Analysis of shared common genetic risk between amyotrophic lateral sclerosis and epilepsy

Because hyper-excitability has been shown to be a shared pathophysiological mechanism, we used the latest and largest genome-wide studies in amyotrophic lateral sclerosis (n = 36,052) and epilepsy (n = 38,349) to determine genetic overlap between these conditions. First, we showed no significant genetic correlation, also when binned on minor allele frequency. Second, we confirmed the absence of polygenic overlap using genomic risk score analysis. Finally, we did not identify pleiotropic variants in meta-analyses of the 2 diseases. Our findings indicate that amyotrophic lateral sclerosis and epilepsy do not share common genetic risk, showing that hyper-excitability in both disorders has distinct origins

Genome-wide Analyses Identify KIF5A as a Novel ALS Gene

To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.Peer reviewe

GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture

Epilepsy is a highly heritable disorder affecting over 50 million people worldwide, of which about one-third are resistant to current treatments. Here we report a multi-ancestry genome-wide association study including 29,944 cases, stratified into three broad categories and seven subtypes of epilepsy, and 52,538 controls. We identify 26 genome-wide significant loci, 19 of which are specific to genetic generalized epilepsy (GGE). We implicate 29 likely causal genes underlying these 26 loci. SNP-based heritability analyses show that common variants explain between 39.6% and 90% of genetic risk for GGE and its subtypes. Subtype analysis revealed markedly different genetic architectures between focal and generalized epilepsies. Gene-set analyses of GGE signals implicate synaptic processes in both excitatory and inhibitory neurons in the brain. Prioritized candidate genes overlap with monogenic epilepsy genes and with targets of current antiseizure medications. Finally, we leverage our results to identify alternate drugs with predicted efficacy if repurposed for epilepsy treatment

Genome-wide identification and phenotypic characterization of seizure-associated copy number variations in 741,075 individuals

Copy number variants (CNV) are established risk factors for neurodevelopmental disorders with seizures or epilepsy. With the hypothesis that seizure disorders share genetic risk factors, we pooled CNV data from 10,590 individuals with seizure disorders, 16,109 individuals with clinically validated epilepsy, and 492,324 population controls and identified 25 genome-wide significant loci, 22 of which are novel for seizure disorders, such as deletions at 1p36.33, 1q44, 2p21-p16.3, 3q29, 8p23.3-p23.2, 9p24.3, 10q26.3, 15q11.2, 15q12-q13.1, 16p12.2, 17q21.31, duplications at 2q13, 9q34.3, 16p13.3, 17q12, 19p13.3, 20q13.33, and reciprocal CNVs at 16p11.2, and 22q11.21. Using genetic data from additional 248,751 individuals with 23 neuropsychiatric phenotypes, we explored the pleiotropy of these 25 loci. Finally, in a subset of individuals with epilepsy and detailed clinical data available, we performed phenome-wide association analyses between individual CNVs and clinical annotations categorized through the Human Phenotype Ontology (HPO). For six CNVs, we identified 19 significant associations with specific HPO terms and generated, for all CNVs, phenotype signatures across 17 clinical categories relevant for epileptologists. This is the most comprehensive investigation of CNVs in epilepsy and related seizure disorders, with potential implications for clinical practice

Stigma ed esclusione sociale nelle malattie mentali: un problema irrisolto

1. Il processo di de-istituzionalizzazione, iniziato nei Paesi dell’Europa Occidentale negli anni cinquanta, ha portato, tra gli anni ‘60 e ’90, a radicali cambiamenti nelle politiche psichiatriche e nella pratica clinica con il tramite della psichiatria di comunità. Nonostante la chiusura delle strutture manicomiali, la drastica riduzione dei posti letto nelle istituzione psichiatriche e la collocazione dei servizi psichiatrici all’interno della comunità, marginalizzazione, esclusione social..

Towards a specialised repository on “Migration studies” through new filters of the SoReCom A.S. de Rosa @-library

The aim of this contribution is to present some recent developments of the So.Re.Com. “A.S. de Rosa” @-Library (Social Representations and Communication ‘A.S. de Rosa’ @-library), already presented in previous publications ([1], [2], [3], [4], [5], [6], [7], [8], [9]) as multi-purpose web-platform for documentation, training and networking in the supra-disciplinary field of Social Representations and Communication Among the many cross-thematic areas of supra-disciplinary interest (environment, health, education, science and technology, communication, politics, economics, etc.) with the high societal impact, the “migration studies” represent a relevant field of transversal knowledge across social sciences developed by the researchers specifically working in “Social Representations and Communication” and by social scientists inspired by other theories and disciplinary fields beyond social psychology. There is a huge literature and documentation aimed at investigating and understanding the complex phenomenon of “migration” on factual elements, that characterise the dynamic of “pull” and “push” factors in the migratory flows in the history, alternating emigration/immigration from/towards countries and world regions or even concurrent migratory flows from the same countries, and the impact with host communities. However in the multi-media communication system of our contemporary society this factual knowledge is almost obscured by “polarised” social representations connoted by opposite attitudes pro-against immigration and perceived as a contemporary emergency due to the “fear” or the “empathy” toward the immigrants depicted as “invaders”, “potential terrorist”, “threat to the employment opportunities of the citizens of their sovereign country”…. or as “victims”, “support for the economy of the country” as workers in fields that no longer interest native citizens, “refugees” who escape from war or natural disasters….The manipulation of emotions induced in the citizens by political leaders or other influential authorities according to their different ideological positions and identity affiliations has a wide “echo chamber” in the social media (Twitter, Facebook, Instagram, YouTube….). However, at some extent, the rhetorical device of these polarised views also organise the semantic dictionary of the policies documents and scientific literature (even only as input for counter-arguments) making significant some variables, like the author’s institutional affiliation geographical location in the specificities analysis . Linked to a wide research program on migratory experiences and discourse, articulated in “multimedia” and “field” studies - led by de Rosa since 2017 and developed in collaboration with a large research team ([10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33]) - the acquisition of a huge documentation at several levels of the discourse has been the occasion of recent developments of the So.Re.Com. “A.S. de Rosa” @-Library through new filters. These specific web-tools further improve the @-library’s functionalities, allowing to extract from distinct repositories the literature specifically inspired by Social Representations in a separate or aggregate way by the literature inspired by other theories in social sciences and communication studies, in view of detecting a large transversal corpus of sources toward a virtual specialised cross-paradigmatic and cross-disciplinary repository on “migration studies”. Selected results will be presented among those obtained by multidimensional analyses of data and meta-data extracted from different repositories of the So.Re.Com. “A.S. de Rosa” @-Library

Egresados ¿terminaron? Las representaciones de los jóvenes acerca del sentido de terminar el nivel Polimodal

Ningun

Mortality and major morbidities in very preterm infants born from assisted conception or naturally conceived: Results of the area-based ACTION study

BACKGROUND: The use of assisted conception (AC) has been associated with higher risk of adverse perinatal outcome. Few data are available on the outcome of AC-neonates when pregnancy ends before 32 weeks of gestational age.The aim of this study was to compare the short-term outcome of AC- and naturally conceived preterm infants <32 weeks gestation. METHODS: The area-based cohort study ACTION collected data on births 22-31 weeks gestation occurred in 2003-05 in 6 Italian regions. Infants born to 2529 mothers with known mode of conception were studied. The main outcomes were hospital mortality and survival free from major morbidities (IVH grade 3-4, cPVL, ROP stage ≥3, BPD), and were assessed separately for single and multiple infants. Other outcomes were also investigated. Multivariable logistic analyses were used to adjust for maternal and infants' characteristics. To account for the correlation of observations within intensive care units, robust variance and standard error estimates of regression parameters were computed. RESULTS: AC was used in 6.4% of mothers. Infants were 2934; 314 (10.7%) were born after AC. Multiples were 86.0% among AC and 21.7% among non-AC babies. In multivariable analysis no statistically significant difference in hospital mortality and survival without major morbidities was found between AC and non-AC infants. The risk of BPD was lower in AC than in non-AC multiples (aOR 0.41, CI 0.20-0.87), and this finding did not change after controlling for mechanical ventilation (aOR 0.42, CI 0.20-0.85) or presence of a patent ductus arteriosus (aOR 0.39, CI 0.18-0.84). CONCLUSION: When the analysis is restricted to very preterm infants and stratified by multiplicity, no significant associations between AC and increased risk of short-term mortality and survival without major morbidities emerge. This result is consistent with previous studies, and may confirm the hypothesis that the adverse effects of AC are mediated by preterm birth. However, larger appropriately powered studies are needed before definitely excluding the possibility of adverse events linked to AC in infants born before 32 weeks gestation

REXIC project: retrospective cross-sectional study of documentation of informed consent for research biobanking in a public research and teaching hospital

<em>Background</em>. The Center for Transfusion Medicine, Cell Therapy and Cryobiology, Milan, Northern Italy, is the headquarter of the POLI-MI biobank. It co-ordinates the biobank activities of the Fondazione Ca’ Granda Ospedale Maggiore Policlinico of Milan. Such activities require specific safeguarding of donors’ rights and protection of sensitive and genetic data. The Fondazione Ca’ Granda Ospedale Maggiore Policlinico has set up a project on informed consent with the aim of developing awareness and understanding of this issue. Within this project, it has been decided to evaluate how consent for biobanking material is expressed. <em>Design and methods.</em> The aim of the study was to evaluate the quality and completeness of consent to biobanking in the POLI-MI biobank. This was a retrospective study carried out in 2012 on samples of consent declarations collected by biobank units in 2011. Some units used a single, standard consent model available from a previous POLI-MI biobank workgroup. Other units used models which had been previouly formulated. Evaluation was made using a form that indicated the essential elements of consent. <em>Results</em>. A total of 48 consent declarations were collected using the single, standard model and 84 were collected using other models. The consent declarations that used the single, standard model were found to be the most complete and were filled in better than other models. <em>Conclusions</em>. Progressive adoption of a simple, standard consent model is expected to improve the quality of consent acquisition. Regular audit of the compliance of consent practices with ethical and legal requirements is mandatory to improve the quality of research biobanking

Mortality and major morbidities in very preterm infants born from assisted conception or naturally conceived: Results of the area-based ACTION study

BACKGROUND: The use of assisted conception (AC) has been associated with higher risk of adverse perinatal outcome. Few data are available on the outcome of AC-neonates when pregnancy ends before 32 weeks of gestational age.The aim of this study was to compare the short-term outcome of AC- and naturally conceived preterm infants <32 weeks gestation. METHODS: The area-based cohort study ACTION collected data on births 22-31 weeks gestation occurred in 2003-05 in 6 Italian regions. Infants born to 2529 mothers with known mode of conception were studied. The main outcomes were hospital mortality and survival free from major morbidities (IVH grade 3-4, cPVL, ROP stage ≥3, BPD), and were assessed separately for single and multiple infants. Other outcomes were also investigated. Multivariable logistic analyses were used to adjust for maternal and infants' characteristics. To account for the correlation of observations within intensive care units, robust variance and standard error estimates of regression parameters were computed. RESULTS: AC was used in 6.4% of mothers. Infants were 2934; 314 (10.7%) were born after AC. Multiples were 86.0% among AC and 21.7% among non-AC babies. In multivariable analysis no statistically significant difference in hospital mortality and survival without major morbidities was found between AC and non-AC infants. The risk of BPD was lower in AC than in non-AC multiples (aOR 0.41, CI 0.20-0.87), and this finding did not change after controlling for mechanical ventilation (aOR 0.42, CI 0.20-0.85) or presence of a patent ductus arteriosus (aOR 0.39, CI 0.18-0.84). CONCLUSION: When the analysis is restricted to very preterm infants and stratified by multiplicity, no significant associations between AC and increased risk of short-term mortality and survival without major morbidities emerge. This result is consistent with previous studies, and may confirm the hypothesis that the adverse effects of AC are mediated by preterm birth. However, larger appropriately powered studies are needed before definitely excluding the possibility of adverse events linked to AC in infants born before 32 weeks gestation