlos III; Agencia Estatal de Investigación (España); Unión Europea. Comisión Europea. NextGenerationEU; Comunidad de Madrid (España); Centro de Investigación Biomédica en Red - CIBERINFEC (Enfermedades Infecciosas); Ministerio de Ciencia e Innovación (España)
Various immune checkpoint proteins have been linked to cirrhosis. This study aimed to explore the association between plasma levels of these proteins measured one year after successful HCV treatment and persistently liver stiffness (defined as liver stiffness measurement (LSM) ≥ 12.5 kPa) five years after HCV treatment in people with HIV (PWH). We conducted a retrospective study involving 39 patients with HIV/HCV-coinfection who had advanced fibrosis or cirrhosis and achieved sustained virologic response (SVR). Plasma samples were obtained one year after treatment, and levels of immune checkpoints along with inflammatory biomarkers were evaluated using a Luminex 200 analyzer. Statistical analyses were performed using Generalized Linear Models (GLMs) with a gamma distribution. Spearman correlation tests were used to analyze the correlation between significant immune checkpoints and inflammatory biomarkers. Although LSM values showed a decreasing trend over the years following successful HCV treatment, this trend was not statistically significant due to substantial variability among PWH. Persistently high liver stiffness was observed in 61.5% of patients five years after HCV treatment. Elevated plasma levels of soluble BTLA, PD-1, and TIM-3 one year after HCV treatment were associated with persistently liver stiffness five years later. These significant immune checkpoints were found to correlate with inflammatory biomarkers in PWH with persistently high liver stiffness. In conclusion, increased plasma concentrations of immune checkpoints one year after successful HCV therapy were linked to persistently high liver stiffness five years later, particularly BTLA, PD-1, and TIM-3. This suggests a potential immunopathological mechanism in ongoing liver stiffness post-HCV eradication.
Similar humoral immune responses against the SARS-CoV-2 spike protein in HIV and non-HIV individuals after COVID-19
(Elsevier, 2022-03) Martin-Vicente, Maria; Berenguer, Juan; Muñoz-Gómez, María José; Díez, Cristina; Micán, Rafael; Pérez-Elías, María-Jesús; García-Fraile, Lucio Jesús; Peraire, Joaquin; Suárez-García, Inés; Jimenez-Sousa, Maria Angeles; Fernandez-Rodriguez, Amanda; Vazquez-Alcaraz, Monica; Ryan, Pablo; González-García, Juan; Jarrin Vera, Inmaculada; Mas-Lloret, Vicente; Resino, Salvador; Martinez, Isidoro
Experience of the national cohort of pregnant women with HIV and their children in Spain: temporal trends in vertical transmission of HIV and associated infections
(Elsevier, 2024-10) Illán Ramos, Marta; Berzosa Sánchez, Arantxa; Carrasco García, Itziar; Diaz Franco, Asuncion; Jarrin Vera, Inmaculada; Prieto Tato, Luis; Polo Rodríguez, Rosa; Navarro Gómez, María Luisa; Ramos Amador, José Tomás; Grupo de Trabajo de la Cohorte Nacional de mujeres embarazadas que viven con VIH y sus hijos en España; Ministerio de Sanidad (España)
Introduction: The vertical transmission rate (VTR) of HIV has decreased to less than 2% in high-income countries, in spite of which perinatal infections continue to occur. We present data from the national cohort of pregnant women living with HIV and their children in Spain. The objectives were to describe the characteristics of this population, evaluate the VTR of HIV, the safety of antiretroviral therapy (ART) and the prevalence of coinfection. Patients and methods: Multicentre prospective, observational and descriptive study with participation of 62 hospitals. The sample included pegnant women living with HIV whose children were born between January 2020 and December 2022. We collected prospective data on the characteristics of mothers and children using an online questionnaire (REDCap web application). Results: The study included 414 mother-child dyads. Most mothers were immigrants (227/349; 65.1%). The main route of HIV infection was heterosexual transmission (160/402; 39.8%), followed by vertical transmission (44/402; 10.9%). The diagnosis was made before conception in 313/389 women (80.4%), 394/402 (98%) received ART during pregnancy and 356/402 (89.3%) had an undetectable viral load at the time of delivery. The delivery was vaginal in 230/388 children (59.3%). The proportion of preterm birth was 11.1%. The most frequent neonatal prophylaxis approach was monotherapy with zidovudine (358/414; 86.5%). There were 3 cases of vertical transmission of HIV (95% CI, 0%-1.54%). Only one newborn was breastfed. Conclusions: At present, most women living with HIV in Spain receive the diagnosis before conception, are of foreign ancestry and achieve good control of the infection. Although the VTR is very low in Spain, there are still infections that could be prevented with early diagnosis and treatment.
Discrimination of the Veterans Aging Cohort Study Index 2.0 for Predicting Cause-specific Mortality Among Persons With HIV in Europe and North America
(Oxford University Press, 2024-07) Ambia, Julie; Ingle, Suzanne M; McGinnis, Kathleen; Pantazis, Nikos; Silverberg, Michael J; Wittkop, Linda; Kusejko, Katharina; Crane, Heidi; van Sighem, Ard; Sarcletti, Mario; Cozzi-Lepri, Alessandro; Domingo, Pere; Jarrin Vera, Inmaculada; Wyen, Christoph; Hessamfar, Mojgan; Zhang, Lei; Cavassini, Matthias; Berenguer, Juan; Sterling, Timothy R; Reiss, Peter; Abgrall, Sophie; Gill, M John; Justice, Amy; Sterne, Jonathan A C; Trickey, Adam; NIH - National Institute on Alcohol Abuse and Alcoholism (NIAAA) (Estados Unidos); Gilead; Agence Nationale de Recherches sur le sida et les hépatites virales (Francia); Ministère de la Santé (Francia); Austrian Agency for Health and Food Safety; Stichting HIV Monitoring; Ministry of Health (Holanda); National Institute for Public Health and the Environment (Holanda); German Center for Infection Research (Alemania); RETICS-Sida (RIS-ISCIII) (España); Plan Nacional de I+D+i (España); Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); ViiV Healthcare; Preben og Anna Simonsens Fond; Institut National de la Santé et de la Recherche Médicale (Francia); Bristol-Myers Squibb; Janssen; Ministerio de Sanidad (España); Swiss National Science Foundation; CFAR Network of Integrated Clinical Systems (CNICS); United States Department of Veterans Affairs; NIH - National Institute of Allergy and Infectious Diseases (NIAID) (Estados Unidos)
Background: Predicting cause-specific mortality among people with HIV (PWH) could facilitate targeted care to improve survival. We assessed discrimination of the Veterans Aging Cohort Study (VACS) Index 2.0 in predicting cause-specific mortality among PWH on antiretroviral therapy (ART). Methods: Using Antiretroviral Therapy Cohort Collaboration data for PWH who initiated ART between 2000 and 2018, VACS Index 2.0 scores (higher scores indicate worse prognosis) were calculated around a randomly selected visit date at least 1 year after ART initiation. Missingness in VACS Index 2.0 variables was addressed through multiple imputation. Cox models estimated associations between VACS Index 2.0 and causes of death, with discrimination evaluated using Harrell's C-statistic. Absolute mortality risk was modelled using flexible parametric survival models. Results: Of 59 741 PWH (mean age: 43 years; 80% male), the mean VACS Index 2.0 at baseline was 41 (range: 0-129). For 2425 deaths over 168 162 person-years follow-up (median: 2.6 years/person), AIDS (n = 455) and non-AIDS-defining cancers (n = 452) were the most common causes. Predicted 5-year mortality for PWH with a mean VACS Index 2.0 score of 38 at baseline was 1% and approximately doubled for every 10-unit increase. The 5-year all-cause mortality C-statistic was .83. Discrimination with the VACS Index 2.0 was highest for deaths resulting from AIDS (0.91), liver-related (0.91), respiratory-related (0.89), non-AIDS infections (0.87), and non-AIDS-defining cancers (0.83), and lowest for suicides/accidental deaths (0.65). Conclusions: For deaths among PWH, discrimination with the VACS Index 2.0 was highest for deaths with measurable physiological causes and was lowest for suicide/accidental deaths.
Cross-sectional and longitudinal associations of adherence to WCRF/AICR cancer prevention recommendations with health-related quality of life in breast cancer survivors. Health-EpiGEICAM study
(Elsevier, 2024-08) Lope Carvajal, Virginia; Guerrero-Zotano, Ángel; Fernandez de Larrea-Baz, Nerea; Antolín, Silvia; Benavent Viñuales, Marta; Bermejo, Begoña; Ruiz Moreno, Emma; Baena-Cañada, José Manuel; París, Lorena; Antón, Antonio; Chacón, José Ignacio; Muñoz, Montserrat; García-Sáenz, José Ángel; Olier, Clara; Sánchez Rovira, Pedro; Arcusa Lanza, Angels; González, Sonia; Brunet, Joan; Oltra, Amparo; Bezares, Susana; Rosell, Libertad; Perez-Gomez, Beatriz; Pastor-Barriuso, Roberto; Martín, Miguel; Pollan-Santamaria, Marina; Asociación Española Contra el Cáncer; Instituto de Salud Carlos III
Objectives: Adherence to healthy lifestyle recommendations has been reported to improve health-related quality of life (HRQL) in breast cancer (BC) patients, but the influence of long-term behavioral changes remains unknown. We evaluated the association between adherence to the 2018 World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) cancer prevention recommendations and HRQL both, at BC diagnosis and the change 7-12 years later. Design: Prospective cohort study. Settings and participants: A total of 406 breast cancer survivors, from the EpiGEICAM study, were recruited in 16 Spanish hospitals. Measurements: Epidemiological, clinical, dietary, physical activity and HRQL information was collected both at recruitment and 7-12 years later. A 7-item score to measure compliance with recommendations was assessed according to the 2018 WCRF/AICR scoring criteria. HRQL was evaluated using SF-36 questionnaire. Linear mixed models for longitudinal data were used to assess the cross-sectional and longitudinal association between adherence score and the physical and mental component summary scores. Results: At diagnosis, for each unit increase in WCRF/AICR score adherence, the HRQL physical domain increased 0.78 points (95%CI: -0.04 to 1.60; P trend:0.06). The mean change in physical HRQL from diagnosis to follow-up per unit increase in within-subject adherence score was 0.73 points (95%CI: -0.18 to 1.65; P trend: 0.12). For the mental domain, no association was observed with compliance with the recommendations at diagnosis, nor with changes in adherence over time. Conclusions: Our results suggest that Increased adherence to WCRF/AICR cancer prevention recommendations over time could contribute to slightly improved long-term physical HRQoL in BC survivors.

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