Impact of clinical phenotypes on management and outcomes in European atrial fibrillation patients: a report from the ESC-EHRA EURObservational Research Programme in AF (EORP-AF) General Long-Term Registry

Background: Epidemiological studies in atrial fibrillation (AF) illustrate that clinical complexity increase the risk of major adverse outcomes. We aimed to describe European AF patients\u2019 clinical phenotypes and analyse the differential clinical course. Methods: We performed a hierarchical cluster analysis based on Ward\u2019s Method and Squared Euclidean Distance using 22 clinical binary variables, identifying the optimal number of clusters. We investigated differences in clinical management, use of healthcare resources and outcomes in a cohort of European AF patients from a Europe-wide observational registry. Results: A total of 9363 were available for this analysis. We identified three clusters: Cluster 1 (n = 3634; 38.8%) characterized by older patients and prevalent non-cardiac comorbidities; Cluster 2 (n = 2774; 29.6%) characterized by younger patients with low prevalence of comorbidities; Cluster 3 (n = 2955;31.6%) characterized by patients\u2019 prevalent cardiovascular risk factors/comorbidities. Over a mean follow-up of 22.5 months, Cluster 3 had the highest rate of cardiovascular events, all-cause death, and the composite outcome (combining the previous two) compared to Cluster 1 and Cluster 2 (all P <.001). An adjusted Cox regression showed that compared to Cluster 2, Cluster 3 (hazard ratio (HR) 2.87, 95% confidence interval (CI) 2.27\u20133.62; HR 3.42, 95%CI 2.72\u20134.31; HR 2.79, 95%CI 2.32\u20133.35), and Cluster 1 (HR 1.88, 95%CI 1.48\u20132.38; HR 2.50, 95%CI 1.98\u20133.15; HR 2.09, 95%CI 1.74\u20132.51) reported a higher risk for the three outcomes respectively. Conclusions: In European AF patients, three main clusters were identified, differentiated by differential presence of comorbidities. Both non-cardiac and cardiac comorbidities clusters were found to be associated with an increased risk of major adverse outcomes

Urinary Metal Levels with Relation to Age, Occupation, and Smoking Habits of Male Inhabitants of Eastern Iran

In low-income and middle-income countries such as Iran, smoking is becoming increasingly popular, especially among young people. This has led to additional exposure to a variety of substances, including metals which may exert a toxic influence and lead to severe diseases. In order to evaluate the influence of smoking on metal concentrations, a case-control study of levels of metal in urine was carried out in smokers (n = 64) and non-smokers (n = 35) from the city of Birjand (Iran). They were divided according to their age and socioeconomic status. Concentrations of cadmium (Cd), cobalt (Co), chromium (Cr), copper (Cu), iron (Fe), nickel (Ni), lead (Pb), and zinc (Zn) were measured using ET-AAS. We found higher concentrations of Cd (0.03 vs. 0.12 μg/L), Co (0.6 vs. 1.22 μg/L), and Cr (14.00 vs. 18.17 μg/L) in the urine of smokers. Age and occupation are factors that also influence the levels of metals. Young smokers demonstrate higher Cd and Pb levels than other age groups. It would also appear that public sector workers and self-employed are the sectors most susceptible to high levels of metals. © 2019, Springer Science+Business Media, LLC, part of Springer Nature

Structural insights into synthetic ligands targeting A A pairs in disease related CAG RNA repeats

The trinucleotide repeat expansion disorders (TREDs) constitute of a group of >40 hereditary neurodegenerative human diseases associated with abnormal expansion of repeated sequences, such as CAG repeats. The pathogenic factor is a transcribed RNA or protein whose function in the cell is compromised. The disorders are progressive and incurable. Consequently, many ongoing studies are oriented at developing therapies. We have analyzed crystal structures of RNA containing CAG repeats in complex with synthetic cyclic mismatch-binding ligands (CMBLs). The models show well-defined interactions between the molecules in which the CMBLs mimic nucleobases as they form pseudo-canonical base pairs with adenosine residues and engage in extensive stacking interactions with neighboring nucleotides. The binding of ligands is associated with major structural changes of the CAG repeats, which is consistent with results of biochemical studies. The results constitute an early characterization of the first lead compounds in the search for therapy against TREDs. The crystallographic data indicate how the compounds could be further refined in future biomedical studies

Metal Risk Assessment Study of Canned Fish Available on the Iranian Market

Iran is the largest fishery producer in the region reaching nearly 1 million tons. Fish provide a good many nutrients that are beneficial for our health. Due to significant deposits of xenobiotics in the water environments, however, fish may also be a source of non-essential metals, causing a variety of disorders. The main challenges to Iranian fisheries are environmental pollution and quality control, so this study aims to estimate the concentration of cadmium (Cd), mercury (Hg), nickel (Ni), and lead (Pb) in canned tuna fish produced and consumed in Iran. We studied four popular brands (N = 4 � 20) with ICP-MS and then looked at the concentrations and calculated the risk assessment parameters. We found that the lowest concentration was observed for Cd (18 μg/kg) and the highest for Ni (132 μg/kg). Among the brands studied, Pb concentrations differed most (42.0 to 113.3 μg/kg) and Hg levels were more consistent (24.0 and 39.4 μg/kg). The concentrations of Cd, Hg, and Pb in all the brands tested were below EU permissible thresholds. The intake estimation risk assessment parameters (EDI, contribution to PTWI, and CR) and non-cancer risk assessment parameters based on reference doses (THQ and HI) demonstrated the safety of tested products in respect to all metal concentrations studied, while the parameters regarding the toxic effects (MoE, and ILCR) showed that the consumption might cause health risks in terms of Cd (ILCR), Ni (ILCR), and Pb (MoE). The consumption of the canned fish studied should therefore be maintained at a reasonable level (2�5 meals containing fish weekly), so that it may provide necessary nutrients, while avoiding the health risk due to metal content. © 2020, Springer Science+Business Media, LLC, part of Springer Nature

Intramolecular signal transmission in a tetrameric repressor of the IclR family

Members of the IclR family control bacterial genes involved in a number of physiological processes. The IclR-family member TtgV crystallizes as a tetramer, with each TtgV monomer consisting of two domains—a DNA binding domain and an effector recognition domain, which are interconnected by an extended α-helix. When bound to DNA, a kink is introduced so that the extended helix is split in two α-helices (helix-4 and -5). Differential scanning calorimetry studies revealed that TtgV unfolds in a single event, suggesting that the two domains unfold cooperatively. When mutations are introduced in helix-5 that disrupt interactions between Arg98 and Glu102, the thermal unfolding of the TtgV domains becomes uncoupled without compromising effector binding. Two of these mutants (TtgVE102R and TtgVE102A) showed impaired release from target DNA, suggesting that these mutations alter signal transmission. By combining various mutants, we found that the mutations in the connecting α-helix exhibited a dominant effect over mutations in DNA binding and effector binding domains. We propose a model in which the loss of cooperativity of unfolding of TtgV reflects perturbed interdomain communication, and that the transition from the continuous to discontinuous helix may mediate interdomain communication necessary for the proper functioning of TtgV