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This music score was submitted for Resonate 2024: An Open Access Call for Scores by the UCLA Music Library with Bent Frequency and Jan Berry Baker.

Tissue hypoxia and even death from methemoglobinemia occur when its levels exceed 2%, and the higher the level, the more severe the symptoms presented by the patient. Its mechanism occurs through the oxidation of hemoglobin from ferrous to ferric state, making the iron in the heme unable to bind to oxygen. It is a congenital or acquired pathology, the latter when there is exposure to certain oxidizing agents, such as pesticides, fertilizers, topical anesthetics, and nitrates, as in the case described. The symptoms are variable, from just grayish pigmentation of the skin to central cyanosis, browning of the blood, syncope, dyspnea, convulsions, and even cardiovascular failure due to tissue hypoxia. But, the main sign is the disparity between saturation on pulse oximetry and arterial oxygen saturation, refractory to oxygen therapy. The agility in the diagnosis and in the institution of the adequate treatment are essential for a good outcome, having as the main curative measure the administration of methylene blue. This paper presents a case report of an adolescent patient with methemoglobinemia acquired after ingestion of ultra-processed food. Structured report from the analysis of the medical record and literature review on the subject. No conflict of interest or external funding source.

A metemoglobinemia é uma causa rara, frequentemente negligenciada e potencialmente grave de cianose na população pediátrica. Pode ocorrer como resultado de defeito congênito ou ad-quirido, por exposição a substâncias que oxidam a hemoglobina. Dentre essas substâncias encontra-se a fenazopiridina, analgésico urinário amplamente disponível. Seu diagnóstico é um desafio clínico, e deve ser aventado em pacientes que apresentem cianose central e baixa satu-ração ao oxímetro de pulso refratários à oxigenoterapia. Em situações com manifestações clíni-cas significativas, o tratamento inclui administração de azul de metileno, além da remoção do agente indutor e administração de oxigênio em alto fluxo. O presente caso demonstra o diag-nóstico clínico de metemoglobinemia secundária à intoxicação intencional por fenazopiridina, com tratamento adequado em tempo hábil e desfecho satisfatório.

Background and aimsWe previously identified subsets of patients with NAFLD with different metabolic phenotypes. Here we align metabolomic signatures with cardiovascular disease (CVD) and genetic risk factors.Approach and resultsWe analyzed serum metabolome from 1154 individuals with biopsy-proven NAFLD, and from four mouse models of NAFLD with impaired VLDL-triglyceride (TG) secretion, and one with normal VLDL-TG secretion. We identified three metabolic subtypes: A (47%), B (27%), and C (26%). Subtype A phenocopied the metabolome of mice with impaired VLDL-TG secretion; subtype C phenocopied the metabolome of mice with normal VLDL-TG; and subtype B showed an intermediate signature. The percent of patients with NASH and fibrosis was comparable among subtypes, although subtypes B and C exhibited higher liver enzymes. Serum VLDL-TG levels and secretion rate were lower among subtype A compared with subtypes B and C. Subtype A VLDL-TG and VLDL-apolipoprotein B concentrations were independent of steatosis, whereas subtypes B and C showed an association with these parameters. Serum TG, cholesterol, VLDL, small dense LDL5,6 , and remnant lipoprotein cholesterol were lower among subtype A compared with subtypes B and C. The 10-year high risk of CVD, measured with the Framingham risk score, and the frequency of patatin-like phospholipase domain-containing protein 3 NAFLD risk allele were lower in subtype A.ConclusionsMetabolomic signatures identify three NAFLD subgroups, independent of histological disease severity. These signatures align with known CVD and genetic risk factors, with subtype A exhibiting a lower CVD risk profile. This may account for the variation in hepatic versus cardiovascular outcomes, offering clinically relevant risk stratification.

Objectives: To make recommendations on the diagnosis and treatment of post-extubation laryngitis (PEL) in children with or without other comorbidities. Methods: A three-iterative modified Delphi method was applied. Specialists were recruited representing pediatric otolaryngologists, pediatric and neonatal intensivists. Questions and statements approached topics encompassing definition, diagnosis, endoscopic airway evaluation, risk factors, comorbidities, management, and follow-up. A consensus was defined as a supermajority >70%. Results: Stridor was considered the most frequent symptom and airway endoscopy was recommended for definitive diagnosis. Gastroesophageal reflux and previous history of intubation were considered risk factors. Specific length of intubation did not achieve a consensus as a risk factor. Systemic corticosteroids should be part of the medical treatment and dexamethasone was the drug of choice. No consensus was achieved regarding dosage of corticosteroids, although endoscopic findings help defining dosage and length of treatment. Non-invasive ventilation, laryngeal rest, and use of comfort sedation scales were recommended. Indications for microlaryngoscopy and bronchoscopy under anesthesia were symptoms progression or failure to improve after the first 72-h of medical treatment post-extubation, after two failed extubations, and/or suspicion of severe lesions on flexible fiberoptic laryngoscopy. Conclusions: Management of post-extubation laryngitis is challenging and can be facilitated by a multidisciplinary approach. Airway endoscopy is mandatory and impacts decision-making, although there is no consensus regarding dosage and length of treatment.

ABSTRACT Objective: Pediatric cardiac tumors are rare and, among them, 90% are benign. Cardiac fibroma is the second most frequent tumor, after rhabdomyoma. The objective of this study is to report a case of cardiac fibroma diagnosed incidentally in a patient admitted with acute viral bronchiolitis. Case description: A 5-month-old male infant was admitted to the pediatric emergency department with acute viral bronchiolitis requiring hospitalization. He presented a detectable respiratory syncytial virus in oropharyngeal swab, blood test with lymphocytosis and a chest radiography revealed cardiomegaly. Further cardiologic testing was performed detecting elevation of cardiac biomarkers, an electrocardiogram with alteration of left ventricular repolarization and echocardiogram with a heterogeneous mass in the left ventricular, with areas of calcification. A chest angiotomography suggested rhabdomyosarcoma or cardiac fibroma and a magnetic resonance showed a mass, with characteristics suggesting fibroma. The final diagnosis was made after two cardiac catheterizations for biopsy of the lesion, confirming cardiac fibroma by anatomopathological examination. Because the patient had moderate to severe systolic dysfunction, he was submitted to heart transplant. Comments: One third of cardiac fibromas are asymptomatic, generally diagnosed late through tests ordered for other reasons. The gold-standard test for definitive diagnosis is biopsy. Cardiac fibroma usually does not present spontaneous regression and, in most cases, partial or total surgical resection is necessary. When tumors are unresectable, heart transplantation should be indicated. It is essential to have detailed characterization of the cardiac mass to establish the most appropriate therapeutic approach for each patient.

MATα1 catalyzes the synthesis of S-adenosylmethionine, the principal biological methyl donor. Lower MATα1 activity and mitochondrial dysfunction occur in alcohol-associated liver disease. Besides cytosol and nucleus, MATα1 also targets the mitochondria of hepatocytes to regulate their function. Here, we show that mitochondrial MATα1 is selectively depleted in alcohol-associated liver disease through a mechanism that involves the isomerase PIN1 and the kinase CK2. Alcohol activates CK2, which phosphorylates MATα1 at Ser114 facilitating interaction with PIN1, thereby inhibiting its mitochondrial localization. Blocking PIN1-MATα1 interaction increased mitochondrial MATα1 levels and protected against alcohol-induced mitochondrial dysfunction and fat accumulation. Normally, MATα1 interacts with mitochondrial proteins involved in TCA cycle, oxidative phosphorylation, and fatty acid β-oxidation. Preserving mitochondrial MATα1 content correlates with higher methylation and expression of mitochondrial proteins. Our study demonstrates a role of CK2 and PIN1 in reducing mitochondrial MATα1 content leading to mitochondrial dysfunction in alcohol-associated liver disease.

Dysregulation of miRNAs is a hallmark of cancer, modulating oncogenes, tumor suppressors, and drug responsiveness. The multi-kinase inhibitor sorafenib is one of the first-line drugs for advanced hepatocellular carcinoma (HCC), although the outcome for treated patients is heterogeneous. The identification of predictive biomarkers and targets of sorafenib efficacy are sorely needed. Thus, selected top upregulated miRNAs from the C19MC cluster were analyzed in different hepatoma cell lines compared to immortalized liver human cells, THLE-2 as control. MiR-518d-5p showed the most consistent upregulation among them. Thus, miR-518d-5p was measured in liver tumor/non-tumor samples of two distinct cohorts of HCC patients (n = 16 and n = 20, respectively). Circulating miR-518d-5p was measured in an independent cohort of HCC patients receiving sorafenib treatment (n = 100), where miR-518d-5p was analyzed in relation to treatment duration and patient's overall survival. In vitro and in vivo studies were performed in human hepatoma BCLC3 and Huh7 cells to analyze the effect of miR-518d-5p inhibition/overexpression during the response to sorafenib. Compared with healthy individuals, miR-518d-5p levels were higher in hepatic and serum samples from HCC patients (n = 16) and in an additional cohort of tumor/non-tumor paired samples (n = 20). MiR-518d-5p, through the inhibition of c-Jun and its mitochondrial target PUMA, desensitized human hepatoma cells and mouse xenograft to sorafenib-induced apoptosis. Finally, serum miR-518d-5p was assessed in 100 patients with HCC of different etiologies and BCLC-stage treated with sorafenib. In BCLC-C patients, higher serum miR-518d-5p at diagnosis was associated with shorter sorafenib treatment duration and survival. Hence, hepatic miR-518d-5p modulates sorafenib resistance in HCC through inhibition of c-Jun/PUMA-induced apoptosis. Circulating miR-518d-5p emerges as a potential lack of response biomarker to sorafenib in BCLC-C HCC patients.

COVID-19 is a systemic infection that exerts significant impact on the metabolism. Yet, there is little information on how SARS-CoV-2 affects metabolism. Using NMR spectroscopy, we measured the metabolomic and lipidomic serum profile from 263 (training cohort) + 135 (validation cohort) symptomatic patients hospitalized after positive PCR testing for SARS-CoV-2 infection. We also established the profiles of 280 persons collected before the coronavirus pandemic started. Principal-component analysis discriminated both cohorts, highlighting the impact that the infection has on overall metabolism. The lipidomic analysis unraveled a pathogenic redistribution of the lipoprotein particle size and composition to increase the atherosclerotic risk. In turn, metabolomic analysis reveals abnormally high levels of ketone bodies (acetoacetic acid, 3-hydroxybutyric acid, and acetone) and 2-hydroxybutyric acid, a readout of hepatic glutathione synthesis and marker of oxidative stress. Our results are consistent with a model in which SARS-CoV-2 infection induces liver damage associated with dyslipidemia and oxidative stress.

BackgroundArachidyl amido cholanoic acid (Aramchol) is a potent downregulator of hepatic stearoyl-CoA desaturase 1 (SCD1) protein expression that reduces liver triglycerides and fibrosis in animal models of steatohepatitis. In a phase IIb clinical trial in patients with nonalcoholic steatohepatitis (NASH), 52 wk of treatment with Aramchol reduced blood levels of glycated hemoglobin A1c, an indicator of glycemic control.AimTo assess lipid and glucose metabolism in mouse hepatocytes and in a NASH mouse model [induced with a 0.1% methionine and choline deficient diet (0.1MCD)] after treatment with Aramchol.MethodsIsolated primary mouse hepatocytes were incubated with 20 μmol/L Aramchol or vehicle for 48 h. Subsequently, analyses were performed including Western blot, proteomics by mass spectrometry, and fluxomic analysis with 13C-uniformly labeled glucose. For the in vivo part of the study, male C57BL/6J mice were randomly fed a control or 0.1MCD for 4 wk and received 1 or 5 mg/kg/d Aramchol or vehicle by intragastric gavage for the last 2 wk. Liver metabolomics were assessed using ultra-high-performance liquid chromatography-time of flight-MS for the determination of glucose metabolism-related metabolites.ResultsCombination of proteomics and Western blot analyses showed increased AMPK activity while the activity of nutrient sensor mTORC1 was decreased by Aramchol in hepatocytes. This translated into changes in the content of their downstream targets including proteins involved in fatty acid (FA) synthesis and oxidation [P-ACCα/β(S79), SCD1, CPT1A/B, HADHA, and HADHB], oxidative phosphorylation (NDUFA9, NDUFB11, NDUFS1, NDUFV1, ETFDH, and UQCRC2), tricarboxylic acid (TCA) cycle (MDH2, SUCLA2, and SUCLG2), and ribosome (P-p70S6K[T389] and P-S6[S235/S236]). Flux experiments with 13C-uniformely labeled glucose showed that TCA cycle cataplerosis was reduced by Aramchol in hepatocytes, as indicated by the increase in the number of rounds that malate remained in the TCA cycle. Finally, liver metabolomic analysis showed that glucose homeostasis was improved by Aramchol in 0.1MCD fed mice in a dose-dependent manner, showing normalization of glucose, G6P, F6P, UDP-glucose, and Rbl5P/Xyl5P.ConclusionAramchol exerts its effect on glucose and lipid metabolism in NASH through activation of AMPK and inhibition of mTORC1, which in turn activate FA β-oxidation and oxidative phosphorylation.

Non-alcoholic steatohepatitis (NASH) is characterized by the accumulation of hepatic fat in an inflammatory/fibrotic background. Herein, we show that the hepatic high-activity glutaminase 1 isoform (GLS1) is overexpressed in NASH. Importantly, GLS1 inhibition reduces lipid content in choline and/or methionine deprivation-induced steatotic mouse primary hepatocytes, in human hepatocyte cell lines, and in NASH mouse livers. We suggest that under these circumstances, defective glutamine fueling of anaplerotic mitochondrial metabolism and concomitant reduction of oxidative stress promotes a reprogramming of serine metabolism, wherein serine is shifted from the generation of the antioxidant glutathione and channeled to provide one-carbon units to regenerate the methionine cycle. The restored methionine cycle can induce phosphatidylcholine synthesis from the phosphatidylethanolamine N-methyltransferase-mediated and CDP-choline pathways as well as by base-exchange reactions between phospholipids, thereby restoring hepatic phosphatidylcholine content and very-low-density lipoprotein export. Overall, we provide evidence that hepatic GLS1 targeting is a valuable therapeutic approach in NASH.

Forming groups in distance education is challenging for teachers because, with this modality, only 20% of the classes are held in person with the students. Thus, it is essential to achieve satisfactory results with automated approaches that can help teachers. In this article, an automated approach is proposed to assist teachers in recommending groups of students to learning management systems. We developed and validated a conceptual framework for group recommendation for collaborative activities using the characterization of learners based on learning paths (LPs). The approach emphasizes the formation of groups by applying the k-means algorithm, associated with three distance metrics of similarity (i.e., Euclidean, Manhattan, and cosine) in conjunction with the attributes derived from LPs. The framework was validated through the implementation of an M-Cluster tool. The M-Cluster presents three solution options, which can be visualized in a descriptive manner or via a bubble graph; it is the teacher who chooses the most acceptable solution for each case. The results of the case study indicate that the tool shows promise for improving the performance of students to up to 75%.