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Objectives: Endovascular aneurysm repair (EVAR) is considered the treatment of choice for abdominal aortic aneurysms with suitable anatomy. In order to improve radiation safety, European Directive (2013/59) requires member states to implement diagnostic reference levels (DRLs) in radio-diagnostic and interventional procedures. This study aimed to determine local DRLs for EVAR across five European centres and identify an interim European DRL, which currently remains unestablished.Methods: Retrospective data was collected for 180 standard EVARs performed between January 2014 and July 2015 from five specialist centres in Ireland (n=2) and Italy (n=3). Data capture included: air kerma-area product (PKA), total air kerma at the reference point (Ka,r), fluoroscopic time (FT), number of acquisitions, frame rate of acquisition, type of acquisition, patient height, weight, and gender.Results: The mean values for each site A, B, C, D, and E were: PKAs of 4343 ± 994 μGym2, 18,200 ± 2141 μGym2, 11,423 ± 1390 μGym2, 7796 ± 704 μGym2, 31,897 ± 5798 μGym2; FTs of 816 ± 92 s, 950 ± 150 s, 708 ± 70 s, 972 ± 61 s, 827 ± 118 s; and number of acquisitions of 6.72 ± 0.56, 10.38 ± 1.54, 4.74 ± 0.19, 5.64 ± 0.36, 7.28 ± 0.65, respectively. The overall pooled 75th percentile PKA was 15,849 μGym2.Conclusion: Local reference levels were identified. The pooled data has been used to establish an interim European DRL for EVAR procedures.Key Points: • Abdominal endovascular aneurysm repair (EVAR) requires the use of ionising radiation. • EVAR is a minimally invasive procedure for the treatment of abdominal aortic aneurysms. • Diagnostic reference levels (DRLs) are used to monitor patient radiation exposure. • Radiation dose data was collected from five European centres for EVAR procedures. • Local DRLs have been determined and an interim European DRL is proposed. [ABSTRACT FROM AUTHOR]

Management of decompensated cirrhosis is currently geared towards the treatment of complications once they occur. To date there is no established disease-modifying therapy aimed at halting progression of the disease and preventing the development of complications in patients with decompensated cirrhosis. The design of clinical trials to investigate new therapies for patients with decompensated cirrhosis is complex. The population of patients with decompensated cirrhosis is heterogeneous (i.e., different etiologies, comorbidities and disease severity), leading to the inclusion of diverse populations in clinical trials. In addition, primary endpoints selected for trials that include patients with decompensated cirrhosis are not homogeneous and at times may not be appropriate. This leads to difficulties in comparing results obtained from different trials. Against this background, the LiverHope Consortium organized a meeting of experts, the goal of which was to develop recommendations for the design of clinical trials and to define appropriate endpoints, both for trials aimed at modifying the natural history and preventing progression of decompensated cirrhosis, as well as for trials aimed at managing the individual complications of cirrhosis., Competing Interests: Conflict of interest ES, CA, RH, EP, SM, CF, RM have nothing to declare. The other authors declare the following: PG has participated on advisory boards for the following: Grifols, Gilead, Intercept, Mallinckrodt and Ferring. He has received Investigator promoted research grants from Mallinckrodt, Gilead and Grifols. All outside the submitted work. SM research group has received consultancy fees and/or research donations from Merz Pharmaceuticals GmbH, Norgine, Alfasigma and Umecrine Cognition. VV speaking fees from Intercept Pharmaceuticals; advisory board fees from Promethera Biosciences PC Grifols SA: advisory board, speaking bureau; Octapharma. SA: speaking bureau; Takeda SA: speaking bureau. JT: reports other from - Gore, Bayer, Alexion, MSD, Gilead, Intercept, Norgine, Grifols, Versantis, Martin Pharmaceuticals outside the submitted work. PSK is Principal Investigator of the Sequana Medical sponsored POSEIDON study in North America. He does not receive any personal remuneration. HW declares he is currently and employee of EVOTEC and has shares in Sanofi, both of which are unrelated to the work submitted. JGA reports grants from Gilead, lecture fees from Ferring, and consulting fees from Gilead, Pfizer, Intercept, Boehringer-Ingelheim, Lupin and Genfit outside the submitted work. UB Research funding from South African PSC Patient Foundation, Netherlands gastroenterology and hepatology (MDLS) Foundation, Investigator initiated research funding from Intercept, USA. AK Speaker and advisory board: Norgine, Siemens. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Both obesity and being underweight have been associated with increased mortality. Underweight, defined as a body mass index (BMI) ≤ 18.5 kg per m(2) in adults and ≤ -2 standard deviations from the mean in children, is the main sign of a series of heterogeneous clinical conditions including failure to thrive, feeding and eating disorder and/or anorexia nervosa. In contrast to obesity, few genetic variants underlying these clinical conditions have been reported. We previously showed that hemizygosity of a ∼600-kilobase (kb) region on the short arm of chromosome 16 causes a highly penetrant form of obesity that is often associated with hyperphagia and intellectual disabilities. Here we show that the corresponding reciprocal duplication is associated with being underweight. We identified 138 duplication carriers (including 132 novel cases and 108 unrelated carriers) from individuals clinically referred for developmental or intellectual disabilities (DD/ID) or psychiatric disorders, or recruited from population-based cohorts. These carriers show significantly reduced postnatal weight and BMI. Half of the boys younger than five years are underweight with a probable diagnosis of failure to thrive, whereas adult duplication carriers have an 8.3-fold increased risk of being clinically underweight. We observe a trend towards increased severity in males, as well as a depletion of male carriers among non-medically ascertained cases. These features are associated with an unusually high frequency of selective and restrictive eating behaviours and a significant reduction in head circumference. Each of the observed phenotypes is the converse of one reported in carriers of deletions at this locus. The phenotypes correlate with changes in transcript levels for genes mapping within the duplication but not in flanking regions. The reciprocal impact of these 16p11.2 copy-number variants indicates that severe obesity and being underweight could have mirror aetiologies, possibly through contrasting effects on energy balance.

Obesity has become a major worldwide challenge to public health, owing to an interaction between the Western 'obesogenic' environment and a strong genetic contribution. Recent extensive genome-wide association studies (GWASs) have identified numerous single nucleotide polymorphisms associated with obesity, but these loci together account for only a small fraction of the known heritable component. Thus, the 'common disease, common variant' hypothesis is increasingly coming under challenge. Here we report a highly penetrant form of obesity, initially observed in 31 subjects who were heterozygous for deletions of at least 593 kilobases at 16p11.2 and whose ascertainment included cognitive deficits. Nineteen similar deletions were identified from GWAS data in 16,053 individuals from eight European cohorts. These deletions were absent from healthy non-obese controls and accounted for 0.7% of our morbid obesity cases (body mass index (BMI) >or= 40 kg m(-2) or BMI standard deviation score >or= 4; P = 6.4 x 10(-8), odds ratio 43.0), demonstrating the potential importance in common disease of rare variants with strong effects. This highlights a promising strategy for identifying missing heritability in obesity and other complex traits: cohorts with extreme phenotypes are likely to be enriched for rare variants, thereby improving power for their discovery. Subsequent analysis of the loci so identified may well reveal additional rare variants that further contribute to the missing heritability, as recently reported for SIM1 (ref. 3). The most productive approach may therefore be to combine the 'power of the extreme' in small, well-phenotyped cohorts, with targeted follow-up in case-control and population cohorts.