CIBERER : Spanish national network for research on rare diseases: A highly productive collaborative initiative

Altres ajuts: Instituto de Salud Carlos III (ISCIII); Ministerio de Ciencia e Innovación.CIBER (Center for Biomedical Network Research; Centro de Investigación Biomédica En Red) is a public national consortium created in 2006 under the umbrella of the Spanish National Institute of Health Carlos III (ISCIII). This innovative research structure comprises 11 different specific areas dedicated to the main public health priorities in the National Health System. CIBERER, the thematic area of CIBER focused on rare diseases (RDs) currently consists of 75 research groups belonging to universities, research centers, and hospitals of the entire country. CIBERER's mission is to be a center prioritizing and favoring collaboration and cooperation between biomedical and clinical research groups, with special emphasis on the aspects of genetic, molecular, biochemical, and cellular research of RDs. This research is the basis for providing new tools for the diagnosis and therapy of low-prevalence diseases, in line with the International Rare Diseases Research Consortium (IRDiRC) objectives, thus favoring translational research between the scientific environment of the laboratory and the clinical setting of health centers. In this article, we intend to review CIBERER's 15-year journey and summarize the main results obtained in terms of internationalization, scientific production, contributions toward the discovery of new therapies and novel genes associated to diseases, cooperation with patients' associations and many other topics related to RD research

Stroke genetics informs drug discovery and risk prediction across ancestries

Previous genome-wide association studies (GWASs) of stroke — the second leading cause of death worldwide — were conducted predominantly in populations of European ancestry1,2. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis3, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach4, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry5. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries

Stroke genetics informs drug discovery and risk prediction across ancestries

Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry(1,2). Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis(3), and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach(4), we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry(5). Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.</p

Ten novel mutations in the NR5A1 gene cause disordered sex development in 46,XY and ovarian insufficiency in 46,XX individuals

Steroidogenic factor-1 (SF-1/NR5A1) is a nuclear receptor that regulates adrenal and reproductive development and function. NR5A1 mutations have been detected in 46,XY individuals with disorders of sexual development (DSD) but apparently normal adrenal function and in 46,XX women with normal sexual development yet primary ovarian insufficiency (POI)

Empleo de policultivos para el manejo de Peregrinus maidis (Ashmead.) en el cultivo de maiz (Zea mays L.)

The work had as objective to evaluate the multicultivations employment keeping in mind the affectation of Peregrinus maidis (Ashmead) in the corn cultivation (Zea mays L.), as well as to determine the main present biocontrols in two agro-ecosystems and the relationship predator-prey. The investigation was carried out in Fomento municipality, Sancti Spíritus province, Cuba, during the years 2011 to 2013, in two agroecosystems and two crops seasons (rainy and not very rainy), carried out on an experimental design of two factors in divided parcels (2 x 5) x 4, in random blocks, where the big parcels were the two agroecosystems and the small parcels the five systems of cultivations (corn monocultivation (M), corn-pumpkin (M+C); corn-bean «caupí» (M+F); corn-benne (M+A) and corn-sunflower (M+G)) The samplings were carried out every seven days and they observed 25 plants for parcels, for a total of 100 plants for treatment. After having carried out the investigation it could be proven that the systems of cultivations M+C, M+A has better answer before the attack for P. maidis that the monocultivation of corn, being significantly lower the incidence of these plagues in the pre-mountainous agroecosystem. 15 species of insects regulators of P.maidis were identified, Scymnus sp was the most representative depredador, while Anagrus sp was its only parasitic in all cultivations systems. The multicultivations shows bigger biological stability given by a bigger relationship Predator-prey and index of global parasitism being favored the systems M+CM+A and M+G.El trabajo tuvo como objetivo evaluar el empleo de policultivos teniendo en cuenta la afectación de Peregrinus maidis (Ashmead) en el cultivo del maíz (Zea mays L.), así como determinar los principales biorreguladores presentes en dos agroecosistemas y la relación predador-presa. La investigación se realizó en el municipio de Fomento, Provincia Sancti Spíritus, Cuba, durante los años 2011 al 2013 en dos agroecosistemas y dos épocas de siembra (lluviosa y poco lluviosa), realizado sobre un diseño experimental de dos factores en parcelas divididas (2 x 5) x 4, en bloques al azar, donde las parcelas grandes fueron los dos agroecosistemas y las parcelas pequeñas los cinco sistemas de cultivos (Maíz monocultivo (M), maíz-calabaza (M+C); maíz-frijol caupí (M+F); maíz-ajonjolí (M+A) y maíz-girasol (M+G)) Los muestreos se realizaron cada siete días y observaron 25 plantas por parcelas, para un total de 100 plantas por tratamiento. Después de realizada la investigación se pudo comprobar que los sistemas de cultivos M+C, M+A tienen mejor respuesta ante el ataque por P. maidis que el monocultivo del maíz, siendo significativamente inferior la incidencia de estas plagas en el agroecosistema premontañoso. Se identificaron 15 especies de insectos reguladores de P.maidis, Scymnus sp fue el depredador más representativo, mientras que Anagrus sp fue su único parasitoide en todos los sistemas de cultivos. Los policultivos muestran mayor estabilidad biológica dado por una mayor relación Predador-Presa e índice de parasitismo global siendo favorecidos los sistemas M+CM+A y M+G

Defoliation triggered by climate induced effects in Spanish ICP Forests monitoring plots

In a context of global change, climate impacts can trigger defoliation processes in different forest species. The ICP Forests network estimates the level of forest defoliation over time in different European countries. Those data are used to related defoliation with potential causal factors. In European Southwestern forests, climate change appears to be the detonating factor of generalized defoliation. The objectives of this study were (i) identity defoliation trends in forest trees at network of Spanish ICP Forests monitoring plots and, (ii) find out if there are underlying climate factors that trigger defoliation process along the time. The spatiotemporal synchronization of the defoliation response was analyzed with cross-correlation using COFECHA software. The relationship between the 88 climatic variables proposed and defoliation was analyzed using Correlated Component Regression models (CCR models) and Discriminant Analysis (DA). The significance of the variables in each model was compared using contingency tables. A peak of defoliation was observed in the mid-1990s with no recovered to the initial values of the early 1990s. The behavior of the different tree species with respect to defoliation, synchronized both in time and space, involves one or several factors that have a general and similar effect on forests in Spain. The most significant factors related to defoliation were the thermal-related factors, particularly average temperatures in April and June and the thermal oscillation of both the current year and the previous year. Only one drought indicator as statistically significant was identified (A, duration of aridity in months) and suggests that it is of limited relevance in the Spanish forest defoliation conditions. © 2014 Elsevier B.V

Contrasting vulnerability and resilience to drought-induced decline of densely planted vs. natural rear-edge Pinus nigra forests

The southernmost European natural and planted pine forests are among the most vulnerable areas to warming-induced drought decline. Both drought stress and management factors (e.g.;stand origin or reduced thinning) may induce decline by reducing the water available to trees but their relative importances have not been properly assessed. The role of stand origin - densely planted vs. naturally regenerated stands - as a decline driver can be assessed by comparing the growth and vigor responses to drought of similar natural vs. planted stands. Here, we compare these responses in natural and planted Black pine (Pinus nigra) stands located in southern Spain. We analyze how environmental factors - climatic (temperature and precipitation anomalies) and site conditions - and biotic factors - stand structure (age, tree size, density) and defoliation by the pine processionary moth - drive radial growth and crown condition at stand and tree levels. We also assess the climatic trends in the study area over the last 60. years. We use dendrochronology, linear mixed-effects models of basal area increment and structural equation models to determine how natural and planted stands respond to drought and current competition intensity. We observed that a temperature rise and a decrease in precipitation during the growing period led to increasing drought stress during the late 20th century. Trees from planted stands experienced stronger growth reductions and displayed more severe crown defoliation after severe droughts than those from natural stands. High stand density negatively drove growth and enhanced crown dieback, particularly in planted stands. Also pine processionary moth defoliation was more severe in the growth of natural than in planted stands but affected tree crown condition similarly in both stand types. In response to drought, sharp growth reduction and widespread defoliation of planted Mediterranean pine stands indicate that they are more vulnerable and less resilient to drought stress than natural stands. To mitigate forest decline of planted stands in xeric areas such as the Mediterranean Basin, less dense and more diverse stands should be created through selective thinning or by selecting species or provenances that are more drought tolerant. © 2013 Elsevier B.V

Spanish National Hip Fracture Registry (SNHFR): a description of its objectives, methodology and implementation

To ascertain the current situation and clinical variability of the provision of care for Hip Fracture (HF) in Spain and the factors related to it by using a National Registry (NHFR) with high patient numbers and territorial representation NHFR, and to compare results on a national and international level and propose standards and criteria to improve healthcare quality.Continuous registry for at least three years of a representative sample of patients admitted to Spanish hospitals due to HF using the Minimum Common Dataset - international Fragility Fracture Network (FFN) MCD, adapted for Spanish. STUDY SCOPE AND SUBJECTS: all patients over the age of 74 years who are hospitalized with a diagnosis of a fragility HF at the participating hospitals distributed throughout the Spanish territory. Initially 48 hospitals are included, and we expect to incorporate the highest number of sites possible.It is expected to ascertain the current situation of provision of care for HF in Spain. Each hospital will be offered information regarding their results and their situation compared to the rest. The results from national hospitals will be compared to others included in the registry and to hospitals abroad, which use the same database. Variability will be studied, care standards will be established, and objectives will be proposed for the continuous improvement of the care process of this condition

Spanish National Hip Fracture Registry (SNHFR): a description of its objectives, methodology and implementation

To ascertain the current situation and clinical variability of the provision of care for Hip Fracture (HF) in Spain and the factors related to it by using a National Registry (NHFR) with high patient numbers and territorial representation NHFR, and to compare results on a national and international level and propose standards and criteria to improve healthcare quality.Continuous registry for at least three years of a representative sample of patients admitted to Spanish hospitals due to HF using the Minimum Common Dataset - international Fragility Fracture Network (FFN) MCD, adapted for Spanish. STUDY SCOPE AND SUBJECTS: all patients over the age of 74 years who are hospitalized with a diagnosis of a fragility HF at the participating hospitals distributed throughout the Spanish territory. Initially 48 hospitals are included, and we expect to incorporate the highest number of sites possible.It is expected to ascertain the current situation of provision of care for HF in Spain. Each hospital will be offered information regarding their results and their situation compared to the rest. The results from national hospitals will be compared to others included in the registry and to hospitals abroad, which use the same database. Variability will be studied, care standards will be established, and objectives will be proposed for the continuous improvement of the care process of this condition

Spanish National Hip Fracture Registry (SNHFR): a description of its objectives, methodology and implementation

To ascertain the current situation and clinical variability of the provision of care for Hip Fracture (HF) in Spain and the factors related to it by using a National Registry (NHFR) with high patient numbers and territorial representation NHFR, and to compare results on a national and international level and propose standards and criteria to improve healthcare quality.Continuous registry for at least three years of a representative sample of patients admitted to Spanish hospitals due to HF using the Minimum Common Dataset - international Fragility Fracture Network (FFN) MCD, adapted for Spanish. STUDY SCOPE AND SUBJECTS: all patients over the age of 74 years who are hospitalized with a diagnosis of a fragility HF at the participating hospitals distributed throughout the Spanish territory. Initially 48 hospitals are included, and we expect to incorporate the highest number of sites possible.It is expected to ascertain the current situation of provision of care for HF in Spain. Each hospital will be offered information regarding their results and their situation compared to the rest. The results from national hospitals will be compared to others included in the registry and to hospitals abroad, which use the same database. Variability will be studied, care standards will be established, and objectives will be proposed for the continuous improvement of the care process of this condition