IRYCIS - Instituto Ramón y Cajal de Investigación Sanitaria (Madrid)

Permanent URI for this collectionhttps://hdl.handle.net/20.500.12105/16988

El IRYCIS es un espacio dedicado a la investigación biomédica de excelencia, dirigida a generar conocimientos útiles para la identificación y tratamiento de enfermedades actuales o potenciales y por tanto con un marcado carácter traslacional en la búsqueda permanente del impacto en sociedad y con vocación de convertirse en referencia de ámbito nacional e internacional aplicando en todas sus acciones una filosofía de calidad y mejora continua. Acreditado por el Instituto de Salud Carlos III como Instituto de Investigación Sanitaria en 2011, 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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Differences in the peripheral blood immune landscape between early-onset and late-onset colorectal cancer
(Frontiers Media, 2025-12-04) Sánchez-Menéndez, Clara; Rodríguez-Pérez, Jaime; Fuertes, Daniel; Leguizamon, Valentina; González-Sanmartín, María; Mateos, Elena; Cervero, Miguel; San José, Esther; Sanz, Gonzalo; Álvaro, Edurne; Ballestero-Pérez, Araceli; Martí-Gallostra, Marc; Rueda, José Antonio; Hurtado-Caballero, Elena; Pastor, Carlos; Balaguer, Francesc; Spinelli, Antonino; Martinez-Laso, Jorge; Torres, Montserrat; Perea, José; Coiras, Mayte; Spanish EOCRC Consortium (SECOC); Instituto de Salud Carlos III; Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); Ministerio de Ciencia e Innovación (España); Centro de Investigación Biomédica en Red - CIBERINFEC (Enfermedades Infecciosas); Unión Europea. Comisión Europea. NextGenerationEU; Comunidad de Madrid (España)
Introduction: Colorectal cancer (CRC) is a leading cause of cancer-related mortality. While screening has reduced incidence in older adults, cases of early-onset CRC (EOCRC), diagnosed before age 50, are rising, highlighting the need to understand its unique biology. Immune responses, particularly T-cell infiltration measured by the tumor-based Immunoscore, are known predictors of CRC prognosis, but less is known about systemic immune differences by age at diagnosis. Methods: Peripheral blood mononuclear cells (PBMCs) from EOCRC (n=19) and late-onset CRC (LOCRC; n=19) participants recruited in Madrid (Spain) were analyzed for immune cell phenotypes, exhaustion markers, soluble cytokines, and metabolic activity. Results: Our study revealed distinct peripheral blood immune profiles differentiating EOCRC from LOCRC. EOCRC patients exhibited a heightened proinflammatory environment, with increased functional capacity of CD4+ Th1, Th9, and Th17 subsets to produce IFNg, IL-9, and IL-17A, respectively, and increased plasma levels of IFNg and CXCL8/IL-8. This suggests an active but potentially ineffective immune response. Conversely, LOCRC patients showed hallmarks of immunosenescence and chronic inflammation, including impaired cytokine production, higher frequencies of CD8+ Tgd and Th22 cells, and increased plasma CCL13/MCP-4, consistent with tissue remodeling and immune suppression. Biomarkers distinguishing EOCRC included reduced Th22 and CD8+ Tgd cell frequencies and higher NKT-like cells with increased IL-13 production by Th22 cells. Conclusions: EOCRC and LOCRC involved different immune mechanisms, where EOCRC showed an altered proinflammatory environment with preserved regulatory pathways, while LOCRC reflected age-related immune decline and inflammaging. Peripheral blood immune profiling offers a minimally invasive liquid Immunoscore for early detection and enables personalized immunotherapies for age-related immune landscapes, particularly benefiting younger individuals at risk of EOCRC.
Characterisation of LGP2 complex multitranscript system in humans: role in the innate immune response and evolution from non-human primates.
(Oxford University Press, 2025-01-23) Martinez-Laso, Jorge; Cervera Hernandez, Isabel; Martinez-Carrasco, Marina S; Briz, Veronica; Crespo-Bermejo, Celia; Sánchez-Menéndez, Clara; Casado-Fernández, Guiomar; Torres, Montserrat; Coiras, Mayte; Instituto de Salud Carlos III; Centro de Investigación Biomédica en Red - CIBERINFEC (Enfermedades Infecciosas); Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); Comunidad de Madrid (España)
Retinoic acid inducible gene I (RIG-I)-like receptors (RLRs), including RIG-I, MDA5 and LGP2, recognize viral RNA to mount an antiviral interferon (IFN) response RLRs share three different protein domains: C-terminal domain, DExD/H box RNA helicase domain, and an N-terminal domain with two tandem repeats (CARDs). LGP2 lacks tandem CARD and is not able to induce an IFN response. However, LGP2 positively enhances MDA5 and negatively regulates RIG-I signaling. In this study, we determined the LGP2 alternative transcripts in humans to further comprehend the mechanism of its regulation, their evolutionary origin, and the isoforms functionallity. The results showed new eight alternative transcripts in the samples tested. The presence of these transcripts demonstrated that the main mechanisms for the regulation of LGP2 expression are both by insertion of introns and by the loss of exons. The phylogenetic analysis of the comparison between sequences from exon 1 to exon 3 of humans and those previously described in non-human primates showed three well-differentiated groups (lineages) originating from gorillas, suggesting that the transspecies evolution has been maintained for 10 million years. The corresponding protein models (isoforms) were also established, obtaining four isoforms: one complete and three others lacking the C-terminal domain or this domain and the partial or total He2 Helicase domain, which would compromise the functionality of LGP2. In conclusion, this is the first study that elucidate the large genomic organization and complex transcriptional regulation of human LGP2, its pattern of sequence generation, and a mode of evolutionary inheritance across species.
Case Report: Long-Term Follow-Up of Visceral Leishmaniasis and HIV Coinfected Patients Without Relapse: Lymphoproliferative Response After Stimulation with Soluble Antigen
(Multidisciplinary Digital Publishing Institute (MDPI), 2025-03-19) Monge-Maillo, Begoña; Roger-Zapata, Daniel; Dronda, Fernando; Carrillo, Eugenia; Moreno, Javier; Corbacho-Loarte, María Dolores; Gayoso Cantero, Diego; Martín, Oihane; Chamorro-Tojeiro, Sandra; Perez-Molina, Jose A; Norman, Francesca; González-Sanz, Marta; López-Vélez, Rogelio
Highly active antiretroviral therapy (HAART) has reduced the incidence of VL/HIV dramatically. However, HAART only partially prevents relapses, with one-year relapse rates ranging from 30 to 60%. Consequently, secondary prophylaxis is recommended for patients with <200 CD4+ cells/μL. In clinical practice, characterizing cellular immune response could help estimate the risk of relapse in VL/HIV coinfected patients. In this study, the lymphoproliferative response after stimulation with soluble antigen was assessed in 2022 and 2023 in three cases of VL/HIV coinfection with long-term follow-up (17, 8 and 19 years). PCR and rK-39 results for , HIV viral load, CD4 cell count, proliferation index, IFN-γ, IL-2, IP-10, IL-10 and TNF-α were determined. Heterogeneous results were obtained, with only one patient having developed specific cellular immunity against . No cases of relapse were observed. The heterogeneity of lymphoproliferative test results in the three cases described highlights the need to identify surrogate markers of cure to guide maintenance or withdrawal of prophylaxis.
A Phase I/IIa Prospective, Randomized, Open-Label Study on the Safety and Efficacy of Nebulized Liposomal Amphotericin for Invasive Pulmonary Aspergillosis
(Multidisciplinary Digital Publishing Institute (MDPI), 2024-03-01) Fortún, Jesús; Gómez-García de la Pedrosa, Elia; Martínez-Lorca, Alberto; Paredes, Patricia; Martín-Dávila, Pilar; Gomez-Lopez, Alicia; Buitrago, Maria Jose; López-Jiménez, Javier; Gioia, Francesca; Escudero, Rosa; Alvarez-Alvarez, Maria Elena; Soriano, Cruz; Moreno-García, Javier; San Miguel, Diana; Vicente, Noelia; Moreno, Santiago; Instituto de Salud Carlos III; Ministerio de Sanidad (España)
Although nebulized liposomal amphotericin B (NLAB) is being used in invasive pulmonary aspergillosis (IPA) prophylaxis, no clinical trial has shown its efficacy as a therapeutic strategy. NAIFI is the inaugural randomized, controlled clinical trial designed to examine the safety and effectiveness of NLAB (dosage: 25 mg in 6 mL, three times per week for 6 weeks) against a placebo, in the auxiliary treatment of IPA. Throughout the three-year clinical trial, thirteen patients (six NLAB, seven placebo) were included, with 61% being onco-hematological with less than 100 neutrophils/μL. There were no significant differences noted in their pre- and post-nebulization results of forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), and oxygen saturation between the groups. Neither bronchospasm nor serum amphotericin B levels were reported in any patients given NLAB. 18F-Fluorodeoxyglucose positron emission tomography (FDG-PET-TC) was carried out at the baseline and after 6 weeks. A notable decrease in median SUV (standardized uptake value) was observed in NLAB patients after 6 weeks (-3.6 vs. -0.95, p: 0.039, one tail). Furthermore, a reduction in serum substance galactomannan and beta-D-Glucan was identified within NLAB recipients. NLAB is well tolerated and safe for patients with IPA. Encouraging indirect efficacy data have been derived from image monitoring or biomarkers. However, further studies involving more patients are necessary.
Screening blood donors for malaria, can we increase the number of eligible donors? An observational retrospective study
(BioMed Central (BMC), 2024-06-06) Corbacho-Loarte, María Dolores; Martín, Oihane; Chamorro-Tojeiro, Sandra; Crespillo-Andújar, Clara; Norman, Francesca F; Pérez-Molina, José A; Sanz, Marta González; Cancio-Suárez, Marta Rosas; Ruiz-Calvo, Gabriel; López, Alberto Richart; Rubio Muñoz, Jose Miguel; López-Vélez, Rogelio; Monge-Maillo, Begoña; Instituto de Salud Carlos III; Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF)
Background: In non-endemic countries, malaria can be transmitted through blood donations from imported cases. To ensure standards of quality and safety of human blood, the European Union and Spanish national law, requires a deferral period, or a screening by immunological or genomic test among those donors with potential risk of malaria. Scientific societies, European Committee on Blood Transfusion, and Spanish Society of Haematology and Haemotherapy, refer only to the result of the immunological test. Methods: An observational retrospective study was performed in potential donors with a positive immunological test for malaria done in the Regional Transfusion Center in Madrid and referred to the National Reference Unit for Tropical Diseases in Madrid between 2015-2020. At consultation a Polymerase Chain Reaction (PCR) for malaria was performed. Results: During the study period, 121 possible donors attended for consultation at NRU-Trop. Median age: 38.5 (IQR:33-48); median time to consultation was 32 months (IQR:12.5-110). Eighty-two (67.8%) donors were migrants and thirty-nine were travellers (32.2%). ELISA values were available for 109 subjects (90.1%), 56 individual left malaria endemic area > 3 years before. All donors tested negative for Plasmodium spp PCR test (n = 121, 100%). Conclusions: None of the subjects with a positive immunologic test deferred as blood donors had a positive genomic test. The presence of Plasmodium spp in collected blood was not detected by molecular techniques. To avoid the loss of potential blood donors, especially those with low incidence red blood cell antigens, as more precise microbiology techniques become available, updating the existing legislation becomes necessary to increase the availability of donated blood.
Monitoring of Pseudomonas aeruginosa mutational resistome dynamics using an enrichment panel for direct sequencing of clinical samples
(Elsevier, 2024-10) Cortes-Lara, Sara; Medina-Reatiga, Paola; Barrio-Tofiño, Ester Del; Gomis-Font, María A; Cabot, Gabriel; Gómez-Romano, Fernando; Ayestarán, Ignacio; Colomar, Asunción; Palou-Rotger, Alexandre; Oteo-Iglesias, Jesus; Campo, Rosa Del; Cantón, Rafael; Horcajada, Juan P; López-Causapé, Carla; Oliver, Antonio; Instituto de Salud Carlos III; Ministerio de Ciencia e Innovación (España); Unión Europea. Comisión Europea. NextGenerationEU
Background: Pseudomonas aeruginosa is a major cause of hospital-acquired and chronic infections, characterised by an extraordinary capacity to develop antimicrobial resistance through the selection of chromosomal mutations, leading to treatment failure. Here, we designed and tested a hybridisation-based capture system for the enrichment of genes of interest before sequencing to monitor resistant populations genomics directly from clinical samples. Methods: A panel for enrichment before sequencing of close to 200 genes related to P. aeruginosa antimicrobial resistance, multilocus sequence typing, mutability or virulence was designed, synthesised (KAPA HyperCap, Roche) and initially validated in vitro using a multidrug-resistant ST175 isolate and representative isolates from major P. aeruginosa clades. In vivo testing included ventilator associated pneumonia by MDR P. aeruginosa in ICU (3-10 sequential samples from 3 patients) and chronic respiratory infection by hypermutable P. aeruginosa in cystic fibrosis (8 sequential samples from a single patient covering a 4-year period). Results from direct sequencing with the enrichment panel were compared with those of whole genome sequencing (WGS) and phenotypic profiling of 10 isolated colonies per sample. Findings: In vitro assays confirmed the selectivity of the enrichment panel and the correct identification of the vast mutational resistome of ST175, including specific mutations even when introduced in a 1:100 proportion. In vivo performance was at least equivalent to sequencing 10 colonies per sample, including the accurate identification of the sequence types and the basal and acquired mutational resistome. To note, specific resistance mutations, such as those in ampC leading to resistance to novel β-lactams, could be traced even at frequencies of 1%. Moreover, the coselection of mutator populations and antibiotic resistance mutations, predicted in theoretical and in vitro studies, was evidenced in vivo. Interpretation: This proof-of-concept study demonstrates that resistance genomics of P. aeruginosa can be analysed directly from clinical samples, determining not only a considerable reduction in turnaround time and cost from a diagnostics perspective, but also an unprecedented potency for accurate monitoring of in vivo population dynamics in bacterial infections.
Evaluation of CHROMagar™ B. cepacia agar for the detection of Burkholderia cepacia complex species from sputum samples of patients with cystic fibrosis
(Springer, 2024-07) Maruri-Aransolo, Ainhize; de Dios Caballero, Juan; Michelena, Malkoa; Medina-Pascual, Maria Jose; Carrasco, Gema; Asensio, Oscar; Cols, Maria; Cantón, Rafael; GEIFQ group; Instituto de Salud Carlos III; Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); Plan Nacional de I+D+i (España); Centro de Investigación Biomédica en Red - CIBERINFEC (Enfermedades Infecciosas)
Introduction: Burkholderia cepacia complex (BCC) are non-fermenting Gram-negative bacteria that can chronically colonize the lungs of people with cystic fibrosis (pwCF), causing a severe and progressive respiratory failure, post-transplant complications and epidemic outbreaks. Therefore, rapid and accurate identification of these bacteria is relevant for pwCF, in order to facilitate early eradication and prevent chronic colonization. However, BCCs are often quite difficult to detect on culture media as they have a slow growth rate and can be hidden by other fast-growing microorganisms, including Pseudomonas aeruginosa and filamentous fungi. Material and methods: We evaluated the sensitivity of CHROMagar™ B. cepacia agar using 11 isolates from a well-characterized BCC collection, using BCA agar (Oxoid, UK) as a gold standard. We also studied 180 clinical sputum samples to calculate positive (PPV) and negative (NPV) predictive values. Furthermore, we used three of the well-characterized BCC isolates to determine the limit of detection (LOD). Results: Eleven isolates grew on CHROMagar™ B. cepacia at 37ºC after 48 h. The NPV and PPV of CHROMagar™ B. cepacia were 100% and 87.5%, respectively. The LOD of CHROMagar™ B. cepacia was around 1 × 103 CFU/ml, requiring a ten-fold dilution lower bacterial load than BCA for BCC detection. Conclusion: CHROMagar™ B. cepacia agar proved to have a very good sensitivity and specificity for the detection of clinical BCCs. Moreover, the chromogenic nature of the medium allowed us to clearly differentiate BCC from other Gram-negative species, filamentous fungi and yeasts, thereby facilitating the identification of contaminants.
Epidemiological and clinical characterization of community, healthcare-associated and nosocomial colonization and infection due to carbapenemase-producing Klebsiella pneumoniae and Escherichia coli in Spain
(Springer, 2024-12) Salamanca-Rivera, Elena; Palacios-Baena, Zaira R; Cañada-Garcia, Javier Enrique; Moure García, Zaira; Perez-Vazquez, Maria; Calvo-Montes, Jorge; Martínez-Martínez, Luis; Cantón, Rafael; Ruiz Carrascoso, Guillermo; Pitart, Cristina; Navarro, Ferran; Bou, Germán; Mulet, Xavier; González-López, Juan José; Sivianes, Fran; Delgado-Valverde, Mercedes; Pascual, Álvaro; Oteo-Iglesias, Jesus; Rodríguez-Baño, Jesús; GEMARA/GEIRAS-SEIMC/REIPI CARB-ES-19 Study Group; Instituto de Salud Carlos III; Ministerio de Ciencia e Innovación (España); Unión Europea. Comisión Europea. NextGenerationEU; Plan Nacional de I+D+i (España); Ministerio de Economía y Competitividad (España); Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); Centro de Investigación Biomédica en Red - CIBERINFEC (Enfermedades Infecciosas)
Background: Community-acquired (CA) and healthcare-associated (HCA) infections caused by carbapenemase-producing Enterobacterales (CPE) are not well characterized. The objective was to provide detailed information about the clinical and molecular epidemiological features of nosocomial, HCA and CA infections caused by carbapenemase-producing Klebsiella pneumoniae (CP-Kp) and Escherichia coli (CP-Ec). Methods: A prospective cohort study was performed in 59 Spanish hospitals from February to March 2019, including the first 10 consecutive patients from whom CP-Kp or CP-Ec were isolated. Patients were stratified according to acquisition type. A multivariate analysis was performed to identify the impact of acquisition type in 30-day mortality. Results: Overall, 386 patients were included (363 [94%] with CP-Kp and 23 [6%] CP-Ec); in 296 patients (76.3%), the CPE was causing an infection. Acquisition was CA in 31 (8.0%) patients, HCA in 183 (47.4%) and nosocomial in 172 (48.3%). Among patients with a HCA acquisition, 100 (54.6%) had been previously admitted to hospital and 71 (38.8%) were nursing home residents. Urinary tract infections accounted for 19/23 (82.6%), 89/130 (68.5%) and 42/143 (29.4%) of CA, HCA and nosocomial infections, respectively. Overall, 68 infections (23%) were bacteremia (8.7%, 17.7% and 30.1% of CA, HCA and nosocomial, respectively). Mortality in infections was 28% (13%, 14.6% and 42.7% of CA, HCA and nosocomial, respectively). Nosocomial bloodstream infections were associated with increased odds for mortality (adjusted OR, 4.00; 95%CI 1.21-13.19). Conclusions: HCA and CA infections caused by CPE are frequent and clinically significant. This information may be useful for a better understanding of the epidemiology of CPE.
Dasatinib interferes with HIV-1 proviral integration and the inflammatory potential of monocyte-derived macrophages from people with HIV
(Elsevier, 2024-11) Rodriguez Mora, Sara; Sánchez-Menéndez, Clara; Bautista-Carrascosa, Guiomar; Mateos, Elena; Moreno-Serna, Lucia; Megias Vazquez, Diego; Cantón, Juan; García-Gutiérrez, Valentín; Murciano-Antón, María Aranzazu; Cervero, Miguel; Spivak, Adam; Planelles, Vicente; Coiras, Mayte; National Institutes of Health (Estados Unidos); Ministerio de Ciencia e Innovación (España); Agencia Estatal de Investigación (España); Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); Centro de Investigación Biomédica en Red - CIBERINFEC (Enfermedades Infecciosas); Fundación para la Investigación Biomédica del Hospital Universitario Ramón y Cajal
HIV-1 infection is efficiently controlled by the antiretroviral treatment (ART) but viral persistence in long-lived reservoirs formed by CD4 + T cells and macrophages impedes viral eradication and creates a chronic inflammatory environment. Dasatinib is a tyrosine kinase inhibitor clinically used against chronic myeloid leukemia (CML) that has also showed an anti-inflammatory potential. We previously reported that dasatinib is very efficient at interfering with HIV-1 infection of CD4 + T cells by preserving the antiviral activity of SAMHD1, an innate immune factor that blocks T-cell activation and proliferation and that is inactivated by phosphorylation at T592 (pSAMHD1). We observed that short-term treatment in vitro with dasatinib significantly reduced pSAMHD1 in monocyte-derived macrophages (MDMs) isolated from people with HIV (PWH) and healthy donors, interfering with HIV-1 infection. This inhibition was based on low levels of 2-LTR circles and proviral integration, while viral reverse transcription was not affected. MDMs isolated from people with CML on long-term treatment with dasatinib also showed low levels of pSAMHD1 and were resistant to HIV-1 infection. In addition, dasatinib decreased the inflammatory potential of MDMs by reducing the release of M1-related cytokines like TNFα, IL-1β, IL-6, CXCL8, and CXCL9, but preserving the antiviral activity through normal levels of IL-12 and IFNγ. Due to the production of M2-related anti-inflammatory cytokines like IL-1RA and IL-10 was also impaired, dasatinib appeared to interfere with MDMs differentiation. The use of dasatinib along with ART could be used against HIV-1 reservoir in CD4 and macrophages and to alleviate the chronic inflammation characteristic of PWH.
Performance of the Idylla microsatellite instability test in endometrial cancer
(Elsevier, 2024-10) Mendiola, Marta; Heredia-Soto, Victoria; Ruz-Caracuel, Ignacio; Baillo, Amparo; Ramon-Patino, Jorge Luis; Berjon, Alberto; Escudero Ruiz, Francisco Javier; Peláez-García, Alberto; Hernandez, Alicia; Feliu, Jaime; Hardisson, David; Redondo, Andres; Agencia Estatal de Investigación (España); Instituto de Salud Carlos III; Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF)
Context: DNA mismatch repair (MMR) deficiency (dMMR) testing is now recommended in endometrial cancer. Defect identification in the molecules participating in this pathway, or the presence of microsatellite instability, are commonly employed for this purpose. Novel methods are continuously evolving to report dMMR/microsatellite instability and to easily perform routine diagnoses. Objective: The main aim of this study was to compare the concordance of the Idylla microsatellite instability test for the identification of dMMR endometrial cancer samples defined by immunohistochemistry and MMR genomic status. Design: We applied the Idylla MSI test to 126 early-stage endometrial cancer cases with MMR testing by immunohistochemistry and genomic characterization (methylation in MLH1 and sequence alterations in MLH1, PMS2, MSH2 and MSH6). Individual markers and overall specific performance indicators were explored. Results: The Idylla platform achieved a higher global concordance rate with MMR genomic status than with immunohistochemistry (75 % and 66 %, respectively). Sensitivity and specificity are also higher (75 % vs 66 % and 96 % vs 90 %, respectively). Clustering analysis split the patients into 2 well-differentiated clusters, the pMMR and the dMMR group, represented by MLH1/PMS2 loss and the MLH1 methylated promoter. Overall, immunohistochemistry and MMR genomic status identified more dMMR cases than did the Idylla test, although correlations were improved with a modified Idylla test cut-off. Conclusions: Performance of the Idylla test was better correlated with MMR genomic status than MMR immunohistochemistry status, which improved with a modified test cut-off. Further studies are needed to confirm the cut-off accuracy.
A genome-wide association meta-analysis of all-cause and vascular dementia
(Wiley, 2024-09) Mega Vascular Cognitive Impairment and Dementia (MEGAVCID) consortium; Calero, Miguel; NIH - National Heart, Lung, and Blood Institute (NHLBI) (Estados Unidos); NIH - National Institute on Aging (NIA) (Estados Unidos); NIH - National Institute of Neurological Disorders and Stroke (NINDS) (Estados Unidos)
Introduction: Dementia is a multifactorial disease with Alzheimer's disease (AD) and vascular dementia (VaD) pathologies making the largest contributions. Yet, most genome-wide association studies (GWAS) focus on AD. Methods: We conducted a GWAS of all-cause dementia (ACD) and examined the genetic overlap with VaD. Our dataset includes 800,597 individuals, with 46,902 and 8702 cases of ACD and VaD, respectively. Known AD loci for ACD and VaD were replicated. Bioinformatic analyses prioritized genes that are likely functionally relevant and shared with closely related traits and risk factors. Results: For ACD, novel loci identified were associated with energy transport (SEMA4D), neuronal excitability (ANO3), amyloid deposition in the brain (RBFOX1), and magnetic resonance imaging markers of small vessel disease (SVD; HBEGF). Novel VaD loci were associated with hypertension, diabetes, and neuron maintenance (SPRY2, FOXA2, AJAP1, and PSMA3). Discussion: Our study identified genetic risks underlying ACD, demonstrating overlap with neurodegenerative processes, vascular risk factors, and cerebral SVD. Highlights: We conducted the largest genome-wide association study of all-cause dementia (ACD) and vascular dementia (VaD). Known genetic variants associated with AD were replicated for ACD and VaD. Functional analyses identified novel loci for ACD and VaD. Genetic risks of ACD overlapped with neurodegeneration, vascular risk factors, and cerebral small vessel disease.
High concentrations of Maraviroc do not alter immunological and metabolic parameters of CD4 T cells
(Nature Publishing Group, 2024-06-17) de la Torre-Tarazona, Humberto Erick; Passaes, Caroline; Moreno, Santiago; Sáez-Cirión, Asier; Alcamí, José; Ministerio de Ciencia e Innovación (España); Gilead Sciences (Spain); Instituto de Salud Carlos III; Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF)
Maraviroc (MVC) is an antiretroviral drug capable of binding to CCR5 receptors and block HIV entry into target cells. Moreover, MVC can activate NF-kB pathway and induce viral transcription in HIV-infected cells, being proposed as a latency reversal agent (LRA) in HIV cure strategies. However, the evaluation of immunological and metabolic parameters induced by MVC concentrations capable of inducing HIV transcription have not been explored in depth. We cultured isolated CD4 T cells in the absence or presence of MVC, and evaluated the frequency of CD4 T cell subpopulations and activation markers levels by flow cytometry, and the oxidative and glycolytic metabolic rates of CD4 T cells using a Seahorse Analyzer. Our results indicate that a high concentration of MVC did not increase the levels of activation markers, as well as glycolytic or oxidative metabolic rates in CD4 T cells. Furthermore, MVC did not induce significant changes in the frequency and activation levels of memory cell subpopulations. Our data support a safety profile of MVC as a promising LRA candidate since it does not induce alterations of the immunological and metabolic parameters that could affect the functionality of these immune cells.
Global and regional molecular epidemiology of HIV-1, 1990-2015: a systematic review, global survey, and trend analysis
(Elsevier, 2019-02) Hemelaar, Joris; Elangovan, Ramyiadarsini; Yun, Jason; Dickson-Tetteh, Leslie; Fleminger, Isabella; Kirtley, Shona; Williams, Brian; Gouws-Williams, Eleanor; Ghys, Peter D; WHO–UNAIDS Network for HIV Isolation Characterisation; Amo, Julia del; Delgado, Elena; Najera-Morrondo, Rafael; Perez-Alvarez, Lucia; Thomson, Michael M
Background: Global genetic diversity of HIV-1 is a major challenge to the development of HIV vaccines. We aimed to estimate the regional and global distribution of HIV-1 subtypes and recombinants during 1990-2015. Methods: We searched PubMed, EMBASE (Ovid), CINAHL (Ebscohost), and Global Health (Ovid) for HIV-1 subtyping studies published between Jan 1, 1990, and Dec 31, 2015. We collected additional unpublished HIV-1 subtyping data through a global survey. We included prevalence studies with HIV-1 subtyping data collected during 1990-2015. We grouped countries into 14 regions and analysed data for four time periods (1990-99, 2000-04, 2005-09, and 2010-15). The distribution of HIV-1 subtypes, circulating recombinant forms (CRFs), and unique recombinant forms (URFs) in individual countries was weighted according to the UNAIDS estimates of the number of people living with HIV (PLHIV) in each country to generate regional and global estimates of HIV-1 diversity in each time period. The primary outcome was the number of samples designated as HIV-1 subtypes A, B, C, D, F, G, H, J, K, CRFs, and URFs. The systematic review is registered with PROSPERO, number CRD42017067164. Findings: This systematic review and global survey yielded 2203 datasets with 383 519 samples from 116 countries in 1990-2015. Globally, subtype C accounted for 46·6% (16 280 897/34 921 639 of PLHIV) of all HIV-1 infections in 2010-15. Subtype B was responsible for 12·1% (4 235 299/34 921 639) of infections, followed by subtype A (10·3%; 3 587 003/34 921 639), CRF02_AG (7·7%; 2 705 110/34 921 639), CRF01_AE (5·3%; 1 840 982/34 921 639), subtype G (4·6%; 1 591 276/34 921 639), and subtype D (2·7%; 926 255/34 921 639). Subtypes F, H, J, and K combined accounted for 0·9% (311 332/34 921 639) of infections. Other CRFs accounted for 3·7% (1 309 082/34 921 639), bringing the proportion of all CRFs to 16·7% (5 844 113/34 921 639). URFs constituted 6·1% (2 134 405/34 921 639), resulting in recombinants accounting for 22·8% (7 978 517/34 921 639) of all global HIV-1 infections. The distribution of HIV-1 subtypes and recombinants changed over time in countries, regions, and globally. At a global level during 2005-15, subtype B increased, subtypes A and D were stable, and subtypes C and G and CRF02_AG decreased. CRF01_AE, other CRFs, and URFs increased, leading to a consistent increase in the global proportion of recombinants over time. Interpretation: Global and regional HIV diversity is complex and evolving, and is a major challenge to HIV vaccine development. Surveillance of the global molecular epidemiology of HIV-1 remains crucial for the design, testing, and implementation of HIV vaccines.
Sustained antiviral response against HIV-1 infection in peripheral blood mononuclear cells from people with chronic myeloid leukemia treated with ponatinib
(Frontiers Media, 2024) Manzanares, Mario; Ramos-Martín, Fernando; Rodriguez Mora, Sara; Casado-Fernández, Guiomar; Sánchez-Menéndez, Clara; Simón-Rueda, Alicia; Mateos, Elena; Cervero, Miguel; Spivak, Adam M; Planelles, Vicente; Torres, Montserrat; García-Gutiérrez, Valentín; Coiras, Mayte; Centro de Investigación Biomédica en Red - CIBERINFEC (Enfermedades Infecciosas); Instituto de Salud Carlos III; Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); Ministerio de Ciencia e Innovación (España); Agencia Estatal de Investigación (España); Comunidad de Madrid (España); Fundación para la Investigación Biomédica del Hospital Universitario Ramón y Cajal; Fundación Teófilo Hernando; Incyte Biosciences Iberia
HIV-1 infection cannot be cured due to long-lived viral reservoirs formed by latently infected CD4 T cells. "Shock and Kill" strategy has been considered to eliminate the viral reservoir and achieve a functional cure but the stimulation of cytotoxic immunity is necessary. Ponatinib is a tyrosine kinase inhibitor (TKI) clinically used against chronic myeloid leukemia (CML) that has demonstrated to be effective against HIV-1 infection . Several TKIs may induce a potent cytotoxic response against cancer cells that makes possible to discontinue treatment in people with CML who present long-term deep molecular response. In this longitudinal study, we analyzed the capacity of ponatinib to induce an antiviral response against HIV-1 infection in peripheral blood mononuclear cells (PBMCs) obtained from people with CML previously treated with imatinib for a median of 10 years who changed to ponatinib for 12 months to boost the anticancer response before discontinuing any TKI as part of the clinical trial NCT04043676. Participants were followed-up for an additional 12 months in the absence of treatment. PBMCs were obtained at different time points and then infected with HIV-1. The rate of infection was determined by quantifying the intracellular levels of p24-gag in CD4 T cells. The levels of p24-gag+ CD4 T-cells were lower when these cells were obtained during and after treatment with ponatinib in comparison with those obtained during treatment with imatinib. Cytotoxicity of PBMCs against HIV-infected target cells was significantly higher during treatment with ponatinib than during treatment with imatinib, and it was maintained at least 12 months after discontinuation. There was a significant negative correlation between the lower levels of p24-gag+ CD4 T-cells and the higher cytotoxicity induced by PBMCs when cells were obtained during and after treatment with ponatinib. This cytotoxic immunity was mostly based on higher levels of Natural Killer and Tγδ cells seemingly boosted by ponatinib. In conclusion, transient treatment with immunomodulators like ponatinib along with ART could be explored to boost the antiviral activity of cytotoxic cells and contribute to the elimination of HIV-1 reservoir.
Executive Summary of the Consensus Statement of the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC), the Spanish Society of Tropical Medicine and International Health (SEMTSI), the Spanish Association of Surgeons (AEC), the Spanish Society of Pneumology and Thoracic Surgery (SEPAR), the Spanish Society of Thoracic Surgery (SECT), the Spanish Society of Vascular and Interventional Radiology (SERVEI), and the Spanish Society of Paediatric Infectious Diseases (SEIP), on the Management of Cystic Echinococcosis
(Elsevier, 2020) Belhassen-García, Moncef; Balboa Arregui, Óscar; Calabuig-Muñoz, Eva; Carmena, David; Esteban Velasco, Maria Del Carmen; Fuentes Gago, Marta; Fumado Pérez, Victoria; García Alonso, Jesús; García López Hortelano, Milagros; González Fernández, Luis Miguel; Herrero Martínez, Juan María; Iglesias Iglesias, Manuel José; Jiménez López, Marcelo; López-Vélez, Rogelio; Muñoz-Bellvis, Luis; Muro, Antonio; Pardo-Lledías, Javier; Peñaranda-Vera, Maria; Perteguer-Prieto, Maria Jesus; Picado, Albert; Quiñones Sampedro, Jose Edecio; Rodríguez-Guardado, Azucena; Royo Crespo, Íñigo; Salvador, Fernando; Sánchez-Montalvá, Adrián; Torrús-Tendero, Diego; Velasco Pelayo, Luis; Sociedad Española de Medicina Tropical y Salud Internacional
[EN] The Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC), the Spanish Society of Tropical Medicine and International Health (SEMTSI), the Spanish Association of Surgeons (AEC), the Spanish Society of Pneumology and Thoracic Surgery (SEPAR), the Spanish Society of Thoracic Surgery (SECT), the Spanish Society of Vascular and Interventional Radiology (SERVEI), and the Spanish Society of Paediatric Infectious Diseases (SEIP) considered it pertinent to issue a consensus statement on the management of cystic echinococcosis (CE) to guide healthcare professionals in the care of patients with CE. Specialists from several fields (clinicians, surgeons, radiologists, microbiologists, and parasitologists) identified the most clinically relevant questions and developed this Consensus Statement, evaluating the available evidence-based data to propose a series of recommendations on the management of this disease. This Consensus Statement is accompanied by the corresponding references on which these recommendations are based. Prior to publication, the manuscript was open for comments and suggestions from the members of the SEIMC and the scientific committees and boards of the various societies involved. [ES] La Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica (SEIMC), la Sociedad Española de Medicina Tropical y Salud Internacional (SEMTSI), la Asociación Española de Cirujanos (AEC), la Sociedad Española de Neumología y Cirugía Torácica (SEPAR), la Sociedad Española de Cirugía Torácica (SECT), la Sociedad Española de Radiología Vascular e Intervencionista (SERVEI) y la Sociedad Española de Infectología Pediátrica (SEIP) han considerado pertinente la elaboración de una declaración de consenso sobre el tratamiento de la equinococosis quística (EQ) que sirva de ayuda al personal sanitario en la atención de pacientes con EQ. Varios tipos de profesionales (médicos, cirujanos, radiólogos, microbiólogos y parasitólogos) han seleccionado las preguntas más clínicamente relevantes y han desarrollado esta Declaración de consenso, en la que evalúan los datos basados en la evidencia disponibles para proponer una serie de recomendaciones sobre el tratamiento de esta enfermedad. Esta Declaración de consenso se acompaña de la bibliografía correspondiente que fundamenta estas recomendaciones. Antes de su publicación, el manuscrito estuvo abierto a comentarios y sugerencias de los miembros de la SEIMC y de los comités científicos y juntas directivas de las diferentes sociedades implicadas.
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
Anal squamous intraepithelial lesions are frequent among young HIV-infected men who have sex with men followed up at the Spanish AIDS Research Network Cohort (CoRIS-HPV)
(Wiley, 2013-09-01) Gonzalez Blazquez, Cristina; Torres, Montserrat; Benito, Amparo; Del Romero, Jorge; Rodríguez, Carmen; Fontillón, María; Trastoy, Mónica; Viciana, Pompeyo; Amo, Julia del; Ortiz Rivera, Marta; Hernández-Novoa, Beatriz; CoRIS-HPV Study Group
The aim of our study was to determine the baseline prevalence of anal squamous intraepithelial lesions (SIL) and associated risk factors in HIV-infected men who have sex with men (MSM) in a Spanish ongoing multicenter cohort. CoRIS-HPV started in 2007, nested in the Spanish AIDS Research Network Cohort (CoRIS). Anal liquid cytology testing was performed. High-risk human papillomavirus (HR-HPV) infection was determined, and positive samples were genotyped. We analyzed all subjects up to April 2011. Multivariate logistic regression analyses were performed. A total of 551 subjects with baseline anal liquid cytologies were analyzed; 37.0% negative for intraepithelial lesion, 9.0% atypical squamous cells of uncertain significance (ASCUS), 41.0% low-grade SIL, 4.0% high-grade SIL and 9.0% inadequate. Prevalence of anal SIL (excluding ASCUS) in valid samples (n = 450) was 54.7% (95% confidence interval [CI] = 49.9-59.3). Globally HR-HPV prevalence was 81.7% (95% CI = 78.0-85.2). Multiple infections (≥2 HR-HPV genotypes) were documented in 77.7% (95% CI = 73.1-82.0). The only risk factor associated with anal SIL was the number of HR-HPV types; MSM with five or more HR-HPV genotypes had an odds ratio (OR) of anal SIL seven times greater (OR = 7.4; 95% CI = 2.8-19.6) than those with one HR-HPV genotype. No associations were found for age, educational level, smoking, geographical origin, CD4 T-cell count, antiretroviral treatment or number of sexual partners. The prevalence of anal SIL in young HIV-positive MSM is high, and the main risk factor is multiple infections with HR-HPV types.
Different polarization and functionality of CD4+ T helper subsets in people with post-COVID condition
(Frontiers Media, 2024) Sánchez-Menéndez, Clara; de la Calle-Jiménez, Olivia; Mateos, Elena; Vigon-Hernandez, Lorena; Fuertes, Daniel; Murciano-Antón, María Aranzazu; San José, Esther; García-Gutiérrez, Valentín; Cervero, Miguel; Torres, Montserrat; Coiras, Mayte; Ministerio de Ciencia e Innovación (España); Instituto de Salud Carlos III; Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); Centro de Investigación Biomédica en Red - CIBERINFEC (Enfermedades Infecciosas); Fundación para la Investigación Biomédica del Hospital Universitario Ramón y Cajal
Introduction: After mild COVID-19 that does not require hospitalization, some individuals develop persistent symptoms that may worsen over time, producing a multisystemic condition termed Post-COVID condition (PCC). Among other disorders, PCC is characterized by persistent changes in the immune system that may not be solved several months after COVID-19 diagnosis. Methods: People with PCC were recruited to determine the distribution and functionality of CD4+ T helper (Th) subsets in comparison with individuals with mild, severe, and critical presentations of acute COVID-19 to evaluate their contribution as risk or protective factors for PCC. Results: People with PCC showed low levels of Th1 cells, similar to individuals with severe and critical COVID-19, although these cells presented a higher capacity to express IFNγ in response to stimulation. Th2/Th1 correlation was negative in individuals with acute forms of COVID-19, but there was no significant Th2/Th1 correlation in people with PCC. Th2 cells from people with PCC presented high capacity to express IL-4 and IL-13, which are related to low ventilation and death associated with COVID-19. Levels of proinflammatory Th9 and Th17 subsets were significantly higher in people with PCC in comparison with acute COVID-19, being Th1/Th9 correlation negative in these individuals, which probably contributed to a more pro-inflammatory than antiviral scenario. Th17 cells from approximately 50% of individuals with PCC had no capacity to express IL-17A and IL-22, similar to individuals with critical COVID-19, which would prevent clearing extracellular pathogens. Th2/Th17 correlation was positive in people with PCC, which in the absence of negative Th1/Th2 correlation could also contribute to the proinflammatory state. Finally, Th22 cells from most individuals with PCC had no capacity to express IL-13 or IL-22, which could increase tendency to reinfections due to impaired epithelial regeneration. Discussion: People with PCC showed skewed polarization of CD4+ Th subsets with altered functionality that was more similar to individuals with severe and critical presentations of acute COVID-19 than to people who fully recovered from mild disease. New strategies aimed at reprogramming the immune response and redirecting CD4+ Th cell polarization may be necessary to reduce the proinflammatory environment characteristic of PCC.
Comparison of seven prognostic tools to identify low-risk pulmonary embolism in patients aged <50 years
(2019-12-27) Jara-Palomares, Luis; Alfonso, Maria; Maestre, Ana; Jimenez, David; Garcia-Bragado, Fernando; Font, Carme; Lopez Reyes, Raquel; Hernandez Blasco, Luis; Vidal, Gemma; Otero, Remedios; Monreal, Manuel; RIETE investigators
In young patients with acute pulmonary embolism (PE), the predictive value of currently available prognostic tools has not been evaluated. Our objective was to compare prognostic value of 7 available tools (GPS, PESI, sPESI, Prognostic Algorithm, PREP, shock index and RIETE) in patients aged <50 years. We used the RIETE database, including PE patients from 2001 to 2017. The major outcome was 30-day all-cause mortality. Of 34,651 patients with acute PE, 5,822 (17%) were aged <50 years. Of these, 83 (1.4%) died during the first 30 days. Number of patients deemed low risk with tools was: PREP (95.9%), GPS (89.6%), PESI (87.2%), Shock index (70.9%), sPESI (59.4%), Prognostic algorithm (58%) and RIETE score (48.6%). The tools with a highest sensitivity were: Prognostic Algorithm (91.6%; 95% CI: 85.6-97.5), RIETE score (90.4%; 95%CI: 84.0-96.7) and sPESI (88%; 95% CI: 81-95). The RIETE, Prognostic Algorithm and sPESI scores obtained the highest overall sensitivity estimates for also predicting 7- and 90-day all-cause mortality, 30-day PE-related mortality, 30-day major bleeding and 30-day VTE recurrences. The proportion of low-risk patients who died within the first 30 days was lowest using the Prognostic Algorithm (0.2%), RIETE (0.3%) or sPESI (0.3%) scores. In PE patients less 50 years, 30-day mortality was low. Although sPESI, RIETE and Prognostic Algorithm scores were the most sensitive tools to identify patients at low risk to die, other tools should be evaluated in this population to obtain more efficient results.
The CARBA-MAP study: national mapping of carbapenemases in Spain (2014-2018)
(Frontiers Media, 2023) Gracia-Ahufinger, Irene; López-González, Laura; Vasallo, Francisco José; Galar, Alicia; Siller, María; Pitart, Cristina; Bloise, Iván; Torrecillas, Miriam; Gijón-Cordero, Desirée; Viñado, Belén; Castillo-García, Javier; Campo, Rainer; Mulet, Xavier; Madueño-Alonso, Ana; Chamizo-López, Francisco Javier; Arrastia-Erviti, Maitane; Galán-Sánchez, Fátima; Fernández-Quejo, Melisa; Rodríguez-Díaz, Juan Carlos; Gutiérrez-Zufiaurre, María Nieves; Rodríguez-Maresca, Manuel Angel; Ortega-Lafont, María Del Pilar; Yague-Guirao, Genoveva; Chaves-Blanco, Lucía; Colomina-Rodríguez, Javier; Vidal-Acuña, María Reyes; Portillo, María Eugenia; Franco-Álvarez de Luna, Francisco; Centelles-Serrano, María José; Azcona-Gutiérrez, José Manuel; Delgado-Iribarren García Campero, Alberto; Rey-Cao, Sonia; Muñoz, Patricia; Calvo-Montes, Jorge; Zboromyrska, Yuliya; Grandioso, David; Càmara, Jordi; Cantón, Rafael; Larrosa-Escartín, Nieves; Díaz-Regañón, Jazmín; Martínez-Martínez, Luis
Introduction: Infections caused by carbapenem-resistant Enterobacterales (CRE) and carbapenem-resistant Pseudomonas aeruginosa, including isolates producing acquired carbapenemases, constitute a prevalent health problem worldwide. The primary objective of this study was to determine the distribution of the different carbapenemases among carbapenemase-producing Enterobacterales (CPE, specifically Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae complex, and Klebsiella aerogenes) and carbapenemase-producing P. aeruginosa (CPPA) in Spain from January 2014 to December 2018. Methods: A national, retrospective, cross-sectional multicenter study was performed. The study included the first isolate per patient and year obtained from clinical samples and obtained for diagnosis of infection in hospitalized patients. A structured questionnaire was completed by the participating centers using the REDCap platform, and results were analyzed using IBM SPSS Statistics 29.0.0. Results: A total of 2,704 carbapenemase-producing microorganisms were included, for which the type of carbapenemase was determined in 2692 cases: 2280 CPE (84.7%) and 412 CPPA (15.3%), most often using molecular methods and immunochromatographic assays. Globally, the most frequent types of carbapenemase in Enterobacterales and P. aeruginosa were OXA-48-like, alone or in combination with other enzymes (1,523 cases, 66.8%) and VIM (365 cases, 88.6%), respectively. Among Enterobacterales, carbapenemase-producing K. pneumoniae was reported in 1821 cases (79.9%), followed by E. cloacae complex in 334 cases (14.6%). In Enterobacterales, KPC is mainly present in the South and South-East regions of Spain and OXA-48-like in the rest of the country. Regarding P. aeruginosa, VIM is widely distributed all over the country. Globally, an increasing percentage of OXA-48-like enzymes was observed from 2014 to 2017. KPC enzymes were more frequent in 2017-2018 compared to 2014-2016. Discussion: Data from this study help to understand the situation and evolution of the main species of CPE and CPPA in Spain, with practical implications for control and optimal treatment of infections caused by these multi-drug resistant organisms.

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