RepisaludEl repositorio digital Repisalud captura, almacena, indexa, preserva y distribuye materiales de investigación en formato digital.http://repisalud.isciii.es:802024-03-19T08:43:50Z2024-03-19T08:43:50ZCharacterization of a selective, iron-chelating antifungal compound that disrupts fungal metabolism and synergizes with fluconazoleCorrales, JeanneRamos-Alonso, LuciaGonzález-Sabín, JavierRíos-Lombardía, NicolásTrevijano-Contador, NuriaEngen Berg, HenrietteSved Skottvoll, FrøydisMoris, FranciscoZaragoza, OscarChymkowitch, PierreGarcia, IgnacioEnserink, Jorrit Mhttp://hdl.handle.net/20.500.12105/190032024-03-19T08:37:32Z2024-02-06T00:00:00ZFungal infections are a growing global health concern due to the limited number of available antifungal therapies as well as the emergence of fungi that are resistant to first-line antimicrobials, particularly azoles and echinocandins. Development of novel, selective antifungal therapies is challenging due to similarities between fungal and mammalian cells. An attractive source of potential antifungal treatments is provided by ecological niches co-inhabited by bacteria, fungi, and multicellular organisms, where complex relationships between multiple organisms have resulted in evolution of a wide variety of selective antimicrobials. Here, we characterized several analogs of one such natural compound, collismycin A. We show that NR-6226C has antifungal activity against several pathogenic Candida species, including C. albicans and C. glabrata, whereas it only has little toxicity against mammalian cells. Mechanistically, NR-6226C selectively chelates iron, which is a limiting factor for pathogenic fungi during infection. As a result, NR-6226C treatment causes severe mitochondrial dysfunction, leading to formation of reactive oxygen species, metabolic reprogramming, and a severe reduction in ATP levels. Using an in vivo model for fungal infections, we show that NR-6226C significantly increases survival of Candida-infected Galleria mellonella larvae. Finally, our data indicate that NR-6226C synergizes strongly with fluconazole in inhibition of C. albicans. Taken together, NR-6226C is a promising antifungal compound that acts by chelating iron and disrupting mitochondrial functions. IMPORTANCE: Drug-resistant fungal infections are an emerging global threat, and pan-resistance to current antifungal therapies is an increasing problem. Clearly, there is a need for new antifungal drugs. In this study, we characterized a novel antifungal agent, the collismycin analog NR-6226C. NR-6226C has a favorable toxicity profile for human cells, which is essential for further clinical development. We unraveled the mechanism of action of NR-6226C and found that it disrupts iron homeostasis and thereby depletes fungal cells of energy. Importantly, NR-6226C strongly potentiates the antifungal activity of fluconazole, thereby providing inroads for combination therapy that may reduce or prevent azole resistance. Thus, NR-6226C is a promising compound for further development into antifungal treatment.
2024-02-06T00:00:00ZCausal mediation for uncausally related mediators in the context of survival analysisDomingo-Relloso, ArceJerolon, AllanTellez-Plaza, MariaBermudez, Jose Dhttp://hdl.handle.net/20.500.12105/190022024-03-19T08:09:08Z2024-02-18T00:00:00ZObjective: The study of the potential intermediate effect of several variables on the association between an exposure and a time-to-event outcome is a question of interest in epidemiologic research. However, to our knowledge, no tools have been developed for the evaluation of multiple correlated mediators in a survival setting. Methods: In this work, we extended the multimediate algorithm, which conducts mediation analysis in the context of multiple uncausally correlated mediators, to a time-to-event setting using the semiparametric additive hazards model. We theoretically demonstrated that, under certain assumptions, indirect, direct and total effects can be calculated using the counterfactual framework with collapsible survival models. We also adapted the algorithm to accommodate exposure-mediator interactions. Results and conclusions: Using simulations, we demonstrated that our algorithm performs better than the product of coefficients method, even for uncorrelated mediators. The additive hazards model quantifies the effects as rate differences, which constitute a measure of impact, with applications that can be highly informative for public health. Our algorithm can be found in the R package multimediate, which is available in Github.
2024-02-18T00:00:00ZAntibodies against the Mycobacterium tuberculosis complex and Brucella spp. in captive and free-living European bison (Bison bonasus) in PolandDidkowska, AnnaFerreras-Colino, ElisaOlech, WandaGloddy, HugguetteAnusz, KrzysztofInfantes-Lorenzo, Jose AntonioGortázar, Christianhttp://hdl.handle.net/20.500.12105/190012024-03-19T07:55:00Z2024-01-01T00:00:00ZBackground: The European bison (Bison bonasus), a symbol of Polish nature, is a protected species that requires active health monitoring. However, conservation efforts are made difficult by the zoonotic diseases such as brucellosis and tuberculosis. Objective: The aim of this study was to screen the Polish European bison population for exposure to the Mycobacterium tuberculosis complex (MTC) and Brucella spp. Methods: A total of 323 free-living and captive European bison from 13 localities were tested serologically for antibodies against the M. bovis P22 multi-protein complex (in-house ELISA) and against Brucella spp. (commercial ELISA). Results: Antibodies against the MTC (P22) were detected in 7% (22/323) of the tested European bison. Anti-MTC antibody positivity was not significantly different by sex, age, and captive/free range status. Anti-MTC antibodies were found in six of 13 populations sampled, always in populations with larger sample sizes including the four free-living ones. Antibodies against Brucella spp. were detected in 36% (116/323) of the tested bison. While Brucella spp. antibody prevalence was not different by sex, it was significantly different by age (lower in adults) and captive/free-living status. Brucella spp. seroprevalence decreased with sample size and seropositive bison were found in 12 of 13 sampling populations. Conclusions: Our findings identify potential emerging threats to the European bison population and confirm the first serological response to P22 in European bison. As Poland is currently officially free of brucellosis and bovine tuberculosis, our results require careful interpretation. Further studies are needed to establish the presence of cross-reactions with atypical mycobacteria in the case of MTC and other bacteria (e.g. Yersinia enterocolitica O:9) in the case of Brucella spp.
2024-01-01T00:00:00ZAnalytical data as a predictor of duration of hospital admission in human parechovirus infectionsGómez-Anca, SilviaFresno Jorge, PaulaCabrerizo, Mariade Ceano-Vivas La Calle, MaríaCalvo, Cristinahttp://hdl.handle.net/20.500.12105/190002024-03-19T07:44:57Z2024-02-01T00:00:00Z2024-02-01T00:00:00ZRAD51 restricts DNA over-replication from re-activated originsMuñoz, SergioBlanco-Romero, ElenaGonzalez-Acosta, DanielRodriguez-Acebes, SaraMegías, DiegoLopes, MassimoMendez, Juanhttp://hdl.handle.net/20.500.12105/189992024-03-19T07:33:16Z2024-03-01T00:00:00ZEukaryotic cells rely on several mechanisms to ensure that the genome is duplicated precisely once in each cell division cycle, preventing DNA over-replication and genomic instability. Most of these mechanisms limit the activity of origin licensing proteins to prevent the reactivation of origins that have already been used. Here, we have investigated whether additional controls restrict the extension of re-replicated DNA in the event of origin re-activation. In a genetic screening in cells forced to re-activate origins, we found that re-replication is limited by RAD51 and enhanced by FBH1, a RAD51 antagonist. In the presence of chromatin-bound RAD51, forks stemming from re-fired origins are slowed down, leading to frequent events of fork reversal. Eventual re-initiation of DNA synthesis mediated by PRIMPOL creates ssDNA gaps that facilitate the partial elimination of re-duplicated DNA by MRE11 exonuclease. In the absence of RAD51, these controls are abrogated and re-replication forks progress much longer than in normal conditions. Our study uncovers a safeguard mechanism to protect genome stability in the event of origin reactivation.
2024-03-01T00:00:00ZEffectiveness of the adapted bivalent mRNA COVID-19 vaccines against hospitalisation in individuals aged ≥ 60 years during the Omicron XBB lineage-predominant period: VEBIS SARI VE network, Europe, February to August, 2023Antunes, LilianaMazagatos, ClaraMartínez-Baz, IvánGomez, VerónicaBorg, Maria-LouisePetrović, GorankaDuffy, RóisínDufrasne, François EDürrwald, RalfLazar, MihaelaJancoriene, LigitaOroszi, BeatrixHusa, PetrHoward, JenniferMelo, ArysePozo Sanchez, FranciscoPérez-Gimeno, GloriaCastilla, JesúsMachado, AusendaDžiugytė, AušraKarabuva, SvjetlanaFitzgerald, MargaretFierens, SébastienTolksdorf, KristinPopovici, Silvia-OdetteMickienė, AuksėTúri, GergőSoučková, LenkaNicolay, NathalieRose, Angela McEuropean Hospital Vaccine Effectiveness Grouphttp://hdl.handle.net/20.500.12105/189982024-03-19T02:06:05Z2024-01-01T00:00:00ZWe conducted a multicentre hospital-based test-negative case-control study to measure the effectiveness of adapted bivalent COVID-19 mRNA vaccines against PCR-confirmed SARS-CoV-2 infection during the Omicron XBB lineage-predominant period in patients aged ≥ 60 years with severe acute respiratory infection from five countries in Europe. Bivalent vaccines provided short-term additional protection compared with those vaccinated > 6 months before the campaign: from 80% (95% CI: 50 to 94) for 14-89 days post-vaccination, 15% (95% CI: -12 to 35) at 90-179 days, and lower to no effect thereafter.
2024-01-01T00:00:00ZExposure to residential traffic and trajectories of unhealthy ageing: results from a nationally-representative cohort of older adultsGómrez Del Río, SergioPlans-Beriso, ElenaRamis, RebecaOrtolá, RosarioPastor-Barriuso, RobertoSotos-Prieto, MercedesCastelló Pastor, AdelaOlmedo-Requena, RocíoMoleón, José Juan JiménezFernández Félix, Borja MaríaMuriel, AlfonsoMiret, MartaAyuso-Mateos, José LuisChoi, Yoon-HyeongRodríguez-Artalejo, FernandoFernandez-Navarro, Pablo LGarcía-Esquinas, Estherhttp://hdl.handle.net/20.500.12105/189972024-03-19T02:06:15Z2024-02-01T00:00:00ZBackground: Traffic exposure has been associated with biomarkers of increased biological ageing, age-related chronic morbidities, and increased respiratory, cardiovascular, and all-cause mortality. Whether it is associated with functional impairments and unhealthy ageing trajectories is unknown. Methods: Nationally representative population-based cohort with 3,126 community-dwelling individuals aged ≥60 years who contributed 8,291 biannual visits over a 10 year period. Unhealthy ageing was estimated with a deficit accumulation index (DAI) based on the number and severity of 52 health deficits, including 22 objectively-measured impairments in physical and cognitive functioning. Differences in DAI at each follow-up across quintiles of residential traffic density (RTD) at 50 and 100 meters, and closest distance to a petrol station, were estimated using flexible marginal structural models with inverse probability of censoring weights. Models were adjusted for sociodemographic and time-varying lifestyle factors, social deprivation index at the census tract and residential exposure to natural spaces. Results: At baseline, the mean (SD) age and DAI score of the participants were 69.0 (6.6) years and 17.02 (11.0) %, and 54.0% were women. The median (IQR) RTD at 50 and 100 meters were 77 (31-467) and 509 (182-1802) vehicles/day, and the mean (SD) distance to the nearest petrol station of 962 (1317) meters. The average increase in DAI (95%CI) for participants in quintiles Q2-Q5 (vs Q1) of RTD at 50 meters was of 1.51 (0.50, 2.53), 0.98 (-0.05, 2.01), 2.20 (1.18, 3.21) and 1.98 (0.90, 3.05), respectively. Consistent findings were observed at 100 meters. By domains, most of the deficits accumulated with increased RTD were of a functional nature, although RTD at 50 meters was also associated with worse self-reported health, increased vitality problems and higher incidence of chronic morbidities. Living closer to a petrol station was associated with a higher incidence of functional impairments and chronic morbidities. Conclusions: Exposure to nearby residential traffic is associated with accelerated trajectories of unhealthy ageing. Diminishing traffic pollution should become a priority intervention for adding healthy years to life in the old age.
2024-02-01T00:00:00ZEpidemiology of reported cases of leptospirosis in the EU/EEA, 2010 to 2021Beauté, JulienInnocenti, FrancescoAristodimou, AristosŠpačková, MichaelaEves, CarolineKerbo, NataliaRimhanen-Finne, RuskaPicardeau, MathieuFaber, MirkoDougas, GeorgiosHalldórsdóttir, Anna MargrétJackson, SarahLeitēna, ViktorijaVergison, AnneBorg, Maria LouisePijnacker, RoanSadkowska-Todys, MałgorzataMartins, João VieiraRusu, Lavinia CiprianaGrilc, EvaEstevez-Reboredo, Rosa MariaNiskanen, TainaWestrell, Theresehttp://hdl.handle.net/20.500.12105/189962024-03-19T02:05:16Z2024-02-01T00:00:00ZBackground:Leptospirosis is a zoonotic disease caused by bacteria of the genus Leptospira. Humans are infected by exposure to animal urine or urine-contaminated environments. Although disease incidence is lower in Europe compared with tropical regions, there have been reports of an increase in leptospirosis cases since the 2000s in some European countries. Aim: We aimed to describe the epidemiology of reported cases of leptospirosis in the European Union/European Economic Area (EU/EEA) during 2010-2021 and to identify potential changes in epidemiological patterns. Methods: We ran a descriptive analysis of leptospirosis cases reported by EU/EEA countries to the European Centre for Disease Prevention and Control with disease during 2010-2021. We also analysed trends at EU/EEA and national level. Results: During 2010-2021, 23 countries reported 12,180 confirmed leptospirosis cases corresponding to a mean annual notification rate of 0.24 cases per 100,000 population. Five countries (France, Germany, the Netherlands, Portugal and Romania) accounted for 79% of all reported cases. The highest notification rate was observed in Slovenia with 0.82 cases per 100,000 population. Overall, the notification rate increased by 5.0% per year from 2010 to 2021 (95% CI: 1.2-8.8%), although trends differed across countries. Conclusion: The notification rate of leptospirosis at EU/EEA level increased during 2010-2021 despite including the first 2 years of the COVID-19 pandemic and associated changes in population behaviours. Studies at (sub)national level would help broaden the understanding of differences at country-level and specificities in terms of exposure to Leptospira, as well as biases in diagnosis and reporting.
2024-02-01T00:00:00ZEffectiveness and safety of bictegravir/emtricitabine/tenofovir alafenamide in HIV late presentersCorona, DianaPérez-Valero, IgnacioCamacho, AngelaGutiérrez Liarte, ÁngelaMontero-Alonso, MartaAlemán, María RemediosRuiz-Seco, PilarPérez González, AlexandreRiera, MelchorJarrin-Vera, InmaculadaRivero-Juárez, AntonioRivero, Antoniohttp://hdl.handle.net/20.500.12105/189952024-03-19T02:06:11Z2024-01-01T00:00:00ZObjectives: The efficacy of BIC/FTC/TAF in HIV late presenters initiating antiretroviral therapy (ART) has not been sufficiently evaluated. Methods: The aim of this study was to assess the effectiveness and tolerability of BIC/FTC/TAF compared to other first-line antiretroviral regimens in treatment-naïve adult individuals from the CoRIS Cohort starting ART with CD4 counts <200 cells/mm3 and/or AIDS-defining conditions between January 1st 2019 and November 30th 2020. Logistic regression models were used to estimate odds ratios (ORs) of association between initial regimen and achievement of viral suppression (VS) (primary objective), defined as HIV RNA <50 cop/mL, and immunological recovery (IR) (secondary objective), defined as CD4 count >200 cells/mm3, at weeks 24 and 48 after initiation of ART. Results: We evaluated 314 individuals (84.7% men, median age 40 years). Of them, 158 initiated with BIC/FTC/TAF. At inclusion, 117 had an AIDS-defining condition. In multivariable analyses, individuals with AIDS-defining conditions initiating ART with BIC/FTC/TAF achieved higher rates of VS at 24 weeks than other regimens (aOR: 0.2; 95% CI: 0.06-0.64) and, at 48 weeks, than DTG/ABC/3TC (aOR: 0.06; 95% CI: 0.01-0.76) and DTG + TDF/3TC (aOR: 0.2; 95% CI: 0.47-0.9). No other differences in VS or IR were observed. At 24 and 48 weeks after ART initiation, treatment discontinuations were lower with BIC/FTC/TAF than with other regimens (3.2% and 7.6% vs. 24.4% and 37.8%, respectively; P < 0.005). Conclusion: Our results suggest that BIC/FTC/TAF could be a preferred regimen as initial therapy in HIV late presenters because of its high effectiveness and good tolerability.
2024-01-01T00:00:00ZDynamics of the double burden of malnutrition in Guatemala: a secondary data analysis of the demographic and health surveys from 1998-2015Sagastume, DPeñalvo, José LRamírez-Zea, MPolman, KBeňová, Lhttp://hdl.handle.net/20.500.12105/189942024-03-19T02:05:03Z2024-03-04T00:00:00ZObjective: We estimated the prevalence and time trends of the double burden of malnutrition (DBM) in Guatemala and explored its occurrence based on socio-demographic factors. Study design: This was a secondary data analysis using information from four Demographic and Health Surveys covering the period 1998-2015. Methods: The unit of analysis was the household within which information was gathered from women 18-49 years and their children, 6-59 months. The main outcome was the prevalence of any DBM in the household (co-existence of undernutrition and overnutrition in a woman, her children or both). We estimated the prevalence of any DBM by survey and analysed time trends. Stepwise logistic regression was used to explore the occurrence of DBM and socio-demographic factors. Results: We analysed 39,749 households across all surveys. The prevalence of any DBM was 25.3% (95%CI: 22.1-28.7) in 1998-99, 23.8% (22.0-25.8) in 2002, 25.9% (24.3-27.5) in 2008-09 and 24.2% (22.9-25.5) in 2014-15, with no significant change over time (P = 0.782). Characteristics associated with lower odds of any DBM were rural residence, female-headed household, wealth and women's secondary education. Higher odds were seen for households with electricity, women >25y, indigenous and with >2 children. Conclusion: Our findings revealed that a quarter of Guatemala's households suffer from DBM, which has remained unchanged for 17 years. Interventions should prioritise urban areas, households of lower socio-economic status and those less educated. To increase awareness of policymakers of this pressing public health concern, further research on DBM could be strengthened by prospective study designs, integrating all household members and expanding the types of malnutrition.
2024-03-04T00:00:00ZCircadian rhythm disruption and retinal dysfunction: a bidirectional link in Alzheimer's disease?Carrero, LauraAntequera, DesireéMunicio, CristinaCarro, Evahttp://hdl.handle.net/20.500.12105/189932024-03-19T02:05:24Z2024-01-01T00:00:00ZDysfunction in circadian rhythms is a common occurrence in patients with Alzheimer's disease. A predominant function of the retina is circadian synchronization, carrying information to the brain through the retinohypothalamic tract, which projects to the suprachiasmatic nucleus. Notably, Alzheimer's disease hallmarks, including amyloid-β, are present in the retinas of Alzheimer's disease patients, followed/associated by structural and functional disturbances. However, the mechanistic link between circadian dysfunction and the pathological changes affecting the retina in Alzheimer's disease is not fully understood, although some studies point to the possibility that retinal dysfunction could be considered an early pathological process that directly modulates the circadian rhythm.
2024-01-01T00:00:00ZVigilancia centinela de Infección Respiratoria Aguda en Atención Primaria (IRAs) y en Hospitales (IRAG) Gripe, COVID-19 y VRS. Informe nº 173. Semana 10/2024 (del 4 de marzo al 10 de marzo del 2024).Instituto de Salud Carlos IIIhttp://hdl.handle.net/20.500.12105/189922024-03-19T02:04:38Z2024-03-10T00:00:00ZLa incidencia de gripe, COVID-19 y VRS en Atención Primaria y en hospitales continua en fase estable con fluctuaciones. Hasta el momento, en la temporada 2023-24 se ha experimentado una actividad de COVID-19 similar, y una epidemia de infección por VRS de menor intensidad, que en la temporada previa. En contraste la actividad gripal ha sido más alta que en las dos temporadas anteriores tanto en Atención Primaria como en hospitales. Entre las semanas 52/2023 y la 04/2024 se han identificado un exceso de 6116 defunciones por todas las causas.
2024-03-10T00:00:00ZVigilancia centinela de Infección Respiratoria Aguda en Atención Primaria (IRAs) y en Hospitales (IRAG) Gripe, COVID-19 y VRS. Informe nº 172. Semana 09/2024 (del 26 de febrero al 3 de marzo del 2024).Instituto de Salud Carlos IIIhttp://hdl.handle.net/20.500.12105/189912024-03-19T02:04:58Z2024-03-03T00:00:00ZPersiste el descenso en la circulación de gripe en la comunidad y se observan fluctuaciones en la circulación de SARS-CoV-2 y VRS. La actividad de gripe, COVID-19 e infección por VRS disminuye o se mantiene estable tanto en Atención Primaria como en el ámbito hospitalario. Entre las semanas 52/2023 y la 04/2024 se han identificado un exceso de 6080 defunciones por todas las causas.
2024-03-03T00:00:00ZVigilancia centinela de Infección Respiratoria Aguda en Atención Primaria (IRAs) y en Hospitales (IRAG) Gripe, COVID-19 y VRS. Informe nº 171. Semana 08/2024 (del 19 de febrero al 25 de febrero del 2024)Instituto de Salud Carlos IIIhttp://hdl.handle.net/20.500.12105/189902024-03-19T02:04:19Z2024-02-25T00:00:00ZLas tasas de infección respiratoria aguda se mantienen estables, con niveles menores en Atención Primaria y valores similares en hospitales que en las mismas semanas de la temporada previa. La circulación de gripe, SARSCoV-2 y VRS sigue en descenso en la comunidad y persiste la disminución de positividad a los tres virus entre los casos de IRAG. La actividad de gripe, COVID-19 y de infección por VRS disminuye en todos los ámbitos de atención sanitaria. Entre la semana 52/2023 y la 03/2024 se ha identificado un exceso de 6021 defunciones por todas las causas.
2024-02-25T00:00:00ZVigilancia centinela de Infección Respiratoria Aguda en Atención Primaria (IRAs) y en Hospitales (IRAG) Gripe, COVID-19 y VRS. Informe nº 170. Semana 07/2024 (del 12 de febrero al 18 de febrero del 2024).Instituto de Salud Carlos IIIhttp://hdl.handle.net/20.500.12105/189892024-03-19T02:03:19Z2024-02-18T00:00:00ZLas tasas de infección respiratoria aguda se mantienen a la baja, con niveles menores en Atención Primaria y valores similares en hospitales que en las mismas semanas de la temporada previa. La circulación de gripe, SARSCoV-2 y VRS sigue en descenso en la comunidad y persiste la disminución de positividad a los tres virus entre los casos de IRAG. La actividad de gripe, COVID-19 y de infección por VRS disminuye en todos los ámbitos de atención sanitaria y en todos los grupos de edad. Entre la semana 52/2023 y la 03/2024 se ha identificado un exceso de 5895 defunciones por todas las causas.
2024-02-18T00:00:00ZVigilancia centinela de Infección Respiratoria Aguda en Atención Primaria (IRAs) y en Hospitales (IRAG) Gripe, COVID-19 y VRS. Informe nº 169. Semana 06/2024 (del 5 de febrero al 11 de febrero del 2024).Instituto de Salud Carlos IIIhttp://hdl.handle.net/20.500.12105/189882024-03-19T02:03:59Z2024-02-11T00:00:00ZLas tasas de infección respiratoria aguda fluctúan con niveles menores en Atención Primaria y valores similares en hospitales, al igual que en las mismas semanas de la temporada previa. La circulación de gripe, SARSCoV-2 y VRS sigue en descenso en la comunidad y persiste la disminución de positividad a los tres virus entre los casos de IRAG. En la semana 06/2024, la incidencia de gripe regresa a valores basales señalando el final del periodo epidémico de esta onda estacional de gripe. Este descenso en la actividad gripal se observa también entre las formas graves de gripe en hospitales. La actividad de COVID-19 y de infección por VRS disminuye en todos los ámbitos de atención sanitaria y en todos los grupos de edad. Entre la semana 52/2023 y 03/2024 se ha identificado un exceso de 5672 defunciones por todas las causas.
2024-02-11T00:00:00Z