Quantifying gaps in the tuberculosis care cascade in Brazil: A mathematical model study using national program data.

BACKGROUND: In Brazil, many individuals with tuberculosis (TB) do not receive appropriate care due to delayed or missed diagnosis, ineffective treatment regimens, or loss-to-follow-up. This study aimed to estimate the health losses and TB program costs attributable to each gap in the care cascade for TB disease in Brazil. METHODS AND FINDINGS: We constructed a Markov model simulating the TB care cascade and lifetime health outcomes (e.g., death, cure, postinfectious sequelae) for individuals developing TB disease in Brazil. We stratified the model by age, human immunodeficiency virus (HIV) status, drug resistance, state of residence, and disease severity, and developed a parallel model for individuals without TB that receive a false-positive TB diagnosis. Models were fit to data (adult and pediatric) from Brazil's Notifiable Diseases Information System (SINAN) and Mortality Information System (SIM) for 2018. Using these models, we assessed current program performance and simulated hypothetical scenarios that eliminated specific gaps in the care cascade, in order to quantify incremental health losses and TB diagnosis and treatment costs along the care cascade. TB-attributable disability-adjusted life years (DALYs) were calculated by comparing changes in survival and nonfatal disability to a no-TB counterfactual scenario. We estimated that 90.0% (95% uncertainty interval [UI]: 85.2 to 93.4) of individuals with TB disease initiated treatment and 10.0% (95% UI: 7.6 to 12.5) died with TB. The average number of TB-attributable DALYs per incident TB case varied across Brazil, ranging from 2.9 (95% UI: 2.3 to 3.6) DALYs in Acre to 4.0 (95% UI: 3.3 to 4.7) DALYs in Rio Grande do Sul (national average 3.5 [95% UI: 2.8 to 4.1]). Delayed diagnosis contributed the largest health losses along the care cascade, followed by post-TB sequelae and loss to follow up from TB treatment, with TB DALYs reduced by 71% (95% UI: 65 to 76), 41% (95% UI: 36 to 49), and 10% (95% UI: 7 to 16), respectively, when these factors were eliminated. Total health system costs were largely unaffected by improvements in the care cascade, with elimination of treatment failure reducing attributable costs by 3.1% (95% UI: 1.5 to 5.4). TB diagnosis and treatment of false-positive individuals accounted for 10.2% (95% UI: 3.9 to 21.7) of total programmatic costs but contributed minimally to health losses. Several assumptions were required to interpret programmatic data for the analysis, and we were unable to estimate the contribution of social factors to care cascade outcomes. CONCLUSIONS: In this study, we observed that delays to diagnosis, post-disease sequelae and treatment loss to follow-up were primary contributors to the TB burden of disease in Brazil. Reducing delays to diagnosis, improving healthcare after TB cure, and reducing treatment loss to follow-up should be prioritized to improve the burden of TB disease in Brazil.

Predictors of unsuccessful tuberculosis treatment outcomes in Brazil: an analysis of 259,484 patient records.

INTRODUCTION: Tuberculosis (TB) causes over 1 million deaths annually. Providing effective treatment is a key strategy for reducing TB deaths. In this study, we identified factors associated with unsuccessful treatment outcomes among individuals treated for TB in Brazil. METHODS: We obtained data on individuals treated for TB between 2015 and 2018 from Brazil's National Disease Notification System (SINAN). We excluded patients with a history of prior TB disease or with diagnosed TB drug resistance. We extracted information on patient-level factors potentially associated with unsuccessful treatment, including demographic and social factors, comorbid health conditions, health-related behaviors, health system level at which care was provided, use of directly observed therapy (DOT), and clinical examination results. We categorized treatment outcomes as successful (cure, completed) or unsuccessful (death, regimen failure, loss to follow-up). We fit multivariate logistic regression models to identify factors associated with unsuccessful treatment. RESULTS: Among 259,484 individuals treated for drug susceptible TB, 19.7% experienced an unsuccessful treatment outcome (death during treatment 7.8%, regimen failure 0.1%, loss to follow-up 11.9%). The odds of unsuccessful treatment were higher with older age (adjusted odds ratio (aOR) 2.90 [95% confidence interval: 2.62-3.21] for 85-100-year-olds vs. 25-34-year-olds), male sex (aOR 1.28 [1.25-1.32], vs. female sex), Black race (aOR 1.23 [1.19-1.28], vs. White race), no education (aOR 2.03 [1.91-2.17], vs. complete high school education), HIV infection (aOR 2.72 [2.63-2.81], vs. no HIV infection), illicit drug use (aOR 1.95 [1.88-2.01], vs. no illicit drug use), alcohol consumption (aOR 1.46 [1.41-1.50], vs. no alcohol consumption), smoking (aOR 1.20 [1.16-1.23], vs. non-smoking), homelessness (aOR 3.12 [2.95-3.31], vs. no homelessness), and immigrant status (aOR 1.27 [1.11-1.45], vs. non-immigrants). Treatment was more likely to be unsuccessful for individuals treated in tertiary care (aOR 2.20 [2.14-2.27], vs. primary care), and for patients not receiving DOT (aOR 2.35 [2.29-2.41], vs. receiving DOT). CONCLUSION: The risk of unsuccessful TB treatment varied systematically according to individual and service-related factors. Concentrating clinical attention on individuals with a high risk of poor treatment outcomes could improve the overall effectiveness of TB treatment in Brazil.

A Mathematical Model for the Impact of 3HP and Social Programme Implementation on the Incidence and Mortality of Tuberculosis: Study in Brazil.

In this paper, we presented a mathematical model for tuberculosis with treatment for latent tuberculosis cases and incorporated social implementations based on the impact they will have on tuberculosis incidence, cure, and recovery. We incorporated two variables containing the accumulated deaths and active cases into the model in order to study the incidence and mortality rate per year with the data reported by the model. Our objective is to study the impact of social program implementations and therapies on latent tuberculosis in particular the use of once-weekly isoniazid-rifapentine for 12 weeks (3HP). The computational experimentation was performed with data from Brazil and for model calibration, we used the Markov Chain Monte Carlo method (MCMC) with a Bayesian approach. We studied the effect of increasing the coverage of social programs, the Bolsa Familia Programme (BFP) and the Family Health Strategy (FHS) and the implementation of the 3HP as a substitution therapy for two rates of diagnosis and treatment of latent at 1% and 5%. Based of the data obtained by the model in the period 2023-2035, the FHS reported better results than BFP in the case of social implementations and 3HP with a higher rate of diagnosis and treatment of latent in the reduction of incidence and mortality rate and in cases and deaths avoided. With the objective of linking the social and biomedical implementations, we constructed two different scenarios with the rate of diagnosis and treatment. We verified with results reported by the model that with the social implementations studied and the 3HP with the highest rate of diagnosis and treatment of latent, the best results were obtained in comparison with the other independent and joint implementations. A reduction of the incidence by 36.54% with respect to the model with the current strategies and coverage was achieved, and a greater number of cases and deaths from tuberculosis was avoided.

Effectiveness of mRNA boosters after homologous primary series with BNT162b2 or ChAdOx1 against symptomatic infection and severe COVID-19 in Brazil and Scotland: A test-negative design case-control study.

BACKGROUND: Brazil and Scotland have used mRNA boosters in their respective populations since September 2021, with Omicron's emergence accelerating their booster program. Despite this, both countries have reported substantial recent increases in Coronavirus Disease 2019 (COVID-19) cases. The duration of the protection conferred by the booster dose against symptomatic Omicron cases and severe outcomes is unclear. METHODS AND FINDINGS: Using a test-negative design, we analyzed national databases to estimate the vaccine effectiveness (VE) of a primary series (with ChAdOx1 or BNT162b2) plus an mRNA vaccine booster (with BNT162b2 or mRNA-1273) against symptomatic Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection and severe COVID-19 outcomes (hospitalization or death) during the period of Omicron dominance in Brazil and Scotland compared to unvaccinated individuals. Additional analyses included stratification by age group (18 to 49, 50 to 64, ≥65). All individuals aged 18 years or older who reported acute respiratory illness symptoms and tested for SARS-CoV-2 infection between January 1, 2022, and April 23, 2022, in Brazil and Scotland were eligible for the study. At 14 to 29 days after the mRNA booster, the VE against symptomatic SARS-CoV-2 infection of ChAdOx1 plus BNT162b2 booster was 51.6%, (95% confidence interval (CI): [51.0, 52.2], p < 0.001) in Brazil and 67.1% (95% CI [65.5, 68.5], p < 0.001) in Scotland. At ≥4 months, protection against symptomatic infection waned to 4.2% (95% CI [0.7, 7.6], p = 0.02) in Brazil and 37.4% (95% CI [33.8, 40.9], p < 0.001) in Scotland. VE against severe outcomes in Brazil was 93.5% (95% CI [93.0, 94.0], p < 0.001) at 14 to 29 days post-booster, decreasing to 82.3% (95% CI [79.7, 84.7], p < 0.001) and 98.3% (95% CI [87.3, 99.8], p < 0.001) to 77.8% (95% CI [51.4, 89.9], p < 0.001) in Scotland for the same periods. Similar results were obtained with the primary series of BNT162b2 plus homologous booster. Potential limitations of this study were that we assumed that all cases included in the analysis were due to the Omicron variant based on the period of dominance and the limited follow-up time since the booster dose. CONCLUSIONS: We observed that mRNA boosters after a primary vaccination course with either mRNA or viral-vector vaccines provided modest, short-lived protection against symptomatic infection with Omicron but substantial and more sustained protection against severe COVID-19 outcomes for at least 3 months.

Adherence to guidelines on the use of amoxicillin for treatment of ambulatory pneumonia in children younger than 5 years, Colombia, 2017-2019.

Objectives: To determine the level of adherence to clinical guidelines in prescribing amoxicillin to children younger than 5 years with pneumonia in outpatient settings in Colombia from 2017 to 2019, and assess the factors associated with adherence. Methods: This was a cross-sectional study of secondary data from the Colombian Integrated Social Protection Information System database. Adherence was defined as prescription of oral amoxicillin for bacterial and unspecified pneumonia and non-prescription for viral pneumonia. Variables examined included: age (< 1 year, 1-4 years) of child; sex; cause of pneumonia (bacterial, viral, unspecified); region (Andean, Amazonian, Pacific, Caribbean, Insular, Orinoquian); and payment mechanism (without prior authorization, capitation, direct payment, pay per case, pay for event). Results: Of 215 925 cases of community-acquired pneumonia reported during 2017-2019, 64.8% were from the Andean region, 73.9% were bacterial pneumonia and 1.8% were viral pneumonia. Adherence to guidelines was observed in 5.8% of cases: this was highest for children diagnosed with viral (86.0%) compared with bacterial (2.0%) pneumonia. For children diagnosed with bacterial pneumonia, 9.4% were prescribed any antibiotic. A greater proportion of children covered by capitated payments (22.3%) were given treatment consistent with the guidelines compared with payment for event (1.3%). Conclusion: In this first study from Colombia, adherence to guidelines for outpatient treatment of children with bacterial pneumonia was low and was better for viral pneumonia. Further qualitative studies are needed to explore the reasons for this lack of adherence and why bacterial pneumonia was the most commonly reported etiology.

Antibiotic resistance and consumption before and during the COVID-19 pandemic in Valle del Cauca, Colombia.

Objective: To assess changes in antibiotic resistance of eight of the World Health Organization priority bug-drug combinations and consumption of six antibiotics (ceftriaxone, cefepime, piperacillin/tazobactam, meropenem, ciprofloxacin, vancomycin) before (March 2018 to July 2019) and during (March 2020 to July 2021) the COVID-19 pandemic in 31 hospitals in Valle del Cauca, Colombia. Methods: This was a before/after study using routinely collected data. For antibiotic consumption, daily defined doses (DDD) per 100 bed-days were compared. Results: There were 23 405 priority bacterial isolates with data on antibiotic resistance. The total number of isolates increased from 9 774 to 13 631 in the periods before and during the pandemic, respectively. While resistance significantly decreased for four selected bug-drug combinations (Klebsiella pneumoniae, extended spectrum beta lactamase [ESBL]-producing, 32% to 24%; K. pneumoniae, carbapenem-resistant, 4% to 2%; Pseudomonas aeruginosa, carbapenem-resistant, 12% to 8%; Acinetobacter baumannii, carbapenem-resistant, 23% to 9%), the level of resistance for Enterococcus faecium to vancomycin significantly increased (42% to 57%). There was no change in resistance for the remaining three combinations (Staphylococcus aureus, methicillin-resistant; Escherichia coli, ESBL-producing; E. coli, carbapenem-resistant). Consumption of all antibiotics increased. However, meropenem consumption decreased in intensive care unit settings (8.2 to 7.1 DDD per 100 bed-days). Conclusions: While the consumption of antibiotics increased, a decrease in antibiotic resistance of four bug-drug combinations was observed during the pandemic. This was possibly due to an increase in community-acquired infections. Increasing resistance of E. faecium to vancomycin must be monitored. The findings of this study are essential to inform stewardship programs in hospital settings of Colombia and similar contexts elsewhere.

Trends in Untreated Tuberculosis in Large Municipalities, Brazil, 2008-2017.

We adapted a mathematical modeling approach to estimate tuberculosis (TB) incidence and fraction treated for 101 municipalities of Brazil during 2008-2017. We found the average TB incidence rate decreased annually (0.95%), and fraction treated increased (0.30%). We estimated that 9% of persons with TB did not receive treatment in 2017.

Physical disabilities caused by leprosy in 100 million cohort in Brazil.

BACKGROUND: Leprosy continues to be an important cause of physical disability in endemic countries such as Brazil. Knowledge of determinants of these events may lead to better control measures and targeted interventions to mitigate its impact on affected individuals. This study investigated such factors among the most vulnerable portion of the Brazilian population. METHODS: A large cohort was built from secondary data originated from a national registry of applicants to social benefit programs, covering the period 2001-2015, including over 114 million individuals. Data were linked to the leprosy notification system utilizing data from 2007 until 2014. Descriptive and bivariate analyses lead to a multivariate analysis using a multinomial logistic regression model with cluster-robust standard errors. Associations were reported as Odds Ratios with their respective 95% confidence intervals. RESULTS: Among the original cohort members 21,565 new leprosy cases were identified between 2007 and 2014. Most of the cases (63.1%) had grade zero disability. Grades 1 and 2 represented 21 and 6%, respectively. Factors associated with increasing odds of grades 1 and 2 disability were age over 15 years old (ORs 2.39 and 1.95, respectively), less schooling (with a clear dose response effect) and being a multibacillary patient (ORs 3.5 and 8.22). Protective factors for both grades were being female (ORs 0.81 and 0.61) and living in a high incidence municipality (ORs 0.85 and 0.67). CONCLUSIONS: The findings suggest that the developing of physical disabilities remains a public health problem which increases the burden of leprosy, mainly for those with severe clinical features and worse socioeconomic conditions. Early diagnosis is paramount to decrease the incidence of leprosy-related disability and our study points to the need for strengthening control actions in non-endemic areas in Brazil, where cases may be missed when presented at early stages in disease. Both actions are needed, to benefit patients and to achieve the WHO goal in reducing physical disabilities among new cases of leprosy.

Challenges facing the More Doctors program (Programa Mais Médicos) in vulnerable and peri-urban areas in Greater Brasilia, Brazil.

BACKGROUND: A shortage of physicians, especially in vulnerable and peri-urban areas, is a global phenomenon that has serious implications for health systems, demanding policies to assure the provision and retention of health workers. The aim of this study was to analyze the strategies employed by the More Doctors Program (Programa Mais Médicos) to provide primary care physicians in vulnerable and peri-urban parts of Greater Brasilia. METHODS: The study used a qualitative approach based on the precepts of social constructivism. Forty-nine semi-structured interviews were conducted: 24 with physicians employed as part of the More Doctors program, five with program medical supervisors, seven with secondary care physicians, twelve with primary care coordinators, and one federal administrator. The interviews occurred between March and September 2019. The transcripts of the interviews were submitted to thematic content analysis. RESULTS: The partnership between the Ministry of Health and local authorities was essential for the provision of doctors-especially foreign doctors, most from Cuba, to assist vulnerable population groups previously without access to the health system. There was a notable presence of doctors with experience working with socioeconomically disadvantaged populations, which was important for gaining a better understanding of the effects of the endemic urban violence in the region. The incentives and other institutional support, such as enhanced salaries, training, and housing, transportation, and food allowances, were factors that helped provide a satisfactory working environment. However, the poor state of the infrastructure at some of the primary care units and limitations of the health service as a whole were factors that hampered the provision of comprehensive care, constituting a cause of dissatisfaction. CONCLUSIONS: More Doctors introduced a range of novel strategies that helped ensure a supply of primary care doctors in vulnerable and peri-urban parts of Greater Brasilia. The inclusion of foreign doctors, most from Cuba, was crucial for the success of the health services provided for the local communities, who subsist in violent and socioeconomically deprived urban areas. However, it became clear that barriers from within the health service itself hampered the physicians' capacity to provide a satisfactory service. As such, what is needed for primary care to be effective is not just the recruitment, training, and deployment of doctors, but also investment in the organization of the whole health system.

The association between a conditional cash transfer programme and malaria incidence: a longitudinal ecological study in the Brazilian Amazon between 2004 and 2015.

BACKGROUND: Malaria causes 400 thousand deaths worldwide annually. In 2018, 25% (187,693) of the total malaria cases in the Americas were in Brazil, with nearly all (99%) Brazilian cases in the Amazon region. The Bolsa Família Programme (BFP) is a conditional cash transfer (CCT) programme launched in 2003 to reduce poverty and has led to improvements in health outcomes. CCT programmes may reduce the burden of malaria by alleviating poverty and by promoting access to healthcare, however this relationship is underexplored. This study investigated the association between BFP coverage and malaria incidence in Brazil. METHODS: A longitudinal panel study was conducted of 807 municipalities in the Brazilian Amazon between 2004 and 2015. Negative binomial regression models adjusted for demographic and socioeconomic covariates and time trends were employed with fixed effects specifications. RESULTS: A one percentage point increase in municipal BFP coverage was associated with a 0.3% decrease in the incidence of malaria (RR = 0.997; 95% CI = 0.994-0.998). The average municipal BFP coverage increased 24 percentage points over the period 2004-2015 corresponding to be a reduction of 7.2% in the malaria incidence. CONCLUSIONS: Higher coverage of the BFP was associated with a reduction in the incidence of malaria. CCT programmes should be encouraged in endemic regions for malaria in order to mitigate the impact of disease and poverty itself in these settings.

Impact of the Programa Mais médicos (more doctors Programme) on primary care doctor supply and amenable mortality: quasi-experimental study of 5565 Brazilian municipalities.

BACKGROUND: Investing in human resources for health (HRH) is vital for achieving universal health care and the Sustainable Development Goals. The Programa Mais Médicos (PMM) (More Doctors Programme) provided 17,000 doctors, predominantly from Cuba, to work in Brazilian primary care. This study assesses whether PMM doctor allocation to municipalities was consistent with programme criteria and associated impacts on amenable mortality. METHODS: Difference-in-differences regression analysis, exploiting variation in PMM introduction across 5565 municipalities over the period 2008-2017, was employed to examine programme impacts on doctor density and mortality amenable to healthcare. Heterogeneity in effects was explored with respect to doctor allocation criteria and municipal doctor density prior to PMM introduction. RESULTS: After starting in 2013, PMM was associated with an increase in PMM-contracted primary care doctors of 15.1 per 100,000 population. However, largescale substitution of existing primary care doctors resulting in a net increase of only 5.7 per 100,000. Increases in both PMM and total primary care doctors were lower in priority municipalities due to lower allocation of PMM doctors and greater substitution effects. The PMM led to amenable mortality reductions of - 1.06 per 100,000 (95%CI: - 1.78 to - 0.34) annually - with greater benefits in municipalities prioritised for doctor allocation and where doctor density was low before programme implementation. CONCLUSIONS: PMM potential health benefits were undermined due to widespread allocation of doctors to non-priority areas and local substitution effects. Policies seeking to strengthen HRH should develop and implement needs-based criteria for resource allocation.

Determinants of sputum smear nonconversion in smear-positive pulmonary tuberculosis patients in Suriname, 2010 - 2015.

OBJECTIVE: To identify factors associated with sputum smear nonconversion in patients with pulmonary tuberculosis (PTB) in Suriname. METHODS: A case-control study was conducted using routinely-collected surveillance data of PTB cases reported in January 2010 - December 2015 and recorded in the database of the National Tuberculosis Program of Suriname. Cases were smear-positive PTB patients whose sputum results were negative 2 months after treatment initiation. Controls were the smear-positive PTB patients whose sputum results were negative in the same timeframe. Multivariate logistic regression analysis was used to examine associations between potential risk factors and smear conversion. RESULTS: The two age groups ≥ 35 years (35 - 54 years, AOR: 2.7, 95%CI: 1.2 - 6.1; and 55+ years, AOR: 2.5, 95%CI: 1.1 - 5.9) and high bacillary load at baseline (AOR 2.34, 95%CI: 1.2 - 4.8) were significantly associated with delayed smear conversion. CONCLUSION: The National TB program of Suriname should develop strategies to address patients at higher risk for delayed smear conversion to prevent further spreading and unfavorable treatment outcomes. To better inform decision-making and future studies, the NTP should expand its data collection to include all risk factors for delayed smear conversion.

Factors associated with mortality in persons co-infected with tuberculosis and HIV in Suriname: a retrospective cohort study.

OBJECTIVE: To identify socio-demographic and clinical factors associated with mortality among persons with tuberculosis (TB) and TB/HIV co-infection in Suriname. METHODS: This was a retrospective cohort study using data from the national TB and HIV databases for 2010 - 2015. The survival probability of TB and TB/HIV co-infected patients was analyzed using the Kaplan-Meier estimates and the log-rank test. A Cox proportional hazard model was applied. RESULTS: The study showed that HIV-seropositivity (aHR: 2.08, 95%CI: 1.48 - 2.92) and older age (aHR: 5.84, 95%CI: 3.00 - 11.4) are statistically associated with higher mortality. For the TB/HIV co-infected patients, TB treatment (aHR: 0.43, 95%CI: 0.35 - 0.53) reduces the risk of death. Similarly, HIV treatment started within 56 days (aHR: 0.15, 95%CI: 0.12 - 0.19) and delayed (aHR: 0.25, 95%CI: 0.13 - 0.47) result in less hazard for mortality; Directly-Observed Treatment (aOR: 0.16, 95%CI: 0.09 - 0.29) further reduces the risk. CONCLUSIONS: The Ministry of Health of Suriname should develop strategies for early case-finding in key populations, such as for HIV and TB in men 60 years of age and older. Implementation of Isoniazid Preventive Therapy for HIV should be pursued. Scaling up TB and HIV treatment, preferably through supervision, are essential to reducing the TB/HIV mortality.

Treatment outcomes of MDR-tuberculosis patients in Brazil: a retrospective cohort analysis.

BACKGROUND: Multidrug-resistant tuberculosis (MDR-TB) is a threat for the global TB epidemic control. Despite existing evidence that individualized treatment of MDR-TB is superior to standardized regimens, the latter are recommended in Brazil, mainly because drug-susceptibility tests (DST) are often restricted to first-line drugs in public laboratories. We compared treatment outcomes of MDR-TB patients using standardized versus individualized regimens in Brazil, a high TB-burden, low resistance setting. METHODS: The 2007-2013 cohort of the national electronic database (SITE-TB), which records all special treatments including drug-resistance, was analysed. Patients classified as MDR-TB in SITE-TB were eligible. Treatment outcomes were classified as successful (cure/treatment completed) or unsuccessful (failure/relapse/death/loss to follow-up). The odds for successful treatment according to type of regimen were controlled for demographic and clinical variables. RESULTS: Out of 4029 registered patients, we included 1972 recorded from 2010 to 2012, who had more complete outcome data. The overall success proportion was 60%. Success was more likely in non-HIV patients, sputum-negative at baseline, with unilateral disease and without prior DR-TB. Adjusted for these variables, those receiving standardized regimens had 2.7-fold odds of success compared to those receiving individualized treatments when failure/relapse were considered, and 1.4-fold odds of success when death was included as an unsuccessful outcome. When loss to follow-up was added, no difference between types of treatment was observed. Patients who used levofloxacin instead of ofloxacin had 1.5-fold odds of success. CONCLUSION: In this large cohort of MDR-TB patients with a low proportion of successful outcomes, standardized regimens had superior efficacy than individualized regimens, when adjusted for relevant variables. In addition to the limitations of any retrospective observational study, database quality hampered the analyses. Also, decision on the use of standard or individualized regimens was possibly not random, and may have introduced bias. Efforts were made to reduce classification bias and confounding. Until higher-quality evidence is produced, and DST becomes widely available in the country, our findings support the Brazilian recommendation for the use of standardized instead of individualized regimens for MDR-TB, preferably containing levofloxacin. Better quality surveillance data and DST availability across the country are necessary to improve MDR-TB control in Brazil.

Prevention of neural tube defects by the fortification of flour with folic acid: a population-based retrospective study in Brazil.

OBJECTIVE: To determine if the fortification of wheat and maize flours with iron and folic acid - which became mandatory in Brazil from June 2004 - is effective in the prevention of neural tube defects. METHODS: Using data from national information systems on births in central, south-eastern and southern Brazil, we determined the prevalence of neural tube defects among live births and stillbirths in a pre-fortification period - i.e. 2001-2004 - and in a post-fortification period - i.e. 2005-2014. We distinguished between anencephaly, encephalocele, meningocele, myelomeningocele and other forms of spina bifida. FINDINGS: There were 8554 neural tube defects for 17,925,729 live births notified between 2001 and 2014. For the same period, 2673 neural tube defects were reported for 194,858 stillbirths. The overall prevalence of neural tube defects fell from 0.79 per 1000 pre-fortification to 0.55 per 1000 post-fortification (prevalence ratio, PR: 1.43; 95% confidence interval, CI: 1.38-1.50). For stillbirths, prevalence fell from 17.74 per 1000 stillbirths pre-fortification to 11.70 per 1000 stillbirths post-fortification. The corresponding values among live births were 0.57 and 0.44, respectively. CONCLUSION: The introduction of the mandatory fortification of flour with iron and folic acid in Brazil was followed by a significant reduction in the prevalence of neural tube defects in our study area.

Creation of complexity assessment tool for patients receiving home care.

OBJECTIVE: To create and validate a complexity assessment tool for patients receiving home care from a public health service. METHOD: A diagnostic accuracy study, with estimates for the tool's validity and reliability. Measurements of sensitivity and specificity were considered when producing validity estimates. The resulting tool was used for testing. Assessment by a specialized team of home care professionals was used as the gold standard. In the tool's reliability study, the authors used the Kappa statistic. The tool's sensitivity and specificity were analyzed using various cut-off points. RESULTS: On the best cut-off point-21-with the gold standard, a sensitivity of 75.5% was obtained, with the limits of confidence interval (95%) at 68.3% and 82.8% and specificity of 53.2%, with the limits of confidence interval (95%) at 43.8% and 62.7%. CONCLUSION: The tool presented evidence of validity and reliability, possibly helping in service organization at patient admission, care type change, or support during the creation of care plans. OBJETIVO: Elaborar e validar instrumento de classificação de complexidade assistencial de pacientes em atenção domiciliar de um serviço público de saúde. MÉTODO: Estudo de acurácia de diagnóstico, com estimativas de validade e de reprodutibilidade do instrumento. Para a estimativa da validade foram consideradas as medidas de sensibilidade e especificidade; como teste, o instrumento elaborado e como padrão ouro, a classificação atribuída por equipe especializada de profissionais de saúde em atenção domiciliar. No estudo de reprodutibilidade do instrumento foi utilizada a estatística Kappa. A sensibilidade e especificidade do instrumento foram analisadas considerando-se diferentes pontos de corte. RESULTADOS: Para o melhor ponto de corte - 21 - com o padrão ouro obteve-se Sensibilidade de 75,5% com os limites do IC (95%) iguais a 68,3% e 82,8% e Especificidade igual a 53,2% com os limites do IC (95%) iguais a 43,8% e 62,7%. CONCLUSÃO: O instrumento apresentou evidências de validade e reprodutibilidade, podendo vir a auxiliar na organização do serviço, quer na admissão do paciente, quer na migração de modalidade assistencial e no suporte para elaboração do plano terapêutico.

Factors associated with tuberculosis by HIV status in the Brazilian national surveillance system: a cross sectional study.

BACKGROUND: Over the last decade tuberculosis (TB) incidence and mortality in Brazil have been steadily declining. However, this downward trend has not been observed among HIV-infected patients. We describe the epidemiological and clinical profile of TB patients by HIV status using the Brazilian National Surveillance System. METHODS: All TB diagnoses with HIV status information between January 1, 2007 and December 31, 2011 were categorized as either HIV or non-HIV at time of TB diagnosis. Co-infected patients (TB-HIV) were compared to TB patients with no HIV-infection using a hierarchical logistic regression model using Stata 13.0. RESULTS: The prevalence of TB-HIV co-infection was 19% among adults ≥ 15 years of age. We analyzed data from 243,676 individuals, of whom 46,466 were TB-HIV and 197,210 were only TB cases. The following factors increased risk of co-infection: male sex (OR: 1.06, 95% CI 1.03-1.10), 20 to 39 years of age (OR = 4.82, 95% CI 4.34-5.36), black (OR = 1.08, 95% CI 1.04-1.13), 4-7 years of education (OR = 1.13, 95% CI 1.19-1.28), diagnosed following default (OR = 2.65, 95% CI 1.13-6.25), presenting with pulmonary and extra-pulmonary forms of TB simultaneously (OR = 2.80, 95% CI 1.56-5.02), presenting with histopathologic examination suggestive of TB (OR = 2.15, 95% CI 1.13-4.07). Co-infected patients were less likely to live in rural areas (OR = 0.45, 95% CI 0.42-0.48), have diabetes (OR = 0.45, 95% CI 0.40-0.50) and be smear positive (OR = 0.55, 95% CI 0.32-0.95), and co-infected patients had higher risk of default (OR = 2.96, 95% CI 2.36-3.71) and death from TB (OR = 5.16, 95% CI 43.04-5.77). CONCLUSIONS: The prevalence of co-infection with HIV among TB patients is 19% in Brazil. By identifying predictors of co-infection targeted interventions can be developed to prevent both TB and HIV, and to diagnose each disease earlier and ultimately decrease poor treatment outcomes and death.

Experimental realization of a multiscroll chaotic oscillator with optimal maximum Lyapunov exponent.

Nowadays, different kinds of experimental realizations of chaotic oscillators have been already presented in the literature. However, those realizations do not consider the value of the maximum Lyapunov exponent, which gives a quantitative measure of the grade of unpredictability of chaotic systems. That way, this paper shows the experimental realization of an optimized multiscroll chaotic oscillator based on saturated function series. First, from the mathematical description having four coefficients (a, b, c, d1 ), an optimization evolutionary algorithm varies them to maximize the value of the positive Lyapunov exponent. Second, a realization of those optimized coefficients using operational amplifiers is given. Herein a, b, c, d1 are implemented with precision potentiometers to tune up to four decimals of the coefficients having the range between 0.0001 and 1.0000. Finally, experimental results of the phase-space portraits for generating from 2 to 10 scrolls are listed to show that their associated value for the optimal maximum Lyapunov exponent increases by increasing the number of scrolls, thus guaranteeing a more complex chaotic behavior.

The effect of conditional cash transfers on tuberculosis incidence and mortality is determined by ethnoracial and socioeconomic factors: a cohort study of 54 million individuals in Brazil.

Background: Conditional Cash Transfers (CCT) are the world's most widely implemented interventions for poverty alleviation. Still, there is no solid evidence of the CCT effects on the reduction of the burden of Tuberculosis (TB) in marginalized and extremely vulnerable populations. We estimated the effect of the Bolsa Família Program (BFP), the largest CCT in the world, on TB incidence, mortality, and case-fatality rate using a nationwide cohort of 54.5 million individuals during a 12-year period in Brazil. Methods: We selected low-income individuals who entered in the 100 Million Brazilians Cohort and were linked to nationwide TB registries between 2004 to 2015, and compared BFP beneficiaries and non-beneficiaries using a quasi-experimental impact evaluation design. We employed inverse probability of treatment weighting (IPTW) multivariable Poisson regressions, adjusted for all relevant socioeconomic, demographic, and healthcare confounding variables - at individual and municipal level. Subsequently, we evaluated BFP effects for different subpopulations according to ethnoracial factors, wealth levels, sex, and age. We also performed several sensitivity and triangulation analyses to verify the robustness of the estimates. Findings: Exposure to BFP was associated with a large reduction in TB incidence in the low-income individuals under study (adjusted rate ratio [aRR]:0.59;95%CI:0.58-0.60) and mortality (aRR:0.69;95%CI:0.65-0.73). The strongest BFP effect was observed in Indigenous people both for TB incidence (aRR:0.37;95%CI:0.32-0.42), and mortality-aRR:0.35;95%CI:0.20-0.62), and in Black and Pardo people (Incidence-aRR:0.58;95%CI:0.57-0.59; Mortality -aRR:0.69;95%CI:0,64-0,73). BFP effects showed a clear gradient according to wealth levels and were considerably stronger among the extremely poor individuals for TB incidence (aRR:0.49, 95%CI:0.49-0.50) and mortality (aRR:0.60;95%CI:0.55-0.65). The BFP effects on case-fatality rates were also positive, however without statistical significance. Interpretation: CCT can strongly reduce TB incidence and mortality in extremely poor, Indigenous, Black and Pardo populations, and could significantly contribute to achieving the End TB Strategy targets and the TB-related Sustainable Development Goals.

Incidence and risk factors of tuberculosis among 420 854 household contacts of patients with tuberculosis in the 100 Million Brazilian Cohort (2004-18): a cohort study.

BACKGROUND: Although household contacts of patients with tuberculosis are known to be particularly vulnerable to tuberculosis, the published evidence focused on this group at high risk within the low-income and middle-income country context remains sparse. Using nationwide data from Brazil, we aimed to estimate the incidence and investigate the socioeconomic and clinical determinants of tuberculosis in a cohort of contacts of tuberculosis patients. METHODS: In this cohort study, we linked individual socioeconomic and demographic data from the 100 Million Brazilian Cohort to mortality data and tuberculosis registries, identified contacts of tuberculosis index patients diagnosed from Jan 1, 2004 to Dec 31, 2018, and followed up the contacts until the contact's subsequent tuberculosis diagnosis, the contact's death, or Dec 31, 2018. We investigated factors associated with active tuberculosis using multilevel Poisson regressions, allowing for municipality-level and household-level random effects. FINDINGS: We studied 420 854 household contacts of 137 131 tuberculosis index patients. During the 15 years of follow-up (median 4·4 years [IQR 1·9-7·6]), we detected 8953 contacts with tuberculosis. The tuberculosis incidence among contacts was 427·8 per 100 000 person-years at risk (95% CI 419·1-436·8), 16-times higher than the incidence in the general population (26·2 [26·1-26·3]) and the risk was prolonged. Tuberculosis incidence was associated with the index patient being preschool aged (<5 years; adjusted risk ratio 4·15 [95% CI 3·26-5·28]) or having pulmonary tuberculosis (2·84 [2·55-3·17]). INTERPRETATION: The high and sustained risk of tuberculosis among contacts reinforces the need to systematically expand and strengthen contact tracing and preventive treatment policies in Brazil in order to achieve national and international targets for tuberculosis elimination. FUNDING: Wellcome Trust and Brazilian Ministry of Health.