Pediatric COVID-19 in Argentina: a comprehensive analysis of disease and economic burden through official data and a systematic literature review.

Background: Limited data are available on the clinical impact and economic burden of COVID-19 in the pediatric population in Argentina. We aimed to estimate the disease and economic burden of COVID-19 on children and adolescents. Methods: We analyzed official national databases and conducted a supplemental systematic review of the published literature with meta-analysis in children aged 0-18. The period of interest was from March 2020 to August 2021, before the introduction of vaccination in this age group as a national strategic plan. In addition, we used a cost of illness analysis to estimate the direct medical costs associated with COVID-19. All costs are reported in US dollars 2023. Results: A total of 450,503 confirmed COVID-19 cases and 180 multisystem inflammatory syndrome (MIS-C) were reported in Argentina in the study period. Fourteen observational clinical studies were identified. The meta-analyses of severity level from hospital patients showed that according to different studies 15%-28% of cases were asymptomatic, 68%-88% were mild or moderate, and 3%-10% were severe or critical. About 28% of children had an underlying disease. In addition, the estimated economic burden associated with COVID-19 was 80 million dollars and 4 million dollars corresponded to MISC. Conclusion: Significant impact of COVID-19 on the healthcare system and substantial economic implications for the pediatric population in Argentina were identified. The findings should help policymakers to make informed decisions and allocate resources effectively.

Irreversible atrophy in memory brain regions over 7 years is predicted by glycemic control in type 2 diabetes without mild cognitive impairment.

Memory-related impairments in type 2 diabetes may be mediated by insulin resistance and hyperglycemia. Previous cross-sectional studies have controversially suggested a relationship between metabolic control and a decrease in hippocampal volumes, but only longitudinal studies can test this hypothesis directly. We performed a longitudinal morphometric study to provide a direct test of a possible role of higher levels of glycated hemoglobin with long term brain structural integrity in key regions of the memory system - hippocampus, parahippocampal gyrus and fusiform gyrus. Grey matter volume was measured at two different times - baseline and after ~7 years. We found an association between higher initial levels of HbA1C and grey matter volume loss in all three core memory regions, even in the absence of mild cognitive impairment. Importantly, these neural effects persisted in spite of the fact that patients had significantly improved their glycemic control. This suggests that early high levels of HbA1c might be irreversibly associated with subsequent long-term atrophy in the medial temporal cortex and that early intensive management is critical.

Comparison between the KARVI scale and the Child Development Evaluation test (EDI) as a screening tool for suspected neurodevelopmental delay.

BACKGROUND: Early detection of suspected neurodevelopmental delay allows for timely diagnosis and appropriate intervention, for which numerous screening tests have been developed. However, most are complex and impractical for health-care workers at the community level. This study aimed to validate the KARVI scale in the neurodevelopment assessment of children under 1 year of age. METHODS: We conducted an observational, longitudinal, comparative, inferential, and prospective study. Healthy children without risk factors for developing neurodevelopmental delay from 0 to 12 months of age were evaluated remotely using the Zoom® application. The Child Development Evaluation Test and the KARVI scale were applied once a month for four consecutive months. RESULTS: Fifty individuals were analyzed, with a predominance of males in 52%. Adequate percentages for a screening test were obtained in the first evaluation with a sensitivity of 70% (confidence interval [CI] 95% 34.75-93.33) and a specificity of 75% (CI 95% 58.8-87.31), and in the fourth evaluation with a sensitivity of 100% (CI 95% 29.4-100) and a specificity of 78.72% (CI 95% 64.34-89.3), being significant in both evaluations (p = 0.007 and p = 0.001, respectively). CONCLUSIONS: The KARVI scale has the elements to be an effective screening test for suspected neurodevelopmental delay, but more extensive studies are needed to obtain more reliable results.

INTRODUCCIÓN: La identificación temprana de retraso en el neurodesarrollo permite un diagnóstico oportuno y una intervención apropiada. Para ello, se han creado diversas pruebas de tamizaje; sin embargo, la mayoría son complejas y poco prácticas para el personal de la salud a nivel comunitario. El objetivo del estudio fue realizar la validación de la escala KARVI en la valoración del neurodesarrollo en niños menores de un año. MÉTODOS: Se realizó un estudio observacional, longitudinal, comparativo inferencial y prospectivo, en el cual se evaluaron, vía remota mediante la aplicación Zoom®, niños sanos de 0 a 12 meses de edad sin factores de riesgo para desarrollar retraso en el neurodesarrollo. Se aplicaron la prueba EDI (Evaluación del Desarrollo Infantil) y la escala KARVI una vez al mes por cuatro meses consecutivos. RESULTADOS: Se analizaron 50 individuos, con predominio del sexo masculino en el 52%. Se obtuvieron porcentajes adecuados para una prueba de tamizaje tanto en la primera evaluación, con sensibilidad de 70% (IC 95% 34.75-93.33) y especificidad de 75% (IC 95% 58.8-87.31), como en la cuarta, con sensibilidad de 100% (IC 95% 29.4-100) y especificidad de 78.72% (IC 95% 64.34-89.3), con significación estadística en ambas evaluaciones (p = 0.007 y p = 0.001, respectivamente). CONCLUSIONES: Se considera que la escala KARVI cuenta con los elementos para considerarla como una prueba de tamizaje efectiva para detectar retraso del neurodesarrollo, sin embargo. Sin requieren estudios más extensos para obtener resultados más confiables.

Functional reorganization of memory processing in the hippocampus is associated with neuroprotector GLP-1 levels in type 2 diabetes.

Type 2 diabetes (T2D) often impairs memory functions, suggesting specific vulnerability of the hippocampus. In vivo neuroimaging studies relating encoding and retrieval of memory information with endogenous neuroprotection are lacking. The neuroprotector glucagon-like peptide (GLP-1) has a high receptor density in anterior/ventral hippocampus, as shown by animal models. Using an innovative event-related fMRI design in 34 participants we investigated patterns of hippocampal activity in T2D (n = 17) without mild cognitive impairment (MCI) versus healthy controls (n = 17) during an episodic memory task. We directly measured neurovascular coupling by estimating the hemodynamic response function using event-related analysis related to encoding and retrieval of episodic information in the hippocampus. We applied a mixed-effects general linear model analysis and a two-factor ANOVA to test for group differences. Significant between-group differences were found for memory encoding, showing evidence for functional reorganization: T2D patients showed an augmented activation in the posterior hippocampus while anterior activation was reduced. The latter was negatively correlated with both GLP-1 pre- and post-breakfast levels, in the absence of grey matter changes. These results suggest that patients with T2D without MCI have pre-symptomatic functional reorganization in brain regions underlying episodic memory, as a function of the concentration of the neuroprotective neuropeptide GLP-1.

Immunoassay interferences: laboratory pitfall in the diagnosis of adrenocortical carcinoma.

A woman in her late 50s with recent onset of hypertension, diabetes, lumbar pain and unintentional weight loss was diagnosed with a cortisol and androgen-producing adrenal mass. Despite this, serum adrenocorticotropic hormone (ACTH) concentration was inappropriately elevated, which was investigated thoroughly. Investigations included a brain magnetic resonance imaging to exclude concomitant pituitary adenoma, a corticotropin-releasing hormone stimulation test and a gallium-68 DOTATATE and 18F-FDOPA PET scan, both excluding ectopic ACTH production. Considering the disparity between clinical presentation and biochemical results, the ACTH was reanalysed using the Cobas immunoassay (Roche, Switzerland), ultimately unveiling the cause for ACTH elevation. ACTH levels had previously been measured with ACTH Immulite (Siemens, Germany), a two-site immunoassay which is prone to interferences causing falsely elevated ACTH concentrations. Inaccurate laboratory levels can lead to diagnosis delay and unnecessary diagnostic procedures and a close communication between the physicians and laboratorians is of utmost importance.

Long-term care needs and the risk of household poverty across Europe: a comparative secondary data study.

PURPOSE: Population ageing and rising poverty are two of the most pressing issues today, even in Western European nations, growing as a result of the recent global economic crisis and the COVID-19 containment measures. This study explores the relationship between long-term care (LTC) needs and risk of poverty at household level in eight European countries, representing the different European care regimes. METHODS: The main international databases were scoured for study variables, categorized according to the following conceptual areas: home care, residential care, health expenditure, service coverage, cash benefits, private services, population, family, education, employment, poverty, disability and care recipients, and life expectancy. We initially identified 104 variables regarding 8 different countries (Austria, Finland, Germany, the Netherlands, Italy, Spain, Poland, Romania). Statistical analyses were conducted as described hereafter: analysis of the Pearson's Bivariate Correlation between the dependent variable and all other variables; a Multivariable Linear Regression Model between the Poverty Index (dependent variable) and the covariates identified in the preceding step; a check for geographical clustering effects and a reduced Multivariable Linear Regression Model for each identified European cluster. RESULTS: The variables that addressed the risk of poverty pertained to the area of policy intervention and service provision. Rising private out-of-pocket health expenditures and proportion of "poor" couples with at least one child are two factors that contributed significantly to poverty increasing. Moreover, rising private out-of-pocket health expenditures for covering LTC needs (even in presence of public financial contribution to the family) is the main contributor to household poverty increasing in presence of ADL disability. CONCLUSION: The results reveal the existence of a clear correlation between the need for LTC and the risk of poverty in households across Europe. These results highlight the central relevance of LTC policies, which are often still treated as marginal and sectoral, for the future sustainability of integrated care strategies.

Outcome improvement over time in reduced intensity conditioning hematopoietic transplantation: a 20-year experience.

The current study includes all consecutive patients (N = 484) who received a reduced-intensity conditioning regimen (RIC) allogeneic hematopoietic stem cell transplantation in our center from 1999 to 2020. Conditioning regimens were based on fludarabine with melphalan or busulfan, with low-dose thiotepa and pharmacological GVHD prophylaxis consisted of cyclosporine A (CsA)-methotrexate (MTX)/mofetil (MMF) (n = 271), tacrolimus-sirolimus (n = 145), and post-transplantation cyclophosphamide (PTCy)-tacrolimus (n = 68). The median time of overall follow-up in survivors was 8 years (1-22 years) and was at least 3 years in all three GVHD prophylaxis groups. Thirty-three percent had a high or very high disease risk index, 56% ≥ 4 European bone marrow transplantation risk, and 65% ≥ 3 hematopoietic stem cell transplantation comorbidity index score-age score. Neutrophil and platelet engraftment was longer for PTCy-tacro (p 0.0001). Cumulative incidence of grade III-IV aGVHD was 17% at 200 days, and that of moderate-severe cGvHD was 36% at 8 years. GVHD prophylaxis was the only prognostic factor in the multivariable analyses for the development of aGVHD and moderate-severe cGVHD (p 0.0001). NRM and relapse incidences were 29% and 30% at 8 years, while OS and PFS rates were 43% and 39% at 8 years. At 3 years, OS was highest in the PTCy-tacro group (68%) than in the tacro-siro (61%) and CsA-MTX/MMF (49%) cohorts (p < 0.01). In the three groups, respectively, the 200-day incidence of grade III-IV aGvHD (6% vs. 12% vs. 23%) and 3-year moderate-severe cGVHD (8% vs. 40% vs. 38%) were lower in the PTCy cohort. These better outcomes were confirmed in multivariable analyses. Based on our recent results, the PTCy could be considered as a real GvHD prophylaxis in the RIC setting due to improve best 3-year GvHD and survival outcomes.

The hospital Israelita Albert Einstein standards for constitutional sequence variants classification: version 2023.

BACKGROUND: Next-generation sequencing has had a significant impact on genetic disease diagnosis, but the interpretation of the vast amount of genomic data it generates can be challenging. To address this, the American College of Medical Genetics and Genomics and the Association for Molecular Pathology have established guidelines for standardized variant interpretation. In this manuscript, we present the updated Hospital Israelita Albert Einstein Standards for Constitutional Sequence Variants Classification, incorporating modifications from leading genetics societies and the ClinGen initiative. RESULTS: First, we standardized the scientific publications, documents, and other reliable sources for this document to ensure an evidence-based approach. Next, we defined the databases that would provide variant information for the classification process, established the terminology for molecular findings, set standards for disease-gene associations, and determined the nomenclature for classification criteria. Subsequently, we defined the general rules for variant classification and the Bayesian statistical reasoning principles to enhance this process. We also defined bioinformatics standards for automated classification. Our workgroup adhered to gene-specific rules and workflows curated by the ClinGen Variant Curation Expert Panels whenever available. Additionally, a distinct set of specifications for criteria modulation was created for cancer genes, recognizing their unique characteristics. CONCLUSIONS: The development of an internal consensus and standards for constitutional sequence variant classification, specifically adapted to the Brazilian population, further contributes to the continuous refinement of variant classification practices. The aim of these efforts from the workgroup is to enhance the reliability and uniformity of variant classification.

The longitudinal impact of type 2 diabetes on brain gyrification.

Type 2 diabetes has an effect on brain structure, including cortical gyrification. The significance of these changes is better understood if assessed over time. However, there is a lack of studies assessing longitudinally the effect of this disease with complex aethology in gyrification. While changes in this feature have been associated mainly with genetic legacy, our study allowed to shed light on the effect of the variation of glycaemic profile over time in gyrification in this metabolic disease. In this longitudinal study, we analysed brain anatomical magnetic resonance images of 15 participants with type 2 diabetes and 13 healthy control participants to investigate the impact of this metabolic disease on the gyrification index over a 7-year period. We observed a significant interaction between time and group in six regions, four of which (left precentral gyrus, left gyrus rectus, left subcentral gyrus and sulci and right inferior temporal gyrus) showed an increase in gyrification in type 2 diabetes and a decrease in the control group and the two others (left pericallosal sulcus and right inferior frontal sulcus) the opposite pattern. The variation of the gyrification was correlated with the variation of the glycaemic profile. Following the interaction, the simple main effect of time in each group separately has shown that in the group with diabetes, there were more regions susceptible to alterations of gyrification. In sum, our results raise credit for the possibility that glycaemic control also might influence gyrification in type 2 diabetes.

Nuanced role for dendritic cell intrinsic IRE1 RNase in the regulation of antitumor adaptive immunity.

In cancer, activation of the IRE1/XBP1s axis of the unfolded protein response (UPR) promotes immunosuppression and tumor growth, by acting in cancer cells and tumor infiltrating immune cells. However, the role of IRE1/XBP1s in dendritic cells (DCs) in tumors, particularly in conventional type 1 DCs (cDC1s) which are cellular targets in immunotherapy, has not been fully elucidated. Here, we studied the role of IRE1/XBP1s in subcutaneous B16/B78 melanoma and MC38 tumors by generating loss-of-function models of IRE1 and/or XBP1s in DCs or in cDC1s. Data show that concomitant deletion of the RNase domain of IRE1 and XBP1s in DCs and cDC1s does not influence the kinetics of B16/B78 and MC38 tumor growth or the effector profile of tumor infiltrating T cells. A modest effect is observed in mice bearing single deletion of XBP1s in DCs, which showed slight acceleration of melanoma tumor growth and dysfunctional T cell responses, however, this effect was not recapitulated in animals lacking XBP1 only in cDC1s. Thus, evidence presented here argues against a general pro-tumorigenic role of the IRE1/XBP1s pathway in tumor associated DC subsets.

Regular physical activity moderates the adverse impact of type 2 diabetes on brain atrophy independently from HbA1c.

Objective: Brain atrophy has been consistently associated with type 2 diabetes, beginning in early stages of dysglycemia, independently from micro and macrovascular complications. On the contrary, physical activity relates with larger brain volumes. Our aim is to assess the influence of regular physical activity on brain volumes in people with type 2 diabetes. Methods: A cross-sectional multimodal evaluation with 3T MRI was performed on 170 individuals: 85 individuals with type 2 diabetes and 85 controls. They underwent clinical examination, blood sampling and 3T MRI. Brain volumes (mm3) were estimated using FreeSurfer 7. Physical activity duration was self-reported by the participants as the number of hours of physical activity per week for at least the previous 6 months. Statistical analysis was performed with IBM SPSS 27. Results: People with type 2 diabetes had significantly lower cortical and subcortical volumes, adjusted for age and individual intracranial volume, comparing to controls. Regression analysis showed that within type 2 diabetes group, lower gray matter volumes were associated with lesser physical activity duration (hours/week), independently from HbA1c. Moreover, there were significant moderate positive correlations between regular physical activity duration and gray matter volumes of cortical and subcortical subregions, specifically in the diabetes group. Conclusions: This study reveals a putative beneficial effect of regular physical activity independently of glycemic control, as assessed by HbA1c, which might contribute to reduce the negative impact of type 2 diabetes in the brain.

SLC26A2/DTDST Spectrum: A Cohort of 12 Patients Associated with a Comprehensive Review of the Genotype-Phenotype Correlation.

Introduction: Pathogenic variants in the SLC26A2/DTDST gene cause the following spectrum of phenotypes: achondrogenesis 1B (ACG1B), atelosteogenesis 2 (AO2), diastrophic dysplasia (DTD), and recessive-multiple epiphyseal dysplasia (rMED), the first 2 being lethal. Here, we report a cohort and a comprehensive literature review on a genotype-phenotype correlation of SLC26A2/DTDST-related disorders. Methods: The local patients were genotyped by Sanger sequencing or next-generation sequencing (NGS). We reviewed data from the literature regarding phenotype, zygosity, and genotype in parallel. Results: The local cohort enrolled 12 patients, including one with a Desbuquois-like phenotype. All but one showed biallelic mutations, however, only one allele mutated in a fetus presenting ACG1B was identified. The literature review identified 42 articles and the analyses of genotype and zygosity included the 12 local patients. Discussion: The R279W variant was the most prevalent among the local patients. It was in homozygosity (hmz) in 2 patients with rMED and in compound heterozygosity (chtz) in 9 patients. The genotype and zygosity review of all patients led to the following conclusions: DTD is the most common phenotype in Finland due to a Finnish mutation (c.727-1G>C). Outside of Finland, rMED is the most prevalent phenotype, usually associated with R279W in hmz. In contrast, DTD's genotype is usually in chtz. Despite a large number of variants (38), just 8 are recurrent (R279W, C653S, c.-26+2T>C, R178*, K575Sfs*10, V340del, G663R, T512K). The last 3 in hmz lead to lethal phenotypes. The Finnish mutation is found only in chtz outside of Finland, being associated with all 4 classical phenotypes. The p.R178* and p.K575Sfs*10 variants should be viewed as lethal mutations since both were mainly described with lethal phenotypes and were never reported in hmz. The existence of 9 patients with only one mutated allele suggests that other mutations in the other allele of these patients still need to be unveiled.

An Uncommon Presentation of Pheochromocytoma in Neurofibromatosis Type 1 and the Importance of Long-Term Follow-Up.

Neurofibromatosis type 1 (NFT1) is a disease caused by mutations in the tumor suppressor gene NF1. It is associated with a higher incidence of chromaffin cell tumors which are usually adrenal, unilateral and benign. The presence of these tumors during pregnancy is extremely rare and frequently associated with fatal outcomes. We report the case of a female patient with NFT1, who presented with paroxysmal spells of headache, palpitations, dizziness and pre-cordial discomfort, starting immediately after the delivery of her third child. Diagnostic work-up came to reveal a bilateral pheochromocytoma and the patient underwent bilateral adrenalectomy. Over 12 years after the initial surgery, metastatic disease was diagnosed, and a reintervention was performed. This is a rare presentation of bilateral malignant pheochromocytoma in a patient with NFT1, with postpartum occurrence of the first symptoms. This text focuses the important details and challenges found at each stage of diagnosis and follow-up.

A neurofibromatose tipo 1 (NFT1) é uma doença causada por mutações no gene supressor de tumor NF1. Está associada a uma maior incidência de tumores de células cromafins que geralmente são adrenais, unilaterais e benignos. A presença destes tumores durante a gravidez é extremamente rara e com frequência associada a resultados fatais. Relatamos o caso de uma doente com NFT1, que apresentou crises paroxísticas de cefaleias, palpitações, tonturas e desconforto pré-cordial, com início imediatamente após o parto de seu terceiro filho. A investigação diagnóstica revelou feocromocitoma bilateral e a doente foi submetida a adrenalectomia bilateral. Mais de 12 anos após a cirurgia inicial, foi diagnosticada doença metastática e efetuada reintervenção. Esta é uma apresentação rara de feocromocitoma maligno bilateral numa doente com NFT1, com ocorrência pós-parto dos primeiros sintomas. Este texto foca detalhes e desafios importantes encontrados em cada fase do diagnóstico e acompanhamento.

Síndrome inflamatorio multisistémico post-COVID en niños: reporte de casos en Montevideo, Uruguay, 2020-2021 / Multsystemic inflammatory syndrome in post-Covid children: clinical case studies in Montevideo, Uruguay, 2020-2021 / Sindrome inflamatório multisistêmico pós-COVID em crianças: relato de casos em Montevdéu, Uruguai, 2020-2021

El síndrome inflamatorio multisistémico asociado a COVID-19 es una presentación postinfecciosa, que puede ser particularmente grave, pudiendo producir una severa disfunción multiorgánica. Se presenta una serie de 6 casos clínicos, asistidos en Servicio Médico Integral, Montevideo-Uruguay, con el fin de exponer las características clínicas y paraclínicas de este nuevo síndrome, y la evolución clínica de los mismos. Se realiza un estudio observacional descriptivo. La edad media fue de 6 años, con predominio en sexo femenino. Estos pacientes tuvieron una presentación clínica leve a moderada, con buena evolución Las manifestaciones clínicas principales fueron: fiebre, compromiso gastrointestinal, mucocutáneo y afectación ocular; dos de estos pacientes presentaron compromiso cardiovascular. Todos tuvieron alteraciones en la paraclínica, destacándose reactantes de fase aguda elevados. Todos los pacientes recibieron inmunoglobulina intravenosa y corticoides, tres de ellos recibieron heparina de bajo peso molecular por valor de D-dímeros 5 veces por encima del valor de referencia. No descartamos el impacto del diagnóstico y tratamiento precoz en la buena evolución de estos niños.

The Multisystem Inflammatory Syndrome associated with COVID-19 is a postinfectious presentation, which can be particularly serious, and can produce severe multiorgan dysfunction. A report of 6 clinical cases, assisted in the Comprehensive Medical Service, Montevideo-Uruguay, is presented in order to expose the clinical and paraclinical characteristics of this new syndrome, and their clinical evolution. A descriptive observational study was carried out. The mean age was 6 years, with a predominance of females. These patients had a mild to moderate clinical presentation, with good evolution. The main clinical manifestations were: fever, gastrointestinal and mucocutaneous involvement, and ocular involvement; two of these patients had cardiovascular compromise. All had alterations in the paraclinical, standing out elevated acute phase reactants. All patients received intravenous immunoglobulin and corticosteroids, three of them received low molecular weight heparin with a value of D-dimers 5 times higher than the reference value. We do not rule out the impact of early diagnosis and treatment on the positive evolution of these children.

A Síndrome Inflamatória Multissistêmica associada à COVID-19 é uma apresentação pósinfecciosa, que pode ser particularmente grave e produzir disfunção grave de múltiplos órgãos. Apresentamos um relato de 6 casos clínicos, atendidos no Serviço Médico Integral, Montevidéu-Uruguai, com o objetivo de expor as características clínicas e para clínicas desta nova síndrome, e sua evolução clínica. Tratase de um estudo observacional descritivo. A média de idade foi de 6 anos, com predomínio do sexo feminino. Esses pacientes tinham apresentação clínica leve a moderada, com boa evolução. As principais manifestações clínicas foram: febre, envolvimento gastrointestinal, muco cutâneo e ocular; dois desses pacientes apresentaram comprometimento cardiovascular. Todos apresentavam alterações para clínicas, destacandose elevados reagentes na fase aguda. Todos os pacientes receberam imunoglobulina e corticosteroides endovenosos, três deles receberam heparina de baixo peso molecular com valor do dímero D 5 vezes acima do valor de referência. Não descartamos o impacto do diagnóstico e tratamento precoces na evolução positiva dessas crianças.

The hemodynamic response function as a type 2 diabetes biomarker: a data-driven approach.

Introduction: There is a need to better understand the neurophysiological changes associated with early brain dysfunction in Type 2 diabetes mellitus (T2DM) before vascular or structural lesions. Our aim was to use a novel unbiased data-driven approach to detect and characterize hemodynamic response function (HRF) alterations in T2DM patients, focusing on their potential as biomarkers. Methods: We meshed task-based event-related (visual speed discrimination) functional magnetic resonance imaging with DL to show, from an unbiased perspective, that T2DM patients' blood-oxygen-level dependent response is altered. Relevance analysis determined which brain regions were more important for discrimination. We combined explainability with deconvolution generalized linear model to provide a more accurate picture of the nature of the neural changes. Results: The proposed approach to discriminate T2DM patients achieved up to 95% accuracy. Higher performance was achieved at higher stimulus (speed) contrast, showing a direct relationship with stimulus properties, and in the hemispherically dominant left visual hemifield, demonstrating biological interpretability. Differences are explained by physiological asymmetries in cortical spatial processing (right hemisphere dominance) and larger neural signal-to-noise ratios related to stimulus contrast. Relevance analysis revealed the most important regions for discrimination, such as extrastriate visual cortex, parietal cortex, and insula. These are disease/task related, providing additional evidence for pathophysiological significance. Our data-driven design allowed us to compute the unbiased HRF without assumptions. Conclusion: We can accurately differentiate T2DM patients using a data-driven classification of the HRF. HRF differences hold promise as biomarkers and could contribute to a deeper understanding of neurophysiological changes associated with T2DM.

Genomic study of nonsyndromic hearing loss in unaffected individuals: Frequency of pathogenic and likely pathogenic variants in a Brazilian cohort of 2,097 genomes.

Hearing loss (HL) is a common sensory deficit in humans and represents an important clinical and social burden. We studied whole-genome sequencing data of a cohort of 2,097 individuals from the Brazilian Rare Genomes Project who were unaffected by hearing loss to investigate pathogenic and likely pathogenic variants associated with nonsyndromic hearing loss (NSHL). We found relevant frequencies of individuals harboring these alterations: 222 heterozygotes (10.59%) for sequence variants, 54 heterozygotes (2.58%) for copy-number variants (CNV), and four homozygotes (0.19%) for sequence variants. The top five most frequent genes and their corresponding combined allelic frequencies (AF) were GJB2 (AF = 1.57%), STRC (AF = 1%), OTOA (AF = 0.69%), TMPRSS3 (AF = 0.41%), and OTOF (AF = 0.29%). The most frequent sequence variant was GJB2:c.35del (AF = 0.72%), followed by OTOA:p. (Glu787Ter) (AF = 0.61%), while the most recurrent CNV was a microdeletion of 57.9 kb involving the STRC gene (AF = 0.91%). An important fraction of these individuals (n = 104; 4.96%) presented variants associated with autosomal dominant forms of NSHL, which may imply the development of some hearing impairment in the future. Using data from the heterozygous individuals for recessive forms and the Hardy-Weinberg equation, we estimated the population frequency of affected individuals with autosomal recessive NSHL to be 1:2,222. Considering that the overall prevalence of HL in adults ranges from 4-15% worldwide, our data indicate that an important fraction of this condition may be associated with a monogenic origin and dominant inheritance.

Evaluation of Plant-Based Byproducts as Green Fining Agents for Precision Winemaking.

Consumers are increasingly looking for foods, including wine, that are free of animal-derived proteins. This study seeks to evaluate patatin, a new, plant-based and allergen-free fining agent, by comparing it with the fining agents polyvinipolypyrrolidone, bovine serum albumin, and methylcellulose. Specifically, its effects on the phenolic profile of enological tannins were analyzed with four spectrophotometric assays: OD 280 nm, Folin−Ciocâlteu, Adams−Harbertson, and methylcellulose. In addition, changes in the polyphenol composition of Sangiovese red wine were determined by UV-Vis spectrophotometry and HPLC with adsorption trials, and the solid−liquid interaction in a wine solution was modeled by both Langmuir and Freundlich equations. Our findings highlight the occurrence of systematic proportional error between the selected spectrophotometric assays. As a result, direct comparisons of protein precipitation assays can be made only among results obtained with the same spectrophotometric method. However, it is clear that patatin has an impact on the phenolic profile of Sangiovese red wine: it removes simple phenolics (gallic acid, (+)-catechin, (−)-epicatechin, epicatechin gallate, syringic acid, fertaric acid, coutaric acid, and rutin) as well as both oligomeric and polymeric tannins to different extents. In concentrations of less than 1 g/L, the patatin isotherm showed a linear relation between the equilibrium concentration and the quantity absorbed, obeying the Freundlich model reasonably well (KF 1.46; 1/n 1.07; R2 0.996 with 1/n > 1). Thus, the adsorption process is strongly dependent on the fining dosage.

[Analysis of budgetary impact of COVID-19 vaccination in Latin AmericaAnálise do impacto orçamentário da vacinação contra a COVID-19 na América Latina]. / Análisis de impacto presupuestal de la vacunación contra COVID-19 en América Latina.

Objective: To estimate the budgetary impact of COVID-19 vaccination in six Latin American countries: Argentina, Brazil, Chile, Colombia, Mexico, and Peru, during the 2021-2022 biennium. Methods: Vaccines from Sinopharm (BBIBP-CorV), Janssen (JNJ-78436735), Gamaleya Institute (Gam-COVID-Vac), Sinovac (CoronaVac), CanSino (Convidecia), AstraZeneca (Vaxzevria), Moderna (mRNA-1273), and Pfizer (BNT162b2) were evaluated, according to their availability in each country. The health system perspective was adopted, so that only direct health care costs were included. The time horizon adopted took into account the implementation times of each vaccination plan, excluding children under 16 years of age and pregnant persons. The following costs were included: cost of vaccination/vaccine administration and costs of hospitalization (general isolation, stepdown care, and intensive care). Two vaccination scenarios were compared: 1) population wanting to be vaccinated (according to national surveys); and 2) population that should be vaccinated (total population susceptible to vaccination). The aggregate costs for each vaccination scenario were compared with the no-vaccination scenario. Deterministic and probabilistic sensitivity analyses were also performed. Results: The different COVID-19 vaccination regimens available in Latin America generate potential savings ranging from USD 100 million to USD 1.5 billion per country for the 2021-2022 biennium, assuming that the vaccination plan proposed for each country is fully implemented. Conclusions: COVID-19 vaccination is a strategy that not only reduces morbidity and mortality in Latin America, but also generates potential savings for health systems in the region.

Objetivo: Estimar o impacto orçamentário da vacinação contra a COVID-19 em seis países da América Latina: Argentina, Brasil, Chile, Colômbia, México e Peru, no período 2021-2022. Métodos: Foram avaliadas as vacinas da Sinopharm (BBIBP-CorV), Janssen (JNJ-78436735), Instituto Gamaleya (Gam-COVID-Vac), Sinovac (CoronaVac), CanSino (Convidecia), AstraZeneca (Vaxzevria), Moderna (mRNA-1273) e Pfizer (BNT162b2), conforme a disponibilidade para cada país. Adotou-se a perspectiva do sistema de saúde, de forma que só foram incluídos custos médicos diretos. O horizonte temporal foi adotado levando em consideração os tempos de implementação de cada plano de vacinação, excluindo crianças menores de 16 anos e gestantes. Foram incluídos os seguintes custos: custos de vacinação e aplicação, custos gerais de hospitalização, isolamento, e cuidados intermediários e intensivos. Compararam-se dois cenários de vacinação: 1) população disposta a se vacinar (com base em pesquisas nacionais) e 2) população que deveria ser vacinada (total elegível de vacinação). Os custos agregados para cada cenário de vacinação foram comparados com o cenário de não vacinação. Além disso, foram realizadas análises de sensibilidade determinísticas e probabilísticas. Resultados: Os diferentes esquemas de vacinação contra a COVID-19 disponíveis na América Latina geram economias potenciais entre 100 milhões e 1,5 bilhão de dólares por país para o período 2021-2022, considerando a implementação completa do plano de vacinação previsto em cada país. Conclusões: A vacinação contra a COVID-19 é uma estratégia que, além de reduzir a morbidade e a mortalidade na América Latina, gera economias potenciais para os sistemas de saúde da região.