Urinary Deoxynivalenol Is Correlated with Cereal Intake in Individuals from the United Kingdom

Background Deoxynivalenol (DON) is a toxic fungal metabolite that frequently contaminates cereal crops. DON is toxic to animals, but the effects on humans are poorly understood, in part because exposure estimates are of limited precision. Objectives In this study we used the U.K. adult National Diet and Nutrition Survey to compare 24-hr urinary DON excretion with cereal intake. Methods One hundred subjects were identified for each of the following cereal consumption groups: low (mean, 107 g cereal/day; range, 88–125), medium (mean, 179 g/day; range, 162–195) and high (mean, 300 g/day; range, 276–325). DON was analyzed in 24-hr urine samples by liquid chromatography–mass spectrometry after purification on immunoaffinity columns. Results DON was detected in 296 of 300 (98.7%) urine samples. Cereal intake was significantly associated with urinary DON (p < 0.0005), with the geometric mean urinary levels being 6.55 μg DON/day [95% confidence interval (CI), 5.71–7.53]; 9.63 μg/day (95% CI, 8.39–11.05); and 13.24 μg/day (95% CI, 11.54–15.19) for low-, medium-, and high-intake groups, respectively. In multivariable analysis, wholemeal bread (p < 0.0005), white bread (p < 0.0005), “other” bread (p < 0.0005), buns/cakes (p = 0.003), high-fiber breakfast cereal (p = 0.016), and pasta (p = 0.017) were significantly associated with urinary DON. Wholemeal bread was associated with the greatest percent increase in urinary DON per unit of consumption, but white bread contributed approximately twice as much as wholemeal bread to the urinary DON levels because it was consumed in higher amounts. Conclusion The majority of adults in the United Kingdom appear to be exposed to DON, and on the basis of the urinary levels, we estimate that some individuals may exceed the European Union (EU) recommended maximum tolerable daily intake of 1,000 ng DON/kg (bw). This exposure biomarker will be a valuable tool for biomonitoring as part of surveillance strategies and in etiologic studies of DON and human disease risk

Understanding storm‐time ring current development through data‐model comparisons of a moderate storm

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/94635/1/jgra18489.pd

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

Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome

Modulation of transcallosal inhibition by bilateral activation of agonist and antagonist proximal arm muscles

Transcallosal inhibitory interactions between proximal representations in the primary motor cortex remain poorly understood. In this study, we used transcranial magnetic stimulation to examine the ipsilateral silent period (iSP; a measure of transcallosal inhibition) in the biceps and triceps brachii during unilateral and bilateral isometric voluntary contractions. Healthy volunteers performed 10% of maximal isometric voluntary elbow flexion or extension with one arm while the contralateral arm remained at rest or performed 30% of maximal isometric voluntary elbow flexion or extension. The iSP was measured in the arm performing 10% contractions, and electromyographic (EMG) recordings were comparable across conditions. The iSP onset and duration in the biceps and triceps brachii were comparable. In both muscles, the iSP depth and area were increased during bilateral contractions of homologous agonist muscles (extension-extension and flexion-flexion) compared with a unilateral contraction, whereas during bilateral contractions of nonhomologous antagonist muscles (extension-flexion and flexion-extension), the iSP depth and area were decreased compared with a unilateral contraction, and sometimes facilitation of EMG was seen. This effect was never observed during bilateral activation of homologous muscles. The size of responses evoked by cervicomedullary electrical stimulation in the arm that made 10% contractions remained unchanged across conditions. Thus transcallosal inhibition targeting triceps and biceps brachii is upregulated by voluntary contraction of the contralateral agonist muscle and downregulated by voluntary contraction of the contralateral antagonist muscle. We speculate that these reciprocal task-dependent interactions between bilateral flexor and extensor arm regions of the motor cortex may contribute to coupling between the arms during motor behavior

Risk and treatment effect heterogeneity: re-analysis of individual participant data from 32 large clinical trials

Background: Risk of the outcome is a mathematical determinant of the absolute treatment benefit of an intervention, yet this can vary substantially within a trial population, complicating interpretation of trial results. Methods: We derived risk models using Cox or logistic regression on a set of large publically available RCTs. Risk heterogeneity was evaluated using the extreme quartile risk ratio (EQRR, the ratio of outcome rates in the lowest risk quartile to that in the highest). Skewness was evaluated with median to mean risk ratio (MMRR, the ratio of risk in the median risk patient to the average). Heterogeneity of treatment effect (HTE) across risk strata was also examined. Results: We describe 39 analyses using data from 32 large trials, with event rates across studies ranging from 3%-63% (median=15%, interquartile range [IQR]=9%-29%). C-statistics of risk models ranged from 0.59-0.89 (median=0.70, IQR=0.65-0.71). The EQRR ranged from 1.9- 35.2 (median=4.0, IQR=3.1-5.4). The MMRR ranged from 0.4-1.0 (median=0.86, IQR=0.80-0.92). EQRRs were predictably higher and MMRRs predictably lower as the C-statistic increased or the overall outcome incidence decreased. Among 18 comparisons with a significant overall treatment effect, there was a significant interaction between treatment and baseline risk on the proportional scale in only one. The difference in the absolute risk reduction between extreme risk quartiles ranged from -3.2-28.3% (median=5.1%; IQR=0.3-10.9). Conclusions: There is typically substantial variation in outcome risk in clinical trials, commonly leading to clinically significant differences in absolute treatment effects. Most patients have outcome risks lower than the trial average reflected in the summary result. Risk stratified trial 3 analyses are feasible and may be clinically informative, particularly when the outcome is predictable and uncommon

Shared genetic contribution to ischemic stroke and Alzheimer's disease:Ischemic Stroke and Alzheimer's Disease

Objective: Increasing evidence suggests epidemiological and pathological links between Alzheimer's disease (AD) and ischemic stroke (IS). We investigated the evidence that shared genetic factors underpin the two diseases. Methods: Using genome‐wide association study (GWAS) data from METASTROKE + (15,916 IS cases and 68,826 controls) and the International Genomics of Alzheimer's Project (IGAP; 17,008 AD cases and 37,154 controls), we evaluated known associations with AD and IS. On the subset of data for which we could obtain compatible genotype‐level data (4,610 IS cases, 1,281 AD cases, and 14,320 controls), we estimated the genome‐wide genetic correlation (rG) between AD and IS, and the three subtypes (cardioembolic, small vessel, and large vessel), using genome‐wide single‐nucleotide polymorphism (SNP) data. We then performed a meta‐analysis and pathway analysis in the combined AD and small vessel stroke data sets to identify the SNPs and molecular pathways through which disease risk may be conferred. Results: We found evidence of a shared genetic contribution between AD and small vessel stroke (rG [standard error] = 0.37 [0.17]; p  = 0.011). Conversely, there was no evidence to support shared genetic factors in AD and IS overall or with the other stroke subtypes. Of the known GWAS associations with IS or AD, none reached significance for association with the other trait (or stroke subtypes). A meta‐analysis of AD IGAP and METASTROKE + small vessel stroke GWAS data highlighted a region (ATP5H/KCTD2/ICT1) associated with both diseases (p  = 1.8 × 10−8). A pathway analysis identified four associated pathways involving cholesterol transport and immune response. Interpretation: Our findings indicate shared genetic susceptibility to AD and small vessel stroke and highlight potential causal pathways and loci. Ann Neurol 2016;79:739–74