Rasmussenstilling3362

The global prevalence of obesity has reached epidemic proportions, paralleled by a rise in cases of atrial fibrillation (AF). Data from epidemiological cohorts support the role of obesity as an independent risk factor for AF. Increasing evidence indicates that obesity may contribute to the AF substrate through a number of pathways including by altering epicardial adipose tissue biology, inflammatory pathways, structural cardiac remodelling and inducing atrial fibrosis. Due to changes in pharmacokinetics and pharmacodynamics, specific therapeutic considerations are required to guide management of patients with AF including anticoagulation and rhythm control. Also, weight loss in patients with AF has been associated with reduced progression from paroxysmal to persistent AF and indeed regression from persistent to proximal AF. However, the role of dietary intervention in AF control remains to be fully elucidated and hard prospective outcome data to support weight loss are required in AF to determine its role as part of a comprehensive risk factor management strategy for AF in obese patients. © Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2020. For permissions, please email journals.permissions@oup.com.BACKGROUND Neuroblastoma is a childhood malignancy that arises from the developing sympathetic nervous system. Although mitochondrial dysfunctions have been implicated in the pathophysiology of neuroblastoma, the role of mitochondrial DNA (mtDNA) has not been extensively investigated. METHODS 2,404 Caucasian children diagnosed with neuroblastoma and 9,310 ancestry-matched controls were recruited at the Children's Hospital of Philadelphia. The mtDNA haplogroups were identified from SNP array data of two independent cohorts. We conducted a case-control study to explore potential associations of mtDNA haplogroups with the susceptibility of neuroblastoma. The genetic effect of neuroblastoma was measured by odds ratios of mitochondrial haplogroups. All tests were two-sided. RESULTS Haplogroup K was statistically significantly associated with reduced risk of neuroblastoma in the discovery cohort consisting 1,474 cases and 5,699 controls (odds ratio 0.72, 95%CI 0.57-0.90, P = 0.005). The association was replicated in an independent cohort (odds ratio 0.69, 95%CI 0.53-0.92, P = 0.01) of 930 cases and 3,611 controls. Pooled analysis was performed by combing the two data sets. The association remained highly statistically significant after correction for multiple testing (odds ratio 0.71, 95%CI 0.59-0.84, P = 1.96 ✕ 10-4, Pcorrected = 0.002). Further analysis focusing on neuroblastoma subtypes indicated haplogroup K was more associated with high-risk neuroblastoma (odds ratio 0.57, 95%CI 0.43-0.76, P = 1.46 ✕ 10-4) than low-risk and intermediate-risk neuroblastoma. CONCLUSIONS Haplogroup K is an independent genetic factor associated with reduced risk of developing neuroblastoma in European descents. These findings provide new insights into the genetic basis of neuroblastoma, implicating mitochondrial DNA encoded proteins in the etiology of neuroblastoma. © The Author(s) 2020. Published by Oxford University Press. RG-7112 All rights reserved. For permissions, please email journals.permissions@oup.com.BACKGROUND Long-acting reversible contraceptives (LARCs) are safe, effective and convenient post-abortal methods. However, there is concern that some LARCs may reduce the effectiveness of abortifacient drugs or result in other adverse outcomes. OBJECTIVE AND RATIONALE We undertook two systematic reviews to examine the early administration of LARCs in women undergoing medical abortion with mifepristone and misoprostol. (i) For women who are having a medical abortion and who plan to use a progestogen-only contraceptive implant or injectable, does administration of the contraception at the same time as mifepristone influence the efficacy of the abortion? (Implant/injectable review). (ii) For women who have had a medical abortion, how soon after expulsion of the products of conception is it safe to insert an intrauterine contraceptive device/system? (LNG-IUS/Cu-IUD review). SEARCH METHODS On 19 November 2018, we searched Embase Classic, Embase; Ovid MEDLINE(R) including Daily and Epub Ahead-of-Print, In-Process ading. WIDER IMPLICATIONS The contraceptive implant or injectable should be offered on the day of taking mifepristone. Intrauterine methods of contraception should be offered as soon as possible after expulsion of the pregnancy. © The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.Over evolutionary time, pathogen challenge shapes the immune phenotype of the host to better respond to an incipient threat. The extent and direction of this selection pressure depends on the local pathogen composition, which is in turn determined by biotic and abiotic features of the environment. However, little is known about adaptation to local pathogen threats in wild animals. The Gentoo penguin (Pygoscelis papua) is a species complex that lends itself to the study of immune adaptation because of its circumpolar distribution over a large latitudinal range, with little or no admixture between different clades. In this study, we examine the diversity in a key family of innate immune genes - the Toll-like receptors (TLRs) - across the range of the Gentoo. The three TLRs that we investigated present varying levels of diversity, with TLR4 and TLR5 greatly exceeding the diversity of TLR7. We present evidence of positive selection in TLR4 and TLR5, which points to pathogen-driven adaptation to the local pathogen milieu. Finally, we demonstrate that two positively selected co-segregating sites in TLR5 are sufficient to alter the responsiveness of the receptor to its bacterial ligand, flagellin. Taken together, these results suggest that Gentoo penguins have experienced distinct pathogen-driven selection pressures in different environments, which may be important given the role of the Gentoo as a sentinel species in some of the world's most rapidly changing environments. © The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.