Application of natural language processing to predict final recommendation of Brazilian health technology assessment reports.

INTRODUCTION: Health technology assessment (HTA) plays a vital role in healthcare decision-making globally, necessitating the identification of key factors impacting evaluation outcomes due to the significant workload faced by HTA agencies. OBJECTIVES: The aim of this study was to predict the approval status of evaluations conducted by the Brazilian Committee for Health Technology Incorporation (CONITEC) using natural language processing (NLP). METHODS: Data encompassing CONITEC's official report summaries from 2012 to 2022. Textual data was tokenized for NLP analysis. Least Absolute Shrinkage and Selection Operator, logistic regression, support vector machine, random forest, neural network, and extreme gradient boosting (XGBoost), were evaluated for accuracy, area under the receiver operating characteristic curve (ROC AUC) score, precision, and recall. Cluster analysis using the k-modes algorithm categorized entries into two clusters (approved, rejected). RESULTS: The neural network model exhibited the highest accuracy metrics (precision at 0.815, accuracy at 0.769, ROC AUC at 0.871, and recall at 0.746), followed by XGBoost model. The lexical analysis uncovered linguistic markers, like references to international HTA agencies' experiences and government as demandant, potentially influencing CONITEC's decisions. Cluster and XGBoost analyses emphasized that approved evaluations mainly concerned drug assessments, often government-initiated, while non-approved ones frequently evaluated drugs, with the industry as the requester. CONCLUSIONS: NLP model can predict health technology incorporation outcomes, opening avenues for future research using HTA reports from other agencies. This model has the potential to enhance HTA system efficiency by offering initial insights and decision-making criteria, thereby benefiting healthcare experts.

Assessment of the ABC2-SPH risk score to predict invasive mechanical ventilation in COVID-19 patients and comparison to other scores.

Background: Predicting the need for invasive mechanical ventilation (IMV) is important for the allocation of human and technological resources, improvement of surveillance, and use of effective therapeutic measures. This study aimed (i) to assess whether the ABC2-SPH score is able to predict the receipt of IMV in COVID-19 patients; (ii) to compare its performance with other existing scores; (iii) to perform score recalibration, and to assess whether recalibration improved prediction. Methods: Retrospective observational cohort, which included adult laboratory-confirmed COVID-19 patients admitted in 32 hospitals, from 14 Brazilian cities. This study was conducted in two stages: (i) for the assessment of the ABC2-SPH score and comparison with other available scores, patients hospitalized from July 31, 2020, to March 31, 2022, were included; (ii) for ABC2-SPH score recalibration and also comparison with other existing scores, patients admitted from January 1, 2021, to March 31, 2022, were enrolled. For both steps, the area under the receiving operator characteristic score (AUROC) was calculated for all scores, while a calibration plot was assessed only for the ABC2-SPH score. Comparisons between ABC2-SPH and the other scores followed the Delong Test recommendations. Logistic recalibration methods were used to improve results and adapt to the studied sample. Results: Overall, 9,350 patients were included in the study, the median age was 58.5 (IQR 47.0-69.0) years old, and 45.4% were women. Of those, 33.5% were admitted to the ICU, 25.2% received IMV, and 17.8% died. The ABC2-SPH score showed a significantly greater discriminatory capacity, than the CURB-65, STSS, and SUM scores, with potentialized results when we consider only patients younger than 80 years old (AUROC 0.714 [95% CI 0.698-0.731]). Thus, after the ABC2-SPH score recalibration, we observed improvements in calibration (slope = 1.135, intercept = 0.242) and overall performance (Brier score = 0.127). Conclusion: The ABC2-SPHr risk score demonstrated a good performance to predict the need for mechanical ventilation in COVID-19 hospitalized patients under 80 years of age.

The Immunological Landscape of M1 and M2 Macrophages and Their Spatial Distribution in Patients with Malignant Pleural Mesothelioma.

BACKGROUND: Several tumor-associated macrophages (TAMs) have shown promise as prognosticators in cancer. Our aim was to validate the importance of TAMs in malignant pleural mesothelioma (MPM) using a two-stage design. METHODS: We explored The Cancer Genome Atlas (TCGA-MESO) to select immune-relevant macrophage genes in MPM, including M1/M2 markers, as a discovery cohort. This computational cohort was used to create a multiplex immunofluorescence panel. Moreover, a cohort of 68 samples of MPM in paraffin blocks was used to validate the macrophage phenotypes and the co-localization and spatial distribution of these immune cells within the TME and the stromal or tumor compartments. RESULTS: The discovery cohort revealed six immune-relevant macrophage genes (CD68, CD86, CD163, CD206, ARG1, CD274), and complementary genes were differentially expressed by M1 and M2 phenotypes with distinct roles in the tumor microenvironment and were associated with the prognosis. In addition, immune-suppressed MPMs with increased enrichment of CD68, CD86, and CD163 genes and high densities of M2 macrophages expressing CD163 and CD206 proteins were associated with worse overall survival (OS). Interestingly, below-median distances from malignant cells to specific M2a and M2c macrophages were associated with worse OS, suggesting an M2 macrophage-driven suppressive component in these tumors. CONCLUSIONS: The interactions between TAMs in situ and, particularly, CD206+ macrophages are highly relevant to patient outcomes. High-resolution technology is important for identifying the roles of macrophage populations in tissue specimens and identifying potential therapeutic candidates in MPM.

A comprehensive model for assessing and classifying patients with thrombotic microangiopathy: the TMA-INSIGHT score.

BACKGROUND: Thrombotic Microangiopathy (TMA) is a syndrome characterized by the presence of anemia, thrombocytopenia and organ damage and has multiple etiologies. The primary aim is to develop an algorithm to classify TMA (TMA-INSIGHT score). METHODS: This was a single-center retrospective cohort study including hospitalized patients with TMA at a single center. We included all consecutive patients diagnosed with TMA between 2012 and 2021. TMA was defined based on the presence of anemia (hemoglobin level < 10 g/dL) and thrombocytopenia (platelet count < 150,000/µL), signs of hemolysis, and organ damage. We classified patients in eight categories: infections; Malignant Hypertension; Transplant; Malignancy; Pregnancy; Thrombotic Thrombocytopenic Purpura (TTP); Shiga toxin-mediated hemolytic uremic syndrome (STEC-SHU) and Complement Mediated TMA (aHUS). We fitted a model to classify patients using clinical characteristics, biochemical exams, and mean arterial pressure at presentation. RESULTS: We retrospectively retrieved TMA phenotypes using automatic strategies in electronic health records in almost 10 years (n = 2407). Secondary TMA was found in 97.5% of the patients. Primary TMA was found in 2.47% of the patients (TTP and aHUS). The best model was LightGBM with accuracy of 0.979, and multiclass ROC-AUC of 0.966. The predictions had higher accuracy in most TMA classes, although the confidence was lower in aHUS and STEC-HUS cases. CONCLUSION: Secondary conditions were the most common etiologies of TMA. We retrieved comorbidities, associated conditions, and mean arterial pressure to fit a model to predict TMA and define TMA phenotypic characteristics. This is the first multiclass model to predict TMA including primary and secondary conditions.

Real-Life Data on Hydroxychloroquine or Chloroquine with or Without Azithromycin in COVID-19 Patients: A Retrospective Analysis in Brazil. / Dados de Vida Real sobre o Uso da Hidroxicloroquina ou da Cloroquina Combinadas ou Não à Azitromicina em Pacientes com Covid-19: Uma Análise Retrospectiva no Brasil.

BACKGROUND: Despite no evidence showing benefits of hydroxychloroquine and chloroquine with or without azithromycin for COVID-19 treatment, these medications have been largely prescribed in Brazil. OBJECTIVES: To assess outcomes, including in-hospital mortality, electrocardiographic abnormalities, hospital length-of-stay, admission to the intensive care unit, and need for dialysis and mechanical ventilation, in hospitalized COVID-19 patients who received chloroquine or hydroxychloroquine, and to compare outcomes between those patients and their matched controls. METHODS: A retrospective multicenter cohort study that included consecutive laboratory-confirmed COVID-19 patients from 37 Brazilian hospitals from March to September 2020. Propensity score was used to select matching controls by age, sex, cardiovascular comorbidities, and in-hospital use of corticosteroid. A p-value <0.05 was considered statistically significant. RESULTS: From 7,850 COVID-19 patients, 673 (8.6%) received hydroxychloroquine and 67 (0.9%) chloroquine. The median age in the study group was 60 years (46 - 71) and 59.1% were women. During hospitalization, 3.2% of patients presented side effects and 2.2% required therapy discontinuation. Electrocardiographic abnormalities were more prevalent in the chloroquine/hydroxychloroquine group (13.2% vs. 8.2%, p=0.01), and the long corrected QT interval was the main difference (3.6% vs. 0.4%, p<0.001). The median hospital length of stay was longer in the HCQ/CQ + AZT group than in controls (9.0 [5.0, 18.0] vs. 8.0 [4.0, 14.0] days). There was no statistical differences between groups in intensive care unit admission (35.1% vs. 32.0%; p=0.282), invasive mechanical ventilation support (27.0% vs. 22.3%; p=0.074) or mortality (18.9% vs. 18.0%; p=0.682). CONCLUSION: COVID-19 patients treated with chloroquine or hydroxychloroquine had a longer hospital length of stay, when compared to matched controls. Intensive care unit admission, invasive mechanical ventilation, dialysis and in-hospital mortality were similar.

FUNDAMENTO: Apesar da ausência de evidência mostrando benefícios da hidroxicloroquina e da cloroquina combinadas ou não à azitromicina no tratamento da covid-19, esses medicamentos têm sido amplamente prescritos no Brasil. OBJETIVOS: Avaliar desfechos, incluindo moralidade hospitalar, alterações eletrocardiográficas, tempo de internação, admissão na unidade de terapia intensiva, e necessidade de diálise e de ventilação mecânica em pacientes hospitalizados com covid-19 que receberam cloroquina ou hidroxicloroquina, e comparar os desfechos entre aqueles pacientes e seus controles pareados. MÉTODOS: Estudo multicêntrico retrospectivo do tipo coorte que incluiu pacientes com diagnóstico laboratorial de covid-19 de 37 hospitais no Brasil de março a setembro de 2020. Escore de propensão foi usado para selecionar controles pareados quanto a idade, sexo, comorbidades cardiovasculares, e uso de corticosteroides durante a internação. Um valor de p<0,05 foi considerado estatisticamente significativo. RESULTADOS: Dos 7850 pacientes com covid-19, 673 (8,6%) receberam hidroxicloroquina e 67 (0,9%) cloroquina. A idade mediana no grupo de estudo foi 60 (46-71) anos e 59,1% eram mulheres. Durante a internação, 3,2% dos pacientes apresentaram efeitos adversos e 2,2% necessitaram de interromper o tratamento. Alterações eletrocardiográficas foram mais prevalentes no grupo hidroxicloroquina/cloroquina (13,2% vs. 8,2%, p=0,01), e o prolongamento do intervalo QT corrigido foi a principal diferença (3,6% vs. 0,4%, p<0,001). O tempo mediano de internação hospitalar foi maior no grupo usando CQ/HCQ em relação aos controles (9,0 [5,0-18,0] vs. 8,0 [4,0-14,0] dias). Não houve diferenças estatisticamente significativas entre os grupos quanto a admissão na unidade de terapia intensiva (35,1% vs. 32,0%; p=0,282), ventilação mecânica invasiva (27,0% vs. 22,3%; p=0,074) ou mortalidade (18,9% vs. 18,0%; p=0,682). CONCLUSÃO: Pacientes com covid-19 tratados com cloroquina ou hidroxicloroquina apresentaram maior tempo de internação hospitalar, em comparação aos controles. Não houve diferença em relação a admissão em unidade de terapia intensiva, necessidade de ventilação mecânica e mortalidade hospitalar.

Economic evaluation of non-invasive liver tests for the diagnosis of liver fibrosis in chronic liver diseases: a systematic review protocol.

OBJECTIVE: The objective of this review is to determine the costs and benefits of non-invasive liver tests versus liver biopsy in patients with chronic liver diseases. INTRODUCTION: Hepatic diseases can lead to liver fibrosis, cirrhosis, and hepatocellular carcinoma. In the past, liver biopsy was the only option for diagnosing fibrosis degree; however, it is an invasive procedure that depends on the sample size to be able to deliver an accurate diagnosis. In recent years, non-invasive liver tests have been increasingly used to estimate liver fibrosis degree, however, there is a lack of economic assessments of technology implementation outcomes. INCLUSION CRITERIA: This review will include partial (cost studies) and complete economic evaluation studies on hepatitis B, hepatitis C, alcoholic liver disease, and non-alcoholic fatty liver disease that compare non-invasive liver tests with liver biopsies. Studies published in English, French, Spanish, German, Italian, or Portuguese will be included. No date limits will be applied to the search. METHODS: This review will identify published and unpublished studies. Published studies will be identified using MEDLINE (PubMed), Cochrane Library (CENTRAL), Embase (Elsevier), Web of Science, Scopus, and LILACS. Sources of unpublished studies and gray literature will include sources from health technology assessment agencies, clinical practice guidelines, regulatory approvals, advisories and warnings, and clinical trial registries, as well as Google Scholar. Two independent reviewers will screen and assess studies, and extract and critically appraise the data. Data extracted from the included studies will be analyzed and summarized to address the review objective using narratives, tables, and the JBI dominance ranking matrix. REVIEW REGISTRATION: PROSPERO CRD42023404278.

Machine Learning Model to Predict Graft Rejection After Kidney Transplantation.

BACKGROUND: There are few predictive studies about early posttransplant outcomes taking into account baseline and posttransplant variables. The objective of this study was to create a predictive model for 30-day graft rejection using machine learning techniques. METHODS: Retrospective study with 1255 patients undergoing transplant from living and deceased donors at a tertiary health service in Brazil. Recipient, donor, transplantation, and postoperative period data were collected from physical and electronic records. We split the data into derivation (training) and validation (test) datasets. Five supervised machine learning algorithms were developed with this subset of variables in the training set: Simple Logistic Regression, Lasso, Multilayer Perceptron, XGBoost, and Light GBM. RESULTS: There were 147 (12.48%) cases of graft rejection within 30 days of transplantation. The best model was XGBoost (accuracy, 0.839; receiver operating characteristic area under the curve, 0.715; precision, 0.900). The model showed that deceased donor transplantation, glomerulopathy as an underlying disease, and donor's use of vasoactive drugs had more than 20% importance as rejection risk factors. The variables with the greatest predictive values were thymoglobulin induction and delayed graft function. CONCLUSIONS: We fitted a machine learning model to predict 30-day graft rejection after kidney transplantation that reaches a higher accuracy and precision. Machine learning models could contribute to predicting kidney survival using nontraditional approaches.

Exploring the COVID-19 Pandemic's Impact on the Health Technology Assessment Process of the National Commission for the Incorporation of Technologies Into the Brazilian Health System.

OBJECTIVES: This study aimed to evaluate the impact of the COVID-19 pandemic on Brazilian health technology assessment processes based on public reports from the National Committee for Health Technology Incorporation (CONITEC). METHODS: This descriptive study analyzed CONITEC's official reports on Brazil available on its website between 2018 and 2021 that aimed to propose recommendations for technologies to be incorporated into its public healthcare system. We used descriptive statistics covering the number of technologies and number of reports about drugs per year, objective, type of technology, demanding sector, and outcome before 2018 to 2019 and during the COVID-19 pandemic (2020-2021). Furthermore, we used logistic regression to explore any association between the final decision labeled as "incorporated" and the emergence of the COVID-19 pandemic. RESULTS: A total of 278 reports were analyzed. Approximately 85% (136 of 278), 79% (220 of 278), and 45% of the reports (125 of 278) were about drugs, for incorporation, and requested by the government, respectively. Moreover, 74 of 130 (57%) and 56 of 148 decisions (38%) were "incorporated" before and during the pandemic, respectively. No significant association was noted between incorporated decisions and the arrival of the COVID-19 pandemic for all technologies (odds ratio 1.43; 95% CI 0.84-2.46; P = .192) and for drugs (odds ratio 1.43; 95% confidence interval 0.81-2.53; P = .223) while adjusting for the type of technology and demandant. CONCLUSIONS: The COVID-19 pandemic has brought many challenges, but it does not seem to have had a significant impact on the health technology assessment approval decisions of CONITEC in Brazil.

Cost-effectiveness analysis of intravenous paricalcitol vs. oral calcitriol in the treatment of hyperparathyroidism secondary to chronic kidney disease / Análise de custo-efetividade do paricalcitol intravenoso vs. calcitriol oral no tratamento do hiperparatireoidismo secundário à doença renal crônica

Abstract Introduction: Hyperparathyroidism (SHPT) secondary to chronic kidney disease (CKD) is characterized by high levels of parathyroid hormone (PTH), hyperplasia of the parathyroid glands and cardiovascular disease. Selective and non-selective and selective vitamin D-receptor activators, calcimimetics, are available in the Brazilian market to reduce PTH levels. Objectives: To develop a cost-effectiveness (C/E) and budgetary impact (BI) analysis of intravenous paricalcitol vs. oral calcitriol for patients on dialysis with SHPT, from the perspective of the Brazilian Public Health Care System (SUS). Methodology: We built a decision-tree model to analyze C/E, which considered the outcome of avoided death and a time horizon of 1 year. As for the BI analysis, two scenarios were considered, one of demand and one of epidemiological approach, based on data from the Brazilian Society of Nephrology. Results: The analysis showed that the C/E ratio was R$ 1,213.68 per year, and an incremental effectiveness of 0.032, referring to avoided death. The incremental C/E ratio was R$37,927.50 per death averted by paricalcitol. It was estimated that the incremental BI with the expansion of paricalcitol use will be between R$1,600,202.28 and R$4,128,565.65 in the first year, considering the main and epidemiological scenarios. At the end of 5 years after the expansion of its use, an incremental BI was estimated between R$ 48,596,855.50 and R$ 62,90,555.73. Conclusion: Intravenous paricalcitol has superior efficacy and similar safety to oral calcitriol, reducing the overall mortality of dialysis patients, although it implies a higher cost.

Resumo Introdução: O hiperparatireoidismo secundário (HPTS) à doença crônica renal (DRC) é caracterizado por elevados níveis de paratormônio (PTH), hiperplasia das glândulas paratireoides e doença cardiovascular. Para a redução dos níveis do PTH, estão disponíveis no mercado brasileiro os ativadores não seletivos e seletivos do receptor da vitamina D e os calcimiméticos. Objetivos: Desenvolver análise de custo-efetividade (C/E) e de impacto orçamentário (IO) do paricalcitol intravenoso vs. calcitriol oral para pacientes em diálise com HPTS, na perspectiva do Sistema Único de Saúde. Metodologia: Foi construído um modelo de árvore de decisão para a análise de C/E, que considerou o desfecho morte evitada e um horizonte temporal de 1 ano. Quanto à análise de IO, foram considerados dois cenários, sendo um de demanda aferida e um de abordagem epidemiológica, baseado nos dados da Sociedade Brasileira de Nefrologia. Resultados: A análise mostrou que a relação de C/E foi de R$ 1.213,68 ao ano, e uma efetividade incremental de 0,032, referente à morte evitada. A razão de C/E incremental foi de R$ 37.927,50 por morte evitada para o paricalcitol. Estimou-se que o IO incremental com a ampliação do uso do paricalcitol estará entre R$ 1.600.202,28 e R$ 4.128.565,65 no primeiro ano, considerando os cenários principal e o epidemiológico. Já no fim de 5 anos após a ampliação do uso, estimou-se IO incremental entre R$ 48.596.855,50 e R$ 62.90.555,73. Conclusão: O paricalcitol intravenoso tem eficácia superior e segurança semelhante ao comparador calcitriol oral, diminuindo a mortalidade geral dos pacientes em diálise, embora implique maior custo.

Clinical characteristics and outcomes of hospital-manifested COVID-19 among Brazilians.

OBJECTIVES: To analyze the clinical characteristics and outcomes of admitted patients with the hospital- versus community-manifested COVID-19 and to evaluate the risk factors related to mortality in the first population. METHODS: This retrospective cohort included consecutive adult patients with COVID-19, hospitalized between March and September 2020. The demographic data, clinical characteristics, and outcomes were extracted from medical records. Patients with hospital-manifested COVID-19 (study group) and those with community-manifested COVID-19 (control group) were matched by the propensity score model. Logistic regression models were used to verify the risk factors for mortality in the study group. RESULTS: Among 7,710 hospitalized patients who had COVID-19, 7.2% developed symptoms while admitted for other reasons. Patients with hospital-manifested COVID-19 had a higher prevalence of cancer (19.2% vs 10.8%) and alcoholism (8.8% vs 2.8%) than patients with community-manifested COVID-19 and also had a higher rate of intensive care unit requirement (45.1% vs 35.2%), sepsis (23.8% vs 14.5%), and death (35.8% vs 22.5%) (P <0.05 for all). The factors independently associated with increased mortality in the study group were increasing age, male sex, number of comorbidities, and cancer. CONCLUSION: Hospital-manifested COVID-19 was associated with increased mortality. Increasing age, male sex, number of comorbidities, and cancer were independent predictors of mortality among those with hospital-manifested COVID-19 disease.

Cost-effectiveness analysis of intravenous paricalcitol vs. oral calcitriol in the treatment of hyperparathyroidism secondary to chronic kidney disease.

INTRODUCTION: Hyperparathyroidism (SHPT) secondary to chronic kidney disease (CKD) is characterized by high levels of parathyroid hormone (PTH), hyperplasia of the parathyroid glands and cardiovascular disease. Selective and non-selective and selective vitamin D-receptor activators, calcimimetics, are available in the Brazilian market to reduce PTH levels. OBJECTIVES: To develop a cost-effectiveness (C/E) and budgetary impact (BI) analysis of intravenous paricalcitol vs. oral calcitriol for patients on dialysis with SHPT, from the perspective of the Brazilian Public Health Care System (SUS). METHODOLOGY: We built a decision-tree model to analyze C/E, which considered the outcome of avoided death and a time horizon of 1 year. As for the BI analysis, two scenarios were considered, one of demand and one of epidemiological approach, based on data from the Brazilian Society of Nephrology. RESULTS: The analysis showed that the C/E ratio was R$ 1,213.68 per year, and an incremental effectiveness of 0.032, referring to avoided death. The incremental C/E ratio was R$37,927.50 per death averted by paricalcitol. It was estimated that the incremental BI with the expansion of paricalcitol use will be between R$1,600,202.28 and R$4,128,565.65 in the first year, considering the main and epidemiological scenarios. At the end of 5 years after the expansion of its use, an incremental BI was estimated between R$ 48,596,855.50 and R$ 62,90,555.73. CONCLUSION: Intravenous paricalcitol has superior efficacy and similar safety to oral calcitriol, reducing the overall mortality of dialysis patients, although it implies a higher cost.

Dados de Vida Real sobre o Uso da Hidroxicloroquina ou da Cloroquina Combinadas ou Não à Azitromicina em Pacientes com Covid-19: Uma Análise Retrospectiva no Brasil / Real-Life Data on Hydroxychloroquine or Chloroquine with or Without Azithromycin in COVID-19 Patients: A Retrospective Analysis in Brazil

Resumo Fundamento Apesar da ausência de evidência mostrando benefícios da hidroxicloroquina e da cloroquina combinadas ou não à azitromicina no tratamento da covid-19, esses medicamentos têm sido amplamente prescritos no Brasil. Objetivos Avaliar desfechos, incluindo moralidade hospitalar, alterações eletrocardiográficas, tempo de internação, admissão na unidade de terapia intensiva, e necessidade de diálise e de ventilação mecânica em pacientes hospitalizados com covid-19 que receberam cloroquina ou hidroxicloroquina, e comparar os desfechos entre aqueles pacientes e seus controles pareados. Métodos Estudo multicêntrico retrospectivo do tipo coorte que incluiu pacientes com diagnóstico laboratorial de covid-19 de 37 hospitais no Brasil de março a setembro de 2020. Escore de propensão foi usado para selecionar controles pareados quanto a idade, sexo, comorbidades cardiovasculares, e uso de corticosteroides durante a internação. Um valor de p<0,05 foi considerado estatisticamente significativo. Resultados Dos 7850 pacientes com covid-19, 673 (8,6%) receberam hidroxicloroquina e 67 (0,9%) cloroquina. A idade mediana no grupo de estudo foi 60 (46-71) anos e 59,1% eram mulheres. Durante a internação, 3,2% dos pacientes apresentaram efeitos adversos e 2,2% necessitaram de interromper o tratamento. Alterações eletrocardiográficas foram mais prevalentes no grupo hidroxicloroquina/cloroquina (13,2% vs. 8,2%, p=0,01), e o prolongamento do intervalo QT corrigido foi a principal diferença (3,6% vs. 0,4%, p<0,001). O tempo mediano de internação hospitalar foi maior no grupo usando CQ/HCQ em relação aos controles (9,0 [5,0-18,0] vs. 8,0 [4,0-14,0] dias). Não houve diferenças estatisticamente significativas entre os grupos quanto a admissão na unidade de terapia intensiva (35,1% vs. 32,0%; p=0,282), ventilação mecânica invasiva (27,0% vs. 22,3%; p=0,074) ou mortalidade (18,9% vs. 18,0%; p=0,682). Conclusão Pacientes com covid-19 tratados com cloroquina ou hidroxicloroquina apresentaram maior tempo de internação hospitalar, em comparação aos controles. Não houve diferença em relação a admissão em unidade de terapia intensiva, necessidade de ventilação mecânica e mortalidade hospitalar.

Abstract Background Despite no evidence showing benefits of hydroxychloroquine and chloroquine with or without azithromycin for COVID-19 treatment, these medications have been largely prescribed in Brazil. Objectives To assess outcomes, including in-hospital mortality, electrocardiographic abnormalities, hospital length-of-stay, admission to the intensive care unit, and need for dialysis and mechanical ventilation, in hospitalized COVID-19 patients who received chloroquine or hydroxychloroquine, and to compare outcomes between those patients and their matched controls. Methods A retrospective multicenter cohort study that included consecutive laboratory-confirmed COVID-19 patients from 37 Brazilian hospitals from March to September 2020. Propensity score was used to select matching controls by age, sex, cardiovascular comorbidities, and in-hospital use of corticosteroid. A p-value <0.05 was considered statistically significant. Results From 7,850 COVID-19 patients, 673 (8.6%) received hydroxychloroquine and 67 (0.9%) chloroquine. The median age in the study group was 60 years (46 - 71) and 59.1% were women. During hospitalization, 3.2% of patients presented side effects and 2.2% required therapy discontinuation. Electrocardiographic abnormalities were more prevalent in the chloroquine/hydroxychloroquine group (13.2% vs. 8.2%, p=0.01), and the long corrected QT interval was the main difference (3.6% vs. 0.4%, p<0.001). The median hospital length of stay was longer in the HCQ/CQ + AZT group than in controls (9.0 [5.0, 18.0] vs. 8.0 [4.0, 14.0] days). There was no statistical differences between groups in intensive care unit admission (35.1% vs. 32.0%; p=0.282), invasive mechanical ventilation support (27.0% vs. 22.3%; p=0.074) or mortality (18.9% vs. 18.0%; p=0.682). Conclusion COVID-19 patients treated with chloroquine or hydroxychloroquine had a longer hospital length of stay, when compared to matched controls. Intensive care unit admission, invasive mechanical ventilation, dialysis and in-hospital mortality were similar.

Modeling extracellular matrix through histo-molecular gradient in NSCLC for clinical decisions.

Lung cancer still represents a global health problem, being the main type of tumor responsible for cancer deaths. In this context, the tumor microenvironment, and the extracellular matrix (ECM) pose as extremely relevant. Thus, this study aimed to explore the prognostic value of epithelial-to-mesenchymal transition (EMT), Wnt signaling, and ECM proteins expression in patients with non-small-cell lung carcinoma (NSCLC) with clinical stages I-IIIA. For that, we used 120 tissue sections from patients and evaluated the immunohistochemical, immunofluorescence, and transmission electron microscopy (TEM) to each of these markers. We also used in silico analysis to validate our data. We found a strong expression of E-cadherin and ß-catenin, which reflects the differential ECM invasion process. Therefore, we also noticed a strong expression of chondroitin sulfate (CS) and collagens III and V. This suggests that, after EMT, the basal membrane (BM) enhanced the motility of invasive cells. EMT proteins were directly associated with WNT5A, and collagens III and V, which suggests that the WNT pathway drives them. On the other hand, heparan sulfate (HS) was associated with WNT3A and SPARC, while WNT1 was associated with CS. Interestingly, the association between WNT1 and Col IV suggested negative feedback of WNT1 along the BM. In our cohort, WNT3A, WNT5A, heparan sulfate and SPARC played an important role in the Cox regression model, influencing the overall survival (OS) of patients, be it directly or indirectly, with the SPARC expression stratifying the OS into two groups: 97 months for high expression; and 65 for low expression. In conclusion, the present study identified a set of proteins that may play a significant role in predicting the prognosis of NSCLC patients with clinical stages I-IIIA.

Proposing Specific Neuronal Epithelial-to-Mesenchymal Transition Genes as an Ancillary Tool for Differential Diagnosis among Pulmonary Neuroendocrine Neoplasms.

Pulmonary neuroendocrine neoplasms (PNENs) are currently classified into four major histotypes, including typical carcinoid (TC), atypical carcinoid (AC), large cell neuroendocrine carcinoma (LCNEC), and small cell lung carcinoma (SCLC). This classification was designed to be applied to surgical specimens mostly anchored in morphological parameters, resulting in considerable overlapping among PNENs, which may result in important challenges for clinicians' decisions in the case of small biopsies. Since PNENs originate from the neuroectodermic cells, epithelial-to-mesenchymal transition (EMT) gene expression shows promise as biomarkers involved in the genotypic transformation of neuroectodermic cells, including mutation burden with the involvement of chromatin remodeling genes, apoptosis, and mitosis rate, leading to modification in final cellular phenotype. In this situation, additional markers also applicable to biopsy specimens, which correlate PNENs subtypes with systemic treatment response, are much needed, and current potential candidates are neurogenic EMT genes. This study investigated EMT genes expression and its association with PNENs histotypes in tumor tissues from 24 patients with PNENs. PCR Array System for 84 EMT-related genes selected 15 differentially expressed genes among the PNENs, allowing to discriminate TC from AC, LCNEC from AC, and SCLC from AC. Functional enrichment analysis of the EMT genes differentially expressed among PNENs subtypes showed that they are involved in cellular proliferation, extracellular matrix degradation, regulation of cell apoptosis, oncogenesis, and tumor cell invasion. Interestingly, four EMT genes (MAP1B, SNAI2, MMP2, WNT5A) are also involved in neurological diseases, in brain metastasis, and interact with platinum-based chemotherapy and tyrosine-kinase inhibitors. Collectively, these findings emerge as an important ancillary tool to improve the strategies of histologic diagnosis in PNENs and unveil the four EMT genes that can play an important role in driving chemical response in PNENs.

Impact of the COVID-19 Pandemic on Solid Organ Transplant and Rejection Episodes in Brazil's Unified Healthcare System.

BACKGROUND: Brazil has the world's largest public organ transplant program, which was severely affected by the COVID-19 pandemic. The primary aim of the study was to evaluate differences in solid organ transplants and rejection episodes during the COVID-19 pandemic compared to the five years before the pandemic in the country. METHODS: A seven-year database was built by downloading data from the DATASUS server. The pandemic period was defined as March 2020 to December 2021. The pre-pandemic period was from January 2015 to March 2020. RESULTS: During the pandemic, the number of solid organ transplants decreased by 19.3% in 2020 and 22.6% in 2021 compared to 2019. We found a decrease for each evaluated organ, which was more pronounced for lung, pancreas, and kidney transplants. The seasonal plot of rejection data indicated a high rejection rate between 2018 and 2021. There was also an 18% (IRR 1.18 (95% CI 1.01 to 1.37), p = 0.04) increase in the rejection rate during the COVID-19 pandemic. CONCLUSIONS: The total number of organ transplants performed in 2021 represents a setback of six years. Transplant procedures were concentrated in the Southeast region of the country, and a higher proportion of rejections occurred during the pandemic. Together, these findings could have an impact on transplant procedures and outcomes in Brazil.

Frequency and burden of neurological manifestations upon hospital presentation in COVID-19 patients: Findings from a large Brazilian cohort.

BACKGROUND: Scientific data regarding the prevalence of COVID-19 neurological manifestations and prognosis in Latin America countries is still lacking. Therefore, the study aims to understand neurological manifestations of SARS-CoV 2 infection and outcomes in the Brazilian population. METHODS: This study is part of the Brazilian COVID-19 Registry, a multicentric cohort, including data from 37 hospitals. For the present analysis, patients were grouped according to the presence of reported symptoms (i.e., headache; anosmia and ageusia; syncope and dizziness) vs. clinically-diagnosed neurological manifestations (clinically-defined neurological syndrome: neurological signs or diagnoses captured by clinical evaluation) and matched with patients without neurological manifestations by age, sex, number of comorbidities, hospital of admission, and whether or not patients had underlying neurological disease. RESULTS: From 6,635 hospitalized patients with COVID-19, 30.8% presented reported neurological manifestations, 10.3% were diagnosed with a neurological syndrome and 60.1% did not show any neurological manifestations. In patients with reported symptoms, the most common ones were headache (20.7%), ageusia (11.1%) and anosmia (8.0%). In patients with neurological syndromes, acute encephalopathy was the most common diagnosis (9.7%). In the matched analysis, patients with neurological syndromes presented more cases of septic shock (17.0 vs. 13.0%, p = 0.045), intensive care unit admission (45.3 vs. 38.9%, p = 0.023), and mortality (38.7 vs. 32.6%, p = 0.026; and 39.2 vs. 30.3%, p < 0.001) when compared to controls. CONCLUSION: COVID-19 in-hospital patients with clinically defined neurological syndromes presented a higher incidence of septic shock, ICU admission and death when compared to controls.

Development and validation of the MMCD score to predict kidney replacement therapy in COVID-19 patients.

BACKGROUND: Acute kidney injury (AKI) is frequently associated with COVID-19, and the need for kidney replacement therapy (KRT) is considered an indicator of disease severity. This study aimed to develop a prognostic score for predicting the need for KRT in hospitalised COVID-19 patients, and to assess the incidence of AKI and KRT requirement. METHODS: This study is part of a multicentre cohort, the Brazilian COVID-19 Registry. A total of 5212 adult COVID-19 patients were included between March/2020 and September/2020. Variable selection was performed using generalised additive models (GAM), and least absolute shrinkage and selection operator (LASSO) regression was used for score derivation. Accuracy was assessed using the area under the receiver operating characteristic curve (AUC-ROC). RESULTS: The median age of the model-derivation cohort was 59 (IQR 47-70) years, 54.5% were men, 34.3% required ICU admission, 20.9% evolved with AKI, 9.3% required KRT, and 15.1% died during hospitalisation. The temporal validation cohort had similar age, sex, ICU admission, AKI, required KRT distribution and in-hospital mortality. The geographic validation cohort had similar age and sex; however, this cohort had higher rates of ICU admission, AKI, need for KRT and in-hospital mortality. Four predictors of the need for KRT were identified using GAM: need for mechanical ventilation, male sex, higher creatinine at hospital presentation and diabetes. The MMCD score had excellent discrimination in derivation (AUROC 0.929, 95% CI 0.918-0.939) and validation (temporal AUROC 0.927, 95% CI 0.911-0.941; geographic AUROC 0.819, 95% CI 0.792-0.845) cohorts and good overall performance (Brier score: 0.057, 0.056 and 0.122, respectively). The score is implemented in a freely available online risk calculator ( https://www.mmcdscore.com/ ). CONCLUSIONS: The use of the MMCD score to predict the need for KRT may assist healthcare workers in identifying hospitalised COVID-19 patients who may require more intensive monitoring, and can be useful for resource allocation.

Dissecting and Reconstructing Matrix in Malignant Mesothelioma Through Histocell-Histochemistry Gradients for Clinical Applications.

Background: Malignant pleural mesotheliomas (MM) are known for their heterogenous histology and clinical behavior. MM histology reveals three major tumor cell populations: epithelioid, sarcomatoid, and biphasic. Using a dissecting approach, we showed that histochemical gradients help us better understand tumor heterogeneity and reconsider its histologic classifications. We also showed that this method to characterize MM tumor cell populations provides a better understanding of the underlying mechanisms for invasion and disease progression. Methods: In a cohort of 87 patients with surgically excised MM, we used hematoxylin and eosin to characterize tumor cell populations and Movat's pentachrome staining to dissect the ECM matrisome. Next, we developed a computerized semi-assisted protocol to quantify and reconstruct the ECM in 3D and examined the clinical association between the matricellular factors and patient outcome. Results: Epithelioid cells had a higher matrix composition of elastin and fibrin, whereas, in the sarcomatoid type, hyaluronic acid and total collagen were most prevalent. The 3D reconstruction exposed the collagen I and III that form channels surrounding the neoplastic cell blocks. The estimated volume of the two collagen fractions was 14% of the total volume, consistent with the median estimated area of total collagen (12.05 mm2) for epithelioid MM. Conclusion: Differential patterns in matricellular phenotypes in MM could be used in translational studies to improve patient outcome. More importantly, our data raise the possibility that cancer cells can use the matrisome for disease expansion and could be effectively targeted by anti-collagen, anti-elastin, and/or anti-hyaluronic acid therapies.

Hypothyroidism does not lead to worse prognosis in COVID-19: findings from the Brazilian COVID-19 registry.

BACKGROUND: It is not clear whether previous thyroid diseases influence the course and outcomes of COVID-19. METHODS: The study is a part of a multicentric cohort of patients with confirmed COVID-19 diagnosis from 37 hospitals. Matching for age, sex, number of comorbidities, and hospital was performed for the paired analysis. RESULTS: Of 7,762 patients with COVID-19, 526 had previously diagnosed hypothyroidism and 526 were matched controls. The median age was 70 years, and 68.3% were females. The prevalence of comorbidities was similar, except for coronary and chronic kidney diseases that were higher in the hypothyroidism group (p=0.015 and p=0.001). D-dimer levels were lower in patients with hypothyroid (p=0.037). In-hospital management was similar, but hospital length-of-stay (p=0.029) and mechanical ventilation requirement (p=0.006) were lower for patients with hypothyroidism. There was a trend of lower in-hospital mortality in patients with hypothyroidism (22.1% vs 27.0%; p=0.062). CONCLUSION: Patients with hypothyroidism had a lower requirement of mechanical ventilation and showed a trend of lower in-hospital mortality. Therefore, hypothyroidism does not seem to be associated with a worse prognosis.