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BACKGROUND: Trastuzumab deruxtecan (T-DXd) is approved for human epidermal growth factor receptor 2 (HER2)-positive and HER2-low advanced breast cancer (ABC). T-DXd has shown encouraging intracranial activity in HER2-positive ABC patients with stable or active brain metastases (BMs); however, its efficacy in patients with HER2-low ABC with BMs is not well established yet. METHODS: DEBBRAH is a single-arm, five-cohort, phase II study evaluating T-DXd in patients with central nervous system involvement from HER2-positive and HER2-low ABC. Here, we report results from patients with heavily pretreated HER2-low ABC and active BMs, enrolled in cohorts 2 (n = 6, asymptomatic untreated BMs) and 4 (n = 6, progressing BMs after local therapy). Patients received 5.4 mg/kg T-DXd intravenously once every 21 days. The primary endpoint was intracranial objective response rate per Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) for both cohorts. RESULTS: Intracranial objective response rate per RANO-BM was 50.0% [3/6 patients; 95% confidence interval (CI) 11.8% to 88.2%] and 33.3% [2/6 patients; 95% CI 4.3% to 77.7%; P = 0.033 (one-sided)] in cohorts 2 and 4, respectively. All responders had partial responses. Median time to intracranial response was 2.3 months (range, 1.5-4.0 months) and median duration of intracranial response was 7.2 months (range, 2.8-16.8 months). Median progression-free survival per RECIST v.1.1. was 5.4 months (95% CI 4.1-10.0 months). Treatment-emergent adverse events occurred in all patients included (16.7% grade 3). Three patients (25.0%) had grade 1 interstitial lung disease/pneumonitis. CONCLUSIONS: T-DXd demonstrated promising intracranial activity in pretreated HER2-low ABC patients with active BMs. Further studies are needed to validate these results in larger cohorts. This trial is registered with ClinicalTrials.gov, NCT04420598.

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PURPOSE OF REVIEW: Viruses are the most common etiological agents of diarrhea in children. Despite rotavirus vaccine introduction, rotavirus remains as the leading cause of death globally, followed by norovirus, which represents a diagnostic challenge. Here, we describe new advances in the diagnosis and management of viral diarrheas. RECENT FINDINGS: Although immunoassays are widely used for their fast turnaround time and low cost, molecular techniques have become the most reliable diagnostic method due to their high sensitivity and capacity to analyze multiple pathogens in gastrointestinal panels. Isothermal nucleic acid amplification assays (LAMP and RPA) are promising techniques since they do not require sophisticated equipment and can be used as point-of-care testing. CRISPR/Cas nucleic acid detection systems are new diagnostic methods with great potential. Several recent published articles describe the role of human intestinal enteroids to characterize norovirus infection, to test new drugs, and for vaccine development. The interaction between the human gut microbiota and gastrointestinal viral infections has been extensively reviewed and offers some innovative mechanisms for therapeutic and preventive measures. SUMMARY: Although important advances have been made, more research is needed to address remaining challenges and further improve diagnostic capabilities and better management strategies for this critical infectious disease.

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Neurodegenerative diseases such as Alzheimer´s (AD) and physiological ageing are characterized by a decline in neurogenesis and in the polysialylated isoforms of neural cell adhesion molecule (PSA-NCAM) expression within the hippocampus and specifically in the dentate gyrus (DG). In the 3xTG-AD mouse model, which mimics the human disease in both pathological and behavioral features, this decline in PSA-NCAM is associated with the presence of Aß plaques at 9 months and Tau tangles at 12-15 months. In this work we studied the presence of PSA-NCAM at early ages (1-6 months) in the same model. Our results demonstrated that even as early as the first month of age there is a strong decrease in PSA-NCAM dendritic tree mainly altering the molecular layer (MolL) coverage affecting the synaptic plasticity and furthermore confirmed by the reduction of PSA-NCAM area density (Sv) in the 3xTG-AD. Similar and more marked early changes were seen during aging in both NTG and 3xTg-AD animals. Our results demonstrate for the first time a precipitate decrease of PSA-NCAM cells at such very early phases of the disease. This result suggests an early effect of the disease in the progression of immature and pluripotent cells resulting in an ulterior and early diminution of neurogenesis and therefore an impaired hippocampal cellular and synaptic plasticity.

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OBJECTIVE: There is early evidence about Valproic acid (VPA) antiviral effect. Our aim was to investigate the incidence and severity of SARS-CoV-2 infection in VPA users as compared with the general population. MATERIAL AND METHODS: A case-control study nested within a cohort, carried out between March 1 and December 17, 2020. Retrospectively, we identified confirmed SARS-CoV-2 infection patients exposed to VPA in our health department (defined as case). We ascertained VPA regimen (all the time (AT) (292 days) or at least 20% of the study period (notAT) (≥58 days) and if VPA levels were in therapeutic range (ATR) (50-100mcg/mL) in the last 24 months. We calculated the cumulative incidence of SARS-CoV-2 infection and hospital admission in the cases, comparing it with the general unexposed VPA population (controls). RESULTS: During the study period, 6183 PCR+ were detected among 281,035 inhabitants, of these, 746 were hospitalized. 691 patients were on VPA notAT and 628 (90.1%) AT. The indication for VPA use was epilepsy in 54.9%. The incidence of PCR+ was 1.736% (OR 0.785 (95%CI 0.443-1.390) and 1.910% (OR 0.865 (95%CI 0.488-1.533), on VPA notAT and VPA AT patients, respectively vs. 2.201% in people without VPA regimen. Those patients with VPA ATR had a lower risk of PCR + (OR 0.233 (95%CI 0.057-0.951) notAT; OR 0.218 (95%CI 0.053-0.890) AT). Hospital admission incidence was lower in patient on VPA (OR was 0.543 (95% CI 0.076-3.871). CONCLUSION: Patients with VPA within the therapeutic range had a reduction of SARS-Cov-2 infection incidence greater than 75%. There is a downward trend in the risk of COVID-19 admission by SARS-CoV-2 in patients on VPA therapy. These findings warrant further investigation.

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Thoracic surgical procedures are increasing in recent years, and there are different types of lung resections. Postsurgical complications vary depending on the type of resection and the time elapsed, with imaging techniques being key in the postoperative follow-up. Multidisciplinary management of these patients throughout the perioperative period is essential to ensure an optimal surgical outcome. This pictorial review will review the different thoracic surgical techniques, normal postoperative findings and postsurgical complications.

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The microbial communities residing in the mosquito midgut play a key role in determining the outcome of mosquito pathogen infection. Elizabethkingia anophelis, originally isolated from the midgut of Anopheles gambiae possess a broad-spectrum antiviral phenotype, yet a gap in knowledge regarding the mechanistic basis of its interaction with viruses exists. The current study aims to identify pathways and genetic factors linked to E. anophelis antiviral activity. The understanding of E. anophelis antiviral mechanism could lead to novel transmission barrier tools to prevent arboviral outbreaks. We utilized a non-targeted multi-omics approach, analyzing extracellular lipids, proteins, metabolites of culture supernatants coinfected with ZIKV and E. anophelis. We observed a significant decrease in arginine and phenylalanine levels, metabolites that are essential for viral replication and progression of viral infection. This study provides insights into the molecular basis of E. anophelis antiviral phenotype. The findings lay a foundation for in-depth mechanistic studies.

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The lungs face constant environmental challenges from harmless molecules, airborne pathogens and harmful agents that can damage the tissue. The lungs' immune system includes numerous tissue-resident lymphocytes that contribute to maintain tissue homeostasis and to the early initiation of immune responses. Amongst tissue-resident lymphocytes, Mucosal Associated Invariant T (MAIT) cells are present in human and murine lungs and emerging evidence supports their contribution to immune responses during infections, chronic inflammatory disorders and cancer. This review explores the mechanisms underpinning MAIT cell functions in the airways, their impact on lung immunity and the potential for targeting pulmonary MAIT cells in a therapeutic context.

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Chronic heart failure (CHF) represents a challenge for the healthy system due to its high prevalence, high burden of morbidity and mortality, and high consumption of health resources. To address this problem, it is necessary to develop efficient management strategies that include both hospital care and outpatient care. The primary objective is to stabilize the patient and prevent decompensation, with the consequent improvement in quality of life, reduction in hospital admissions and emergency department care, and, consequently, reduction in healthcare costs. In this context, the heart failure and atrial fibrilation working group of the Spanish Society of Internal Medicine has developed a protocol for the management of outpatient CHF, that addresses, from the perspective of Internal medicine, all the problems suffered by the patient with CHF. This protocol aims to optimize pharmacological treatment, control cardiovascular risk factors and various comorbidities, educate the patient and their environment about the disease, promote adherence to treatment and stablish follow-up adapted to their condition.

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Photobioreactors (PBRs) are used to grow the light-requiring microalgae in diverse commercial processes. Often, they are operated as continuous culture over months period. However, with time, biofouling layer develops on the inner surfaces of their walls. The fouling layer formation deteriorates the PBR performance as foulants reduce light penetration in it. Light is essential for photosynthetic cultures, and a deterioration in lighting adversely impacts algae growth and biomass productivity. Fouling requires a frequent shutdown to clean the PBR and add to the environmental impact of the operation by generating many wastewaters contaminated with the cleaning chemicals. Antibiofouling coatings could be used to modify the surfaces of existing and future PBRs. Therefore, transparent and non-toxic fouling-release coatings, produced using hydrogel technology, could transform the existing PBRs into efficient and enduring microalgae culture systems, requiring only the application of the coating to the inner walls, without additional investments in new PBRs.

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BACKGROUND: Atherosclerosis, a leading cause of mortality, necessitates effective management of hypercholesterolemia, specifically elevated low-density lipoprotein cholesterol (LDL-C). The emergence of proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) has revolutionised lipid-lowering. PCSK9i demonstrates substantial LDL-C reduction and cardiovascular benefits, particularly in statin-intolerant or nonresponsive individuals. However, the potential pleiotropic effects of PCSK9i, especially on arterial stiffness, remain a subject of investigation. This systematic review and meta-analysis seek to provide a nuanced understanding of the potential pleiotropic effects of PCSK9i, specifically on arterial health. The primary objective was to analyse the influence of PCSK9i on arterial stiffness, extending beyond traditional lipid-lowering metrics and contributing to a more comprehensive approach to cardiovascular risk reduction. METHODS: A systematic search was conducted across major databases, clinical trial registries and grey literature. Inclusion criteria comprised adults in prospective cohort studies undergoing PCSK9i augmentation in lipid-lowering therapy, with a focus on arterial stiffness measured by pulse wave velocity (PWv). Random-effects meta-analyses, sensitivity analyses and meta-regression models were employed to assess the pooled effect of adding PCSK9i to lipid-lowering interventions on arterial stiffness. RESULTS: Five studies (158 participants) met the inclusion criteria, demonstrating a significant reduction in PWv (mean difference: -2.61 m/s [95% CI: -3.70, -1.52]; ES: -1.62 [95% CI: -2.53, -.71]) upon adding PCSK9i to lipid-lowering interventions. Subgroup analysis and meta-regression models suggested potential sex-based and baseline PWv-dependent variations, emphasising patient-specific characteristics. CONCLUSION: The meta-analysis provides robust evidence that adding PCSK9i to lipid-lowering interventions significantly improves arterial stiffness, indicating broader vascular benefits beyond LDL-C reduction.

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AIM: This study aimed to investigate the effects of age, period, and cohort on the incidence of psoriasis in Spain from 1990 through 2019 using the Global Burden of Disease (GBD) database and age-period-cohort (A-P-C) analysis. METHODS: We conducted an ecological trend study to analyze the incidence rates of psoriasis in Spain from 1990 through 2019. Joinpoint Regression Program, Version 5.0.2 - May 2023; Surveillance Research Program, National Cancer Institute and National Cancer Institute A-P-C tools were used to identify trends and assess the effects of age, period, and cohort. RESULTS: From 1990 through 2019, an estimated 2.99 million cases of psoriasis were diagnosed in Spain, with a mean annual increase of 0.49%. Significant decreases in age-standardized incidence rates (ASIR) were reported for both sexes, with women consistently maintaining a slightly higher ASIR. Joinpoint analysis revealed multiple turning points in the downward trend, indicating periods of stabilization. A-P-C analysis demonstrated significant declines in both net (overall trend) and local drift (age-specific trends), indicating a broad decrease in the incidence of psoriasis across most age groups. While the risk of psoriasis increased with age, peaking in the 50-54 age group, it declined thereafter. Furthermore, the analysis revealed a continuous decline in risk from 1990 through 2019 for both sexes, with individuals born in the early 21st century exhibiting a significantly lower risk vs those born in the early 20th century. CONCLUSION: This study observed a slight decline in the reported psoriasis ASIR in Spain, potentially due to reduced exposure to risk factors. However, limitations in data and the complexity of factors influencing the incidence of psoriasis require further research.

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Asteroids smaller than 10 km are thought to be rubble piles formed from the reaccumulation of fragments produced in the catastrophic disruption of parent bodies. Ground-based observations reveal that some of these asteroids are today binary systems, in which a smaller secondary orbits a larger primary asteroid. However, how these asteroids became binary systems remains unclear. Here, we report the analysis of boulders on the surface of the stony asteroid (65803) Didymos and its moonlet, Dimorphos, from data collected by the NASA DART mission. The size-frequency distribution of boulders larger than 5 m on Dimorphos and larger than 22.8 m on Didymos confirms that both asteroids are piles of fragments produced in the catastrophic disruption of their progenitors. Dimorphos boulders smaller than 5 m have size best-fit by a Weibull distribution, which we attribute to a multi-phase fragmentation process either occurring during coalescence or during surface evolution. The density per km2 of Dimorphos boulders ≥1 m is 2.3x with respect to the one obtained for (101955) Bennu, while it is 3.0x with respect to (162173) Ryugu. Such values increase once Dimorphos boulders ≥5 m are compared with Bennu (3.5x), Ryugu (3.9x) and (25143) Itokawa (5.1x). This is of interest in the context of asteroid studies because it means that contrarily to the single bodies visited so far, binary systems might be affected by subsequential fragmentation processes that largely increase their block density per km2. Direct comparison between the surface distribution and shapes of the boulders on Didymos and Dimorphos suggest that the latter inherited its material from the former. This finding supports the hypothesis that some asteroid binary systems form through the spin up and mass shedding of a fraction of the primary asteroid.

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OBJECTIVE: This study aims to analyze the prescription of antihypertensive drugs in patients with type 2 diabetes (T2D) in Andalusia, comparing it with the SEH-LELHA 2022 guidelines, and to assess the direct cost of these treatments. MATERIALS AND METHODS: A multicentric, cross-sectional, and descriptive study was conducted with 385 T2D patients. Participants were randomly selected from the patient lists of 120 primary care physicians from Andalusia. Inclusion criteria included a diagnosis of T2D and complete clinical records for the year 2022. Demographic data and drug prescription information were collected, with the average cost per patient being calculated. RESULTS: The mean age of the subjects was 70.72 years, with 53.51% being male. A total of 70.9% of the patients were taking antihypertensive drugs, the most common being ACE inhibitors/ARBs (70.9%), diuretics (70.1%), beta-blockers (40.0%), and calcium channel blockers (20.0%). Each patient took an average of 2.46±1.06 antihypertendsive, and fixed association of 2 or more antihypertensive drugs were used by 40.9% of the studied patients. The annual cost per patient was 141.45€/year. CONCLUSIONS: The study reveals strong adherence to the SEH-LELHA 2022 guidelines among physicians in Andalusia regarding the of antihypertensives for T2D patients, with a significant preference for Renin-Angiotensin System blockers, diuretics, and beta-blockers. However, a notable deviation in prescription practices was observed with the frequent choice of doxazosin over spironolactone, despite the latter being the recommended option for resistant hypertension. Although the overall expenditure on antihypertensives is moderate, their cost-effectiveness is enhanced by the efficacy of these treatments in preventing cardiovascular complications.

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Cancer mice models are critical for immune-oncology research; they provide conditions to explore tumor immunoenviroment aiming to advance knowledge and treatment development. Often, research groups breed their own mice colonies. To assess the effect of C57BL/6 mice breeding nuclei in prostate cancer development and intratumoral macrophage populations, an isotransplantation experiment was performed. C57BL/6J mice from two breeding nuclei (nA and nB) were employed for prostate adenocarcinoma TRAMP-C1 cell implantation; tumor growth period and intratumoral macrophage profile were measured. BL/6nB mice (54%) showed tumor implantation after 69-day growth period while BL/6nA implantation reached 100% across tumor growth period (28 days). No difference in total macrophage populations was observed between groups within several tumoral regions; significantly higher M2 macrophage profile was observed in tumor microenvironments from both mice groups. Nevertheless, BL/6nB tumors showed around twice the population of M1 profile (11-27%) than BL6nA (4-15%) and less non-polarized macrophages. The M1:M2 average ratio was 1:8 for group A and 1:4 for B. Our results demonstrate different tumor progression and intratumoral macrophage populations among mice from the same substrain. Data obtained in this study shows the relevance of animal source renewal for better control of murine cancer model variables.

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Introduction: Preterm birth is a growing problem worldwide. Staying at a neonatal intensive care unit (NICU) after birth is critical for the survival of preterm infants whose feeding often requires the use of nasogastric enteral feeding tubes (NEFT). These can be colonized by hospital-associated pathobionts that can access the gut of the preterm infants through this route. Since the gut microbiota is the most impactful factor on maturation of the immune system, any disturbance in this may condition their health. Therefore, the aim of this study is to assess the impact of NEFT-associated microbial communities on the establishment of the gut microbiota in preterm infants. Material and methods: A metataxonomic analysis of fecal and NEFT-related samples obtained during the first 2 weeks of life of preterm infants was performed. The potential sharing of strains isolated from the same set of samples of bacterial species involved in NICU's outbreaks, was assessed by Random Amplification of Polymorphic DNA (RAPD) genotyping. Results: In the samples taken 48 h after birth (NEFT-1 and Me/F1), Staphylococcus spp. was the most abundant genera (62% and 14%, respectively) and it was latter displaced to 5.5% and 0.45%, respectively by Enterobacteriaceae. Significant differences in beta diversity were detected in NEFT and fecal samples taken at day 17 after birth (NEFT-3 and F3) (p = 0.003 and p = 0.024, respectively). Significant positive correlations were found between the most relevant genera detected in NEFT-3 and F3. 28% of the patients shared at least one RAPD-PCR profile in fecal and NEFT samples and 11% of the total profiles were found at least once simultaneously in NEFT and fecal samples from the same patient. Conclusion: The results indicate a parallel bacterial colonization of the gut of preterm neonates and the NEFTs used for feeding, potentially involving strain sharing between these niches. Moreover, the same bacterial RAPD profiles were found in neonates hospitalized in different boxes, suggesting a microbial transference within the NICU environment. This study may assist clinical staff in implementing best practices to mitigate the spread of pathogens that could threaten the health of preterm infants.

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Persistent and unresolved inflammation is a common underlying factor observed in several and seemingly unrelated human diseases, including cardiovascular and neurodegenerative diseases. Particularly, in atopic conditions, acute inflammatory responses such as those triggered by insect venom, food or drug allergies possess also a life-threatening potential. However, respiratory allergies predominantly exhibit late immune responses associated with chronic inflammation, that can eventually progress into a severe phenotype displaying similar features as those observed in other chronic inflammatory diseases, as is the case of uncontrolled severe asthma. This review aims to explore the different facets and systems involved in chronic allergic inflammation, including processes such as tissue remodelling and immune cell dysregulation, as well as genetic, metabolic and microbiota alterations, which are common to other inflammatory conditions. Our goal here was to deepen on the understanding of an entangled disease as is chronic allergic inflammation and expose potential avenues for the development of better diagnostic and intervention strategies.

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INTRODUCTION: metatarsophalangeal resection arthroplasty is considered a salvage surgical procedure able to improve the quality of life of patients with major forefoot deformities. MATERIAL AND METHODS: a retrospective observational study of 31 patients (36 feet) with major forefoot deformities operated at our institution was performed. Thirty two feet required additional surgery involving the first ray, most of them (72.2%) through MTP joint fusion. The mean follow-up period was 10.3 ± 4.6 years. Most patients were women (87.1%), the mean age was 74.2 ± 11.5 years. RESULTS: at the final follow-up, mean AOFAS score was 77.9 ± 10.2 points and mean MOxFQ score was 18.3 ± 8.3 points. Visual analog scale (VAS) for pain improved significantly from 7.5 ± 1.2 points to 3.4 ± 2.1 points on average. Good clinical results were also reported on ability to put on shoes comfortably. The mean resection arthroplasty spaces at the end of the study were 1.3, 1.8, 2.5 and 4.4 mm, for second to fifth rays, respectively. The mean sizes of remodeling osteophytes at the end of the study were 1.6, 1.4, 1.1 and 0.7 mm, respectively. Significant improvement was also achieved in the hallux valgus angle (HVA) and intermetatarsal angle (IMA) at the end of the study. CONCLUSION: in our experience, metatarsophalangeal resection arthroplasty continues to be a valid choice in patients with major forefoot deformities, with satisfactory long-term clinical and radiographic results.

INTRODUCCIÓN: la artroplastía de resección metatarsofalángica se considera un procedimiento quirúrgico de salvamento capaz de mejorar la calidad de vida de pacientes con deformidades importantes en el antepié. MATERIAL Y MÉTODOS: se realizó un estudio observacional retrospectivo de 31 pacientes (36 pies) con deformidades importantes en el antepié operados en nuestra institución. Treinta y dos pies requirieron cirugía adicional que involucró el primer metatarsiano, la mayoría de ellos (72.2%) a través de la fusión de la articulación metatarsofalángica. El período de seguimiento promedio fue 10.3 ± 4.6 años. La mayoría de los pacientes fueron mujeres (87.1%), con una edad promedio de 74.2 ± 11.5 años. RESULTADOS: en la última visita de seguimiento, la puntuación AOFAS promedio fue de 77.9 ± 10.2 puntos y la puntuación MOxFQ promedio fue de 18.3 ± 8.3 puntos. La escala visual analógica (EVA) para el dolor mejoró significativamente, pasando de 7.5 ± 1.2 puntos a 3.4 ± 2.1 puntos de media. También se constataron buenos resultados clínicos en cuanto a la capacidad de calzarse con comodidad. Los espacios de resección promedio al final del estudio fueron 1.3, 1.8, 2.5 y 4.4 mm para el segundo al quinto radio, respectivamente. Los tamaños promedio de los osteofitos por remodelación al final del estudio fueron de 1.6, 1.4, 1.1 y 0.7 mm, respectivamente. También se logró una mejora significativa en el ángulo de hallux valgus (AHV) y en el ángulo intermetatarsiano (IMA) al final del estudio. CONCLUSIÓN: en nuestra experiencia, la artroplastía de resección metatarsofalángica sigue siendo una opción válida en pacientes con deformidades graves del antepié, con resultados clínicos y radiográficos satisfactorios a largo plazo.

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The rising prices of fishery derivatives limits their use in aquafeeds. Therefore, other alternatives are used to replace those ingredients. Among them, microalgae are of great interest both as an ingredient and as a potential stabilising agent against lipid oxidation. This study evaluates on the use of Nannochloropsis gaditana to prevent lipid oxidation in a set of 12 aquafeeds over 540 days of storage. Aquafeeds were formulated with/without 15 % N. gaditana combined with two antioxidants -butylhydroxytoluene (25-150 mg·kg-1) or vitamin E (500-3000 mg·kg-1). The effect of i) storage period, ii) presence of microalgae and iii) antioxidant addition on lipid oxidation was assessed. Results showed higher fatty acid degradation in diets lacking microalgae. The microalgae supplemented diets is enough for preserving feeds presenting the highest antioxidant effect at the end, without significant differences with the microalgae-supplemented feeds and those including antioxidants after 540 days of storage.

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