Aims The first aim was to critically evaluate the extent to which familial hypercholesterolaemia (FH) is underdiagnosed and undertreated. The second aim was to provide guidance for screening and treatment of FH, in order to prevent coronary heart disease (CHD). Methods and results Of the theoretical estimated prevalence of 1/500 for heterozygous FH, <1% are diagnosed in most countries. Recently, direct screening in a Northern European general population diagnosed approximately 1/200 with heterozygous FH. All reported studies document failure to achieve recommended LDL cholesterol targets in a large proportion of individuals with FH, and up to 13-fold increased risk of CHD. Based on prevalences between 1/500 and 1/200, between 14 and 34 million individuals worldwide have FH. We recommend that children, adults, and families should be screened for FH if a person or family member presents with FH, a plasma cholesterol level in an adult ≥8 mmol/L(≥310 mg/dL) or a child ≥6 mmol/L(≥230 mg/dL), premature CHD, tendon xanthomas, or sudden premature cardiac death. In FH, low-density lipoprotein cholesterol targets are <3.5 mmol/L(<135 mg/dL) for children, <2.5 mmol/L(<100 mg/dL) for adults, and <1.8 mmol/L(<70 mg/dL) for adults with known CHD or diabetes. In addition to lifestyle and dietary counselling, treatment priorities are (i) in children, statins, ezetimibe, and bile acid binding resins, and (ii) in adults, maximal potent statin dose, ezetimibe, and bile acid binding resins. Lipoprotein apheresis can be offered in homozygotes and in treatment-resistant heterozygotes with CHD. Conclusion Owing to severe underdiagnosis and undertreatment of FH, there is an urgent worldwide need for diagnostic screening together with early and aggressive treatment of this extremely high-risk condition.
Andreas Sturm,a Christian Maaser,b Emma Calabrese,c Vito Annese,d Gionata Fiorino,e Torsten Kucharzik,f Stephan R. Vavricka,g Bram Verstockt,h, Patrick van Rheenen,i Damian Tolan,j Stuart A. Taylor,k Jordi Rimola,l Florian Rieder,m Jimmy K. Limdi,n Andrea Laghi,o Eduards Krustiņš,p Paulo G. Kotze,q Uri Kopylov,r Konstantinos Katsanos,s Steve Halligan,t Hannah Gordon,u Yago González Lama,v Pierre Ellul,w Rami Eliakim,r Fabiana Castiglione,x Johan Burisch,y, Paula Borralho Nunes,z, Dominik Bettenworth,aa Daniel C. Baumgart,bb Jaap Stoker,cc on behalf of the European Crohn’s and Colitis Organisation [ECCO] and the European Society of Gastrointestinal and Abdominal Radiology [ESGAR]
The presence of a patent foramen ovale (PFO) is implicated in the pathogenesis of a number of medical conditions; however, the subject remains controversial and no official statements have been published. This interdisciplinary paper, prepared with involvement of eight European scientific societies, aims to review the available trial evidence and to define the principles needed to guide decision making in patients with PFO. In order to guarantee a strict process, position statements were developed with the use of a modified grading of recommendations assessment, development, and evaluation (GRADE) methodology. A critical qualitative and quantitative evaluation of diagnostic and therapeutic procedures was performed, including assessment of the risk/benefit ratio. The level of evidence and the strength of the position statements of particular management options were weighed and graded according to predefined scales. Despite being based often on limited and non-randomised data, while waiting for more conclusive evidence, it was possible to conclude on a number of position statements regarding a rational general approach to PFO management and to specific considerations regarding left circulation thromboembolism. For some therapeutic aspects, it was possible to express stricter position statements based on randomised trials. This position paper provides the first largely shared, interdisciplinary approach for a rational PFO management based on the best available evidence.
Dirk Dietz de Loos, E. Lourijsen, M. Wildeman
et al.
Background The prevalence of chronic rhinosinusitis (CRS) measured in epidemiologic studies is 5% to 12%. This might be an overestimation because of overlap with other diseases, such as allergic rhinitis. Objective We aimed to calculate the prevalence of CRS using a combination of epidemiologically based CRS according to the European Position Paper on Rhinosinusitis and Nasal Polyps (EPOS) together with sinonasal opacification on imaging. Methods Subjects who underwent a computed tomographic or magnetic resonance imaging scan of the head for any nonrhinologic indication were asked to fill in the Global Allergy and Asthma European Network survey containing EPOS symptom criteria. The scans were evaluated according to the Lund‐Mackay (LM) scoring system. Epidemiologically based CRS is based on nasal symptoms according to EPOS; clinically based CRS also encompasses endoscopy and/or CT scanning. Results Eight hundred thirty‐four subjects were included. One hundred seven (12.8%) had epidemiologically based CRS according to EPOS. Of these subjects, 50% had an LM score of 0, 26% had an LM score of 1 to 3, and 23% had an LM score of 4 or greater. Twenty‐five (3.0%) subjects had clinically based CRS (based on LM score ≥4), and 53 (6.4%) subjects had clinically based CRS (based on LM score >0). Allergic rhinitis was reported by 167 (20%) subjects. In subjects who did not report upper airway symptoms, 57% had an LM score of 0, 30% had an LM score of 1 to 3, and 12% had an LM score of 4 or greater. Conclusion We found a prevalence of 3.0% to 6.4% of clinically based CRS (depending on an LM cutoff point; ie, LM ≥ 4 or LM > 0, respectively) in a relatively randomly selected group of subjects.
The presence of a patent foramen ovale (PFO) is implicated in the pathogenesis of a number of medical conditions; however, the subject remains controversial and no official statements have been published. This interdisciplinary paper, prepared with involvement of eight European scientific societies, aims to review the available trial evidence and to define the principles needed to guide decision making in patients with PFO. In order to guarantee a strict process, position statements were developed with the use of a modified grading of recommendations assessment, development, and evaluation (GRADE) methodology. A critical qualitative and quantitative evaluation of diagnostic and therapeutic procedures was performed, including assessment of the risk/benefit ratio. The level of evidence and the strength of the position statements of particular management options were weighed and graded according to predefined scales. Despite being based often on limited and non-randomised data, while waiting for more conclusive evidence, it was possible to conclude on a number of position statements regarding a rational general approach to PFO management and to specific considerations regarding left circulation thromboembolism. For some therapeutic aspects, it was possible to express stricter position statements based on randomised trials. This position paper provides the first largely shared, interdisciplinary approach for a rational PFO management based on the best available evidence.
This paper addresses the inverse problem of qualitatively recovering a clamped cavity in a thin elastic plate using far-field measurements. We present a strengthened analysis of the linear sampling method by carefully examining the range of the far-field operator and employing the reciprocity relation of the biharmonic far-field pattern. In addition, we implement both the linear sampling method for reconstructing the cavity and the extended sampling method for localizing the cavity under limited-aperture data. Numerical experiments demonstrate the effectiveness and robustness of both methods.
Rafael Ceja Ayala, Isaac Harris, General Ozochiawaeze
This work extends the factorization method to the inverse scattering problem of reconstructing the shape and location of an absorbing penetrable scatterer embedded in a thin infinite elastic (Kirchhoff--Love) plate. With the assumption that the plate thickness is small compared to the wavelength of the incident wave, the propagation of flexural perturbations is modeled by the two--dimensional biharmonic wave equation in the frequency domain. Within this setting, we provide a rigorous justification of the factorization method and demonstrate that it yields a binary criterion for distinguishing whether a sampling point lies inside or outside the scatterer, using only the spectral data of the far--field operator. In addition, we numerically analyze the Born approximation for weak scatterers in this biharmonic scattering context and compute the relative error against exact far--field data for sample weak scatterers, thereby quantifying its validity as a limited but useful approximation.
The forthcoming European Union (EU) Fertilizing Products Regulation1 proposes a claim-based definition of plant biostimulants, stipulating that “plant biostimulant” means a product stimulating plant nutrition processes independently of the product’s nutrient content, with the aim of improving one or more of the following characteristics of the plant: nutrient use efficiency, tolerance to abiotic stress, crop quality traits or availability of confined nutrients in the soil and rhizosphere. The future regulation also specifies that a plant biostimulant “shall have the effects that are claimed on the label for the plants specified thereon.” This creates an onus for manufacturers to demonstrate to regulators and customers that product claims are justified. Consequently, the justification of the agronomic claim of a given plant biostimulant will be an important element to allow it to be placed on the EU market once this new European regulation is applied. In this article, members of the European Biostimulant Industry Council (EBIC) propose some general guiding principles to follow when justifying plant biostimulant claims, that are outlined in this article. These principles are expected to be incorporated into harmonized European standards that are being developed by the European Committee for Standardization (CEN) to support the implementation of the regulation.
The history of the concept of perseverance, particularly but not only in the early modern age, is reconstructed here by identifying its various ancestry and lines of development, and especially by distinguishing from the religious notion a secular use and function of this virtue, with the intention of thus honoring the unwavering perseverance that characterized the late Leibnizian scholar Marine Picon.
This study addresses critical challenges of cybersecurity in digital substations by proposing an innovative task-oriented dialogue (ToD) system for anomaly detection (AD) in multicast messages, specifically, generic object oriented substation event (GOOSE) and sampled value (SV) datasets. Leveraging generative artificial intelligence (GenAI) technology, the proposed framework demonstrates superior error reduction, scalability, and adaptability compared with traditional human-in-the-loop (HITL) processes. Notably, this methodology offers significant advantages over machine learning (ML) techniques in terms of efficiency and implementation speed when confronting novel and/or unknown cyber threats, while also maintaining model complexity and precision. The research employs advanced performance metrics to conduct a comparative assessment between the proposed AD and HITL-based AD frameworks, utilizing a hardware-in-the-loop (HIL) testbed for generating and extracting features of IEC61850 communication messages. This approach presents a promising solution for enhancing the reliability of power system operations in the face of evolving cybersecurity challenges.
Supplemental Digital Content is available in the text. The General Data Protection Regulation (GDPR) became binding law in the European Union Member States in 2018, as a step toward harmonizing personal data protection legislation in the European Union. The Regulation governs almost all types of personal data processing, hence, also, those pertaining to biomedical research. The purpose of this article is to highlight the main practical issues related to data and biological sample sharing that biomedical researchers face regularly, and to specify how these are addressed in the context of GDPR, after consulting with ethics/legal experts. We identify areas in which clarifications of the GDPR are needed, particularly those related to consent requirements by study participants. Amendments should target the following: (1) restricting exceptions based on national laws and increasing harmonization, (2) confirming the concept of broad consent, and (3) defining a roadmap for secondary use of data. These changes will be achieved by acknowledged learned societies in the field taking the lead in preparing a document giving guidance for the optimal interpretation of the GDPR, which will be finalized following a period of commenting by a broad multistakeholder audience. In parallel, promoting engagement and education of the public in the relevant issues (such as different consent types or residual risk for re-identification), on both local/national and international levels, is considered critical for advancement. We hope that this article will open this broad discussion involving all major stakeholders, toward optimizing the GDPR and allowing a harmonized transnational research approach.
Strictly confidential reports from the Albanian Ministry of Foreign Affairs add a new dimension to events in Serbia and Yugoslavia in the second half of the 1960s. According to their content, the strengthening of the autonomy of Kosovo and Metohija was the result of a change in the balance of power at the top of the League of Communists of Yugoslavia after the Brioni Plenum in 1966. Leading Croatian and Slovenian officials held the majority of the party’s control. According to the reports, party leaders Vladimir Bakarić and Edvard Kardelj intended to disintegrate Yugoslavia and allow Croatia and Slovenia to gain independence, and the League of Communists of Yugoslavia’s Kosovo policy was a key component of that strategy. Leader of Kosovo Albanians Fadilj Hoxha gained complete control of the province’s party, judicial, and security apparatuses thanks to the political support he received from Broz, Kardelj, and Bakarić. Reports also confirm the emergence of mass emigration of Serbs from Kosovo and Metohija, owing to threatened security and ethnically motivated persecution from the province’s companies and institutions. The Albanian population in Kosovo and Metohija developed national euphoria as a result of the new circumstances, which was reflected in public demands for the province’s separation from Serbia, the use of the Albanian flag in state institutions, and the establishment of a special official status for the Albanian language in the province. According to the report, the German intelligence service aimed at the secession of Kosovo and Metohija from Serbia and Yugoslavia and the establishment of another Albanian state in the Balkans.
Testimonies of Holocaust survivors have had an essential influence on public engagement with the Shoah in recent decades. Given this importance, the imminent end of the “era of the witness” has sparked fears that the history of the Holocaust could soon be forgotten. The past decades have therefore seen unprecedented efforts to record the testimonies of Holocaust survivors in order to safeguard the immediacy of their accounts. In this essay, I trace how different temporal entanglements have affected the narrated memory of Holocaust survivors and thus also shaped the knowledge of those born later. Focusing on four interviews conducted with a Jewish Holocaust survivor in 1946, 1995, 1998, and 2004 respectively, I explore how biological time, historical time, recording time, and the temporality of narrative have shaped the narrated memories. As I argue, the different temporal entanglements have allowed for starkly different reconfigurations and reconstructions of the past. This renders the study of the epistemic constitutive nature of entangled temporalities important not only for Holocaust studies, but also for the history of knowledge, a field which has recently turned to processes of forgetting and ignorance.
History (General), History of scholarship and learning. The humanities
The article is devoted to the analysis of the digitization process and cooperation between Ukraine and the member states of the European Union. The peculiarities of digitization in Ukraine are analyzed as integral components of the process of reconstruction, modernization of the Ukrainian economy and the construction of high-quality European infrastructure, with the aim of joining the state to the European and Euro-Atlantic community. An analysis of the state of reforms in Ukraine in the direction of digitization of services, their accessibility to citizens, the development of electronic governance, and ensuring the transparency of public information in the form of open data was carried out. Legislative and regulatory support in the field of functioning and development of e-government in the EU countries and in Ukraine, in particular, in the direction of digital transformation of the government and fulfillment of international obligations by Ukraine, is analyzed. The research data of European and international institutions on the development of e-governance, ICT, human potential, open data and e-services in the world and Ukraine are analyzed and systematized. It has been established that in Ukraine there is a high readiness to use digital technologies. One of the forms of direct support by EU countries for digitalization in Ukraine is the signing in September 2022 of an agreement with the European Commission on Ukraine's accession to the Digital Europe Program. It is determined that Ukrainian enterprises, organizations and public administration bodies will be able to benefit from the financing and support of the Program in such areas as artificial intelligence, supercomputing and digital skills. It has been proven that since digitization in Ukraine contributes to the technological and democratic development of the country, the modernization of its economy, the availability of public services, and the transparency of government, accordingly, Ukraine will need support and further cooperation from the world's leading technology companies in Europe and the world to implement systemic reforms and post-war reconstruction.
Political institutions and public administration (General)
We integrate foundational theories of meaning with a mathematical formalism of artificial general intelligence (AGI) to offer a comprehensive mechanistic explanation of meaning, communication, and symbol emergence. This synthesis holds significance for both AGI and broader debates concerning the nature of language, as it unifies pragmatics, logical truth conditional semantics, Peircean semiotics, and a computable model of enactive cognition, addressing phenomena that have traditionally evaded mechanistic explanation. By examining the conditions under which a machine can generate meaningful utterances or comprehend human meaning, we establish that the current generation of language models do not possess the same understanding of meaning as humans nor intend any meaning that we might attribute to their responses. To address this, we propose simulating human feelings and optimising models to construct weak representations. Our findings shed light on the relationship between meaning and intelligence, and how we can build machines that comprehend and intend meaning.