Hun Jee Choe, Talal Almas, Ian J. Neeland, Soo Lim, Jean-Pierre Després
Background
Obesity and atherogenic dyslipidemias are interrelated disorders that substantially contribute to the development of atherosclerotic cardiovascular disease (ASCVD) and the broader cardiovascular–kidney–metabolic (CKM) syndrome. The heterogeneity of obesity, particularly the role of visceral, ectopic and dysfunctional adipose tissue, drives the dyslipidemia phenotype characterized by hypertriglyceridemia, reduced high-density lipoprotein cholesterol and elevated apolipoprotein B–containing lipoproteins.
Methods
We review the epidemiological studies, imaging analyses, genetic data and clinical trial evidence linking obesity phenotypes with dyslipidemias and cardiovascular outcomes. We further evaluated lifestyle, pharmacological and surgical strategies targeting obesity-related lipid abnormalities.
Results
Visceral and ectopic fat accumulation, rather than body mass index alone, strongly predicts adverse lipid patterns, insulin resistance and cardiovascular events. Atherogenic dyslipidemias contribute to substantial residual ASCVD risk despite low-density lipoprotein cholesterol lowering. Lifestyle interventions—including diet modification, physical activity and improved cardiorespiratory fitness—demonstrate favourable effects on lipid metabolism independent of weight loss. Traditional pharmacotherapies such as statins, fibrates and omega-3 fatty acids offer partial benefits, while novel incretin-based agents and dual or triple receptor agonists provide robust weight loss and metabolic improvements. Metabolic and bariatric surgery remains an effective approach for sustained weight reduction and remission of dyslipidemias in the appropriate patient and is increasingly integrated with pharmacotherapy.
Conclusions
Atherogenic dyslipidemias are a hallmark of high-risk obesity phenotypes and a major contributor to ASCVD within the CKM framework. Precision medicine approaches that incorporate obesity phenotyping, targeted treatment strategies and population-level interventions are needed to reduce the burden of dyslipidemias and their cardiovascular sequelae.
{"title":"Obesity phenotypes and atherogenic dyslipidemias","authors":"Hun Jee Choe, Talal Almas, Ian J. Neeland, Soo Lim, Jean-Pierre Després","doi":"10.1111/eci.70151","DOIUrl":"10.1111/eci.70151","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Obesity and atherogenic dyslipidemias are interrelated disorders that substantially contribute to the development of atherosclerotic cardiovascular disease (ASCVD) and the broader cardiovascular–kidney–metabolic (CKM) syndrome. The heterogeneity of obesity, particularly the role of visceral, ectopic and dysfunctional adipose tissue, drives the dyslipidemia phenotype characterized by hypertriglyceridemia, reduced high-density lipoprotein cholesterol and elevated apolipoprotein B–containing lipoproteins.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We review the epidemiological studies, imaging analyses, genetic data and clinical trial evidence linking obesity phenotypes with dyslipidemias and cardiovascular outcomes. We further evaluated lifestyle, pharmacological and surgical strategies targeting obesity-related lipid abnormalities.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Visceral and ectopic fat accumulation, rather than body mass index alone, strongly predicts adverse lipid patterns, insulin resistance and cardiovascular events. Atherogenic dyslipidemias contribute to substantial residual ASCVD risk despite low-density lipoprotein cholesterol lowering. Lifestyle interventions—including diet modification, physical activity and improved cardiorespiratory fitness—demonstrate favourable effects on lipid metabolism independent of weight loss. Traditional pharmacotherapies such as statins, fibrates and omega-3 fatty acids offer partial benefits, while novel incretin-based agents and dual or triple receptor agonists provide robust weight loss and metabolic improvements. Metabolic and bariatric surgery remains an effective approach for sustained weight reduction and remission of dyslipidemias in the appropriate patient and is increasingly integrated with pharmacotherapy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Atherogenic dyslipidemias are a hallmark of high-risk obesity phenotypes and a major contributor to ASCVD within the CKM framework. Precision medicine approaches that incorporate obesity phenotyping, targeted treatment strategies and population-level interventions are needed to reduce the burden of dyslipidemias and their cardiovascular sequelae.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12013,"journal":{"name":"European Journal of Clinical Investigation","volume":"56 1","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145563337","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Alberto M. Borobia, Juliette Guillot, Amanda Bok, Lea Proulx, Sandra Pla, Paloma Moraga, Ron Hillel, Silvia Bornengo, Bruno Jolain, Mónica García, Jose Luis Narro
<p>Clinical studies (CS) have often struggled to recruit and retain participants that represent the population who will ultimately receive the treatments. This lack of representation leads to gaps in understanding diseases, preventive factors and the safety and effectiveness of treatments across diverse populations.<span><sup>1</sup></span> In this way, access to experimental health technologies—such as medicinal drugs, vaccines and medical devices—remains limited to specific populations.</p><p>Improving inclusiveness and representativeness in clinical studies is not just a matter of equity but a crucial step to ensure the quality and impact of clinical studies.<span><sup>2</sup></span> Thus, broadening the scope of those who are included in clinical studies can be regarded as an attempt to ensure that innovations in healthcare are accessible to all, reducing disparities not only in Europe but across the globe. This approach will ultimately lead to more reliable data and more effective treatments that truly serve the needs of a diverse population.</p><p>Various factors are associated with health disparities, including but not limited to demographic characteristics such as ethnicity, sex, gender, socio-economic status or age. Clinical studies must actively consider populations that have historically been underserved (US) and underrepresented (UR) in clinical studies. However, several barriers hinder participation, particularly among US and UR populations. These include geographic limitations, mistrust, restricted access to relevant information, ineffective communication, societal prejudices, financial constraints among other factors.<span><sup>3, 4</sup></span></p><p>Addressing these challenges requires a fundamental transformation in the design and execution of clinical studies to ensure a truly representative patient population is identified and provided with equitable opportunities to participate. To drive this transformation, it is essential that relevant clinical study information is widely distributed and accessible to all populations, that professionals involved are properly trained and empowered to design, develop and manage innovative studies tailored to diverse populations, and that key stakeholders—including patients, caregivers and patient organizations—are actively involved in design, educated and engaged, as their participation is vital to the success of clinical studies.<span><sup>7</sup></span></p><p>In this challenging context, the Research in Europe and Diversity Inclusion (READI) Project aims to create a more integrated and democratic ecosystem for clinical studies by identifying barriers to inclusiveness and representativeness, setting a new standard for equity in clinical studies and fostering the empowerment of all stakeholders. Through this engaged ecosystem, stakeholders can provide and share innovative approaches, tools, training programs and valuable insights to facilitate reach, engagement, recruitment and retention of u
临床研究（CS）常常难以招募和留住代表最终接受治疗的人群的参与者。这种代表性的缺乏导致在了解不同人群的疾病、预防因素以及治疗的安全性和有效性方面存在差距这样，获得实验性卫生技术——如药品、疫苗和医疗设备——仍然仅限于特定人群。提高临床研究的包容性和代表性不仅是公平问题，而且是确保临床研究质量和影响的关键一步因此，扩大临床研究对象的范围可被视为一种尝试，以确保所有人都能获得医疗保健方面的创新，不仅在欧洲而且在全球范围内缩小差距。这种方法最终将产生更可靠的数据和更有效的治疗方法，真正满足不同人群的需求。与健康差异有关的因素有很多，包括但不限于人口特征，如种族、性别、社会经济地位或年龄。临床研究必须积极考虑在临床研究中历史上服务不足（US）和代表性不足（UR）的人群。然而，一些障碍阻碍了参与，特别是在美国和UR人群中。这些因素包括地理限制、不信任、获取相关信息受限、沟通无效、社会偏见、财政限制等因素。解决这些挑战需要从根本上改变临床研究的设计和执行，以确保确定真正具有代表性的患者群体，并为其提供公平的参与机会。为了推动这一转变，至关重要的是，相关的临床研究信息被广泛分发，所有人群都可以访问，相关专业人员得到适当的培训和授权，以设计、开发和管理针对不同人群的创新研究，关键利益相关者——包括患者、护理人员和患者组织——积极参与设计、教育和参与，因为他们的参与对临床研究的成功至关重要。在这种具有挑战性的背景下，欧洲研究和多样性包容性（READI）项目旨在通过识别包容性和代表性的障碍，为临床研究的公平性设定新标准，并促进所有利益相关者的赋权，为临床研究创造一个更加整合和民主的生态系统。通过这个参与式生态系统，利益相关者可以提供和分享创新方法、工具、培训计划和有价值的见解，以促进服务不足和代表性不足的参与者的接触、参与、招募和保留，增强CS的包容性和代表性。READI项目将通过一个创新的数字平台进一步加速和维持其影响，该平台旨在增强对临床研究信息的获取并加强利益相关者的联系。通过采用交叉和整体的方法，READI将确保项目持续时间之外的长期可持续性，最终改变欧洲临床研究的进行方式。此外，READI将与各种全球临床研究计划保持一致，如世卫组织国际临床试验注册平台（ICTRP）8和Vulcan加速器9等。为了实现其雄心勃勃的目标，READI已经组建了欧洲临床研究计划中最大的联盟之一由来自18个国家的73个组织组成：比利时、塞浦路斯、丹麦、法国、德国、爱尔兰、意大利、立陶宛、卢森堡、荷兰、葡萄牙、罗马尼亚、西班牙、瑞典、瑞士、英国、美国和巴西（图1）。这些组织涵盖了参与临床研究的所有利益相关者：患者组织（参与此类项目的人数最多）、学术研究中心、医院、技术公司、欧洲制药工业和协会联合会（EFPIA）、监管机构、伦理专家、卫生技术评估和临床研究专业人员。这个多学科联盟的预算为6680万欧元，旨在促进交叉合作，以确保临床研究的各个方面——从研究设计到实施——都体现包容性和公平性的原则，从而使每个人都能获得医疗保健领域的创新。 此外，该项目围绕4个主要支柱和10个相互关联的工作包（WPs）构建，每个工作包都涉及项目目标的一个关键组成部分（图2）：所有这些工作包并行推进，由学术机构、患者代表、民间社会和EFPIA成员共同领导，确保公共和私营部门之间的平衡合作（表1），所有这些工作包都参与指导委员会。该项目的整体协调工作由Alberto Borobia （SERMAS）担任协调员，Juliette Guillot（诺华）担任项目负责人，Amanda Bok （The Synergist）担任数字和可持续发展协调员。这种结构确保了所有项目合作伙伴之间的适当开发、WP互连和协作工作，从而保证了其目标的成功和实现。正如前文所述，READI项目将改变欧洲临床研究的开展方式。它旨在改变临床试验生态系统和能力，以患者为中心，关键利益相关者从设计阶段到交付阶段进行协作。这样，所产生的知识不仅本身有益，而且有助于提出建议，以促进社会服务的包容性代表性和制定道德标准。它将提供一种创新的方法来招募服务不足和代表性不足的人群，并通过扩大能够在欧洲开展CS的站点网络，通过为不同的实体提供招募和留住美国和欧洲人口的必要能力，改变CS通信。具体来说，它有望扩大对服务不足和代表性不足人群的理解，与历史数据相比，CS招聘代表性增加60%。在此过程中，将制定一套商定的人口统计描述符数据标准，以及一个患者招募工具箱，其中包括覆盖至少100个组织的数字平台。测试这些工具是至关重要的，因此将开发至少四个临床用例来证明它们的影响和有效性。READI项目解决了临床研究中包容性的关键系统性障碍，如地理限制或不信任。通过利用整体、交叉的方法，READI旨在使临床研究的可及性民主化，并提高美国和UR人群在CS中的代表性。关键的创新，如人工智能驱动的数字平台和为美国和欧洲人群开发一套标准化的描述符，将提高招聘效率，提高保留率，并增加临床研究结果的普遍性。为了进一步支持患者参与，社区集群和有针对性的教育活动将有助于消除参与障碍。此外，对能力建设的关注确保了欧洲各地的临床站点配备了必要的技能和工具，以有效地接触美国和尿道口人群并与之互动。用例的实现为验证这些创新和生成支持长期可持续性的可操作的见解提供了一个实用的框架。READI项目代表了欧洲临床研究行为的范式转变，增强了包容性和公平性。通过解决限制服务不足和代表性不足人群参与的系统性障碍，READI有可能使临床研究更具代表性和影响力。该项目的成果不仅将有助于在欧洲及其他地区建立道德、有效和包容的CS实践，而且还将促进医疗保健领域的创新。未来的研究应以这些成就为基础，完善方法并促进全球采用包容性CS标准。Alberto M. Borobia：项目协调，概念化，手稿准备和关键审查的监督。Juliette Guillot：项目领导，财团协调和起草关键部分。Amanda Bok, l<s:1> prooulx, Ron Hillel, Bruno Jolain, Sandra Pla, Mónica García, Paloma Moraga， Jose Luis Narro和Silvia Bornengo：提供内容专业知识，为撰写和审查与其机构工作包相关的特定部分做出贡献。所有作者都对稿件做出了贡献，审阅了最终版本并批准提交。导致本出版物的项目由创新健康倡议联合事业（IHI JU）支持，赠款协议号为101166227。JU得到了欧盟地平线欧洲研究和创新计划、COCIR、EFPIA、EuropaBio、MedTech Europe、Vaccines Europe、药品和保健产品监管机构和Breakthrough T1D的支持。
{"title":"The READI European project: Enhancing inclusivity in clinical research","authors":"Alberto M. Borobia, Juliette Guillot, Amanda Bok, Lea Proulx, Sandra Pla, Paloma Moraga, Ron Hillel, Silvia Bornengo, Bruno Jolain, Mónica García, Jose Luis Narro","doi":"10.1111/eci.70146","DOIUrl":"10.1111/eci.70146","url":null,"abstract":"<p>Clinical studies (CS) have often struggled to recruit and retain participants that represent the population who will ultimately receive the treatments. This lack of representation leads to gaps in understanding diseases, preventive factors and the safety and effectiveness of treatments across diverse populations.<span><sup>1</sup></span> In this way, access to experimental health technologies—such as medicinal drugs, vaccines and medical devices—remains limited to specific populations.</p><p>Improving inclusiveness and representativeness in clinical studies is not just a matter of equity but a crucial step to ensure the quality and impact of clinical studies.<span><sup>2</sup></span> Thus, broadening the scope of those who are included in clinical studies can be regarded as an attempt to ensure that innovations in healthcare are accessible to all, reducing disparities not only in Europe but across the globe. This approach will ultimately lead to more reliable data and more effective treatments that truly serve the needs of a diverse population.</p><p>Various factors are associated with health disparities, including but not limited to demographic characteristics such as ethnicity, sex, gender, socio-economic status or age. Clinical studies must actively consider populations that have historically been underserved (US) and underrepresented (UR) in clinical studies. However, several barriers hinder participation, particularly among US and UR populations. These include geographic limitations, mistrust, restricted access to relevant information, ineffective communication, societal prejudices, financial constraints among other factors.<span><sup>3, 4</sup></span></p><p>Addressing these challenges requires a fundamental transformation in the design and execution of clinical studies to ensure a truly representative patient population is identified and provided with equitable opportunities to participate. To drive this transformation, it is essential that relevant clinical study information is widely distributed and accessible to all populations, that professionals involved are properly trained and empowered to design, develop and manage innovative studies tailored to diverse populations, and that key stakeholders—including patients, caregivers and patient organizations—are actively involved in design, educated and engaged, as their participation is vital to the success of clinical studies.<span><sup>7</sup></span></p><p>In this challenging context, the Research in Europe and Diversity Inclusion (READI) Project aims to create a more integrated and democratic ecosystem for clinical studies by identifying barriers to inclusiveness and representativeness, setting a new standard for equity in clinical studies and fostering the empowerment of all stakeholders. Through this engaged ecosystem, stakeholders can provide and share innovative approaches, tools, training programs and valuable insights to facilitate reach, engagement, recruitment and retention of u","PeriodicalId":12013,"journal":{"name":"European Journal of Clinical Investigation","volume":"56 1","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12825408/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145534264","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The C statistic, also known as the concordance index (C-index), is widely used in clinical research to assess the discriminative ability of risk prediction models. Its appeal lies in its intuitive interpretation and broad applicability, particularly in fields such as cardiovascular medicine and oncology, where accurate risk stratification is essential. However, despite its popularity, the C statistic has notable limitations that can undermine its utility in both research and clinical practice. Chief among these is its inherent conservativeness: the C statistic is often insensitive to meaningful improvements in model performance when new biomarkers or risk factors are added to an already robust model. This insensitivity stems from its rank-based nature, which focuses solely on the correct ordering of risk predictions rather than the magnitude of improvement. As a result, significant advances in risk estimation may be overlooked, potentially discouraging the adoption of clinically valuable innovations. Furthermore, the C statistic does not account for calibration—the agreement between predicted and observed outcomes—or the clinical consequences of misclassification. Alternative metrics, such as the Mean Absolute Difference (MAD), Brier score and Net Reclassification Improvement (NRI), offer complementary perspectives by capturing aspects of predictive accuracy and clinical relevance that the C statistic may miss. A comprehensive evaluation of risk models should therefore integrate these alternative measures to ensure that predictive tools are both statistically robust and clinically meaningful, ultimately advancing patient care and the practice of precision medicine.
{"title":"The conservativeness of standard C statistics in the prediction of clinical events","authors":"Carmine Zoccali, Giovanni Tripepi","doi":"10.1111/eci.70150","DOIUrl":"10.1111/eci.70150","url":null,"abstract":"<p>The C statistic, also known as the concordance index (C-index), is widely used in clinical research to assess the discriminative ability of risk prediction models. Its appeal lies in its intuitive interpretation and broad applicability, particularly in fields such as cardiovascular medicine and oncology, where accurate risk stratification is essential. However, despite its popularity, the C statistic has notable limitations that can undermine its utility in both research and clinical practice. Chief among these is its inherent conservativeness: the C statistic is often insensitive to meaningful improvements in model performance when new biomarkers or risk factors are added to an already robust model. This insensitivity stems from its rank-based nature, which focuses solely on the correct ordering of risk predictions rather than the magnitude of improvement. As a result, significant advances in risk estimation may be overlooked, potentially discouraging the adoption of clinically valuable innovations. Furthermore, the C statistic does not account for calibration—the agreement between predicted and observed outcomes—or the clinical consequences of misclassification. Alternative metrics, such as the Mean Absolute Difference (MAD), Brier score and Net Reclassification Improvement (NRI), offer complementary perspectives by capturing aspects of predictive accuracy and clinical relevance that the C statistic may miss. A comprehensive evaluation of risk models should therefore integrate these alternative measures to ensure that predictive tools are both statistically robust and clinically meaningful, ultimately advancing patient care and the practice of precision medicine.</p>","PeriodicalId":12013,"journal":{"name":"European Journal of Clinical Investigation","volume":"56 1","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145534188","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Diana Santos, Ana Burgeiro, Ana Catarina R. G. Fonseca, Cândida Dias, Teresa Cunha-Oliveira, Aryane Oliveira, João Laranjinha, António Canotilho, Gonçalo Coutinho, David Prieto, Pedro Antunes, Manuel Antunes, Eugenia Carvalho
Background
Epicardial adipose tissue (EAT) exhibits brown-like features, including the expression of uncoupling protein 1 (UCP1). EAT interacts dynamically with cardiac cells to modulate local cardiac tissue physiology and metabolic function. No studies have evaluated the impact of UCP1 inhibition on oxidative phosphorylation (OXPHOS) in fresh EAT explants. This study aimed to determine the unique bioenergetic characteristics of fresh EAT explants by comparing it to subcutaneous adipose tissue (SAT). Furthermore, the key impact of UCP1 inhibition on EAT respiration and how this process is influenced by the presence of type 2 diabetes mellitus (DM) or coronary artery disease (CAD), was also evaluated.
Methods
EAT and SAT biopsies were collected from 205 (151 male and 51 female) study participants, undergoing cardiac surgery. Participants were stratified according to the presence/absence of DM or CAD. Markers of mitochondrial content and bioenergetics were evaluated.
Results
EAT demonstrated a higher bioenergetic activity compared to SAT, in both nicotinamide adenine dinucleotide (NADH)-linked and fatty acid oxidation (FAO)-linked OXPHOS. Importantly, UCP1 inhibition with guanosine 5′-diphosphate (GDP), flattens the differences between the tissues in the NADH-linked OXPHOS; in contrast these differences were potentiated in the FAO-linked OXPHOS. Minor differences in mitochondrial content and respiration were observed when subjects were stratified according to either DM or CAD.
Conclusions
This study emphasizes the important bioenergetic differences between EAT and SAT, which are crucial in the context of the local cardiomyocyte metabolism, as well as the impact of UCP1 inhibition in EAT. A deeper understanding of the unique characteristics of EAT and its metabolic micro-environment may provide valuable insights into the cardiovascular disease pathologies.
{"title":"Assessing the interaction of the UCP system and fatty acids on epicardial adipose tissue mitochondrial respiration","authors":"Diana Santos, Ana Burgeiro, Ana Catarina R. G. Fonseca, Cândida Dias, Teresa Cunha-Oliveira, Aryane Oliveira, João Laranjinha, António Canotilho, Gonçalo Coutinho, David Prieto, Pedro Antunes, Manuel Antunes, Eugenia Carvalho","doi":"10.1111/eci.70149","DOIUrl":"10.1111/eci.70149","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Epicardial adipose tissue (EAT) exhibits brown-like features, including the expression of uncoupling protein 1 (UCP1). EAT interacts dynamically with cardiac cells to modulate local cardiac tissue physiology and metabolic function. No studies have evaluated the impact of UCP1 inhibition on oxidative phosphorylation (OXPHOS) in fresh EAT explants. This study aimed to determine the unique bioenergetic characteristics of fresh EAT explants by comparing it to subcutaneous adipose tissue (SAT). Furthermore, the key impact of UCP1 inhibition on EAT respiration and how this process is influenced by the presence of type 2 diabetes mellitus (DM) or coronary artery disease (CAD), was also evaluated.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>EAT and SAT biopsies were collected from 205 (151 male and 51 female) study participants, undergoing cardiac surgery. Participants were stratified according to the presence/absence of DM or CAD. Markers of mitochondrial content and bioenergetics were evaluated.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>EAT demonstrated a higher bioenergetic activity compared to SAT, in both nicotinamide adenine dinucleotide (NADH)-linked and fatty acid oxidation (FAO)-linked OXPHOS. Importantly, UCP1 inhibition with guanosine 5′-diphosphate (GDP), flattens the differences between the tissues in the NADH-linked OXPHOS; in contrast these differences were potentiated in the FAO-linked OXPHOS. Minor differences in mitochondrial content and respiration were observed when subjects were stratified according to either DM or CAD.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>This study emphasizes the important bioenergetic differences between EAT and SAT, which are crucial in the context of the local cardiomyocyte metabolism, as well as the impact of UCP1 inhibition in EAT. A deeper understanding of the unique characteristics of EAT and its metabolic micro-environment may provide valuable insights into the cardiovascular disease pathologies.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12013,"journal":{"name":"European Journal of Clinical Investigation","volume":"56 1","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12820919/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145523246","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Alberto Cook-Calvete, Silvia Moreta, Maria Delgado-Marin, Blanca Fernandez-Rodriguez, Carlos Zaragoza, Marta Saura
Background
Calcific aortic valve disease (CAVD) is the predominant valvular pathology in older adults, advancing from aortic sclerosis to life-threatening stenosis. Without effective medical therapies, intervention mainly relies on timely valve replacement, although silent myocardial and valvular damage may progress before symptoms arise. Early, non-invasive detection of disease activity is a crucial unmet need.
Aims
To review circulating and mechanistic biomarkers reflecting the core pathogenic pathways of CAVD and asses their potential for early detection and patient-specific risk stratification.
Methods
Narrative review of literature focusing on traditional protein biomarkers, emerging non-coding RNAs, and extracellular vesicles (EVs) associated with lipid oxidation and inflammation, bone and mineral metabolism, extracellular matrix (ECM) remodelling, endothelial dysfunction and non-coding RNA regulation.
Results
Traditional protein biomarkers—such as lipoprotein(a), osteopontin, fetuin-A, galectin-3 and matrix metalloproteinases—offer insights into the disease and correlate with disease burden but lack sensitivity for detecting early-stage CAVD. Emerging non-coding RNA markers, including long non-coding RNAs (lncRNAs) and microRNAs (like miR-30b and miR-125b), show promise as predictive and diagnostic tools by mediating key molecular pathways involved in calcification and inflammation. EVs, which carry proteins, lipids and nucleic acids across all pathogenic pathways, provide stable and comprehensive signatures that enhance risk stratification compared to conventional markers. Notably, no single biomarker has demonstrated sufficient sensitivity or specificity across all stages of the disease. Combining proteins, RNAs and EV cargo into integrative, multimodal panels—supported by proteomics and transcriptomics—provides the greatest potential for early detection and patient-specific management. However, further validation in prospective cohorts and standardization of assays are necessary before clinical implementation.
Conclusion
Biomarker-guided approaches could revolutionize CAVD management by enabling early detection and patient stratification before irreversible valvular damage occurs.
{"title":"Integrated biomarker landscape for the early detection and management of calcific aortic valve disease","authors":"Alberto Cook-Calvete, Silvia Moreta, Maria Delgado-Marin, Blanca Fernandez-Rodriguez, Carlos Zaragoza, Marta Saura","doi":"10.1111/eci.70147","DOIUrl":"10.1111/eci.70147","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Calcific aortic valve disease (CAVD) is the predominant valvular pathology in older adults, advancing from aortic sclerosis to life-threatening stenosis. Without effective medical therapies, intervention mainly relies on timely valve replacement, although silent myocardial and valvular damage may progress before symptoms arise. Early, non-invasive detection of disease activity is a crucial unmet need.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Aims</h3>\u0000 \u0000 <p>To review circulating and mechanistic biomarkers reflecting the core pathogenic pathways of CAVD and asses their potential for early detection and patient-specific risk stratification.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Narrative review of literature focusing on traditional protein biomarkers, emerging non-coding RNAs, and extracellular vesicles (EVs) associated with lipid oxidation and inflammation, bone and mineral metabolism, extracellular matrix (ECM) remodelling, endothelial dysfunction and non-coding RNA regulation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Traditional protein biomarkers—such as lipoprotein(a), osteopontin, fetuin-A, galectin-3 and matrix metalloproteinases—offer insights into the disease and correlate with disease burden but lack sensitivity for detecting early-stage CAVD. Emerging non-coding RNA markers, including long non-coding RNAs (lncRNAs) and microRNAs (like miR-30b and miR-125b), show promise as predictive and diagnostic tools by mediating key molecular pathways involved in calcification and inflammation. EVs, which carry proteins, lipids and nucleic acids across all pathogenic pathways, provide stable and comprehensive signatures that enhance risk stratification compared to conventional markers. Notably, no single biomarker has demonstrated sufficient sensitivity or specificity across all stages of the disease. Combining proteins, RNAs and EV cargo into integrative, multimodal panels—supported by proteomics and transcriptomics—provides the greatest potential for early detection and patient-specific management. However, further validation in prospective cohorts and standardization of assays are necessary before clinical implementation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Biomarker-guided approaches could revolutionize CAVD management by enabling early detection and patient stratification before irreversible valvular damage occurs.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12013,"journal":{"name":"European Journal of Clinical Investigation","volume":"56 1","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12820923/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145523227","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Overweight and obesity are highly prevalent in atrial fibrillation (AF) patients, yet the best anticoagulant strategy for this group is still unclear. We evaluated the risk of all-cause mortality and cardiovascular events (CVEs) in overweight and obese AF patients treated with direct oral anticoagulants (DOACs) or vitamin K antagonists (VKAs).
Methods
We analysed 10,259 AF patients on anticoagulants from the prospective nationwide START registry. Overweight was defined as BMI 25–29.9 kg/m2 and obesity as BMI ≥30 kg/m2. Mortality risk was assessed with Cox proportional hazards models, and CVEs with Fine–Grey models accounting for competing risks. Additional modelling strategies, subgroup analyses, and propensity score matching were performed to explore data and ensure robustness.
Results
Overall, 6534 (63.7%) patients had BMI >25 kg/m2 (65.7% overweight, 34.3% obese). Over a median follow-up of 17.4 months, 408 deaths and 481 CVEs occurred. DOACs' use was associated with a lower risk of all-cause mortality (HR 0.57, 95% CI 0.46–0.70, p < 0.001) and CVEs (sHR 0.71, 95% CI 0.59–0.86, p < 0.001) versus VKAs. The inverse association of DOACs with mortality was evident in both overweight (HR 0.52, 95% CI 0.39–0.68, p < 0.001) and obese patients (HR 0.69, 95% CI 0.48–0.98, p = 0.040), while the reduction in CVEs reached significance only in the overweight group.
Conclusions
In this nationwide registry, DOACs were associated with lower risks of mortality and CVEs compared with VKAs across BMI groups, though the CVE effect was not evident in obese patients. These findings suggest a potential mortality advantage of DOACs irrespective of BMI, warranting further confirmation.
背景：超重和肥胖在房颤（AF）患者中非常普遍，但这一群体的最佳抗凝策略仍不清楚。我们评估了直接口服抗凝剂（DOACs）或维生素K拮抗剂（VKAs）治疗的超重和肥胖房颤患者的全因死亡率和心血管事件（CVEs）风险。方法：我们分析了来自全国前瞻性START登记的10259例使用抗凝剂的房颤患者。超重定义为BMI 25-29.9 kg/m2，肥胖定义为BMI≥30 kg/m2。采用Cox比例风险模型评估死亡风险，采用细灰模型评估cve竞争风险。额外的建模策略，亚组分析和倾向评分匹配进行探索数据和确保稳健性。结果：总体而言，6534例（63.7%）患者BMI为bbb25 kg/m2（65.7%超重，34.3%肥胖）。在17.4个月的中位随访期间，发生了408例死亡和481例cve。DOACs的使用与全因死亡风险较低相关（HR 0.57, 95% CI 0.46-0.70, p）。结论：在这个全国性的登记中，与vka相比，DOACs在BMI组中与较低的死亡率和CVE风险相关，尽管CVE效应在肥胖患者中并不明显。这些发现表明doac的潜在死亡率优势与BMI无关，值得进一步证实。
{"title":"Effectiveness of direct oral anticoagulants for all-cause mortality and cardiovascular events in overweight and obese patients with atrial fibrillation: Insight from the nationwide START registry","authors":"Danilo Menichelli, Gianluca Gazzaniga, Emilia Antonucci, Gualtiero Palareti, Daniela Poli, Pasquale Pignatelli, Daniele Pastori, the START2 Register Investigators","doi":"10.1111/eci.70148","DOIUrl":"10.1111/eci.70148","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Overweight and obesity are highly prevalent in atrial fibrillation (AF) patients, yet the best anticoagulant strategy for this group is still unclear. We evaluated the risk of all-cause mortality and cardiovascular events (CVEs) in overweight and obese AF patients treated with direct oral anticoagulants (DOACs) or vitamin K antagonists (VKAs).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We analysed 10,259 AF patients on anticoagulants from the prospective nationwide START registry. Overweight was defined as BMI 25–29.9 kg/m<sup>2</sup> and obesity as BMI ≥30 kg/m<sup>2</sup>. Mortality risk was assessed with Cox proportional hazards models, and CVEs with Fine–Grey models accounting for competing risks. Additional modelling strategies, subgroup analyses, and propensity score matching were performed to explore data and ensure robustness.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Overall, 6534 (63.7%) patients had BMI >25 kg/m<sup>2</sup> (65.7% overweight, 34.3% obese). Over a median follow-up of 17.4 months, 408 deaths and 481 CVEs occurred. DOACs' use was associated with a lower risk of all-cause mortality (HR 0.57, 95% CI 0.46–0.70, <i>p</i> < 0.001) and CVEs (sHR 0.71, 95% CI 0.59–0.86, <i>p</i> < 0.001) versus VKAs. The inverse association of DOACs with mortality was evident in both overweight (HR 0.52, 95% CI 0.39–0.68, <i>p</i> < 0.001) and obese patients (HR 0.69, 95% CI 0.48–0.98, <i>p</i> = 0.040), while the reduction in CVEs reached significance only in the overweight group.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>In this nationwide registry, DOACs were associated with lower risks of mortality and CVEs compared with VKAs across BMI groups, though the CVE effect was not evident in obese patients. These findings suggest a potential mortality advantage of DOACs irrespective of BMI, warranting further confirmation.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12013,"journal":{"name":"European Journal of Clinical Investigation","volume":"56 1","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12820908/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145502898","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Giorgio Busto, Andrea Morotti, Ilaria Casetta, Federico Mazzacane, Giuseppe Martucci, Francesca Danesi, Francesco Loverre, Andrea Ginestroni, Francesca Pescini, Fabrizio Montecucco, Alessandro Padovani, Enrico Fainardi
Background
Venous outflow (VO) is a promising prognostic imaging biomarker in acute ischemic stroke (AIS) patients selected for endovascular treatment (EVT). However, the best score for properly assessing VO profiles on multi-phase CT-Angiography (mCTA) remains to be identified.
Methods
A series of consecutive AIS patients undergoing EVT for large vessel occlusion within 24 h from symptom onset were investigated. The following scores were rated: cortical vein score difference in stroke (PRECISE, range 0–8), cortical vein opacification score (COVES, range 0–6), comprehensive venous outflow (CVO, range 0–8) and internal cerebral vein (ICV) asymmetry. Receiver operating characteristic curves and multivariable logistic regression analyses were performed to explore the performance of the different VO scores for prediction of a good outcome (modified Rankin Scale 0–2 at 3 months).
Results
Three hundred and thirty-six subjects (56.2% females, mean age 74.8) were included, of whom 145 (43.1%) had good outcomes. In multivariable logistic analysis, the CVO score (odds ratio = 2.51, 95% CI = 1.49–4.18, p = .001) was the only independent predictor of good functional outcomes. The AUC of the CVO score was .75 (95% CI = .70–.80), with an optimal cut-off of ≥4 (sensitivity 56%, specificity 69%). Patients with favourable CVO profiles had better pial arterial (70.7%, p < .001) and hypoperfusion intensity ratio (HIR) tissue-related collaterals (HIR = .35, p = .005), higher rates of successful recanalization (95.7%, p < .001) and lower symptomatic intracranial haemorrhage occurrence (6%, p = .020) than those with unfavourable CVO profiles.
Conclusion
The CVO score measured on mCTA had the best discriminative performance and was independently associated with functional outcome in AIS patients undergoing EVT within 24 h from onset.
背景：静脉流出（VO）是急性缺血性卒中（AIS）患者选择血管内治疗（EVT）的预后成像生物标志物。然而，在多期ct血管造影（mCTA）中正确评估VO谱的最佳分数仍有待确定。方法：对发病24小时内连续行EVT治疗大血管闭塞的AIS患者进行研究。评分：脑卒中皮质静脉评分差异（PRECISE，范围0-8）、皮质静脉混浊评分（COVES，范围0-6）、综合静脉流出（CVO，范围0-8）和脑内静脉（ICV）不对称。采用受试者工作特征曲线和多变量logistic回归分析，探讨不同VO评分对预测良好预后的作用（3个月时修改的Rankin量表0-2）。结果：共纳入336例（女性56.2%，平均年龄74.8岁），其中145例（43.1%）预后良好。在多变量logistic分析中，CVO评分(优势比= 2.51,95% CI = 1.49 ~ 4.18, p =。001)是良好功能预后的唯一独立预测因子。CVO评分的AUC为。75 (95% CI = 0.70 - 0.80)，最佳临界值≥4（敏感性56%，特异性69%）。结论：在发病24小时内接受EVT的AIS患者中，mCTA测量的CVO评分具有最佳的判别性能，并且与功能结局独立相关。
{"title":"Comprehensive venous outflow is the optimal venous score in predicting functional outcome in acute ischemic stroke patients","authors":"Giorgio Busto, Andrea Morotti, Ilaria Casetta, Federico Mazzacane, Giuseppe Martucci, Francesca Danesi, Francesco Loverre, Andrea Ginestroni, Francesca Pescini, Fabrizio Montecucco, Alessandro Padovani, Enrico Fainardi","doi":"10.1111/eci.70145","DOIUrl":"10.1111/eci.70145","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Venous outflow (VO) is a promising prognostic imaging biomarker in acute ischemic stroke (AIS) patients selected for endovascular treatment (EVT). However, the best score for properly assessing VO profiles on multi-phase CT-Angiography (mCTA) remains to be identified.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A series of consecutive AIS patients undergoing EVT for large vessel occlusion within 24 h from symptom onset were investigated. The following scores were rated: cortical vein score difference in stroke (PRECISE, range 0–8), cortical vein opacification score (COVES, range 0–6), comprehensive venous outflow (CVO, range 0–8) and internal cerebral vein (ICV) asymmetry. Receiver operating characteristic curves and multivariable logistic regression analyses were performed to explore the performance of the different VO scores for prediction of a good outcome (modified Rankin Scale 0–2 at 3 months).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Three hundred and thirty-six subjects (56.2% females, mean age 74.8) were included, of whom 145 (43.1%) had good outcomes. In multivariable logistic analysis, the CVO score (odds ratio = 2.51, 95% CI = 1.49–4.18, <i>p</i> = .001) was the only independent predictor of good functional outcomes. The AUC of the CVO score was .75 (95% CI = .70–.80), with an optimal cut-off of ≥4 (sensitivity 56%, specificity 69%). Patients with favourable CVO profiles had better pial arterial (70.7%, <i>p</i> < .001) and hypoperfusion intensity ratio (HIR) tissue-related collaterals (HIR = .35, <i>p</i> = .005), higher rates of successful recanalization (95.7%, <i>p</i> < .001) and lower symptomatic intracranial haemorrhage occurrence (6%, <i>p</i> = .020) than those with unfavourable CVO profiles.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>The CVO score measured on mCTA had the best discriminative performance and was independently associated with functional outcome in AIS patients undergoing EVT within 24 h from onset.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12013,"journal":{"name":"European Journal of Clinical Investigation","volume":"56 1","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145502926","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yun Seo Kim, Min Seo Kim, Seoyeon Park, Lee Smith, Joaquim Radua, Sarah Soyeon Oh, Stefania I. Papatheodorou, Hoon-Chul Kang, Ara Ko, Dong Keon Yon, Jae Il Shin
Background
Epilepsy is a common neurological disease that heavily impacts children and adolescents and carries serious physical, cognitive, psychological, social and economic consequences for patients and their caregivers.
Methods
Data was obtained via the Global Burden of Disease Study 2021. We reported numbers, rates and percentage changes of prevalence, mortality and disability-adjusted life years (DALYs).
Results
In 2021, there were 18.15 million [95% UI: 14.61–21.85] prevalent cases of epilepsy in children and adolescents worldwide, 8.24 million [5.77–11.13] of which were idiopathic epilepsy and 9.91 million [8.72–11.06] of which were secondary epilepsy. While mortality and DALY rates of idiopathic epilepsy declined between 1990 and 2021, the burden of secondary epilepsy remained substantial and, in some cases, increased—particularly in low-SDI regions. The prevalence rate of secondary epilepsy increased by 16.14% [4.28–29.24], driven by increases in epilepsy attributable to neonatal encephalopathy (82.02%), neonatal jaundice (18.45%) and malaria (77.03%). There were notable geographic variations in the burden of epilepsy, with the burden generally concentrated in Sub-Saharan Africa, Latin America and the Caribbean and Southeast Asia.
Conclusions
While efforts to reduce premature mortality of epilepsy have been successful, the burden on children and adolescents living with epilepsy is still significant. A healthcare gap remains for vulnerable populations with increased risk of infectious diseases, perinatal insults, poor sanitation and limited access to healthcare. Global and national action is needed to improve access to specialist care and medication, manage comorbidities, address stigma and discrimination and strengthen primary prevention initiatives.
{"title":"Global, regional and national burden of epilepsy in children and adolescents, 1990–2021: A systematic analysis for the Global Burden of Disease Study 2021","authors":"Yun Seo Kim, Min Seo Kim, Seoyeon Park, Lee Smith, Joaquim Radua, Sarah Soyeon Oh, Stefania I. Papatheodorou, Hoon-Chul Kang, Ara Ko, Dong Keon Yon, Jae Il Shin","doi":"10.1111/eci.70139","DOIUrl":"10.1111/eci.70139","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Epilepsy is a common neurological disease that heavily impacts children and adolescents and carries serious physical, cognitive, psychological, social and economic consequences for patients and their caregivers.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Data was obtained via the Global Burden of Disease Study 2021. We reported numbers, rates and percentage changes of prevalence, mortality and disability-adjusted life years (DALYs).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>In 2021, there were 18.15 million [95% UI: 14.61–21.85] prevalent cases of epilepsy in children and adolescents worldwide, 8.24 million [5.77–11.13] of which were idiopathic epilepsy and 9.91 million [8.72–11.06] of which were secondary epilepsy. While mortality and DALY rates of idiopathic epilepsy declined between 1990 and 2021, the burden of secondary epilepsy remained substantial and, in some cases, increased—particularly in low-SDI regions. The prevalence rate of secondary epilepsy increased by 16.14% [4.28–29.24], driven by increases in epilepsy attributable to neonatal encephalopathy (82.02%), neonatal jaundice (18.45%) and malaria (77.03%). There were notable geographic variations in the burden of epilepsy, with the burden generally concentrated in Sub-Saharan Africa, Latin America and the Caribbean and Southeast Asia.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>While efforts to reduce premature mortality of epilepsy have been successful, the burden on children and adolescents living with epilepsy is still significant. A healthcare gap remains for vulnerable populations with increased risk of infectious diseases, perinatal insults, poor sanitation and limited access to healthcare. Global and national action is needed to improve access to specialist care and medication, manage comorbidities, address stigma and discrimination and strengthen primary prevention initiatives.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12013,"journal":{"name":"European Journal of Clinical Investigation","volume":"56 1","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12820917/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145458073","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Derralynn A. Hughes, Guillem Pintos-Morell, Christoph Kampmann, Christina Anagnostopoulou, Jaco Botha, Siddharth Jain, Kathleen Nicholls, Dau-Ming Niu, Ricardo Reisin, Michael L. West, Jörn Schenk, Uma Ramaswami, Roberto Giugliani
Background
We present the final report from the Fabry Outcome Survey (FOS) on long-term effectiveness and safety of agalsidase alfa in adults (≥18 years old).
Methods
FOS was an international, multicentre, observational registry (NCT03289065), designed to enhance the understanding of Fabry disease and improve clinical management. Primary effectiveness endpoints were annualized change in estimated glomerular filtration rate (eGFR) and left ventricular mass index (LVMI), and time to and age at composite morbidity event (comprising renal, cardiac or stroke events) and death. Safety outcomes were also assessed.
Results
FOS included data for 1864 adults (female/male, n = 907/957) who received agalsidase alfa only for a median (minimum, maximum) of 6.0 (0, 21.6) years, and 1613 untreated adults (female/male, n = 1235/378). At baseline, mean (standard deviation [SD]) eGFR was 94.01 (27.60) mL/min/1.73 m2 in treated adults; annualized changes in eGFR (slope [standard error; SE]) remained relatively stable in females and declined slightly in males (−1.07 [.12] vs. −2.17 [.12] mL/min/1.73 m2). At baseline, mean (SD) LVMI was 58.25 (25.01) g/m2.7 and LVMI (slope [SE]) remained stable (.34 [.16] vs. .38 [.15] g/m2.7/year in females and males, respectively). Time (median [95% confidence interval]) from treatment initiation to first composite event was longer for females than males (83.4 [65.7–98.0] vs. 56.3 [45.6–66.7] months); age (median [minimum, maximum]) at death was also higher for treated females than males (69.9 [32.5, 87.7] vs. 59.1 [26.2, 79.6] years). Agalsidase alfa was generally well tolerated.
Conclusions
This report further supports the long-term effectiveness and safety of agalsidase alfa in adults with Fabry disease.
{"title":"Long-term effectiveness and safety outcomes in adults with Fabry disease treated with agalsidase alfa: 20 years of data from the Fabry Outcome Survey","authors":"Derralynn A. Hughes, Guillem Pintos-Morell, Christoph Kampmann, Christina Anagnostopoulou, Jaco Botha, Siddharth Jain, Kathleen Nicholls, Dau-Ming Niu, Ricardo Reisin, Michael L. West, Jörn Schenk, Uma Ramaswami, Roberto Giugliani","doi":"10.1111/eci.70142","DOIUrl":"10.1111/eci.70142","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>We present the final report from the Fabry Outcome Survey (FOS) on long-term effectiveness and safety of agalsidase alfa in adults (≥18 years old).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>FOS was an international, multicentre, observational registry (NCT03289065), designed to enhance the understanding of Fabry disease and improve clinical management. Primary effectiveness endpoints were annualized change in estimated glomerular filtration rate (eGFR) and left ventricular mass index (LVMI), and time to and age at composite morbidity event (comprising renal, cardiac or stroke events) and death. Safety outcomes were also assessed.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>FOS included data for 1864 adults (female/male, <i>n =</i> 907/957) who received agalsidase alfa only for a median (minimum, maximum) of 6.0 (0, 21.6) years, and 1613 untreated adults (female/male, <i>n =</i> 1235/378). At baseline, mean (standard deviation [SD]) eGFR was 94.01 (27.60) mL/min/1.73 m<sup>2</sup> in treated adults; annualized changes in eGFR (slope [standard error; SE]) remained relatively stable in females and declined slightly in males (−1.07 [.12] vs. −2.17 [.12] mL/min/1.73 m<sup>2</sup>). At baseline, mean (SD) LVMI was 58.25 (25.01) g/m<sup>2.7</sup> and LVMI (slope [SE]) remained stable (.34 [.16] vs. .38 [.15] g/m<sup>2.7</sup>/year in females and males, respectively). Time (median [95% confidence interval]) from treatment initiation to first composite event was longer for females than males (83.4 [65.7–98.0] vs. 56.3 [45.6–66.7] months); age (median [minimum, maximum]) at death was also higher for treated females than males (69.9 [32.5, 87.7] vs. 59.1 [26.2, 79.6] years). Agalsidase alfa was generally well tolerated.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>This report further supports the long-term effectiveness and safety of agalsidase alfa in adults with Fabry disease.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12013,"journal":{"name":"European Journal of Clinical Investigation","volume":"56 1","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12820918/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145451251","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Katja Schnidrig, Manovriti Thakur, Aleksandra Tuleja, Sarah Maike Bernhard, Heidi Noels, Drosos Kotelis, Marc Schindewolf, Yvonne Döring
Background
Lower extremity arterial disease (LEAD) affects over 200 million people globally and is largely driven by chronic vascular inflammation. However, the complex interplay between inflammatory pathways, their prognostic value and potential sex-specific differences remains insufficiently understood.
Methods and Results
Literature indicates that elevated inflammatory markers—such as (high-sensitivity) C-reactive protein, fibrinogen, D-dimer, interleukin-6, α-defensins and soluble adhesion molecules as well as newly arising parameters such as neutrophil counts and markers of clonal haematopoiesis—may predict both the onset and progression of LEAD, from declining ankle–brachial indices and impaired walking performance to higher rates of amputation, cardiovascular events and mortality. Moreover, women with LEAD frequently present at older ages with more advanced disease, exhibit distinct lesion patterns and greater functional impairment, and often have higher baseline CRP levels than men, although the strength of association between inflammatory markers and adverse outcomes may be attenuated in women. However, it remains unclear how inflammatory markers can guide (sex) specific patient stratification in LEAD or which markers provide the most clinical utility in general.
Conclusion
Together, these findings underscore the need for comprehensive inflammatory profiling in LEAD risk stratification and highlight the importance of joining sex-specific analyses, new (bio)markers and machine learning to integrate clinical, genomic, proteomic and functional data into future studies to inform patient-tailored prevention and treatment strategies.
{"title":"Implications of inflammation and sex in lower extremity arterial disease","authors":"Katja Schnidrig, Manovriti Thakur, Aleksandra Tuleja, Sarah Maike Bernhard, Heidi Noels, Drosos Kotelis, Marc Schindewolf, Yvonne Döring","doi":"10.1111/eci.70144","DOIUrl":"10.1111/eci.70144","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Lower extremity arterial disease (LEAD) affects over 200 million people globally and is largely driven by chronic vascular inflammation. However, the complex interplay between inflammatory pathways, their prognostic value and potential sex-specific differences remains insufficiently understood.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods and Results</h3>\u0000 \u0000 <p>Literature indicates that elevated inflammatory markers—such as (high-sensitivity) C-reactive protein, fibrinogen, D-dimer, interleukin-6, α-defensins and soluble adhesion molecules as well as newly arising parameters such as neutrophil counts and markers of clonal haematopoiesis—may predict both the onset and progression of LEAD, from declining ankle–brachial indices and impaired walking performance to higher rates of amputation, cardiovascular events and mortality. Moreover, women with LEAD frequently present at older ages with more advanced disease, exhibit distinct lesion patterns and greater functional impairment, and often have higher baseline CRP levels than men, although the strength of association between inflammatory markers and adverse outcomes may be attenuated in women. However, it remains unclear how inflammatory markers can guide (sex) specific patient stratification in LEAD or which markers provide the most clinical utility in general.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Together, these findings underscore the need for comprehensive inflammatory profiling in LEAD risk stratification and highlight the importance of joining sex-specific analyses, new (bio)markers and machine learning to integrate clinical, genomic, proteomic and functional data into future studies to inform patient-tailored prevention and treatment strategies.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12013,"journal":{"name":"European Journal of Clinical Investigation","volume":"56 1","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12820922/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145451314","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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