HTAD patient pathway: Strategy for diagnostic work-up of patients and families with (suspected) heritable thoracic aortic diseases (HTAD). A statement from the HTAD working group of VASCERN

Loeys-dietz syndrome; Marfan syndrome; Thoracic aortic aneurysmSíndrome de Loeys-dietz; Síndrome de Marfan; Aneurisma aòrtic toràcicSíndrome de loeys-dietz; Síndrome de Marfan; Aneurisma aórtico torácicoHeritable thoracic aortic diseases (HTAD) are rare pathologies associated with thoracic aortic aneurysms and dissection, which can be syndromic or non-syndromic. They may result from genetic defects. Associated genes identified to date are classified into those encoding components of the (a) extracellular matrix (b) TGFβ pathway and (c) smooth muscle contractile mechanism. Timely diagnosis allows for prompt aortic surveillance and prophylactic surgery, hence improving life expectancy and reducing maternal complications as well as providing reassurance to family members when a diagnosis is ruled out. This document is an expert opinion reflecting strategies put forward by medical experts and patient representatives involved in the HTAD Rare Disease Working Group of VASCERN. It aims to provide a patient pathway that improves patient care by diminishing time to diagnosis, facilitating the establishment of a correct diagnosis using molecular genetics when possible, excluding the diagnosis in unaffected persons through appropriate family screening and avoiding overuse of resources. It is being recommended that patients are referred to an expert centre for further evaluation if they meet at least one of the following criteria: (1) thoracic aortic dissection (3.5 or 2.5–3.5 if non-hypertensive or hypertensive and 3), (3) family history of HTAD with/without a pathogenic variant in a gene linked to HTAD, (4) ectopia lentis without other obvious explanation and (5) a systemic score of >5 in adults and >3 in children. Aortic imaging primarily relies on transthoracic echocardiography with magnetic resonance imaging or computed tomography as needed. Genetic testing should be considered in those with a high suspicion of underlying genetic aortopathy. Though panels vary among centers, for patients with thoracic aortic aneurysm or dissection or systemic features these should include genes with a definitive or strong association to HTAD. Genetic cascade screening and serial aortic imaging should be considered for family screening and follow-up. In conclusion, the implementation of these strategies should help standardise the diagnostic work-up and follow-up of patients with suspected HTAD and the screening of their relatives.CHAFEA Specific Grant Agreement for Year 1 HP-ERN-SGA-2016 10 Project n° 769036 (from March 2017 to February 2018) 11 - CHAFEA Specific Grant Agreement for Year 2 HP-ERN-SGA-2017 12 Project n° 811609 (from March 2018 to February 2019) 13 - CHAFEA Specific Grant Agreement for Year 3 to 5 HP-ERN-SGA-2018 14 Project n° 847081 (from March 2019 to February 2022)

European reference network for rare vascular diseases (VASCERN) consensus statement for the screening and management of patients with pathogenic ACTA2 variants

Malaltia aòrtica; Dissecció; Aneurisma aòrtic toràcicEnfermedad aórtica; Disección; Aneurisma de aorta torácicaAortic disease; Dissection; Thoracic aortic aneurysmThe ACTA2 gene encodes for smooth muscle specific α-actin, a critical component of the contractile apparatus of the vascular smooth muscle cell. Pathogenic variants in the ACTA2 gene are the most frequently encountered genetic cause of non-syndromic hereditary thoracic aortic disease (HTAD). Although thoracic aortic aneurysm and/or dissection is the main clinical manifestation, a variety of occlusive vascular disease and extravascular manifestations occur in ACTA2-related vasculopathy. Current data suggest possible mutation-specific manifestations of vascular and extra-aortic traits. Despite its relatively high prevalence, comprehensive recommendations on the care of patients and families with pathogenic variants in ACTA2 have not yet been established. We aimed to develop a consensus document to provide medical guidance for health care professionals involved in the diagnosis and treatment of patients and relatives with pathogenic variants in ACTA2. The HTAD Working Group of the European Reference Network for Rare Vascular Diseases (VASCERN) convened to review current literature and discuss expert opinions on clinical management of ACTA2 related vasculopathy. This consensus statement summarizes our recommendations on diagnosis, monitoring, treatment, pregnancy, genetic counselling and testing in patients with ACTA2-related vasculopathy. However, there is a clear need for additional prospective multicenter studies to further define proper guidelines.This work was supported by the Dutch Heart Foundation (2014 T007) and by an Erasmus University Rotterdam Fellowship (I.M.B.H. van de Laar)

Early sac shrinkage predicts a low risk of late complications after endovascular aortic aneurysm repair

Background Aneurysm shrinkage has been proposed as a marker of successful endovascular aneurysm repair (EVAR). Patients with early postoperative shrinkage may experience fewer subsequent complications, and consequently require less intensive surveillance. Methods Patients undergoing EVAR from 2000 to 2011 at three vascular centres (in 2 countries), who had two imaging examinations (postoperative and after 6-18 months), were included. Maximum diameter, complications and secondary interventions during follow-up were registered. Patients were categorized according to early sac dynamics. The primary endpoint was freedom from late complications. Secondary endpoints were freedom from secondary intervention, postimplant rupture and direct (type I/III) endoleaks. Results Some 597 EVARs (71·1 per cent of all EVARs) were included. No shrinkage was observed in 284 patients (47·6 per cent), moderate shrinkage (5-9 mm) in 142 (23·8 per cent) and major shrinkage (at least 10 mm) in 171 patients (28·6 per cent). Four years after the index imaging, the rate of freedom from complications was 84·3 (95 per cent confidence interval 78·7 to 89·8), 88·1 (80·6 to 95·5) and 94·4 (90·1 to 98·7) per cent respectively. No shrinkage was an independent risk factor for late complications compared with major shrinkage (hazard ratio (HR) 3·11; P < 0·001). Moderate compared with major shrinkage (HR 2·10; P = 0·022), early postoperative complications (HR 3·34; P < 0·001) and increasing abdominal aortic aneurysm baseline diameter (HR 1·02; P = 0·001) were also risk factors for late complications. Freedom from secondary interventions and direct endoleaks was greater for patients with major sac shrinkage. Conclusion Early change in aneurysm sac diameter is a strong predictor of late complications after EVAR. Patients with major sac shrinkage have a very low risk of complications for up to 5 years. This parameter may be used to tailor postoperative surveillance. Towards personalized surveillanc

Warm Atlantic surface water inflow to the Nordic seas 34–10 calibrated ka B.P.

Author Posting. © American Geophysical Union, 2008. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Paleoceanography 23 (2008): PA1201, doi:10.1029/2007PA001453.A number of short-lasting warm periods (interstadials) interrupted the otherwise cold climate of the last glacial period. These events are supposedly linked to the inflow of the warm Atlantic surface water to the Nordic seas. However, previous investigations of planktonic foraminifera from the Nordic seas have not been able to resolve any significant difference between the interstadials and intervening cold stadials, as the faunas are continuously dominated by the polar species Neogloboquadrina pachyderma s. Here we examine the planktonic foraminifera assemblages from a high-resolution core, LINK17, taken at 1500 m water depth off northern Scotland below the warmest part of the inflowing Atlantic water. The core comprises the time period 34–10 calibrated ka B.P., the coldest period of the last glaciation and the deglaciation. The results reveal a hitherto unknown faunistic variability indicating significant fluctuations in both surface water inflow and in summer sea surface temperatures. During the interstadials, relatively warm Atlantic surface water (4–7°C) flowed north into the eastern Norwegian Sea. During the stadials and Heinrich events the surface inflow stopped and the temperatures in the study area dropped to <2°C. The Last Glacial Maximum was nearly as warm as the interstadials, but the inflow was much more unstable. The data reveal two previously unrecognized warming events each lasting more than 1600 years and preceding Heinrich events HE3 and HE2, respectively. By destabilizing the ice sheets on the shelves the warmings may have played a crucial role for the development of Heinrich events HE2 and HE3.The study of LINK17 was financed by UNIS as a part of the ESF-EuroClimate Program Resolution (grant 04-ECLIM-FP33)

Periodontal Ehlers-Danlos Syndrome Is Caused by Mutations in C1R and C1S, which Encode Subcomponents C1r and C1s of Complement

Periodontal Ehlers-Danlos syndrome (pEDS) is an autosomal-dominant disorder characterized by early-onset periodontitis leading to premature loss of teeth, joint hypermobility, and mild skin findings. A locus was mapped to an approximately 5.8 Mb region at 12p13.1 but no candidate gene was identified. In an international consortium we recruited 19 independent families comprising 107 individuals with pEDS to identify the locus, characterize the clinical details in those with defined genetic causes, and try to understand the physiological basis of the condition. In 17 of these families, we identified heterozygous missense or in-frame insertion/deletion mutations in C1R (15 families) or C1S (2 families), contiguous genes in the mapped locus that encode subunits C1r and C1s of the first component of the classical complement pathway. These two proteins form a heterotetramer that then combines with six C1q subunits. Pathogenic variants involve the subunit interfaces or inter-domain hinges of C1r and C1s and are associated with intracellular retention and mild endoplasmic reticulum enlargement. Clinical features of affected individuals in these families include rapidly progressing periodontitis with onset in the teens or childhood, a previously unrecognized lack of attached gingiva, pretibial hyperpigmentation, skin and vascular fragility, easy bruising, and variable musculoskeletal symptoms. Our findings open a connection between the inflammatory classical complement pathway and connective tissue homeostasis

Identification of a novel proinsulin-associated SNP and demonstration that proinsulin is unlikely to be a causal factor in subclinical vascular remodelling using Mendelian randomisation

Background and aims Increased proinsulin relative to insulin levels have been associated with subclinical atherosclerosis (measured by carotid intima-media thickness (cIMT)) and are predictive of future cardiovascular disease (CVD), independently of established risk factors. The mechanisms linking proinsulin to atherosclerosis and CVD are unclear. A genome-wide meta-analysis has identified nine loci associated with circulating proinsulin levels. Using proinsulin-associated SNPs, we set out to use a Mendelian randomisation approach to test the hypothesis that proinsulin plays a causal role in subclinical vascular remodelling. Methods We studied the high CVD-risk IMPROVE cohort (n = 3345), which has detailed biochemical phenotyping and repeated, state-of-the-art, high-resolution carotid ultrasound examinations. Genotyping was performed using Illumina Cardio-Metabo and Immuno arrays, which include reported proinsulin-associated loci. Participants with type 2 diabetes (n = 904) were omitted from the analysis. Linear regression was used to identify proinsulin-associated genetic variants. Results We identified a proinsulin locus on chromosome 15 (rs8029765) and replicated it in data from 20,003 additional individuals. An 11-SNP score, including the previously identified and the chromosome 15 proinsulin-associated loci, was significantly and negatively associated with baseline IMTmean and IMTmax (the primary cIMT phenotypes) but not with progression measures. However, MR-Eggers refuted any significant effect of the proinsulin-associated 11-SNP score, and a non-pleiotropic SNP score of three variants (including rs8029765) demonstrated no effect on baseline or progression cIMT measures. Conclusions We identified a novel proinsulin-associated locus and demonstrated that whilst proinsulin levels are associated with cIMT measures, proinsulin per se is unlikely to have a causative effect on cIMT

Användandet av inbäddningar för att hitta likheter mellan hierarkiskt strukturerade temakoder

In this thesis, embeddings have been used to find similarities between hierarchically related Thema Subject Categories (Thema codes), which are short alphanumeric sequences commonly used to categorize books. More specifically, the graph embedding approach known as DeepWalk was applied to three different models to learn similarities between Thema codes. The data consisted of pairs of Thema codes gathered from user preferences of books in the Swedish online book application Storytel. By constructing graphs from Thema codes and their pairwise occurrences, high dimensional similarities between Thema codes could be learned. To evaluate the models, three different offline evaluation methods, and one online evaluation method was used. In the online evaluation, it was shown through one week of A/B testing that click-through rate increased in two recommendation lists in the Storytel application when the embeddings were used for Thema code similarities between books. The results show that DeepWalk is suitable to use when learning the embeddings of Thema codes for the task of recommendation. Valuable future research could thus include investigating other embedding approaches of Thema codes.Den här rapporten undersökte möjligheten att använda inbäddningar för att hitta likheter mellan hierarkiskt strukturerade temakoder, som är korta sekvenser av bokstäver och siffror som används för att kategorisera böcker. Mer specifikt så användes en graf-inbäddning som kallas DeepWalk på tre olika modeller för att hitta dessa likheter. Dataseten som användes för att träna modellerna bestod av par av temakoder som var insamlade från användarpreferenser av böcker i den svenska ljudboksapplikationen Storytel. Genom att konstruera grafer utifrån temakoderna och deras parvisa förekomster kunde DeepWalk lära sig likheter mellan temakoderna i ett högt antal dimensioner. För att evaluera modellerna användes tre olika offlinemetoder, samt A/B-testning live i applikationen. A/B-testningen kördes en vecka och visade att antalet klick i två av Storytels rekommendationslistor ökade när inbäddningarna av temakoderna användes för att hitta likheter mellan temakoderna i böckerna. Resultaten visade att det är möjligt att använda inbäddningar för att hitta likheter mellan temakoder. Det vore därför värdefullt att i framtiden undersöka om andra inbäddningar av temakoder skulle ge ännu bättre resultat

Användandet av inbäddningar för att hitta likheter mellan hierarkiskt strukturerade temakoder

In this thesis, embeddings have been used to find similarities between hierarchically related Thema Subject Categories (Thema codes), which are short alphanumeric sequences commonly used to categorize books. More specifically, the graph embedding approach known as DeepWalk was applied to three different models to learn similarities between Thema codes. The data consisted of pairs of Thema codes gathered from user preferences of books in the Swedish online book application Storytel. By constructing graphs from Thema codes and their pairwise occurrences, high dimensional similarities between Thema codes could be learned. To evaluate the models, three different offline evaluation methods, and one online evaluation method was used. In the online evaluation, it was shown through one week of A/B testing that click-through rate increased in two recommendation lists in the Storytel application when the embeddings were used for Thema code similarities between books. The results show that DeepWalk is suitable to use when learning the embeddings of Thema codes for the task of recommendation. Valuable future research could thus include investigating other embedding approaches of Thema codes.Den här rapporten undersökte möjligheten att använda inbäddningar för att hitta likheter mellan hierarkiskt strukturerade temakoder, som är korta sekvenser av bokstäver och siffror som används för att kategorisera böcker. Mer specifikt så användes en graf-inbäddning som kallas DeepWalk på tre olika modeller för att hitta dessa likheter. Dataseten som användes för att träna modellerna bestod av par av temakoder som var insamlade från användarpreferenser av böcker i den svenska ljudboksapplikationen Storytel. Genom att konstruera grafer utifrån temakoderna och deras parvisa förekomster kunde DeepWalk lära sig likheter mellan temakoderna i ett högt antal dimensioner. För att evaluera modellerna användes tre olika offlinemetoder, samt A/B-testning live i applikationen. A/B-testningen kördes en vecka och visade att antalet klick i två av Storytels rekommendationslistor ökade när inbäddningarna av temakoderna användes för att hitta likheter mellan temakoderna i böckerna. Resultaten visade att det är möjligt att använda inbäddningar för att hitta likheter mellan temakoder. Det vore därför värdefullt att i framtiden undersöka om andra inbäddningar av temakoder skulle ge ännu bättre resultat