Évaluation de la pertinence d'utiliser les critères de pneumonie associée aux soins de santé au Centre Hospitalier Universitaire de Sherbrooke (CHUS) : étude de cohorte rétrospective 1997-2008 chez les adultes

Traditionnellement, la pneumonie se divisait en 3 catégories : la pneumonie acquise en communauté (PAC), la pneumonie nosocomiale et la pneumonie acquise sous ventilation. Afin de représenter adéquatement les changements imposés par le virage ambulatoire, une nouvelle catégorie a été ajoutée en 2005 : la pneumonie associée aux soins de santé (PASS). La littérature rapporte que la PASS est une pathologie plus sévère et les pathogènes multi-résistants sont plus fréquents comparativement à la PAC. L'antibiothérapie empirique de la PASS demeure controversée et les lignes directrices ne semblent pas être respectées. Une étude épidémiologique rétrospective a été menée chez des adultes ayant un diagnostic principal de pneumonie et nécessitant une hospitalisation au CHUS (1997-2008) afin de comparer les caractéristiques cliniques, microbiologiques et l'antibiothérapie empirique entre la PAC et la PASS. La fréquence des pathogènes multi-résistants est plus élevée chez la PASS, mais elle demeure plus faible que celle relatée dans la littérature. Les patients avec PASS possèdent davantage de co-morbidités, un taux de mortalité à 30 jours (toutes causes confondues) plus élevé (73/660 [11%] versus 212/3022 [7%], p<0,001) et nécessite plus fréquemment une intubation/ventilation mécanique (90/660 [14%] vs. 300/3022 [10%] p=0.006). Chez la PASS, la mortalité à 30 jours est similaire selon la concordance ou non du traitement empirique avec les lignes directrices (6/44 [14%] si concordant ; 19/165 [12%] si discordant, p=NS). Par contre, une différence a été observée pour la mortalité à 30 jours selon que le traitement empirique était efficace contre le pathogène causal ou non (7/30 [23%] si actif vs. 14/203 [7%] si inefficace, p=0.009). En conclusion, la PASS est associée avec des issues plus sévères que la PAC, les pathogènes multi-résistants sont retrouvés en proportion plus faible que celles rapportées dans la littérature. Les stratégies thérapeutiques de la PASS devraient tenir compte du contexte microbiologique local

Analysis of shared heritability in common disorders of the brain

ience, this issue p. eaap8757 Structured Abstract INTRODUCTION Brain disorders may exhibit shared symptoms and substantial epidemiological comorbidity, inciting debate about their etiologic overlap. However, detailed study of phenotypes with different ages of onset, severity, and presentation poses a considerable challenge. Recently developed heritability methods allow us to accurately measure correlation of genome-wide common variant risk between two phenotypes from pools of different individuals and assess how connected they, or at least their genetic risks, are on the genomic level. We used genome-wide association data for 265,218 patients and 784,643 control participants, as well as 17 phenotypes from a total of 1,191,588 individuals, to quantify the degree of overlap for genetic risk factors of 25 common brain disorders. RATIONALE Over the past century, the classification of brain disorders has evolved to reflect the medical and scientific communities' assessments of the presumed root causes of clinical phenomena such as behavioral change, loss of motor function, or alterations of consciousness. Directly observable phenomena (such as the presence of emboli, protein tangles, or unusual electrical activity patterns) generally define and separate neurological disorders from psychiatric disorders. Understanding the genetic underpinnings and categorical distinctions for brain disorders and related phenotypes may inform the search for their biological mechanisms. RESULTS Common variant risk for psychiatric disorders was shown to correlate significantly, especially among attention deficit hyperactivity disorder (ADHD), bipolar disorder, major depressive disorder (MDD), and schizophrenia. By contrast, neurological disorders appear more distinct from one another and from the psychiatric disorders, except for migraine, which was significantly correlated to ADHD, MDD, and Tourette syndrome. We demonstrate that, in the general population, the personality trait neuroticism is significantly correlated with almost every psychiatric disorder and migraine. We also identify significant genetic sharing between disorders and early life cognitive measures (e.g., years of education and college attainment) in the general population, demonstrating positive correlation with several psychiatric disorders (e.g., anorexia nervosa and bipolar disorder) and negative correlation with several neurological phenotypes (e.g., Alzheimer's disease and ischemic stroke), even though the latter are considered to result from specific processes that occur later in life. Extensive simulations were also performed to inform how statistical power, diagnostic misclassification, and phenotypic heterogeneity influence genetic correlations. CONCLUSION The high degree of genetic correlation among many of the psychiatric disorders adds further evidence that their current clinical boundaries do not reflect distinct underlying pathogenic processes, at least on the genetic level. This suggests a deeply interconnected nature for psychiatric disorders, in contrast to neurological disorders, and underscores the need to refine psychiatric diagnostics. Genetically informed analyses may provide important "scaffolding" to support such restructuring of psychiatric nosology, which likely requires incorporating many levels of information. By contrast, we find limited evidence for widespread common genetic risk sharing among neurological disorders or across neurological and psychiatric disorders. We show that both psychiatric and neurological disorders have robust correlations with cognitive and personality measures. Further study is needed to evaluate whether overlapping genetic contributions to psychiatric pathology may influence treatment choices. Ultimately, such developments may pave the way toward reduced heterogeneity and improved diagnosis and treatment of psychiatric disorders

Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease

We identified rare coding variants associated with Alzheimer’s disease (AD) in a 3-stage case-control study of 85,133 subjects. In stage 1, 34,174 samples were genotyped using a whole-exome microarray. In stage 2, we tested associated variants (P<1×10-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, an additional 14,997 samples were used to test the most significant stage 2 associations (P<5×10-8) using imputed genotypes. We observed 3 novel genome-wide significant (GWS) AD associated non-synonymous variants; a protective variant in PLCG2 (rs72824905/p.P522R, P=5.38×10-10, OR=0.68, MAFcases=0.0059, MAFcontrols=0.0093), a risk variant in ABI3 (rs616338/p.S209F, P=4.56×10-10, OR=1.43, MAFcases=0.011, MAFcontrols=0.008), and a novel GWS variant in TREM2 (rs143332484/p.R62H, P=1.55×10-14, OR=1.67, MAFcases=0.0143, MAFcontrols=0.0089), a known AD susceptibility gene. These protein-coding changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified AD risk genes. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to AD development

A novel Alzheimer disease locus located near the gene encoding tau protein

This is the author accepted manuscript. The final version is available from the publisher via the DOI in this recordAPOE ε4, the most significant genetic risk factor for Alzheimer disease (AD), may mask effects of other loci. We re-analyzed genome-wide association study (GWAS) data from the International Genomics of Alzheimer's Project (IGAP) Consortium in APOE ε4+ (10 352 cases and 9207 controls) and APOE ε4- (7184 cases and 26 968 controls) subgroups as well as in the total sample testing for interaction between a single-nucleotide polymorphism (SNP) and APOE ε4 status. Suggestive associations (P<1 × 10-4) in stage 1 were evaluated in an independent sample (stage 2) containing 4203 subjects (APOE ε4+: 1250 cases and 536 controls; APOE ε4-: 718 cases and 1699 controls). Among APOE ε4- subjects, novel genome-wide significant (GWS) association was observed with 17 SNPs (all between KANSL1 and LRRC37A on chromosome 17 near MAPT) in a meta-analysis of the stage 1 and stage 2 data sets (best SNP, rs2732703, P=5·8 × 10-9). Conditional analysis revealed that rs2732703 accounted for association signals in the entire 100-kilobase region that includes MAPT. Except for previously identified AD loci showing stronger association in APOE ε4+ subjects (CR1 and CLU) or APOE ε4- subjects (MS4A6A/MS4A4A/MS4A6E), no other SNPs were significantly associated with AD in a specific APOE genotype subgroup. In addition, the finding in the stage 1 sample that AD risk is significantly influenced by the interaction of APOE with rs1595014 in TMEM106B (P=1·6 × 10-7) is noteworthy, because TMEM106B variants have previously been associated with risk of frontotemporal dementia. Expression quantitative trait locus analysis revealed that rs113986870, one of the GWS SNPs near rs2732703, is significantly associated with four KANSL1 probes that target transcription of the first translated exon and an untranslated exon in hippocampus (P≤1.3 × 10-8), frontal cortex (P≤1.3 × 10-9) and temporal cortex (P≤1.2 × 10-11). Rs113986870 is also strongly associated with a MAPT probe that targets transcription of alternatively spliced exon 3 in frontal cortex (P=9.2 × 10-6) and temporal cortex (P=2.6 × 10-6). Our APOE-stratified GWAS is the first to show GWS association for AD with SNPs in the chromosome 17q21.31 region. Replication of this finding in independent samples is needed to verify that SNPs in this region have significantly stronger effects on AD risk in persons lacking APOE ε4 compared with persons carrying this allele, and if this is found to hold, further examination of this region and studies aimed at deciphering the mechanism(s) are warranted

COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study

Background: The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. Methods: International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. Results: ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P &lt; 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. Interpretation: This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men

Évaluation de la pertinence d'utiliser les critères de pneumonie associée aux soins de santé au Centre Hospitalier Universitaire de Sherbrooke (CHUS) : étude de cohorte rétrospective 1997-2008 chez les adultes

Traditionnellement, la pneumonie se divisait en 3 catégories : la pneumonie acquise en communauté (PAC), la pneumonie nosocomiale et la pneumonie acquise sous ventilation. Afin de représenter adéquatement les changements imposés par le virage ambulatoire, une nouvelle catégorie a été ajoutée en 2005 : la pneumonie associée aux soins de santé (PASS). La littérature rapporte que la PASS est une pathologie plus sévère et les pathogènes multi-résistants sont plus fréquents comparativement à la PAC. L'antibiothérapie empirique de la PASS demeure controversée et les lignes directrices ne semblent pas être respectées. Une étude épidémiologique rétrospective a été menée chez des adultes ayant un diagnostic principal de pneumonie et nécessitant une hospitalisation au CHUS (1997-2008) afin de comparer les caractéristiques cliniques, microbiologiques et l'antibiothérapie empirique entre la PAC et la PASS. La fréquence des pathogènes multi-résistants est plus élevée chez la PASS, mais elle demeure plus faible que celle relatée dans la littérature. Les patients avec PASS possèdent davantage de co-morbidités, un taux de mortalité à 30 jours (toutes causes confondues) plus élevé (73/660 [11%] versus 212/3022 [7%], p<0,001) et nécessite plus fréquemment une intubation/ventilation mécanique (90/660 [14%] vs. 300/3022 [10%] p=0.006). Chez la PASS, la mortalité à 30 jours est similaire selon la concordance ou non du traitement empirique avec les lignes directrices (6/44 [14%] si concordant ; 19/165 [12%] si discordant, p=NS). Par contre, une différence a été observée pour la mortalité à 30 jours selon que le traitement empirique était efficace contre le pathogène causal ou non (7/30 [23%] si actif vs. 14/203 [7%] si inefficace, p=0.009). En conclusion, la PASS est associée avec des issues plus sévères que la PAC, les pathogènes multi-résistants sont retrouvés en proportion plus faible que celles rapportées dans la littérature. Les stratégies thérapeutiques de la PASS devraient tenir compte du contexte microbiologique local