Multilevel analysis of social determinants of advanced stage colorectal cancer diagnosis.

The advanced stage at diagnosis of colorectal cancer (CRC) may be related to individual factors, socioeconomic conditions, and healthcare service availability. The objective of the study was to analyze the prevalence of advanced stage CRC at the time of diagnosis and its association with individual, contextual, socioeconomic, and healthcare service indicators. An observational, cross-sectional study was conducted, analyzing cases of malignant neoplasms of the colon and rectum in individuals of both sexes, aged between 18 and 99 years, diagnosed between 2010 and 2019 in Brazil (n = 69,047). Data were collected from the Hospital Cancer Registry (HCR), Atlas of Human Development in Brazil, and from the National Registry of Health Institutions (NRHI). A Multilevel Poisson Regression model with random intercept was used. The prevalence of advanced stage CRC at diagnosis was 65.6%. Advanced stage was associated with older age groups prevalence ratio (PR) 4.40 and younger age groups (PR 1.84), low Human Development Index (HDI) (PR 1.22), and low density of family health strategy teams (PR 1.10). The study highlights the unequal distribution of social determinants of health in the diagnosis CRC in Brazil, revealing the need to evaluate and redirect public policies aimed at improving early detection and prevention of CRC in the country.

What does Google Trends reveal about the proportion of waterpipe users in the Brazilian population?

OBJECTIVE: To analyze the relationship between internet search volume and the prevalence of waterpipe use among young Brazilians in 2019. METHODS: This was a descriptive study with data from Brazil in 2019, using the relative search volume on waterpipes extracted from Google Trends and the proportion of waterpipe users aged between 15 and 24 years, as measured by the National Health Survey (Pesquisa Nacional de Saúde - PNS), and aged between 13 and 17 years, as measured by the National Adolescent School-based Health Survey (Pesquisa Nacional de Saúde do Escolar - PeNSE). The relationship was assessed by means of Spearman's correlation. RESULTS: The point prevalence of waterpipe use across the Brazilian Federative Units (FUs) showed a moderate (r = 0.51; PNS) to strong correlation (r = 0.74 and r = 0.80; PeNSE) with the relative search volume (p-value < 0.05). CONCLUSION: Google Trends can support the monitoring system on waterpipe use in the FUs, providing additional information to existing population-based surveys. MAIN RESULTS: The search volume for waterpipes by states in Brazil, as measured by Google Trends, showed a moderate to high correlation with the respective proportions of current use and experimentation of waterpipe among the adolescent/young adult population. IMPLICATIONS FOR SERVICES: The use of Google Trends as a support to the monitoring system for waterpipe consumption in Brazil warrants further exploration in terms of the validity of additional information to existing population surveys. PERSPECTIVES: Expanding the use of Google Trends searches to assess its potential in monitoring other health risk products and detecting (or predicting) incidence or seasonality of health-related events.

Human Papillomavirus 16 Lineage D is Associated with High Risk of Cervical Cancer in the Brazilian Northeast Region.

OBJECTIVE: Similar to Human Papillomavirus (HPV) genotypes, different lineages of a genotype also have different carcinogenic capabilities. Studies have shown that specific genotype lineages of oncogenic HPV are associated with variable risks for the development of cervical intraepithelial neoplasia (CIN2/CIN3) and cervical cancer. The present study aimed to analyze the genetic diversity of the HPV16 genotype in women with CIN2/CIN3 and cervical cancer, from the northeast region of Brazil. METHODS: A cross-sectional multicenter study was conducted in the northeast region of Brazil, from 2014 to 2016. This study included 196 cases of HPV16 variants (59 and 137 cases of CIN2/CIN3 and cervical cancer, respectively). The difference of proportion test was used to compare patients with CIN2/CIN3 and cervical cancer, based on the prevalent HPV16 lineage (p < 0.05). RESULTS: According to the histopathological diagnosis, the percentage of lineage frequencies revealed a marginal difference in the prevalence of lineage A in CIN2/CIN3, compared with that in cervical cancer (p = 0.053). For lineage D, the proportion was higher in cancer cases (32.8%), than in CIN2/CIN3 cases (16.9%), with p = 0.023. CONCLUSION: HPV16 lineage A was the most frequent lineage in both CIN2/CIN3 and cervical cancer samples, while lineage D was predominant in cervical cancer, suggesting a possible association between HPV16 lineage D and cervical cancer.

OBJETIVO: Tanto os tipos quanto as linhagens do Papilomavírus Humano (HPV) parecem ter diferentes capacidades carcinogênicas e estão associados a riscos variados para o desenvolvimento de neoplasia intraepitelial cervical (NIC) e câncer de colo do útero. O presente estudo tem como objetivo analisar a diversidade genética do genótipo HPV 16 nos casos de NIC2/NIC3 e câncer de colo de útero em mulheres da região Nordeste do Brasil. MéTODOS: Estudo transversal de base hospitalar realizado na região Nordeste do Brasil no período de 2014 a 2016. A amostra foi composta por 196 casos da variante HPV-16 (59 casos de NIC2/NIC3 e 137 de câncer do colo do útero). O teste de diferença de proporção foi usado para comparar os grupos NIC2/NIC3 e câncer de colo do útero por linhagem viral em relação à prevalência da linhagem HPV-16. Foi considerada significância estatística o valor de p < 0,05. RESULTADOS: As frequências de linhagem por diagnóstico histopatológico mostraram diferença limítrofe da linhagem A no grupo NIC2/NIC3 em relação ao grupo câncer de colo de útero (p = 0,053). Por outro lado, em relação à linhagem D, houve uma proporção maior nos casos de câncer (32,8%) quando comparado ao grupo NIC2/NIC3 (16,9%) e esta diferença se mostrou estatisticamente significante (p = 0,023). CONCLUSãO: A linhagem A do HPV-16 foi a mais frequente tanto nas amostras CIN2/CIN3 quanto nas amostras de câncer de colo de útero, enquanto a linhagem D predominou no câncer de colo do útero, sugerindo uma possível associação da linhagem D de HPV-16 com câncer de colo de útero.

The economic impact of cancer mortality among working-age individuals in Brazil from 2001 to 2030.

BACKGROUND: About half of cancer deaths in Brazil occur among individuals of working-age (under 65 years for men, under 60 for women), resulting in a substantial economic impact for the country. We aimed to estimate the years of potential productive life lost (YPPLL) and value the productivity lost due to premature deaths from cancer between 2001 and 2015 and the projected to 2030. METHODS: We used the Human Capital Approach to estimate the productivity losses corresponding to YPPLL for cancer deaths in working age people (15-64 years). Mortality data were obtained from the Mortality Information System from 2001 to 2015 and projected between 2016 and 2030. Economic data were obtained from the Continuous National Household Sample Survey and forecasted to 2030. Productivity lost was calculated as the monetary value arising from YPPLL in Int$(2016). RESULTS: Between 2001 and 2030, a total of 2.3 million premature deaths from all cancers combined were observed and forecasted in Brazil (57% men, 43% women), corresponding to 32 million YPPLL and Int$141.3 billion in productivity losses (men: Int$102.5 billion, women: Int$38.8 billion). Between 2001 and 2030, among men, lung (Int$ 12.6 billion), stomach (Int$ 10.6 billion) and colorectal (Int$ 9.4 billion) cancers were expected to contribute to the greatest productivity losses; and among women, it will be for breast (Int$ 10.0 billion), cervical (Int$ 6.4 billion) and colorectal (Int$ 3.2 billion) cancers. CONCLUSIONS: Many preventable cancers result in high lost productivity, suggesting measure to reduce smoking prevalence, alcohol consumption, physical inactivity and inadequate diet, improving screening programs and increasing vaccination coverage for human papillomavirus and hepatitis B would have a positive impact on the economy, as well as reducing morbidity and mortality from cancer.

What does Google Trends reveal about the proportion of waterpipe users in the Brazilian population? / ¿Qué tiene que decir Google Trends sobre la proporción de usuarios de narguile en la población brasileña? / O que o Google Trends tem a dizer sobre a proporção de usuários de narguilé na população brasileira?

ABSTRACT Objective To analyze the relationship between internet search volume and the prevalence of waterpipe use among young Brazilians in 2019. Methods This was a descriptive study with data from Brazil in 2019, using the relative search volume on waterpipes extracted from Google Trends and the proportion of waterpipe users aged between 15 and 24 years, as measured by the National Health Survey (Pesquisa Nacional de Saúde - PNS), and aged between 13 and 17 years, as measured by the National Adolescent School-based Health Survey (Pesquisa Nacional de Saúde do Escolar - PeNSE). The relationship was assessed by means of Spearman's correlation. Results The point prevalence of waterpipe use across the Brazilian Federative Units (FUs) showed a moderate (r = 0.51; PNS) to strong correlation (r = 0.74 and r = 0.80; PeNSE) with the relative search volume (p-value < 0.05). Conclusion Google Trends can support the monitoring system on waterpipe use in the FUs, providing additional information to existing population-based surveys.

RESUMEN Objetivo Analizar la relación entre el volumen de búsquedas en Internet y la prevalencia del uso de narguile entre los jóvenes brasileños en 2019. Métodos Estudio descriptivo con datos de Brasil en 2019, utilizando el volumen relativo de búsqueda sobre narguile extraído de Google Trends y la proporción de usuarios de narguile entre 15 y 24 años, medida por la Encuesta Nacional de Salud (PNS), y con edades entre 13 y 17 años, medida por la Encuesta Nacional de Salud Escolar (PeNSE). La relación fue respaldada por el método de correlación de Spearman. Resultados La prevalencia puntual del uso de narguile en las Unidades Federativas brasileñas presentó una correlación moderada (r = 0,51; PNS) a fuerte (r = 0,74 y r = 0,80; PeNSE) con el volumen relativo de búsqueda (p-valor < 0,05). Conclusión Google Trends puede apoyar el sistema de monitoreo del uso de narguile en las UFs, ofreciendo información adicional a las encuestas poblacionales existentes.

RESUMO Objetivo Analisar a relação entre o volume de pesquisas na internet e a prevalência de uso de narguilé entre jovens brasileiros em 2019. Métodos Estudo descritivo com dados do Brasil em 2019, utilizando o volume relativo de pesquisa sobre o narguilé extraído do Google Trends e a proporção de usuários de narguilé com idade entre 15 e 24 anos, medida pela Pesquisa Nacional de Saúde (PNS), e com idade entre 13 e 17 anos, medida pela Pesquisa Nacional de Saúde do Escolar (PeNSE). A relação foi avaliada por meio da correlação de Spearman. Resultados A prevalência pontual de uso de narguilé das Unidades da Federação (UFs) brasileiras apresentou correlação moderada (r = 0,51; PNS) a forte (r = 0,74 e r = 0,80; PeNSE) com o volume de pesquisas relativo (p-valor < 0,05). Conclusão O Google Trends pode apoiar o sistema de monitoramento sobre o uso do narguilé nas UFs brasileiras, oferecendo informações adicionais às pesquisas populacionais existentes.

Human Papillomavirus 16 Lineage D is Associated with High Risk of Cervical Cancer in the Brazilian Northeast Region / Papillomavirus humano 16 da linhagem D associado a alto risco de câncer de colo do útero em região do nordeste brasileiro

Abstract Objective Similar to Human Papillomavirus (HPV) genotypes, different lineages of a genotype also have different carcinogenic capabilities. Studies have shown that specific genotype lineages of oncogenic HPV are associated with variable risks for the development of cervical intraepithelial neoplasia (CIN2/CIN3) and cervical cancer. The present study aimed to analyze the genetic diversity of the HPV16 genotype in women with CIN2/CIN3 and cervical cancer, from the northeast region of Brazil. Methods A cross-sectional multicenter study was conducted in the northeast region of Brazil, from 2014 to 2016. This study included 196 cases of HPV16 variants (59 and 137 cases of CIN2/CIN3 and cervical cancer, respectively). The difference of proportion test was used to compare patients with CIN2/CIN3 and cervical cancer, based on the prevalent HPV16 lineage (p < 0.05). Results According to the histopathological diagnosis, the percentage of lineage frequencies revealed a marginal difference in the prevalence of lineage A in CIN2/CIN3, compared with that in cervical cancer (p = 0.053). For lineage D, the proportion was higher in cancer cases (32.8%), than in CIN2/CIN3 cases (16.9%), with p = 0.023. Conclusion HPV16 lineage A was the most frequent lineage in both CIN2/CIN3 and cervical cancer samples, while lineage D was predominant in cervical cancer, suggesting a possible association between HPV16 lineage D and cervical cancer.

Resumo Objetivo Tanto os tipos quanto as linhagens do Papilomavírus Humano (HPV) parecem ter diferentes capacidades carcinogênicas e estão associados a riscos variados para o desenvolvimento de neoplasia intraepitelial cervical (NIC) e câncer de colo do útero. O presente estudo tem como objetivo analisar a diversidade genética do genótipo HPV 16 nos casos de NIC2/NIC3 e câncer de colo de útero em mulheres da região Nordeste do Brasil. Métodos Estudo transversal de base hospitalar realizado na região Nordeste do Brasil no período de 2014 a 2016. A amostra foi composta por 196 casos da variante HPV-16 (59 casos de NIC2/NIC3 e 137 de câncer do colo do útero). O teste de diferença de proporção foi usado para comparar os grupos NIC2/NIC3 e câncer de colo do útero por linhagem viral em relação à prevalência da linhagem HPV-16. Foi considerada significância estatística o valor de p < 0,05. Resultados As frequências de linhagem por diagnóstico histopatológico mostraram diferença limítrofe da linhagem A no grupo NIC2/NIC3 em relação ao grupo câncer de colo de útero (p = 0,053). Por outro lado, em relação à linhagem D, houve uma proporção maior nos casos de câncer (32,8%) quando comparado ao grupo NIC2/NIC3 (16,9%) e esta diferença se mostrou estatisticamente significante (p = 0,023). Conclusão A linhagem A do HPV-16 foi a mais frequente tanto nas amostras CIN2/CIN3 quanto nas amostras de câncer de colo de útero, enquanto a linhagem D predominou no câncer de colo do útero, sugerindo uma possível associação da linhagem D de HPV-16 com câncer de colo de útero.

Impacto da pandemia da Covid-19 sobre o Serviço e Cuidado à Pessoa Tabagista no SUS / Impact of the Covid-19 pandemic on the Service and Care for Smokers in the SUS

Resumo Durante a pandemia da Covid-19, o serviço para tratamento do fumante foi impactado. Este artigo avaliou o impacto da pandemia sobre o serviço no SUS. Trata-se de um estudo observacional descritivo ecológico utilizando o banco de dados do Programa Nacional de Controle do Tabagismo (PNCT) anos 2019, 2020 e 2021, de cinco estados (PA, PB, GO, RJ e RS) referente ao segundo quadrimestre. Foram estimadas as diferenças relativas no número de unidades que ofereceram o serviço e no número de atendimentos para avaliação clínica, primeira e quarta sessões. Para os anos de 2019 e 2020, observou-se diferença percentual no número de unidades que ofereceram o serviço em todos os estados estudados de -51,9%. Para os anos de 2019 e 2021, a diferença relativa para as unidades de saúde foi de -20,96% e, para a avaliação clínica, primeira e quarta sessões foram: -54,19%, -55,07% e -61,31%, respectivamente. Essas diferenças foram maiores para as capitais quando comparadas com os demais municípios. Apesar do impacto negativo, principalmente no primeiro ano da pandemia, o estudo mostrou que os serviços não interromperam suas atividades e mostraram alguma recuperação em 2021.Também foi importante observar que os tabagistas, apesar das recomendações, não deixaram de procurar o tratamento.

Abstract During the Covid-19 pandemic, the smoker treatment service was impacted. This article evaluated the impact of the pandemic on the service in the SUS. This is an ecological descriptive observational study using the National Tobacco Control Program (PNCT) database for the years 2019, 2020 and 2021, from five states (PA, PB, GO, RJ and RS) for the second four months. Relative differences were estimated in the number of units that offered the service and in the number of consultations for clinical evaluation, first and fourth sessions. For the years 2019 and 2020, there was a percentage difference of -51.9% in the number of units that offered the service in all states studied. For the years 2019 and 2021, the relative difference for the health units was -20.96% and, for the clinical evaluation, the first and fourth sessions were: -54.19%, -55.07% and -61 .31%, respectively. These differences were greater for the capitals when compared to the other municipalities. Despite the negative impact, especially in the first year of the pandemic, the study showed that the services did not interrupt their activities and showed some recovery in 2021. It was also important to note that smokers, despite the recommendations, did not stop seeking treatment.

Estimativa de Incidência de Câncer no Brasil, 2023-2025 / Estimated Cancer Incidence in Brazil, 2023-2025 / Incidencia Estimada de Cáncer en Brasil, 2023-2025

O câncer é um problema de saúde pública mundial. Na última década, houve um aumento de 20% na incidência e espera-se que, para 2030, ocorram mais de 25 milhões de casos novos. Estimativas do número de casos novos de câncer são uma ferramenta poderosa para fundamentar políticas públicas e alocação racional de recursos para o combate ao câncer. A vigilância do câncer é um elemento crucial para planejamento, monitoramento e avaliação das ações de controle do câncer. Objetivo: Estimar e descrever a incidência de câncer no país, Regiões geográficas, Unidades da Federação, Distrito Federal e capitais, por sexo, para o triênio 2023-2025. Método: As informações foram extraídas do Sistema de Informação sobre Mortalidade e dos Registros de Câncer de Base Populacional. Foram estimados os casos novos e suas respectivas taxas de incidência pelos modelos de predição tempo-linear ou pela razão de incidência e mortalidade. Resultados: São esperados 704 mil casos novos de câncer para o triênio 2023-2025. Excetuando o câncer de pele não melanoma, ocorrerão 483 mil casos novos. O câncer de mama feminina e o de próstata foram os mais incidentes com 73 mil e 71 mil casos novos, respectivamente. Em seguida, o câncer de cólon e reto (45 mil), pulmão (32 mil), estômago (21 mil) e o câncer do colo do útero (17 mil). Conclusão: No Brasil, por suas dimensões continentais e heterogeneidade, em termos de território e população, o perfil da incidência reflete a diversidade das Regiões geográficas, coexistindo padrões semelhantes ao de países desenvolvidos e em desenvolvimento

Cancer is a worldwide public health problem, in the last decade there was an increase of 20% of the incidence and more than 25 million new cases are expected by 2030. Estimates of the number of new cancer cases are a powerful tool to support public policies and rational allocation of resources to fight cancer. Cancer surveillance is paramount for planning, monitoring and evaluating cancer control programs. Objective: To estimate and to describe the incidence of cancer in the country, geographic regions, states, Federal District and capitals, by sex, for the 2023-2025 period. Method: Cancer mortality and incidence information were extracted from the Mortality Information System and from Population-Based Cancer Registries. The number of new cases and their respective incidence rates were estimated by time-linear prediction models or by the incidence and mortality ratio. Results: 704,000 new cases of cancer are expected for the triennium 2023-2025. Except for nonmelanoma skin cancer, 483,000 new cases will occur. Female breast cancer and prostate cancer were the most frequent with 73,000 and 71,000 new cases, respectively, followed by colorectal cancer (45,000), lung (32,000) and stomach (21,000), and cervical cancer (17,000). Conclusion: In Brazil, due to its continental dimensions and heterogeneity both in terms of population and territory, the incidence profile reflects the diversity of geographic regions, and patterns similar to developed and developing countries.

Introducción: El cáncer es un problema de salud pública mundial, en la última década, hubo un incremento de un 20% en la incidencia y se espera, para 2030, más de 25 millones de nuevos casos. Estimaciones del número de nuevos casos de cáncer son una herramienta poderosa para fundamentar políticas públicas y la asignación racional de recursos para el combate contra el cáncer. La vigilancia es un elemento crucial para la planificación, monitoreo y evaluación de las acciones de control del cáncer. Objetivo: Estimar y describir la incidencia de cáncer en el país, regiones geográficas, Unidades de la Federación, Distrito Federal y capitales, por género, para el trienio 2023-2025. Método: Las informaciones fueron extraídas del Sistema de Información sobre Mortalidad y de los Registros de Cáncer de Base Poblacional. Fueron estimados los nuevos casos y sus respectivas tasas de incidencia mediante los modelos de predicción tiempo-lineal o por la razón de incidencia y mortalidad. Resultados: Se prevén 704 mil nuevos casos de cáncer para el trienio 2023-2025. Exceptuando el cáncer de piel no-melanoma, ocurrirán 483 mil nuevos casos. El cáncer de mama femenino y el de próstata fueron los que tuvieron mayor incidencia con 73 mil y 71 mil nuevos casos, respectivamente. Les siguen el cáncer de colon y recto (45 mil), pulmón (32 mil), estómago (21 mil) y el cáncer del cuello uterino (17 mil). Conclusión: En el Brasil, por sus dimensiones continentales y heterogeneidad, en términos de territorio y población, el perfil de la incidencia refleja la diversidad de las regiones geográficas, coexistiendo estándares similares al de los países desarrollados y en vías de desarrollo

Completeness of cervical cancer staging information in Brazil: A national hospital-based study.

BACKGROUND: Cancer staging information in Hospital Cancer Registries (HCR) is essential for cancer care quality evaluations. This study aimed to analyze the completeness of cervical cancer staging in Brazilian HCR and identify individual and contextual factors associated with unknown staging. METHODS: The outcome analyzed was missing or unknown staging (Malignant Tumor Classification System and/or International Federation of Gynecology and Obstetrics) in 2006-2015. Individual data on cancer cases were collected from the HCR Integrator. Contextual variables were collected from the Atlas of Human Development in Brazil, the National Registry of Health Facilities, and the Outpatient Information System. The random intercept multilevel Poisson regression model was performed to identify the factors associated with the outcome. RESULTS: The prevalence of unknown staging data was 32.4% (95% confidence interval [CI], 32.1-32.7). Women aged 18-29 years (prevalence ratio [PR], 1.48; 95% CI, 1.42-1.54), referred by the public health system (PR, 1.16; 95% CI, 1.11-1.21), living in states with a low density of oncologists (PR, 1.70; 95% CI, 1.62-1.79), and with a low cytopathological testing rate (PR, 1.69; 95% CI, 1.57-1.82) showed a higher prevalence of unknown tumor staging data. A lower level of education (PR, 0.91; 95% CI, 0.84-0.98) was associated with complete staging data. CONCLUSIONS: Individual and contextual factors were associated with missing staging data. It is necessary to improve information on cancer in the HCRs by improving the awareness and training of Brazilian cancer care professionals.

Cross-validation of four different survey methods used to estimate illicit cigarette consumption in Brazil.

OBJECTIVE: To cross-validate estimates of the size of the illicit cigarette trade based on the results of four different survey methods. METHODS: In 2018/2019, four non-industry-funded, large-scale studies were conducted in selected Brazilian cities: packs discarded in household garbage/PDG (1 city), packs littered in the streets/PLS (5 cities), a phone survey of tobacco users' purchase behaviors/VIGITEL (5 cities), and a face-to-face household survey of tobacco users' purchase behaviors/FTF-household (2 cities). The proportions of illicit cigarettes consumed were based on the price paid by smokers in their last purchase (VIGITEL or FTF-household) and/or direct observation of brand names and health warnings (PDG, PLS or FTF-household). RESULTS: Based on PLS, the share of packs that avoided taxation ranged from 30.4% (95% CI 25.6% to 35.7%) in Rio de Janeiro to 70.1% (95% CI 64.6% to 75.0%) in Campo Grande; and PDG conducted in Rio de Janeiro found an even lower proportion point estimate of illicit cigarette use (26.8%, 95% CI 25.1% to 28.6%). In FTF-household, the share of illicit cigarette consumption based on the self-reported price ranged from 29.1% (95% CI 22.4% to 35.7%) in Rio de Janeiro to 37.5% (95% CI 31.2% to 43.7%) in São Paulo, while estimates based on pack observation ranged from 29.9% (95% CI 23.3% to 36.5%) in Rio de Janeiro to 40.7% (95% CI 34.3% to 47.0%) in São Paulo. For all cities, VIGITEL presented the lowest levels of illicit consumption, and most illicit brands were produced in Paraguay. CONCLUSIONS: Small differences in the estimated levels of illicit trade across methods were found, except for the phone survey. The cross-validation of estimates from independent studies is important to help effectively implement tobacco excise tax policy in Brazil and other low-income and middle-income countries.

Contributions of the analysis of discarded cigarette packages in household waste in the Brazilian city of Rio de Janeiro, Brazil, to estimate the illegal market. / Contribuições da análise de embalagens de cigarros descartadas nos resíduos domiciliares do Município do Rio de Janeiro, Brasil, para estimativa de mercado ilegal.

The illicit trade of tobacco products, by enabling access to cheaper cigarettes, favors smoking initiation and hinders its cessation, minimizing the effects of price policy and taxes on reducing the demand for tobacco. This is especially the case among populations with lower income and schooling, where smoking is concentrated. Its confrontation requires multisectoral actions, aligned with the World Health Organization Framework Convention on Tobacco Control, supported by estimates of the illicit trade magnitude and the analysis of its characteristics. This study analyzes, based on samples of household solid waste collected in 2018 in the city of Rio de Janeiro, Brazil, the conformity of discarded cigarette packages with criteria for their regular commercialization in Brazil, classifying them as legal or illegal. The evaluation was also carried out for the 15 Planning Areas (PA) of the municipality. The Social Progress Index (SPI) was chosen to represent heterogeneities among PA. The average percentage of illegal cigarette packs found was 26.79%, ranging from 3.36% to 46.29% among PA. The PAs with high illegality presented lower Social Progress Index and lower percentages of legal cigarette packages with a price equal to or greater than BRL 7.25. Among the illegal packages, 98.07% were manufactured in Paraguay. The study contributes methodologically to measure the consumption of illegal cigarettes in the second economic capital of Brazil, supporting the National Tobacco Control Policy in the struggle against illicit trade of tobacco products and in the effective implementation of the pricing and tax policy on these products.

O comércio ilícito de produtos de tabaco, ao possibilitar acesso a cigarros mais baratos, favorece a iniciação do tabagismo e dificulta sua cessação, minimizando os efeitos da política de preços e impostos sobre a redução da demanda por tabaco, sobretudo entre populações de menor renda e escolaridade, onde se concentra o tabagismo. Seu enfrentamento requer ações multissetoriais, alinhadas à Convenção-Quadro para o Controle do Tabaco da Organização Mundial da Saúde e seus protocolos, e respaldadas em estimativas de sua magnitude e na análise de suas características. O estudo pretende analisar, por meio de amostras de resíduos sólidos domiciliares coletados em 2018 no Município do Rio de Janeiro, Brasil, a conformidade das embalagens de cigarros descartadas com critérios para a sua comercialização regular no país, classificando-as como legais ou ilegais. A avaliação foi feita também para as 15 Áreas de Planejamento (AP) do município. Escolheu-se o Índice de Desenvolvimento Social (IDS) para representar as heterogeneidades entre as AP. O percentual médio de embalagens de cigarros ilegais encontrado foi de 26,79%, variando de 3,36% a 46,29% entre as AP. As AP com alta ilegalidade apresentavam menores IDS e menores percentuais de embalagens de cigarros legais com preço igual ou superior a R$ 7,25. Dentre as embalagens ilegais, 98,07% apresentavam o Paraguai como país fabricante. O estudo contribui metodologicamente para dimensionar o consumo de cigarros ilegais na segunda capital econômica do Brasil, subsidiando a Política Nacional de Controle do Tabaco no combate ao comércio ilícito de produtos de tabaco e na efetiva implementação da política de preços e impostos sobre estes produtos.

El comercio ilícito de productos del tabaco, al posibilitar el acceso a cigarrillos más baratos, favorece la iniciación del tabaquismo y dificulta la interrupción de su consumo, minimizando los efectos de la política de precios e impuestos sobre la reducción de la demanda de tabaco, sobre todo entre poblaciones de menor renta y escolaridad, donde se concentra el tabaquismo. Su combate requiere acciones multisectoriales, alineadas con la Convención-Marco para el Control del Tabaco de la Organización Mundia de la Salud, y sus protocolos, y respaldadas en estimaciones de su magnitud y en el análisis de sus características. El estudio pretende analizar, mediante muestras de residuos sólidos domiciliarios, recogidos en 2018 en el Municipio de Rio de Janeiro, Brasil, la conformidad de los paquetes de cigarrillos tirados a la basura con criterios para su comercialización regular en el país, clasificándolos como legales o ilegales. La evaluación se realizó también para las 15 Áreas de Planificación (AP) del municipio. Se escogió el Índice de Desarrollo Social (IDS) para representar heterogeneidades entre las AP. El porcentaje medio de paquetes de cigarrillos ilegales encontrado fue de un 26,79%, variando de 3,36% a 46,29% entre las AP. Las AP con alta ilegalidad presentaban menores IDS y menores porcentajes de paquetes de cigarrillos legales con un precio igual o superior a BRL 7,25. Entre los embalajes ilegales, un 98,07% presentaban Paraguay como el país fabricante. El estudio contribuye metodológicamente para dimensionar el consumo de cigarrillos ilegales en la segunda capital económica de Brasil, apoyando la Política Nacional de Control del Tabaco en el combate al comercio ilícito de productos del tabaco y en la efectiva implementación de la política de precios e impuestos sobre estos productos.

Spatial distribution of advanced stage diagnosis and mortality of breast cancer: Socioeconomic and health service offer inequalities in Brazil.

Breast cancer presents high incidence and mortality rates, being considered an important public health issue. Analyze the spatial distribution pattern of late stage diagnosis and mortality for breast cancer and its correlation with socioeconomic and health service offer-related population indicators. Ecological study, developed with 161 Intermediate Region of Urban Articulation (IRUA). Mortality data were collected from the Mortality Information System (MIS). Tumor staging data were extracted from the Hospital Cancer Registry (HCR). Socioeconomic variables were obtained from the Atlas of Human Development in Brazil; data on medical density and health services were collected from the National Registry of Health Institutions (NRHI) and Supplementary National Health Agency. Global Moran's Index and Local Indicator of Spatial Association (LISA) were utilized to verify the existence of territorial clusters. Multivariate analysis used models with global spatial effects. The proportion of late stage diagnosis of breast cancer was 39.7% (IC 39.4-40.0). The mean mortality rate for breast cancer, adjusted by the standard world population was 10.65 per 100,000 women (± 3.12). The proportion of late stage diagnosis presented positive spatial correlation with Gini's Index (p = 0.001) and negative with the density of gynecologist doctors (p = 0.009). The adjusted mortality rates presented a positive spatial correlation with the Human Development Index (p<0.001) and density of gynecologist doctors (p<0.001). Socioeconomic and health service offer-related inequalities of the Brazilian territory are determinants of the spatial pattern of breast cancer morbimortality in Brazil.

A multilevel assessment of the social determinants associated with the late stage diagnosis of breast cancer.

The advanced-stage diagnosis of breast cancer reveals the inequalities associated with socioeconomic conditions and the offer of health services. This study analyzes the prevalence of advanced breast cancer and its relationship with individual and contextual socioeconomic indicators and offer of health service. A cross-sectional study is presented herein, on the assessment of malignant breast neoplasms in women diagnosed between 2006 and 2015 (n = 195,201). Data were collected from the Hospital Cancer Registry (HCR), Atlas of Human Development in Brazil, and from the National Registry of Health Institutions (NRHI). A multilevel Poisson Regression was carried out with random intercept. The prevalence of advanced breast cancer diagnosis was 40.0%. Advanced staging was associated with younger age groups (PR 1.41), race/nonwhite (PR 1.13), lower education levels (PR 1.38), and public access to health services (PR 1.25). There was also an association with a low density of mammographic equipment (PR 1.08), and with low indices of local social inequality (PR 1.33) and human development (PR 0.80). This study maps and highlights the causes related to inequalities in the diagnosis of advanced breast cancer in Brazil, and presents essential data to reorient public policies and health-related actions to strengthen the control of breast cancer in Brazil.

Contribuições da análise de embalagens de cigarros descartadas nos resíduos domiciliares do Município do Rio de Janeiro, Brasil, para estimativa de mercado ilegal / Contribuciones del análisis de paquetes de cigarrillos desechados como residuos domiciliarios en el Municipio de Rio de Janeiro, Brasil, para estimar mercado ilegal / Contributions of the analysis of discarded cigarette packages in household waste in the Brazilian city of Rio de Janeiro, Brazil, to estimate the illegal market

Resumo: O comércio ilícito de produtos de tabaco, ao possibilitar acesso a cigarros mais baratos, favorece a iniciação do tabagismo e dificulta sua cessação, minimizando os efeitos da política de preços e impostos sobre a redução da demanda por tabaco, sobretudo entre populações de menor renda e escolaridade, onde se concentra o tabagismo. Seu enfrentamento requer ações multissetoriais, alinhadas à Convenção-Quadro para o Controle do Tabaco da Organização Mundial da Saúde e seus protocolos, e respaldadas em estimativas de sua magnitude e na análise de suas características. O estudo pretende analisar, por meio de amostras de resíduos sólidos domiciliares coletados em 2018 no Município do Rio de Janeiro, Brasil, a conformidade das embalagens de cigarros descartadas com critérios para a sua comercialização regular no país, classificando-as como legais ou ilegais. A avaliação foi feita também para as 15 Áreas de Planejamento (AP) do município. Escolheu-se o Índice de Desenvolvimento Social (IDS) para representar as heterogeneidades entre as AP. O percentual médio de embalagens de cigarros ilegais encontrado foi de 26,79%, variando de 3,36% a 46,29% entre as AP. As AP com alta ilegalidade apresentavam menores IDS e menores percentuais de embalagens de cigarros legais com preço igual ou superior a R$ 7,25. Dentre as embalagens ilegais, 98,07% apresentavam o Paraguai como país fabricante. O estudo contribui metodologicamente para dimensionar o consumo de cigarros ilegais na segunda capital econômica do Brasil, subsidiando a Política Nacional de Controle do Tabaco no combate ao comércio ilícito de produtos de tabaco e na efetiva implementação da política de preços e impostos sobre estes produtos.

Resumen: El comercio ilícito de productos del tabaco, al posibilitar el acceso a cigarrillos más baratos, favorece la iniciación del tabaquismo y dificulta la interrupción de su consumo, minimizando los efectos de la política de precios e impuestos sobre la reducción de la demanda de tabaco, sobre todo entre poblaciones de menor renta y escolaridad, donde se concentra el tabaquismo. Su combate requiere acciones multisectoriales, alineadas con la Convención-Marco para el Control del Tabaco de la Organización Mundia de la Salud, y sus protocolos, y respaldadas en estimaciones de su magnitud y en el análisis de sus características. El estudio pretende analizar, mediante muestras de residuos sólidos domiciliarios, recogidos en 2018 en el Municipio de Rio de Janeiro, Brasil, la conformidad de los paquetes de cigarrillos tirados a la basura con criterios para su comercialización regular en el país, clasificándolos como legales o ilegales. La evaluación se realizó también para las 15 Áreas de Planificación (AP) del municipio. Se escogió el Índice de Desarrollo Social (IDS) para representar heterogeneidades entre las AP. El porcentaje medio de paquetes de cigarrillos ilegales encontrado fue de un 26,79%, variando de 3,36% a 46,29% entre las AP. Las AP con alta ilegalidad presentaban menores IDS y menores porcentajes de paquetes de cigarrillos legales con un precio igual o superior a BRL 7,25. Entre los embalajes ilegales, un 98,07% presentaban Paraguay como el país fabricante. El estudio contribuye metodológicamente para dimensionar el consumo de cigarrillos ilegales en la segunda capital económica de Brasil, apoyando la Política Nacional de Control del Tabaco en el combate al comercio ilícito de productos del tabaco y en la efectiva implementación de la política de precios e impuestos sobre estos productos.

Abstract: The illicit trade of tobacco products, by enabling access to cheaper cigarettes, favors smoking initiation and hinders its cessation, minimizing the effects of price policy and taxes on reducing the demand for tobacco. This is especially the case among populations with lower income and schooling, where smoking is concentrated. Its confrontation requires multisectoral actions, aligned with the World Health Organization Framework Convention on Tobacco Control, supported by estimates of the illicit trade magnitude and the analysis of its characteristics. This study analyzes, based on samples of household solid waste collected in 2018 in the city of Rio de Janeiro, Brazil, the conformity of discarded cigarette packages with criteria for their regular commercialization in Brazil, classifying them as legal or illegal. The evaluation was also carried out for the 15 Planning Areas (PA) of the municipality. The Social Progress Index (SPI) was chosen to represent heterogeneities among PA. The average percentage of illegal cigarette packs found was 26.79%, ranging from 3.36% to 46.29% among PA. The PAs with high illegality presented lower Social Progress Index and lower percentages of legal cigarette packages with a price equal to or greater than BRL 7.25. Among the illegal packages, 98.07% were manufactured in Paraguay. The study contributes methodologically to measure the consumption of illegal cigarettes in the second economic capital of Brazil, supporting the National Tobacco Control Policy in the struggle against illicit trade of tobacco products and in the effective implementation of the pricing and tax policy on these products.

The papillomavirus E5 gene does not affect EGFR transcription and overall survival in cervical cancer.

INTRODUCTION: The human papillomavirus (HPV) E5 gene encodes a small and highly hydrophobic oncoprotein that affects immune evasion, cell proliferation, loss of apoptotic capacity and angiogenesis in tumors. E5 shows an affinity for biological membranes and was associated with an increase of epidermal growth factor/epidermal growth factor receptor (EGF/EGFR) signaling through the accumulation of EGFR in cellular membranes. Due to the frequent integration of the HPV genome into the host cell genome, E5 is frequently not transcribed in cervical tumors. AIM: In this study we looked forward to verifying whether the potential expression of E5 protein in human papillomavirus 16 positive (HPV16+ ) and human papillomavirus 18 positive (HPV18+ ) cervical tumors was associated with levels of EGFR and vascular endothelial growth factor A (VEGFA) transcription and with patients overall survival. RESULTS: Association between the presence of E5 transcripts and viral genome disruption was observed for HPV16+ and HPV18+ tumors. Association was not observed between tumors potentially capable of translating E5 and EGFR or VEGFA transcriptional levels. Similarly, the capability of translating E5 and overall survival in patients with HPV16+ squamous cell carcinoma tumors stage ≥ IB2 were not associated. CONCLUSION: The likely presence of E5 transcripts was neither associated to a higher activity of the EGFR-VEGFA pathway nor to the overall survival of patients with HPV16+ squamous cell carcinoma in stages ≥ IB2.

Methylation at 3'LCR of HPV16 can be affected by patient age and disruption of E1 or E2 genes.

CpG methylation at early promoter of HPV16 DNA, in the 3' end of the Long Control Region (3'LCR), has been associated to the presence of episomal forms of viral genome and, consequently, intact E1 and E2 ORFs. The DNA methylation would block the access of E2 viral protein to the E2 binding sites at early-promoter. However, is still unclear if methylation at 3'LCR of HPV16 DNA can also vary depending of other tumor characteristics in addition to viral DNA physical state. In this study, we evaluate whether the methylation level at the five CpG located at 3'LCR of HPV16 is associated to patient age and E1 and/or E2 ORFs integrity. DNA pyrosequencing was used to measure the methylation level in 69 invasive cervical cancer samples obtained from biopsies of patients attended at Brazilian National Institute of Cancer (INCA). PCR amplifications were performed to assess disruption status of E1 and E2 genes of HPV16. The methylation average per sample ranged widely, from <1 to 88.00%. Presence of intact E1/E2 genes and patient age were positively associated with average methylation in both bivariate analyses (p=0.003 and p=0.006, respectively), and multivariate analysis (p=0.002 and p=0.021, respectively), adjusted for tumor type (squamous cell carcinomas or adenocarcinomas) and HPV16 lineage. These findings showed that presence of intact E1/E2 open reading frames was associated with high levels of DNA methylation, and older patients showed higher levels of methylation than younger ones independently of viral genome disruption.

Genetic diversity of HPV16 and HPV18 in Brazilian patients with invasive cervical cancer.

Cervical cancer is the fourth most common cancer among women, and ∼70-80% of these cancers are associated with two human papillomavirus types: HPV16 and HPV18. Several studies have reported that intra-type diversity is associated with the progression of infection to invasive cancer. Herein, we report the genetic diversity of HPV16 and HPV18 in a cohort of 594 Brazilian women with invasive cervical cancer and describe the prevalence of lineages and intra-type diversity prior to the implementation of the public immunization program in Brazil. HPV detection and genotyping were performed using PCR, PGMY/GP primers, and DNA extracted from fresh tumors. The HPV16 (378 women) and HPV18 (80 women) lineages were identified by PCR and sequencing of the LCR and E6 fragments, followed by SNV comparison and phylogenetic analysis. In our cohort, was found a higher frequency of the lineage A (in 217 women), followed by lineage D (in 97 women) and lineages B and C (in 10 women each) for HPV16; and a higher frequency of lineage A (in 56 women) followed by lineage B (in 15 women) in HPV18. The genetic diversity of HPV16 indicated a recent expansion of specific variants or a selective advantage that is associated with invasive cancer; this pattern was not observed for HPV18.

Factors related to inadequate cervical cancer screening in two Brazilian state capitals / Fatores associados ao rastreamento inadequado do câncer cervical em duas capitais brasileiras / Factores asociados al rastreo inadecuado del cáncer cervical en dos capitales brasileras

OBJECTIVE:To analyze factors associated with cervical cancer screening failure. METHODS:Population-based cross-sectional study with self-weighted two-stage cluster sampling conducted in the cities of Fortaleza (Northeastern Brazil) and Rio de Janeiro (Southeastern Brazil) in 2002. Subjects were women aged 25-59 years in the last three years prior to the study. Data were analyzed through Poisson regression using a hierarchical model. RESULTS: The proportion of women who did not undergo the Pap smear test in Fortaleza and Rio de Janeiro was 19.1 percent (95 percent CI: 16.1;22.1) and 16.5 percent (95 percent CI: 14.1;18.9), respectively. Higher prevalence ratios of cervical cancer screening failure in both cities were seen among women with low education and low per capita income, old age, unmarried, who never underwent mammography, clinical breast examination, and blood glucose and cholesterol level testing. Smokers also had lower screening rates compared to non-smoker women and this difference was only statistically significant in Rio de Janeiro. CONCLUSIONS:The study findings point to the need of intervention focusing particularly women in worse socioeconomic conditions and access to healthcare, old-aged and unmarried. Education activities must prioritize screening of asymptomatic women and early diagnosis for symptomatic women and access to adequate diagnostic methods and treatment should be provided.

OBJETIVO: Analisar fatores associados à não-realização do exame de Papanicolaou. MÉTODOS:Estudo transversal, de base populacional, com amostragem por conglomerados com dois estágios de seleção e autoponderada em 2002. As participantes foram mulheres de 25 a 59 anos de idade nos três anos anteriores à pesquisa, nos municípios de Fortaleza (CE) e Rio de Janeiro (RJ). Os dados foram analisados por regressão de Poisson por meio de modelo hierárquico. RESULTADOS: O percentual de mulheres não submetidas ao exame de Papanicolaou foi de 19,1 por cento (IC 95 por cento: 16,1;22,1) em Fortaleza e 16,5 por cento (IC 95 por cento: 14,1;18,9) no Rio de Janeiro. As maiores razões de prevalência para a não-realização do exame nas duas localidades foram entre mulheres com baixa escolaridade, de menor renda per capita, com idade mais avançada, não-casadas e que nunca foram submetidas à mamografia, ao exame clínico das mamas e aos exames de glicemia e colesterolemia. Além disso, as fumantes foram menos submetidas ao exame de Papanicolaou quando comparadas às demais mulheres, sendo a diferença estatisticamente significativa somente no Rio de Janeiro. CONCLUSÕES: Os achados apontam a necessidade de intervenção principalmente em mulheres de piores condições socioeconômicas e de acesso à saúde, com idade mais avançada e não-casadas. As atividades de educação para o diagnóstico precoce e para o rastreamento em mulheres sintomáticas e assintomáticas devem ser priorizadas com garantia de acesso aos métodos de diagnóstico e tratamento adequados.

OBJETIVO:Analizar factores asociados a la no realización del examen de Papanicolaou. MÉTODOS: Estudio transversal, de base poblacional, con muestreo por conglomerado con dos fases de selección y autoponderación en 2002. Las participantes fueron mujeres de 25 a 59 años de edad en los tres años anteriores a la investigación, en los municipios de Fortaleza y Río de Janeiro (Noreste y Sureste de Brasil). Los datos fueron analizados por regresión de Poisson por medio de modelo jerárquico. RESULTADOS:El porcentaje de mujeres no sometidas al examen de Papanicolaou fue de 19,1 por ciento (IC 95 por ciento: 16,1;22,1) en Fortaleza y 16,5 por ciento (IC 95 por ciento: 14,1;18,9) en Río de Janeiro. Las mayores razones de prevalencia para la no realización del examen en las dos localidades fueron entre mujeres con baja escolaridad, de menor renta per capita, con edad más avanzada, no casadas y que nunca fueron sometidas a la mamografía, al examen clínico de las mamas y a los exámenes de glicemia y colesterolemia. Así mismo, las fumadoras fueron menos sometidas al examen de Papanicolaou cuando se compararon con las demás mujeres, siendo la diferencia estadísticamente significativa solamente en Río de Janeiro. CONCLUSIONES: Los resultados apuntan la necesidad de intervención principalmente en mujeres de peores condiciones socioeconómicas y de acceso a la salud, con edades más avanzadas y no casadas. Las actividades de educación para el diagnóstico precoz y para el rastreo en mujeres sintomáticas y asintomáticas deben ser priorizadas con garantía de acceso a los métodos de diagnóstico y tratamiento adecuados.

Factors related to inadequate cervical cancer screening in two Brazilian state capitals.

OBJECTIVE: To analyze factors associated with cervical cancer screening failure. METHODS: Population-based cross-sectional study with self-weighted two-stage cluster sampling conducted in the cities of Fortaleza (Northeastern Brazil) and Rio de Janeiro (Southeastern Brazil) in 2002. Subjects were women aged 25-59 years in the last three years prior to the study. Data were analyzed through Poisson regression using a hierarchical model. RESULTS: The proportion of women who did not undergo the Pap smear test in Fortaleza and Rio de Janeiro was 19.1% (95% CI: 16.1;22.1) and 16.5% (95% CI: 14.1;18.9), respectively. Higher prevalence ratios of cervical cancer screening failure in both cities were seen among women with low education and low per capita income, old age, unmarried, who never underwent mammography, clinical breast examination, and blood glucose and cholesterol level testing. Smokers also had lower screening rates compared to non-smoker women and this difference was only statistically significant in Rio de Janeiro. CONCLUSIONS: The study findings point to the need of intervention focusing particularly women in worse socioeconomic conditions and access to healthcare, old-aged and unmarried. Education activities must prioritize screening of asymptomatic women and early diagnosis for symptomatic women and access to adequate diagnostic methods and treatment should be provided.

Cobertura do exame de Papanicolaou no Brasil e seus fatores determinantes: uma revisão sistemática da literatura / Coverage of the Pap smear in Brazil and its determining factors: a systematic literature review

OBJETIVO: apresentar o panorama da cobertura do exame de Papanicolaou no Brasil, com ênfase nos seus fatores determinantes. MÉTODOS: foram pesquisadas as bases de dados "on line" LILACS (Literatura Latino-Americana e do Caribe em Ciências da Saúde), MEDLINE - 1966 a 2004 (Literatura Internacional em Ciências da Saúde), PAHO (Acervo da Biblioteca da Organização Pan-Americana de Saúde) e WHOLIS (Sistema de Informação da Biblioteca da OMS). A revisão foi ampliada por meio da busca a referências bibliográficas dos estudos relevantes, solicitação de estudos publicados e não publicados a especialistas e outras fontes. Foram selecionados artigos que preenchiam os seguintes critérios: ser um estudo transversal, ter sido realizado no Brasil, conter informações sobre a cobertura do exame Papanicolaou (alguma vez na vida ou nos últimos três anos) ou sobre seus fatores determinantes. Foram excluídas as duplicidades e os artigos sem resumo. Um total de 13 artigos foram selecionados atendendo a esses critérios. RESULTADOS: são poucos os estudos sobre a cobertura do exame de Papanicolaou no Brasil. A maioria concentra-se nas grandes cidades das regiões Sul e Sudeste do país. Além da escassez, existe pouca padronização metodológica em relação à amostragem e perfil das mulheres a serem investigadas, o que torna difícil a comparação entre si. Estas diferenças metodológicas devem ter contribuído para a grande variabilidade nas coberturas encontradas. Entretanto, apesar de todos os problemas, observa-se tendência de aumento temporal no percentual de mulheres que foram submetidas a pelo menos um exame de Papanicolaou: os dois únicos estudos realizados nos anos 80 mostram coberturas de 55,0 e 68,9 por cento na vida, ao passo que um inquérito domiciliar realizado em 15 capitais e no Distrito Federal entre 2002 e 2003 apresenta valores que variam de 73,4 a 92,9 por cento; porém, dois estudos de abrangência nacional realizados em 2003 apresentaram coberturas abaixo de 70,0 por cento nos últimos três anos. Por outro lado, algumas variáveis foram mais freqüentemente observadas nas mulheres não submetidas ao exame de Papanicolaou: ter baixo nível socioeconômico, ter baixa escolaridade, ter baixa renda familiar e pertencer às faixas etárias mais jovens. CONCLUSAO: os dados aqui apresentados apontam para desigualdades regionais na cobertura do exame de Papanicolaou na população feminina brasileira e para a necessidade de intervenção junto àqueles fatores a ela associados