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BACKGROUND: Sequential population-based household serosurveys of SARS-CoV-2 covering the COVID-19 pre- and post-vaccination periods are scarce in Brazil. This study investigated seropositivity trends in the municipality of São Paulo. METHODS: We conducted seven cross-sectional surveys of adult population-representative samples between June 2020 and April 2022. The study design included probabilistic sampling, test for SARS-CoV-2 antibodies using the Roche Elecsys anti-nucleocapsid assay, and statistical adjustments for population demographics and non-response. The weighted seroprevalences with 95% confidence intervals (CI) were estimated by sex, age group, race, schooling, and mean income study strata. Time trends in seropositivity were assessed using the Joinpoint model. We compared infection-induced seroprevalences with COVID-19 reported cases in the pre-vaccination period. RESULTS: The study sample comprised 8,134 adults. The overall SARS-CoV-2 seroprevalence increased from 11.4% (95%CI: 9.2-13.6) in June 2020 to 24.9% (95%CI: 21.0-28.7) in January 2021; from 38.1% (95%CI: 34.3-41.9) in April 2021 to 77.7% (95%CI: 74.4-81.0) in April 2022. The prevalence over time was higher in the subgroup 18-39 years old than in the older groups from Survey 3 onwards. The self-declared Black or mixed (Pardo) group showed a higher prevalence in all surveys compared to the White group. Monthly prevalence rose steeply from January 2021 onwards, particularly among those aged 60 years or older. The infection-to-case ratios ranged from 8.9 in June 2020 to 4.3 in January 2021. CONCLUSIONS: The overall seroprevalence rose significantly over time and with age and race subgroup variations. Increases in the 60 years or older age and the White groups were faster than in younger ages and Black or mixed (Pardo) race groups in the post-vaccination period. Our data may add to the understanding of the complex and changing population dynamics of the SARS-CoV-2 infection, including the impact of vaccination strategies and the modelling of future epidemiological scenarios.
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Anticorpos Antivirais , COVID-19 , SARS-CoV-2 , Humanos , Brasil/epidemiologia , Adulto , Masculino , COVID-19/epidemiologia , COVID-19/imunologia , Estudos Soroepidemiológicos , Pessoa de Meia-Idade , Feminino , SARS-CoV-2/imunologia , Estudos Transversais , Adulto Jovem , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Idoso , AdolescenteRESUMO
Optimizing early breast cancer (BC) detection requires effective risk assessment tools. This retrospective study from Brazil showcases the efficacy of machine learning in discerning complex patterns within routine blood tests, presenting a globally accessible and cost-effective approach for risk evaluation. We analyzed complete blood count (CBC) tests from 396,848 women aged 40-70, who underwent breast imaging or biopsies within six months after their CBC test. Of these, 2861 (0.72%) were identified as cases: 1882 with BC confirmed by anatomopathological tests, and 979 with highly suspicious imaging (BI-RADS 5). The remaining 393,987 participants (99.28%), with BI-RADS 1 or 2 results, were classified as controls. The database was divided into modeling (including training and validation) and testing sets based on diagnostic certainty. The testing set comprised cases confirmed by anatomopathology and controls cancer-free for 4.5-6.5 years post-CBC. Our ridge regression model, incorporating neutrophil-lymphocyte ratio, red blood cells, and age, achieved an AUC of 0.64 (95% CI 0.64-0.65). We also demonstrate that these results are slightly better than those from a boosting machine learning model, LightGBM, plus having the benefit of being fully interpretable. Using the probabilistic output from this model, we divided the study population into four risk groups: high, moderate, average, and low risk, which obtained relative ratios of BC of 1.99, 1.32, 1.02, and 0.42, respectively. The aim of this stratification was to streamline prioritization, potentially improving the early detection of breast cancer, particularly in resource-limited environments. As a risk stratification tool, this model offers the potential for personalized breast cancer screening by prioritizing women based on their individual risk, thereby indicating a shift from a broad population strategy.
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Neoplasias da Mama , Aprendizado de Máquina , Humanos , Neoplasias da Mama/sangue , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/patologia , Feminino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto , Idoso , Contagem de Células Sanguíneas/métodos , Medição de Risco/métodos , Detecção Precoce de Câncer/métodos , Brasil/epidemiologiaRESUMO
Atherosclerotic Cardiovascular Disease (ASCVD) represents the leading cause of death worldwide, and individual screening should be based on behavioral, metabolic, and genetic profile derived from data collected in large population-based studies. Due to the polygenic nature of ASCVD, we aimed to assess the association of genomics with ASCVD risk and its impact on the occurrence of acute myocardial infarction, stroke, or peripheral artery thrombotic-ischemic events at population level. CardioVascular Genes (CV-GENES) is a nationwide, multicenter, 1:1 case-control study of 3,734 patients in Brazil. Inclusion criterion for cases is the first occurrence of one of the ASCVD events. Individuals without known ASCVD will be eligible as controls. A core lab will perform the genetic analyses through low-pass whole genome sequencing and whole exome sequencing. In order to estimate the independent association between genetic polymorphisms and ASCVD, a polygenic risk score (PRS) will be built through a hybrid approach including effect size of each Single Nucleotide Polymorphism (SNP), number of effect alleles observed, sample ploidy, total number of SNPs included in the PRS, and number of non-missing SNPs in the sample. In addition, the presence of pathogenic or likely pathogenic variants will be screened in 8 genes (ABCG5, ABCG8, APOB, APOE, LDLR, LDLRAP1, LIPA, PCSK9) associated with atherosclerosis. Multiple logistic regression will be applied to estimate adjusted odds ratios (OR) and 95% confidence intervals (CI), and population attributable risks will be calculated. Clinical trial registration: This study is registered in clinicaltrials.gov (NCT05515653).
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Aterosclerose , Doenças Cardiovasculares , Humanos , Pró-Proteína Convertase 9 , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/prevenção & controle , Estudos de Casos e Controles , Brasil/epidemiologia , Fatores de Risco , Aterosclerose/genética , Aterosclerose/epidemiologia , Patrimônio Genético , Estudos Multicêntricos como AssuntoRESUMO
Data-independent acquisition (DIA) allows comprehensive proteome coverage, while it also potentially works as a unified protocol to determine a multitude of proteins found in blood. Because of its high specificity, mass spectrometry may greatly reduce the interference observed in other assays to evaluate blood markers. Here, we combined DIA with volumetric absorptive microsampling (VAMS) and automated proteomics sample processing in a platform to assess clinical markers. As a proof of concept, we evaluated two hemoglobin-related biomarkers: the glycated hemoglobin (HbA1c) and hemoglobin (Hb) variants. HbA1c by DIA showed good correlation with the reference method, but method imprecision did not meet the quality requirement for this biomarker. We developed a strategy to identify Hb variants based on a customized database combined with a workflow for DIA data extraction and rigorous peptide evaluation. Data are available via ProteomeXchange with identifier PXD029918.
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Coleta de Amostras Sanguíneas , Teste em Amostras de Sangue Seco , Biomarcadores , Coleta de Amostras Sanguíneas/métodos , Teste em Amostras de Sangue Seco/métodos , Hemoglobinas Glicadas , Espectrometria de Massas/métodosRESUMO
Background: The Complete Blood Count (CBC) is a commonly used low-cost test that measures white blood cells, red blood cells, and platelets in a person's blood. It is a useful tool to support medical decisions, as intrinsic variations of each analyte bring relevant insights regarding potential diseases. In this study, we aimed at developing machine learning models for COVID-19 diagnosis through CBCs, unlocking the predictive power of non-linear relationships between multiple blood analytes. Methods: We collected 809,254 CBCs and 1,088,385 RT-PCR tests for SARS-Cov-2, of which 21% (234,466) were positive, from 900,220 unique individuals. To properly screen COVID-19, we also collected 120,807 CBCs of 16,940 individuals who tested positive for other respiratory viruses. We proposed an ensemble procedure that combines machine learning models for different respiratory infections and analyzed the results in both the first and second waves of COVID-19 cases in Brazil. Results: We obtain a high-performance AUROC of 90 + % for validations in both scenarios. We show that models built solely of SARS-Cov-2 data are biased, performing poorly in the presence of infections due to other RNA respiratory viruses. Conclusions: We demonstrate the potential of a novel machine learning approach for COVID-19 diagnosis based on a CBC and show that aggregating information about other respiratory diseases was essential to guarantee robustness in the results. Given its versatile nature, low cost, and speed, we believe that our tool can be particularly useful in a variety of scenarios-both during the pandemic and after.
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Next-generation sequencing (NGS) has altered clinical genetic testing by widening the access to molecular diagnosis of genetically determined rare diseases. However, physicians may face difficulties selecting the best diagnostic approach. Our goal is to estimate the rate of possible molecular diagnoses missed by different targeted gene panels using data from a cohort of patients with rare genetic diseases diagnosed with exome sequencing (ES). For this purpose, we simulated a comparison between different targeted gene panels and ES: the list of genes harboring clinically relevant variants from 158 patients was used to estimate the theoretical rate of diagnoses missed by NGS panels from 53 different NGS panels from eight different laboratories. Panels presented a mean rate of missed diagnoses of 64% (range 14%-100%) compared to ES, representing an average predicted sensitivity of 36%. Metabolic abnormalities represented the group with highest mean of missed diagnoses (86%), while seizure represented the group with lowest mean (46%). Focused gene panels are restricted in covering select sets of genes implicated in specific diseases and they may miss molecular diagnoses of rare diseases compared to ES. However, their role in genetic diagnosis remains important especially for well-known genetic diseases with established genetic locus heterogeneity.
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BACKGROUND: São Paulo city has been one of the regions most affected by the COVID-19 pandemic in Brazil. Frequent asymptomatic and oligosymptomatic infections and poor access to diagnostic tests make serosurveys crucial to monitor the magnitude of the epidemic and to inform public health policies, such as vaccination plans. OBJECTIVES: To estimate, early in the epidemic, the seroprevalence of antibodies to SARS-CoV-2 in adults living in the six most affected districts in São Paulo city, and to assess potential associated risk factors. METHODS: This was a cross-sectional population-based survey of 1,152 households randomly selected from 72 census tracts. During the period May 4-12, 2020, 463 participants completed a questionnaire on sociodemographic characteristics and history of symptoms in the past two weeks, and provided a blood sample. Prevalence of SARS-CoV-2 antibodies was the outcome of interest and was estimated based on results of two immunoassays, Maglumi SARS-CoV-2 chemiluminescence assay Immunoglobulin (Ig) M (IgM) and IgG, and Roche electrochemiluminescence assay total Ig. Serum samples reactive to either assay were considered positive. RESULTS: Weighted overall seroprevalence was 6% (95%CI 3.9-8.3%). No association was observed between seropositivity and sex, age group or education level. Participants who reported black and brown skin color showed a 2.7 fold higher prevalence than people with white skin (p = 0.007). Among the 30 seropositive individuals, 14 (46.6%) reported no COVID-19 compatible symptoms in the past two weeks. CONCLUSION: This study represents the first assessment of SARS-CoV-2 seroprevalence in the city of São Paulo and 6% is the baseline estimate of a series of population-based seroprevalence surveys. Serological screening using sound serological assays is the key tool to monitoring temporal and geographic changes in the spread of the virus through an important epicenter of the COVID-19 pandemic in Brazil. Ultimately, it may inform prevention and control efforts.
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COVID-19 , SARS-CoV-2 , Adulto , Anticorpos Antivirais , Brasil/epidemiologia , Estudos Transversais , Humanos , Imunoglobulina G , Pandemias , Estudos SoroepidemiológicosRESUMO
Several Mendelian disorders follow an autosomal recessive inheritance pattern. Epidemiological information on many inherited disorders may be useful to guide health policies for rare diseases, but it is often inadequate, particularly in developing countries. We aimed to calculate the carrier frequencies of rare autosomal recessive Mendelian diseases in a cohort of Brazilian patients using whole exome sequencing (WES). We reviewed the molecular findings of WES from 320 symptomatic patients who had carrier status for recessive diseases. Using the Hardy-Weinberg equation, we estimated recessive disease frequencies (q2 ) considering the respective carrier frequencies (2pq) observed in our study. We calculated the sensitivity of carrier screening tests based on lists of genes from five different clinical laboratories that offer them in Brazil. A total of 425 occurrences of 351 rare variants were reported in 278 different genes from 230 patients (71.9%). Almost half (48.8%) were carriers of at least one heterozygous pathogenic/likely pathogenic variant for rare metabolic disorders, while 25.9% of epilepsy, 18.1% of intellectual disabilities, 15.6% of skeletal disorders, 10.9% immune disorders, and 9.1% of hearing loss. We estimated that an average of 67% of the variants would not have been detected by carrier screening panels. The combined frequencies of autosomal recessive diseases were estimated to be 26.39/10,000 (or ~0.26%). This study shows the potential research utility of WES to determine carrier status, which may be a possible strategy to evaluate the clinical and social burden of recessive diseases at the population level and guide the optimization of carrier screening panels.
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Deficiência Intelectual , Doenças Raras , Brasil/epidemiologia , Estudos de Coortes , Humanos , Sequenciamento do ExomaRESUMO
ABSTRACT Background: São Paulo city has been one of the regions most affected by the COVID-19 pandemic in Brazil. Frequent asymptomatic and oligosymptomatic infections and poor access to diagnostic tests make serosurveys crucial to monitor the magnitude of the epidemic and to inform public health policies, such as vaccination plans. Objectives: To estimate, early in the epidemic, the seroprevalence of antibodies to SARS-CoV-2 in adults living in the six most affected districts in São Paulo city, and to assess potential associated risk factors. Methods: This was a cross-sectional population-based survey of 1,152 households randomly selected from 72 census tracts. During the period May 4-12, 2020, 463 participants completed a questionnaire on sociodemographic characteristics and history of symptoms in the past two weeks, and provided a blood sample. Prevalence of SARS-CoV-2 antibodies was the outcome of interest and was estimated based on results of two immunoassays, Maglumi SARS-CoV-2 chemiluminescence assay Immunoglobulin (Ig) M (IgM) and IgG, and Roche electrochemiluminescence assay total Ig. Serum samples reactive to either assay were considered positive. Results: Weighted overall seroprevalence was 6% (95%CI 3.9-8.3%). No association was observed between seropositivity and sex, age group or education level. Participants who reported black and brown skin color showed a 2.7 fold higher prevalence than people with white skin (p = 0.007). Among the 30 seropositive individuals, 14 (46.6%) reported no COVID-19 compatible symptoms in the past two weeks. Conclusion: This study represents the first assessment of SARS-CoV-2 seroprevalence in the city of São Paulo and 6% is the baseline estimate of a series of population-based seroprevalence surveys. Serological screening using sound serological assays is the key tool to monitoring temporal and geographic changes in the spread of the virus through an important epicenter of the COVID-19 pandemic in Brazil. Ultimately, it may inform prevention and control efforts.
Assuntos
Humanos , Adulto , SARS-CoV-2 , COVID-19 , Brasil/epidemiologia , Imunoglobulina G , Estudos Soroepidemiológicos , Estudos Transversais , Pandemias , Anticorpos AntiviraisRESUMO
The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is pressing public health systems around the world, and large population testing is a key step to control this pandemic disease. Here, we develop a high-throughput targeted proteomics assay to detect SARS-CoV-2 nucleoprotein peptides directly from nasopharyngeal and oropharyngeal swabs. A modified magnetic particle-based proteomics approach implemented on a robotic liquid handler enables fully automated preparation of 96 samples within 4 hours. A TFC-MS system allows multiplexed analysis of 4 samples within 10 min, enabling the processing of more than 500 samples per day. We validate this method qualitatively (Tier 3) and quantitatively (Tier 1) using 985 specimens previously analyzed by real-time RT-PCR, and detect up to 84% of the positive cases with up to 97% specificity. The presented strategy has high sample stability and should be considered as an option for SARS-CoV-2 testing in large populations.
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Teste para COVID-19/métodos , Técnicas de Laboratório Clínico , Espectrometria de Massas/métodos , Humanos , Nasofaringe/virologia , Orofaringe/virologia , Proteômica , SARS-CoV-2/isolamento & purificação , Sensibilidade e Especificidade , Proteínas ViraisRESUMO
Rare diseases comprise a diverse group of conditions, most of which involve genetic causes. We describe the variable spectrum of findings and clinical impacts of exome sequencing (ES) in a cohort of 500 patients with rare diseases. In total, 164 primary findings were reported in 158 patients, representing an overall diagnostic yield of 31.6%. Most of the findings (61.6%) corresponded to autosomal dominant conditions, followed by autosomal recessive (25.6%) and X-linked (12.8%) conditions. These patients harbored 195 variants, among which 43.6% are novel in the literature. The rate of molecular diagnosis was considerably higher for prenatal samples (67%; 4/6), younger children (44%; 24/55), consanguinity (50%; 3/6), gastrointestinal/liver disease (44%; 16/36) and syndromic/malformative conditions (41%; 72/175). For 15.6% of the cohort patients, we observed a direct potential for the redirection of care with targeted therapy, tumor screening, medication adjustment and monitoring for disease-specific complications. Secondary findings were reported in 37 patients (7.4%). Based on cost-effectiveness studies in the literature, we speculate that the reports of secondary findings may influence an increase of 123.2 years in the life expectancy for our cohort, or 0.246 years/cohort patient. ES is a powerful method to identify the molecular bases of monogenic disorders and redirect clinical care.
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Exoma , Doenças Raras , Criança , Estudos de Coortes , Consanguinidade , Exoma/genética , Feminino , Humanos , Gravidez , Doenças Raras/diagnóstico , Doenças Raras/genética , Sequenciamento do ExomaRESUMO
INTRODUCTION: Pro-inflammatory markers play a significant role in the disease severity of patients with COVID-19. Thus, anti-inflammatory therapies are attractive agents for potentially combating the uncontrolled inflammatory cascade in these patients. We designed a trial testing tocilizumab versus standard of care intending to improve the outcomes by inhibiting interleukin-6, an important inflammatory mediator in COVID-19. METHODS AND ANALYSIS: This open-label multicentre randomized controlled trial will compare clinical outcomes of tocilizumab plus standard of care versus standard of care alone in patients with moderate to severe COVID-19. Two of the following four criteria are required for protocol enrolment: D-dimer > 1,000ng/mL; C reactive protein > 5mg/dL, ferritin > 300mg/dL, and lactate dehydrogenase > upper limit of normal. The primary objective will be to compare the clinical status on day 15, as measured by a 7-point ordinal scale applied in COVID-19 trials worldwide. The primary endpoint will be assessed by an ordinal logistic regression assuming proportional odds ratios adjusted for stratification variables (age and sex). ETHICS AND DISSEMINATION: The TOCIBRAS protocol was approved by local and central (national) ethical committees in Brazil following current national and international guidelines/directives. Each participating center had the study protocol approved by their institutional review boards before initiating protocol enrolment. The data derived from this trial will be published regardless of the results. If proven active, this strategy could alleviate the consequences of the inflammatory response in COVID-19 patients and improve their clinical outcomes.
INTRODUÇÃO: Os marcadores pró-inflamatórios desempenham papel importante na severidade de pacientes com COVID-19. Assim, terapêuticas anti-inflamatórias são agentes interessantes para potencialmente combater a cascata inflamatória descontrolada em tais pacientes. Delineamos um ensaio para testar tocilizumabe em comparação com o tratamento padrão, tendo como objetivo melhorar os desfechos por meio da inibição da interleucina 6, um importante mediador inflamatório na COVID-19. MÉTODOS E ANÁLISES: Este será um estudo aberto multicêntrico, randomizado e controlado, que comparará os desfechos de pacientes tratados com tocilizumabe mais tratamento padrão com o tratamento padrão isoladamente em pacientes com COVID-19 moderada a grave. Como critérios de inclusão, serão exigidos dois dos quatro critérios a seguir: dosagens de dímero D acima de 1.000ng/mL, proteína C-reativa acima de 5mg/dL, ferritina acima de 300mg/dL e desidrogenase lática acima do limite superior do normal. O objetivo primário será comparar a condição clínica no dia 15, conforme avaliação por meio de escala ordinal de 7 pontos aplicada nos estudos de COVID-19 em todo o mundo. O desfecho primário será avaliado por regressão logística ordinal assumindo razões de propensão proporcionais ajustadas pelas variáveis de estratificação (idade e sexo). ÉTICA E DISSEMINAÇÃO: O TOCIBRAS foi aprovado pelos comitês de ética locais e central (nacional) do Brasil em conformidade com as atuais diretrizes e orientações nacionais e internacionais. Cada centro participante obteve aprovação do estudo por parte de seu comitê de ética em pesquisa, antes de iniciar as inscrições no protocolo. Os dados derivados deste ensaio serão publicados independentemente de seus resultados. Se tiver sua efetividade comprovada, esta estratégia terapêutica poderá aliviar as consequências da resposta inflamatória na COVID-19 e melhorar os resultados clínicos.
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Anti-Inflamatórios/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Anti-Inflamatórios/farmacologia , Anticorpos Monoclonais Humanizados/farmacologia , Brasil , COVID-19 , Infecções por Coronavirus/fisiopatologia , Humanos , Interleucina-6/antagonistas & inibidores , Pandemias , Pneumonia Viral/fisiopatologia , Índice de Gravidade de DoençaRESUMO
RESUMO Introdução: Os marcadores pró-inflamatórios desempenham papel importante na severidade de pacientes com COVID-19. Assim, terapêuticas anti-inflamatórias são agentes interessantes para potencialmente combater a cascata inflamatória descontrolada em tais pacientes. Delineamos um ensaio para testar tocilizumabe em comparação com o tratamento padrão, tendo como objetivo melhorar os desfechos por meio da inibição da interleucina 6, um importante mediador inflamatório na COVID-19. Métodos e análises: Este será um estudo aberto multicêntrico, randomizado e controlado, que comparará os desfechos de pacientes tratados com tocilizumabe mais tratamento padrão com o tratamento padrão isoladamente em pacientes com COVID-19 moderada a grave. Como critérios de inclusão, serão exigidos dois dos quatro critérios a seguir: dosagens de dímero D acima de 1.000ng/mL, proteína C-reativa acima de 5mg/dL, ferritina acima de 300mg/dL e desidrogenase lática acima do limite superior do normal. O objetivo primário será comparar a condição clínica no dia 15, conforme avaliação por meio de escala ordinal de 7 pontos aplicada nos estudos de COVID-19 em todo o mundo. O desfecho primário será avaliado por regressão logística ordinal assumindo razões de propensão proporcionais ajustadas pelas variáveis de estratificação (idade e sexo). Ética e disseminação: O TOCIBRAS foi aprovado pelos comitês de ética locais e central (nacional) do Brasil em conformidade com as atuais diretrizes e orientações nacionais e internacionais. Cada centro participante obteve aprovação do estudo por parte de seu comitê de ética em pesquisa, antes de iniciar as inscrições no protocolo. Os dados derivados deste ensaio serão publicados independentemente de seus resultados. Se tiver sua efetividade comprovada, esta estratégia terapêutica poderá aliviar as consequências da resposta inflamatória na COVID-19 e melhorar os resultados clínicos.
ABSTRACT Introduction: Pro-inflammatory markers play a significant role in the disease severity of patients with COVID-19. Thus, anti-inflammatory therapies are attractive agents for potentially combating the uncontrolled inflammatory cascade in these patients. We designed a trial testing tocilizumab versus standard of care intending to improve the outcomes by inhibiting interleukin-6, an important inflammatory mediator in COVID-19. Methods and analysis: This open-label multicentre randomized controlled trial will compare clinical outcomes of tocilizumab plus standard of care versus standard of care alone in patients with moderate to severe COVID-19. Two of the following four criteria are required for protocol enrolment: D-dimer > 1,000ng/mL; C reactive protein > 5mg/dL, ferritin > 300mg/dL, and lactate dehydrogenase > upper limit of normal. The primary objective will be to compare the clinical status on day 15, as measured by a 7-point ordinal scale applied in COVID-19 trials worldwide. The primary endpoint will be assessed by an ordinal logistic regression assuming proportional odds ratios adjusted for stratification variables (age and sex). Ethics and dissemination: The TOCIBRAS protocol was approved by local and central (national) ethical committees in Brazil following current national and international guidelines/directives. Each participating center had the study protocol approved by their institutional review boards before initiating protocol enrolment. The data derived from this trial will be published regardless of the results. If proven active, this strategy could alleviate the consequences of the inflammatory response in COVID-19 patients and improve their clinical outcomes.
Assuntos
Humanos , Pneumonia Viral/tratamento farmacológico , Infecções por Coronavirus/tratamento farmacológico , Anticorpos Monoclonais Humanizados/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Pneumonia Viral/fisiopatologia , Índice de Gravidade de Doença , Brasil , Interleucina-6/antagonistas & inibidores , Pandemias , Anticorpos Monoclonais Humanizados/farmacologia , COVID-19 , Anti-Inflamatórios/farmacologiaRESUMO
BACKGROUND: Progestogen-only contraceptives (POCs) are suitable for women with thrombophilia and/or a history of venous thromboembolism (VTE). Several of these women, however, use oral anticoagulant therapy (OAT), which can impair the bleeding pattern associated with POC use. We evaluated the effects of OAT use on the bleeding pattern associated with the levonorgestrel-releasing intrauterine system (LNG-IUS) in women with thrombophilia and/or a history of VTE. STUDY DESIGN: This prospective cohort study followed two groups of women, all of whom were thrombophilic and/or had a history of VTE: OAT users and nonusers. Bleeding patterns, blood pressure, body mass index (BMI), weight, complete blood count and waist circumference were compared between the two groups before and 6 and 12 months after LNG-IUS insertion. RESULTS: The patient cohort consisted of 33 women aged 18 to 45 years old, including 16 OAT users and 17 nonusers. Body weight increased by 3.9% and BMI by 3.8% in OAT users 12 months after LNG-IUS insertion. Hemoglobin and hematocrit levels increased by approximately 10% in both groups. There was no difference between the groups in bleeding patterns, with amenorrhea being the most frequent pattern in both groups (41.2% each) 12 months after LNG-IUS insertion. OAT did not increase the frequency of prolonged and/or frequent bleeding. CONCLUSION: OAT users and nonusers had similar bleeding patterns after insertion of the LNG-IUS. Hemoglobin and hematocrit levels increased in both groups.
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Anticoagulantes/farmacologia , Dispositivos Intrauterinos Medicados , Menstruação/efeitos dos fármacos , Trombofilia/tratamento farmacológico , Tromboembolia Venosa/prevenção & controle , Administração Oral , Adulto , Anticoagulantes/uso terapêutico , Feminino , Humanos , Estudos Prospectivos , Adulto JovemRESUMO
In thrombophilic families, protein S deficiency is clearly associated with venous thrombosis. We aimed to determine whether the same holds true in a population-based case-control study (n = 5317). Subjects were regarded protein S deficient when protein S levels were < 2.5th percentile of the controls. Free and total protein S deficiency was not associated with venous thrombosis: free protein S < 53 U/dL, odds ratio [OR] 0.82 (95% confidence interval [CI], 0.56-1.21) and total protein S < 68 U/dL, OR 0.90 (95% CI, 0.62-1.31). When lower cutoff values were applied, it appeared that subjects at risk of venous thrombosis could be identified at levels < 0.10th percentile of free protein S (< 33 U/dL, OR 5.4; 95% CI, 0.61-48.8). In contrast, even extremely low total protein S levels were not associated with venous thrombosis. PROS1 was sequenced in 48 subjects with free protein S level < 1st percentile (< 4 6 U/dL), and copy number variations were investigated in 2718 subjects, including all subjects with protein S (free or total) < 2.5th percentile. Mutations in PROS1 were detected in 5 patients and 5 controls reinforcing the observation that inherited protein S deficiency is rare in the general population. Protein S testing and PROS1 testing should not be considered in unselected patients with venous thrombosis.
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Deficiência de Proteína S/metabolismo , Proteína S/metabolismo , Trombose Venosa/metabolismo , Adulto , Idoso , Estudos de Casos e Controles , Variações do Número de Cópias de DNA , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Razão de Chances , Proteína S/genética , Deficiência de Proteína S/sangue , Deficiência de Proteína S/genética , Medição de Risco , Fatores de Risco , Análise de Sequência de DNA , Trombose Venosa/sangueRESUMO
Patients with von Willebrand disease (VWD) are often heterozygous for a missense mutation in the von Willebrand factor (VWF) gene. Investigating the pathogenic features of VWF mutations in cells directly derived from patients has been challenging. Here, we have used blood outgrowth endothelial cells (BOECs) isolated from human peripheral blood to analyze the storage and secretion of VWF. BOECs showed full endothelial characteristics and responded to Weibel-Palade body (WPB) secretagogues except desmopressin. We examined BOECs derived from a single subject heterozygous for a type 2N mutation (p.Arg854Gln) and from 4 patients with type 1 VWD who were, respectively, heterozygous for p.Ser1285Pro, p.Leu1307Pro, p.Tyr1584Cys, and p.Cys2693Tyr. Compared with normal BOECs, BOECs heterozygous for p.Ser1285Pro, p.Leu1307Pro, or p.Cys2693Tyr showed morphologically abnormal WPB and retention of VWF in the endoplasmic reticulum, whereas BOECs heterozygous for p.Arg854Gln or p.Tyr1584Cys showed normal WPB. The agonist-induced exocytosis of WPB from BOECs and formation of VWF strings on BOECs heterozygous for p.Ser1285Pro, p.Leu1307Pro, or p.Cys2693Tyr, but not for p.Arg854Gln or p.Tyr1584Cys, were reduced. In conclusion, VWD phenotype can be recapitulated in BOECs, and thus BOECs provide a feasible bona fide cell model to study the pathogenic effects of VWF mutations.
Assuntos
Células Endoteliais/citologia , Células Endoteliais/metabolismo , Corpos de Weibel-Palade/metabolismo , Doença de von Willebrand Tipo 1/metabolismo , Fator de von Willebrand/metabolismo , Células Cultivadas , Retículo Endoplasmático/metabolismo , Células Endoteliais/fisiologia , Exocitose/fisiologia , Feminino , Citometria de Fluxo , Genótipo , Heterozigoto , Humanos , Masculino , Mutação de Sentido Incorreto , Fenótipo , Doença de von Willebrand Tipo 1/genética , Doença de von Willebrand Tipo 1/patologia , Fator de von Willebrand/genéticaRESUMO
Parenteral anticoagulation is a cornerstone in the management of venous and arterial thrombosis. Unfractionated heparin has a wide dose/response relationship, requiring frequent and troublesome laboratorial follow-up. Because of all these factors, low-molecular-weight heparin use has been increasing. Inadequate dosage has been pointed out as a potential problem because the use of subjectively estimated weight instead of real measured weight is common practice in the emergency department (ED). To evaluate the impact of inadequate weight estimation on enoxaparin dosage, we investigated the adequacy of anticoagulation of patients in a tertiary ED where subjective weight estimation is common practice. We obtained the estimated, informed, and measured weight of 28 patients in need of parenteral anticoagulation. Basal and steady-state (after the second subcutaneous shot of enoxaparin) anti-Xa activity was obtained as a measure of adequate anticoagulation. The patients were divided into 2 groups according the anticoagulation adequacy. From the 28 patients enrolled, 75% (group 1, n = 21) received at least 0.9 mg/kg per dose BID and 25% (group 2, n = 7) received less than 0.9 mg/kg per dose BID of enoxaparin. Only 4 (14.3%) of all patients had anti-Xa activity less than the inferior limit of the therapeutic range (<0.5 UI/mL), all of them from group 2. In conclusion, when weight estimation was used to determine the enoxaparin dosage, 25% of the patients were inadequately anticoagulated (anti-Xa activity <0.5 UI/mL) during the initial crucial phase of treatment.
Assuntos
Anticoagulantes/administração & dosagem , Peso Corporal , Enoxaparina/administração & dosagem , Heparina de Baixo Peso Molecular/administração & dosagem , Trombose/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Distribuição de Qui-Quadrado , Serviço Hospitalar de Emergência , Feminino , Humanos , Injeções Subcutâneas , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Estatísticas não ParamétricasRESUMO
UNLABELLED: Background Associations between aplastic anemia and numerous drugs, pesticides and chemicals have been reported. However, at least 50% of the etiology of aplastic anemia remains unexplained. DESIGN AND METHODS: This was a case-control, multicenter, multinational study, designed to identify risk factors for agranulocytosis and aplastic anemia. The cases were patients with diagnosis of aplastic anemia confirmed through biopsy or bone marrow aspiration, selected through an active search of clinical laboratories, hematology clinics and medical records. The controls did not have either aplastic anemia or chronic diseases. A total of 224 patients with aplastic anemia were included in the study, each case was paired with four controls, according to sex, age group, and hospital where the case was first seen. Information was collected on demographic data, medical history, laboratory tests, medications, and other potential risk factors prior to diagnosis. RESULTS: The incidence of aplastic anemia was 1.6 cases per million per year. Higher rates of benzene exposure (>/=30 exposures per year) were associated with a greater risk of aplastic anemia (odds ratio, OR: 4.2; 95% confidence interval, CI: 1.82-9.82). Individuals exposed to chloramphenicol in the previous year had an adjusted OR for aplastic anemia of 8.7 (CI: 0.87-87.93) and those exposed to azithromycin had an adjusted OR of 11.02 (CI 1.14-108.02). Conclusions The incidence of aplastic anemia in Latin America countries is low. Although the research study centers had a high coverage of health services, the underreporting of cases of aplastic anemia in selected regions can be discussed. Frequent exposure to benzene-based products increases the risk for aplastic anemia. Few associations with specific drugs were found, and it is likely that some of these were due to chance alone.
Assuntos
Agranulocitose/epidemiologia , Anemia Aplástica/epidemiologia , Adolescente , Adulto , Agranulocitose/etiologia , Agranulocitose/patologia , Anemia Aplástica/etiologia , Anemia Aplástica/patologia , Derivados de Benzeno/toxicidade , Medula Óssea , Brasil/epidemiologia , Estudos de Casos e Controles , Criança , Pré-Escolar , Exposição Ambiental/efeitos adversos , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
PURPOSE: LATIN is a multinational case-control study designed to identify risk factors for agranulocytosis and to estimate the incidence rate of the disease in some Latin American countries. METHODS: Each study site in Brazil, Argentina and Mexico conducted an active search of agranulocytosis patients in hematology clinics and looked for possible associations with drug use. RESULTS: The overall incidence rate was 0.38 cases per 1 million inhabitant-years. Agranulocytosis patients more often took medications already associated with agranulocytosis than controls (p = 0.01), mainly methimazole (OR 44.2, 95% CI 6.8 to infinity). The population attributable risk percentage (etiologic fraction) was 56%. The use of nutrient supplements was more frequent among patients than controls (p = 0.03). CONCLUSIONS: Agranulocytosis seems to be very rare in Latin America. The lower than expected number of cases identified during the study period precluded estimation of the risk associated to individual drugs, with the exception of methimazol. However, this is the longest series of agranulocytosis cases ever gathered in Latin America, and information on drug exposures was collected prospectively. The conclusion is that drug-induced agranulocytosis does not seem to be a major public health problem in the study regions.
Assuntos
Agranulocitose/epidemiologia , Idoso , Agranulocitose/induzido quimicamente , Antitireóideos/efeitos adversos , Estudos de Casos e Controles , Criança , Coleta de Dados , Feminino , Humanos , Incidência , Entrevistas como Assunto , América Latina/epidemiologia , Masculino , Metimazol/efeitos adversos , Pessoa de Meia-Idade , Exposição Ocupacional , Fatores de Risco , Inquéritos e QuestionáriosRESUMO
BACKGROUND: The most primitive leukemic precursor in acute myeloid leukemia (AML) is thought to be the leukemic stem cell (LSC), which retains the properties of self-renewal and high proliferative capacity and quiescence of the hematopoietic stem cell. LSC seems to be immunophenotypically distinct and more resistant to chemotherapy than the more committed blasts. Considering that the multidrug resistance (MDR) constitutive expression may be a barrier to therapy in AML, we have investigated whether various MDR transporters were differentially expressed at the protein level by different leukemic subsets. METHODS: The relative expression of the drug-efflux pumps P-gp, MRP, LRP, and BCRP was evaluated by mean fluorescence index (MFI) and the Kolmogorov-Smirnov analysis (D values) in five leukemic subpopulations: CD34+CD38-CD123+ (LSCs), CD34+CD38+CD123-, CD34+CD38+CD123+, CD34+CD38+CD123-, and CD34- mature cells in 26 bone marrow samples of CD34+ AML cases. RESULTS: : The comparison between the two more immature subsets (LSC versus CD34+CD38-CD123- cells) revealed a higher P-gp, MRP, and LRP expression in LSCs. The comparative analysis between LSCs and subsets of intermediate maturation (CD34+CD38+) demonstrated the higher BCRP expression in the LSCs. In addition, P-gp expression was also significantly higher in the LSC compared to CD34+CD38+CD123- subpopulation. Finally, the comparative analysis between LSC and the most mature subset (CD34-) revealed higher MRP and LRP and lower P-gp expression in the LSCs. CONCLUSIONS: Considering the cellular heterogeneity of AML, the higher MDR transporters expression at the most immature, self-renewable, and quiescent LSC population reinforces that MDR is one of the mechanisms responsible for treatment failure.