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AIMS: PCSK9 inhibition intensively lowers low density lipoprotein cholesterol and is well tolerated in adults and paediatric patients with familial hypercholesterolaemia (FH). HAUSER-RCT showed that 24 weeks of treatment with evolocumab in paediatric patients did not affect cognitive function. This study determined the effects of 80 additional weeks of evolocumab treatment on cognitive function in paediatric patients with heterozygous FH. METHODS AND RESULTS: HAUSER-OLE was an 80-week open-label extension of HAUSER-RCT, a randomized, double-blind, 24-week trial evaluating the efficacy and safety of evolocumab in paediatric patients (ages 10-17 years) with FH. During the OLE, all patients received monthly 420 mg subcutaneous evolocumab injections. Tests of psychomotor function, attention, visual learning, and executive function were administered at baseline and Weeks 24 and 80 of the OLE. Changes over time were analysed descriptively and using analysis of covariance. Cohen's d statistic was used to evaluate the magnitude of treatment effects. Analysis of covariance results indicated no decrease in performance across visits during 80 weeks of evolocumab treatment for Groton Maze Learning, One Card Learning accuracy, Identification speed, or Detection speed (all P > 0.05). Performance on all tasks was similar for those who received placebo or evolocumab in the RCT (all P > 0.05). For all tests, the least square mean differences between patients who received placebo vs. evolocumab in the parent study were trivial (all Cohen's d magnitude < 0.2). CONCLUSION: In paediatric patients with FH, 80 weeks of open-label evolocumab treatment had no negative impact on cognitive function. REGISTRATION: ClinicalTrials.gov identifier: NCT02624869.

Some children are born with a genetic disorder that causes high cholesterol, which leads to heart disease. Children with high cholesterol can be treated with evolocumab, a medication that lowers blood cholesterol. Because cholesterol is important for development and adequate function of the brain, there is a concern that lowering cholesterol in children may affect mental ability. In this study, we tested whether treating children with evolocumab for 80 weeks affected mental ability in performing several tasks. A battery of tests that measure executive function (Groton Maze Learning Test), visual learning (One Card Learning Test), visual attention (Identification Test), and psychomotor function (Detection Test) showed no decrease in performance across visits during 80 weeks of evolocumab treatment. Performance on all tasks was similar for the children who received placebo for the first 24 weeks then received evolocumab for an additional 80 weeks (placebo/evolocumab) and those who received evolocumab for 24 weeks then received evolocumab for an additional 80 weeks (evolocumab/evolocumab).

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BACKGROUND: The HAUSER-RCT study showed that 24 weeks of evolocumab (a proprotein convertase subtilisin/kexin type 9 [PCSK9] inhibitor) in paediatric patients with heterozygous familial hypercholesterolaemia was safe and improved lipid parameters compared to placebo. Here, we aimed to evaluate the safety and efficacy of evolocumab in this population for an additional 80 weeks. METHODS: HAUSER-OLE was an 80-week, single-arm, open-label extension of HAUSER-RCT, a randomised controlled trial, and was conducted at 46 centres in 23 countries. Paediatric patients aged 10-17 years with heterozygous familial hypercholesterolaemia who completed 24 weeks of monthly treatment with subcutaneously administered placebo or 420 mg evolocumab in HAUSER-RCT with no serious treatment-emergent adverse events were eligible to enrol in HAUSER-OLE. All patients received open-label subcutaneous evolocumab 420 mg monthly with background statins with or without ezetimibe for 80 additional weeks. The primary endpoint was treatment-emergent adverse events. Efficacy was evaluated by changes in lipids from the baseline of HAUSER-RCT to the end of HAUSER-OLE (104 weeks). This study is registered with ClinicalTrials.gov (NCT02624869) and is now completed. FINDINGS: Between Sept 10, 2016, and Nov 25, 2019, 157 patients were enrolled in HAUSER-RCT and received randomised treatment; 150 continued to HAUSER-OLE, received evolocumab treatment, and were included in the full analysis set, presented here. 146 (97%) of 150 patients completed the open-label extension. The incidence of treatment-emergent adverse events in HAUSER-OLE was 70% (105 of 150). Overall, the most common treatment-emergent adverse events were nasopharyngitis (22 [15%] of 150), headache (14 [9%]), and influenza-like illness (13 [9%]). Serious treatment-emergent adverse events occurred in four (3%) of 150 patients (perforated appendicitis and peritonitis, wrist fracture, anorexia nervosa, and headache); none was considered related to evolocumab. No treatment-emergent adverse events led to treatment discontinuation. At week 80, the mean percentage change from baseline in LDL cholesterol was -35·3% (SD 28·0). INTERPRETATION: After 80 weeks of treatment, evolocumab was safe, well tolerated, and led to sustained reductions in LDL cholesterol in paediatric patients with heterozygous familial hypercholesterolaemia. When lipid goals cannot be achieved with conventional treatments, evolocumab is an effective add-on therapy in paediatric patients. FUNDING: Amgen. TRANSLATIONS: For the French, Spanish, Spanish, Portuguese, Italian and Dutch translations of the abstract see Supplementary Materials section.

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Resumen: La Red de Editores de la Sociedad Europea de Cardiología (ESC, por su sigla en inglés) constituye un foro dinámico dedicado a discusiones editoriales y respalda las recomendaciones del Comité Internacional de Editores de Revistas Médicas (ICMJE, por su sigla en inglés) destinadas a mejorar la calidad científica de las revistas biomédicas. La paternidad literaria confiere crédito, además de importantes recompensas académicas. Recientemente, sin embargo, el ICMJE ha destacado que la autoría también exige que los autores sean responsables y se hagan cargo de lo que publican. Estas cuestiones ahora están cubiertas por el nuevo (cuarto) criterio para la autoría. Los autores deben aceptar hacerse responsables de lo que escriben y garantizar un adecuado enfoque de las cuestiones concernientes a la precisión e integridad de todo el trabajo. Esta revisión analiza las implicancias de este cambio de paradigma en los requisitos de autoría con el objetivo de aumentar la conciencia sobre las buenas prácticas científicas y editoriales.

Summary: The Editors´ Network of the European Society of Cardiology provides a dynamic forum for editorial discussions and endorses the recommendations of the International Committee of Medical Journal Editors to improve the scientific quality of biomedical journals. Authorship confers credit and important academic rewards. Recently, however, the International Committee of Medical Journal Editors emphasized that authorship also requires responsibility and accountability. These issues are now covered by the new (fourth) criterion for authorship. Authors should agree to be accountable and ensure that questions regarding the accuracy and integrity of the entire work will be appropriately addressed. This review discusses the implications of this paradigm shift on authorship requirements with the aim of increasing awareness on good scientific and editorial practices.

Resumo: A Rede de Editores da Sociedade Europeia de Cardiologia é um fórum dinâmico para discussões editoriais e apoia as recomendações do Comitê Internacional de Editores de Revistas Médicas, visando melhorar a qualidade científica das revistas biomédicas. A autoria confere crédito, além de importantes recompensas acadêmicas. Recentemente, no entanto, o Comitê Internacional de Editores de Revistas Médicas enfatizou que a autoria também requer que os autores sejam responsáveis do que escrevem e se encarreguem do que publicam. Essas questões agora estão cobertas pelo novo (quarto) critério de autoria. Os autores devem concordar em ser responsáveis e garantir que as questões relativas à precisão e integridade de todo o trabalho sejam abordadas de maneira apropriada. Esta revisão discute as implicações dessa mudança de paradigma nos requisitos de autoria, com o objetivo de aumentar a conscientização sobre as boas práticas científicas e editoriais.

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The International Committee of Medical Journal Editors (ICMJE) provides recommendations to improve the editorial standards and scientific quality of biomedical journals. These recommendations range from uniform technical requirements to more complex and elusive editorial issues including ethical aspects of the scientific process. Recently, registration of clinical trials, conflicts of interest disclosure, and new criteria for authorship - emphasizing the importance of responsibility and accountability-, have been proposed. Last year, a new editorial initiative to foster sharing of clinical trial data was launched. This review discusses this novel initiative with the aim of increasing awareness among readers, investigators, authors and editors belonging to the Editors´ Network of the European Society of Cardiology. Resumo O Comitê Internacional de Editores de Revistas Médicas (ICMJE) fornece recomendações para aprimorar o padrão editorial e a qualidade científica das revistas biomédicas. Tais recomendações variam desde requisitos técnicos de uniformização até assuntos editoriais mais complexos e elusivos, como os aspectos éticos do processo científico. Recentemente, foram propostos registro de ensaios clínicos, divulgação de conflitos de interesse e novos critérios de autoria, enfatizando a importância da responsabilidade e da responsabilização. No último ano, lançou-se uma nova iniciativa editorial para fomentar o compartilhamento dos dados de ensaios clínicos. Esta revisão discute essa nova iniciativa visando a aumentar a conscientização de leitores, investigadores, autores e editores filiados à Rede de Editores da Sociedade Europeia de Cardiologia.

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Abstract: The International Committee of Medical Journal Editors (ICMJE) provides recommendations to improve the editorial standards and scientific quality of biomedical journals. These recommendations range from uniform technical requirements to more complex and elusive editorial issues including ethical aspects of the scientific process. Recently, registration of clinical trials, conflicts of interest disclosure, and new criteria for authorship - emphasizing the importance of responsibility and accountability -, have been proposed. Last year, a new editorial initiative to foster sharing of clinical trial data was launched. This review discusses this novel initiative with the aim of increasing awareness among readers, investigators, authors and editors belonging to the Editors' Network of the European Society of Cardiology.

Resumen: El Comite internacional de editores de revistas medicas (CIERM) propone recomendaciones para mejorar los standares editoriales y la calidad científica de las revistas biomédicas. Estas recomendaciones abarcan desde requerimeintos ténicos uniformados a temas editoriales mas complejos y evasivos, como los aspectos bioéticos relacionados con el proceso científico. Recientemente se han propuesto algunas iniciativas editoriales, como el registro de los ensayos clinicos, la declaración de los conflictos de interés y los nuevos criterios para autoría (que destacan la responsabilidad de los autores sobre el estudio). El año pasado se presentó una nueva iniciativa editorial para resaltar la importancia de compartir los datos generados en los estudios clinicos. En este artículo se discute esta nueva iniciativa editorial, con la idea de difundir su conocimiento entre los lectores, investigadores, autores y editores de la red de editores de revistas cardiovasculares nacionales de la Sociedad Europea de Cardiología.

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The International Committee of Medical Journal Editors (ICMJE) provides recommendations to improve the editorial standards and scientific quality of biomedical journals. These recommendations range from uniform technical requirements to more complex and elusive editorial issues including ethical aspects of the scientific process. Recently, registration of clinical trials, conflicts of interest disclosure, and new criteria for authorship - emphasizing the importance of responsibility and accountability -, have been proposed. Last year, a new editorial initiative to foster sharing of clinical trial data was launched. This review discusses this novel initiative with the aim of increasing awareness among readers, investigators, authors and editors belonging to the Editors' Network of the European Society of Cardiology.

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Abstract The International Committee of Medical Journal Editors (ICMJE) provides recommendations to improve the editorial standards and scientific quality of biomedical journals. These recommendations range from uniform technical requirements to more complex and elusive editorial issues including ethical aspects of the scientific process. Recently, registration of clinical trials, conflicts of interest disclosure, and new criteria for authorship - emphasizing the importance of responsibility and accountability-, have been proposed. Last year, a new editorial initiative to foster sharing of clinical trial data was launched. This review discusses this novel initiative with the aim of increasing awareness among readers, investigators, authors and editors belonging to the Editors´ Network of the European Society of Cardiology.

Resumo O Comitê Internacional de Editores de Revistas Médicas (ICMJE) fornece recomendações para aprimorar o padrão editorial e a qualidade científica das revistas biomédicas. Tais recomendações variam desde requisitos técnicos de uniformização até assuntos editoriais mais complexos e elusivos, como os aspectos éticos do processo científico. Recentemente, foram propostos registro de ensaios clínicos, divulgação de conflitos de interesse e novos critérios de autoria, enfatizando a importância da responsabilidade e da responsabilização. No último ano, lançou-se uma nova iniciativa editorial para fomentar o compartilhamento dos dados de ensaios clínicos. Esta revisão discute essa nova iniciativa visando a aumentar a conscientização de leitores, investigadores, autores e editores filiados à Rede de Editores da Sociedade Europeia de Cardiologia.

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Experimental data from animal models and clinical studies support connections between the haemostasis and inflammation in atherogenesis. These interfaces among inflammation and thrombogenesis have been suggested as targets for pharmacological intervention to reduce disease progression. We hypothesize that the recently discovered antithrombotic drug Sulphated Galactan (SG) (isolated from the red marine alga Acanthophora muscoides) might reduce atherosclerotic plaque vulnerability and inflammatory gene expression in 10-week aged apolipoprotein E deficient (ApoE-/-) mice under high-cholesterol diet for additional 11weeks. Then, the underlying cellular mechanisms were investigated in vitro. SG (10mg/kg) or Vehicle was subcutaneously injected from week 6 until week 11 of the diet. Treatment with SG reduced intraplaque macrophage and Tissue Factor (TF) content as compared to Vehicle-treated animals. Intraplaque TF co-localized and positively correlated with macrophage rich-areas. No changes on atherosclerotic plaque size, and other intraplaque features of vulnerability (such as lipid, neutrophil, MMP-9 and collagen contents) were observed. Moreover, mRNA expression of MMPs, chemokines and genetic markers of Th1/2/reg/17 lymphocyte polarization within mouse aortic arches and spleens was not affected by SG treatment. In vitro, treatment with SG dose-dependently reduced macrophage chemotaxis without affecting TF production. Overall, the chronic SG treatment was well tolerated. In conclusion, our results indicate that SG treatment reduced intraplaque macrophage content (by impacting on cell recruitment) and, concomitantly, intraplaque TF content of potential macrophage origin in atherosclerotic mice.

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OBJECTIVES: To assess the level of serum resistin in obese and lean children and to establish a relationship with circulating inflammatory and vascular markers. STUDY DESIGN: This is a cross-sectional study including 67 obese and 62 lean children (mean age 10.9 ± 2.8 years, age range 5.4-16.6 years). We assessed circulating hormones (insulin, leptin, insulin-like growth factor 1), markers of inflammation (resistin, high sensitivity C-reactive protein, interleukin-6, chemokine ligand 2), and endothelial cell activation (vascular and intercellular adhesion molecules: vascular cell adhesion molecule 1 and intercellular adhesion molecule; E-selectin; P-selectin; endothelin 1). RESULTS: Body weight, body mass index (BMI), insulin, leptin, high-sensitivity C-reactive protein, vascular adhesion molecule 1, and E-selectin levels were significantly higher in obese than in lean subjects. Resistin was similar among the groups in the prepubertal period, but increased significantly in the obese adolescents (18.6 ± 24.9) compared with lean subjects (7.9 ± 10.7 ng/mL; P = .038). Resistin was not associated with BMI z score (P > .05). Subjects with resistin levels above 9 (ng/mL) had higher concentration of interleukin-6, chemokine ligand 2, endothelin-1, and insulin-like growth factor 1 but not of leptin, insulin, or BMI. CONCLUSION: Resistin was increased in obese adolescents independently of the quantity of the adipose tissue. In this population, increased resistin levels were related to inflammation and endothelial activation. We may hypothesize that interventions aiming to diminish resistin expression may slow down atherogenesis in adolescents.

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