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0AbstractWhole genome sequencing (WGS) at high-depth (30X) allows the accurate discovery of variants in the coding and non-coding DNA regions and helps elucidate the genetic underpinnings of human health and diseases. Yet, due to the prohibitive cost of high-depth WGS, most large-scale genetic association studies use genotyping arrays or high-depth whole exome sequencing (WES). Here we propose a novel, cost-effective method, which we call “Whole Exome Genome Sequencing” (WEGS), that combines low-depth WGS and high-depth WES with up to 8 samples pooled and sequenced simultaneously (multiplexed). We experimentally assess the performance of WEGS with four different depth of coverage and sample multiplexing configurations. We show that the optimal WEGS configurations are 1.7-2.0 times cheaper than standard WES (no-plexing), 1.8-2.1 times cheaper than high-depth WGS, reach similar recall and precision rates in detecting coding variants as WES, and capture more population-specific variants in the rest of the genome that are difficult to recover when using genotype imputation methods. We apply WEGS to 862 patients with peripheral artery disease and show that it directly assesses more known disease-associated variants than a typical genotyping array and thousands of non-imputable variants per disease-associated locus.

Community-based physical activity opportunities have been shown to help adults with physical disabilities improve their participation in daily activities and reduce social isolation. Despite the known benefits, substantial barriers and challenges inhibit accessibility to these physical activity opportunities. To facilitate the co-construction of strategies to overcome accessibility issues pertaining to community-based physical activity opportunities. In total, 45 individuals with physical disabilities, patients at a rehabilitation hospital, staff members of disability organizations, staff of local or provincial government agencies/departments, kinesiologists, occupational therapists, graduate students, and peer mentors participated in one of four World Cafés held in their respective cities. World Café is a methodology for fostering collaborative, solution-focused conversation that aims to solve problems through collective intelligence. Participants were divided into groups of three to four people and invited to engage in evolving rounds of discussions responding to prompts about accessibility to physical activity in their communities. Transcripts were analyzed using content analysis. In total, 17 strategies were identified, addressing 5 areas: representation and visibility (e.g., prioritize hiring people with a disability), finances (e.g., reduce direct costs for participants), connection and social support (e.g., foster social networks that provide informational support), education and programming (e.g., enhance awareness of existing services and resources), and government programs and policies (e.g., enforce accessibility standards for indoor and outdoor spaces). The findings of this study provide strategies and practical applications for community programs and governments to consider for increasing access to physical activity opportunities for people with physical disabilities.

Background Québec was the Canadian province most impacted by COVID-19, with 401,462 cases as of September 24th, 2021, and 11,347 deaths due mostly to a very severe first pandemic wave. In April 2020, we assembled the Coronavirus Sequencing in Québec (CoVSeQ) consortium to sequence SARS-CoV-2 genomes in Québec to track viral introduction events and transmission within the province. Methods Using genomic epidemiology, we investigated the arrival of SARS-CoV-2 to Québec. We report 2921 high-quality SARS-CoV-2 genomes in the context of > 12,000 publicly available genomes sampled globally over the first pandemic wave (up to June 1st, 2020). By combining phylogenetic and phylodynamic analyses with epidemiological data, we quantify the number of introduction events into Québec, identify their origins, and characterize the spatiotemporal spread of the virus. Results Conservatively, we estimated approximately 600 independent introduction events, the majority of which happened from spring break until 2 weeks after the Canadian border closed for non-essential travel. Subsequent mass repatriations did not generate large transmission lineages (> 50 sequenced cases), likely due to mandatory quarantine measures in place at the time. Consistent with common spring break and “snowbird” destinations, most of the introductions were inferred to have originated from Europe via the Americas. Once introduced into Québec, viral lineage sizes were overdispersed, with a few lineages giving rise to most infections. Consistent with founder effects, the earliest lineages to arrive tended to spread most successfully. Fewer than 100 viral introductions arrived during spring break, of which 7–12 led to the largest transmission lineages of the first wave (accounting for 52–75% of all sequenced infections). These successful transmission lineages dispersed widely across the province. Transmission lineage size was greatly reduced after March 11th, when a quarantine order for returning travellers was enacted. While this suggests the effectiveness of early public health measures, the biggest transmission lineages had already been ignited prior to this order. Conclusions Combined, our results reinforce how, in the absence of tight travel restrictions or quarantine measures, fewer than 100 viral introductions in a week can ensure the establishment of extended transmission chains.

Des équations précédemment développées prédisent la valeur nutritive de la luzerne ou de mélanges luzerne–graminée avant la récolte. Cette étude valide cinq de ces équations avec des échantillons de luzerne pure cultivée sous conditions québécoises. Ces équations de prédiction ont été évaluées en utilisant les statistiques associées aux régressions linéaires. Parmi les équations évaluées, celle du Wisconsin et de New York semblaient les plus appropriées. Cependant, la présence de biais limite leur utilisation. Le développement d’une équation québécoise devrait donc être considéré afin d’aider les producteurs à identifier le moment de récolte de toutes les cultures à base de luzerne.

A recent report found that rare predicted loss-of-function (pLOF) variants across 13 candidate genes in TLR3- and IRF7-dependent type I IFN pathways explain up to 3.5% of severe COVID-19 cases. We performed whole-exome or whole-genome sequencing of 1,864 COVID-19 cases (713 with severe and 1,151 with mild disease) and 15,033 ancestry-matched population controls across 4 independent COVID-19 biobanks. We tested whether rare pLOF variants in these 13 genes were associated with severe COVID-19. We identified only 1 rare pLOF mutation across these genes among 713 cases with severe COVID-19 and observed no enrichment of pLOFs in severe cases compared to population controls or mild COVID-19 cases. We found no evidence of association of rare LOF variants in the 13 candidate genes with severe COVID-19 outcomes.

Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types., Graphical abstract, D’Antonio et al. characterize associations between GWAS signals for COVID-19 disease and eQTLs in 69 human tissues to identify causal variants and their underlying molecular mechanisms. They show that diverse symptoms and disease severity of COVID-19 are associated with variants affecting gene expression in a wide variety of tissues.

A recent report found that rare predicted loss-of-function (pLOF) variants across 13 candidate genes in TLR3- and IRF7-dependent type I IFN pathways explain up to 3.5% of severe COVID-19 cases. We performed whole-exome or whole-genome sequencing of 1,934 COVID-19 cases (713 with severe and 1,221 with mild disease) and 15,251 ancestry-matched population controls across four independent COVID-19 biobanks. We then tested if rare pLOF variants in these 13 genes were associated with severe COVID-19. We identified only one rare pLOF mutation across these genes amongst 713 cases with severe COVID-19 and observed no enrichment of pLOFs in severe cases compared to population controls or mild COVID-19 cases. We find no evidence of association of rare loss-of-function variants in the proposed 13 candidate genes with severe COVID-19 outcomes.

I present a statistical discrimination model of the labor market in which employers are initially uncertain about the productivity of worker groups and endogenously learn about it through their hiring. Previous hiring experiences with groups shape subsequent incentives of employers to hire from these groups again and learn more about their productivity, leading to differential learning across employers and biased beliefs about the productivity of groups. Given a market-clearing wage, optimal hiring follows a cutoff rule in posterior beliefs: employers with sufficiently negative experiences with workers from a group stop hiring from the group, preserving negative biases and leading to a negatively-skewed distribution of beliefs about their productivity. When employers have noisier initial information on the productivity of one worker group, discrimination against the group can arise and persist without productivity differentials or prior employer biases, with market competition, and with or without worker signaling or investment decisions. The model generates steady state predictions analogous to the Becker (1957) taste-based model, in a statistical framework with beliefs replacing preferences, explaining apparent prejudice as the result of "incorrect" statistical discrimination. The model also generates additional predictions with policy implications that contrast with traditional models of discrimination.

Prior analyses of racial bias in the New York City’s Stop-and-Frisk program implicitly assumed that potential bias of police officers did not vary by crime type and that their decision of which type of crime to report as the basis for the stop did not exhibit any bias. In this paper, we first extend the hit rates model to consider crime type heterogeneity in racial bias and police officer decisions of reported crime type. Second, we reevaluate the program while accounting for heterogeneity in bias along crime types and for the sample selection which may arise from conditioning on crime type. We present evidence that differences in biases across crime types are substantial and specification tests support incorporating corrections for selective crime reporting. However, the main findings on racial bias do not differ sharply once accounting for this choice-based selection.

The purpose of this study was to understand the learning experiences and acquisition of knowledge of youth parasport coaches. Five able-bodied male participants (M = 39 years old), who coached youth with a physical disability for an average of 7.4 years, participated in individual interviews. An inductive thematic analysis identified patterns within and across the data, allowing for description and interpretation of the meaning and importance of the themes. The results showed that coaches learned mostly from informal experiences, particularly through mentoring, trial and error, or use of technology. In addition, these learning opportunities were influenced by personal, environmental, and social factors. These findings can help to guide current and future generations of coaches of youth participants with a physical disability by highlighting available resources and addressing several barriers and facilitators to their learning.

In many US states, punishment severity for drug offenses increases discontinuously at established quantity limits. Theory predicts that these laws create bunching of offenders at these limits and dominated regions beyond, where it ex-ante appears irrational to locate. These policies provide a novel setting to test for deterrence along a different margin that typically considered in the literature and generate new evidence on the extent to which offenders respond to incentives. Using arrest reports from 28 states and leveraging variation from quantity cutoff changes through time, I find evidence of strategic bunching by offenders in response to cutoff policies.

International audience; Previous observations suggested that microbial communities contribute to coral health and the ecological resilience of coral reefs. However, most studies of coral microbiology focused on prokaryotes and the endosymbiotic algae Symbiodinium. In contrast, knowledge concerning diversity of other protists is still lacking, possibly due to methodological constraints. As most eukaryotic DNA in coral samples was derived from hosts, protist diversity was missed in metagenome analyses. To tackle this issue, we designed blocking primers for Scleractinia sequences amplified with two primer sets that targeted variable loops of the 18S rRNA gene (18SV1V2 and 18SV4). These blocking primers were used on environmental colonies of Pocillopora damicornis sensu lato from two regions with contrasting thermal regimes (Djibouti and New Caledonia). In addition to Symbiodinium clades A/C/D, Licnophora and unidentified coccidia genera were found in many samples. In particular, coccidian sequences formed a robust monophyletic clade with other protists identified in Agaricia, Favia, Montastraea, Mycetophyllia, Porites, and Siderastrea coral colonies. Moreover, Licnophora and coccidians had different distributions between the two geographic regions. A similar pattern was observed between Symbiodinium clades C and A/D. Although we were unable to identify factors responsible for this pattern, nor were we able to confirm that these taxa were closely associated with corals, we believe that these primer sets and the associated blocking primers offer new possibilities to describe the hidden diversity of protists within different coral species.

Pilocytic astrocytoma (PA) is the most common brain tumor in children but is rare in adults, and hence poorly studied in this age group. We investigated 222 PA and report increased aneuploidy in older patients. Aneuploid genomes were identified in 45% of adult compared with 17% of pediatric PA. Gains were non-random, favoring chromosomes 5, 7, 6 and 11 in order of frequency, and preferentially affecting non-cerebellar PA and tumors with BRAF V600E mutations and not with KIAA1549-BRAF fusions or FGFR1 mutations. Aneuploid PA differentially expressed genes involved in CNS development, the unfolded protein response, and regulators of genomic stability and the cell cycle (MDM2, PLK2),whose correlated programs were overexpressed specifically in aneuploid PA compared to other glial tumors. Thus, convergence of pathways affecting the cell cycle and genomic stability may favor aneuploidy in PA, possibly representing an additional molecular driver in older patients with this brain tumor.

Over the last few years, the number of remote patient monitoring (RPM) products and of videoconferencing systems has exploded. There is also a significant number of research initiatives addressing the use of service robots for assistance in daily living activities. From a technological standpoint, providing telehomecare services is certainly feasible. However, one technological barrier is to have access to a telecommunication platform that can be adapted to address the broad range of specifications and requirements of clinical and telehealth applications. Handling the full spectrum of possibilities requires a telecommunication framework that can transmit vital sign data from patients to clinicians, bidirectional audio-video from a standard computing device, and also multiple video streams and bidirectional transmission of control data. This paper presents a framework that integrates such capabilities. It also illustrates the versatility of the framework by presenting custom-designed devices allowing integration of capabilities ranging from RPM to video visits and robot telepresence.

Background Epigenetic modifications of DNA, such as 5-methylcytosine and 5-hydroxymethycytosine, play important roles in development and disease. Here, we present a cost-effective and versatile methodology for the analysis of DNA methylation in targeted genomic regions, which comprises multiplexed, PCR-based preparation of bisulfite DNA libraries followed by customized MiSeq sequencing. Results Using bisulfite and oxidative bisulfite conversion of DNA, we have performed multiplexed targeted sequencing to analyse several kilobases of genomic DNA in up to 478 samples, and achieved high coverage data of 5-methylcytosine and 5-hydroxymethycytosine at single-base resolution. Our results demonstrate the ability of this methodology to detect all levels of cytosine modifications at greater than 100× coverage in large sample sets at low cost compared to other targeted methods. Conclusions This approach can be applied to multiple settings, from candidate gene to clinical studies, and is especially useful for validation of differentially methylated or hydroxymethylated regions following whole-genome analyses. Electronic supplementary material The online version of this article (doi:10.1186/s12864-017-3489-9) contains supplementary material, which is available to authorized users.

Individuals harboring germ-line DICER1 mutations are predisposed to a rare cancer syndrome, the DICER1 Syndrome or pleuropulmonary blastoma-familial tumor and dysplasia syndrome [online Mendelian inheritance in man (OMIM) #601200]. In addition, specific somatic mutations in the DICER1 RNase III catalytic domain have been identified in several DICER1-associated tumor types. Pituitary blastoma (PitB) was identified as a distinct entity in 2008, and is a very rare, potentially lethal early childhood tumor of the pituitary gland. Since the discovery by our team of an inherited mutation in DICER1 in a child with PitB in 2011, we have identified 12 additional PitB cases. We aimed to determine the contribution of germ-line and somatic DICER1 mutations to PitB. We hypothesized that PitB is a pathognomonic feature of a germ-line DICER1 mutation and that each PitB will harbor a second somatic mutation in DICER1. Lymphocyte or saliva DNA samples ascertained from ten infants with PitB were screened and nine were found to harbor a heterozygous germ-line DICER1 mutation. We identified additional DICER1 mutations in nine of ten tested PitB tumor samples, eight of which were confirmed to be somatic in origin. Seven of these mutations occurred within the RNase IIIb catalytic domain, a domain essential to the generation of 5p miRNAs from the 5' arm of miRNA-precursors. Germ-line DICER1 mutations are a major contributor to PitB. Second somatic DICER1 "hits" occurring within the RNase IIIb domain also appear to be critical in PitB pathogenesis.

Les accords franco-britanniques nés de l’Entente cordiale de l’année 1904 laissent espérer la participation d’un Corps expéditionnaire britannique aux côtés de l’armée française dans l’hypothèse où l’Empire allemand se livrerait à une agression armée contre la France ou contre le royaume de Belgique. En pareil cas l’état-major français a étudié un plan de transport du contingent britannique débarqué initialement dans les ports du Havre, de Rouen et de Boulogne et acheminé vers le front de bataille par les réseaux ferroviaires français. Entre août 1914 et novembre 1918, l’armée française comme l’armée britannique s’adaptent à la dimension industrielle de la guerre. Elle implique la mise en œuvre d’une énorme logistique et son transport, particulièrement complexes dans la région de Rouen et lors de l’engagement britannique massif sur la Somme en 1916. Il s’ensuit sur les réseaux ferroviaires très surchargés du Nord et de l’État des difficultés d’exploitation marqués par une crise des matériels roulants et par les travaux massifs conduits par les compagnies de sapeurs des chemins de fer et les sections de chemins de fer de campagne. Le trafic dépasse parfois les limites de la saturation. Le service automobile, un expédient initialement, conquiert peu à peu une place prépondérante stratégiquement, notamment aux moments décisifs des batailles de 1918. Sur le plan des relations humaines, les commissaires militaires et techniques sont solidaires et les rapports des régulateurs militaires français avec leurs homologues britanniques sont cordiaux mais les relations entre les dirigeants des deux réseaux du Nord et de l’État sont difficiles. La priorité accordée aux transports de guerre ne peut occulter le climat de concurrence commerciale qui existait avant-guerre entre les deux compagnies notamment en Haute-Normandie. La suggestion avancée par les militaires d’un réseau unifié conduit le gouvernement français à reprendre la main à la fin de 1917 par la création d’un ministère des Transports, puis à confier l’autorité sur les réseaux ferroviaires au ministère des Travaux publics, agissant par délégation du ministre de la Guerre, gage d’une meilleure efficacité dans la gestion de ces réseaux confrontés à de graves difficultés financières et techniques par suite des épreuves d’un conflit interminable. The Franco-British agreements resulting of the Entente Cordiale of 1904 suggested a British Expeditionary Corps involvement alongside the French Army in case of an armed aggression of France or of Belgian Kingdom by the German Empire. For such a case, the French Staff had studied a transportation plan of the British contingent originally landed in the ports of Le Havre, Rouen and Boulogne and routed to the front of battle by the French rail networks. From August 1914 to November 1918, the French army and the British army coped with the industrial dimension of the war. It brought to implement enormous capabilities in the field of logistics and transport, particularly complex in the region of Rouen and during the massive British engagement on the Somme in 1916. On the overloaded “Nord” and “État” networks, this resulted in operating problems related to rolling stock shortage and to massive works carried out by the sappers of the Engineers Railway companies and Field Railway sections. Traffic sometimes exceeded the limits of saturation. Mechanical Transport, initially an expedient, conquered a prominent strategic role, notably during the decisive moments of the battles of 1918. On the human level, the military and technical commissioners remained supportive of each other’s while the relationships of French military regulators with their British counterparts were cordial. On the contrary, the leaders of the “Nord” and “État” networks had difficulties to work together. The priority given to war transportation could not overshadow the climate of commercial competition that existed before the war between the two companies, especially in Haute-Normandie. The suggestion made by the military of a unified network led the French Government to take over at the end of 1917, firstly by the creation of a Ministry of transportation, then entrusting the authority on the rail networks to the Ministry of public works, by delegation of the Minister of war. It was the guarantee of greater efficiency in the management of these networks, which, before long, would face serious financial and technical difficulties caused by an endless conflict.

La Presse Medicale - In Press.Proof corrected by the author Available online since mardi 30 septembre 2014

Facial palsy can be defined as a decrease in function of the facial nerve, the primary motor nerve of the facial muscles. When the facial palsy is peripheral, it affects both the superior and inferior areas of the face as opposed to central palsies, which affect only the inferior portion. The main cause of peripheral facial palsies is Bell's palsy, which remains a diagnosis of exclusion. The prognosis is good in most cases. In cases with significant cosmetic sequelae, a variety of surgical procedures are available (such as hypoglossal-facial anastomosis, temporalis myoplasty and Tenzel external canthopexy) to rehabilitate facial aesthetics and function.

Recurrent mutations affecting the histone H3.3 residues Lys27 or indirectly Lys36 are frequent drivers of pediatric high-grade gliomas (over 30 % of HGGs). To identify additional driver mutations in HGGs, we investigated a cohort of 60 pediatric HGGs using whole-exome sequencing (WES) and compared them to 543 exomes from non-cancer control samples. We identified mutations in SETD2, a H3K36 trimethyltransferase, in 15 % of pediatric HGGs, a result that was genome-wide significant (FDR = 0.029). Most SETD2 alterations were truncating mutations. Sequencing the gene in this cohort and another validation cohort (123 gliomas from all ages and grades) showed SETD2 mutations to be specific to high-grade tumors affecting 15 % of pediatric HGGs (11/73) and 8 % of adult HGGs (5/65) while no SETD2 mutations were identified in low-grade diffuse gliomas (0/45). Furthermore, SETD2 mutations were mutually exclusive with H3F3A mutations in HGGs (P = 0.0492) while they partly overlapped with IDH1 mutations (4/14), and SETD2-mutant tumors were found exclusively in the cerebral hemispheres (P = 0.0055). SETD2 is the only H3K36 trimethyltransferase in humans, and SETD2-mutant tumors showed a substantial decrease in H3K36me3 levels (P

Iron-refractory iron-deficiency anemia (IRIDA) is an autosomal recessive disorder caused by mutations in TMPRSS6. Patients have hypochromic microcytic anemia refractory to oral iron and are only partially responsive to parenteral iron administration. We report a French-Canadian kindred in which 2 siblings presented in early childhood with severe microcytic anemia, hypoferremia, and hyperferritinemia. Both children have been successfully treated solely with low-dose oral iron since diagnosis. Clinical and biological presentation did not fit any previously described genetic iron-deficiency anemia. Whole exome sequencing identified in both patients compound heterozygous mutations of TMPRSS6 leading to p.G442R and p.E522K, 2 mutations previously reported to cause classic IRIDA, and no additional mutations in known iron-regulatory genes. Thus, the phenotype associated with the unique combination of mutations uncovered in both patients expands the spectrum of disease associated with TMPRSS6 mutations to include iron deficiency anemia that is accompanied by hyperferritinemia at initial presentation and is responsive to continued oral iron therapy. Our results have implications for genetic testing in early childhood iron deficiency anemia. Importantly, they emphasize that whole exome sequencing can be used as a diagnostic tool and greatly facilitate the elucidation of the genetic basis of unusual clinical presentations, including hypomorphic mutations or compound heterozygosity leading to different phenotypes in known Mendelian diseases.