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Karine Lino Rodrigues,1 Vivian Vieira Dias Da Silva,1 Evelyn Nunes Goulart da Silva Pereira,1 Raquel Rangel Silvares,1 Beatriz Peres de Araujo,1 Edgar Eduardo Ilaquita Flores,1 Isalira Peroba Ramos,2 Juliana Pereira Borges,3 Caroline Fernandes-Santos,1,4 Anissa Daliry1 1Laboratory of Cardiovascular Investigation, Oswaldo Cruz Institute, FIOCRUZ, Rio de Janeiro, RJ, Brazil; 2National Center of Structural Biology and Bio-imaging, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil; 3Laboratory of Physical Activity and Health Promotion, University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil; 4Department of Basic Sciences, Federal Fluminense University, Nova Friburgo, RJ, BrazilCorrespondence: Anissa Daliry, Laboratory of Cardiovascular Investigation, Oswaldo Cruz Institute, FIOCRUZ, Pavilhão Ozorio de Almeida Av. Brasil, 4365 (Room 14), Manguinhos, Rio de Janeiro, RJ, CEP: 21040-900, Brazil, Tel +55 212562-1312, Email daliry@ioc.fiocruz.brPurpose: Type 2 diabetic (T2D) patients have liver and adipose tissue microcirculation disturbances associated with metabolic dysfunction and disease progression. However, the potential role of aerobic training on hepatic and white adipose tissue (WAT) microcirculation and the underlying mechanisms have not been elucidated to date. Therefore, we investigated the role of aerobic training on liver and WAT microcirculation and AGE-RAGE modulation in T2D mice.Methods: The control group (CTL) was fed standard chow, and T2D was induced by feeding male C57BL/6 a high-fat, high-carbohydrate diet for 24 weeks. In the following 12 weeks, mice underwent aerobic training (CTL EX and T2D EX groups), or were kept sedentary (CTL and T2D groups). We assessed metabolic parameters, biochemical markers, oxidative damage, the AGE-RAGE axis, hepatic steatosis, hepatic stellate cells activation (HSC) and liver and WAT microcirculation.Results: Hepatic microcirculation was improved in T2D EX mice which were associated with improvements in body, liver and fat mass, blood pressure, hepatic steatosis and fibrosis, and decreased HSC and AGE-RAGE activation. In contrast, improvement in WAT microcirculation, that is, decreased leukocyte recruitment and increased perfusion, was associated with increased catalase antioxidant activity.Conclusion: Physical training improves hepatic and adipose tissue microcirculatory dysfunction associated with T2D, likely due to downregulation of AGE-RAGE axis, decreased HSC activation and increased antioxidant activity.Keywords: microcirculation, physical training, AGE-RAGE, hyperglycemia

Background: Artificial intelligence (AI) models analyzing embryo time-lapse images have been developed to predict the likelihood of pregnancy following in vitro fertilization (IVF). However, limited research exists on methods ensuring AI consistency and reliability in clinical settings during its development and validation process. We present a methodology for developing and validating an AI model across multiple datasets to demonstrate reliable performance in evaluating blastocyst-stage embryos. Methods: This multicenter analysis utilizes time-lapse images, pregnancy outcomes, and morphologic annotations from embryos collected at 10 IVF clinics across 9 countries between 2018 and 2022. The four-step methodology for developing and evaluating the AI model include: (I) curating annotated datasets that represent the intended clinical use case; (II) developing and optimizing the AI model; (III) evaluating the AI's performance by assessing its discriminative power and associations with pregnancy probability across variable data; and (IV) ensuring interpretability and explainability by correlating AI scores with relevant morphologic features of embryo quality. Three datasets were used: the training and validation dataset (n = 16,935 embryos), the blind test dataset (n = 1,708 embryos; 3 clinics), and the independent dataset (n = 7,445 embryos; 7 clinics) derived from previously unseen clinic cohorts. Results: The AI was designed as a deep learning classifier ranking embryos by score according to their likelihood of clinical pregnancy. Higher AI score brackets were associated with increased fetal heartbeat (FH) likelihood across all evaluated datasets, showing a trend of increasing odds ratios (OR). The highest OR was observed in the top G4 bracket (test dataset G4 score ≥ 7.5: OR 3.84; independent dataset G4 score ≥ 7.5: OR 4.01), while the lowest was in the G1 bracket (test dataset G1 score < 4.0: OR 0.40; independent dataset G1 score < 4.0: OR 0.45). AI score brackets G2, G3, and G4 displayed OR values above 1.0 (P < 0.05), indicating linear associations with FH likelihood. Average AI scores were consistently higher for FH-positive than for FH-negative embryos within each age subgroup. Positive correlations were also observed between AI scores and key morphologic parameters used to predict embryo quality. Conclusions: Strong AI performance across multiple datasets demonstrates the value of our four-step methodology in developing and validating the AI as a reliable adjunct to embryo evaluation. [ABSTRACT FROM AUTHOR]

Miguel Vaz,1 Vítor Silva,1 Cristina Monteiro,2 Samuel Silvestre1,3 1CICS-UBI - Health Sciences Research Centre, Faculty of Health Sciences, University of Beira Interior, Covilhã, 6200-506, Portugal; 2UFBI – Pharmacovigilance Unit of Beira Interior, University of Beira Interior, Covilhã, 6200-506, Portugal; 3CNC- Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, 3004-517, PortugalCorrespondence: Miguel Vaz; Samuel Silvestre, CICS-UBI - Health Sciences Research Centre, Faculty of Health Sciences, University of Beira Interior, Av. Infante D. Henrique, Covilhã, 6200-506, Portugal, Tel +351 275 329002/3, Fax +351 275 329099, Email miguel.vaz@ubi.pt; sms@ubi.ptAbstract: Aducanumab is a monoclonal antibody selective for amyloid β (Aβ) aggregates. In June 2021, aducanumab became the first drug underlying the pathophysiology of Alzheimer’s disease (AD) approved by the US Food and Drug Administration (FDA), under the accelerated approval pathway. The decision was based on the ability of aducanumab to remove Aβ plaques, without any evidence that the Aβ clearance is correlated with less cognitive or functional decline. This decision has generated a considerable debate in the scientific community, especially because the results from the two Phase 3 trials, EMERGE and ENGAGE, were divergent and, even after the post hoc analysis, the data were insufficient to prove aducanumab efficacy. Moreover, some researchers think that this approval will be an obstacle to the progress and also demonstrated concerns about aducanumab cost and its safety profile. The European Medicines Agency’s rejection of aducanumab in December 2021 just brought more controversy over FDA’s decision. Now, Biogen is designing the FDA’s required confirmatory study, named ENVISION, which should be complete in 2026. Despite the controversy, the aducanumab showed to affect downstream tau pathology, which could open doors for a combination therapy approach for AD (anti-tau and anti-amyloid drug). This review summarizes the clinical development of aducanumab until regulatory agencies’ decisions, the available trials data and the controversy over aducanumab approval for AD.Keywords: anti-Aβ monoclonal antibody, ARIA, clinical trials, European Medicines Agency, Food and Drug Administration, tau protein