Behavior of total alkaline phosphatase after radium-233 therapy in metastatic castration-resistant prostate cancer: a single-center, real-world retrospective study.

Objective: To describe the behavior of total alkaline phosphatase (tALP) in patients with metastatic castration-resistant prostate cancer receiving radium-223 therapy, in a real-world scenario, and to describe overall survival (OS) among such patients. Materials and Methods: This was a retrospective study involving 97 patients treated between February 2017 and September 2020. Patients were stratified by the baseline tALP (normal/elevated). A tALP response was defined as a ≥ 30% reduction from baseline at week 12. For patients with elevated baseline tALP, we also evaluated treatment response as a ≥ 10% reduction in tALP after the first cycle of treatment. We defined OS as the time from the first treatment cycle to the date of death. Results: There was a significant reduction in the median tALP after each cycle of treatment (p < 0.05 for all). Data for tALP at week 12 were available for 71 of the 97 patients. Of those 71 patients, 26 (36.6%) responded. Elevated baseline tALP was observed in 47 patients, of whom 19 (40.4%) showed a response. Longer OS was observed in the patients with normal baseline tALP, in those with elevated baseline tALP that showed a response to treatment (≥ 10% reduction), and in those who received 5-6 cycles of therapy. Conclusion: The tALP may be used to predict which patients will benefit from treatment with a greater number of cycles of radium-223 therapy and will have longer OS.

Objetivo: Descrever o comportamento da fosfatase alcalina total (tALP) em pacientes com carcinoma de próstata metastático resistente a castração, submetidos a terapia com rádio-223 em um cenário do mundo real, e a sobrevida global (SG) desses pacientes. Materiais e Métodos: Estudo retrospectivo envolvento 97 pacientes, no período de fevereiro/2017 a setembro/2020. Os pacientes foram estratificados de acordo com a tALP basal (normal/elevada). A resposta à tALP foi definida como uma redução em relação à linha de base de ≥ 30% na semana-12. Para pacientes com tALP basal elevada, também foi avaliada a resposta ao tratamento como uma redução de ≥ 10% de tALP após o primeiro ciclo. A SG foi definida como o tempo entre o primeiro ciclo e a data do óbito. Resultados: A redução da tALP média após cada ciclo foi significativa (p < 0,05). A tALP na semana 12 estava disponível para 71 dos 97 pacientes. Desses 71 pacientes, 26 (36,6%) responderam. Dezenove (40,4%) dos 47 pacientes com tALP elevada apresentaram resposta. Foi observada uma SG mais longa nos pacientes com tALP basal normal, nos pacientes com tALP basal elevada que apresentaram resposta ao tratamento (redução de ≥ 10%) e nos pacientes que receberam 5-6 ciclos. Conclusão: A tALP pode ser usada para prever parte dos pacientes que se beneficiarão do tratamento com um maior número de ciclos e uma SG mais longa.

Behavior of total alkaline phosphatase after radium-233 therapy in metastatic castration-resistant prostate cancer: a single-center, real-world retrospective study / Estudo retrospectivo de vida-real, em centro único, para avaliação do comportamento da fosfatase alcalina total após terapia com rádio-223 no câncer de próstata resistente a castração

Abstract Objective: To describe the behavior of total alkaline phosphatase (tALP) in patients with metastatic castration-resistant prostate cancer receiving radium-223 therapy, in a real-world scenario, and to describe overall survival (OS) among such patients. Materials and Methods: This was a retrospective study involving 97 patients treated between February 2017 and September 2020. Patients were stratified by the baseline tALP (normal/elevated). A tALP response was defined as a ≥ 30% reduction from baseline at week 12. For patients with elevated baseline tALP, we also evaluated treatment response as a ≥ 10% reduction in tALP after the first cycle of treatment. We defined OS as the time from the first treatment cycle to the date of death. Results: There was a significant reduction in the median tALP after each cycle of treatment (p < 0.05 for all). Data for tALP at week 12 were available for 71 of the 97 patients. Of those 71 patients, 26 (36.6%) responded. Elevated baseline tALP was observed in 47 patients, of whom 19 (40.4%) showed a response. Longer OS was observed in the patients with normal baseline tALP, in those with elevated baseline tALP that showed a response to treatment (≥ 10% reduction), and in those who received 5-6 cycles of therapy. Conclusion: The tALP may be used to predict which patients will benefit from treatment with a greater number of cycles of radium-223 therapy and will have longer OS.

Resumo Objetivo: Descrever o comportamento da fosfatase alcalina total (tALP) em pacientes com carcinoma de próstata metastático resistente a castração, submetidos a terapia com rádio-223 em um cenário do mundo real, e a sobrevida global (SG) desses pacientes. Materiais e Métodos: Estudo retrospectivo envolvento 97 pacientes, no período de fevereiro/2017 a setembro/2020. Os pacientes foram estratificados de acordo com a tALP basal (normal/elevada). A resposta à tALP foi definida como uma redução em relação à linha de base de ≥ 30% na semana-12. Para pacientes com tALP basal elevada, também foi avaliada a resposta ao tratamento como uma redução de ≥ 10% de tALP após o primeiro ciclo. A SG foi definida como o tempo entre o primeiro ciclo e a data do óbito. Resultados: A redução da tALP média após cada ciclo foi significativa (p < 0,05). A tALP na semana 12 estava disponível para 71 dos 97 pacientes. Desses 71 pacientes, 26 (36,6%) responderam. Dezenove (40,4%) dos 47 pacientes com tALP elevada apresentaram resposta. Foi observada uma SG mais longa nos pacientes com tALP basal normal, nos pacientes com tALP basal elevada que apresentaram resposta ao tratamento (redução de ≥ 10%) e nos pacientes que receberam 5-6 ciclos. Conclusão: A tALP pode ser usada para prever parte dos pacientes que se beneficiarão do tratamento com um maior número de ciclos e uma SG mais longa.

"The first shot": the context of first injection of illicit drugs, ongoing injecting practices, and hepatitis C infection in Rio de Janeiro, Brazil / O contexto da primeira injeção de drogas ilícitas, práticas atuais de injeção e infecção pelo vírus da hepatite C no Rio de Janeiro, Brasil

O trabalho investiga o contexto da primeira injeção de drogas e sua associação com práticas atuais de injeção e infecção pelo HCV (vírus da hepatite C). Usuários de drogas injetáveis (UDI) (N = 606) foram recrutados em cenas de uso (ruas, bares) do Rio de Janeiro, Brasil, entrevistados e testados (anti-HCV). A freqüência de compartilhamento de agulhas e seringas foi superior na primeira injeção (51,3%), se comparada à atualmente referida (36,8%). Usuários que iniciaram o uso injetável compartilhando agulhas/seringas relataram uma freqüência significativamente maior de compartilhamento direto/indireto de agulhas/seringas nos últimos seis meses. A infecção pelo HCV foi quatro vezes mais prevalente entre UDI jovens (< 30 anos) que compartilharam agulhas e seringas na primeira injeção. A prevalência de anti-HCV foi 11% entre UDI ativos (n = 272) e se mostrou independentemente associada à história de prisão e à duração do uso de drogas injetáveis. A prevenção da disseminação do HCV nesta população requer a adoção de medidas de redução de riscos e danos associados à injeção de drogas já desde a primeira injeção ou, antes, um desestímulo à transição do uso não injetável para injetável.

Primeira injeção de drogas e hepatite C: achados preliminares / The First Drug Injection and Hepatitis C: Preliminary Findings

Investigou-se o contexto da primeira injeção de drogas e sua possível associação com a infecção pelo vírus da hepatite C (HCV). Usuários de drogas injetáveis (UDI) ­ N=606 ­ foram recrutados em "cenas de uso" no Rio de Janeiro, Brasil. Os voluntários foram entrevistados e testados para a presença de anti-HCV. A utilização anterior, não injetável, da mesma droga injetada (basicamente cocaína) foi relatada por 92,0% dos UDI (último mês), administrada semanal/diariamente (86,2%). O primeiro injetador foi um amigo próximo (51,7%), utilizando uma seringa/agulha usada (51,5%), e as drogas foram obtidas como "presente" em 40,0% dos casos. Cerca de 68,0% dos UDI introduziram novos usuários: 88,1% iniciaram um a cinco outros indivíduos. A prevalência de anti-HCV foi menor entre injetadores que iniciaram o uso de drogas após 1980. Visando controlar a infecção pelo HCV nessa população, as estratégias voltadas à prevenção/redução de danos deveriam considerar distintos cenários e gerações de usuários, desde a primeira injeção.

The role of ''long-term'' and ''new'' injectors in a declining HIV/AIDS epidemic in Rio de Janeiro, Brazil

Background. A substantial decline of HIV prevalence has been observed in injection drug users (IDUs) from Rio de Janeiro, in recent years. Differential characteristics and behaviors of new (injecting for <6 years) and long-term (>»6 y) injectors may help to understand recent changes and to implement appropriate prevention strategies. recruited from different communities, interviewed, and tested for HIV. Contingency table analysis and t-tests were used to assess differences between new and long-term injectors. Multiple logistic regression was used to identify independent predictors of HIV serostatus for long-term and new injectors. Results. HIV prevalence was 11.7% for 309 long-term injectors (95% CI 8.1­ 15.3) and 4.3% for 300 new injectors (95% CI 2.0­6.6). New injectors reported having engaged in treatment and having received syringes from needle exchange programs (NEPs) more frequently than long-term injectors in the last 6 months, but sharing behaviors remained frequent and even increased vis-a`-vis long-term injectors. For male new injectors, ''sexual intercourse with another man'' was found to be the sole significant risk factor for HIV infection (Adj OR»8.03; 95% CI 1.52­42.48). Among male long-term injectors, ''to have ever injected with anyone infected with HIV'' (Adj OR»3.91; 95% CI 1.09­14.06) and to have ''ever been in prison'' (Adj OR»2.56; 95% CI 1.05­6.24) were found to be significantly associated with HIV infection. Discussion. New injectors are seeking help in drug treatment centers or needle exchange programs. They differ from long-term injectors in terms of their risk factors for HIV infection and have lower prevalence levels for HIV. Such differences may help to understand the recent dynamics of HIV/AIDS in this population and highlight the need to reinforce new injectors' help-seeking behavior and to reduce current unacceptably high levels of unprotected sex and syringe sharing in new injectors despite attendance of prevention/treatment programs.

A window of opportunity: declining rates of hepatitis B virus infection among injection drug users in Rio de Janeiro, and prospects for targeted hepatitis B vaccination / Ventana de oportunidad: reducción de las tasas de infección por el virus de la hepatitis B entre usuarios de drogas inyectadas en Río de Janeiro, Brasil, y planes futuros en torno a la vacunación contra la hepatitis B

OBJECTIVES: To measure hepatitis B virus (HBV) infection rates among injection drug users in Rio de Janeiro, Brazil, and to report their knowledge of and attitudes toward hepatitis and HBV vaccination. METHODS: 609 injection drug users recruited in Rio de Janeiro between 1999 and 2001 answered a questionnaire and were tested for hepatitis B and other blood-borne infections. Questions covered sociodemographic information, alcohol and illicit drug consumption, drug injection and sexual practices, medical history, and knowledge about HIV, AIDS and viral hepatitis. RESULTS: The prevalence of HBV infection was 27.1% , with 3.4% of the sample positive for HbsAg (active infection) and 0.8% positive for anti-HBs (indicating previous HBV vaccination). Most interviewees (81.3%) were aware of at least one form of viral hepatitis and received information from many different sources. In agreement with laboratory findings, 96.7% of the interviewees stated they had never been vaccinated against hepatitis B, but almost all unvaccinated interviewees (97.8%) said they would volunteer to be vaccinated if HBV vaccination were available. CONCLUSIONS: Few of the injection drug users surveyed had ever been vaccinated against HBV. Although most were aware of the risks posed by viral hepatitis, this awareness seldom translated into consistent behavioral change. The participants' willingness to be vaccinated against HBV suggests that the implementation of vaccination for this population may help decrease rates of hepatitis B infection

Análise dos padröes de difusäo espacial dos casos de AIDS por estados brasileiros / Analysis of spatial diffusion patterns for AIDS cases in some Brazilian States

Açöes preventivas ainda säo essenciais ao controle da epidemia de AIDS; contudo, programas de prevençäo eficazes dependem da distribuiçäo correta e eficiente dos recursos de saúde. Assim, informaçöes acerca de onde, quando, com que intensidade e como se difundirá a epidemia säo valiosos. Visou obter melhor compreensäo do processo de difusäo espacial dos casos de AIDS em quatro estados brasileiros. Tais padröes foram avaliados qualitativamente - estudo de mapas seqüênciais - e quantitativamente - análise de correlogramas espaciais - ao longo de dez anos, agrupados em três períodos: 1987-1989, 1990-1992 e 1993-1996. O processo de difusäo foi estudado para o total de casos de AIDS e para os do sexo feminino e masculino. De modo geral, houve difusäo significativa dos casos de AIDS nos períodos, mas o processo exibiu características específicas a cada estado. As informaçöes obtidas - em especial, os resultados da análise de correlogramas - permitem entender melhor os padröes de difusäo espacial da epidemia em diferentes partes do país e podem ser empregadas para fixar parâmetros a outros modelos epidemiológicos da AIDS.

Infecção pelo HIV entre usuários de drogas injetáveis: análise dos fatores de risco no Município do Rio de Janeiro, Brasil / HIV-infection among injecting drug users: analysis of risk factors in Rio de Janeiro City, Brazil.

O trabalho visa a determinar os fatores de risco para a infecção pelo HIV (Human Immunodeficiency Virus ­ vírus da aids) entre usuários de drogas injetáveis (UDI), no Município do Rio de Janeiro. Os entrevistados foram recrutados em centros de tratamento para usuários de drogas e nas "cenas de uso" ("ruas"). Foram utilizados três questionários: um destinado a colher informações mais gerais acerca dos UDI, adaptado de estudo anterior da Organização Mundial da Saúde (OMS); um segundo voltado para a pesquisa de informações suplementares sobre conhecimentos, comportamentos e atitudes em relação à aids; além de um terceiro instrumento destinado a avaliar níveis de disfunção psicológica. O estudo consistiu de 110 entrevistados que voluntariamente realizaram testes laboratoriais para a presença do HIV, além de outros agentes infecciosos de transmissão sangüínea (HBV, HCV, HDV, HGV/GBVC, HTLV-I/II). A soroprevalência para o HIV-1 foi de 28,7%. Utilizando-se um modelo de regressão logística múltipla (Estatística de Hosmer-Lemeshow, c2 = 1,89; p=0,98), foram identificados como fatores de risco para a infecção pelo HIV: "local de moradia de baixa renda" (OR=5,57; IC 95%: [1,39 - 22,27]), "fonte de renda irregular" (OR=3,26; IC 95%: [1,01 - 10,51]), "menor idade de início quando do consumo de drogas injetáveis" (OR=2,50; IC: 90%: [0,99 -6,28]), "local de recrutamento nos centros de tratamento para uso de drogas" (vs. recrutamento nas "ruas") (OR=7,91; IC 95%: [2,03 - 30,87]) e "maior freqüência de compartilhamento do material de injeção nos 6 meses anteriores à entrevista" (OR=4,41; IC 95%: [1,33 - 14,64]).

Risk behavior and HIV seroprevalence among injecting drug users in Rio de Janeiro, Brazil

Objective: To characterize HIV seroprevalence and reisk behavior among injecting drug users (IDUS) in Rio de Janeiro, Brazil, between 1990 and 1996. Design: We report data from three separate cross-sectional samples of IDUS in Rio de Janeiro: the World Health Organization (WHO) sample (n=479), the Proviva sample (n=138) and thr Brasil sample (n=110). These data provide the most comprehensive view available, to date, of this understudied population im Rio. Methods: Demographic characteristics, HIV/AIDS risk behavior and HIV seroprevalence were compared across the three samples and combined analyses were performed to determine the factors associated with injecting risk behavior, sexual risk behavior and HIV seropositivity. Results: The overal HIV seroprevalence among IDUS 25%. Two encouraging findings of the present analysis were the lower levels of needle-sharing among participants recruited in the latest years (1995-1996) andthe lower HIV serprevalence in the Proviva sample composed mainly of less educated, poorer IDUS living im deprived neighborhoods. No trends toward safer behavior were foundfor sexual risk, younger age being the principal factor associated with high risk. Conclusions: Levels of needle-sharing and sexual risk among IDUS in Rio remain high, demonstrating the urgent need to increase the limites preventive measures under-taken so far. Seroprevalence levels for HIV remain significantly lower in the most deprived sample, arguing for the fundamental importance of prompt and effective prevention strategies to keep infections rates from rising among the poorest and largest strata of Rio's IDUS.

Retrovirus infections in a sample of injecting drug users in Rio de Janeiro City, Brazil: prevalence of HIV-1 subtypes, and co-infection with HTLV-I/II

Background :Retrovirus infections among injecting drug users (IDUs), a core at-risk population for both HIV-1 and HTLV-I/II infections in Brazil, were assessed within an ongoing cooperative research. Objecti e : The study assessed the seroprevalences of HIV-1 and HTLV-I/II infections, as well as the prevalence of HIV-1 subtypes in a sample of IDUs from Rio de Janeiro, Brazil. An attempt to evaluate HIV incidence was carried out using a dual 'sensitive/less sensitive' testing strategy. Study design : Cross-sectional evaluation of 175 IDUs. Serostatus for HIV-1 and HTLV-I/II were established by enzyme-linked immunosorbent assays, and confirmed by western blot. The dual testing strategy aimed to estimate HIV-1 incidence rates. Differentiation between HTLV-I and -II was performed by western blot. DNA samples were polymerase chain reaction amplified by a nested protocol, and HIV-1 subtyping was determined by heteroduplex mobility assay. Results : Forty-six and 29 samples were found to be, respectively, positive for HIV-1 and HTLV-I/II, 15 of them co-infected by both viruses. Among HTLV-I/II-infected patients, 75.9% were infected by HTLV-I. Thirty-one HIV samples were identified as B subtype, with seven of them showing the typical 'Brazilian B' pattern in the gp120 V3 loop, and ten were identified as F subtype. The use of less sensitive assays for HIV infection wrongly identified a deeply immunocompromised patient as an incident case. Conclusion :Moderately high seroprevalences were found for both HIV-1 and HTLV-I/II infections, HIV-1/HTLV-I co-infections being of special concern. A non-statistically significant higher prevalence of F subtype was observed, when compared with the distribution of F/B subtypes among Brazilian patients from other exposure categories. No recent HIV-1 infections were detected, but a limitation of the 'sensitive/less-sensitive' testing strategy was made evident.

Prevalence and risk factors for HBV, HCV and HDV infections among injecting drug users from Rio de Janeiro, Brazil

Viral hepatitis constitutes a major health issue, with high prevalence among injecting drug users (IDUs). The present study assessed the prevalence and risk determinants for hepatitis B, C and D viruses (HBV, HCV and HDV) infections among 102 IDUs from Rio de Janeiro, Brazil. Serological markers and HCV-RNA were detected by enzyme immunoassay and nested PCR, respectively. HCV genotyping was determined by restriction fragment length polymorphism analysis (RFLP). HBsAg, anti-HBc and anti-HBs were found in 7.8, 55.8 and 24.7% of IDUs, respectively. In the final logistic regression, HBV infection was independently associated with male homosexual intercourse within the last 5 years (odds ratio (OR) 3.1; 95% confidence interval (CI) 1.1-8.8). No subject presented anti-delta (anti-HD). Anti- HCV was detected in 69.6% of subjects, and was found to be independently associated with needle sharing in the last 6 months (OR 3.4; 95% CI 1.3-9.2) and with longer duration of iv drug use (OR 3.1; 95% CI 1.1-8.7). These data demonstrate that this population is at high risk for both HBV and HCV infection. Among IDUs from Rio de Janeiro, unprotected sexual intercourse seems to be more closely associated with HBV infection, whereas HCV is positively correlated with high risk injecting behavior. Comprehensive public health interventions targeting this population and their sexual partners must be encouraged.

HIV-1 infection among injection and ex-injection drug users from Rio de Janeiro, Brazil: prevalence, estimated incidence and genetic diversity

Background and objectives: Due to their behavioral conditions and vulnerability, injection drug users (IDUs) are prone to multiple simultaneous or sequential infections with distinct HIV-1 subtypes and variants, making them a key population for molecular epidemiology surveillance. In the present study, we evaluated HIV-1 infection seroprevalence, genetic diversity and estimated incidence among IDUs and ex-injection drug users (ex-IDUs) from Rio de Janeiro, Brazil. Study design: Six hundred and eight IDUs and ex-IDUs, recruited between 1999 and 2001, were interviewed and agreed to donate 30 ml of blood. The serologic status for HIV infection was determined by two ELISAs and confirmed by IFA. CD4+ T-cell percentages were assessed by flow cytometry. HIV-1 positive samples were submitted to viral load quantification. DNA samples were PCR amplified and HIV-1 subtypes were determined using env and gag HMA. Results and conclusions: Forty-eight (7.89%) individuals were seropositive for HIV-1 infection. The seroincidence of HIV-1 infection was estimated as 0.76%. HIV-1 env and gag subtyping identified 29 (69%) samples as belonging to subtype B, 7 (16.7%) to subtype F, and 6 (14.3%) discordant env/gag genomes infections, indicating the circulation of recombinant viruses in this population.

Anti-HIV-1 seroreactivity and HIV transmission route[R1]

Background: antibody binding assays carried out by our group have consistently indicated a higher reactivity of sera from male HIV-1 infected individuals. This study was carried out in order to analyze the importance of gender, route of transmission, disease progression and HIV-1 genotype in seroreactivity assays. Study design: specificity of antibody binding was studied in plasma of 247 HIV-1 seropositive individuals belonging to patient groups of pregnant women, injecting drug users (IDUs) and recent seroconvertors, resident in Rio de Janeiro, RJ. Recognition of synthetic peptides corresponding to antigenically important epitopes in the envelope of HIV-1 (gp41 immunodominant epitope, V3 loop, V2 loop and gp41 735­752 epitope) was determined. Results: the immunodominant gp41 peptide (amino acids 594­613, HIV-1 MN sequence) was recognized by 85% of all plasma tested. Reactivity with the gp41 735­752 peptide and gp120 V2 loop peptides was low but quite variable, being generally more often specific to a Brazilian V2 peptide used than to the HIV-1 MN derived V2 peptide. The overall recognition of the different V3 peptides tested varied from 41 to 76%. Patients with more advanced disease showed a more frequent reactivity with the peptides studied than did asymptomatic patients. Statistically significant differences in peptide recognition were observed by multiple logistic analyses comparing plasma derived from individuals infected by blood or sexual HIV transmission, adjusting for disease progression and gender. Plasma from individuals infected by sexual transmission showed lower peptide recognition than did plasma from individuals infected through HIV positive blood. Association attempts between seroreactivity and genotype indicated that plasma derived from patients infected with HIV-1 of the F subtype showed highest recognition of heterologous V3 peptides, as well as a slightly more frequent recognition of the non-V3 peptides tested. Recognition of homologous peptides was generally higher than recognition of heterologous peptides. Differences were most pronounced between the prototypical HIV-1 B subtype and the Brazilian B'' variant of this subtype but almost non-existent between the HIV-1 B and F subtypes. Conclusions: individual gender was shown to be a confounder when investigating the relationships of peptide reaction to HIV-1 route of transmission through multivariate statistical methods: patients infected by blood transmission (IDU) present higher frequency of peptide recognition than individuals infected by sexual HIV-1 transmission. Plasma from individuals infected with the B'' variant (GWG) of B subtype HIV-1 showed lower heterologous peptide recognition than that from HIV-1 B (GPG) or F infected individuals.

Perfil de usuários de drogas I: Estudo de características de pacientes do NEPAD/UERJ - 1986/1987 / Profile of drug users: I. Study of characteristics of patients attending the NEPAD/UERJ - 1986/1987

O estudo descreve características sócio-demográficas de 100 usuários de drogas demandantes ao NEPAD/UERJ (Núcleo de Estudos e Pesquisas em Atençäo ao Uso de Drogas da Unviersidade do Estado do Rio de Janeiro). Um questionário, de tipo fechado e elaborado pela equipe de Epidemiologia do NEPAD, foi aplicado a esses usuários no período de maio a dezembro de 1986. A análise dos dados demonstrou ser essa uma clientela composta principalmente de adultos jovens do sexo masculino, com baixa inserçäo profissional ou escolar. As drogas mais consumidadas entre esses usuários foram a cocaína e a maconha, sendo raro porém o uso exclusivo da maconha. Desses usuários, um percentual expressivo utilizava a via endovenosa como forma de administraçäo da droga, cocaína em sua grande maioria. Os autores pretendem em este estudo chamar a atençäo sobre um tipo de clientela, considerado a priori suas características de espontaneidade quanto a procura do atendimento, anonimato e graves problemas com o uso abusivo de drogas. Näo houve preocupaçäo de estabelecerem-se associaçöes causais entre as variáveis e a amostra estudada