IDIPHIM - Instituto de Investigación Sanitaria Puerta de Hierro (Madrid)

Permanent URI for this collectionhttps://hdl.handle.net/20.500.12105/16964

El IIS Puerta de Hierro-Segovia de Arana surge de la asociación entre: Hospital Universitario Puerta de Hierro Majadahonda, Universidad Autónoma de Madrid y Fundación para la Investigación Biomédica del Hospital Universitario Puerta de Hierro Majadahonda, nuestro hospital ha potenciado la actividad investigadora convirtiéndose así en una de las referencias más importantes en el mundo de la investigación biomédica. De esta forma, uno de los principales objetivos es competir en primera línea en la Investigación Científica con Hospitales y Centros de Excelencia por lo que en noviembre de 2012 quedó formalmente constituido el Instituto de Investigación Sanitaria de Puerta de Hierro-Segovia de Arana. Acreditado por el Instituto de Salud Carlos III como Instituto de Investigación Sanitaria en 2014, 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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Zoonosis screening in Spanish immunocompromised children and their pets
(Frontiers Media, 2024) Garcia-Sanchez, Paula; Romero-Trancón, David; Falces-Romero, Iker; Navarro Carrera, Paula; Ruiz-Carrascoso, Guillermo; Carmena, David; Casares Jiménez, María; Rivero-Juarez, Antonio; Moya, Laura; Rodón, Jaume; Esperón, Fernando; Pérez-Hernando, Belén; Sánchez-León, Rocío; Hurtado-Gallego, Jara; Alcolea, Sonia; Sainz, Talia; Calvo, Cristina; Méndez-Echevarría, Ana; Asociación Española de Pediatría; Fundación Mapfre; Ministerio de Ciencia e Innovación (España); Instituto de Salud Carlos III; Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); European Society for Paediatric Infectious Diseases; Centro de Investigación Biomédica en Red - CIBERINFEC (Enfermedades Infecciosas); Comunidad de Madrid (España); Regional Government of Andalusia (España)
Introduction: Although pets provide several social-emotional benefits for children, the risk of zoonosis must be considered among immunocompromised individuals. Methods: A prospective study was conducted in a tertiary hospital including immunocompromised patients younger than 20 years owning dogs and/or cats. Colonization and/or infection was evaluated by stool studies, bacterial swabs, blood polymerase chain reaction and serological studies in both patients and their pets, to evaluate potential zoonotic transmission occurrence. Results: We included 74 patients and their 92 pets (63 dogs, 29 cats). Up to 44.6% of the patients and 31.5% of the pets had at least 1 positive result. Up to 18.4% of pets' fecal samples were positive (bacteria, parasites or hepatitis E virus). No helminths were observed despite the high frequency of incorrect intestinal deworming practices. Among children, gastrointestinal microorganisms were found in 37.3% (primarily Clostridium difficile). Colonization by Staphylococcus pseudintermedius was common among pets (8.0%) but not among children (0.0%). No shared colonization between owners and pets was observed, except in one case (Blastocystis in both patient and pet feces). Among patients, serologies were positive for Strongyloides stercoralis (14.8%), Toxocara canis (3.2%), Bartonella henselae (19.1%) and hepatitis E (5.6%). Serology was positive for Rickettsia spp. (22.6%) and Babesia spp. (6.5%) in dogs and for Leishmania spp. (14.3%) and Toxoplasma spp. (14.3%) in cats. Conclusion: Exposure to zoonotic agents was detected in both patients and pets; however, shared colonization events were almost nonexistent. In our cohort, dogs and cats do not appear to entail high zoonosis transmission risk for immunocompromised patients.
Gut and respiratory tract microbiota in children younger than 12 months hospitalized for bronchiolitis compared with healthy children: can we predict the severity and medium-term respiratory outcome?
(American Society for Microbiology (ASM), 2024-07-02) Cabrera-Rubio, Raul; Calvo, Cristina; Alcolea, Sonia; Bergia, María; Atucha, Jorge; Pozo Sanchez, Francisco; Casas Flecha, Inmaculada; Arroyas, María; Collado, Maria Carmen; García-García, María Luz; Fundación Universidad Alfonso X el Sabio; Merck, Sharp & Dohme; Instituto de Salud Carlos III; Generalitat Valenciana (España); Ministerio de Ciencia e Innovación. Centro de Excelencia Severo Ochoa (España); Ministerio de Ciencia e Innovación (España); Agencia Estatal de Investigación (España)
Growing evidence indicates that gut and respiratory microbiota have a potential key effect on bronchiolitis, mainly caused by respiratory syncytial virus (RSV). This was a prospective study of 96 infants comparing infants with bronchiolitis (n = 57, both RSV and non-RSV associated) to a control group (n = 39). Gut (feces) and respiratory [nasopharyngeal aspirate (NPA)] microbial profiles were analyzed by 16S rRNA amplicon sequencing, and respiratory viruses were identified by PCR. Clinical data of the acute episode and follow-up during the first year after infection were recorded. Pairwise comparisons showed significant differences in the gut (R2 = 0.0639, P = 0.006) and NPA (R2 = 0.0803, P = 0.006) microbiota between cases and controls. A significantly lower gut microbial richness and an increase in the NPA microbial diversity (mainly due to an increase in Haemophilus, Streptococcus, and Neisseria) were observed in the infants with bronchiolitis, in those with the most severe symptoms, and in those who subsequently developed recurrent wheezing episodes after discharge. In NPA, the higher microbial richness differed significantly between the control group and the non-RSV bronchiolitis group (P = 0.01) and between the control group and the RSV bronchiolitis group (P = 0.001). In the gut, the richness differed significantly between the control group and the non-RSV group (P = 0.01) and between the control group and the RSV bronchiolitis group (P = 0.001), with higher diversity in the RSV group. A distinct respiratory and intestinal microbial pattern was observed in infants with bronchiolitis compared with controls. The presence of RSV was a main factor for dysbiosis. Lower gut microbial richness and increased respiratory microbial diversity were associated with respiratory morbidity during follow-up. Importance: Both the intestinal and respiratory microbiota of children with bronchiolitis, especially those with respiratory syncytial virus infection, are altered and differ from that of healthy children. The microbiota pattern in the acute episode could identify those children who will later have other respiratory episodes in the first year of life. Preventive measures could be adopted for this group of infants.
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].
Incidence and prevalence of multiple sclerosis in Spain: a systematic review
(Elsevier, 2024-10) Garcia Lopez, Fernando Jose; García-Merino, A; Alcalde-Cabero, Enrique; Pedro-Cuesta, Jesus de; Biogen
[EN] Introduction: Greater understanding of the prevalence and incidence of multiple sclerosis in Spain and their temporal trends is necessary to improve the allocation of healthcare resources and to study aetiological factors. Methods: We performed a systematic search of the MedLine database and reviewed the reference lists of the articles gathered. We collected studies reporting prevalence or incidence rates of multiple sclerosis in any geographical location in Spain, with no time limits. In 70% of cases, data were extracted by 2 researchers (FGL and EAC); any discrepancies were resolved by consensus. Results: We identified 51 prevalence and 33 incidence studies published between 1968 and 2018. In the adjusted analysis, the number of prevalent cases per 100 000 population increased by 26.6 (95% confidence interval [CI], 21.5-31.8) every 10 years. After adjusting for year and latitude, the number of incident cases per 100 000 population increased by 1.34 (95% CI, 0.98-1.69) every 10 years. We observed a trend toward higher prevalence and incidence rates at higher latitudes. Conclusions: The prevalence of multiple sclerosis in Spain has increased in recent decades, although case ascertainment appears to be incomplete in many studies. Incidence rates have also increased, but this may be due to recent improvements in the detection of new cases. [ES] Introducción: El conocimiento de la prevalencia y de la incidencia de la esclerosis múltiple en España y de sus tendencias temporales es necesario para planificar mejor los servicios clínicos y estudiar los factores etiológicos. Método: Se efectuó una revisión sistemática mediante una búsqueda en Medline y en las referencias de cada artículo, de todos los estudios que describieran cifras de prevalencia o de incidencia de la esclerosis múltiple en algún lugar geográfico de España, sin límites temporales. En el 70% de los casos la extracción de datos la hicieron 2 observadores (FGL y EAC), que resolvieron las discrepancias por consenso. Resultados: Se identificaron 51 estudios de prevalencia y 33 de incidencia entre 1968 y 2018. En el análisis ajustado, por cada 10 años la prevalencia por 100.000 habitantes aumentó en 26,6 (intervalo de confianza [IC] del 95%: 21,5-31,8). Según los datos del análisis ajustado por el año y la latitud, por cada 10 años la incidencia por 100.000 habitantes aumentó en 1,34 (IC 95%: 0,98-1,69). Se observó una tendencia de mayores prevalencias e incidencias en latitudes más altas. Conclusiones: La prevalencia de la esclerosis múltiple aumentó en las últimas décadas en España, aunque en muchos estudios la verificación de casos parece haber sido incompleta. La incidencia también aumentó, pero eso puede deberse a una detección de casos nuevos más exhaustiva en los últimos años.
Efficacy and Safety of Sarilumab in patients with COVID19 Pneumonia: A Randomized, Phase III Clinical Trial (SARTRE Study)
(Springer, 2021-12) Sancho-López, Aránzazu; Caballero-Bermejo, Antonio F; Ruiz-Antoran, Belen; Munez Rubio, Elena; García-Gasalla, Mercedes; Bonilla, Alfonso; Gonzalez Rozas, Marta; Lopez Veloso, Maria; Muñoz Gomez, Ana; Cuenca Abarca, Ana; Duran del Campo, Pedro; Ibanez, Fatima; Diaz de Santiago, Alberto; Romero, Yolanda; Calderon, Jorge; Pintos, Ilduara; Ferré Beltrán, Adrián; Centeno Soto, Gustavo; Campos, Jose; Ramos Martinez, Antonio; Avendano-Sola, Cristina; Fernandez Cruz, Ana; SARTRE-Study Group
Introduction: SARS-CoV-2 pneumonia is often associated with hyper-inflammation. The cytokine-storm-like is one of the targets of current therapies for coronavirus disease 2019 (COVID-19). High Interleukin-6 (IL6) blood levels have been identified in severe COVID-19 disease, but there are still uncertainties regarding the actual role of anti-IL6 antagonists in COVID-19 management. Our hypothesis was that the use of sarilumab plus corticosteroids at an early stage of the hyper-inflammatory syndrome would be beneficial and prevent progression to acute respiratory distress syndrome (ARDS). Methods: We randomly assigned (in a 1:1 ratio) COVID-19 pneumonia hospitalized patients under standard oxygen therapy and laboratory evidence of hyper-inflammation to receive sarilumab plus usual care (experimental group) or usual care alone (control group). Corticosteroids were given to all patients at a 1 mg/kg/day of methylprednisolone for at least 3 days. The primary outcome was the proportion of patients progressing to severe respiratory failure (defined as a score in the Brescia-COVID19 scale >= 3) up to day 15. Results: A total of 201 patients underwent randomization: 99 patients in the sarilumab group and 102 patients in the control group. The rate of patients progressing to severe respiratory failure (Brescia-COVID scale score >= 3) up to day 15 was 16.16% in the Sarilumab group versus 15.69% in the control group (RR 1.03; 95% CI 0.48-2.20). No relevant safety issues were identified. Conclusions: In hospitalized patients with Covid-19 pneumonia, who were under standard oxygen therapy and who presented analytical inflammatory parameters, an early therapeutic intervention with sarilumab plus standard of care (including corticosteroids) was not shown to be more effective than current standard of care alone. The study was registered at EudraCT with number: 2020-002037-15.
Response to Novel Drugs before and after Allogeneic Stem Cell Transplantation in Patients with Relapsed Multiple Myeloma
(Elsevier, 2019-09) Lopez-Corral, Lucia; Caballero-Velazquez, Teresa; Lopez-Godino, Oriana; Rosinol, Laura; Perez-Vicente, Sabina; Fernandez-Aviles, Francesc; Krsnik, Isabel; Morillo, Daniel; Heras, Inmaculada; Morgades, Mireia; Rifon, Jose J; Sampol Mayol, Antonia; Iniesta, Francisca; Ocio, Enrique-Maria; Martin, Jesus; Rovira, Montserrat; Cabero, Martin; Castilla-Llorente, Cristina; Ribera, Josep-Maria; Torres-Juan, Marta; Maria Moraleda, Jose; Martinez, Carmen; Vazquez, Alejandro; Gutierrez, Gonzalo; Caballero, Dolores; San Miguel, Jesus F; Mateos, Maria-Victoria; Perez-Simon, Jose Antonio
Multiple myeloma (MM) remains as an incurable disease and, although allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative approach, most patients ultimately relapse, and their treatment remains challenging. Because allo-HSCT can modify not only the biology of the disease, but also the immune system and the microenvironment, it can potentially enhance the response to rescue therapies. Information on the efficacy and safety of novel drugs in patients relapsing after allo-HSCT is lacking, however. The objectives of this study were to evaluate the efficacy and toxicity of rescue therapies in patients with MM who relapsed after allo-HSCT, as well as to compare their efficacy before and after allo-HSCT. This retrospective multicenter study included 126 consecutive patients with MM who underwent allo-HSCT between 2000 and 2013 at 8 Spanish centers. All patients engrafted. The incidence of grade II-IV acute graft-versus-host disease (GVHD) was 47%, and nonrelapse mortality within the first 100 days post-transplantation was 13%. After a median follow-up of 92 months, overall survival (OS) was 51% at 2 years and 43% at 5 years. The median progression-free survival after allo-HSCT was 7 months, whereas the median OS after relapse was 33 months. Patients relapsing in the first 6 months after transplantation had a dismal prognosis compared with those who relapsed later (median OS, 11 months versus 120 months; P < .001). The absence of chronic GVHD was associated with reduced OS after relapse (hazard ratio, 3.44; P < .001). Most patients responded to rescue therapies, including proteasome inhibitors (PIs; 62%) and immunomodulatory drugs (IMiDs; 77%), with a good toxicity profile. An in-depth evaluation, including the type and intensity of PI- and IMiD-based combinations used before and after allo-HSCT, showed that the overall response rate and duration of response after allo-HSCT were similar to those seen in the pretransplantation period. Patients with MM who relapse after allo-HSCT should be considered candidates for therapy with new drugs, which can achieve similar response rates with similar durability as seen in the pretransplantation period. This pattern does not follow the usual course of the disease outside the transplantation setting, where response rates and time to progression decreases with each consecutive line of treatment.
Impact of Chronic Disease Self-Management Program on the Self-Perceived Health of People in Areas of Social Vulnerability in Asturias, Spain
(Multidisciplinary Digital Publishing Institute (MDPI), 2024-04-09) García-Ovejero, Ester; Pisano-González, Marta; Salcedo-Diego, Isabel; Serrano-Gallardo, Pilar; Unión Europea
The Chronic Disease Self-Management Program (CDSMP) focuses on a health promotion perspective with a salutogenic approach, reinforcing the pillars of self-efficacy. The aim of this study was to assess the impact of the CDSMP on Self-perceived Health (SPH) in disadvantaged areas of Asturias, España. The study included vulnerable adults with experience of chronic diseases for over six months, along with their caregivers. The intervention consisted of a six-session workshop led by two trained peers. SPH was evaluated by administering the initial item of the SF-12 questionnaire at both baseline and six months post-intervention. To evaluate the variable "Change in SPH" [improvement; remained well; worsening/no improvement (reference category)], global and disaggregated by sex multivariate multinomial logistic regression models were applied. There were 332 participants (mean = 60.5 years; 33.6% were at risk of social vulnerability; 66.8% had low incomes). Among the participants, 22.9% reported an improvement in their SPH, without statistically significant sex-based differences, while 38.9% remained in good health. The global model showed age was linked to decreased "improvement" probability (RRRa = 0.96), and the "remaining well" likelihood drops with social risk (RRRa = 0.42). In men, the probability of "remaining well" decreased by having secondary/higher education (RRRa = 0.25) and increased by cohabitation (RRRa = 5.11). Women at social risk were less likely to report "remaining well" (RRRa = 0.36). In conclusion, six months after the intervention, 22.9% of the participants had improved SPH. Age consistently decreased the improvement in the different models.
Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2
(Nature Publishing Group, 2024-02-19) Pérez-Jurado, Luis Alberto; Cáceres, Alejandro; Balagué-Dobón, Laura; Esko, Tonu; López de Heredia, Miguel; Quintela, Inés; Cruz, Raquel; Lapunzina, Pablo; Carracedo, Ángel; SCOURGE Cohort Group; González, Juan R; Meijome, Xose M; Brochado-Kith, Oscar; Ceballos, Francisco C; Fernandez-Rodriguez, Amanda; Jimenez-Sousa, Maria Angeles; Martin-Vicente, Maria; Resino, Salvador; Virseda-Berdices, Ana; Government of Catalonia (España); Ministerio de Ciencia e Innovación. Centro de Excelencia Severo Ochoa (España); Ministerio de Ciencia e Innovación (España); Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF); Estonian Research Council; Instituto de Salud Carlos III; Amancio Ortega Foundation; Banco Santander
The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people.
Antibiotic Utilization in Hospitalized Children with Bronchiolitis: A Prospective Study Investigating Clinical and Epidemiological Characteristics at a Secondary Hospital in Madrid (2004-2022)
(Multidisciplinary Digital Publishing Institute (MDPI), 2023-11-28) García-García, María Luz; Alcolea, Sonia; Alonso-López, Patricia; Martín-Martín, Clara; Tena-García, Guadalupe; Casas Flecha, Inmaculada; Pozo Sanchez, Francisco; Méndez-Echevarría, Ana; Hurtado-Gallego, Jara; Calvo, Cristina; Instituto de Salud Carlos III
Bronchiolitis is a viral respiratory infection, with respiratory syncytial virus (RSV) being the most frequent agent, requiring hospitalization in 1% of affected children. However, there continues to be a noteworthy incidence of antibiotic prescription in this setting, further exacerbating the global issue of antibiotic resistance. This study, conducted at Severo Ochoa Hospital in Madrid, Spain, focused on antibiotic usage in children under 2 years of age who were hospitalized for bronchiolitis between 2004 and 2022. In that time, 5438 children were admitted with acute respiratory infection, and 1715 infants (31.5%) with acute bronchiolitis were included. In total, 1470 (87%) had a positive viral identification (66% RSV, 32% HRV). Initially, antibiotics were prescribed to 13.4% of infants, but this percentage decreased to 7% during the COVID-19 pandemic thanks to adherence to guidelines and the implementation of rapid and precise viral diagnostic methods in the hospital. HBoV- and HAdV-infected children and those with viral coinfections were more likely to receive antibiotics in the univariate analysis. A multivariate logistic regression analysis revealed a statistically independent association between antibiotic prescription and fever > 38 °C (p < 0.001), abnormal chest-X ray (p < 0.001), ICU admission (p = 0.015), and serum CRP (p < 0.001). In conclusion, following guidelines and the availability of rapid and reliable viral diagnostic methods dramatically reduces the unnecessary use of antibiotics in infants with severe bronchiolitis.
Ethnicity and Clinical Outcomes in Patients Hospitalized for COVID-19 in Spain: Results from the Multicenter SEMI-COVID-19 Registry.
(2022-03-31) Ramos-Rincon, Jose-Manuel; Cobos-Palacios, Lidia; López-Sampalo, Almudena; Ricci, Michele; Rubio-Rivas, Manuel; Martos-Pérez, Francisco; Lalueza-Blanco, Antonio; Moragón-Ledesma, Sergio; Fonseca-Aizpuru, Eva-María; García-García, Gema-María; Beato-Perez, Jose-Luis; Josa-Laorden, Claudia; Arnalich-Fernández, Francisco; Molinos-Castro, Sonia; Torres-Peña, José-David; Vargas-Núñez, Juan-Antonio; Mendez-Bailon, Manuel; Loureiro-Amigo, Jose; Hernández-Garrido, María-Soledad; Peris-García, Jorge; López-Reboiro, Manuel-Lorenzo; Barón-Franco, Bosco; Casas-Rojo, Jose-Manuel; Gómez-Huelgas, Ricardo; On Behalf Of The Semi-Covid-Network,
Background: This work aims to analyze clinical outcomes according to ethnic groups in patients hospitalized for COVID-19 in Spain. Methods: This nationwide, retrospective, multicenter, observational study analyzed hospitalized patients with confirmed COVID-19 in 150 Spanish hospitals (SEMI-COVID-19 Registry) from 1 March 2020 to 31 December 2021. Clinical outcomes were assessed according to ethnicity (Latin Americans, Sub-Saharan Africans, Asians, North Africans, Europeans). The outcomes were in-hospital mortality (IHM), intensive care unit (ICU) admission, and the use of invasive mechanical ventilation (IMV). Associations between ethnic groups and clinical outcomes adjusted for patient characteristics and baseline Charlson Comorbidity Index values and wave were evaluated using logistic regression. Results: Of 23,953 patients (median age 69.5 years, 42.9% women), 7.0% were Latin American, 1.2% were North African, 0.5% were Asian, 0.5% were Sub-Saharan African, and 89.7% were European. Ethnic minority patients were significantly younger than European patients (median (IQR) age 49.1 (40.5−58.9) to 57.1 (44.1−67.1) vs. 71.5 (59.5−81.4) years, p < 0.001). The unadjusted IHM was higher in European (21.6%) versus North African (11.4%), Asian (10.9%), Latin American (7.1%), and Sub-Saharan African (3.2%) patients. After further adjustment, the IHM was lower in Sub-Saharan African (OR 0.28 (0.10−0.79), p = 0.017) versus European patients, while ICU admission rates were higher in Latin American and North African versus European patients (OR (95%CI) 1.37 (1.17−1.60), p < 0.001) and (OR (95%CI) 1.74 (1.26−2.41), p < 0.001). Moreover, Latin American patients were 39% more likely than European patients to use IMV (OR (95%CI) 1.43 (1.21−1.71), p < 0.001). Conclusion: The adjusted IHM was similar in all groups except for Sub-Saharan Africans, who had lower IHM. Latin American patients were admitted to the ICU and required IMV more often.
Tumor microenvironment gene expression profiles associated to complete pathological response and disease progression in resectable NSCLC patients treated with neoadjuvant chemoimmunotherapy.
(2022) Casarrubios, Marta; Provencio, Mariano; Nadal, Ernest; Insa, Amelia; Del Rosario García-Campelo, María; Lázaro-Quintela, Martín; Dómine, Manuel; Majem, Margarita; Rodriguez-Abreu, Delvys; Martinez-Marti, Alex; De Castro Carpeño, Javier; Cobo, Manuel; López Vivanco, Guillermo; Del Barco, Edel; Bernabé, Reyes; Viñolas, Nuria; Barneto Aranda, Isidoro; Massuti, Bartomeu; Sierra-Rodero, Belén; Martinez-Toledo, Cristina; Fernández-Miranda, Ismael; Serna-Blanco, Roberto; Romero, Atocha; Calvo, Virginia; Cruz-Bermúdez, Alberto
Neoadjuvant chemoimmunotherapy for non-small cell lung cancer (NSCLC) has improved pathological responses and survival rates compared with chemotherapy alone, leading to Food and Drug Administration (FDA) approval of nivolumab plus chemotherapy for resectable stage IB-IIIA NSCLC (AJCC 7th edition) without ALK or EGFR alterations. Unfortunately, a considerable percentage of tumors do not completely respond to therapy, which has been associated with early disease progression. So far, it is impossible to predict these events due to lack of knowledge. In this study, we characterized the gene expression profile of tumor samples to identify new biomarkers and mechanisms behind tumor responses to neoadjuvant chemoimmunotherapy and disease recurrence after surgery. Tumor bulk RNA sequencing was performed in 16 pretreatment and 36 post-treatment tissue samples from 41 patients with resectable stage IIIA NSCLC treated with neoadjuvant chemoimmunotherapy from NADIM trial. A panel targeting 395 genes related to immunological processes was used. Tumors were classified as complete pathological response (CPR) and non-CPR, based on the total absence of viable tumor cells in tumor bed and lymph nodes tested at surgery. Differential-expressed genes between groups and pathway enrichment analysis were assessed using DESeq2 and gene set enrichment analysis. CIBERSORTx was used to estimate the proportions of immune cell subtypes. CPR tumors had a stronger pre-established immune infiltrate at baseline than non-CPR, characterized by higher levels of IFNG, GZMB, NKG7, and M1 macrophages, all with a significant area under the receiver operating characteristic curve (ROC) >0.9 for CPR prediction. A greater effect of neoadjuvant therapy was also seen in CPR tumors with a reduction of tumor markers and IFNγ signaling after treatment. Additionally, the higher expression of several genes, including AKT1, BST2, OAS3, or CD8B; or higher dendritic cells and neutrophils proportions in post-treatment non-CPR samples, were associated with relapse after surgery. Also, high pretreatment PD-L1 and tumor mutational burden levels influenced the post-treatment immune landscape with the downregulation of proliferation markers and type I interferon signaling molecules in surgery samples. Our results reinforce the differences between CPR and non-CPR responses, describing possible response and relapse immune mechanisms, opening the possibility of therapy personalization of immunotherapy-based regimens in the neoadjuvant setting of NSCLC.
Lenalidomide plus R-GDP (R2-GDP) in Relapsed/Refractory Diffuse Large B-Cell Lymphoma: Final Results of the R2-GDP-GOTEL Trial and Immune Biomarker Subanalysis.
(2022) Palazón-Carrión, Natalia; Martín García-Sancho, Alejandro; Nogales-Fernández, Esteban; Jiménez-Cortegana, Carlos; Carnicero-González, Fernando; Ríos-Herranz, Eduardo; de la Cruz-Vicente, Fátima; Rodríguez-García, Guillermo; Fernández-Álvarez, Rubén; Martínez-Banaclocha, Natividad; Gumà-Padrò, Josep; Gómez-Codina, José; Salar-Silvestre, Antonio; Rodríguez-Abreu, Delvys; Gálvez-Carvajal, Laura; Labrador, Jorge; Guirado-Risueño, María; García-Domínguez, Daniel J; Hontecillas-Prieto, Lourdes; Espejo-García, Pablo; Fernández-Román, Isabel; Provencio-Pulla, Mariano; Sánchez-Beato, Margarita; Navarro, Marta; Marylene, Lejeune; Álvaro-Naranjo, Tomás; Casanova-Espinosa, Maria; Sánchez-Margalet, Victor; Rueda-Domínguez, Antonio; de la Cruz-Merino, Luis
New therapeutic options are needed in relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL). Lenalidomide-based schedules can reverse rituximab refractoriness in lymphoma. In the phase II R2-GDP trial, 78 patients unsuitable for autologous stem cell transplant received treatment with the following schedule: lenalidomide 10 mg Days (D)1-14, rituximab 375 mg/m2 D1, cisplatin 60 mg/m2 D1, gemcitabine 750 mg/m2 D1 and D8, and dexamethasone 20 mg D1-3, up to 6 cycles (induction phase), followed by lenalidomide 10 mg (or last lenalidomide dose received) D1-21 every 28 days (maintenance phase). Primary endpoint was overall response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), safety, and monitorization of key circulating immune biomarkers (EU Clinical Trials Register number: EudraCT 2014-001620-29). After a median follow-up of 37 months, ORR was 60.2% [37.1% complete responses (CR) and 23.1% partial responses (PR)]. Median OS was 12 months (47 vs. 6 months in CR vs. no CR); median PFS was 9 months (34 vs. 5 months in CR vs. no CR). In the primary refractory population, ORR was 45.5% (21.2% CR and 24.3% PR). Most common grade 3-4 adverse events were thrombocytopenia (60.2%), neutropenia (60.2%), anemia (26.9%), infections (15.3%), and febrile neutropenia (14.1%). Complete responses were associated with a sharp decrease in circulating myeloid-derived suppressor cells and regulatory T cells. R2-GDP schedule is feasible and highly active in R/R DLBCL, including the primary refractory population. Immune biomarkers showed differences in responders versus progressors.
CKD: The burden of disease invisible to research funders.
(2021-11-17) AIRG-E, EKPF, ALCER, FRIAT, REDINREN, RICORS2040, SENEFRO; SET, ONT
The uptake of the current concept of chronic kidney disease (CKD) by the public, physicians and health authorities is low. Physicians still mix up CKD with chronic kidney insufficiency or failure. In a recent manuscript, only 23% of participants in a cohort of persons with CKD had been diagnosed by their physicians as having CKD while 29% has a diagnosis of cancer and 82% had a diagnosis of hypertension. For the wider public and health authorities, CKD evokes kidney replacement therapy (KRT). In Spain, the prevalence of KRT is 0.13%. A prevalent view is that for those in whom kidneys fail, the problem is "solved" by dialysis or kidney transplantation. However, the main burden of CKD is accelerated aging and all-cause and cardiovascular premature death. CKD is the most prevalent risk factor for lethal COVID-19 and the factor that most increases the risk of death in COVID-19, after old age. Moreover, men and women undergoing KRT still have an annual mortality which is 10-100-fold higher than similar age peers, and life expectancy is shortened by around 40 years for young persons on dialysis and by 15 years for young persons with a functioning kidney graft. CKD is expected to become the fifth global cause of death by 2040 and the second cause of death in Spain before the end of the century, a time when 1 in 4 Spaniards will have CKD. However, by 2022, CKD will become the only top-15 global predicted cause of death that is not supported by a dedicated well-funded CIBER network research structure in Spain. Leading Spanish kidney researchers grouped in the kidney collaborative research network REDINREN have now applied for the RICORS call of collaborative research in Spain with the support of the Spanish Society of Nephrology, ALCER and ONT: RICORS2040 aims to prevent the dire predictions for the global 2040 burden of CKD from becoming true. However, only the highest level of research funding through the CIBER will allow to adequately address the issue before it is too late.
Frequency, risk factors, and outcomes of hospital readmissions of COVID-19 patients.
(2021-07-02) Ramos-Martínez, Antonio; Parra-Ramírez, Lina Marcela; Morrás, Ignacio; Carnevali, María; Jiménez-Ibañez, Lorena; Rubio-Rivas, Manuel; Arnalich, Francisco; Beato, José Luis; Monge, Daniel; Asín, Uxua; Suárez, Carmen; Freire, Santiago Jesús; Méndez-Bailón, Manuel; Perales, Isabel; Loureiro-Amigo, José; Gómez-Belda, Ana Belén; Pesqueira, Paula María; Gómez-Huelgas, Ricardo; Mella, Carmen; Díez-García, Luis Felipe; Fernández-Sola, Joaquim; González-Ferrer, Ruth; Aroza, Marina; Antón-Santos, Juan Miguel; Bermejo, Carlos Lumbreras
To determine the proportion of patients with COVID-19 who were readmitted to the hospital and the most common causes and the factors associated with readmission. Multicenter nationwide cohort study in Spain. Patients included in the study were admitted to 147 hospitals from March 1 to April 30, 2020. Readmission was defined as a new hospital admission during the 30 days after discharge. Emergency department visits after discharge were not considered readmission. During the study period 8392 patients were admitted to hospitals participating in the SEMI-COVID-19 network. 298 patients (4.2%) out of 7137 patients were readmitted after being discharged. 1541 (17.7%) died during the index admission and 35 died during hospital readmission (11.7%, p = 0.007). The median time from discharge to readmission was 7 days (IQR 3-15 days). The most frequent causes of hospital readmission were worsening of previous pneumonia (54%), bacterial infection (13%), venous thromboembolism (5%), and heart failure (5%). Age [odds ratio (OR): 1.02; 95% confident interval (95% CI): 1.01-1.03], age-adjusted Charlson comorbidity index score (OR: 1.13; 95% CI: 1.06-1.21), chronic obstructive pulmonary disease (OR: 1.84; 95% CI: 1.26-2.69), asthma (OR: 1.52; 95% CI: 1.04-2.22), hemoglobin level at admission (OR: 0.92; 95% CI: 0.86-0.99), ground-glass opacification at admission (OR: 0.86; 95% CI:0.76-0.98) and glucocorticoid treatment (OR: 1.29; 95% CI: 1.00-1.66) were independently associated with hospital readmission. The rate of readmission after hospital discharge for COVID-19 was low. Advanced age and comorbidity were associated with increased risk of readmission.
Osimertinib in advanced EGFR-T790M mutation-positive non-small cell lung cancer patients treated within the Special Use Medication Program in Spain: OSIREX-Spanish Lung Cancer Group.
(2021-03-06) Provencio, Mariano; Terrasa, Josefa; Garrido, Pilar; Campelo, Rosario García; Aparisi, Francisco; Diz, Pilar; Aguiar, David; García-Giron, Carlos; Hidalgo, Julia; Aguado, Carlos; González, Jorge García; Esteban, Emilio; Gómez-Aldavarí, Lorenzo; Moran, Teresa; Juan, Oscar; Chara, Luís Enrique; Marti, Juan L; Castro, Rafael López; Ortega, Ana Laura; Moreno, Elia Martínez; Coves, Juan; Sánchez Peña, Ana M; Bosch-Barrera, Joaquim; Gastaldo, Amparo Sánchez; Núñez, Natalia Fernández; Del Barco, Edel; Cobo, Manuel; Isla, Dolores; Majem, Margarita; Navarro, Fátima; Calvo, Virginia
AURA study reported 61% objective response rate and progression-free survival of 9.6 months with osimertinib in patients with EGFR/T790M+ non-small cell lung cancer. Due to lack of real-world data, we proposed this study to describe the experience with osimertinib in Spain. Post-authorization, non-interventional Special Use Medication Program, multicenter, retrospective study in advanced EGFR/T790M+ non-small cell lung cancer. One hundred-fifty five patients were enrolled (August 2016-December 2018) from 30 sites. progression-free survival. Secondary objectives: toxicity profile, objective response rate, and use of health service resources. 70% women, median age 66. 63.9% were non-smokers and 99% had adenocarcinoma. Most patients had received at least one prior treatment (97%), 91.7% had received previous EGFR-tyrosine kinase inhibitors and 2.8% osimertinib as first-line treatment. At data cutoff, median follow-up was 11.8 months. One hundred-fifty five patients were evaluable for response, 1.3% complete response, 40.6% partial response, 31% stable disease and 11.6% disease progression. Objective response rate was 42%. Median progression-free survival was 9.4 months. Of the 155 patients who received treatment, 76 (49%) did not reported any adverse event, 51% presented some adverse event, most of which were grade 1 or 2. The resource cost study indicates early use is warranted. This study to assess the real-world clinical impact of osimertinib showed high drug activity in pretreated advanced EGFR/T790M+ non-small cell lung cancer, with manageable adverse events. Clinical trial registration number: NCT03790397 .
Proposal and validation of a method to classify genetic subtypes of diffuse large B cell lymphoma.
(2021-01-21) Pedrosa, Lucía; Fernández-Miranda, Ismael; Pérez-Callejo, David; Quero, Cristina; Rodríguez, Marta; Martín-Acosta, Paloma; Gómez, Sagrario; González-Rincón, Julia; Santos, Adrián; Tarin, Carlos; García, Juan F; García-Arroyo, Francisco R; Rueda, Antonio; Camacho, Francisca I; García-Cosío, Mónica; Heredero, Ana; Llanos, Marta; Mollejo, Manuela; Piris-Villaespesa, Miguel; Gómez-Codina, José; Yanguas-Casás, Natalia; Sánchez, Antonio; Piris, Miguel A; Provencio, Mariano; Sánchez-Beato, Margarita
Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease whose prognosis is associated with clinical features, cell-of-origin and genetic aberrations. Recent integrative, multi-omic analyses had led to identifying overlapping genetic DLBCL subtypes. We used targeted massive sequencing to analyze 84 diagnostic samples from a multicenter cohort of patients with DLBCL treated with rituximab-containing therapies and a median follow-up of 6 years. The most frequently mutated genes were IGLL5 (43%), KMT2D (33.3%), CREBBP (28.6%), PIM1 (26.2%), and CARD11 (22.6%). Mutations in CD79B were associated with a higher risk of relapse after treatment, whereas patients with mutations in CD79B, ETS1, and CD58 had a significantly shorter survival. Based on the new genetic DLBCL classifications, we tested and validated a simplified method to classify samples in five genetic subtypes analyzing the mutational status of 26 genes and BCL2 and BCL6 translocations. We propose a two-step genetic DLBCL classifier (2-S), integrating the most significant features from previous algorithms, to classify the samples as N12-S, EZB2-S, MCD2-S, BN22-S, and ST22-S groups. We determined its sensitivity and specificity, compared with the other established algorithms, and evaluated its clinical impact. The results showed that ST22-S is the group with the best clinical outcome and N12-S, the more aggressive one. EZB2-S identified a subgroup with a worse prognosis among GCB-DLBLC cases.
Combination of Tocilizumab and Steroids to Improve Mortality in Patients with Severe COVID-19 Infection: A Spanish, Multicenter, Cohort Study.
(2020-12-06) Ruiz-Antorán, Belén; Sancho-López, Aránzazu; Torres, Ferrán; Moreno-Torres, Víctor; de Pablo-López, Itziar; García-López, Paulina; Abad-Santos, Francisco; Rosso-Fernández, Clara M; Aldea-Perona, Ana; Montané, Eva; Aparicio-Hernández, Ruth M; Llop-Rius, Roser; Pedrós, Consuelo; Gijón, Paloma; Hernández-Carballo, Carolina; Pedrosa-Martínez, María J; Rodríguez-Jiménez, Consuelo; Prada-Ramallal, Guillermo; Cabrera-García, Lourdes; Aguilar-García, Josefa A; Sanjuan-Jimenez, Rocío; Ortiz-Barraza, Evelyn I; Sánchez-Chica, Enrique; Fernández-Cruz, Ana; TOCICOV-study group
We aimed to determine the impact of tocilizumab use on severe COVID-19 (coronavirus disease 19) pneumonia mortality. We performed a multicentre retrospective cohort study in 18 tertiary hospitals in Spain from March to April 2020. Consecutive patients admitted with severe COVID-19 treated with tocilizumab were compared to patients not treated with tocilizumab, adjusting by inverse probability of the treatment weights (IPTW). Tocilizumab's effect in patients receiving steroids during the 48 h following inclusion was analysed. During the study period, 506 patients with severe COVID-19 fulfilled the inclusion criteria. Among them, 268 were treated with tocilizumab and 238 patients were not. Median time to tocilizumab treatment from onset of symptoms was 11 days [interquartile range (IQR) 8-14]. Global mortality was 23.7%. Mortality was lower in patients treated with tocilizumab than in controls: 16.8% versus 31.5%, hazard ratio (HR) 0.514 [95% confidence interval (95% CI) 0.355-0.744], p These results show that survival of patients with severe COVID-19 is higher in those treated with tocilizumab than in those not treated and that tocilizumab's effect adds to that of steroids administered to non-intubated patients with COVID-19 during the first 48 h of presenting with respiratory failure despite oxygen therapy. Randomised controlled studies are needed to confirm these results. European Union electronic Register of Post-Authorization Studies (EU PAS Register) identifier, EUPAS34415.
Study design of Heart failure Events reduction with Remote Monitoring and eHealth Support (HERMeS).
(2020-09-17) Yun, Sergi; Enjuanes, Cristina; Calero, Esther; Hidalgo, Encarnación; Cobo, Marta; Llàcer, Pau; García-Pinilla, José Manuel; González-Franco, Álvaro; Núñez, Julio; Morales-Rull, José Luis; Beltrán, Paola; Delso, Cristina; Freixa-Pamias, Román; Moliner, Pedro; Corbella, Xavier; Comín-Colet, Josep; HERMeS trial investigators group
The role of non-invasive telemedicine (TM) combining telemonitoring and teleintervention by videoconference (VC) in patients recently admitted due to heart failure (HF) ('vulnerable phase' HF patients) is not well established. The aim of the Heart failure Events reduction with Remote Monitoring and eHealth Support (HERMeS) trial is to assess the impact on clinical outcomes of implementing a TM service based on mobile health (mHealth), which includes remote daily monitoring of biometric data and symptom reporting (telemonitoring) combined with VC structured, nurse-based follow-up (teleintervention). The results will be compared with those of the comprehensive HF usual care (UC) strategy based on face-to-face on-site visits at the vulnerable post-discharge phase. We designed a 24 week nationwide, multicentre, randomized, controlled, open-label, blinded endpoint adjudication trial to assess the effect on cardiovascular (CV) mortality and non-fatal HF events of a TM-based comprehensive management programme, based on mHealth, for patients with chronic HF. Approximately 508 patients with a recent hospital admission due to HF decompensation will be randomized (1:1) to either structured follow-up based on face-to-face appointments (UC group) or the delivery of health care using TM. The primary outcome will be a composite of death from CV causes or non-fatal HF events (first and recurrent) at the end of a 6 month follow-up period. Key secondary endpoints will include components of the primary event analysis, recurrent event analysis, and patient-reported outcomes. The HERMeS trial will assess the efficacy of a TM-based follow-up strategy for real-world 'vulnerable phase' HF patients combining telemonitoring and teleintervention.
A mixed methods study using case studies prepared by nursing students as a clinical practice evaluation tool
(Wiley, 2023-09) Palmar-Santos, Ana María; Oter-Quintana, Cristina; Olmos, Ricardo; Pedraz-Marcos, Azucena; Robledo-Martin, Juana; Autonomous University of Madrid (España); Fundación para la Investigación Biomédica del Hospital Universitario Puerta de Hierro Majadahonda
Aim: To identify the presence of variability in the evaluation of case studies prepared by nursing students during their primary care rotations based on the existing evaluation rubric. To explore the difficulties experienced by link lecturers and students in preparing and evaluating case studies. Design: A mixed methods study. Methods: The scores for the rubric items and the final grades for the case studies were collected from a sample of 132 cases. Qualitative information was collected by conducting open-ended interviews with lecturers and a focus group session with students. Results: Statistically significant differences were identified between the lecturers' mean final grades [F(5.136) = 3.984, p = 0.002] and a variety of items in the evaluation rubric (p < 0.05). In addition, effect sizes [η2 (≈0.14)] of considerable magnitude were found. Two themes emerged from the qualitative data: (1). the challenge of preparing the case studies and (2). the variable nature of the evaluations.
Resilience among primary care professionals in a time of pandemic: a qualitative study in the Spanish context
(BMJ Publishing Group, 2023-06-30) Palmar-Santos, Ana María; Pedraz-Marcos, Azucena; Rubio-Casado, Laura Alicia; Pulido-Fuentes, Montserrat; García-Perea, María Eva; Navarta-Sánchez, María Víctoria; Banco Santander; Ministerio de Ciencia e Innovación (España)
Objectives: This study explores the impact of the COVID-19 pandemic on the Spanish primary care structure and services and the mechanisms implemented by the primary care workforce to restore and reinforce their reference care model. Design: An exploratory, qualitative study with semistructured interviews and a focus group discussion conducted during the fall semester of 2020. Setting: Primary health centres in Madrid (Spain), chosen based on factors such as infection rates during the earliest stages of the pandemic and demographic and socioeconomic aspects. Participants: A total of 19 primary health and social care professionals were purposively selected. Criteria for inclusion were gender (male/female), at least 5 years of experience in their current position, category (health/social/administrative worker), and whether they worked in a rural or urban healthcare setting. Results: Two main themes were identified: (1) reflecting on a model in crisis-particularly the reopening of centres to users and the proactive, participative strategies implemented by primary care professionals to reach their community; and (2) regaining a sense of purpose-how healthcare professionals implemented strategies to sustain their vision of their reference model. The COVID-19 pandemic exposed leadership deficiencies that, together with the initial unavailability of resources and difficulties maintaining face-to-face contact with users, triggered a sense of loss of professional identity. On the other hand, the analysis revealed potential strategies to restore and reinforce the traditional model, such as the adoption of digital technologies and reliance on community networks. Conclusion: This study highlights the importance of a solid reference framework and enhances the strengths and skills of the workforce to reinforce the community-based service provision model.

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