Evaluation and prioritization of biological risk in Ready-To-Eat (RTE) meat products through mathematical modelling

[SPA] La producción moderna de alimentos ha reducido el coste y ha aumentado la variedad de alimentos disponibles, pero esta centralización del suministro de alimentos presenta una oportunidad para que los patógenos y toxinas transmitidos por los alimentos infecten y envenenen a un gran número de consumidores. El modelado es una herramienta clave para garantizar la seguridad de los alimentos producidos a partir de materias primas para el consumidor final. La hipótesis inicial es que es posible mejorar la seguridad de los productos cárnicos listos para comer (LPC) mediante la evaluación/priorización de riesgos biológicos. La clasificación de riesgos de los riesgos para la salud de los alimentos y la seguridad alimentaria y nutricional se reconoce generalmente como el punto de partida para el establecimiento de prioridades basadas en el riesgo y la asignación de recursos, ya que permite a los encargados de formular políticas asignar sus recursos al problema de salud pública más importante. El resultado de esta tesis será una herramienta sólida de gestión de la inocuidad de los alimentos que puede ser implementada por todos los interesados, como las agencias de protección al consumidor (EFSA, ECDC) y la industria. [ENG] Modern food production has reduced the cost and increased the variety of food available, but this centralisation of the food supply presents an opportunity for foodborne pathogens and toxins to infect and poison large numbers of consumers. Modelling is a key tool to ensure the safety of food produced from raw material to the final consumer. The starting hypothesis is that it is possible to improve the safety of Ready To Eat (RTE) meat products by evaluation / prioritization of biological risks. Risk ranking of feed/food safety and nutritional related health risks is generally recognised as the starting point for risk-based priority setting and resource allocation, as it permits policymakers to allocate their resources on the most significant public health problem. The outcome of the thesis will be a robust tool for food safety management that can be implemented by all stakeholders, such as agencies related to consumer protection (EFSA, ECDC) and industry.Leonidas Georgalis is grateful to the MINECO for awarding him a pre−doctoral grant, through Project AGL2017-86840-C2-1-R. To EFSA for awarding him an EU FORA fellowship, 2019-2020

TCERG1L allelic variation is associated with cisplatin-induced hearing loss in childhood cancer, a PanCareLIFE study.

In children with cancer, the heterogeneity in ototoxicity occurrence after similar treatment suggests a role for genetic susceptibility. Using a genome-wide association study (GWAS) approach, we identified a genetic variant in TCERG1L (rs893507) to be associated with hearing loss in 390 non-cranial irradiated, cisplatin-treated children with cancer. These results were replicated in two independent, similarly treated cohorts (n = 192 and 188, respectively) (combined cohort: P = 5.3 × 10-10, OR 3.11, 95% CI 2.2-4.5). Modulating TCERG1L expression in cultured human cells revealed significantly altered cellular responses to cisplatin-induced cytokine secretion and toxicity. These results contribute to insights into the genetic and pathophysiological basis of cisplatin-induced ototoxicity

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

Differences in replication kinetics and cell tropism between neurovirulent and non-neurovirulent EHV1 strains during the acute phase of infection in horses

International audienceEquine herpesvirus 1 (EHV1) replicates in the respiratory tract of horses, after which infected leukocytes transport virus throughout the body, resulting in abortion or nervous system disorders. Two EHV1 strains circulate in the field: neurovirulent and non-neurovirulent. To investigate differences in replication in the upper respiratory tract (URT), an experimental inoculation study in ponies was performed with both strains. Two groups of six ponies, were inoculated intranasally with 10 TCID of either strain. Clinical signs, nasal shedding and viremia were evaluated. At early time points post inoculation (pi), one pony of each group was euthanized. Tnoculation with either strain resulted in nasal shedding and replication in several tissues of the URT. Both strains replicated in a plaquewise manner in epithelium of the nasal mucosa, but replication in epithelium of the nasopharynx was largely limited to non-neurovirulent EHV1. Plaques were never able to cross the basement membrane, but individual infected cells were noticed in the connective tissue of all examined tissues for both strains. The total number of these cells however, was 3-7 times lower with non-neurovirulent EHV1 compared to neurovirulent EHV1. CD172a cells and CD5+ lymphocytes were important target cells for both strains. Interestingly, in lymph nodes, B-lymphocytes were also important target cells for EHV1, irrespective of the strain. Viremia was detected very early pi and infected cells were mainly CD172a for both strains. In summary, these results are valuable for understanding EHV1 pathogenesis at the port of entry, the URT

TCERG1L allelic variation is associated with cisplatin-induced hearing loss in childhood cancer, a PanCareLIFE study

In children with cancer, the heterogeneity in ototoxicity occurrence after similar treatment suggests a role for genetic susceptibility. Using a genome-wide association study (GWAS) approach, we identified a genetic variant in TCERG1L to be associated with hearing loss in 390 non-cranial irradiated, cisplatin-treated children with cancer. These results were replicated in two independent, similarly treated cohorts. Modulating TCERG1L expression in cultured human cells revealed significantly altered cellular responses to cisplatin-induced cytokine secretion and toxicity. These results contribute to insights into the genetic and pathophysiological basis of cisplatin-induced ototoxicity.</p

A saturated map of common genetic variants associated with human height

Common single-nucleotide polymorphisms (SNPs) are predicted to collectively explain 40-50% of phenotypic variation in human height, but identifying the specific variants and associated regions requires huge sample sizes(1). Here, using data from a genome-wide association study of 5.4 million individuals of diverse ancestries, we show that 12,111 independent SNPs that are significantly associated with height account for nearly all of the common SNP-based heritability. These SNPs are clustered within 7,209 non-overlapping genomic segments with a mean size of around 90 kb, covering about 21% of the genome. The density of independent associations varies across the genome and the regions of increased density are enriched for biologically relevant genes. In out-of-sample estimation and prediction, the 12,111 SNPs (or all SNPs in the HapMap 3 panel(2)) account for 40% (45%) of phenotypic variance in populations of European ancestry but only around 10-20% (14-24%) in populations of other ancestries. Effect sizes, associated regions and gene prioritization are similar across ancestries, indicating that reduced prediction accuracy is likely to be explained by linkage disequilibrium and differences in allele frequency within associated regions. Finally, we show that the relevant biological pathways are detectable with smaller sample sizes than are needed to implicate causal genes and variants. Overall, this study provides a comprehensive map of specific genomic regions that contain the vast majority of common height-associated variants. Although this map is saturated for populations of European ancestry, further research is needed to achieve equivalent saturation in other ancestries