Possible impact of the “yellow card” antimicrobial scheme on meat inspection lesions in Danish finisher pigs

In 2010, the “yellow card scheme” adopted by the Danish Veterinary and Food Administration imposed restrictions on pig farmers who used more antimicrobials than twice the average. We studied the impact on antimicrobial consumption and vaccine use based on data from the monitoring programme Vetstat covering the time period January 2010 and July 2011. The decrease in antimicrobial consumption was pronounced for all age groups treated for either gastro-intestinal or respiratory disease. Data from meat inspection of finisher pigs from before and after introduction of the scheme were compared (N=1.7 million finisher pigs)

Risk and Subtypes of Stroke Following New-Onset Postoperative Atrial Fibrillation in Coronary Bypass Surgery:A Population-Based Cohort Study

BACKGROUND: New‐onset postoperative atrial fibrillation (POAF) develops in approximately one‐third of patients undergoing cardiac surgery and is associated with a higher incidence of ischemic stroke and increased mortality. However, it remains unknown to what extent ischemic stroke events in patients with POAF are cardioembolic and whether anticoagulant therapy is indicated. We investigated the long‐term risk and pathogenesis of postoperative stroke in patients undergoing coronary artery bypass grafting experiencing POAF. METHODS AND RESULTS: This was a register‐based cohort study. Data from the WDHR (Western Denmark Heart Registry) were linked with the DNPR (Danish National Patient Register), the Danish National Prescription Register, and the Cause of Death Register. All stroke diagnoses were verified, and ischemic stroke cases were subclassified according to pathogenesis. Furthermore, investigations of all‐cause mortality and the use of anticoagulation medicine for the individual patient were performed. A total of 7813 patients without a preoperative history of atrial fibrillation underwent isolated coronary artery bypass grafting between January 1, 2010, and December 31, 2018, in Western Denmark. POAF was registered in 2049 (26.2%) patients, and a postoperative ischemic stroke was registered in 195 (2.5%) of the patients. After adjustment, there was no difference in the risk of ischemic stroke (hazard ratio [HR], 1.08 [95% CI, 0.74–1.56]) or all‐cause mortality (HR, 1.09 [95% CI, 0.98–1.23]) between patients who developed POAF and non‐POAF patients. Although not statistically significant, patients with POAF had a higher incidence rate (IR; per 1000 patient‐years) of cardioembolic stroke (IR, 1 [95% CI, 0.6–1.6] versus IR, 0.5 [95% CI, 0.3–0.8]), whereas non‐POAF patients had a higher incidence rate of large‐artery occlusion stroke (IR, 1.1 [95% CI, 0.8–1.5] versus IR, 0.7 [95% CI, 0.4–1.4]). Early initiation of anticoagulation medicine was not associated with a lower risk of ischemic stroke. However, patients with POAF were more likely to die of cardiovascular causes than non‐POAF patients (P<0.001). CONCLUSIONS: We found no difference in the adjusted risk of postoperative stroke or all‐cause mortality in POAF versus non‐POAF patients. Patients with POAF after coronary artery bypass grafting presented with a higher, although not significant, proportion of ischemic strokes of the cardioembolic type

Statin initiation and acute kidney injury following elective cardiovascular surgery: a population cohort study in Denmark

OBJECTIVES: Acute kidney injury (AKI) is a serious complication of cardiac surgery. Statins may prevent post-surgical AKI, yet methodological concerns about existing studies raise questions about the magnitude of a protective effect. We sought to determine the effect of initiating a statin prior to elective cardiac surgery on post-surgical AKI in a regional Danish surgical cohort. METHODS: We identified adults who underwent cardiac surgery during 2006-11 using the Western Denmark Heart Registry. Presurgical medication use, pre- and post-surgical serum creatinine (sCr) measures, and other patient characteristics were obtained from Danish population-based registries. Post-surgical AKI was assessed using sCr measures within 5 days of surgery. The adjusted risk ratio (RR) of AKI and 95% confidence interval (CI) were estimated for patients who initiated a statin within 100 days prior to surgery compared with patients without prior statin use; long-term statin users were excluded to reduce healthy-user bias. Subanalyses were stratified by surgery type: coronary artery bypass grafting (CABG) and non-CABG surgeries. RESULTS: We identified 1929 CABG and 1775 non-CABG patients. AKI occurred in 25% of CABG and 28% of non-CABG surgeries, and in 29% of the non-users and 21% of the statin initiators. Half of CABG patients and 9% of non-CABG patients initiated a statin prior to surgery. The adjusted RRs for the effect of statin initiation on AKI were as follows: all surgeries combined, RR = 0.86 (95% CI: 0.74, 0.98); CABG, RR = 0.88 (0.74, 1.05); non-CABG RR = 0.87 (0.68, 1.11). CONCLUSIONS: Presurgical statin initiation is associated with a reduction in AKI risk after cardiac surgery

First Administration of the Fc-Attenuated Anti-beta Amyloid Antibody GSK933776 to Patients with Mild Alzheimer's Disease: A Randomized, Placebo-Controlled Study

Objectiv

Multi-trait analysis characterizes the genetics of thyroid function and identifies causal associations with clinical implications

To date only a fraction of the genetic footprint of thyroid function has been clarified. We report a genome-wide association study meta-analysis of thyroid function in up to 271,040 individuals of European ancestry, including reference range thyrotropin (TSH), free thyroxine (FT4), free and total triiodothyronine (T3), proxies for metabolism (T3/FT4 ratio) as well as dichotomized high and low TSH levels. We revealed 259 independent significant associations for TSH (61% novel), 85 for FT4 (67% novel), and 62 novel signals for the T3 related traits. The loci explained 14.1%, 6.0%, 9.5% and 1.1% of the total variation in TSH, FT4, total T3 and free T3 concentrations, respectively. Genetic correlations indicate that TSH associated loci reflect the thyroid function determined by free T3, whereas the FT4 associations represent the thyroid hormone metabolism. Polygenic risk score and Mendelian randomization analyses showed the effects of genetically determined variation in thyroid function on various clinical outcomes, including cardiovascular risk factors and diseases, autoimmune diseases, and cancer. In conclusion, our results improve the understanding of thyroid hormone physiology and highlight the pleiotropic effects of thyroid function on various diseases.</p

Multi-trait analysis characterizes the genetics of thyroid function and identifies causal associations with clinical implications

To date only a fraction of the genetic footprint of thyroid function has been clarified. We report a genome-wide association study meta-analysis of thyroid function in up to 271,040 individuals of European ancestry, including reference range thyrotropin (TSH), free thyroxine (FT4), free and total triiodothyronine (T3), proxies for metabolism (T3/FT4 ratio) as well as dichotomized high and low TSH levels. We revealed 259 independent significant associations for TSH (61% novel), 85 for FT4 (67% novel), and 62 novel signals for the T3 related traits. The loci explained 14.1%, 6.0%, 9.5% and 1.1% of the total variation in TSH, FT4, total T3 and free T3 concentrations, respectively. Genetic correlations indicate that TSH associated loci reflect the thyroid function determined by free T3, whereas the FT4 associations represent the thyroid hormone metabolism. Polygenic risk score and Mendelian randomization analyses showed the effects of genetically determined variation in thyroid function on various clinical outcomes, including cardiovascular risk factors and diseases, autoimmune diseases, and cancer. In conclusion, our results improve the understanding of thyroid hormone physiology and highlight the pleiotropic effects of thyroid function on various diseases

Cleavage of the urokinase receptor (uPAR) on oral cancer cells : regulation by transforming growth factor - beta 1 (TGF-beta 1) and potential effects on migration and invasion

Background: Urokinase plasminogen activator (uPA) receptor (uPAR) is up-regulated at the invasive tumour front of human oral squamous cell carcinoma (OSCC), indicating a role for uPAR in tumour progression. We previously observed elevated expression of uPAR at the tumour-stroma interface in a mouse model for OSCC, which was associated with increased proteolytic activity. The tumour microenvironment regulated uPAR expression, as well as its glycosylation and cleavage. Both full-length- and cleaved uPAR (uPAR (II-III)) are involved in highly regulated processes such as cell signalling, proliferation, migration, stem cell mobilization and invasion. The aim of the current study was to analyse tumour associated factors and their effect on uPAR cleavage, and the potential implications for cell proliferation, migration and invasion. Methods: Mouse uPAR was stably overexpressed in the mouse OSCC cell line AT84. The ratio of full-length versus cleaved uPAR as analysed by Western blotting and its regulation was assessed by addition of different protease inhibitors and transforming growth factor - beta 1 (TGF-beta 1). The role of uPAR cleavage in cell proliferation and migration was analysed using real- time cell analysis and invasion was assessed using the myoma invasion model. Results: We found that when uPAR was overexpressed a proportion of the receptor was cleaved, thus the cells presented both full-length uPAR and uPAR (II-III). Cleavage was mainly performed by serine proteases and urokinase plasminogen activator (uPA) in particular. When the OSCC cells were stimulated with TGF-beta 1, the production of the uPA inhibitor PAI-1 was increased, resulting in a reduction of uPAR cleavage. By inhibiting cleavage of uPAR, cell migration was reduced, and by inhibiting uPA activity, invasion was reduced. We could also show that medium containing soluble uPAR (suPAR), and cleaved soluble uPAR (suPAR (II-III)), induced migration in OSCC cells with low endogenous levels of uPAR. Conclusions: These results show that soluble factors in the tumour microenvironment, such as TGF-beta 1, PAI-1 and uPA, can influence the ratio of full length and uPAR (II-III) and thereby potentially effect cell migration and invasion. Resolving how uPAR cleavage is controlled is therefore vital for understanding how OSCC progresses and potentially provides new targets for therapy.Peer reviewe

Genetic analyses of the electrocardiographic QT interval and its components identify additional loci and pathways

The QT interval is an electrocardiographic measure representing the sum of ventricular depolarization and repolarization, estimated by QRS duration and JT interval, respectively. QT interval abnormalities are associated with potentially fatal ventricular arrhythmia. Using genome-wide multi-ancestry analyses (&gt;250,000 individuals) we identify 177, 156 and 121 independent loci for QT, JT and QRS, respectively, including a male-specific X-chromosome locus. Using gene-based rare-variant methods, we identify associations with Mendelian disease genes. Enrichments are observed in established pathways for QT and JT, and previously unreported genes indicated in insulin-receptor signalling and cardiac energy metabolism. In contrast for QRS, connective tissue components and processes for cell growth and extracellular matrix interactions are significantly enriched. We demonstrate polygenic risk score associations with atrial fibrillation, conduction disease and sudden cardiac death. Prioritization of druggable genes highlight potential therapeutic targets for arrhythmia. Together, these results substantially advance our understanding of the genetic architecture of ventricular depolarization and repolarization