Lack of association between hyperglycaemia at arrival and clinical outcomes in acute stroke patients treated with tissue plasminogen activator

Hyperglycaemia is associated with adverse outcomes in some studies of acute ischaemic stroke.We hypothesised that in thrombolytic-treated stroke patients, hyperglycaemia would be independently associated with haemorrhagic transformation and unfavourable outcome.Consecutive rt-PA-treated acute ischaemic stroke patients presenting to four emergency departments were analysed. Associations of initial blood glucose and survival to hospital discharge, symptomatic intracerebral haemorrhage, any form of intracerebral haemorrhage, and disability at hospital discharge were determined. Potentially confounding factors of age, National Institutes of Health Stroke Scale, and smoking were analysed by univariate logistic regression and those with P <0·3 included in the multivariate model.In 268 patients, initial glucose values ranged from 62 to 507 mg/dl (mean 131). Elevated glucose at arrival was not significantly associated with any adverse clinical outcomes. A trend towards higher mortality in hyperglycaemic patients (odds ratio 1·71 per 100 mg/dl increase in glucose, 95% confidence interval 0·92–3·13, P =0·08) was seen, but is of unclear significance, and was not corroborated by effects on discharge disability, symptomatic intracerebral haemorrhage or intracerebral haemorrhage.Thrombolytic-treated stroke patients with hyperglycaemia at presentation did not have significantly worse outcomes than others in this cohort. These data fail to confirm previously described associations seen in similarly sized studies. Further study of these associations and their magnitude are necessary to better define the relationship between serum glucose and outcome in thrombolytic-treated acute ischaemic stroke.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/79242/1/j.1747-4949.2010.00425.x.pd

The prevalence and incidence of mental ill-health in adults with autism and intellectual disabilities

The prevalence, and incidence, of mental ill-health in adults with intellectual disabilities and autism were compared with the whole population with intellectual disabilities, and with controls, matched individually for age, gender, ability-level, and Down syndrome. Although the adults with autism had a higher point prevalence of problem behaviours compared with the whole adult population with intellectual disabilities, compared with individually matched controls there was no difference in prevalence, or incidence of either problem behaviours or other mental ill-health. Adults with autism who had problem behaviours were less likely to recover over a two-year period than were their matched controls. Apparent differences in rates of mental ill-health are accounted for by factors other than autism, including Down syndrome and ability level

The Eye of the Beholder: Youths and Parents Differ on What Matters in Mental Health Services

The goal of this study was to examine the degree to which youths and caregivers attend to different factors in evaluating their experiences with mental health programs. Youth (n = 251) receiving mental health services at community agencies and their caregivers (n = 275) were asked open-ended questions regarding the positive and negative aspects of the services. Qualitative analyses revealed some agreement but also divergence between youth and caregivers regarding the criteria by which services were evaluated and aspects of services that were valued most highly. Youths’ positive comments primarily focused on treatment outcomes while caregivers focused more on characteristics of the program and provider. Youths’ negative comments reflected dissatisfaction with the program, provider, and types of services offered while caregivers expressed dissatisfaction mainly with program characteristics. Results support the importance of assessing both youth and caregivers in attempts to understand the factors used by consumers to evaluate youth mental health services

Genomic investigations of unexplained acute hepatitis in children

Since its first identification in Scotland, over 1000 cases of unexplained pediatric hepatitis in children have been reported worldwide, including 278 cases in the UK 1. Here we report investigation of 38 cases, 66 age-matched immunocompetent controls and 21 immunocompromised comparator subjects, using a combination of genomic, transcriptomic, proteomic and immunohistochemical methods. We detected high levels of adeno-associated virus 2 (AAV2) DNA in liver, blood, plasma or stool from 27/28 cases. We found low levels of Adenovirus (HAdV) and Human Herpesvirus 6B (HHV-6B), in 23/31 and 16/23 respectively of the cases tested. In contrast, AAV2 was infrequently detected at low titre in blood or liver from control children with HAdV, even when profoundly immunosuppressed. AAV2, HAdV and HHV-6 phylogeny excluded emergence of novel strains in cases. Histological analyses of explanted livers showed enrichment for T-cells and B-lineage cells. Proteomic comparison of liver tissue from cases and healthy controls, identified increased expression of HLA class 2, immunoglobulin variable regions and complement proteins. HAdV and AAV2 proteins were not detected in the livers. Instead, we identified AAV2 DNA complexes reflecting both HAdV and HHV-6B-mediated replication. We hypothesize that high levels of abnormal AAV2 replication products aided by HAdV and in severe cases HHV-6B, may have triggered immune-mediated hepatic disease in genetically and immunologically predisposed children

Common, low-frequency, rare, and ultra-rare coding variants contribute to COVID-19 severity

The combined impact of common and rare exonic variants in COVID-19 host genetics is currently insufficiently understood. Here, common and rare variants from whole-exome sequencing data of about 4000 SARS-CoV-2-positive individuals were used to define an interpretable machine-learning model for predicting COVID-19 severity. First, variants were converted into separate sets of Boolean features, depending on the absence or the presence of variants in each gene. An ensemble of LASSO logistic regression models was used to identify the most informative Boolean features with respect to the genetic bases of severity. The Boolean features selected by these logistic models were combined into an Integrated PolyGenic Score that offers a synthetic and interpretable index for describing the contribution of host genetics in COVID-19 severity, as demonstrated through testing in several independent cohorts. Selected features belong to ultra-rare, rare, low-frequency, and common variants, including those in linkage disequilibrium with known GWAS loci. Noteworthily, around one quarter of the selected genes are sex-specific. Pathway analysis of the selected genes associated with COVID-19 severity reflected the multi-organ nature of the disease. The proposed model might provide useful information for developing diagnostics and therapeutics, while also being able to guide bedside disease management. © 2021, The Author(s)

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Nonstandard Errors

In statistics, samples are drawn from a population in a data-generating process (DGP). Standard errors measure the uncertainty in estimates of population parameters. In science, evidence is generated to test hypotheses in an evidence-generating process (EGP). We claim that EGP variation across researchers adds uncertainty-nonstandard errors (NSEs). We study NSEs by letting 164 teams test the same hypotheses on the same data. NSEs turn out to be sizable, but smaller for more reproducible or higher rated research. Adding peer-review stages reduces NSEs. We further find that this type of uncertainty is underestimated by participants

Non-Standard Errors

In statistics, samples are drawn from a population in a data-generating process (DGP). Standard errors measure the uncertainty in estimates of population parameters. In science, evidence is generated to test hypotheses in an evidence-generating process (EGP). We claim that EGP variation across researchers adds uncertainty: Non-standard errors (NSEs). We study NSEs by letting 164 teams test the same hypotheses on the same data. NSEs turn out to be sizable, but smaller for better reproducible or higher rated research. Adding peer-review stages reduces NSEs. We further find that this type of uncertainty is underestimated by participants