👤 Armanda E Santos

The progressive accumulation of physiological stress as we age, known as allostatic load, is linked to an increased risk of dementia. Fostering brain resilience through physical exercise can counteract allostatic load and improve adaptation to age-related brain alterations. Fibronectin type III domain-containing protein 5 (FNDC5)/irisin is a neuroprotective exercise-linked hormone found in extracellular vesicles (EV-FNDC5/irisin). Here, we sought to analyse EV-FNDC5/irisin in ageing as a promising biomarker of brain resilience. We measured exercise-associated factors, including EV-FNDC5/irisin, brain-derived neurotrophic factor (BDNF), and cathepsin B in the serum of 31 young (18-28 years) and 19 older subjects (65-79 years). Levels of FNDC5/irisin in serum-derived EVs are markedly reduced in older subjects compared to young ( Show less

Stress is defined as a disruption of homeostasis that elicits adaptive responses aimed at restoring physiological balance. However, when stress becomes chronic or overwhelming, maladaptive changes may occur, contributing to endocrine, behavioral, and neuropsychiatric dysfunctions. Beyond the classical neuroendocrine axes, such as the sympatho-adrenomedullary and hypothalamic-pituitary-adrenal (HPA) axes, the renin-angiotensin system has also being implicated in stress modulation. Previous studies have shown that angiotensin-(1-7), acting through its receptor Mas, exerts a modulatory effect on the stress response, attenuating anxiety- and depression-like behaviors induced by various stressors. Here we investigated the impact of genetic deletion of Mas on the consequences of chronic unpredictable stress (CUS) exposure. Over 21 consecutive days, mice were subjected to random stressors, after which endocrine, behavioral and neurochemical assessments were performed. Mas knockout (KO) mice exposed to CUS exhibited significantly elevated corticosterone and blood glucose levels compared to stressed wild-type mice. In behavioral tests, stressed Mas KO mice displayed the highest immobility times in the forced swimming test, indicating enhanced depressive-like behavior. Anxiety-like behavior was also heightened in Mas KO mice, as evidenced by a significant reduction in the percentage of time spent in the open arms of the elevated plus maze test. Neurochemical analysis revealed a marked reduction in brain-derived neurotrophic factor (BDNF) levels in key brain regions of stressed Mas KO animals. Together, these findings suggest that Mas plays a critical role in the neurobiology of stress, since its absence exacerbates HPA axis hyperactivity, depression- and anxiety-like behaviors, as well as BDNF reduction. Overall, these results highlight the potential neuroprotective role of Mas in stress-related disorders. Show less

Cognitive impairment in schizophrenia (SCZ) is associated with neuroinflammation and neurotrophic dysregulation. The role of pro-inflammatory interleukins and brain-derived neurotrophic factor (BDNF) in cognitive deficits remains unclear. We aimed to examine the associations between IL-1β, IL-2, IL-6, BDNF, and cognitive function in patients with SCZ with typical or atypical antipsychotics. Participants included 162 healthy controls (mean age = 33.6 ± 2.0 years), 88 patients with SCZ receiving typical antipsychotics (36.4 ± 6.4 years), and 62 receiving atypical antipsychotics (34.0 ± 4.0 years). Cognitive performance was evaluated using a battery of attentional, executive, and visuospatial working memory tasks. Data were analyzed using machine-learning approaches, multivariate statistics, and structural equation modeling. SCZ Patients exhibited marked cognitive impairments alongside lower BDNF concentrations and elevated interleukin levels, with the greatest deviations observed among those receiving typical antipsychotic treatment. Higher medication dosages and longer illness duration were associated with greater cognitive decline and stronger neuroimmune dysregulation. The findings indicate that elevated cytokines and reduced neurotrophic support may contribute to cognitive impairment, whereas persistent cognitive dysfunction can further amplify inflammatory activity. This complexity suggests the need to broaden current assessment approaches and systematically examine biomarkers together with clinical features. Show less

The increase in cannabinoid use among adolescents has become a public health concern in North America, with more than one-third of 12th graders in the United States reporting consumption of some form of cannabis within the past year (2023). Male adolescent Sprague-Dawley rats received two intraperitoneal injections, either WIN (0.8 mg/kg) or saline solution (0.9% NaCl) every 48 h, from postnatal day (PND) 30 to 37. On the final day (PND 38), a single injection of either WIN or saline was administered. The rat's whole brain tissue was collected an hour after the last injection. Chronic WIN administration during adolescence caused a significant increase in pro-BDNF levels in the brain's CbVr and m-BDNF in the mPFC. Our findings suggest that chronic WIN administration can alter the baseline levels of pro and m-BDNF in the brains of male adolescent rats, which may have implications for synaptic plasticity and neurodevelopment. Show less

Rodent studies have shown that psychedelic drugs can enhance fear extinction. However, investigations to date have relied on normative aversive conditioning procedures, which limit their relevance to trauma-related memories, as these tend to be overgeneralized and resistant to extinction. Fear extinction depends on activity and plasticity within the infralimbic (IL) region of the medial prefrontal cortex and is regulated by brain-derived neurotrophic factor (BDNF). Ayahuasca (AYA), a brew containing the serotonergic psychedelic N,N-dimethyltryptamine (DMT), facilitates fear extinction in rodents and increases BDNF levels/signaling. Here, we investigated whether AYA attenuates extinction deficits and generalized fear induced by preconditioning restraint stress or high-intensity contextual fear conditioning, and whether these effects depend on BDNF-TrkB receptor signaling in the IL cortex. Adult male and female rats underwent the protocols above and received oral AYA one hour before each of the two extinction sessions conducted on consecutive days. Repeated administration of AYA containing 0.3 mg/kg of DMT enhanced extinction learning and its retention, effects that were abolished by bilateral intra-IL cortex infusion of an anti-BDNF antibody or the TrkB receptor antagonist ANA-12. AYA treatment also reduced fear generalization, an action that was BDNF-dependent in the IL cortex of females but not males. Overall, these findings indicate that AYA can modulate maladaptive fear memories through cortical mechanisms involving BDNF signaling, highlighting the potential of psychedelics as enhancers for extinguishing difficult-to-treat memories like those underlying post-traumatic stress disorder. Show less

Human bone marrow-derived mesenchymal stromal cells (hBM-MSCs) are known to exert immunomodulatory and pro-reparative effects in vivo. This makes hBM-MSCs an enticing therapeutic candidate for inflammatory diseases, such as acute respiratory distress syndrome (ARDS). The ARDS microenvironment is complex and contains an abundance of free fatty acids (FFAs), which are known to differentially impact MSC functionality. PPARβ/δ is a ubiquitously expressed nuclear receptor that is activated in response to FFA-binding. PPARβ/δ has been shown to impact the therapeutic efficacy of mouse MSCs. This study sought to investigate the impact of PPARβ/δ-modulation on human MSC functionality in vitro and in vivo. hBM-MSCs were exposed to a synthetic PPARβ/δ agonist/antagonist in the presence or absence of ARDS patient serum and the immunomodulatory and pro-reparative capacity of the MSC secretome was investigated using in vitro assays and a pre-clinical model of LPS-induced acute lung inflammation (ALI). Our results highlighted enhanced pro-reparative capacity of PPARβ/δ-agonized hBM-MSCs secretome in CALU-3 lung epithelial cells, mediated by MSC derived angiopoietin-like 4 (ANGPTL4). PPARβ/δ-induced ANGPTL4-high MSC secretome facilitated enhanced endothelial barrier integrity in the lungs of ALI mice. Therapeutic effects of PPARβ/δ-agonized hBM-MSCs secretome were further enhanced by licensing MSCs with human ARDS patient serum. ARDS-licensed PPARβ/δ-induced ANGPTL4-high MSC secretome had reduced clinical score and weight loss. The role ANGPL4 in these protective effects was confirmed using an anti-ANGPTL4 antibody. These findings conclude that the MSC secretome therapeutic effects can be enhanced both in vitro and in vivo through licensing strategies that upregulate the angiogenic factor ANGPTL4. Show less

Familial chylomicronemia syndrome (FCS) is a rare autosomal recessive disorder characterized by severe hypertriglyceridemia and caused by mutations in genes involved in chylomicron metabolism. Dietary management includes a very-low-fat diet, restriction of simple carbohydrates and alcohol, supplementation with medium-chain triglycerides, essential fatty acids, and fat-soluble vitamins; however, long-term adherence is often poor and nutritional therapy alone is insufficient. We report two adult Chilean sisters with FCS caused by the homozygous Q97X mutation in the APOA5 gene. Both patients experienced severe hypertriglyceridemia (>5,000 mg/dL) and recurrent episodes of acute pancreatitis. One sister was treated with volanesorsen, an antisense oligonucleotide, receiving a weekly dose of 285 mg, which was repeated every 3 weeks due to thrombocytopenia. When combined with structured nutritional counseling, pharmacological treatment achieved a marked reduction in plasma triglycerides to <250 mg/dL and a substantial improvement in quality of life. The other sister was managed with conventional therapy due to a lack of health insurance coverage for volanesorsen. She presented persistent hypertriglyceridemia and recurrent hospitalizations, underscoring the challenges of access to advanced therapies in limited-resource settings. While volanesorsen offers a promising therapeutic alternative, equitable access remains a critical issue, particularly in health systems of low-to middle-income regions. Show less

Alzheimer's disease (AD) is the most prevalent cause of dementia and has been closely linked to βSupplemental data for this article can be accessed online at ht tps://doi.org/-amyloid accumulation. However, the efficacy and safety of anti-β-amyloid monoclonal antibodies remain debated. We systematically searched PubMed, Embase, and Cochrane databases for RCTs comparing anti-β-amyloid monoclonal antibodies with placebo in early-stage AD. Eligible trials enrolled participants with biomarker-supported AD and reported global, cognitive, or safety outcomes, including the CDR-SB, ADAS-Cog 13/14, ARIA, and brain volumetric measures. Six RCTs including 7837 participants were analyzed. Mean age ranged from 69.8 to 75.4 years, and 57.4% were APOE ε4 carriers. Anti-β-amyloid therapy was associated with small differences in global and cognitive outcomes, best described as a modest slowing of decline on the CDR-SB and ADAS-Cog scales. Treatment was associated with increased risks of ARIA-E (RR, 9.40; 95% CI, 6.98-12.66) and ARIA-H (RR, 2.40; 95% CI, 2.08-2.78), as well as greater ventricular enlargement and hippocampal atrophy. In early AD, anti-β-amyloid monoclonal antibodies are associated with modest slowing of decline accompanied by increased ARIA risk and unfavorable structural brain changes, limiting clinical applicability. www.crd.york.ac.uk/prospero identifier is CRD420251071393. Show less

Familial hypercholesterolemia (FH) is characterized by elevated low-density lipoprotein cholesterol (LDL-C) and increased risk of premature coronary atherosclerosis. Functional aspects of high-density lipoprotein (HDL), including cholesterol transfer capacity, may contribute to cardiovascular risk heterogeneity in FH. To investigate whether cholesterol transfer to HDL and other HDL-related parameters are associated with coronary artery disease (CAD) in patients with heterozygous FH (HeFH). Fifty-three genetically confirmed FH patients (mean age: 49.2 years; 73.6% female) were included. Twenty-seven had plaques, while 26 had no vessel abnormalities as determined by coronary computed tomography angiography. The transfer of both unesterified and esterified cholesterol (UC and EC) to HDL, as well as HDL antioxidant capacity, particle size, and subfractions, plasma concentrations of cholesteryl ester transfer protein (CETP) and lecithin-cholesterol acyltransferase (LCAT), and paraoxonase-1 (PON-1) activity were assessed. Family history of premature CAD (P < .028) and tendinous xanthomas (P = .014) were more frequent in those with plaques. No differences were found in apolipoprotein (apo) B, LDL-C, LDL-C year score, lipoprotein(a), non-HDL-C, apo A-I, HDL-C, HDL subfractions, or triglycerides. Transfer of lipids to HDL and antioxidant capacity did not differ between the groups. LCAT concentrations and PON-1 activity were also similar. In contrast, CETP concentration was higher in those with plaques (P < .008). However, only family history of early CAD (odds ratio [OR]: 4.12, 95% CI, 1.23-13.80, P = .022) and xanthomas (OR: 3.65, 95% CI, 1.06-12.60, P = .040) were independently associated with plaques. Among patients with HeFH, no HDL-related parameter was independently associated with subclinical CAD. Show less

Efficient utilization of complex biomass-derived sugars and tolerance to inhibitors are key requirements for the viability of lignocellulosic-based biorefineries. In this study, a two-stage evolution of an industrial yeast strain engineered with a xylose isomerase pathway yielded strain AceY.14, which exhibited improved fermentative performance and increased tolerance to acetic acid. Whole-genome sequencing of the evolved strain identified SNPs in ZWF1, a component of the pentose phosphate pathway (PPP), and in the G1 cyclin gene CLN3, both of which were functionally validated through CRISPR and reverse engineering. The zwf1 Show less

The innate immune response and cytokine milieu in airway mucosa, mediated by bronchial epithelial cells, are critical in determining susceptibility or protection against cryptococcosis. In experimental models, Th2 and Th1 responses are linked to susceptibility and protection, respectively, while the roles of other cytokines remain less understood. To evaluate the in vitro effects of IL-4, IFN-γ, and IL-27 (100ng/mL) on human bronchial epithelial cells (BEAS-2B) infected with a strain of Cryptococcus neoformans sensu stricto (multiplicities of infection [MOI] 1-100). Cells were stimulated with each cytokine, followed by C. neoformans infection (MOI 100). After 24h, supernatants were collected to measure CCL2, IL-6, and IL-8 production. STAT1 and STAT6 activation was analyzed by flow cytometry. Phagocytosis and colony-forming unit assays assessed fungal internalization and growth. Cytokine-stimulated, infected cells displayed reduced IL-6 and/or CCL2 production and decreased STAT6 activation (IL-4) or STAT1 activation (IL-27, IFN-γ) compared with cells stimulated with C. neoformans sensu stricto or cytokines alone. IL-27 reduced fungal internalization, while IL-4 and IFN-γ increased it. All cytokines promoted higher fungal growth. The interaction of bronchial epithelial cells stimulated with IL-4, IFN-γ, or IL-27, with yeasts of C. neoformans induced an anti-inflammatory profile in the cells that impaired STAT activation and favored fungal proliferation. These findings suggest that certain cytokine environments within the airway epithelium may create conditions conducive to C. neoformans persistence, potentially influencing the progression of the infection. Show less

Osteosarcoma is the most common primary malignant bone tumor, predominantly affecting young individuals. Despite standard chemotherapy and surgical resection, the overall survival rate has reached a plateau, emphasizing the need for more effective treatments. Flavonoids are antioxidant molecules with recognized anti-inflammatory and anticancer properties. In this study, we aimed to investigate the therapeutic potential of five flavonoids against four different osteosarcoma cell lines (MG-63, Saos-2 HOS, and 143B). Among the five structurally different flavonoids, robinetin exhibited the highest toxicity against osteosarcoma cells while sparing healthy human lung fibroblasts (MRC-5). Robinetin synergized with doxorubicin, reducing 143B cell viability, delaying migration, and downregulating metastasis-related transcription factors c-Jun, Snail, Slug, and Twist2. In vivo, robinetin inhibited the growth of osteosarcoma tumor xenografts in a chick chorioallantoic membrane model. Our study highlights and reports for the first time the therapeutic value of robinetin and demonstrates the potential of robinetin in osteosarcoma treatment. Show less

The melanocortin receptors are a class of centrally and peripherally expressed G protein-coupled receptors, of which the MC3R and MC4R subtypes are implicated in the regulation of appetite and energy homeostasis and can serve as potential therapeutic targets for disorders such as obesity and cachexia. An unbiased high-throughput mixture-based library screen was implemented to identify novel ligands with an emphasis on the identification of nanomolar-potent agonists of the mouse melanocortin-3 receptor. This screen yielded the discovery of an N-branched tricyclic guanidine scaffold (TPI2408) that contained three nanomolar potent mMC3R agonists and additional compounds that possessed antagonism for the mMC4R. The antagonist character of this scaffold library at the mMC4R was confirmed by a follow-up positional scanning antagonist screen. Additionally, molecular dynamics simulations herein provide mechanistic insight into the polypharmacological characteristics of melanocortin receptors. The disclosed materials have the potential to serve as important tools and SAR scaffolds in the study of melanocortin receptor function. Show less

This review examines the physiological functions of Angiopoietin-like proteins (ANGPTLs) in lipid metabolism and the epidemiology of atherosclerotic cardiovascular disease (ASCVD), while discussing their potential as therapies for dyslipidemias. A review of contemporary literature on ANGPTLs was conducted. ANGPTLs comprise eight secreted proteins that share structural similarities with the angiopoietin family and serve as key regulators of various physiological and biochemical functions. Notably, ANGPTL3, ANGPTL4, and ANGPTL8 act as physiological inhibitors of lipoprotein lipase (LPL), playing a crucial role in lipoprotein and triglyceride metabolism in response to the body's nutritional status. A deficiency in these proteins is linked to hypolipidemia, characterized by a decrease in all lipid fractions, and genetic studies indicate a reduced risk of ASCVD in individuals with loss-of-function variants in ANGPTL3 and ANGPTL4. Conversely, elevated levels of ANGPTL3, ANGPTL4, and ANGPTL8 seem to increase the risk of cardiovascular disease. The role of ANGPTLs in regulating lipid metabolism underscores their potential in targeted therapies for managing dyslipidemias and lowering ASCVD risk, particularly in patients with difficult-to-control dyslipidemia phenotypes, such as homozygous Familial Hypercholesterolemia and mixed dyslipidemia. The development of ANGPTL inhibitors could provide an effective strategy for preventing ASCVD. Show less

Familial hypercholesterolaemia (FH) is an autosomal dominant genetic disorder, characterised by markedly elevated levels of low-density lipoprotein cholesterol (LDL-C) from birth, which confers a substantially increased risk of premature atherosclerotic cardiovascular disease (ASCVD). Pathogenic variants primarily occur in the genes encoding the low-density lipoprotein receptor (LDLR), apolipoprotein B (ApoB), low-density lipoprotein receptor adaptor protein 1 (LDLRAP1), or proprotein convertase subtilisin/kexin type 9 (PCSK9). Early diagnosis, based on clinical criteria, family history, and genetic testing, is imperative to promptly initiate aggressive therapeutic strategies. Standard treatment involves lifestyle modifications and high-intensity pharmacotherapy, primarily with statins, often in combination with ezetimibe. For patients who do not achieve their therapeutic goals or are intolerant, PCSK9 inhibitors represent a significant evolution in the treatment paradigm. In this article, we present a case of homozygous familial hypercholesterolaemia. Show less

Alzheimer's disease (AD) is the most common form of dementia worldwide, accounting for an estimated 60-70 % of cases. β-secretase 1 (BACE1), is one of the main therapeutic targets involved in the disease's pathology, as it is involved in the production of amyloid β. Butrylcholinesterase (BuChE) which is active in the advanced stages of the disease, is targeted for symptomatic relief. AD is a complex illness that needs to be tackled from different angles for which the Multi-target inhibitor approach is a viable current strategy. This work focuses on the development of novel acyl-oxindole molecules - some containing fluorine units, obtained via a structure-based drug design approach, for inhibition of BACE1 and BuChE. This study explored the development of a sustainable metal-based synthetic procedure for rapid and sustainable assess of libraries of these new oxindole derivatives. The compounds were screened to determine their ability to inhibit BACE1, and demonstrated reasonable levels of inhibition, with some of these inhibitors being selected for docking studies to determine the binding mode to the target's active site. One of the key molecules 12a underwent a cytotoxicity screen in a mouse neuroblastoma cell line expressing the APPswe protein (N2A-APPswe cells) and was an inhibitor of both AChE and BuChE (more potent against the latter, including the human version). Some compounds (3a, 3b, 3i and 12a) have shown moderate BuChE inhibitory activity. Show less

The dual specificity phosphatase 6 (DUSP6) was recently implicated in autoimmune arthritis pathogenesis. However, it remains unclear which cell mediates its pathogenic activity in a mouse model of rheumatoid arthritis (RA). Bone marrow (BM) CD11b + Gr1 + cells were isolated from DUSP6 +/+ mice and transferred into DUSP6 -/- recipients. Six weeks later mice were administered the KRN serum to induce arthritis (KSIA), and analyzed for arthritis severity clinical scores. The same strategy was used in the opposite direction with cells from DUSP6-/- cells transferred in DUSP6 +/+ mice. BM CD11b + Gr1 + cells from DUSP6 +/+ and DUSP6 -/ - were stimulated with PMA and used for RNA sequencing, and also used for real-time measurements of mitochondrial respiration with the Seahorse XF Analyzer. Transfer of CD11 + Gr1 + cells DUSP6 We describe a new arthritogenic role for DUSP6, which is mediated by CD11b + Gr1 + cells and their glycolytic activity and oxidative burst. Our findings also implicate these myeloid cells in arthritis pathogenesis and raise the possibility that DUSP6 may be a good target for the development of new therapies for RA. Show less

The opioid epidemic continues to grow, placing a significant strain on Emergency Departments (EDs), resulting in patients presenting daily with opioid-related concerns including intoxication, withdrawal, infections, injury, and death. Consequently, in recent years many EDs, including our own, have utilized Emergency Department Observation Units (EDOU) to not only manage withdrawal and overdose, but also initiate long-term treatment. This study aims to evaluate the outcomes of patients with opioid use disorder (OUD) who were managed in our EDOU. This was a retrospective study of patients placed in an EDOU who had the primary diagnosis of OUD in a single large, urban, tertiary academic hospital from May to November 2021. Demographic data and factors related to the ED visit and EDOU actions (e.g., use of peer navigator services, buprenorphine dose and prescription, distribution of naloxone discharge kits, and addiction clinic referral) were analyzed. The primary outcome variables were complications after buprenorphine use (e.g., precipitated withdrawal), the number of repeat ED visits or subsequent hospitalizations within 30 days for both all causes and opioid-related causes, and fatalities within 30 days of EDOU discharge. Twenty-nine patients were identified for chart review. Of these, 59 % were male. The median age was 55 years. Additionally, 93 % of the patients were insured, 66 % had housing, 72 % possessed a phone, and none were employed. During EDOU stays, 48 % [95 % CI 0.2989, 0.6711] of patients received buprenorphine with a total mean dose of 19 mg (SD, 10.6 mg). Upon discharge from the EDOU, 48 % [95 % CI 0.2989, 0.6711] were prescribed buprenorphine, 14 % [95 % CI 0.0451, 0.3257] received a naloxone discharge kit, and 45 % [95 % CI 0.2696, 0.6402] received an addiction clinic appointment. No patients had precipitated withdrawal, serious adverse events, or upgrades to inpatient care. Within 30-days of EDOU discharge, 38 % [95 % CI 0.213, 0.5764] of patients had a subsequent ED visit for any cause, and 6.9 % [95 % CI 1.2, 2.2] had a subsequent hospitalization for any cause. There were no fatalities within 30 days of EDOU discharge. The EDOU can serve as a promising location to provide quality care for patients presenting to the ED with OUD, with minimal adverse effects. There were few subsequent hospitalizations following discharge from the EDOU. Further non-observational studies regarding OUD management in an EDOU setting should be performed to optimize care and improve clinical outcomes and healthcare utilization. Show less

Childhood obesity and associated comorbidities in adulthood are of great concern worldwide. Evidence highlights the importance of lactation in later disease development. In this sense, obese children are at great risk of developing adult obesity, insulin resistance, type 2 diabetes, and cardiovascular disease at adulthood. PPARα activation during lactation promotes the expression of key enzymes involved in lipid oxidation, and it was associated with reduced adiposity in children. Therefore, we hypothesized that an animal model of childhood obesity, small litter (SL), would lead to the development of obesity and metabolic dysfunction in adulthood, which could be prevented by postnatal PPARα agonism. Wistar dams had their litter reduced, leading to postnatal overfeeding and obesity early in life. SL male pups were treated with fenofibrate, an PPARα agonist, during lactation, from postnatal day (PND) 1 until weaning (PND21), to verify whether PPARα activation prevents the developmental programming at adulthood (PND120). Childhood obesity induced by postnatal overfeeding leads to decreased markers for oxidative metabolism during infancy, leading to increased visceral adiposity and oxidative stress, insulin resistance, hepatic microvesicular steatosis, and increased fibroblast growth factor 21 (Fgf21) expression, followed by decreased brown adipose tissue (BAT) sympathetic nerve activity and decreased Fgfr1 hypothalamic expression in adulthood. Agonist-induced PPARα activation during lactation mitigated the development of aforementioned alterations in adulthood. Postnatal fenofibrate treatment prevents the developmental programming of visceral obesity, liver-associated metabolic dysfunction and BAT autonomic sympathetic hypoactivity in an animal model of childhood obesity. Show less

Coronavirus disease 2019 (COVID-19) has been widely associated with intense systemic inflammation, endothelial injury, and a high incidence of thrombotic complications, which together contribute to disease severity and poor clinical outcomes. While endothelial dysfunction, dysregulated cytokine production, and oxidative stress are recognized features of severe COVID-19, the direct impact of circulating factors from infected individuals on endothelial cell behavior remains insufficiently characterized. Here, we examined how serum from patients with severe COVID-19 and from convalescent individuals modulates endothelial activation, inflammatory responses, and oxidative stress using human umbilical vein endothelial cells as an in vitro model. Venous blood samples were collected from individuals with severe COVID-19 (n = 13), convalescent patients (n = 11), and healthy volunteers (n = 7) during the initial phase of the COVID-19 pandemic. Human umbilical vein endothelial cells (HUVEC) were maintained in culture and exposed to 15% serum from each study group after a period of serum deprivation. The expression of genes associated with endothelial activation, thrombosis, inflammation, and oxidative stress was analyzed by quantitative real-time PCR at defined time points. In addition, the endothelial secretory profile was evaluated in cell culture supernatants using multiplex bead-based immunoassays. Statistical analyses were performed using one-way ANOVA followed by appropriate post hoc tests, receiver operating characteristic (ROC) curve analysis to assess the discriminatory capacity of biomarkers, and multivariate linear regression to identify factors associated with disease severity. We investigated the role of the endothelium in modulating the cytokine storm in severe COVID-19. HUVEC were stimulated with serum from patients with severe COVID-19, convalescent individuals, and healthy volunteers. Stimulation with serum from severe cases induces significant increases in These findings suggest that HUVEC serves as a promising biological sensor for detecting inflammatory responses in COVID-19 patients and shows the crucial role of the endothelium in sustaining the cytokine storm that contributes to patient severity and mortality. Show less

Understanding the immunopathogenesis of COVID-19 has yielded valuable insights into predicting adverse outcomes-particularly mortality. However, significant gaps persist in our comprehension of the complex interplay among the proposed pathophysiological mechanisms. Here, we aim to investigate the immunological factors associated with mortality in critically ill, unvaccinated COVID-19 patients admitted to the intensive care unit (ICU). We conducted a single-center, prospective study involving 56 unvaccinated COVID-19 patients admitted to the ICU. Plasma cytokine levels at admission were quantified using enzyme-linked immunosorbent assay (ELISA). Continuous variables were presented as median (IQR), and categorical variables as frequencies and percentages. Non-parametric tests assessed group differences. Logistic regression and receiver operating characteristic (ROC) curve analyses identified predictors of mortality, with bootstrapping (1000 re-samplings; 95 % BCa CI) applied for model validation. Deceased patients exhibited significantly higher levels of interleukin (IL)-1β, IL-2, IL-6, transforming growth factor (TGF)-β, and interferon (IFN)-γ compared to survivors. Conversely, IL-10 and IL-27 were associated with favorable outcomes. Logistic regression modeling identified elevated IL-2 and IFN-γ levels as significant predictors of mortality. Notably, individual ROC curve analyses demonstrated that IL-1β and TGF-β had excellent discriminatory ability for mortality, while IFN-γ, IL-2, and IL-27 showed very good to excellent discriminatory capacity. Our results indicate that distinct cytokine profiles differentiate survivors from non-survivors in critically ill, unvaccinated COVID-19 patients. These findings highlight the importance of cytokine dysregulation in severe COVID-19 cases and suggest potential targets for prognostic approaches. Further research is warranted to validate these results and translate them into effective clinical management strategies. Show less

Interventions have focused on evaluating effective strategies for increasing physical activity (PA) and reducing sedentary behavior (SB) in children and adolescents, which is still a challenge mainly in low- and middle-income countries. Thus, this study aimed to assess the effect of the Movimente Study on device-measured PA and SB in two-time segments of the school day amongst Brazilian adolescents. Six elementary schools were randomized into the intervention (IG) or control group (CG). Participants were in 7th -9th grades. A school year (2017) multicomponent intervention was delivered consisting of three components: (1) teacher training, (2) education curriculum, and (3) school environment. PA and SB were assessed using GT3x + ActiGraph hip-worn accelerometers. The trial's primary outcome was overall device-measured PA and SB. Exploratory secondary analyses examined PA and SB within in-School (08:00-11:59) and out-of-school (12:00-22:00) time segments. A two-level linear mixed model assessed the effect of the intervention on light-intensity PA (LPA), moderate- to vigorous-intensity PA (MVPA), SB, and MVPA/SB ratio within and between groups. There was a significant effect on the IG compared to the CG for MVPA (Coefficient [Coef.] = 16.2; 95% Confidence Interval [95%CI] = 6.9;25.5; p-value = 0.001), SB (Coef. = -22.7; 95%CI = -44.7;-0.7; p-value = 0.043), and MVPA/SB ratio (Coef. = 3.2; 95%CI = 1.2;5.3; p-value = 0.002) performed in the out-of-school segment, but not in the In-school segment. However, there were no significant differences within- nor between-group differences in LPA in both day segments. The Movimente Study was associated with greater increases in MVPA, improvements in the MVPA/SB ratio, and reductions in SB during the out-of-school period compared with control peers. Clinical Trials - NCT02944318. Registration Date: 10/24/2016. Show less

Cost-effectiveness of Lipoprotein(a) [Lp(a)] testing is not established. We aimed to evaluate the cost-effectiveness of Lp(a) testing in the cardiovascular disease (CVD) primary prevention population from healthcare and societal perspectives. We constructed and validated a multi-state microsimulation Markov model for a population of 10,000 individuals aged between 40 and 69 years without CVD, selected randomly from the UK Biobank. The model evaluated Lp(a) testing in individuals not initially classified as high-risk based on age, diabetes status, or the SCORE-2 algorithm. Those with an Lp(a) level ≥105 nmol/L (50 mg/dL) were treated as high risk (initiation of a statin plus blood pressure lowering). The Lp(a) testing intervention was compared to standard of care. The primary analyses were conducted from the Australian and UK healthcare perspectives in 2023AUD/GBP. A cost adaptation method estimated cost-effectiveness in multiple European countries, Canada, and the USA. Among 10,000 individuals, 1,807 had their treatment modified from Lp(a) testing. This led to 217 and 255 quality-adjusted life years gained in Australia and the UK, respectively, with corresponding incremental cost-effectiveness ratios of 12,134 (cost-effective) and -3,491 (cost-saving). From a societal perspective, Lp(a) testing saved $85 and £263 per person in Australia and the UK, respectively. Lp(a) testing was cost-saving among all countries tested in the cost adaptation analysis. Lp(a) testing in the primary prevention population to reclassify CVD risk and treatment is cost-saving and warranted to prevent CVD. Show less

Familial chylomicronemia syndrome (FCS) is an autosomal recessive disorder that affects approximately 1 to 10 individuals per million and is caused by variants in the genes encoding for the lipoprotein lipase (LPL) enzyme. In addition to its heterogeneous clinical presentation, FCS is characterized by a higher risk of life-threatening, recurrent acute pancreatitis and type 3 diabetes. Since available evidence on FCS in Latin America is limited, there is a clear need for a consensus document that provides relevant recommendations to guide the management of suspected cases and optimize disease diagnosis across the region. A panel of specialists from Latin America with extensive experience in the diagnosis of chylomicronemia was invited to participate in the creation of this document. The modified Delphi technique was used to reach group consensus through multiple rounds of questionnaires using statistical techniques and controlled feedback. Results and discussion: Seventeen recommendations on diagnosis of FCS were generated. This consensus reflects the collaborative efforts of Latin American scientific societies and is essential to suspect and diagnose FCS. The organizations that support this document, including Sociedad Argentina de Lípidos, Federación Argentina de Sociedades de Endocrinología, Fundación Bioquímica Argentina, Corporación Grupo Chileno de Trabajo en Ateroesclerosis, Asociación Colombiana de Endocrinología, Diabetes y Metabolismo, Departamento de Aterosclerose da Sociedade Brasileira de Cardiología, and Sociedad Mexicana de Nutrición y Endocrinología, are a robust support network that might aid the adoption of these recommendations in local healthcare systems. Show less

Studies addressing the methylation pattern in adamantinomatous craniopharyngioma (ACP) are lacking. To identify methylation signatures in ACPs regarding clinical presentation and outcome. Clinical and pathology data were collected from 35 patients with ACP (54% male; 18.1 years [2-68]). CTNNB1 mutations and methylation profile (MethylationEPIC/Array-Illumina) were analyzed in tumoral DNA. Unsupervised machine learning analysis of this comprehensive methylome sample was achieved using hierarchical clustering and multidimensional scaling. Statistical associations between clusters and clinical features were achieved using the Fisher test and global biological process interpretations were aided by Gene Ontology enrichment analyses. Two clusters were revealed consistently by all unsupervised methods (ACP-1: n = 18; ACP-2: n = 17) with strong bootstrap statistical support. ACP-2 was enriched by CTNNB1 mutations (100% vs 56%, P = .0006), hypomethylated in CpG island, non-CpG Island sites, and globally (P < .001), and associated with greater tumor size (24.1 vs 9.5 cm3, P = .04). Enrichment analysis highlighted pathways on signaling transduction, transmembrane receptor, development of anatomical structures, cell adhesion, cytoskeleton organization, and cytokine binding, and cell type-specific biological processes as regulation of oligodendrocytes, keratinocyte, and epithelial cells differentiation. Two clusters of patients with ACP were consistently revealed by unsupervised machine learning methods, with one of them significantly hypomethylated, enriched by CTNNB1 mutated ACPs, and associated with increased tumor size. Enrichment analysis reinforced pathways involved in tumor proliferation and in cell-specific tumoral microenvironment. Show less

Kefir is a complex microbial community that plays a critical role in the fermentation and production of bioactive peptides, and has health-improving properties. The composition of kefir can vary by geographic localization and weather, and this paper focuses on a Brazilian sample and continues previous work that has successful anti-Alzheimer properties. In this study, we employed shotgun metagenomics and peptidomics approaches to characterize Brazilian kefir further. We successfully assembled the novel genome of Lactobacillus kefiranofaciens (LkefirU) and conducted a comprehensive pangenome analysis to compare it with other strains. Furthermore, we performed a peptidome analysis, revealing the presence of bioactive peptides encrypted by L. kefiranofaciens in the Brazilian kefir sample, and utilized in silico prospecting and molecular docking techniques to identify potential anti-Alzheimer peptides, targeting β-amyloid (fibril and plaque), BACE, and acetylcholinesterase. Through this analysis, we identified two peptides that show promise as compounds with anti-Alzheimer properties. These findings not only provide insights into the genome of L. kefiranofaciens but also serve as a promising prototype for the development of novel anti-Alzheimer compounds derived from Brazilian kefir. Show less