Kateryna Sopova, Dimitrios Delialis, Evmorfia Aivalioti, Georgios Georgiopoulos, Stravros Athanasopoulos, Georgios Zervas, Christina Konstantaki, Marco Sachse, Martin Sigl, Daniel Duerschmied, Simon Tual-Chalot, Kimon Stamatelopoulos, Konstantinos Stellos
Background
Amyloid-beta 1–40 peptide (Aβ40) has recently emerged as a blood-based biomarker of cardiovascular disease (CVD). However, whether plasma levels of Aβ40 are associated with metabolic traits in humans without established CVD remains poorly understood.
Methods
Aβ40 was measured in plasma by ELISA and metabolic traits (waist circumference, fasting triglycerides, fasting HDL cholesterol and fasting glucose) were determined in a general population (n = 449) of individuals who did not have clinically overt CVD. Triglyceride-glucose index (TyG) was used to calculate the risk for insulin resistance. BARD score was used to calculate the risk for metabolic liver disease.
Results
Aβ40 levels were associated with the presence of metabolic syndrome (OR: 1.41 95% CI: 1.13–1.76, p = .003), and with higher odds for increasing incidence of metabolic syndrome components, characterized by decreased HDL-C levels (OR: 1.31 95% CI: 1.03–1.58, p = .017) and increased triglyceride levels (OR: 1.30 95% CI: 1.04–1.57, p = .033) after adjustment for traditional cardiovascular risk factors. Further, Aβ40 levels were associated with increased odds for TyG (OR: 1.26 95% CI: 1.03–1.57, p = .042) and increased odds for the presence of diabetes mellitus (OR: 1.35 95% CI: 1.04–1.76, p = .018) after adjustment for age and sex, smoking status, hypertension and dyslipidemia. Increased Aβ40 levels were associated with increased odds for BARD score ≥2 (OR: 1.41 95% CI: 1.04–2.04, p = .045) after adjustment for traditional cardiovascular risk factors.
Conclusion
Our findings suggest that Aβ40 peptide is associated with metabolic traits and risk for metabolic disease. Future longitudinal studies are warranted to determine the prognostic value of Aβ40 for the development and progression of metabolic diseases.
背景：淀粉样蛋白- β 1-40肽（a - β40）最近被认为是一种基于血液的心血管疾病（CVD）生物标志物。然而，在没有心血管疾病的人群中，血浆Aβ40水平是否与代谢特征相关仍然知之甚少。方法：采用ELISA法测定血浆中a β40的含量，并测定无临床明显CVD的一般人群（n = 449）的代谢特征（腰围、空腹甘油三酯、空腹高密度脂蛋白胆固醇和空腹血糖）。使用甘油三酯-葡萄糖指数（TyG）计算胰岛素抵抗的风险。BARD评分用于计算代谢性肝病的风险。结果：Aβ40水平与代谢综合征的存在相关(OR: 1.41 95% CI: 1.13-1.76, p =。003)，并且代谢综合征成分发生率增加的几率更高，其特征是HDL-C水平降低(OR: 1.31 95% CI: 1.03-1.58, p =。017)和甘油三酯水平升高(OR: 1.30 95% CI: 1.04-1.57, p =。033)在调整传统心血管危险因素后。此外，Aβ40水平与TyG发病几率增加相关（OR: 1.26 95% CI: 1.03-1.57, p =）。042)和糖尿病存在的几率增加(OR: 1.35 95% CI: 1.04-1.76, p =。（18）在调整了年龄、性别、吸烟状况、高血压和血脂异常后。Aβ40水平升高与BARD评分≥2的几率增加相关（OR: 1.41 95% CI: 1.04-2.04, p =）。045)在调整传统心血管危险因素后。结论：我们的研究结果提示Aβ40肽与代谢特征和代谢性疾病的风险相关。未来的纵向研究有必要确定Aβ40对代谢性疾病的发生和进展的预后价值。
{"title":"Amyloid-beta (1–40) peptide is associated with systemic metabolic health","authors":"Kateryna Sopova, Dimitrios Delialis, Evmorfia Aivalioti, Georgios Georgiopoulos, Stravros Athanasopoulos, Georgios Zervas, Christina Konstantaki, Marco Sachse, Martin Sigl, Daniel Duerschmied, Simon Tual-Chalot, Kimon Stamatelopoulos, Konstantinos Stellos","doi":"10.1111/eci.70171","DOIUrl":"10.1111/eci.70171","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Amyloid-beta 1–40 peptide (Aβ40) has recently emerged as a blood-based biomarker of cardiovascular disease (CVD). However, whether plasma levels of Aβ40 are associated with metabolic traits in humans without established CVD remains poorly understood.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Aβ40 was measured in plasma by ELISA and metabolic traits (waist circumference, fasting triglycerides, fasting HDL cholesterol and fasting glucose) were determined in a general population (<i>n</i> = 449) of individuals who did not have clinically overt CVD. Triglyceride-glucose index (TyG) was used to calculate the risk for insulin resistance. BARD score was used to calculate the risk for metabolic liver disease.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Aβ40 levels were associated with the presence of metabolic syndrome (OR: 1.41 95% CI: 1.13–1.76, <i>p</i> = .003), and with higher odds for increasing incidence of metabolic syndrome components, characterized by decreased HDL-C levels (OR: 1.31 95% CI: 1.03–1.58, <i>p</i> = .017) and increased triglyceride levels (OR: 1.30 95% CI: 1.04–1.57, <i>p</i> = .033) after adjustment for traditional cardiovascular risk factors. Further, Aβ40 levels were associated with increased odds for TyG (OR: 1.26 95% CI: 1.03–1.57, <i>p</i> = .042) and increased odds for the presence of diabetes mellitus (OR: 1.35 95% CI: 1.04–1.76, <i>p</i> = .018) after adjustment for age and sex, smoking status, hypertension and dyslipidemia. Increased Aβ40 levels were associated with increased odds for BARD score ≥2 (OR: 1.41 95% CI: 1.04–2.04, <i>p</i> = .045) after adjustment for traditional cardiovascular risk factors.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Our findings suggest that Aβ40 peptide is associated with metabolic traits and risk for metabolic disease. Future longitudinal studies are warranted to determine the prognostic value of Aβ40 for the development and progression of metabolic diseases.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12013,"journal":{"name":"European Journal of Clinical Investigation","volume":"56 1","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12827831/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145917410","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}
Óscar Fonseca, Paulo J. Oliveira, Martina U. Muckenthaler, Ana C. Moreira, M. Salomé Gomes
Background
The liver is widely recognized as a central hub for metabolic processes. Additionally, it plays critical roles in immune responses and in the regulation of iron homeostasis. Liver disorders have a profound impact on overall health and often involve iron dysregulation. Different cell types contribute to the completion of the plethora of different liver functions, including iron homeostasis.
Methods
A comprehensive literature search was conducted to identify recent advances in the understanding of the main mechanisms of intercellular communication in the liver that determine iron regulation and flow in health and disease.
Results
Hepatocytes are crucial to secure proper and safe iron storage and to regulate systemic iron distribution. For that, they contribute with the production of key proteins, such as ferritin, transferrin and hepcidin. Hepcidin production by hepatocytes is regulated by other liver cell types, including endothelial cells and macrophages. Macrophages significantly contribute to iron homeostasis by recycling iron from erythrocytes. Moreover, they modulate the physiology of other liver cells through the production of cytokines. Paracrine communication, involving soluble factors, extracellular vesicles or mitochondrial transfer, has been described as important mechanisms of iron regulation in the liver, critically contributing to its pathophysiology. Juxtacrine communication involving gap junctions or tunnelling nanotubes are mechanisms under investigation. This review highlights the recent advances in our understanding of the main mechanisms of intercellular communication in the liver that determine iron regulation and flow in health and disease.
Conclusions
Iro-nrelated communication between different liver cell types is fundamental to maintaining its proper function.
{"title":"Iron-related intercellular communication in the liver: Main players and mechanisms","authors":"Óscar Fonseca, Paulo J. Oliveira, Martina U. Muckenthaler, Ana C. Moreira, M. Salomé Gomes","doi":"10.1111/eci.70168","DOIUrl":"10.1111/eci.70168","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>The liver is widely recognized as a central hub for metabolic processes. Additionally, it plays critical roles in immune responses and in the regulation of iron homeostasis. Liver disorders have a profound impact on overall health and often involve iron dysregulation. Different cell types contribute to the completion of the plethora of different liver functions, including iron homeostasis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A comprehensive literature search was conducted to identify recent advances in the understanding of the main mechanisms of intercellular communication in the liver that determine iron regulation and flow in health and disease.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Hepatocytes are crucial to secure proper and safe iron storage and to regulate systemic iron distribution. For that, they contribute with the production of key proteins, such as ferritin, transferrin and hepcidin. Hepcidin production by hepatocytes is regulated by other liver cell types, including endothelial cells and macrophages. Macrophages significantly contribute to iron homeostasis by recycling iron from erythrocytes. Moreover, they modulate the physiology of other liver cells through the production of cytokines. Paracrine communication, involving soluble factors, extracellular vesicles or mitochondrial transfer, has been described as important mechanisms of iron regulation in the liver, critically contributing to its pathophysiology. Juxtacrine communication involving gap junctions or tunnelling nanotubes are mechanisms under investigation. This review highlights the recent advances in our understanding of the main mechanisms of intercellular communication in the liver that determine iron regulation and flow in health and disease.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Iro-nrelated communication between different liver cell types is fundamental to maintaining its proper function.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12013,"journal":{"name":"European Journal of Clinical Investigation","volume":"56 1","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12827848/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145917386","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}
Sandra Vladimirov, Tamara Gojković, Nataša Bogavac-Stanojevic, Aleksandra Zeljković, Vesna Spasojević-Kalimanovska
Background
Sex-related differences in cholesterol metabolism may influence cardiovascular disease risk and outcomes. Understanding these differences in the context of SCORE2 predicted cardiovascular risk could support the implementation of sex-specific prevention and therapeutic protocols.
Methods
In this cross-sectional study, serum levels of non-cholesterol sterols, desmosterol, lathosterol (markers of cholesterol synthesis) and campesterol and β-sitosterol (markers of cholesterol absorption) were analysed in 100 healthy adults (50 men, 50 women). CVD risk was assessed with SCORE2. Principal component analysis (PCA) was used to identify latent structures linking cholesterol homeostasis to sex and cardiovascular risk. K-means clustering and linear regression were used to examine sex-specific and SCORE2-related patterns.
Results
Men had significantly higher cholesterol synthesis markers, while women had higher cholesterol absorption markers. The desmosterol/lathosterol ratio was significantly higher in women, indicating preferential utilization of the Bloch biosynthetic pathway. PCA revealed three principal components (PCs), with PC1 distinguishing sex (p < .0001) and PC2 correlating with SCORE2 risk category (p < .0001). Cluster analysis based on PC1 and PC2 revealed two groups that correlated strongly with biological sex (χ2 = 18.7, p < .0001). Elevated synthesis and absorption markers were associated with a higher risk according to SCORE2, especially in women.
Conclusions
Our results showed higher cholesterol synthesis in men and higher cholesterol absorption in women. PC1 reflected sex-specific differences, while PC2 was sex-independent but SCORE2-dependent. D/L, L, K, B, which contributed to PC3, accounted for a substantial proportion of the variance encompassing both sex and SCORE2 risk. These findings suggest differences in cholesterol metabolism between sexes, with possible implications for future CVD risk management.
{"title":"Sex differences in cholesterol metabolism and their association with SCORE2 cardiovascular risk based on cholesterol homeostasis markers and principal component analysis","authors":"Sandra Vladimirov, Tamara Gojković, Nataša Bogavac-Stanojevic, Aleksandra Zeljković, Vesna Spasojević-Kalimanovska","doi":"10.1111/eci.70169","DOIUrl":"10.1111/eci.70169","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Sex-related differences in cholesterol metabolism may influence cardiovascular disease risk and outcomes. Understanding these differences in the context of SCORE2 predicted cardiovascular risk could support the implementation of sex-specific prevention and therapeutic protocols.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>In this cross-sectional study, serum levels of non-cholesterol sterols, desmosterol, lathosterol (markers of cholesterol synthesis) and campesterol and β-sitosterol (markers of cholesterol absorption) were analysed in 100 healthy adults (50 men, 50 women). CVD risk was assessed with SCORE2. Principal component analysis (PCA) was used to identify latent structures linking cholesterol homeostasis to sex and cardiovascular risk. K-means clustering and linear regression were used to examine sex-specific and SCORE2-related patterns.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Men had significantly higher cholesterol synthesis markers, while women had higher cholesterol absorption markers. The desmosterol/lathosterol ratio was significantly higher in women, indicating preferential utilization of the Bloch biosynthetic pathway. PCA revealed three principal components (PCs), with PC1 distinguishing sex (<i>p</i> < .0001) and PC2 correlating with SCORE2 risk category (<i>p</i> < .0001). Cluster analysis based on PC1 and PC2 revealed two groups that correlated strongly with biological sex (<i>χ</i><sup>2</sup> = 18.7, <i>p</i> < .0001). Elevated synthesis and absorption markers were associated with a higher risk according to SCORE2, especially in women.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Our results showed higher cholesterol synthesis in men and higher cholesterol absorption in women. PC1 reflected sex-specific differences, while PC2 was sex-independent but SCORE2-dependent. D/L, L, K, B, which contributed to PC3, accounted for a substantial proportion of the variance encompassing both sex and SCORE2 risk. These findings suggest differences in cholesterol metabolism between sexes, with possible implications for future CVD risk management.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12013,"journal":{"name":"European Journal of Clinical Investigation","volume":"56 1","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145899579","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}
Gabriela O. Girón, Sergi Otero, Panagiota Efstathia Nikolaou, Sebastià Alcover, Lisaidy Ramos-Regalado, Carlos Zaragoza, Luca Liberale, María Borrell-Pages, Teresa Padró, Rosa Suades, Gemma Vilahur
Background
A significant proportion of patients continue to experience cardiovascular (CV) events despite achieving recommended low-density lipoprotein cholesterol (LDL-C) targets, a phenomenon referred to as residual CV risk.
Methods
Clinical evidence from large outcome trials highlights the impact of residual risk on cardiovascular disease (CVD) burden, underscoring the need for therapeutic strategies beyond LDL-C lowering. Residual CV risk arises from diverse mechanisms, including persistent atherogenic dyslipidaemia [elevated triglyceride-rich lipoproteins (TRL), high triglycerides (TG), low high-density lipoprotein cholesterol (HDL-C) levels and increased apolipoprotein B (ApoB), Lipoprotein(a) (Lp[a]) and non-HDL-C], chronic inflammation, metabolic disorders and a prothrombotic state. These abnormalities continue to drive atherosclerotic progression in optimally treated patients, underscoring that managing residual CV risk requires a multifaceted approach.
Results
Lifestyle and dietary interventions remain foundational, targeting weight reduction, smoking cessation or adoption of a Mediterranean diet. Pharmacological options include statins (as first-line therapy), or the use of ezetimibe, or bempedoic acid since they both have complementary effects to LDL-C lowering. Emerging therapies, including proprotein convertase subtilisin/kexin type 9 (PCSK9), apolipoprotein C-III (ApoC3) and angiopoietin-like 3 (ANGPTL3) inhibitors, demonstrate potential efficacy in favourably modulating lipid profiles and targeting specific components of atherogenic dyslipidaemia (AD). Combination therapies tailored to individual lipid profiles show promise to reduce residual CV risk.
Conclusion
The following review aims to provide a comprehensive overview of the latest evidence on the factors driving residual CV risk and the therapeutic interventions available to treat atherogenic dyslipidaemia beyond LDL-C reduction.
{"title":"Atherogenic dyslipidaemia and residual cardiovascular risk: Understanding the link to heart disease","authors":"Gabriela O. Girón, Sergi Otero, Panagiota Efstathia Nikolaou, Sebastià Alcover, Lisaidy Ramos-Regalado, Carlos Zaragoza, Luca Liberale, María Borrell-Pages, Teresa Padró, Rosa Suades, Gemma Vilahur","doi":"10.1111/eci.70167","DOIUrl":"10.1111/eci.70167","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>A significant proportion of patients continue to experience cardiovascular (CV) events despite achieving recommended low-density lipoprotein cholesterol (LDL-C) targets, a phenomenon referred to as residual CV risk.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Clinical evidence from large outcome trials highlights the impact of residual risk on cardiovascular disease (CVD) burden, underscoring the need for therapeutic strategies beyond LDL-C lowering. Residual CV risk arises from diverse mechanisms, including persistent atherogenic dyslipidaemia [elevated triglyceride-rich lipoproteins (TRL), high triglycerides (TG), low high-density lipoprotein cholesterol (HDL-C) levels and increased apolipoprotein B (ApoB), Lipoprotein(a) (Lp[a]) and non-HDL-C], chronic inflammation, metabolic disorders and a prothrombotic state. These abnormalities continue to drive atherosclerotic progression in optimally treated patients, underscoring that managing residual CV risk requires a multifaceted approach.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Lifestyle and dietary interventions remain foundational, targeting weight reduction, smoking cessation or adoption of a Mediterranean diet. Pharmacological options include statins (as first-line therapy), or the use of ezetimibe, or bempedoic acid since they both have complementary effects to LDL-C lowering. Emerging therapies, including proprotein convertase subtilisin/kexin type 9 (PCSK9), apolipoprotein C-III (ApoC3) and angiopoietin-like 3 (ANGPTL3) inhibitors, demonstrate potential efficacy in favourably modulating lipid profiles and targeting specific components of atherogenic dyslipidaemia (AD). Combination therapies tailored to individual lipid profiles show promise to reduce residual CV risk.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>The following review aims to provide a comprehensive overview of the latest evidence on the factors driving residual CV risk and the therapeutic interventions available to treat atherogenic dyslipidaemia beyond LDL-C reduction.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12013,"journal":{"name":"European Journal of Clinical Investigation","volume":"56 1","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145892251","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}
Gonçalo José Martins Afonso, Carla Cavaleiro, Sofia Marlene Nunes, Francisco Pereira, Paulo Jorge Oliveira, Jorge Valero, Sandra Isabel Mota, Elisabete Ferreiro
Background: Urine-derived stem cells (UDSC) are an emerging, non-invasive source of human stem cells combining easy collection, broad accessibility and high patient compliance with multilineage differentiation capacity. However, key gaps remain in UDSC research, particularly in understanding sex-related differences and the lack of a validated cryopreservation protocol, a critical aspect for primary cells, given their variability in colony formation, proliferation rates and experimental timing. To address these limitations, this study aimed to establish, for the first time, a reliable protocol for UDSC cryopreservation and to explore potential sex-related differences, with a specific focus on glycolysis and mitochondrial respiration.
Methods: UDSC were isolated from urine samples of healthy donors (aged 27-50, 4 males and 4 females), cultured in 1:1 DMEM:KSFM supplemented with 10% fetal bovine serum and cryopreserved at passages 2-4 using the same medium with the sole addition of 5% dimethyl sulfoxide. Cells were evaluated for viability, apoptosis/necrosis, metabolic profile and multilineage differentiation potential. Comparisons were performed based on donor sex, as well as before and after cryopreservation.
Results: Male- and female-derived UDSC displayed no significant differences in viability and cell death or metabolic profile. Moreover, supervised and unsupervised machine learning methods were unable to discriminate between the two groups, allowing for pooled data analysis and improved statistical power. Similarly, fresh and cryopreserved UDSC displayed comparable viability, metabolic activity and multilineage differentiation relative to fresh cells, with no detectable differences in computational analyses.
Conclusions: These findings support UDSC adoption for biobanking, disease modelling and regenerative medicine.
{"title":"Advancing urine-derived stem cells: Cryopreservation validation and sex-specific metabolism.","authors":"Gonçalo José Martins Afonso, Carla Cavaleiro, Sofia Marlene Nunes, Francisco Pereira, Paulo Jorge Oliveira, Jorge Valero, Sandra Isabel Mota, Elisabete Ferreiro","doi":"10.1111/eci.70172","DOIUrl":"10.1111/eci.70172","url":null,"abstract":"<p><strong>Background: </strong>Urine-derived stem cells (UDSC) are an emerging, non-invasive source of human stem cells combining easy collection, broad accessibility and high patient compliance with multilineage differentiation capacity. However, key gaps remain in UDSC research, particularly in understanding sex-related differences and the lack of a validated cryopreservation protocol, a critical aspect for primary cells, given their variability in colony formation, proliferation rates and experimental timing. To address these limitations, this study aimed to establish, for the first time, a reliable protocol for UDSC cryopreservation and to explore potential sex-related differences, with a specific focus on glycolysis and mitochondrial respiration.</p><p><strong>Methods: </strong>UDSC were isolated from urine samples of healthy donors (aged 27-50, 4 males and 4 females), cultured in 1:1 DMEM:KSFM supplemented with 10% fetal bovine serum and cryopreserved at passages 2-4 using the same medium with the sole addition of 5% dimethyl sulfoxide. Cells were evaluated for viability, apoptosis/necrosis, metabolic profile and multilineage differentiation potential. Comparisons were performed based on donor sex, as well as before and after cryopreservation.</p><p><strong>Results: </strong>Male- and female-derived UDSC displayed no significant differences in viability and cell death or metabolic profile. Moreover, supervised and unsupervised machine learning methods were unable to discriminate between the two groups, allowing for pooled data analysis and improved statistical power. Similarly, fresh and cryopreserved UDSC displayed comparable viability, metabolic activity and multilineage differentiation relative to fresh cells, with no detectable differences in computational analyses.</p><p><strong>Conclusions: </strong>These findings support UDSC adoption for biobanking, disease modelling and regenerative medicine.</p>","PeriodicalId":12013,"journal":{"name":"European Journal of Clinical Investigation","volume":"56 1","pages":"e70172"},"PeriodicalIF":3.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12834848/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146051004","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}
Alexander Schmitt, Ibrahim Akin, Marielen Reinhardt, Noah Abel, Felix Lau, Jonas Dudda, Mohammad Abumayyaleh, Kathrin Weidner, Thomas Bertsch, Daniel Duerschmied, Michael Behnes, Tobias Schupp
Background
This study investigates the prognostic impact of albumin, the urea-to-albumin ratio (UAR), and albumin-to-creatinine ratio (ACR) in patients with heart failure with mildly reduced ejection fraction (HFmrEF), since hypoalbuminemia, renal disease and malnutrition often coincide with heart failure (HF).
Methods
Consecutive patients hospitalized with HFmrEF at one university medical centre were retrospectively included from 2016 to 2022. Patients were stratified into quartiles based on albumin, the UAR, and ACR. The primary endpoint was all-cause mortality at 30 months (median follow-up), key secondary endpoint was long-term HF-related rehospitalization.
Results
The study cohort comprised 2,061 patients with HFmrEF with a median albumin level of 32.4 g/L. Albumin levels, the UAR and ACR were predictive for the risk of long-term all-cause mortality, which was still observed after multivariable adjustment (albumin Q1 vs. Q4: HR = 2.260; 95% CI 1.623–3.148; p = .001 / UAR Q4 vs. Q1: HR = 1.507; 95% CI 1.071–2.119; p = .019/ACR Q1 vs. Q4: HR = 2.208; 95% CI 1.528–3.190; p = .001). However, neither albumin nor the UAR or ACR predicted the risk of HF-related rehospitalization (albumin Q1 vs. Q4: HR = 1.117; 95% CI .678–1.842; p = .664 / UAR Q4 vs. Q1: HR = 1.589; 95% CI .922–2.738; p = .095 / ACR Q1 vs. Q4: HR = 1.112; 95% CI .624–1.981; p = .720).
Conclusions
Hypoalbuminemia is common in hospitalized HFmrEF patients. Low albumin levels, ACRs, and elevated UARs independently predicted long-term all-cause mortality, but not HF-related rehospitalization. The UAR and ACR did not provide a clinically significant predictive advantage over albumin levels alone.
Trial Registration
ClinicalTrials.gov Identifier: NCT05603390 (date of registration: 10.10.2020)
背景：由于低白蛋白血症、肾脏疾病和营养不良常伴随心力衰竭（HF），本研究探讨了白蛋白、尿白蛋白比（UAR）和白蛋白与肌酐比（ACR）对心力衰竭伴轻度射血分数降低（HFmrEF）患者预后的影响。方法：回顾性纳入2016年至2022年在一所大学医疗中心连续住院的HFmrEF患者。根据白蛋白、UAR和ACR将患者分为四分位数。主要终点是30个月时的全因死亡率（中位随访），关键的次要终点是长期hf相关再住院。结果：研究队列包括2061例HFmrEF患者，中位白蛋白水平为32.4 g/L。白蛋白水平、UAR和ACR是长期全因死亡风险的预测指标，在多变量调整后仍可观察到(白蛋白Q1 vs. Q4: HR = 2.260; 95% CI 1.623-3.148; p =。001 / UAR Q4 vs. Q1: HR = 1.507；95% ci 1.071-2.119；p =。019/ACR Q1 vs. Q4: HR = 2.208；95% ci 1.528-3.190；p = .001)。然而，白蛋白、UAR或ACR均不能预测hf相关再住院的风险(白蛋白Q1 vs. Q4: HR = 1.117; 95% CI .678-1.842; p =。664 / UAR Q4 vs Q1: HR = 1.589；95% ci: 0.922 -2.738；p =。Q1 vs. Q4: HR = 1.112；95% ci为624-1.981；p = .720)。结论：低白蛋白血症在住院HFmrEF患者中很常见。低白蛋白水平、acr和uar升高独立预测长期全因死亡率，但不能预测hf相关的再住院。与单独的白蛋白水平相比，UAR和ACR没有提供临床显著的预测优势。试验注册：ClinicalTrials.gov标识符：NCT05603390（注册日期：10.10.2020）。
{"title":"Albumin, urea-to-albumin ratio, or the albumin-to-creatinine ratio to predict outcomes in heart failure with mildly reduced ejection fraction","authors":"Alexander Schmitt, Ibrahim Akin, Marielen Reinhardt, Noah Abel, Felix Lau, Jonas Dudda, Mohammad Abumayyaleh, Kathrin Weidner, Thomas Bertsch, Daniel Duerschmied, Michael Behnes, Tobias Schupp","doi":"10.1111/eci.70165","DOIUrl":"10.1111/eci.70165","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>This study investigates the prognostic impact of albumin, the urea-to-albumin ratio (UAR), and albumin-to-creatinine ratio (ACR) in patients with heart failure with mildly reduced ejection fraction (HFmrEF), since hypoalbuminemia, renal disease and malnutrition often coincide with heart failure (HF).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Consecutive patients hospitalized with HFmrEF at one university medical centre were retrospectively included from 2016 to 2022. Patients were stratified into quartiles based on albumin, the UAR, and ACR. The primary endpoint was all-cause mortality at 30 months (median follow-up), key secondary endpoint was long-term HF-related rehospitalization.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The study cohort comprised 2,061 patients with HFmrEF with a median albumin level of 32.4 g/L. Albumin levels, the UAR and ACR were predictive for the risk of long-term all-cause mortality, which was still observed after multivariable adjustment (albumin Q1 vs. Q4: HR = 2.260; 95% CI 1.623–3.148; <i>p</i> = .001 / UAR Q4 vs. Q1: HR = 1.507; 95% CI 1.071–2.119; <i>p</i> = .019/ACR Q1 vs. Q4: HR = 2.208; 95% CI 1.528–3.190; <i>p</i> = .001). However, neither albumin nor the UAR or ACR predicted the risk of HF-related rehospitalization (albumin Q1 vs. Q4: HR = 1.117; 95% CI .678–1.842; <i>p</i> = .664 / UAR Q4 vs. Q1: HR = 1.589; 95% CI .922–2.738; <i>p</i> = .095 / ACR Q1 vs. Q4: HR = 1.112; 95% CI .624–1.981; <i>p</i> = .720).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Hypoalbuminemia is common in hospitalized HFmrEF patients. Low albumin levels, ACRs, and elevated UARs independently predicted long-term all-cause mortality, but not HF-related rehospitalization. The UAR and ACR did not provide a clinically significant predictive advantage over albumin levels alone.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Trial Registration</h3>\u0000 \u0000 <p>ClinicalTrials.gov Identifier: NCT05603390 (date of registration: 10.10.2020)</p>\u0000 </section>\u0000 </div>","PeriodicalId":12013,"journal":{"name":"European Journal of Clinical Investigation","volume":"56 1","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12827846/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145843198","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}
Yiting Luo, Fan Yang, Yanlin He, Jin Lin, Weiqian Chen
Background
Giant cell arteritis (GCA) and (PMR) are inflammatory rheumatic disorders whose pathogenesis are unclear. The interleukin (IL)-6 receptor inhibitor is the first approved biologic agent for GCA and PMR, reducing relapse rates and cumulative glucocorticoid (GC) doses. Notably, IL-6, also a key pro-inflammatory factor secreted by senescent cells, contributes to tissue aging and chronic inflammation. We aim to explore the role of senescence-associated secretory phenotype (SASP) in the pathogenesis of GCA and PMR.
Methods
A narrative synthesis of literature published in the last 10 years was conducted utilizing keywords such as “Giant cell arteritis,” “Polymyalgia rheumatica,” “cellular senescence,” “senescence-associated secretory phenotype,” or “aging”.
Results
Evidence links cellular senescence and SASP to the pathogenesis of GCA and PMR, with key components like IL-6, IL-1β, and matrix metalloproteinases (MMPs) driving inflammation and tissue damage. We highlight how key SASP components, such as IL-6, IL-1β, and MMPs promote inflammation and tissue damage in GCA and PMR. Targeting SASP factors (senomorphics) or selectively eliminating senescent cells (senolytics) offers therapeutic potential. Further research into the mechanisms linking senescence to disease phenotypes is needed to develop effective therapies that mitigate disease progression and improve clinical outcomes.
Conclusion
We demonstrated age-related stress and senescence in the pathogenesis of GCA and PMR. We provide an overview of senomorphics, which have shown promise in clinical trials, and emphasize the need for further research to develop effective therapies.
{"title":"Cellular senescence in giant cell arteritis and polymyalgia rheumatica: From mechanisms to therapeutic opportunities","authors":"Yiting Luo, Fan Yang, Yanlin He, Jin Lin, Weiqian Chen","doi":"10.1111/eci.70166","DOIUrl":"10.1111/eci.70166","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Giant cell arteritis (GCA) and (PMR) are inflammatory rheumatic disorders whose pathogenesis are unclear. The interleukin (IL)-6 receptor inhibitor is the first approved biologic agent for GCA and PMR, reducing relapse rates and cumulative glucocorticoid (GC) doses. Notably, IL-6, also a key pro-inflammatory factor secreted by senescent cells, contributes to tissue aging and chronic inflammation. We aim to explore the role of senescence-associated secretory phenotype (SASP) in the pathogenesis of GCA and PMR.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A narrative synthesis of literature published in the last 10 years was conducted utilizing keywords such as “Giant cell arteritis,” “Polymyalgia rheumatica,” “cellular senescence,” “senescence-associated secretory phenotype,” or “aging”.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Evidence links cellular senescence and SASP to the pathogenesis of GCA and PMR, with key components like IL-6, IL-1β, and matrix metalloproteinases (MMPs) driving inflammation and tissue damage. We highlight how key SASP components, such as IL-6, IL-1β, and MMPs promote inflammation and tissue damage in GCA and PMR. Targeting SASP factors (senomorphics) or selectively eliminating senescent cells (senolytics) offers therapeutic potential. Further research into the mechanisms linking senescence to disease phenotypes is needed to develop effective therapies that mitigate disease progression and improve clinical outcomes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>We demonstrated age-related stress and senescence in the pathogenesis of GCA and PMR. We provide an overview of senomorphics, which have shown promise in clinical trials, and emphasize the need for further research to develop effective therapies.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12013,"journal":{"name":"European Journal of Clinical Investigation","volume":"56 1","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145827138","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}
Moattar Raza Rizvi, Ankita Sharma, Faizan Z. Kashoo, Abdul Rahim Shaik, Mohamed K. Seyam, Basant Hamdy Elrefaey, Zeinab A. Ali, Ahmed Abdullah Asiri, Irshad Ahmad, Fuzail Ahmad
<div> <section> <h3> Background</h3> <p>Elderly frailty is a multifaceted clinical condition with diminished physiological reserves and increased stress susceptibility. It increases disability, hospitalization and mortality rates, requiring multidomain therapy. Structured physical-activity-based medical treatment can reduce frailty in physical, mental and emotional areas. This assessment distinguishes outcomes among validated frailty models (phenotype-based vs. deficit-accumulation) to highlight model-specific effects.</p> </section> <section> <h3> Objectives</h3> <p>The present systematic review assesses the efficacy of structured physical-activity-based physiotherapy in reducing frailty and enhancing physical, cognitive and emotional outcomes in persons aged ≥60. It highlights a critical data gap neglected by past studies by distinguishing intervention effects across proven frailty models (phenotype-based and deficit-accumulation frameworks).</p> </section> <section> <h3> Methodology</h3> <p>The review used PRISMA criteria and the PICOS framework to find relevant papers published between January 2002 and December 2025. PubMed, Scopus, Cochrane Library and Embase were searched. RCTs and longitudinal cohort studies on physiotherapy or structured physical-activity therapies (e.g. resistance training, aerobic conditioning, balance exercises, multimodal programs) for individuals aged ≥60 years were eligible. Frailty, physical performance and quality of life were evaluated. Cochrane Risk of Bias 2.0 was used for randomised studies and ROBINS-I for non-randomised designs.</p> </section> <section> <h3> Results</h3> <p>36 trials covered varied physiotherapy and structured physical-activity regimens. Participants, mostly aged ≥60, were mostly women (approximately two-thirds of the sample). The majority of investigations found that resistance training increased muscle strength and decreased frailty by 20%–35%. Exercises involving balance reduced fall risk by 25%–35%, while aerobic workouts improved gait and cardiovascular fitness. Multimodal interventions reversed frailty in 41%–50% of individuals and improved cognitive and emotional outcomes the highest. Physical performance, quality of life and functional independence improved across frailty models in weighted summaries.</p> </section> <section> <h3> Conclusion</h3> <p>Structured physical-activity-based physiotherapy therapies, especially multimodal programs, reduce frailty and enhance physical, cognitive and emotional resilience in older persons, highlighting their value in comprehensive geriatric care.</p>
背景：老年虚弱是一种多方面的临床状况，伴有生理储备减少和应激易感性增加。它增加了残疾率、住院率和死亡率，需要多领域治疗。有组织的以身体活动为基础的医疗可以减少身体、精神和情感方面的脆弱。该评估区分了经过验证的脆弱性模型（基于表型与缺陷积累）的结果，以突出模型特异性效应。目的：本系统综述评估结构化体力活动为基础的物理治疗在减少虚弱和提高身体，认知和情绪结果≥60岁的人的疗效。通过区分已证实的脆弱性模型（基于表型和缺陷积累框架）的干预效果，它突出了过去研究所忽视的一个关键数据缺口。方法：采用PRISMA标准和PICOS框架查找2002年1月至2025年12月期间发表的相关论文。检索PubMed、Scopus、Cochrane Library和Embase。适用于年龄≥60岁的个体的物理治疗或结构化体力活动治疗（如阻力训练、有氧调节、平衡运动、多模式项目）的随机对照试验和纵向队列研究。对虚弱程度、身体表现和生活质量进行评估。随机研究采用Cochrane Risk of Bias 2.0，非随机设计采用ROBINS-I。结果：36项试验涵盖了各种物理治疗和有组织的体育活动方案。参与者大多数年龄≥60岁，大多数是女性（约占样本的三分之二）。大多数调查发现，阻力训练可以增加20%-35%的肌肉力量，减少虚弱。平衡运动可以降低25%-35%的跌倒风险，而有氧运动可以改善步态和心血管健康。多模式干预在41%-50%的个体中逆转了虚弱，对认知和情绪结果的改善最大。在加权总结中，虚弱模型的身体表现、生活质量和功能独立性得到改善。结论：结构化的以身体活动为基础的物理治疗疗法，特别是多模式方案，可以减少老年人的脆弱性，提高他们的身体、认知和情绪恢复能力，突出了他们在综合老年护理中的价值。
{"title":"Reversing frailty: The transformative effects of structured physical-activity-based physiotherapy on physical, cognitive and emotional health in older adults—An evidence-based systematic review","authors":"Moattar Raza Rizvi, Ankita Sharma, Faizan Z. Kashoo, Abdul Rahim Shaik, Mohamed K. Seyam, Basant Hamdy Elrefaey, Zeinab A. Ali, Ahmed Abdullah Asiri, Irshad Ahmad, Fuzail Ahmad","doi":"10.1111/eci.70158","DOIUrl":"10.1111/eci.70158","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Elderly frailty is a multifaceted clinical condition with diminished physiological reserves and increased stress susceptibility. It increases disability, hospitalization and mortality rates, requiring multidomain therapy. Structured physical-activity-based medical treatment can reduce frailty in physical, mental and emotional areas. This assessment distinguishes outcomes among validated frailty models (phenotype-based vs. deficit-accumulation) to highlight model-specific effects.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>The present systematic review assesses the efficacy of structured physical-activity-based physiotherapy in reducing frailty and enhancing physical, cognitive and emotional outcomes in persons aged ≥60. It highlights a critical data gap neglected by past studies by distinguishing intervention effects across proven frailty models (phenotype-based and deficit-accumulation frameworks).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methodology</h3>\u0000 \u0000 <p>The review used PRISMA criteria and the PICOS framework to find relevant papers published between January 2002 and December 2025. PubMed, Scopus, Cochrane Library and Embase were searched. RCTs and longitudinal cohort studies on physiotherapy or structured physical-activity therapies (e.g. resistance training, aerobic conditioning, balance exercises, multimodal programs) for individuals aged ≥60 years were eligible. Frailty, physical performance and quality of life were evaluated. Cochrane Risk of Bias 2.0 was used for randomised studies and ROBINS-I for non-randomised designs.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>36 trials covered varied physiotherapy and structured physical-activity regimens. Participants, mostly aged ≥60, were mostly women (approximately two-thirds of the sample). The majority of investigations found that resistance training increased muscle strength and decreased frailty by 20%–35%. Exercises involving balance reduced fall risk by 25%–35%, while aerobic workouts improved gait and cardiovascular fitness. Multimodal interventions reversed frailty in 41%–50% of individuals and improved cognitive and emotional outcomes the highest. Physical performance, quality of life and functional independence improved across frailty models in weighted summaries.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Structured physical-activity-based physiotherapy therapies, especially multimodal programs, reduce frailty and enhance physical, cognitive and emotional resilience in older persons, highlighting their value in comprehensive geriatric care.</p>","PeriodicalId":12013,"journal":{"name":"European Journal of Clinical Investigation","volume":"56 1","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145803504","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}
Teresa Padro, Natàlia Muñoz-García, Marta Fanlo-Maresma, Virginia Esteve-Luque, Paula Cabré-Fernandez, Gemma Vilahur, Antoni Riera-Mestre, Lina Badimon, Xavier Pintó
Background
Emerging evidence demonstrates a J-shaped relationship between HDL-C levels and atherosclerotic cardiovascular disease (ASCVD) with very high HDL-C concentrations paradoxically associated with increased ASCVD events. This study aims to determine whether individuals with very high HDL-C (>80 mg/dL) and ASCVD exhibit altered HDL composition and impaired HDL functionality.
Methods
We investigated the HDL profile and functionality in 49 subjects (mean age: 62 ± 2 years, 83% female) with very high HDL-C levels (>80 mg/dL), including 23 with ASCVD. All ASCVD patients and 46% of those without ASCVD (non-ASCVD) were on lipid-lowering treatment.
Results
Plasma atherogenic lipoprotein-cholesterol levels were significantly lower in ASCVD patients than in those without ASCVD, despite matched HDL-C levels. CEC differences were evident after tertile stratification, with ASCVD participants overrepresented in the lowest tertile and showing lower median [IQR] CEC than non-ASCVD (p = 0.030). Total radical-trapping antioxidative potential showed no significant group differences in HDL ability to inhibit copper-induced LDL oxidation. However, basal HDL oxidative level was significantly higher in the ASCVD compared with the non-ASCVD group (p = 0.007). Inflammatory glycoproteins were inversely associated with CEC and HDL-C levels in ASCVD patients, but not in non-ASCVD patients. By NMR, mean HDL particle diameter did not differ between groups, yet ASCVD patients had fewer percent of large HDL particles compared to the non-ASCVD (0.84 ± 0.02% vs. 0.91 ± 0.02%; p = 0.034) and a trend toward more small particles. HDL-C content increased with particle size in ASCVD (p = 0.008; r = 0.531), but not in non-ASCVD, while HDL-TG levels did not differ across tertiles. Functional cell-based assays showed attenuated endothelial proliferation (normalized Cell-Index) in ASCVD compared with non-ASCVD, most evident in the largest HDL particle tertile.
Conclusions
These findings suggest that HDL functionality and particle distribution may offer more clinically relevant insights into cardiovascular risk than plasma HDL-C concentrations alone, particularly in individuals with very high HDL-C levels.
{"title":"HDL function and composition in atherothrombotic cardiovascular disease with very high HDL-C","authors":"Teresa Padro, Natàlia Muñoz-García, Marta Fanlo-Maresma, Virginia Esteve-Luque, Paula Cabré-Fernandez, Gemma Vilahur, Antoni Riera-Mestre, Lina Badimon, Xavier Pintó","doi":"10.1111/eci.70159","DOIUrl":"10.1111/eci.70159","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Emerging evidence demonstrates a J-shaped relationship between HDL-C levels and atherosclerotic cardiovascular disease (ASCVD) with very high HDL-C concentrations paradoxically associated with increased ASCVD events. This study aims to determine whether individuals with very high HDL-C (>80 mg/dL) and ASCVD exhibit altered HDL composition and impaired HDL functionality.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We investigated the HDL profile and functionality in 49 subjects (mean age: 62 ± 2 years, 83% female) with very high HDL-C levels (>80 mg/dL), including 23 with ASCVD. All ASCVD patients and 46% of those without ASCVD (non-ASCVD) were on lipid-lowering treatment.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Plasma atherogenic lipoprotein-cholesterol levels were significantly lower in ASCVD patients than in those without ASCVD, despite matched HDL-C levels. CEC differences were evident after tertile stratification, with ASCVD participants overrepresented in the lowest tertile and showing lower median [IQR] CEC than non-ASCVD (<i>p</i> = 0.030). Total radical-trapping antioxidative potential showed no significant group differences in HDL ability to inhibit copper-induced LDL oxidation. However, basal HDL oxidative level was significantly higher in the ASCVD compared with the non-ASCVD group (<i>p</i> = 0.007). Inflammatory glycoproteins were inversely associated with CEC and HDL-C levels in ASCVD patients, but not in non-ASCVD patients. By NMR, mean HDL particle diameter did not differ between groups, yet ASCVD patients had fewer percent of large HDL particles compared to the non-ASCVD (0.84 ± 0.02% vs. 0.91 ± 0.02%; <i>p</i> = 0.034) and a trend toward more small particles. HDL-C content increased with particle size in ASCVD (<i>p</i> = 0.008; <i>r</i> = 0.531), but not in non-ASCVD, while HDL-TG levels did not differ across tertiles. Functional cell-based assays showed attenuated endothelial proliferation (normalized Cell-Index) in ASCVD compared with non-ASCVD, most evident in the largest HDL particle tertile.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>These findings suggest that HDL functionality and particle distribution may offer more clinically relevant insights into cardiovascular risk than plasma HDL-C concentrations alone, particularly in individuals with very high HDL-C levels.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12013,"journal":{"name":"European Journal of Clinical Investigation","volume":"56 1","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12827843/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145780501","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}
Controlled Human Infection Models (CHIMs) offer a powerful approach to expedite vaccine development by enabling early evaluation of vaccine candidate efficacy and immune responses. Their role is increasingly relevant for neglected tropical diseases (NTDs), where traditional trial approaches may be slow, costly, or unfeasible. This review explores the scientific, ethical and translational dimensions of CHIMs, with a focus on the recently developed Leishmania major CHIM for cutaneous leishmaniasis (CL).
Methods
A narrative synthesis of peer-reviewed literature and regulatory guidance documents published over the past two decades was conducted, with additional insights drawn from original fieldwork and the first-in-human sand fly-transmitted CHIM for CL. Considerations included CHIM design principles, immunological outcomes, safety considerations and translational utility, including integration with omics and early phase trials.
Results
CHIMs provide early efficacy data, help identify immune correlates of protection and facilitate the prioritisation of vaccine candidates. The Leishmania major CHIM demonstrated safety, high participant acceptability and revealed insights into lesion kinetics and host–parasite interactions. Ethical and regulatory frameworks remain heterogeneous across regions, limiting scalability. Barriers to CHIM deployment in low- and middle-income countries include infrastructure, governance and community engagement challenges.
Conclusions
CHIMs represent a critical translational tool for NTD vaccine research. Lessons from the CL CHIM underscore the potential and challenges of broader implementation. Harmonised regulation, ethical innovation and global collaboration will be essential for future impact.
{"title":"Harnessing controlled human infection models to accelerate vaccine development for neglected tropical diseases: Lessons from leishmaniasis","authors":"Vivak Parkash","doi":"10.1111/eci.70160","DOIUrl":"10.1111/eci.70160","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Controlled Human Infection Models (CHIMs) offer a powerful approach to expedite vaccine development by enabling early evaluation of vaccine candidate efficacy and immune responses. Their role is increasingly relevant for neglected tropical diseases (NTDs), where traditional trial approaches may be slow, costly, or unfeasible. This review explores the scientific, ethical and translational dimensions of CHIMs, with a focus on the recently developed <i>Leishmania major</i> CHIM for cutaneous leishmaniasis (CL).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A narrative synthesis of peer-reviewed literature and regulatory guidance documents published over the past two decades was conducted, with additional insights drawn from original fieldwork and the first-in-human sand fly-transmitted CHIM for CL. Considerations included CHIM design principles, immunological outcomes, safety considerations and translational utility, including integration with omics and early phase trials.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>CHIMs provide early efficacy data, help identify immune correlates of protection and facilitate the prioritisation of vaccine candidates. The <i>Leishmania major</i> CHIM demonstrated safety, high participant acceptability and revealed insights into lesion kinetics and host–parasite interactions. Ethical and regulatory frameworks remain heterogeneous across regions, limiting scalability. Barriers to CHIM deployment in low- and middle-income countries include infrastructure, governance and community engagement challenges.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>CHIMs represent a critical translational tool for NTD vaccine research. Lessons from the CL CHIM underscore the potential and challenges of broader implementation. Harmonised regulation, ethical innovation and global collaboration will be essential for future impact.</p>\u0000 </section>\u0000 </div>","PeriodicalId":12013,"journal":{"name":"European Journal of Clinical Investigation","volume":"56 1","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12827841/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145773921","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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