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Publication Molecular epidemiology of paediatric invasive pneumococcal disease in Andalusia, Spain.(2022-08-22) de Felipe, Beatriz; Obando Pacheco, Pablo; Carazo Gallego, Begoña; López Martín, David; Santos Pérez, Juan Luis; González Jiménez, Yolanda; Muñoz Vilches, María José; Cardelo Autero, Nerea; González Galán, Verónica; Morón, Francisco José; Cordero Varela, Juan Antonio; Torres Sánchez, María José; Medina Claros, Antonio; Moreno Pérez, David; Obando, IgnacioThis study aimed to assess the impact of the introduction of pneumococcal conjugate vaccine 13 (PCV13) on the molecular epidemiology of invasive pneumococcal disease (IPD) in children from Andalusia. A population-based prospective surveillance study was conducted on IPD in children agedPublication Efficacy of niraparib by time of surgery and postoperative residual disease status: A post hoc analysis of patients in the PRIMA/ENGOT-OV26/GOG-3012 study.(2022-05-09) O'Cearbhaill, Roisin E; Pérez-Fidalgo, Jose-Alejandro; Monk, Bradley J; Tusquets, Ignacio; McCormick, Colleen; Fuentes, Jose; Moore, Richard G; Vulsteke, Christof; Shahin, Mark S; Forget, Frédéric; Bradley, William H; Hietanen, Sakari; O'Malley, David M; Dørum, Anne; Slomovitz, Brian M; Baumann, Klaus; Selle, Frédéric; Calvert, Paula M; Artioli, Grazia; Levy, Tally; Kumar, Aalok; Malinowska, Izabela A; Li, Yong; Gupta, Divya; González-Martín, AntonioTo evaluate the association between surgical timing and postoperative residual disease status on the efficacy of niraparib first-line maintenance therapy in patients with newly diagnosed advanced ovarian cancer at high risk of recurrence. Post hoc analysis of the phase 3 PRIMA/ENGOT-OV26/GOG-3012 (NCT02655016) study of niraparib in patients with newly diagnosed primary advanced ovarian, primary peritoneal, or fallopian tube cancer with a complete/partial response to first-line platinum-based chemotherapy. Progression-free survival (PFS) was assessed by surgical status (primary debulking surgery [PDS] vs neoadjuvant chemotherapy/interval debulking surgery [NACT/IDS]) and postoperative residual disease status (no visible residual disease [NVRD] vs visible residual disease [VRD]) in the intent-to-treat population. In PRIMA (N = 733), 236 (32.2%) patients underwent PDS, and 481 (65.6%) received NACT/IDS before enrollment. Median PFS (niraparib vs placebo) and hazard ratios (95% CI) for progression were similar in PDS (13.7 vs 8.2 months; HR, 0.67 [0.47-0.96]) and NACT/IDS (14.2 vs 8.2 months; HR, 0.57 [0.44-0.73]) subgroups. In patients who received NACT/IDS and had NVRD (n = 304), the hazard ratio (95% CI) for progression was 0.65 (0.46-0.91). In patients with VRD following PDS (n = 183) or NACT/IDS (n = 149), the hazard ratios (95% CI) for progression were 0.58 (0.39-0.86) and 0.41 (0.27-0.62), respectively. PFS was not evaluable for patients with PDS and NVRD because of sample size (n = 37). In this post hoc analysis, niraparib efficacy was similar across PDS and NACT/IDS subgroups. Patients who had NACT/IDS and VRD had the highest reduction in the risk of progression with niraparib maintenance.Publication Antimalarials exert a cardioprotective effect in lupus patients: Insights from the Spanish Society of Rheumatology Lupus Register (RELESSER) analysis of factors associated with heart failure.(2022-01-02) Rúa-Figueroa, Iñigo; Rúa-Figueroa, David; Pérez-Veiga, Natalia; Anzola, Ana M; Galindo-Izquierdo, María; Calvo-Alén, Jaime; Fernández-Nebro, Antonio; Sangüesa, Clara; Menor-Almagro, Raúl; Tomero, Eva; Del Val, Natividad; Uriarte-Isazelaya, Esther; Blanco, Ricardo; Andreu, José L; Boteanu, Alina; Narváez, Javier; Cobo, Tatiana; Bohórquez, Cristina; Montilla, Carlos; Salas, Esteban; Toyos, Francisco J; Bernal, José A; Salgado, Eva; Freire, Mercedes; Mas, Antonio J; Expósito, Lorena; Hernández-Beriain, José A; Ibarguengoitia, Oihane; Velloso-Feijoo, María L; Lozano-Rivas, Nuria; Bonilla, Gemma; Moreno, Mireia; Jiménez, Inmaculada; Quevedo-Vila, Víctor; Pecondón, Angela; Aurrecoechea, Elena; Valls, Elia; Mouriño, Coral; Vázquez-Rodríguez, Tomás; Pego-Reigosa, José MFactors associated with chronic heart failure (CHF) in patients with systemic lupus erythematosus (SLE) have received little attention. Recent data on the use of hydroxychloroquine in the treatment of SARS-CoV-2 infection have cast doubt on its cardiac safety. The factors associated with CHF, including therapy with antimalarials, were analyzed in a large multicenter SLE cohort. Cross-sectional study including all patients with SLE (ACR-1997 criteria) included in the Spanish Society of Rheumatology Lupus Register (RELESSER), based on historically gathered data. Patients with CHF prior to diagnosis of SLE were excluded. A multivariable analysis exploring factors associated with CHF was conducted. The study population comprised 117 patients with SLE (ACR-97 criteria) and CHF and 3,506 SLE controls. Ninety percent were women. Patients with CHF were older and presented greater SLE severity, organ damage, and mortality than those without CHF. The multivariable model revealed the factors associated with CHF to be ischemic heart disease (7.96 [4.01-15.48], p Patients with SLE and CHF experience more severe SLE. Treatment with antimalarials appears to confer a cardioprotective effect.Publication Has stroke mortality stopped declining in Spain?(2019-11-25) Cayuela, A; Cayuela, L; Ortega Belmonte, M J; Rodríguez-Domínguez, S; Escudero-Martínez, I; González, ATo analyse the changes in stroke mortality trends in Spain by autonomous community and by sex during the period 1980-2016, using joinpoint regression models. Mortality data were obtained from the Spanish National Statistics Institute. Crude and standardised rates were calculated for each Spanish autonomous community, and for each sex. Joinpoint analysis was used to identify the best-fitting points showing a statistically significant change in the trend. Joinpoint analysis enabled us to differentiate between communities in which mortality rates showed a continuous decline throughout the study period in both sexes (Asturias, Cantabria, Castile and Leon, Ceuta, and Melilla) or in men only (Extremadura). In men, in all those communities in which changes in the trend were observed (all but Aragon, the Balearic Islands, and Murcia, where rates remained stable), we observed an initial period of decline (ranging from -3.4% in Catalonia and Extremadura, to -6.0% in Madrid) and a final period where the trends diverged: mortality rates continued to fall in Andalusia, Aragon, the Balearic Islands, and Madrid, but began to stabilise in Castile-La Mancha and Murcia and to increase in the Canary Islands. In women, in those communities where changes were observed (all but Aragon, Murcia, and the Basque Country, where rates remained stable), we observed an initial period of decline (ranging from -3.1% in Catalonia to -6.4% in Navarre) and a final period where divergent trends were observed: rates continued to decline in Andalusia, Aragon, Catalonia, Galicia, Madrid, and the Basque Country, but began to stabilise in Extremadura and Murcia and to increase in the Canary Islands. Current data show that stroke mortality rates have decreased (in women in Andalusia), stabilised (in both sexes in Murcia, in men in Castile-La Mancha, and in women in Extremadura), and have even reversed (in both sexes in the Canary Islands). Further study is needed to identify the causes of these trends.Publication Predictive factors of six-week mortality in critically ill patients with SARS-CoV-2: A multicenter prospective study.(2022) Estella, Á; Garcia Garmendia, J L; de la Fuente, C; Machado Casas, J F; Yuste, M E; Amaya Villar, R; Estecha, M A; Yaguez Mateos, L; Cantón Bulnes, M L; Loza, A; Mora, J; Fernández Ruiz, L; Díez Del Corral Fernández, B; Rojas Amezcua, M; Rodriguez Higueras, M I; Díaz Torres, I; Recuerda Núñez, M; Zaheri Beryanaki, M; Rivera Espinar, F; Matallana Zapata, D F; Moreno Cano, S G; Gimenez Beltrán, B; Muñoz, N; Sainz de Baranda Piñero, A; Bustelo Bueno, P; Moreno Barriga, E; Rios Toro, J J; Pérez Ruiz, M; Gómez González, C; Breval Flores, A; de San José Bermejo Gómez, A; Ruiz Cabello Jimenez, M A; Guerrero Marín, M; Ortega Ordiales, A; Tejero-Aranguren, J; Rodriguez Mejías, C; Gomez de Oña, J; de la Hoz, C; Ocaña Fernández, D; Ibañez Cuadros, S; Garnacho Montero, J; Work Group of Infectious Disease (GTEI) de la Sociedad Andaluza de Medicina Intensiva y Unidades coronarias SAMIUCThe objective of the study is to identify the risk factors associated with mortality at six weeks, especially by analyzing the role of antivirals and munomodulators. Prospective descriptive multicenter cohort study. 26 Intensive care units (ICU) from Andalusian region in Spain. Consecutive critically ill patients with confirmed SARS-CoV-2 infection were included from March 8 to May 30. None. Variables analyzed were demographic, severity scores and clinical condition. Support therapy, drug and mortality were analyzed. An univariate followed by multivariate Cox regression with propensity score analysis was applied. 495 patients were enrolled, but 73 of them were excluded for incomplete data. Thus, 422 patients were included in the final analysis. Median age was 63 years and 305 (72.3%) were men. ICU mortality: 144/422 34%; 14 days mortality: 81/422 (19.2%); 28 days mortality: 121/422 (28.7%); 6-week mortality 152/422 36.5%. By multivariable Cox proportional analysis, factors independently associated with 42-day mortality were age, APACHE II score, SOFA score at ICU admission >6, Lactate dehydrogenase at ICU admission >470U/L, Use of vasopressors, extrarenal depuration, %lymphocytes 72h post-ICU admission 6, Lactate dehydrogenase at ICU admission >470U/L, Use of vasopressors, extrarenal depuration, %lymphocytes 72h post-ICU admission 470U/L, Use of vasopressors, extrarenal depuration, %lymphocytes 72h post-ICU admission Age, APACHE II, SOFA>value of 6 points, along with vasopressor requirements or renal replacement therapy have been identified as predictor factors of mortality at six weeks. Administration of corticosteroids showed no benefits in mortality, as did treatment with tocilizumab. Lopinavir/ritonavir administration is identified as a protective factor.Publication Prognostic implications of comorbidity patterns in critically ill COVID-19 patients: A multicenter, observational study.(2022-05-29) Benítez, Iván D; de Batlle, Jordi; Torres, Gerard; González, Jessica; de Gonzalo-Calvo, David; Targa, Adriano D S; Gort-Paniello, Clara; Moncusí-Moix, Anna; Ceccato, Adrián; Fernández-Barat, Laia; Ferrer, Ricard; Garcia-Gasulla, Dario; Menéndez, Rosario; Motos, Anna; Peñuelas, Oscar; Riera, Jordi; Bermejo-Martin, Jesús F; Peñasco, Yhivian; Ricart, Pilar; Martin Delgado, María Cruz; Aguilera, Luciano; Rodríguez, Alejandro; Boado Varela, Maria Victoria; Suarez-Sipmann, Fernando; Pozo-Laderas, Juan Carlos; Solé-Violan, Jordi; Nieto, Maite; Novo, Mariana Andrea; Barberán, José; Amaya Villar, Rosario; Garnacho-Montero, José; García-Garmendia, Jose Luis; Gómez, José M; Lorente, José Ángel; Blandino Ortiz, Aaron; Tamayo Lomas, Luis; López-Ramos, Esther; Úbeda, Alejandro; Catalán-González, Mercedes; Sánchez-Miralles, Angel; Martínez Varela, Ignacio; Jorge García, Ruth Noemí; Franco, Nieves; Gumucio-Sanguino, Víctor D; Huerta Garcia, Arturo; Bustamante-Munguira, Elena; Valdivia, Luis Jorge; Caballero, Jesús; Gallego, Elena; Martínez de la Gándara, Amalia; Castellanos-Ortega, Álvaro; Trenado, Josep; Marin-Corral, Judith; Albaiceta, Guillermo M; de la Torre, Maria Del Carmen; Loza-Vázquez, Ana; Vidal, Pablo; Lopez Messa, Juan; Añón, Jose M; Carbajales Pérez, Cristina; Sagredo, Victor; Bofill, Neus; Carbonell, Nieves; Socias, Lorenzo; Barberà, Carme; Estella, Angel; Valledor Mendez, Manuel; Diaz, Emili; López Lago, Ana; Torres, Antoni; Barbé, Ferran; CIBERESUCICOVID Project (COV20/00110, ISCIII)The clinical heterogeneity of COVID-19 suggests the existence of different phenotypes with prognostic implications. We aimed to analyze comorbidity patterns in critically ill COVID-19 patients and assess their impact on in-hospital outcomes, response to treatment and sequelae. Multicenter prospective/retrospective observational study in intensive care units of 55 Spanish hospitals. 5866 PCR-confirmed COVID-19 patients had comorbidities recorded at hospital admission; clinical and biological parameters, in-hospital procedures and complications throughout the stay; and, clinical complications, persistent symptoms and sequelae at 3 and 6 months. Latent class analysis identified 3 phenotypes using training and test subcohorts: low-morbidity (n=3385; 58%), younger and with few comorbidities; high-morbidity (n=2074; 35%), with high comorbid burden; and renal-morbidity (n=407; 7%), with chronic kidney disease (CKD), high comorbidity burden and the worst oxygenation profile. Renal-morbidity and high-morbidity had more in-hospital complications and higher mortality risk than low-morbidity (adjusted HR (95% CI): 1.57 (1.34-1.84) and 1.16 (1.05-1.28), respectively). Corticosteroids, but not tocilizumab, were associated with lower mortality risk (HR (95% CI) 0.76 (0.63-0.93)), especially in renal-morbidity and high-morbidity. Renal-morbidity and high-morbidity showed the worst lung function throughout the follow-up, with renal-morbidity having the highest risk of infectious complications (6%), emergency visits (29%) or hospital readmissions (14%) at 6 months (p Comorbidity-based phenotypes were identified and associated with different expression of in-hospital complications, mortality, treatment response, and sequelae, with CKD playing a major role. This could help clinicians in day-to-day decision making including the management of post-discharge COVID-19 sequelae. ISCIII, UNESPA, CIBERES, FEDER, ESF.Publication Negative predictive value of procalcitonin to rule out bacterial respiratory co-infection in critical covid-19 patients.(2022-06-30) Carbonell, Raquel; Urgelés, Silvia; Salgado, Melina; Rodríguez, Alejandro; Reyes, Luis Felipe; Fuentes, Yuli V; Serrano, Cristian C; Caceres, Eder L; Bodí, María; Martín-Loeches, Ignacio; Solé-Violán, Jordi; Díaz, Emili; Gómez, Josep; Trefler, Sandra; Vallverdú, Montserrat; Murcia, Josefa; Albaya, Antonio; Loza, Ana; Socias, Lorenzo; Ballesteros, Juan Carlos; Papiol, Elisabeth; Viña, Lucía; Sancho, Susana; Nieto, Mercedes; Del, M; Lorente, Carmen; Badallo, Oihane; Fraile, Virginia; Arméstar, Fernando; Estella, Angel; Abanses, Paula; Sancho, Isabel; Guasch, Neus; Moreno, Gerard; COVID-19 SEMICYUC Working Group and the LIVEN-Covid-19 InvestigatorsProcalcitonin (PCT) and C-Reactive Protein (CRP) are useful biomarkers to differentiate bacterial from viral or fungal infections, although the association between them and co-infection or mortality in COVID-19 remains unclear. The study represents a retrospective cohort study of patients admitted for COVID-19 pneumonia to 84 ICUs from ten countries between (March 2020-January 2021). Primary outcome was to determine whether PCT or CRP at admission could predict community-acquired bacterial respiratory co-infection (BC) and its added clinical value by determining the best discriminating cut-off values. Secondary outcome was to investigate its association with mortality. To evaluate the main outcome, a binary logistic regression was performed. The area under the curve evaluated diagnostic performance for BC prediction. 4635 patients were included, 7.6% fulfilled BC diagnosis. PCT (0.25[IQR 0.1-0.7] versus 0.20[IQR 0.1-0.5]ng/mL, p These biomarkers at ICU admission led to a poor ability to predict BC among patients with COVID-19 pneumonia. Baseline values of PCTPublication Orthohepevirus C infection as an emerging cause of acute hepatitis in Spain: First report in Europe.(2022-02-12) Rivero-Juarez, Antonio; Frias, Mario; Perez, Ana Belen; Pineda, Juan Antonio; Reina, Gabriel; Fuentes-Lopez, Ana; Freyre-Carrillo, Carolina; Ramirez-Arellano, Encarnación; Alados, Juan Carlos; Rivero, Antonio; HEPAVIR and GEHEP-014 Study GroupsHepatitis E virus (HEV) was considered the only member of the Hepeviridae family with zoonotic potential. Nevertheless, this consideration has been reassessed owing to several reported cases of acute and chronic hepatitis linked to the Orthohepevirus C genus. Because the circulation of Orthohepevirus C in rodents has been described worldwide, the risk of zoonotic transmission is plausibly global. Orthohepevirus C RNA was retrospectively evaluated in 2 cohorts of patients in Spain. The first cohort included patients with acute hepatitis without etiological diagnosis after screening for hepatotropic virus infection. The second cohort included patients diagnosed with acute HEV infection, defined as positivity for anti-HEV-IgM antibodies and/or detectable HEV RNA in serum. Cohort 1 comprised 169 patients (64.4% male, median age 43 years) and cohort 2 comprised 98 individuals (68.3% male, median age 45 years). Of the individuals included in Cohort 1, two (1.18%; 95% CI 0.2-3.8) had detectable Orthohepevirus C RNA in serum. In Cohort 2, of the 98 included patients, 58 showed detectable HEV RNA, while 40 only showed positivity for IgM antibodies. Among those bearing only IgM antibodies, Orthohepevirus C RNA was detected in 1 (2.5%; 95% CI 0.06-13.1) individual. All strains were consistent with genotype C1. The infection resulted in mild self-limiting acute hepatitis in 2 patients. Infection caused severe acute hepatitis in the remaining patient who died as a result of liver and renal failure. We described 3 cases of Orthohepevirus C in patients with acute hepatitis, resulting in the first description of this infection in Europe. The prevalence obtained in our study suggests that Orthohepevirus C could be an emerging disease in Europe. We describe the first cases of acute hepatitis related to rat hepatitis E virus in Europe. The prevalence found in our study suggest that rat hepatitis E virus could be considered an emerging disease in Europe.Publication Dexamethasone as risk-factor for ICU-acquired respiratory tract infections in severe COVID-19.(2022-02-23) Reyes, Luis Felipe; Rodriguez, Alejandro; Bastidas, Alirio; Parra-Tanoux, Daniela; Fuentes, Yuli V; García-Gallo, Esteban; Moreno, Gerard; Ospina-Tascon, Gustavo; Hernandez, Glenn; Silva, Edwin; Díaz, Ana Maria; Jibaja, Manuel; Vera, Magdalena; Díaz, Emilio; Bodí, María; Solé-Violán, Jordi; Ferrer, Ricard; Albaya-Moreno, Antonio; Socias, Lorenzo; Estella, Ángel; Loza-Vazquez, Ana; Jorge-García, Ruth; Sancho, Isabel; Martin-Loeches, Ignacio; LIVEN-COVID-19 Investigators and COVID-19 SEMICYUC Study GroupDexamethasone is the only drug that has consistently reduced mortality in patients with COVID-19, especially in patients needing oxygen or invasive mechanical ventilation. However, there is a growing concern about the relation of dexamethasone with the unprecedented rates of ICU-acquired respiratory tract infections (ICU-RTI) observed in patients with severe COVID-19. This was a multicenter, prospective cohort study; conducted in ten countries in Latin America and Europe. We included patients older than 18 with confirmed SARS-CoV-2 requiring ICU admission. A multivariate logistic regression and propensity score matching (PSM) analysis was conducted to determine the relation between dexamethasone treatment and ICU-RTI. A total of 3777 patients were included. 2065 (54.7%) were treated with dexamethasone within the first 24 h of admission. After performing the PSM, patients treated with dexamethasone showed significantly higher proportions of VAP (282/1652 [17.1%] Vs. 218/1652 [13.2%], p = 0.014). Also, dexamethasone treatment was identified as an adjusted risk factor of ICU-RTI in the multivariate logistic regression model (OR 1.64; 95%CI: 1.37-1.97; p Patients treated with dexamethasone for severe COVID-19 had a higher risk of developing ICU-acquired respiratory tract infections after adjusting for days of invasive mechanical ventilation and ICU length of stay, suggesting a cautious use of this treatment.Publication Community-acquired pneumonia - An EFIM guideline critical appraisal adaptation for internists.(2022-10-19) Er, Ahmet Gorkem; Alonso, Alberto Antonio Romero; Marin-Leon, Ignacio; Sayiner, Abdullah; Bassetti, Stefano; Demirkan, Kutay; Lacor, Patrick; Lode, Hartmut; Lesniak, Wiktoria; Tanriover, Mine Durusu; Kalyoncu, Ali Fuat; Merchante, Nicolás; Unal, SerhatIn real-life settings, guidelines frequently cannot be followed since many patients are multimorbid and/or elderly or have other complicating conditions which carry an increased risk of drug-drug interactions. This document aimed to adapt recommendations from existing clinical practice guidelines (CPGs) to assist physicians' decision-making processes concerning specific and complex scenarios related to acute CAP. The process for the adaptation procedure started with the identification of unsolved clinical questions (PICOs) in patients with CAP and continued with critically appraising the updated existing CPGs and choosing the recommendations, which are most applicable to these specific scenarios. Seventeen CPGs were appraised to address five PICOs. Twenty-seven recommendations were endorsed based on 7 high, 9 moderate, 10 low, and 1 very low-quality evidence. The most valid recommendations applicable to the clinical practice were the following ones: Respiratory virus testing is strongly recommended during periods of increased respiratory virus activity. Assessing the severity with a validated prediction rule to discriminate where to treat the patient is strongly recommended along with reassessing the patient periodically for improvement as expected. In adults with multiple comorbidities, polypharmacy, or advanced age, it is strongly recommended to check for possible drug interactions before starting treatment. Strong graded recommendations exist on antibiotic treatment and its duration. Recommendations on the use of biomarkers such as C-reactive protein or procalcitonin to improve severity assessment are reported. This document provides a simple and reliable updated guide for clinical decision-making in the management of complex patients with multimorbidity and CAP in the real-life setting.Publication Multi-institutional expert update on the use of laparoscopic bile duct exploration in the management of choledocholithiasis: Lesson learned from 3950 procedures.(2022-02-17) Lopez-Lopez, Víctor; Gil-Vazquez, Pedro José; Ferreras, David; Nassar, Ahmad H M; Bansal, Virinder K; Topal, Baki; Zhu, Jie-Gao; Chuang, Shu-Hung; Jorba, Rosa; Bekheit, Mohamed; Martinez-Cecilia, David; Parra-Membrives, Pablo; Sgourakis, Georgios; Mattila, Anne; Bove, Aldo; Quaresima, Silvia; Barreras González, Javier Ernesto; Sharma, Anil; Ruiz, Juan Jose; Sánchez-Bueno, Francisco; Robles-Campos, Ricardo; Martinez-Isla, AlbertoRecently there has been a growing interest in the laparoscopic management of common bile duct stones with gallbladder in situ (LBDE), which is favoring the expansion of this technique. Our study identified the standardization factors of LBDE and its implementation in the single-stage management of choledocholithiasis. A retrospective multi-institutional study among 17 centers with proven experience in LBDE was performed. A cross-sectional survey consisting of a semi-structured pretested questionnaire was distributed covering the main aspects on the use of LBDE in the management of choledocholithiasis. A total of 3950 LBDEs were analyzed. The most frequent indication was jaundice (58.8%). LBDEs were performed after failed ERCP in 15.2%. The most common approach used was the transcystic (63.11%). The overall series failure rate of LBDE was 4% and the median rate for each center was 6% (IQR, 4.5-12.5). Median operative time ranged between 60-120 min (70.6%). Overall morbidity rate was 14.6%, with a postoperative bile leak and complications ≥3a rate of 4.5% and 2.5%, respectively. The operative time decreased with experience (P = .03) and length of hospital stay was longer in the presence of a biliary leak (P = .04). Current training of LBDE was defined as poor or very poor by 82.4%. Based on this multicenter survey, LBDE is a safe and effective approach when performed by experienced teams. The generalization of LBDE will be based on developing training programs.Publication Association of Rare APOE Missense Variants V236E and R251G With Risk of Alzheimer Disease.(2022) Le Guen, Yann; Belloy, Michael E; Grenier-Boley, Benjamin; de Rojas, Itziar; Castillo-Morales, Atahualpa; Jansen, Iris; Nicolas, Aude; Bellenguez, Céline; Dalmasso, Carolina; Küçükali, Fahri; Eger, Sarah J; Rasmussen, Katrine Laura; Thomassen, Jesper Qvist; Deleuze, Jean-François; He, Zihuai; Napolioni, Valerio; Amouyel, Philippe; Jessen, Frank; Kehoe, Patrick G; van Duijn, Cornelia; Tsolaki, Magda; Sánchez-Juan, Pascual; Sleegers, Kristel; Ingelsson, Martin; Rossi, Giacomina; Hiltunen, Mikko; Sims, Rebecca; van der Flier, Wiesje M; Ramirez, Alfredo; Andreassen, Ole A; Frikke-Schmidt, Ruth; Williams, Julie; Ruiz, Agustín; Lambert, Jean-Charles; Greicius, Michael D; Members of the EADB, GR@ACE, DEGESCO, DemGene, GERAD, and EADI Groups; Arosio, Beatrice; Benussi, Luisa; Boland, Anne; Borroni, Barbara; Caffarra, Paolo; Daian, Delphine; Daniele, Antonio; Debette, Stéphanie; Dufouil, Carole; Düzel, Emrah; Galimberti, Daniela; Giedraitis, Vilmantas; Grimmer, Timo; Graff, Caroline; Grünblatt, Edna; Hanon, Olivier; Hausner, Lucrezia; Heilmann-Heimbach, Stefanie; Holstege, Henne; Hort, Jakub; Jürgen, Deckert; Kuulasmaa, Teemu; van der Lugt, Aad; Masullo, Carlo; Mecocci, Patrizia; Mehrabian, Shima; de Mendonça, Alexandre; Moebus, Susanne; Nacmias, Benedetta; Nicolas, Gael; Olaso, Robert; Papenberg, Goran; Parnetti, Lucilla; Pasquier, Florence; Peters, Oliver; Pijnenburg, Yolande A L; Popp, Julius; Rainero, Innocenzo; Ramakers, Inez; Riedel-Heller, Steffi; Scarmeas, Nikolaos; Scheltens, Philip; Scherbaum, Norbert; Schneider, Anja; Seripa, Davide; Soininen, Hilkka; Solfrizzi, Vincenzo; Spalletta, Gianfranco; Squassina, Alessio; van Swieten, John; Tegos, Thomas J; Tremolizzo, Lucio; Verhey, Frans; Vyhnalek, Martin; Wiltfang, Jens; Boada, Mercè; García-González, Pablo; Puerta, Raquel; Real, Luis M; Álvarez, Victoria; Bullido, María J; Clarimon, Jordi; García-Alberca, José María; Mir, Pablo; Moreno, Fermin; Pastor, Pau; Piñol-Ripoll, Gerard; Molina-Porcel, Laura; Pérez-Tur, Jordi; Rodríguez-Rodríguez, Eloy; Royo, Jose Luís; Sánchez-Valle, Raquel; Dichgans, Martin; Rujescu, DanThe APOE ε2 and APOE ε4 alleles are the strongest protective and risk-increasing, respectively, genetic variants for late-onset Alzheimer disease (AD). However, the mechanisms linking APOE to AD-particularly the apoE protein's role in AD pathogenesis and how this is affected by APOE variants-remain poorly understood. Identifying missense variants in addition to APOE ε2 and APOE ε4 could provide critical new insights, but given the low frequency of additional missense variants, AD genetic cohorts have previously been too small to interrogate this question robustly. To determine whether rare missense variants on APOE are associated with AD risk. Association with case-control status was tested in a sequenced discovery sample (stage 1) and followed up in several microarray imputed cohorts as well as the UK Biobank whole-exome sequencing resource using a proxy-AD phenotype (stages 2 and 3). This study combined case-control, family-based, population-based, and longitudinal AD-related cohorts that recruited referred and volunteer participants. Stage 1 included 37 409 nonunique participants of European or admixed European ancestry, with 11 868 individuals with AD and 11 934 controls passing analysis inclusion criteria. In stages 2 and 3, 475 473 participants were considered across 8 cohorts, of which 84 513 individuals with AD and proxy-AD and 328 372 controls passed inclusion criteria. Selection criteria were cohort specific, and this study was performed a posteriori on individuals who were genotyped. Among the available genotypes, 76 195 were excluded. All data were retrieved between September 2015 and November 2021 and analyzed between April and November 2021. In primary analyses, the AD risk associated with each missense variant was estimated, as appropriate, with either linear mixed-model regression or logistic regression. In secondary analyses, associations were estimated with age at onset using linear mixed-model regression and risk of conversion to AD using competing-risk regression. A total of 544 384 participants were analyzed in the primary case-control analysis; 312 476 (57.4%) were female, and the mean (SD; range) age was 64.9 (15.2; 40-110) years. Two missense variants were associated with a 2-fold to 3-fold decreased AD risk: APOE ε4 (R251G) (odds ratio, 0.44; 95% CI, 0.33-0.59; P = 4.7 × 10-8) and APOE ε3 (V236E) (odds ratio, 0.37; 95% CI, 0.25-0.56; P = 1.9 × 10-6). Additionally, the cumulative incidence of AD in carriers of these variants was found to grow more slowly with age compared with noncarriers. In this genetic association study, a novel variant associated with AD was identified: R251G always coinherited with ε4 on the APOE gene, which mitigates the ε4-associated AD risk. The protective effect of the V236E variant, which is always coinherited with ε3 on the APOE gene, was also confirmed. The location of these variants confirms that the carboxyl-terminal portion of apoE plays an important role in AD pathogenesis. The large risk reductions reported here suggest that protein chemistry and functional assays of these variants should be pursued, as they have the potential to guide drug development targeting APOE.Publication Severe immunosuppression is related to poorer immunogenicity to SARS-CoV-2 vaccines among people living with HIV.(2022-05-28) Corma-Gómez, Anaïs; Fernández-Fuertes, Marta; García, Estefanía; Fuentes-López, Ana; Gómez-Ayerbe, Cristina; Rivero-Juárez, Antonio; Domínguez, Carmen; Santos, Marta; Viñuela, Laura; Palacios, Rosario; Real, Luis M; Rivero, Antonio; Macías, Juan; Pineda, Juan A; García, FedericoThe aim of this study was to assess the immunogenicity of SARS-CoV-2 available vaccines among people living with HIV (PLWH) after a complete vaccination scheme, and determine predictors of seroconversion. This multicentre prospective cohort study included 420 PLWH who had received a standard immunization, either with mRNA or adenoviral-vectored COVID-19 vaccines. Antibody response was evaluated within 1 to 2 months after the last dose of the vaccine with a quantitative determination of antitrimeric spike protein-specific IgG antibodies and IgG neutralizing antibodies. Overall, 384 of 420 PLWH (91%) showed antibody response to vaccination. Seroconversion was observed in 308 of 326 individuals with cluster of differentiation 4 (CD4) counts ≥350 cells/mm3 (95%), 55 of 61 PLWH with 200 to 349 cells/mm3 (90%), and 21 of 33 PLWH with CD4 counts HIV-related immunosuppression impairs the antibody response to SARS-CoV-2 vaccines. Specific vaccination schemes should be urgently tailored in this setting, particularly in patients with CD4 cell countsPublication Lower probability of persistence of total anti-SARS-CoV-2 antibodies after COVID-19 among people living with HIV.(2022-02-10) Macías, Juan; Fernández-Fuertes, Marta; Oliver, Noemí; Corma-Gómez, Anaïs; Real, Luis M; Pineda, Juan APublication Standardized incidence ratios and risk factors for cancer in patients with systemic sclerosis: Data from the Spanish Scleroderma Registry (RESCLE).(2022-08-02) Carbonell, Cristina; Marcos, Miguel; Guillén-Del-Castillo, Alfredo; Rubio-Rivas, Manuel; Argibay, Ana; Marín-Ballvé, Adela; Rodríguez-Pintó, Ignasi; Baldà-Masmiquel, Maria; Callejas-Moraga, Eduardo; Colunga, Dolores; Sáez-Comet, Luis; González-Echávarri, Cristina; Ortego-Centeno, Norberto; Marí-Alfonso, Begoña; Vargas-Hitos, José-Antonio; Todolí-Parra, José-Antonio; Trapiella, Luis; Herranz-Marín, María-Teresa; Freire, Mayka; Castro-Salomó, Antoni; Perales-Fraile, Isabel; Madroñero-Vuelta, Ana-Belén; Sánchez-García, María-Esther; Ruiz-Muñoz, Manuel; González-García, Andrés; Sánchez-Redondo, Jorge; de-la-Red-Bellvis, Gloria; Fernández-Luque, Alejandra; Muela-Molinero, Alberto; Lledó, Gema-María; Tolosa-Vilella, Carles; Fonollosa-Pla, Vicent; Chamorro, Antonio-Javier; Simeón-Aznar, Carmen-Pilar; RESCLE Investigators, Autoimmune Diseases Study Group (GEAS)Patients with systemic sclerosis (SSc) are at increased risk of cancer, a growing cause of non-SSc-related death among these patients. We analyzed the increased cancer risk among Spanish patients with SSc using standardized incidence ratios (SIRs) and identified independent cancer risk factors in this population. Spanish Scleroderma Registry data were analyzed to determine the demographic characteristics of patients with SSc, and logistic regression was used to identify cancer risk factors. SIRs with 95% confidence intervals (CIs) relative to the general Spanish population were calculated. Of 1930 patients with SSc, 206 had cancer, most commonly breast, lung, hematological, and colorectal cancers. Patients with SSc had increased risks of overall cancer (SIR 1.48, 95% CI 1.36-1.60; P Spanish patients with SSc had an increased cancer risk compared with the general population. Some characteristics, including specific autoantibodies, may be related to this increased risk.Publication Methodology of a Large Multicenter Observational Study of Patients with COVID-19 in Spanish Intensive Care Units.(2022-04-15) Torres, Antoni; Motos, Anna; Ceccato, Adrián; Bermejo-Martin, Jesús; de Gonzalo-Calvo, David; Pérez, Raquel; Barroso, Marta; Pascual, Ion Zubizarreta; Gonzalez, Jessica; Fernández-Barat, Laia; Ferrer, Ricard; Riera, Jordi; García-Gasulla, Dario; Peñuelas, Oscar; Lorente, José Ángel; Almansa, Raquel; Menéndez, Rosario; Kiarostami, Kasra; Canseco, Joan; Villar, Rosario Amaya; Añón, José M; Mariño, Ana Balan; Barberà, Carme; Barberán, José; Ortiz, Aaron Blandino; Boado, Maria Victoria; Bustamante-Munguira, Elena; Caballero, Jesús; Cantón-Bulnes, María Luisa; Pérez, Cristina Carbajales; Carbonell, Nieves; Catalán-González, Mercedes; de Frutos, Raúl; Franco, Nieves; Galbán, Cristóbal; Gumucio-Sanguino, Víctor D; Torre, María Del Carmen de la; Díaz, Emili; Estella, Ángel; Gallego, Elena; Garmendia, José Luis García; Gómez, José M; Huerta, Arturo; García, Ruth Noemí Jorge; Loza-Vázquez, Ana; Marin-Corral, Judith; Delgado, María Cruz Martin; Gándara, Amalia Martínez de la; Varela, Ignacio Martínez; Messa, Juan López; Albaiceta, Guillermo M; Nieto, Maite; Novo, Mariana Andrea; Peñasco, Yhivian; Pérez-García, Felipe; Pozo-Laderas, Juan Carlos; Ricart, Pilar; Sagredo, Víctor; Sánchez-Miralles, Ángel; Chinesta, Susana Sancho; Serra-Fortuny, Mireia; Socias, Lorenzo; Solé-Violan, Jordi; Suárez-Sipmann, Fernando; Lomas, Luis Tamayo; Trenado, José; Úbeda, Alejandro; Valdivia, Luis Jorge; Vidal, Pablo; Barbé, Ferran; CIBERESUCICOVID Project (COV20/00110, ISCIII)The COVID-19 pandemic created tremendous challenges for health-care systems. Intensive care units (ICU) were hit with a large volume of patients requiring ICU admission, mechanical ventilation, and other organ support with very high mortality. The Centro de Investigación Biomédica en Red-Enfermedades Respiratorias (CIBERES), a network of Spanish researchers to investigate in respiratory disease, commissioned the current proposal in response to the Instituto de Salud Carlos III (ISCIII) call. CIBERESUCICOVID is a multicenter, observational, prospective/retrospective cohort study of patients with COVID-19 admitted to Spanish ICUs. Several work packages were created, including study population and ICU data collection, follow-up, biomarkers and miRNAs, data management and quality. This study included 6102 consecutive patients admitted to 55 ICUs homogeneously distributed throughout Spain and the collection of blood samples from more than 1000 patients. We enrolled a large population of COVID-19 ICU-admitted patients including baseline characteristics, ICU and MV data, treatments complications, and outcomes. The in-hospital mortality was 31%, and 76% of patients required invasive mechanical ventilation. A 3-6 month and 1 year follow-up was performed. Few deaths after 1 year discharge were registered. Low anti-SARS-CoV-2 S antibody levels predict mortality in critical COVID-19. These antibodies contribute to prevent systemic dissemination of SARS-CoV-2. The severity of COVID-19 impacts the circulating miRNA profile. Plasma miRNA profiling emerges as a useful tool for risk-based patient stratification in critically ill COVID-19 patients. We present the methodology used in a large multicenter study sponsored by ISCIII to determine the short- and long-term outcomes in patients with COVID-19 admitted to more than 50 Spanish ICUs.Publication Metabolic subtypes of patients with NAFLD exhibit distinctive cardiovascular risk profiles.(2022-03-17) Martínez-Arranz, Ibon; Bruzzone, Chiara; Noureddin, Mazen; Gil-Redondo, Ruben; Mincholé, Itziar; Bizkarguenaga, Maider; Arretxe, Enara; Iruarrizaga-Lejarreta, Marta; Fernández-Ramos, David; Lopitz-Otsoa, Fernando; Mayo, Rebeca; Embade, Nieves; Newberry, Elizabeth; Mittendorf, Bettina; Izquierdo-Sánchez, Laura; Smid, Vaclav; Arnold, Jorge; Iruzubieta, Paula; Pérez Castaño, Ylenia; Krawczyk, Marcin; Marigorta, Urko M; Morrison, Martine C; Kleemann, Robert; Martín-Duce, Antonio; Hayardeny, Liat; Vitek, Libor; Bruha, Radan; Aller de la Fuente, Rocío; Crespo, Javier; Romero-Gomez, Manuel; Banales, Jesus M; Arrese, Marco; Cusi, Kenneth; Bugianesi, Elisabetta; Klein, Samuel; Lu, Shelly C; Anstee, Quentin M; Millet, Oscar; Davidson, Nicholas O; Alonso, Cristina; Mato, José MWe previously identified subsets of patients with NAFLD with different metabolic phenotypes. Here we align metabolomic signatures with cardiovascular disease (CVD) and genetic risk factors. We analyzed serum metabolome from 1154 individuals with biopsy-proven NAFLD, and from four mouse models of NAFLD with impaired VLDL-triglyceride (TG) secretion, and one with normal VLDL-TG secretion. We identified three metabolic subtypes: A (47%), B (27%), and C (26%). Subtype A phenocopied the metabolome of mice with impaired VLDL-TG secretion; subtype C phenocopied the metabolome of mice with normal VLDL-TG; and subtype B showed an intermediate signature. The percent of patients with NASH and fibrosis was comparable among subtypes, although subtypes B and C exhibited higher liver enzymes. Serum VLDL-TG levels and secretion rate were lower among subtype A compared with subtypes B and C. Subtype A VLDL-TG and VLDL-apolipoprotein B concentrations were independent of steatosis, whereas subtypes B and C showed an association with these parameters. Serum TG, cholesterol, VLDL, small dense LDL5,6 , and remnant lipoprotein cholesterol were lower among subtype A compared with subtypes B and C. The 10-year high risk of CVD, measured with the Framingham risk score, and the frequency of patatin-like phospholipase domain-containing protein 3 NAFLD risk allele were lower in subtype A. Metabolomic signatures identify three NAFLD subgroups, independent of histological disease severity. These signatures align with known CVD and genetic risk factors, with subtype A exhibiting a lower CVD risk profile. This may account for the variation in hepatic versus cardiovascular outcomes, offering clinically relevant risk stratification.Publication Infectious Exacerbations of Idiopathic Pulmonary Fibrosis.(2021-06-17) Fouz-Rosón, Natalia; Romero-Ortiz, Ana Dolores; Jiménez-Rodríguez, Beatriz María; López-Bauzá, Ángela; Rodríguez-Portal, José Antonio; Palacios-Hidalgo, Zulema; Ferrer-Galván, Marta; Guerrero-Zamora, Patricia; Morales, María Pérez; Expósito-Ruiz, ManuelaPublication Patritumab deruxtecan (HER3-DXd) in early-stage HR+/HER2-breast cancer: Final results of the SOLTI TOT-HER3 window of opportunity trial(Elsevier, 2022-05-05) Prat, A.; Falato, C.; Pare Brunet, L.; Martinez Saez, O.; Cejalvo Andujar, J. M.; Margeli Vila, M.; Tolosa, P.; Salvador Bofill, F. J.; Cruz Jurado, J.; Gonzalez-Farre, B.; Sanfeliu Torres, E.; Ciruelos, E. M.; Espinosa-Bravo, M.; Izarzugaza Peron, Y.; Pernas Simon, S.; Esker, S.; Fan, P-D.; Ferrero Cafiero, J. M.; Pascual, T.; Oliveira, M.; [Prat, A.] Hosp Clin Barcelona SOLTI IDIBAPS, Dept Med Oncol, Barcelona, Spain; [Falato, C.] IDIBAPS August Pi Sunyer Biomed Res Inst, SOLTI Canc Res Grp, Barcelona, Spain; [Pare Brunet, L.] SOLTI Canc Res Grp, Data Management, Barcelona, Spain; [Martinez Saez, O.] Hosp Clin Barcelona, Dept Med Oncol, SOLTI Canc Res Grp, Barcelona, Spain; [Cejalvo Andujar, J. M.] Hosp Clin Univ Valencia, Dept Med Oncol, SOLTI Canc Res Grp, Valencia, Spain; [Margeli Vila, M.] ICO Inst Catala Oncol Badalona Hosp Univ Germans, Dept Med Oncol, SOLTI Canc Res Grp, Badalona, Spain; [Tolosa, P.] Inst Invest Sanitaria Hosp 12 Octubre, Dept Med Oncol, SOLTI Canc Res Grp, Madrid, Spain; [Salvador Bofill, F. J.] Hosp Univ Virgen Valme, Med Oncol, Seville, Spain; [Cruz Jurado, J.] Hosp Univ Canarias, Dept Med Oncol, San Cristobal, Spain; [Gonzalez-Farre, B.] Hosp Clin Barcelona, Pathol Dept, SOLTI Canc Res Grp, Barcelona, Spain; [Sanfeliu Torres, E.] Hosp Clin Barcelona, Pathol Dept, SOLTI Canc Res Grp, Barcelona, Spain; [Ciruelos, E. M.] Hosp Univ 12 Octubre, Dept Med Oncol, SOLTI Canc Res Grp, Madrid, Spain; [Espinosa-Bravo, M.] Vall dHebron Univ Hosp, Breast Surg Unit, Barcelona, Spain; [Izarzugaza Peron, Y.] Hosp Univ Fdn Jimenez Diaz, Dept Oncol, Madrid, Spain; [Pernas Simon, S.] ICO Inst Catala Oncol Hosp Hosp Duran, Dept Med Oncol, SOLTI Canc Res Grp, Lhospitalet De Llobregat, Spain; [Esker, S.] Daiichi Sankyo Inc, Global Med Dept, Basking Ridge, NJ USA; [Fan, P-D.] Daiichi Sankyo Pharma Dev USA, Global Oncol, Edison, NJ USA; [Ferrero Cafiero, J. M.] SOLTI Canc Res Grp, Dept Clin Res, Barcelona, Spain; [Pascual, T.] Hosp Clin Barcelona, Dept Med Oncol, SOLTI Canc Res Grp, Barcelona, Spain; [Oliveira, M.] Vall dHebron Inst Oncol VHIO, SOLTI Canc Res Grp, Breast Canc Unit, Barcelona, SpainPublication SOLTI-1910: Predicting olaparib sensitivity in patients with unresectable locally advanced/metastatic HER2-negative breast cancer with BRCA1/2, PALB2, RAD51C/D mutations or HRD by the RAD51 test: RADIOLA trial(Elsevier, 2022-05-05) Balmana, J.; Pascual, T.; Llop-Guevara, A.; Tolosa, P.; Blancas Lopez-Barajas, I.; Perez Lopez, M. E.; Adamo, B.; Teruel-Garcia, I.; Ponce, J.; Gonzalez-Cordero, M.; Vinas Villaro, G.; Lema Roso, L.; Salvador Bofill, F. J.; Martinez, M. T. M.; Guerrero, A. N. E.; Prat, A.; Serra Elizalde, V.; [Balmana, J.] Vall dHebron Univ Hosp, Med Oncol Dept, Barcelona, Spain; [Pascual, T.] Hosp Clin Barcelona, SOLTI Canc Res Grp, Clin Res Dept, Barcelona, Spain; [Llop-Guevara, A.] Vall dHebron Inst Oncol VHIO, Cellex Ctr, Barcelona, Spain; [Tolosa, P.] Univ Hosp 12 Octubre, Med Oncol, Madrid, Spain; [Blancas Lopez-Barajas, I.] Hosp Clin San Cecilio, Oncol Dept, Granada, Spain; [Perez Lopez, M. E.] CHUAC Complexo Hosp Univ A Coruna, Oncol, La Coruna, Spain; [Adamo, B.] Hosp Clin Barcelona, Breast Canc Dept, Barcelona, Spain; [Teruel-Garcia, I.] Hosp Badalona Germans Trias & Pujol, ICO Inst Catala Oncol Badalona, Med Oncol, Badalona, Spain; [Ponce, J.] Hosp Gen Univ Alicante, Med Oncol Dept, Alicante, Spain; [Gonzalez-Cordero, M.] Hosp Univ Badajoz, Hosp Infanta Cristina, Med Oncol Dept, Badajoz, Spain; [Vinas Villaro, G.] Hosp Univ Josep Trueta, Catalan Inst Oncol ICO, Med Oncol, Girona, Spain; [Lema Roso, L.] Hosp Univ 12 Octubre, Med Oncol Dept, Madrid, Spain; [Salvador Bofill, F. J.] Hosp Univ Virgen Valme, Med Oncol Dept, Seville, Spain; [Martinez, M. T. M.] Hosp Clin Univ Valencia, Oncol Dept, Valencia, Spain; [Guerrero, A. N. E.] SOLTI Canc Res Grp, Sci, Barcelona, Spain; [Prat, A.] Hosp Clin Barcelona, Med Oncol Dept, Barcelona, Spain; [Serra Elizalde, V.] Vall dHebron Inst Oncol VHIO Cellex Ctr, Expt Therapeut Grp Dept, Barcelona, Spain