Familial hypercholesterolaemia in children and adolescents from 48 countries: a cross-sectional study

Background: Approximately 450 000 children are born with familial hypercholesterolaemia worldwide every year, yet only 2·1% of adults with familial hypercholesterolaemia were diagnosed before age 18 years via current diagnostic approaches, which are derived from observations in adults. We aimed to characterise children and adolescents with heterozygous familial hypercholesterolaemia (HeFH) and understand current approaches to the identification and management of familial hypercholesterolaemia to inform future public health strategies. Methods: For this cross-sectional study, we assessed children and adolescents younger than 18 years with a clinical or genetic diagnosis of HeFH at the time of entry into the Familial Hypercholesterolaemia Studies Collaboration (FHSC) registry between Oct 1, 2015, and Jan 31, 2021. Data in the registry were collected from 55 regional or national registries in 48 countries. Diagnoses relying on self-reported history of familial hypercholesterolaemia and suspected secondary hypercholesterolaemia were excluded from the registry; people with untreated LDL cholesterol (LDL-C) of at least 13·0 mmol/L were excluded from this study. Data were assessed overall and by WHO region, World Bank country income status, age, diagnostic criteria, and index-case status. The main outcome of this study was to assess current identification and management of children and adolescents with familial hypercholesterolaemia. Findings: Of 63 093 individuals in the FHSC registry, 11 848 (18·8%) were children or adolescents younger than 18 years with HeFH and were included in this study; 5756 (50·2%) of 11 476 included individuals were female and 5720 (49·8%) were male. Sex data were missing for 372 (3·1%) of 11 848 individuals. Median age at registry entry was 9·6 years (IQR 5·8-13·2). 10 099 (89·9%) of 11 235 included individuals had a final genetically confirmed diagnosis of familial hypercholesterolaemia and 1136 (10·1%) had a clinical diagnosis. Genetically confirmed diagnosis data or clinical diagnosis data were missing for 613 (5·2%) of 11 848 individuals. Genetic diagnosis was more common in children and adolescents from high-income countries (9427 [92·4%] of 10 202) than in children and adolescents from non-high-income countries (199 [48·0%] of 415). 3414 (31·6%) of 10 804 children or adolescents were index cases. Familial-hypercholesterolaemia-related physical signs, cardiovascular risk factors, and cardiovascular disease were uncommon, but were more common in non-high-income countries. 7557 (72·4%) of 10 428 included children or adolescents were not taking lipid-lowering medication (LLM) and had a median LDL-C of 5·00 mmol/L (IQR 4·05-6·08). Compared with genetic diagnosis, the use of unadapted clinical criteria intended for use in adults and reliant on more extreme phenotypes could result in 50-75% of children and adolescents with familial hypercholesterolaemia not being identified. Interpretation: Clinical characteristics observed in adults with familial hypercholesterolaemia are uncommon in children and adolescents with familial hypercholesterolaemia, hence detection in this age group relies on measurement of LDL-C and genetic confirmation. Where genetic testing is unavailable, increased availability and use of LDL-C measurements in the first few years of life could help reduce the current gap between prevalence and detection, enabling increased use of combination LLM to reach recommended LDL-C targets early in life

Riociguat treatment in patients with chronic thromboembolic pulmonary hypertension: Final safety data from the EXPERT registry

Objective: The soluble guanylate cyclase stimulator riociguat is approved for the treatment of adult patients with pulmonary arterial hypertension (PAH) and inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH) following Phase

Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues

Efecto de la inclusión de tres fuentes de lípidos en el alimento sobre los parámetros productivos y los ácidos grasos de la carne de cuy.

El objetivo del presente estudio fue evaluar la inclusión de aceite de soya, sebo de vacuno y manteca de cerdo en el alimento sobre los parámetros productivos y los ácidos grasos de la carne en cuyes (Cavia porcellus) durante la etapa de crecimiento. Se utilizaron 60 cuyes hembras tipo I, de 25 a 30 días de edad, con un peso promedio de 437 ± 49g y asignados dentro de tres tratamientos en un diseño completo al azar: dieta con aceite de soya (T1), dieta con sebo de vacuno (T2), dieta con manteca de cerdo (T3). Las variables evaluadas fueron ganancia de peso, consumo de alimento, conversión de alimento, rendimiento de carcasa, longitud de tejido adiposo y contenido de ácidos grasos. No se encontraron diferencias significativas en ganancia de peso, consumo de alimento y conversión alimenticia. El rendimiento de carcasa fue menor en los animales de T1 y T3 (p<0.05) y los animales de T1 y T3 tuvieron una menor longitud de tejido adiposo (p<0.05). Asimismo, los cuyes de T1 tuvieron una mayor concentración de ácidos grasos poliinsaturados (p<0.05). Se concluye que el perfil de ácidos grasos poliinsaturados omega 3 y omega-6 de la carne de cuy durante la etapa de crecimiento puede ser modificado favorablemente y sin afectar los índices productivos con la por inclusión de aceite de soya en la dieta en comparación con la inclusión de manteca de cerdo o sebo de vacuno

Changes in salivary biomarkers of stress, inflammation, redox status, and muscle damage due to Streptococcus suis infection in pigs

peer-reviewedBackground Streptococcus suis (S. suis) is a Gram-positive bacteria that infects pigs causing meningitis, arthritis, pneumonia, or endocarditis. This increases the mortality in pig farms deriving in severe economic losses. The use of saliva as a diagnostic fluid has various advantages compared to blood, especially in pigs. In this study, it was hypothesized that saliva could reflect changes in different biomarkers related to stress, inflammation, redox status, and muscle damage in pigs with S. suis infection and that changes in these biomarkers could be related to the severity of the disease. Results A total of 56 growing pigs from a farm were selected as infected pigs (n = 28) and healthy pigs (n = 28). Results showed increases in biomarkers related to stress (alpha-amylase and oxytocin), inflammation (haptoglobin, inter-alpha-trypsin inhibitor heavy chain 4 (ITIH4), total protein, S100A8-A9 and S100A12), redox status (advanced oxidation protein producs (AOPP)) and muscle damage (creatine kinase (CK), CK-MB, troponin I, lactate, aspartate aminotransferase, and lactate dehydrogenase). An increase in adenosine deaminase (ADA), procalcitonin, and aldolase in infected animals were also observed, as previously described. The grade of severity of the disease indicated a significant positive correlation with total protein concentrations, aspartate aminotransferase, aldolase, and AOPP. Conclusions This report revealed that S. suis infection caused variations in analytes related to stress, inflammation, redox status, and muscle damage in the saliva of pigs and these can be considered potential biomarkers for this disease.This study was supported by a Grant Reference PID2019-105950RB-100 funded by MCIN/AEI/10.13039/501100011033. It was also supported by a Grant Reference PCI2020-120712-2 from MCIN/AEI/10.13039/501100011033 and European Union “NextGenerationEU”/PRTR (1st ICRAD Joint Cofund Call). M.J.L-M. was funded by 21293/FPI/19, Fundación Séneca, Región de Murcia (Spain). D.E. was funded by the postdoctoral contract “Generational renewal to promote research” of the University of Murcia. M.L-A. has a postdoctoral fellowship “Juan de la Cierva Formación” supported by the Ministerio de Ciencia e Innovación (FJC2021-047105-I). A.M-P. T has a post-doctoral fellowship “Ramón y Cajal” supported by the Ministerio de Ciencia e Innovación, Agencia Estatal de Investigación (AEI), Spain, and The European Next Generation Funds (NextgenerationEU) (RYC2021-033660-I)

Promoter DNA Hypermethylation and Gene Repression in Undifferentiated Arabidopsis Cells

María Berdasco is with the Spanish National Cancer Centre, University of Oviedo, and Catalan Institute of Oncology; Rubén Alcázar is with University of Barcelona; María Victoria García-Ortiz is with University of Córdoba; Esteban Ballestar is with the Spanish National Cancer Centre; Agustín F. Fernández is with the Spanish National Cancer Centre; Teresa Roldán-Arjona is with University of Córdoba; Antonio F. Tiburcio is with University of Barcelona; Teresa Altabella is with University of Barcelona; Nicolas Buisine is with CNRS; Hadi Quesneville is with INRA; Antoine Baudry is with INRA; Loïc Lepiniec is with INRA; Miguel Alaminos is with University of Granada; Roberto Rodríguez is with University of Oviedo; Alan Lloyd is with UT Austin; Vincent Colot is with CNRS; Judith Bender is with Johns Hopkins University; María Jesús Canal is with University of Oviedo; Manel Esteller is with the Spanish National Cancer Centre and Catalan Institute of Oncology; Mario F. Fraga is with the Spanish National Cancer Centre and Spanish National Centre for Biotechnology.Maintaining and acquiring the pluripotent cell state in plants is critical to tissue regeneration and vegetative multiplication. Histone-based epigenetic mechanisms are important for regulating this undifferentiated state. Here we report the use of genetic and pharmacological experimental approaches to show that Arabidopsis cell suspensions and calluses specifically repress some genes as a result of promoter DNA hypermethylation. We found that promoters of the MAPK12, GSTU10 and BXL1 genes become hypermethylated in callus cells and that hypermethylation also affects the TTG1, GSTF5, SUVH8, fimbrin and CCD7 genes in cell suspensions. Promoter hypermethylation in undifferentiated cells was associated with histone hypoacetylation and primarily occurred at CpG sites. Accordingly, we found that the process specifically depends on MET1 and DRM2 methyltransferases, as demonstrated with DNA methyltransferase mutants. Our results suggest that promoter DNA methylation may be another important epigenetic mechanism for the establishment and/or maintenance of the undifferentiated state in plant cells.This work was supported by the Health (FIS01-04) (PI061267), Education and Science (I+D+I MCYT08-03, FU2004-02073/BMC and Consolider MEC09-05) Departments of the Spanish Government, the European Grant TRANSFOG LSHC-CT-2004-503438, and the Spanish Association Against Cancer (AECC). M.B. is funded by the Association Against Cancer (AECC).Cellular and Molecular Biolog

New insights into the genetic etiology of Alzheimer’s disease and related dementias

Characterization of the genetic landscape of Alzheimer’s disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/‘proxy’ AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele