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Background: Leprosy is a chronic infectious disease neglected, caused by Mycobacterium leprae, considered a public health problem because may cause permanent physical disabilities and deformities, leading to severe limitations. This review presents an overview of the results of epidemiological studies on leprosy occurrence in childhood in Brazil, aiming to alert health planners and managers to the actual need to institute special control strategies. Methodology/Principal findings: Data collection consisted of an electronic search for publications in eight databases: Literatura Latino-Americana e do Caribe em Ciências da Saúde (LILACS), Scientific Electronic Library Online (SciELO), PuBMed, Biblioteca Virtual em Saúde (BVS), SciVerse Scopus (Scopus), CAPES theses database, CAPES journals database and Web of Science of papers published up to 2016. After apply selection criteria, twenty-two papers of studies conducted in four different regions of Brazil and published between 2001 and 2016 were included in the review. The leprosy detection rate ranged from 10.9 to 78.4 per 100,000 inhabitants. Despite affecting both sexes, leprosy was more common in boys and in 10-14-year-olds. Although the authors reported a high cure proportion (82–90%), between 1.7% and 5.5% of the individuals developed a disability resulting from the disease. Conclusions/Significance: The findings of this review shows that leprosy situation in Brazilian children under 15 years is extremely adverse in that the leprosy detection rate remains high in the majority of studies. The proportion of cases involving disability is also high and reflects the difficulties and the poor effectiveness of actions aimed at controlling the disease. The authors suggest the development of studies in spatial clusters of leprosy, where beyond the routine actions established, are included news strategies of active search and campaigns and actions of educations inside the clusters of this disease. The new agenda needs to involve the precepts of ethical, humane and supportive care, in order to achieve a new level of leprosy control in Brazil. Author summary: Leprosy remains as a severe health problem in Brazil and its transmission in children under 15 years of age occurs mainly through intradomiciliary contacts. The number of leprosy cases in this age group is considered an important indicator for the surveillance of this disease. To understand how the epidemiological studies in Brazil have shown the situation of young people affected by leprosy, we performed a systematic review of the literature, searching for published articles about the situation of leprosy in this age group. We reviewed 22 studies published during 2001 to 2016 and concluded that the negative effects of leprosy still remain high in most of studied places in Brazil. This disease was more common in boys, aged between 10 to 14 years old, with a remarkable proportion of disabilities due to leprosy. These disabilities can limit their routine activities and reflect failure in the public medical care. We hope that our review should contribute to arguments in order to improve the control of this disease in children. [ABSTRACT FROM AUTHOR]

Introduction: Pure Neural Leprosy (PNL) is a rare clinical form of leprosy in which patients do not present with the classical skin lesions but have a high burden of the disability associated with the disease. Clinical characteristics and follow up of patients in PNL are still poorly described in the literature. Objective: This paper aims to describe the clinical, electrophysiological and histopathological characteristics of PNL patients, as well as their evolution after multidrug therapy (MDT). Methods: Fifty-two PNL patients were selected. Clinical, nerve conduction studies (NCS), histopathological and anti-PGL-1serology were evaluated. Patients were also assessed monthly during the MDT. At the end of the MDT, all of the patients had a new neurological examination and 44 were submitted to another NCS. Results: Paresthesia was the complaint most frequently reported by patients, and in the neurological examination the most common pattern observed was impairment in sensory and motor examination and a mononeuropathy multiplex. Painful nerve enlargement, a classical symptom of leprosy neuropathy, was observed in a minority of patients and in the motor NCS axonal injuries, alone or in combination with demyelinating features, were the most commonly observed. 88% of the patients did not present any leprosy reaction during MDT. There was no statistically significant difference between the neurological examinations, nor the NCS pattern, performed before and after the MDT. Discussion: The classical hallmarks of leprosy neuropathy are not always present in PNL making the diagnosis even more challenging. Nerve biopsy is an important tool for PNL diagnosis as it may guide therapeutic decisions. This paper highlights unique characteristics of PNL in the spectrum of leprosy in an attempt to facilitate the diagnosis and management of these patients. Author summary: Neuropathy is responsible for most of the disability associated with leprosy disease. The pure neural leprosy (PNL), in spite of being a rare clinical presentation of that, has some singular characteristics that are still poorly studied. In this study, we selected 52 patients at the diagnosis to describe their clinical, neurophysiological and histopathological presentation patterns as well as their evolution during the multidrug therapy (MDT). We confirmed that sensitive symptoms were the most commonly described by PNL patients but neural pain is rare. Also confirmed that mononeuropathy mutiplex was the most common pattern observed at neurological examination and at the nerve conduction studies at the moment of the diagnosis. However we showed that painful nerve enlargement other cardinal signs of leprosy, besides the skin lesions, is not common in this group of patients, There was no statistically significant difference between the neurological examination and NCS performed before and after the MDT.During the MDT88.4% of the patients did not have any leprosy reaction. This may suggest that that MDT was effective in stopping disease progression. Our results highlight the difficulties in the diagnosis of PNL and the progression following MDT in an attempt to prevent further disability in PNL patients. [ABSTRACT FROM AUTHOR]

Visceral leishmaniasis (VL) is a neglected tropical disease that is globally distributed and has the potential to cause very serious illness. Prior literature highlights the emergence and spread of VL is influenced by multiple factors, such as socioeconomic status, sanitation levels or animal and human reservoirs. The study aimed to retrospectively investigate the presence and infectiousness of VL in Rio Grande do Norte (RN), Brazil between 2007 and 2020. We applied a hierarchical Bayesian approach to estimate municipality-specific relative risk of VL across space and time. The results show evidence that lower socioeconomic status is connected to higher municipality-specific VL risk. Overall, estimates reveal spatially heterogeneous VL risks in RN, with a high probability that VL risk for municipalities within the West Potiguar mesoregion are more than double the expected VL risk. Additionally, given the data available, results indicate there is a high probability of increasing VL risk in the municipalities of Natal, Patu and Pau dos Ferros. These findings demonstrate opportunities for municipality-specific public health policy interventions and warrant future research on identifying epidemiological drivers in at-risk regions. Author summary: As a neglected tropical disease (NTD), Leishmaniasis contributes to poor health outcomes, suffering, and death of vulnerable populations. Leishmania infantum or Leishmania donovani is transmitted from animals to humans through the sandfly vector and can be fatal in 5% of the cases even with treatment. Visceral leishmaniasis is a severe form of Leishmaniasis. The purpose of this study was to estimate regions of high Visceral leishmaniasis risk in Rio Grande do Norte, Brazil between 2007 and 2020 to help inform public health initiatives and potential health policy interventions for this disease. Visceral leishmaniasis is a reportable disease and therefore VL cases are documented to the Brazilian Ministry of Health database through passive surveillance. Passive surveillance data can suffer from missing information; individuals may be asymptomatic, or may not seek medical care allowing for diagnosis. When modeling disease risk from passive surveillance data, assuming there is an absence of disease in regions without documented cases can underestimate disease risk. In this paper we estimate disease risk and identify areas with high-risk and increasing infection trends over time while considering data characteristics such as missing information and high correlation of risk factors. [ABSTRACT FROM AUTHOR]

Background: Adult T-cell leukemia/lymphoma (ATLL), a peripheral T-cell leukemia/lymphoma associated with the human T-cell lymphotropic virus type-1 (HTLV-1), has been classified following the clinical forms defined by Shimoyama in 1991. A suggestion to modify Shimoyama's classification was proposed in 2007 to differentiate within the smoldering patients those who presented nodules or tumors in the skin without lung involvement, which was named the primary cutaneous tumoral (PCT) form of ATLL. In the present study, according to their clinicopathological characteristics, we estimated the mortality rates of 143 ATLL patients from Bahia, Brazil. We also evaluated the importance of classifying PCT/ATLL separately from the smoldering type on disease prognosis. Methodology/Principal findings: Diagnosis of ATLL was established based on a positive serology for HTLV-1, histopathological and/or cytological diagnosis of peripheral T-cell leukemia/lymphoma. Patients were clinically grouped according to Shimoyama's classification, considering PCT variants separately from the smoldering cases. Bivariate and multivariable survival analyses were applied to identify factors associated with disease prognosis. Significant differences in the median survival time were observed between the clinical types, with the smoldering type presenting the longest median survival (109 months) compared to the other forms (<50 months); the median survival for PCT/ATLL was 20 months. Multivariable analysis confirmed that ATLL clinical types were associated with survival, with a better prognosis for patients with the smoldering and chronic types. Furthermore, skin involvement was related to a worse outcome in the multivariable analysis, regardless of the clinical form and presence of lymphadenopathy. Conclusions/Significance: Our results reinforce the importance of considering the PCT/ATLL separately from the smoldering type when classifying ATLL to better define prognosis and treatment, given the significant difference in the survival of patients between the smoldering form and PCT/ATLL. Skin involvement should also be considered an independent prognostic factor in patients with ATLL. Author summary: The human T-cell lymphotropic virus type-1 (HTLV-1) may cause serious diseases, such as adult T-cell leukemia/lymphoma (ATLL), which can manifest itself in different clinical forms. In this paper, we investigated the survival of 143 Brazilian ATLL patients, according to the clinical form and other clinicopathological characteristics using bivariate and multivariable analyses. The original clinical classification of ATLL was employed; however, we considered the primary cutaneous tumoral (PCT) ATLL and the smoldering type separately. We found statistically significant differences in the mortality rates by clinical types and highlighted the better prognosis of patients with the smoldering type (mortality rate: 0.6 per 100 person-years) compared to those with PCT (mortality rate: 5.3 per 100 person-years). This finding emphasizes the importance of considering the PCT/ATLL separately from the smoldering type when using the ATLL classification to determine prognosis and treatment. PCT/ATLL should be treated with more aggressive ATLL protocols than the smoldering type without skin nodules or tumors. [ABSTRACT FROM AUTHOR]

The Peruvian-Brazilian border is a highly endemic tegumentary leishmaniasis region in South America. The interoceanic highway is a commercial route that connects Peru and Brazil through Madre de Dios and has raised concerns about its impact on previously undisturbed areas. In order to assess leishmaniasis transmission risk along this highway, we conducted a surveillance study of the sand fly populations in this area. Sand flies were collected between 2009 and 2010 along transects at 200 m, 600 m and 1000 m from six study sites located along the highway (Iberia, La Novia, Alto Libertad, El Carmen, Florida Baja, Mazuko and Mavila) and an undisturbed area (Malinowski). Collected specimens were identified based on morphology and non-engorged females of each species were pooled and screened by kinetoplast PCR to detect natural Leishmania infections. A total of 9,023 specimens were collected belonging to 54 different Lutzomyia species including the first report of Lu. gantieri in Peru. Four species accounted for 50% of all specimens (Lutzomyia carrerai carrerai, Lu. davisi, Lu. shawi and Lu. richardwardi). El Carmen, Alto Libertad, Florida Baja and Malinowski presented higher Shannon diversity indexes (H = 2.36, 2.30, 2.17 and 2.13, respectively) than the most human disturbed sites of Mazuko and La Novia (H = 1.53 and 1.06, respectively). PCR detected 10 positive pools belonging to Lu. carrerai carrerai, Lu. yuilli yuilli, Lu. hirsuta hirsuta, Lu. (Trichophoromyia) spp., and Lu. (Lutzomyia) spp. Positive pools from 1,000 m transects had higher infectivity rates than those from 600 m and 200 m transects (9/169 = 5.3% vs 0/79 = 0% and 1/127 = 0.8%, p = 0.018). El Carmen, accounted for eight out of ten positives whereas one positive was collected in Florida Baja and Mazuko each. Our study has shown differences in sand fly diversity, abundance and species composition across and within sites. Multiple clustered Lutzomyia pools with natural Leishmania infection suggest a complex, diverse and spotty role in leishmaniasis transmission in Madre de Dios, with increased risk farther from the highway. Author summary: Leishmaniasis is a neglected disease that is endemic in tropical and subtropical regions affecting up to 2 million people every year. Currently, there is concern about the effects of human-made environmental changes on the transmission of leishmaniasis due to increased exposure to the sand fly vector. In this paper, the authors explored changes in the distribution of sand flies and natural leishmania infection across communities located along the interoceanic highway that connects Peru and Brazil. The study found differences in sand fly species composition and abundance between and within sites as well as a lower sand fly diversity in communities with high human disturbance. Ten pools belonging to Lutzomyia shawi, Lu. carrerai carrerai, Lu. yuilli yuilli, Lu. hirsuta hirsuta, Lu. (Helcocyrtomyia) spp. and Lu. (Lutzomyia) spp. were found positive for Leishmania spp. The majority of these positive pools were collected from a single community and far from the highway. The information provided by this manuscript will serve as a baseline to assess the effects of human activities in the region and guide future surveillance and intervention strategies. [ABSTRACT FROM AUTHOR]

Sporotrichosis is a chronic subcutaneous mycosis caused by Sporothrix species, of which the main aetiological agents are S. brasiliensis, S. schenckii, and S. globosa. Infection occurs after a traumatic inoculation of Sporothrix propagules in mammals' skin and can follow either a classic route through traumatic inoculation by plant debris (e.g., S. schenckii and S. globosa) or an alternative route through zoonotic transmission from animals (e.g., S. brasiliensis). Epizootics followed by a zoonotic route occur in Brazil, with Rio de Janeiro as the epicenter of a recent cat-transmitted epidemic. DNA-based markers are needed to explore the epidemiology of these Sporothrix expansions using molecular methods. This paper reports the use of amplified-fragment-length polymorphisms (AFLP) to assess the degree of intraspecific variability among Sporothrix species. We used whole-genome sequences from Sporothrix species to generate 2,304 virtual AFLP fingerprints. In silico screening highlighted 6 primer pair combinations to be tested in vitro. The protocol was used to genotype 27 medically relevant Sporothrix. Based on the overall scored AFLP markers (97–137 fragments), the values of polymorphism information content (PIC = 0.2552–0.3113), marker index (MI = 0.002–0.0039), effective multiplex ratio (E = 17.8519–35.2222), resolving power (Rp = 33.6296–63.1852), discriminating power (D = 0.9291–0.9662), expected heterozygosity (H = 0.3003–0.3857), and mean heterozygosity (Havp = 0.0001) demonstrated the utility of these primer combinations for discriminating Sporothrix. AFLP markers revealed cryptic diversity in species previously thought to be the most prevalent clonal type, such as S. brasiliensis, responsible for cat-transmitted sporotrichosis, and S. globosa responsible for large sapronosis outbreaks in Asia. Three combinations (#3 EcoRI-FAM-GA/MseI-TT, #5 EcoRI-FAM-GA/MseI-AG, and #6 EcoRI-FAM-TA/MseI-AA) provide the best diversity indices and lowest error rates. These methods make it easier to track routes of disease transmission during epizooties and zoonosis, and our DNA fingerprint assay can be further transferred between laboratories to give insights into the ecology and evolution of pathogenic Sporothrix species and to inform management and mitigation strategies to tackle the advance of sporotrichosis. Author summary: Sporotrichosis is a subacute or chronic infection characterized by nodular lesions of the (sub)cutaneous tissues and adjacent lymphatics. Sporothrix brasiliensis, S. schenckii, and S. globosa are the main agents of sporotrichosis in humans and other mammals. Sporothrix propagules gain entrance by traumatic implantation in the skin following two main routes of infection, which include animal transmission (e.g., cat-cat and cat-human) and plant origin. In recent years there has been a significant increase in the number of atypical and more severe cases of sporotrichosis, along with the expansion of the area of occurrence of Sporothrix species, such as the highly virulent S. brasiliensis. We investigated the usefulness of the AFLP technology, a DNA fingerprinting technique, which is based on the selective amplification of genomic restriction fragments by PCR to explore genetic diversity and population structure in Sporothrix during ongoing outbreaks. We report six highly effective sets of AFLP markers to discriminate Sporothrix at species and strain level, thus allowing tracking the spread of sporotrichosis. Adding molecular data in an outbreak response context can reveal better ways to improve public policies to contain the advance of sporotrichosis, by early detection, response, intervention, and follow-up. [ABSTRACT FROM AUTHOR]

Background: Between January 2015 and August 2016, two epidemic waves of Zika virus (ZIKV) disease swept the Northeastern (NE) region of Brazil. As a result, two waves of Guillain-Barré Syndrome (GBS) were observed concurrently. The mandatory reporting of ZIKV disease began region-wide in February 2016, and it is believed that ZIKV cases were significantly under-reported before that. The changing reporting rate has made it difficult to estimate the ZIKV infection attack rate, and studies in the literature vary widely from 17% to > 50%. The same applies to other key epidemiological parameters. In contrast, the diagnosis and reporting of GBS cases were reasonably reliable given the severity and easy recognition of the disease symptoms. In this paper, we aim to estimate the real number of ZIKV cases (i.e., the infection attack rate) and their dynamics in time, by scaling up from GBS surveillance data in NE Brazil. Methodology: A mathematical compartmental model is constructed that makes it possible to infer the true epidemic dynamics of ZIKV cases based on surveillance data of excess GBS cases. The model includes the possibility that asymptomatic ZIKV cases are infectious. The model is fitted to the GBS surveillance data and the key epidemiological parameters are inferred by using a plug-and-play likelihood-based estimation. We make use of regional weather data to determine possible climate-driven impacts on the reproductive number R0 , and to infer the true ZIKV epidemic dynamics. Findings and conclusions: The GBS surveillance data can be used to study ZIKV epidemics and may be appropriate when ZIKV reporting rates are not well understood. The overall infection attack rate (IAR) of ZIKV is estimated to be 24.1% (95% confidence interval: 17.1%—29.3%) of the population. By examining various asymptomatic scenarios, the IAR is likely to be lower than 33% over the two ZIKV waves. The risk rate from symptomatic ZIKV infection to develop GBS was estimated as ρ = 0.0061% (95% CI: 0.0050%—0.0086%) which is significantly less than current estimates. We found a positive association between local temperature and the basic reproduction number, R0. Our analysis revealed that asymptomatic infections affect the estimation of ZIKV epidemics and need to also be carefully considered in related modelling studies. According to the estimated effective reproduction number and population wide susceptibility, we comment that a ZIKV outbreak would be unlikely in NE Brazil in the near future. Author summary: The mandatory reporting of the Zika virus (ZIKV) disease began region-wide in February 2016, and it is believed that ZIKV cases could have been highly under-reported before that. Given the Guillain-Barré syndrome (GBS) is relatively well reported, the GBS surveillance data has the potential to act as a reasonably reliable proxy for inferring the true ZIKV epidemics. We developed a mathematical model incorporating weather effects to study the ZIKV-GBS epidemics and estimated the key epidemiological parameters. It was found that the attack rate of ZIKV was likely to be lower than 33% over the two epidemic waves. The risk rate from symptomatic ZIKV case to develop GBS was estimated to be approximately 0.0061%. The analysis suggests that it would be difficult for another ZIKV outbreak to appear in Northeastern Brazil in the near future. [ABSTRACT FROM AUTHOR]

Defining cases of Zika virus (ZIKV) infection is a critical challenge for epidemiological research. Due to ZIKV’s overlapping clinical features and potential immunologic cross-reactivity with other flaviviruses and the current lack of an optimal ZIKV-specific diagnostic assay, varying approaches for identifying ZIKV infections have been employed to date. This paper presents the laboratory results and diagnostic criteria developed by the Microcephaly Epidemic Research Group for defining cases of maternal ZIKV infection in a cohort of pregnant women with rash (N = 694) recruited during the declining 2015–2017 epidemic in northeast Brazil. For this investigation, we tested maternal sera for ZIKV by quantitative reverse transcription polymerase chain reaction (qRT-PCR), Immunoglobulin (Ig) M and IgG3 enzyme-linked immunosorbent assays (ELISAs), and Plaque Reduction Neutralization Test (PRNT50). Overall, 23.8% of participants tested positive by qRT-PCR during pregnancy (range of detection: 0–72 days after rash onset). However, the inter-assay concordance was lower than expected. Among women with qRT-PCR-confirmed ZIKV and further testing, only 10.1% had positive IgM tests within 90 days of rash, and only 48.5% had ZIKV-specific PRNT50 titers ≥20 within 1 year of rash. Given the complexity of these data, we convened a panel of experts to propose an algorithm for identifying ZIKV infections in pregnancy based on all available lines of evidence. When the diagnostic algorithm was applied to the cohort, 26.9% of participants were classified as having robust evidence of a ZIKV infection during pregnancy, 4.0% as having moderate evidence, 13.3% as having limited evidence of a ZIKV infection but with uncertain timing, and 19.5% as having evidence of an unspecified flavivirus infection before or during pregnancy. Our findings suggest that integrating longitudinal data from nucleic acid and serologic testing may enhance diagnostic sensitivity and underscore the need for an on-going dialogue regarding the optimization of strategies for defining cases of ZIKV in research. [ABSTRACT FROM AUTHOR]

Effective radical cure of Plasmodium vivax malaria is essential for malaria elimination in Brazil. P. vivax radical cure requires administration of a schizonticide, such as chloroquine, plus an 8-aminoquinoline. However, 8-aminoquinolines cause hemolysis in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency, requiring prior screening to exclude those at risk. Brazil is pioneering the implementation of tafenoquine, a single-dose 8-aminoquinoline indicated for P. vivax patients with >70% of normal G6PD activity. Tafenoquine implementation in Manaus and Porto Velho, two municipalities located in the western Brazilian Amazon, included comprehensive training of healthcare professionals (HCPs) on point-of-care quantitative G6PD testing and a new treatment algorithm for P. vivax radical cure incorporating tafenoquine. Training was initially provided to higher-level facilities (phase one) and later adapted for primary care units (phase two). This study analyzed HCP experiences during training and implementation and identified barriers and facilitators. In-depth interviews and focus discussion groups were conducted 30 days after each training for a purposive random sample of 115 HCPs. Thematic analysis was employed using MAXQDA software, analyzing data through inductive and deductive coding. Analysis showed that following the initial training for higher-level facilities, some HCPs did not feel confident performing quantitative G6PD testing and prescribing the tafenoquine regimen. Modifications to the training in phase two resulted in an improvement in understanding the implementation process of the G6PD test and tafenoquine, as well as in the knowledge acquired by HCPs. Additionally, knowledge gaps were addressed through in situ training, peer communication via a messaging app, and educational materials. Training supported effective deployment of the new tools in Manaus and Porto Velho and increased awareness of the need for pharmacovigilance. A training approach for nationwide implementation of these tools was devised. Implementing quantitative G6PD testing and tafenoquine represents a significant shift in P. vivax malaria case management. Consistent engagement with HCPs is needed to overcome challenges in fully integrating these tools within the Brazilian health system. Author summary: Brazil has implemented tafenoquine and quantitative G6PD testing as a crucial component of its comprehensive strategy to eliminate Plasmodium vivax malaria. Training of healthcare professionals (HCPs) has played a pivotal role in facilitating the adoption of these new strategies. In any implementation, it is necessary to identify barriers and facilitators and consider data that cannot typically be collected in purely quantitative studies. This qualitative study describes the perceptions of HCPs regarding the training they received and the knowledge gaps that only became apparent in their professional practice after the training. These insights were instrumental in developing various communication and continuing education strategies that enhanced HCP knowledge following training. Finally, the study presents a training approach for applying quantitative G6PD testing and the tafenoquine treatment regimen, including the most effective educational activities and materials to support the HCP learning process. [ABSTRACT FROM AUTHOR]

Background: Dengue is spreading in (sub)tropical areas, and half of the global population is at risk. The macroeconomic impact of dengue extends beyond healthcare costs. This study evaluated the impact of dengue on gross domestic product (GDP) based on approaches tailored to two dengue-endemic countries, Thailand and Brazil, from the tourism and workforce perspectives, respectively. Findings: Because the tourism industry is a critical economic sector for Thailand, lost tourism revenues were estimated to analyze the impact of a dengue outbreak. An input-output model estimated that the direct effects (on international tourism) and indirect effects (on suppliers) of dengue on tourism reduced overall GDP by 1.43 billion US dollars (USD) (0.26%) in the outbreak year 2019. The induced effect (reduced employee income/spending) reduced Thailand's GDP by 375 million USD (0.07%). Overall, lost tourism revenues reduced Thailand's GDP by an estimated 1.81 billion USD (0.33%) in 2019 (3% of annual tourism revenue). An inoperability input-output model was used to analyze the effect of workforce absenteeism on GDP due to a dengue outbreak in Brazil. This model calculates the number of lost workdays associated with ambulatory and hospitalized dengue. Input was collected from state-level epidemiological and economic data for 2019. An estimated 22.4 million workdays were lost in the employed population; 39% associated with the informal sector. Lost workdays due to dengue reduced Brazil's GDP by 876 million USD (0.05%). Conclusions: The economic costs of dengue outbreaks far surpass the direct medical costs. Dengue reduces overall GDP and inflicts national economic losses. With a high proportion of the population lacking formal employment in both countries and low income being a barrier to seeking care, dengue also poses an equity challenge. A combination of public health measures, like vector control and vaccination, against dengue is recommended to mitigate the broader economic impact of dengue. Author summary: Dengue is a viral illness spread by mosquitoes in Southeast Asia and South America, and about half of the world's population is at risk. Burden-of-illness studies on the economic impact of dengue typically focus on medical costs. However, the impact of this infectious disease extends far beyond healthcare costs. This study evaluated the impact of dengue on gross domestic product (GDP) based on approaches tailored to two dengue-endemic countries, Thailand and Brazil. The analyses estimated that the dengue outbreak in 2019 had a profound impact on Thailand's tourism industry, reducing GDP by an estimated US$1.81 billion, equivalent to 3% of annual tourism revenues or 0.33% of total GDP. Dengue also impacted Brazil's workforce in 2019, leading to an estimated 22.4 million lost workdays, of which 39% were associated with the informal sector, and reducing GDP overall by US$876 million (0.05% of total GDP). Informal workers are vulnerable to dengue-related financial burdens, and a low income can be a barrier to seeking medical care for dengue. This study highlights the broader economic impact of dengue beyond healthcare costs and underscores the importance of a combination of public health measures, such as vector control and vaccination. [ABSTRACT FROM AUTHOR]

Background: Leptospirosis is a zoonosis caused by pathogenic species of bacteria belonging to the genus Leptospira. Most studies infer the epidemiological patterns of a single serogroup or aggregate all serogroups to estimate overall seropositivity, thus not exploring the risks of exposure to distinct serogroups. The present study aims to delineate the demographic, socioeconomic and environmental factors associated with seropositivity of Leptospira serogroup Icterohaemorraghiae and serogroup Cynopteri in an urban high transmission setting for leptospirosis in Brazil. Methods/Principal findings: We performed a cross-sectional serological study in five informal urban communities in the city of Salvador, Brazil. During the years 2018, 2020 2021, we recruited 2.808 residents and collected blood samples for serological analysis using microagglutination assays. We used a fixed-effect multinomial logistic regression model to identify risk factors associated with seropositivity for each serogroup. Seropositivity to Cynopteri increased with each year of age (OR 1.03; 95% CI 1.01–1.06) and was higher in those living in houses with unplastered walls (exposed brick) (OR 1.68; 95% CI 1.09–2.59) and where cats were present near the household (OR 2.00; 95% CI 1.03–3.88). Seropositivity to Icterohaemorrhagiae also increased with each year of age (OR 1.02; 95% CI 1.01–1.03) and was higher in males (OR 1.51; 95% CI 1.09–2.10), in those with work-related exposures (OR 1.71; 95% CI 1.10–2.66) or who had contact with sewage (OR 1.42; 95% CI 1.00–2.03). Spatial analysis showed differences in distribution of seropositivity to serogroups Icterohaemorrhagiae and Cynopteri within the five districts where study communities were situated. Conclusions/Significance: Our data suggest distinct epidemiological patterns associated with the Icterohaemorrhagiae and Cynopteri serogroups in the urban environment at high risk for leptospirosis and with differences in spatial niches. We emphasize the need for studies that accurately identify the different pathogenic serogroups that circulate and infect residents of low-income areas. Author summary: In this study, we investigated specific epidemiological patterns related to the Icterohaemorrhagiae and Cynopteri serogroups in urban environments at high risk for leptospirosis. Our results indicate that seropositivity for the Cynopteri serogroup increases with age. Seropositivity is also higher in places where houses have unplastered walls and where there are cats in the vicinity of the residences. Seropositivity for the Icterohaemorrhagiae serogroup also increases with age, and is more prevalent in men and in individuals exposed to work or who have contact with sewage. Spatial analysis reveals variations in the distribution of seropositivity for these serogroups within the five urban areas studied. We emphasize the importance of evaluating the epidemiological pattern for the different Leptospira serogroups, since each serogroup may be associated with different animal reservoirs. Our data suggest that the Icterohaemorrhagiae and Cynopteri serogroups present different epidemiological pattern, thus highlighting the need to understand the complex interactions between serogroups and reservoirs. These findings not only contribute to our understanding of the epidemiology of leptospirosis, but also have practical public health implications by helping to identify risk factors and thereby develop more effective preventive measures. [ABSTRACT FROM AUTHOR]

Background: Aedes aegypti, vector of dengue, chikungunya and Zika viruses, is found at high densities in tropical urban areas. The dissemination of this vector is partially the consequence of failures in current vector control methods, still mainly relying upon insecticides. In the State of São Paulo (SP), Brazil, public health managers employed pyrethroids against Ae. aegypti adults from 1989 to 2000, when a robust insecticide resistance monitoring system detected resistance to pyrethroids in several Ae. aegypti populations. However, pyrethroids are also the preferred compounds engaged in household applications due to their rapid knockdown effect, lower toxicity to mammals and less irritating smell. Methodology/Principal findings: We evaluated pyrethroid resistance in Ae. aegypti populations over the course of a decade, from 2004 to 2015, after interruption of pyrethroid public applications in SP. Qualitative bioassays with papers impregnated with a deltamethrin diagnostic dose (DD) performed with insects from seven SP municipalities and evaluated yearly from 2006 to 2014, detected resistance in most of the cases. Quantitative bioassays were also carried out with four populations in 2011, suggesting a positive correlation between resistance level and survivorship in the DD bioassays. Biochemical tests conducted with seven insect populations in 2006 and 2015, detected increasing metabolic alterations of all major classes of detoxifying enzymes, mostly of mixed function oxidases. Genotyping of the voltage-gated sodium channel (AaNaV, the pyrethroid target-site) with a TaqMan real time PCR based technique was performed from 2004 to 2014 in all seven localities. The two kdr mutations, Val1016Ile and Phe1534Cys, known to be spread throughout Brazil, were always present with a severe decrease of the susceptible allele over time. Conclusions/Significance: These results are discussed in the context of public and domestic insecticide use, the necessity of implementation of a strong integrated vector control strategy and the conceptual misunderstanding between 'vector control' and 'chemical control of vectors'. [ABSTRACT FROM AUTHOR]

Zika virus (ZIKV), an arbovirus from the Flaviviridae family, is the causative agent of Zika fever, a mild and frequent oligosymptomatic disease in humans. Nonetheless, on rare occasions, ZIKV infection can be associated with Guillain-Barré Syndrome (GBS), and severe congenital complications, such as microcephaly. The oligosymptomatic disease, however, presents symptoms that are quite similar to those observed in infections caused by other frequent co-circulating arboviruses, including dengue virus (DENV). Moreover, the antigenic similarity between ZIKV and DENV, and even with other members of the Flaviviridae family, complicates serological testing due to the high cross-reactivity of antibodies. Here, we designed, produced in a prokaryotic expression system, and purified three multiepitope proteins (ZIKV-1, ZIKV-2, and ZIKV-3) for differential diagnosis of Zika. The proteins were evaluated as antigens in ELISA tests for the detection of anti-ZIKV IgG using ZIKV- and DENV-positive human sera. The recombinant proteins were able to bind and detect anti-ZIKV antibodies without cross-reactivity with DENV-positive sera and showed no reactivity with Chikungunya virus (CHIKV)- positive sera. ZIKV-1, ZIKV-2, and ZIKV-3 proteins presented 81.6%, 95%, and 66% sensitivity and 97%, 96%, and 84% specificity, respectively. Our results demonstrate the potential of the designed and expressed antigens in the development of specific diagnostic tests for the detection of IgG antibodies against ZIKV, especially in regions with the circulation of multiple arboviruses. Author summary: From 2015 onward, Zika virus (ZKV) caused major epidemics in Brazil and other South American countries, where many children were born with congenital problems, such as microcephaly, as a result of infections in pregnant women. Additionally, many cases of Guillain Barré Syndrome in adults were also caused by infections with the virus. Detection of ZKV infection is, therefore, very important; nonetheless, most patients infected by ZKV develop either no symptoms or symptoms that are not distinguishable from diseases caused by other co-circulating arboviruses, including dengue. To complicate matters, Zika, and dengue viruses show intense genetic resemblance, and serological diagnosis presents high levels of uncertainty due to extensive cross-reactivity. In this work, we developed proteins to serologically differentiate Zika from dengue infections with no or minimum cross-reactivity. We produced three multiepitope, recombinant proteins which were able to differentiate zika-positive samples from dengue-positive sera. The tests employing the recombinant proteins had high sensitivity and specificity, especially in the case of ZIKV-1 and ZIKV-2 proteins, whilst the ZIKV-3 protein was less efficient. The recombinant proteins showed clear potential to be used as diagnostic tools for detecting antibodies against ZIKV infections with no cross-reactivity to other prevalent arbovirus. [ABSTRACT FROM AUTHOR]

Introduction: Chagas disease is a severe parasitic illness that is prevalent in Latin America and often goes unaddressed. Early detection and treatment are critical in preventing the progression of the illness and its associated life-threatening complications. In recent years, machine learning algorithms have emerged as powerful tools for disease prediction and diagnosis. Methods: In this study, we developed machine learning algorithms to predict the risk of Chagas disease based on five general factors: age, gender, history of living in a mud or wooden house, history of being bitten by a triatomine bug, and family history of Chagas disease. We analyzed data from the Retrovirus Epidemiology Donor Study (REDS) to train five popular machine learning algorithms. The sample comprised 2,006 patients, divided into 75% for training and 25% for testing algorithm performance. We evaluated the model performance using precision, recall, and AUC-ROC metrics. Results: The Adaboost algorithm yielded an AUC-ROC of 0.772, a precision of 0.199, and a recall of 0.612. We simulated the decision boundary using various thresholds and observed that in this dataset a threshold of 0.45 resulted in a 100% recall. This finding suggests that employing such a threshold could potentially save 22.5% of the cost associated with mass testing of Chagas disease. Conclusion: Our findings highlight the potential of applying machine learning to improve the sensitivity and effectiveness of Chagas disease diagnosis and prevention. Furthermore, we emphasize the importance of integrating socio-demographic and environmental factors into neglected disease prediction models to enhance their performance. Author summary: Chagas disease, a severe parasitic illness prevalent in Latin America, poses significant challenges due to delayed detection and treatment. Machine learning algorithms, advanced computer programs, have emerged as valuable tools for disease prediction and diagnosis. In our study, we utilized these algorithms to forecast Chagas disease risk based on factors such as age, gender, and living conditions. Drawing on data from the Retrovirus Epidemiology Donor Study (REDS), we trained five algorithms, with one showing promising results, achieving an impressive score of 0.772 out of 1. By establishing a specific threshold, we could potentially reduce testing costs while maintaining high detection rates. This research highlights the potential of machine learning in improving Chagas disease diagnosis and prevention by incorporating socio-demographic and environmental factors. Integrating these elements into predictive models has the potential to enhance their effectiveness and sensitivity, thereby improving disease management outcomes and ultimately reducing the burden of Chagas disease in affected regions. [ABSTRACT FROM AUTHOR]

Animal hoarding disorder (AHD) is classified as a psychiatric obsessive-compulsive condition characterized by animal accumulation and often accompanied by unsanitary conditions and animal cruelty. Although AHD may increase pathogen transmission and spread, particularly for zoonotic diseases, human and dog exposure in such cases has yet to be fully established. Accordingly, this study aimed to assess Brucella canis in 19 individuals with AHD (11 households) and their 264 dogs (21 households) in Curitiba, the eighth largest city in Brazil, with approximately 1.8 million habitants. Anti-B. canis antibodies were detected by the 2-mercaptoethanol microplate agglutination test (2ME-MAT) and by a commercial lateral flow immunoassay (LFIA), while molecular detection of previously positive seropositive samples was performed by conventional PCR. Although all the human samples were 2ME-MAT negative, 12/264 (4.5%, 95% Confidence Interval: 2.0–7.0%) dog samples were 2ME-MAT and LFIA positive, with 2ME-MAT titers ranging from 20 to 640. At least one dog in 4/21 (19.0%, 95% CI: 2.0–46.0%) households was seropositive. Despite the absence of seropositivity in individuals with AHD and the comparatively low seroprevalence in dogs, B. canis circulation and outbreaks should be considered in such human populations due to the high burden and recurrent character of B. canis exposure in high-density dog populations and the constant introduction of susceptible animals. Author summary: Individuals with animal hoarding disorder (AHD), a psychiatric obsessive-compulsive disorder, are considered among the most vulnerable people due to their precarious sanitary conditions and exposure to several zoonoses, including canine brucellosis, a neglected and underreported disease of public health concern worldwide. Close and continuous human contact with unhealthy and unassisted dogs may increase pathogen transmission and spread, which is worsened by elderly people's difficulty accessing health services and lack of hoarding control and management programs. The present study assessed B. canis as a silent pathogen in this hard-to-access vulnerable population, along with their dogs. Although all the individuals with AHD included herein were seronegative and their dogs presented relatively low seroprevalence, B. canis infection and outbreaks should always be considered, particularly due to unsanitary household conditions, the high density of dog populations, and the constant introduction of susceptible dogs of unknown origin. Thus, dogs seropositive for B. canis living in households of people with AHD should be considered a warning to local public health authorities. In conclusion, serological and molecular assessments of B. canis in people with AHD and other vulnerable populations may serve as instruments for effective public health policies, including diagnosis, control, monitoring, and prevention. [ABSTRACT FROM AUTHOR]

Background: Target Product Profiles (TPPs) are instrumental to help optimise the design and development of therapeutics, vaccines, and diagnostics–these products, in order to achieve the intended impact, should be aligned with users' preferences and needs. However, patients are rarely involved as key stakeholders in building a TPP. Methodology: Thirty-three cutaneous leishmaniasis (CL) patients from Brazil, Colombia, and Austria, infected with New-World Leishmania species, were recruited using a maximum variation approach along geographic, sociodemographic and clinical criteria. Semi-structured interviews were conducted in the respective patient's mother tongue. Transcripts, translated into English, were analysed using a framework approach. We matched disease experiences, preferences, and expectations of CL patients to a TPP developed by DNDi (Drug for Neglected Diseases initiative) for CL treatment. Principal findings: Patients' preferences regarding treatments ranged from specific efficacy and safety endpoints to direct and significant indirect costs. Respondents expressed views about trade-offs between efficacy and experienced discomfort/adverse events caused by treatment. Reasons for non-compliance, such as adverse events or geographical and availability barriers, were discussed. Considerations related to accessibility and affordability were relevant from the patients' perspective. Conclusions/Significance: NTDs affect disadvantaged populations, often with little access to health systems. Engaging patients in designing adapted therapies could significantly contribute to the suitability of an intervention to a specific context and to compliance, by tailoring the product to the end-users' needs. This exploratory study identified preferences in a broad international patient spectrum. It provides methodological guidance on how patients can be meaningfully involved as stakeholders in the construction of a TPP of therapeutics for NTDs. CL is used as an exemplar, but the approach can be adapted for other NTDs. Author summary: Our study addresses the challenge of involving patients in defining which medical product would work for their condition. When designing a new medical product, it is customary to identify a "target product profile" (TPP), which identifies the characteristics the product should have to meet in order to address the medical need it is intended for. For the product to be used as intended and achieve the desired effects, it should be adapted to the conditions and the people who will use it, so, patients' views are important, but rarely heard. Here, we use as an example cutaneous leishmaniasis, a skin and mucosal disease caused by a protozoan parasite, which disproportionally affects poor people across tropical and subtropical areas of the world. We collected patients' views about product safety, efficacy, costs, treatment administration, and perceived barriers, that contribute to specifying product characteristics in the TPP. Overall, our study contributes to the limited body of knowledge with an example and an adaptable methodology to give patients a voice in designing adapted medical products. Patients input may also contribute to redefining aspects of a TPP, such as affordability, instead of just the cost per unit. The methodology used here can be adapted and used for other neglected diseases to give patients a voice in designing medical products. [ABSTRACT FROM AUTHOR]

Background: An important issue associated with the control of visceral leishmaniasis is the need to identify and understand the relevance of asymptomatic infection caused by Leishmania infantum. The aim of this study was to follow the course of asymptomatic L. infantum infection in children in an area of Brazil where it is endemic. The children were assessed twice during a 12-month period. Methodology: In this population study, 1875 children, ranging from 6 months to 7 years of age, were assessed. Blood samples were collected on filter papers via finger prick and tested by ELISA (L. infantum soluble antigen and rk39). Seropositives samples (n = 317) and a number of seronegatives samples (n = 242) were subjected to qPCR. After 12 months, blood samples were collected from a subgroup of 199 children and tested for Leishmania spp. to follow the course of infection. Principal Findings: At baseline qPCR testing identified 82 positive samples. The prevalence rate, as estimated for 1875 children based on the qPCR results, was 13.9%. The qPCR testing of whole blood samples collected from a cohort of children after 12 months (n = 199) yielded the following results: of the 44 (22.1%) children with positive qPCR results at baseline, only 10 (5.0%) remained positive, and 34 (17.1%) became negative; and of the 155 (77.9%) children with negative qPCR results, 131 (65.8%) remained negative, and 24 (12.1%) became positive at the follow-up measurement. The samples with positive findings at baseline (n = 82) had a mean of 56.5 parasites/mL of blood; and at follow-up the mean positive result was 7.8 parasites/mL. Conclusions: The peripheral blood of asymptomatic children had a low and fluctuating quantity of Leishmania DNA and a significant decrease in parasitemia at 1-year follow-up. Quantitative PCR enables adequate monitoring of Leishmania infection. Author Summary: In Brazil, visceral leishmaniasis (VL) is caused by the parasite protozoon Leishmania (Leishmania) infantum (syn chagasi), which is transmitted to humans by sandflies that have widespread wild and domestic animal reservoirs. An important issue associated with the control of VL is the need to identify and understand the relevance of asymptomatic infection in the transmission cycle of the parasite. We evaluated the course of asymptomatic infection in children by using molecular methods to detect parasite DNA and to monitor parasitemia level over time. The prevalence of VL, as detected by means of a molecular method, for 1875 children was 13.9%. The data demonstrated a significant decrease in parasitemia after 1 year. Furthermore, the level of parasitemia was generally lower in asymptomatic children than in sick children. None of the asymptomatic children showed signs or clinical symptoms associated with VL throughout the duration of the study. This molecular method of measuring parasitemia is adequate for monitoring VL transmission in areas where it is endemic. [ABSTRACT FROM AUTHOR]

Background: Currently, antivenoms are the only specific treatment available for snakebite envenoming. In Brazil, over 30% of patients cannot access antivenom within its critical care window. Researchers have therefore proposed decentralizing to community health centers to decrease time-to-care and improve morbidity and mortality. Currently, there is no evidence-based method to evaluate the capacity of health units for antivenom treatment, nor what the absolute minimum supplies and staff are necessary for safe and effective antivenom administration and clinical management. Methods: This study utilized a modified-Delphi approach to develop and validate a checklist to evaluate the minimum requirements for health units to adequately treat snakebite envenoming in the Amazon region of Brazil. The modified-Delphi approach consisted of four rounds: 1) iterative development of preliminary checklist by expert steering committee; 2) controlled feedback on preliminary checklist via expert judge survey; 3) two-phase nominal group technique with new expert judges to resolve pending items; and 4) checklist finalization and closing criteria by expert steering committee. The measure of agreement selected for this study was percent agreement defined a priori as ≥75%. Results: A valid, reliable, and feasible checklist was developed. The development process highlighted three key findings: (1) the definition of community health centers and its list of essential items by expert judges is consistent with the Brazilian Ministry of Health, WHO snakebite strategic plan, and a general snakebite capacity guideline in India (internal validity), (2) the list of essential items for antivenom administration and clinical management is feasible and aligns with the literature regarding clinical care (reliability), and (3) engagement of local experts is critical to developing and implementing an antivenom decentralization strategy (feasibility). Conclusion: This study joins an international set of evidence advocating for decentralization, adding value in its definition of essential care items; identification of training needs across the care continuum; and demonstration of the validity, reliability, and feasibility provided by engaging local experts. Specific to Brazil, further added value comes in the potential use of the checklist for health unit accreditation as well as its applications to logistics and resource distribution. Future research priorities should apply this checklist to health units in the Amazon region of Brazil to determine which community health centers are or could be capable of receiving antivenom and translate this expert-driven checklist and approach to snakebite care in other settings or other diseases in low-resource settings. Author summary: Checklists have been developed and validated to improve patient safety and effectiveness of care in several fields, including emergency medicine, intensive care, and surgery. The Brazilian Ministry of Health (MoH) supplies antivenoms (AVs) to the health system at no cost to patients. AV access is thus limited to hospitals, most of which are in urban areas and difficult for rural, remote, and indigenous populations to reach. Currently, there is no evidence-based method to evaluate the capacity of health units for AV treatment, nor what the absolute minimum supplies and staff are necessary for safe and effective AV administration and clinical management. In this study, we aim to develop and validate a checklist to evaluate the minimum requirements for community health centers to adequately treat snakebite envenoming in the Amazon region of Brazil. This study joins an international set of evidence advocating for decentralization, adding value in its definition of essential care items, represented by Human Resources, and Equipment, Supplies and Medicines, to provide safe and effective treatment for SBE patients in remote endemic areas. [ABSTRACT FROM AUTHOR]

Background: The first chikungunya virus (CHIKV) outbreaks during the modern scientific era were identified in the Americas in 2013, reaching high attack rates in Caribbean countries. However, few cohort studies have been performed to characterize the initial dynamics of CHIKV transmission in the New World. Methodology/Principal findings: To describe the dynamics of CHIKV transmission shortly after its introduction in Brazil, we performed semi-annual serosurveys in a long-term community-based cohort of 652 participants aged ≥5 years in Salvador, Brazil, between Feb-Apr/2014 and Nov/2016-Feb/2017. CHIKV infections were detected using an IgG ELISA. Cumulative seroprevalence and seroincidence were estimated and spatial aggregation of cases was investigated. The first CHIKV infections were identified between Feb-Apr/2015 and Aug-Nov/2015 (incidence: 10.7%) and continued to be detected at low incidence in subsequent surveys (1.7% from Aug-Nov/2015 to Mar-May/2016 and 1.2% from Mar-May/2016 to Nov/206-Feb/2017). The cumulative seroprevalence in the last survey reached 13.3%. It was higher among those aged 30–44 and 45–59 years (16.1% and 15.6%, respectively), compared to younger (12.4% and 11.7% in <15 and 15–29 years, respectively) or older (10.3% in ≥60 years) age groups, but the differences were not statistically significant. The cumulative seroprevalence was similar between men (14.7%) and women (12.5%). Yet, among those aged 15–29 years, men were more often infected than women (18.1% vs. 7.4%, respectively, P = 0.01), while for those aged 30–44, a non-significant opposite trend was observed (9.3% vs. 19.0%, respectively, P = 0.12). Three spatial clusters of cases were detected in the study site and an increased likelihood of CHIKV infection was detected among participants who resided with someone with CHIKV IgG antibodies. Conclusions/Significance: Unlike observations in other settings, the initial spread of CHIKV in this large urban center was limited and focal in certain areas, leaving a high proportion of the population susceptible to further outbreaks. Additional investigations are needed to elucidate the factors driving CHIKV spread dynamics, including understanding differences with respect to dengue and Zika viruses, in order to guide prevention and control strategies for coping with future outbreaks. Author summary: The chikungunya virus (CHIKV) was introduced to the Americas in 2013, causing large outbreaks that rapidly affected a substantial portion of the population in several countries. The virus was first detected in Brazil in 2014 and has since spread across the country. However, prospective studies have not been performed to investigate the force of CHIKV transmission shortly after its introduction in Brazil. To fill this gap, we followed 652 participants through a series of six semi-annual serological surveys from Feb/2014 to Feb/2017 in Salvador, Brazil, a city that has been an epicenter of several Aedes aegypti-transmitted arbovirus epidemics. As the study started before the detection of CHIKV in Brazil, we were able to estimate the proportion of participants who became infected between each of the surveys by detecting the appearance of CHIKV IgG antibodies. We found that CHIKV transmission was higher between Feb-Apr/2015 and Aug-Nov/2015, when 10.7% of the participants were infected. Transmission was largely focal in space. However, unlike in other American countries, the transmission was limited, with >85% of the participants still susceptible to infection ~1.5 years later. Given the difference in the speed of CHIKV spread among countries, further studies should investigate which factors influence the intensity of CHIKV transmission, aiming to guide prevention and control strategies for coping with future outbreaks. [ABSTRACT FROM AUTHOR]

Background: Arthropod-borne viruses, known as arboviruses, pose substantial risks to global public health. Dengue (DENV), Chikungunya (CHIKV) and Zika (ZIKV) viruses stand out as significant concerns in Brazil and worldwide. Their overlapping clinical manifestations make accurate diagnosis a challenge, underscoring the need for reliable laboratory support. This study employs a comprehensive molecular diagnostic approach to track viral infections in individuals with acute febrile illness, a period marked by widespread outbreaks of DENV, CHIKV and ZIKV. Methods: Between January and August 2016, we received a total of 713 serum samples obtained from individuals with acute febrile illness, previously tested for DENV, CHIKV or ZIKV, with initial negative results, from LACEN-NATAL. Of the total 713 samples, 667 were from females (354 of them pregnant) and 46 from males. Molecular diagnosis was conducted using the Multiplex RT-qPCR technique for simultaneous detection of DENV, CHIKV and ZIKV. Additionally, we performed differential diagnosis by RT-qPCR for other viruses of the Flavivirus, Alphavirus Enterovirus genera and qPCR for Primate Erythroparvovirus 1 (B19V) species, in accordance with Ministry of Health guidelines. Results: Among the 713 cases, 78.2% tested positive for viral infections, including 48% with CHIKV viremia, 0.6% with DENV and 0.1% with ZIKV. Arboviral coinfections totaled 2.4%, including DENV-CHIKV (1.7%) and CHIKV-ZIKV (0.7%). Moreover, 8% exhibited B19V viremia. Simultaneous infections were identified in 17.5%, encompassing B19V-CHIKV (17.1%), B19V-DENV (0.1%), and B19V-ZIKV (0.3%) Triple infections were observed in 1.3% of cases with B19V-DENV-CHIKV (1%) and B19V-CHIKV-ZIKV (0.3%). Conclusion: Molecular testing demonstrated high efficacy in diagnosing prevalent arboviruses and detecting multiple coinfections. This approach helps to elucidate etiologies for symptomatic cases, especially during arbovirus outbreaks, and aids comprehensive surveillance. Our findings underscore the importance of monitoring co-circulating pathogens, such as B19V, with implications for clinical management, particularly in pregnant individuals. This study enhances our understanding of arbovirus epidemiology and reinforces the critical role of molecular diagnosis in disease surveillance and control. Author summary: Fever is one of the most common reasons for seeking health care in Latin America and is a substantial contributor to continental morbidity and mortality. Viruses transmitted by arthropods, known as arboviruses, represent one of the predominant etiologic agents responsible for causing febrile illness in Latin America. In the current epidemiological scenario in Brazil, due to shared characteristics of DENV, CHIKV and ZIKV, the Ministry of Health recommends performing a differential diagnosis for other clinical syndromes. In this study, we performed the differential molecular diagnosis in 713 samples of individuals with acute febrile illness suspected of arboviruses belonging to the state of Rio Grande do Norte in 2016. The samples were submitted to RT-qPCR and qPCR tests for DENV, CHIKV and ZIKV, together with other agents responsible for causing febrile syndrome and exanthematous fever syndrome. These include Enterovirus, other arboviruses of the Flavivirus and Alphavirus genera and the species Primate Erythroparvovirus 1 (B19V). We report the concomitant detection of CHIKV and B19V in 17.1% of cases, highlighting the importance of a broad diagnostic approach, since the detection of simultaneous infections may be occurring between arboviruses and/ or other viruses during epidemics in different regions of Brazil. [ABSTRACT FROM AUTHOR]

Rabies is a viral zoonosis affecting mammal species and causes large economic losses. Included among the neglected diseases, it is still insufficiently addressed by governments and the international community, despite formal surveillance and control programs. This study used a dataset of 10,112 rabies diagnoses in animals provided by the Brazilian passive surveillance system from 2001 to 2012. The positivity rate of the tested samples was 26.4%, and a reduction in the total samples sent during the last six years was observed. The kernel density map indicated case concentration in the south region and a decrease in density of rabies cases in the second period studied (2007 to 2012). The directional trend of positive rabies diagnoses remained in the south region, as shown by the standard deviational ellipse. The spatial scan statistic identified three large clusters of positive diagnoses, one in the first period (2001-2006) and two in the second period (2007-2012), indicating an expansion of risk areas. The decrease in rabies cases from 2006 to 2012 does not necessarily reflect lower viral circulation or improvement in actions by epidemiological surveillance; this decrease could indicate a deficiency in epidemiological surveillance during the observation period due to the increase in the silent areas. Surveillance should maintain an increasing or constant number of tests during the years in addition to a reduction in the number of outbreaks of rabies, which would indicate a lower positivity rate. The findings in this study indicate deterioration in the effectiveness of the passive surveillance for rabies. The number of rabies cases, total number of tests performed and positivity rate are good indicators for evaluating passive surveillance. This paper can function as a guide for the assessment and improvement of the actions in passive surveillance of rabies. Author Summary: The approach proposed in this study can provide a valuable contribution to strengthen the efforts to reduce rabies incidence, a relevant public health problem worldwide. In Brazil during the period from 2001–2012, 129 human cases of rabies were notified, with 128 deaths. It is imperative to decrease rabies virus circulation both in domestic and wildlife species, which has been reinforced by many studies demonstrating that rabies incidence is often much higher than the official reports. This study used a dataset of 10,112 rabies diagnoses in animals provided by the Brazilian passive surveillance and applied spatial analysis in addition to many indicators to highlight high positivity rate areas and accurately identify silent areas and regions where underreporting occurs. This type of approach is vital to establish priorities for epidemiologic surveillance strategically and to precisely focus actions in the required regions. These spatial analysis techniques combined with other sources of information can also be used to evaluate the effectiveness of passive surveillance for rabies and improve the strategies already adopted by government programs to control and prevent the disease. We consider our results an important achievement in envisioning effectiveness in the process to eliminate rabies worldwide. [ABSTRACT FROM AUTHOR]

Background: Malaria and dengue are the most prevalent vector-borne diseases worldwide and represent major public health problems. Both are endemic in tropical regions, propitiating co-infection. Only few co-infection cases have been reported around the world, with insufficient data so far to enhance the understanding of the effects of co-infection in the clinical presentation and severity. Methodology/Principal Findings: A cross-sectional study was conducted (2009 to 2011) in hospitalized patients with acute febrile syndrome in the Brazilian Amazon. All patients were submitted to thick blood smear and PCR for Plasmodium sp. detection, ELISA, PCR and NS1 tests for dengue, viral hepatitis, HIV and leptospirosis. In total, 1,578 patients were recruited. Among them, 176 (11.1%) presented P. vivax malaria mono-infection, 584 (37%) dengue fever mono-infection, and 44 (2.8%) were co-infected. Co-infected patients had a higher chance of presenting severe disease (vs. dengue mono-infected), deep bleeding (vs. P. vivax mono-infected), hepatomegaly, and jaundice (vs. dengue mono-infected). Conclusions/Significance: In endemic areas for dengue and malaria, jaundice (in dengue patients) and spontaneous bleeding (in malaria patients) should raise the suspicion of co-infection. Besides, whenever co-infection is confirmed, we recommend careful monitoring for bleeding and hepatic complications, which may result in a higher chance of severity, despite of the fact that no increased fatality rate was seen in this group. Author Summary: Malaria and dengue fever are typical diseases in tropical regions of developing countries; such as the Brazilian Amazon. They become serious problems in public health as they mostly affect vulnerable populations. Both diseases are mosquito-borne. These diseases present similar signs and symptoms. Brazil registers most of the malaria cases in the Amazon. The four dengue serotypes also circulate in this region. Similar to malaria, there are records of dengue outbreaks during the first months of the year, and isolated cases in the remaining months. Official records of malaria and dengue co-infection are infrequent in Brazil; however, we believe that this event is more frequent than usually reported. Our study detected high prevalence of the co-infection in the hospitalized patients infected with malaria or dengue in a tertiary health care unit, reference in the treatment of tropical and infectious diseases in Manaus, Amazonas, Brazil. We highlight the high likelihood of co-infected patients to present clinical complications. Besides, we observed that the presence of jaundice in dengue patients, and bleeding in malaria patients, are possible indications of co-infection. Therefore, this paper is useful to physicians working in the tropics, enabling the clinical suspicion of a not so rare condition. [ABSTRACT FROM AUTHOR]

Background: Tuberculosis (TB) is a preventable and a curable disease. In Brazil, TB treatment outcomes are particularly worse among homeless populations who are either of black race, malnourished or living with HIV/AIDS and other comorbidities. This study therefore evaluated factors associated with unsuccessful TB treatment among homeless population (HP) compared to those with shelter. Methodology/Principal findings: The study population was composed of 284,874 people diagnosed with TB in Brazil between 2015 and 2020 and reported in the Information System for Notifiable Diseases (SINAN), among which 7,749 (2.72%) were homeless and 277,125 (97.28%) were sheltered. Cox regression analysis was performed with both populations to identify factors associated with unsuccessful TB treatment, and significant predictors of TB treatment outcomes. Results show that HP are more susceptible to unfavorable outcomes when compared to sheltered people (Hazard Ratio (HR): 2.04, 95% CI 1.82–2.28). Among the HP, illicit drug use (HR: 1.38, 95% CI 1.09–1.74), mental disorders (HR: 2.12, 95% CI 1.08–4.15) and not receiving directed observed treatment (DOT) (HR: 18.37, 95% CI 12.23–27.58) are significant predictors of poor treatment outcomes. The use of illicit drugs (HR: 1.53, 95% CI 1.21–1.93) and lack of DOT (HR: 17.97, 95% CI 11.71–27.59) are associated with loss to follow-up, while lack of DOT (HR: 15.66, 95% CI 4.79–51.15) was associated with mortality among TB patients. Conclusion/significance: Homeless population living in Brazil are twice at risk of having an unsuccessful treatment, compared to those who are sheltered, with illicit drugs use, mental disorders and lack of DOT as risk factors for unsuccessful TB outcomes. Our findings reinforce the arguments for an intersectoral and integral approach to address these determinants of health among the vulnerable homeless populations. Author summary: Tuberculosis is one of the world's most deadly disease and is responsible for 4,000 deaths daily. People living in impoverished conditions, especially those who are homeless are among the worst affected. In Brazil, the population of homeless persons is rising. This population is affected by socioeconomic issues such as worst jobs, structural racism, lack of civil rights, limited access to health care service and stigmatization. Our study therefore investigated the reasons why tuberculosis treatments are unsuccessful among homeless people in Brazil in comparison to populations with shelter. We found out that homeless population living in Brazil are twice at risk of having an unsuccessful treatment, compared to those who are with shelter. In addition, we found that homeless population who use illicit drugs and had mental illness were the most affected. Also, the non-implementation of directly observed treatment is a major reason why most patients do not complete their treatment, and a major predictor of death among these homeless populations. Since tuberculosis is a preventable and curable disease and diagnosis and treatment are freely available in the Unified Health System (SUS, Sistema Único de Saúde) of Brazil, it therefore becomes important to understand and address these barriers that have limited the access of homeless populations to existing health services. [ABSTRACT FROM AUTHOR]

Background: We evaluate the drug treatment for pregnant women with acute toxoplasmosis to reduce the risk of congenital infection, side effects (prenatal and postnatal treatment in children) and the hazard of discontinuing the infant's medication. Methods: We conducted a prospective cohort study to assess the risks of congenital toxoplasmosis among children born to acutely infected women with and without treatment. We examined the relationship between "exposed" and "infected children", "number of infant neutrophils", "prenatal" and "postnatal treatment". Factor analysis of mixed data (FAMD) was used to analyze the data. All children started treatment at the hospital. Findings: Between 2017 and 2021, 233 pregnant women were evaluated at the University Hospital of Maringá; ninety-four met criteria for acute gestational toxoplasmosis. We followed up 61 children; eleven (18%) had the infection confirmed and 50 (82%) were free of toxoplasmosis (exposed). Children born to untreated mothers have 6.5-times higher risk of being infected; the transmission rate among untreated mothers was 50% versus 8.3% among treated ones. Three decreasing values of immunoglobulin G were a security parameter for stopping the child's medication in the exposed group (50/61). Neutropenia was the leading side effect among children and the infected had a 2.7 times higher risk. There was no correlation between maternal use of pyrimethamine and children's neutropenia. Interpretation: The follow-up of women with acute T. gondii infection and their children, through a multidisciplinary team, availability of anti-T. gondii serology and pre- and post-natal treatments reduced the risk of toxoplasmosis transmission. Author summary: South America is the region with the highest burden of congenital toxoplasmosis and with the most pathogenic genotypes. Brazil is considered a country with a high prevalence of toxoplasmosis and a hotspot for outbreaks. The outcome of congenital transmission is influenced by factors such as T. gondii genotype, strain virulence, maternal immune status, maternal parasitemia, gestational age at the time of infection, and prenatal treatment. The last point mentioned is still controversial and raises several concerns, such as the financial impact of the monitoring and treatment of pregnant women and their children, the side effects of the medications used, and the benefit of investing in public health policies to mitigate toxoplasmosis. Information on the effectiveness of prenatal treatment is limited since it is challenging to carry out randomized studies. In the present manuscript, we evaluated the benefit of drug treatment for pregnant women with acute toxoplasmosis as a protective factor in reducing the risk of congenital infection. Also, we evaluated the side effects of prenatal and postnatal drug use in children and assessed the risk of discontinuing the medication in infants. We used the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) to report this study. [ABSTRACT FROM AUTHOR]

Introduction: Familial clustering of HTLV-1 and related diseases has been reported in Brazil. However, intrafamilial transmission of HTLV-1 based on molecular analysis has been studied only in a few communities of Japanese immigrants and African-Brazilians. Objective: To investigate the familial clustering of HTLV-1 infection and to determine the likely routes of transmission through epidemiological and genetic analyzes. Methods: Medical records of 1,759 HTLV-1+ patients from de the Center for HTLV in Salvador, Brazil, were evaluated to identify first-degree relatives previously tested for HTLV-1. Familial clustering was assumed if more than one member of the same family was HTLV-1+. LTR regions of HTLV-1 sequences were analyzed for the presence of intrafamilial polymorphisms. Family pedigrees were constructed and analyzed to infer the likely transmission routes of HTLV-1. Results: In 154 patients at least one other family member had tested positive for HTLV-1 (a total of 182 first-degree relatives). Of the 91 couples (182 individuals), 51.6% were breastfed, and 67.4% reported never using a condom. Of the 42 mother-child pairs, 23.8% had a child aged 13 years or younger; all mothers reported breastfeeding their babies. Pedigrees of families with 4 or more members suggests that vertical transmission is a likely mode of transmission in three families. Three families may have had both vertical and sexual transmission routes for HTLV-1. The genetic signatures of the LTR region of 8 families revealed 3 families with evidence of vertical transmission, another 3 families (spouses) with sexual transmission, and one family with both transmission routes. HTLV-1 sequences belonged to Cosmopolitan subtype HTLV-1a Transcontinental subgroup A. Conclusion: Sexual and vertical transmission routes contribute to the intrafamilial spread of HTLV-1 in the state of Bahia. Author summary: Human T-lymphotropic virus type 1 (HTLV-1) was the first human retrovirus isolated in the early 1980s. It is estimated that approximately 10 million people worldwide are currently infected with HTLV-1, and most people living with HTLV (PLwHTLV) live in developing countries. The virus is associated with a wide range of diseases, including neoplasms such as adult T-cell leukemia/lymphoma and progressive and disabling myelopathy, but most PLwHTLV are unaware of their serologic status. HTLV-1 is transmitted through contact with contaminated blood and derivatives, sexually, and from mother to child, especially through breastfeeding. Only recently has WHO recognized HTLV-1 as a as threatening pathogen to human, but in many parts of the world HTLV screening is not performed in blood banks or in pregnant women. This may promote silent intrafamilial transmission of the virus across generations and promote familial clustering of the virus and associated diseases. In this study, we investigated the familial clustering of HTLV-1 infection in the state of Bahia, an endemic area for this virus in Brazil. We found that both sexual and vertical pathways contribute to the transmission and persistence of the virus in families across multiple generations. Therefore, in addition to expanding screening for pregnant women and providing infant formula to infected mothers, it is of utmost importance to combat sexual transmission through effective measures that can help address this serious and neglected public health problem. [ABSTRACT FROM AUTHOR]

Since 2014, Brazil has experienced an unprecedented epidemic caused by chikungunya virus (CHIKV), with several waves of East-Central-South-African (ECSA) lineage transmission reported across the country. In 2018, Rio de Janeiro state, the third most populous state in Brazil, reported 41% of all chikungunya cases in the country. Here we use evolutionary and epidemiological analysis to estimate the timescale of CHIKV-ECSA-American lineage and its epidemiological patterns in Rio de Janeiro. We show that the CHIKV-ECSA outbreak in Rio de Janeiro derived from two distinct clades introduced from the Northeast region in mid-2015 (clade RJ1, n = 63/67 genomes from Rio de Janeiro) and mid-2017 (clade RJ2, n = 4/67). We detected evidence for positive selection in non-structural proteins linked with viral replication in the RJ1 clade (clade-defining: nsP4-A481D) and the RJ2 clade (nsP1-D531G). Finally, we estimate the CHIKV-ECSA's basic reproduction number (R0) to be between 1.2 to 1.6 and show that its instantaneous reproduction number (Rt) displays a strong seasonal pattern with peaks in transmission coinciding with periods of high Aedes aegypti transmission potential. Our results highlight the need for continued genomic and epidemiological surveillance of CHIKV in Brazil, particularly during periods of high ecological suitability, and show that selective pressures underline the emergence and evolution of the large urban CHIKV-ECSA outbreak in Rio de Janeiro. Author summary: Chikungunya is a mosquito-borne viral disease that has emerged as a significant public health concern in many regions worldwide. The state of Rio de Janeiro, a key economic and tourism hub in Brazil, has experienced multiple outbreaks of chikungunya in recent years, resulting in significant morbidity and economic burden. However, our understanding of the establishment and epidemiology of chikungunya in Rio de Janeiro remains limited. We conducted an analysis of chikungunya epidemiology in Rio de Janeiro, focusing on the first four years of virus circulation in the state. We estimated the magnitude of chikungunya transmission during this period, providing evidence that the trends of incidence and transmissibility can be influenced by climatic fluctuations, which impact vector abundance. Through analysis of novel genetic data, we inferred the evolutionary history of the virus, providing evidence of molecular adaptation in the lineage circulating in Rio de Janeiro. These findings highlight the need for designing effective vector control strategies to prevent and mitigate chikungunya in Rio de Janeiro and similar settings. Further research is needed to continue monitoring viral epidemiological trends and to better understand the complex interactions between climatic factors, vector dynamics, and viral evolution in shaping the transmission of this emerging disease. [ABSTRACT FROM AUTHOR]

Background: Dengue fever is a mosquito-borne viral disease that is associated with four serotypes of the dengue virus. Children are vulnerable to infection with the dengue virus, particularly those who have been previously infected with a different dengue serotype. Sufficient knowledge, positive attitudes, and proper practices (KAP) are essential for dengue prevention and control. This study aims to estimate the dengue seropositivity for study participants and to examine the association between households' dengue-related knowledge, attitudes, and practices (KAP), and children's risk of dengue seropositivity, while accounting for socioeconomic and demographic differences in Brazil. Methodology/Principal findings: This analysis was based on a cross-sectional study from Fortaleza, Brazil between November 2019, and February 2020. There were 392 households and 483 participant children who provided a sample of sufficient quality for serological analysis. The main exposure was a household's dengue-related knowledge, attitudes, and practices, assessed through a questionnaire to construct a composite KAP score categorized into three levels: low, moderate, and high. The main outcome is dengue immunoglobulin G(IgG) antibodies, collected using dried blood spots and assessed with Panbio Dengue IgG indirect ELISA (enzyme-linked immunosorbent assays) test commercial kits. The estimated crude dengue seroprevalence among participating children (n = 483) was 25%. Five percent of households (n = 20) achieved a score over 75% for KAP, sixty-nine percent of households (n = 271) scored between 50% and 75%, and twenty-six percent of households (n = 101) scored lower than 50%. Each KAP domain was significantly and positively associated with the others. The mean percentage scores for the three domains are 74%, 63%, and 39% respectively. We found high household KAP scores were associated with an increased adjusted relative risk (aRR) of seropositivity (aRR: 2.11, 95% CI: 1.11–4.01, p = 0.023). Household adult respondents' education level of elementary school or higher was negatively associated with children's risk of being seropositive (aRR: 0.65, 95% CI: 0.48–0.87, p = 0.005). The risk of seropositivity in older children (6–12 years old) was over 6 times that of younger children (2–5 years old) (aRR: 6.08, 95% CI: 3.47–10.64, p<0.001). Children living in households with sealed water tanks or no water storage had a lower risk of being seropositive (aRR: 0.73, 95% CI: 0.54–0.98, p = 0.035). Conclusions/Significance: Our results provide insight into the prevalence of dengue seropositivity in Fortaleza, Brazil in children, and certain demographic and socioeconomic characteristics associated with children's risk of being seropositive. They also suggest that KAP may not identify those more at-risk for dengue, although understanding and enhancing households' KAP is crucial for effective community dengue control and prevention initiatives. Author summary: Dengue fever has become an increasing threat to public health, with its global expansion and increased presence in dengue endemic countries. This study provides insight into the prevalence of dengue seropositivity in children in Fortaleza, Brazil, a city which has been a hotspot for arbovirus infections. We estimated seroprevalence for certain study population characteristics and identified characteristics that were associated with an increased risk of dengue seropositivity. We also explored the associations of a composite measure of knowledge, attitudes, and practice (KAP) with seropositivity and found an inverse relationship between KAP for dengue control and children's seropositivity. KAP could change due to previous infection experience, which is a potential limitation of using KAP as a potential predictor of dengue seropositivity in cross-sectional studies. Despite this, KAP remains useful for identifying gaps in knowledge, attitude, and practice that can be used to inform public health measures, such as education campaigns. Measures of social acceptability of interventions should also be considered for inclusion in similar studies, as it would provide an indication of likelihood of adoption of interventions, which provides additional insight for different dengue interventions. [ABSTRACT FROM AUTHOR]

Background: Erythema Nodosum Leprosum (ENL) is a humoral immunological response in leprosy that leads to inflammatory skin nodules which may result in nerve and organ damage, and may occur years after antibiotic treatment. Multiple episodes are frequent and suppression requires high doses of immunosuppressive drugs. Global occurrence is unknown. Methodology/Principal Findings: Systematic review of evidence on ENL incidence resulted in 65 papers, predominantly from India (24) and Brazil (9), and inclusive of four reviews. Average incidences are based on cumulative incidence and size of study populations (n>100). In field-based studies 653/54,737 (1.2%) of all leprosy cases, 194/4,279 (4.5%) of MB cases, and 86/560 (15.4%) of LL cases develop ENL. Some studies found a range of 1–8 per 100 person-years-at-risk (PYAR) amongst MB cases. Hospital samples indicate that 2,393/17,513 (13.7%) of MB cases develop ENL. Regional differences could not be confirmed. Multiple ENL episodes occurred in 39 to 77% of ENL patients, with an average of 2.6. Some studies find a peak in ENL incidence in the first year of treatment, others during the second and third year after starting MDT. The main risk factor for ENL is a high bacteriological index. Conclusions/Significance: Few studies reported on ENL as a primary outcome, and definitions of ENL differed between studies. Although, in this review averages are presented, accurate data on global and regional ENL incidence is lacking. Large prospective studies or accurate surveillance data would be required to clarify this. Health staff needs to be aware of late reactions, as new ENL may develop as late as five years after MDT completion, and reoccurrences up to 8 years afterwards. Author Summary: This systematic review addresses an underpublicized and yet highly significant leprosy topic. Erythema Nodosum Leprosum (ENL) is a serious complication in multi-bacillary (MB) leprosy that may lead to severe disability. Inflammatory skin nodules may result in nerve and organ damage and require high doses of immunosuppressive drugs. ENL can occur long after patients are released from antibiotic treatment. Frequency and severity of ENL is unknown; this review confirms the lack of accurate data at global, regional, and national levels. Available data indicates that ENL incidence ranges between 0.7–4.6% of all MB cases and late reoccurrence up to 8 years after release from treatment. ENL episodes often reoccur, with an average of 2.6 times. The main risk factor for ENL is a high bacteriological index. Additionally, data indicate a wide variation of ENL occurrence between and within countries. The conclusions demonstrate the need for increased awareness about ENL, in research, patient surveillance, and in programme management. [ABSTRACT FROM AUTHOR]

Background: Visceral leishmaniasis belongs to the list of neglected tropical diseases and is considered a public health problem worldwide. Spatial correlation between the occurrence of the disease in humans and high rates of canine infection suggests that in the presence of the vector, canine visceral leishmaniasis is the key factor for triggering transmission to humans. Despite the control strategies implemented, such as the sacrifice of infected dogs being put down, the incidence of American visceral leishmaniasis remains high in many Latin American countries. Methodology/Principal Findings: Mathematical models were developed to describe the transmission dynamics of canine leishmaniasis and its control by culling. Using these models, imperfect control scenarios were implemented to verify the possible factors which alter the effectiveness of controlling this disease in practice. Conclusions/Significance: A long-term continuous program targeting both asymptomatic and symptomatic dogs should be effective in controlling canine leishmaniasis in areas of low to moderate transmission (R0 up to 1.4). However, the indiscriminate sacrifice of asymptomatic dogs with positive diagnosis may jeopardize the effectiveness of the control program, if tests with low specificity are used, increasing the chance of generating outrage in the population, and leading to lower adherence to the program. Therefore, culling must be planned accurately and implemented responsibly and never as a mechanical measure in large scale. In areas with higher transmission, culling alone is not an effective control strategy. Author Summary: Visceral leishmaniasis is listed as a neglected tropical disease and is considered a public health problem worldwide. The disease has been documented since 1885, the first case being reported in India. After over 120 years, the incidence of the disease remains high despite control strategies implemented. In areas where the disease is zoonotic, such as in Brazil, identification as well as removal of infected dogs is recommended in highly endemic areas for they are considered to be the reservoir of the Leishmania chagasi parasite. The theoretical basis that supports the culling of infected dogs is the assumption that the incidence of human infection is directly related to the number of infectious dogs. However, there is no consensus among researchers on the effectiveness of this strategy for controlling either human or canine visceral leishmaniasis. In this context, mathematical models can provide a basis for determining the strategies with the greatest potential for success. This paper aims to contribute to this discussion by introducing further complexities into the problem, in particular, the imperfect diagnosis of this infection and the time gap between laboratory diagnosis and culling and the presence of asymptomatic infections. [ABSTRACT FROM AUTHOR]

Background: There are no effective vaccines for visceral leishmaniasis (VL), a neglected parasitic disease second only to malaria in global mortality. We previously identified 14 protective candidates in a screen of 100 Leishmania antigens as DNA vaccines in mice. Here we employ whole blood assays to evaluate human cytokine responses to 11 of these antigens, in comparison to known defined and crude antigen preparations. Methods: Whole blood assays were employed to measure IFN-γ, TNF-α and IL-10 responses to peptide pools of the novel antigens R71, Q51, L37, N52, L302.06, J89, M18, J41, M22, M63, M57, as well as to recombinant proteins of tryparedoxin peroxidase (TRYP), Leishmania homolog of the receptor for activated C kinase (LACK) and to crude soluble Leishmania antigen (SLA), in Indian patients with active (n = 8) or cured (n = 16) VL, and in modified Quantiferon positive (EHC+ve, n = 20) or modified Quantiferon negative (EHC−ve, n = 9) endemic healthy controls (EHC). Results: Active VL, cured VL and EHC+ve groups showed elevated SLA-specific IFN-γ, but only active VL patients produced IL-10 and EHC+ve did not make TNF-α. IFN-γ to IL-10 and TNF-α to IL-10 ratios in response to TRYP and LACK antigens were higher in cured VL and EHC+ve exposed individuals compared to active VL. Five of the eleven novel candidates (R71, L37, N52, J41, and M22) elicited IFN-γ and TNF-α, but not IL-10, responses in cured VL (55–87.5% responders) and EHC+ve (40–65% responders) subjects. Conclusions: Our results are consistent with an important balance between pro-inflammatory IFNγ and TNFγ cytokine responses and anti-inflammatory IL-10 in determining outcome of VL in India, as highlighted by response to both crude and defined protein antigens. Importantly, cured VL patients and endemic Quantiferon positive individuals recognise 5 novel vaccine candidate antigens, confirming our recent data for L. chagasi in Brazil, and their potential as cross-species vaccine candidates. Author Summary: Visceral leishmaniasis is a parasitic infection that results in death in susceptible people unless they are treated. Current drugs are expensive and toxic, and there are no vaccines in use in humans. We know that it is possible to become immune to infection with this parasite because people who have been cured using drug treatment are resistant to further infection. In addition, a large percentage of people infected with the parasite remain asymptomatic and develop a specific immune response that can be measured using crude leishmanial antigens. We hypothesized that these resistant people might hold the key to understanding the kind of immune response required for protection. In this paper we compared the immune response to a series of novel vaccine candidates in people with active disease, in those drug-cured from the disease, and in the naturally resistant individuals. We show that immune individuals make strong cytokine responses to five of eleven novel vaccine candidates that were tested, making them ideal candidates to take forward in the development of a defined vaccine against leishmaniasis. [ABSTRACT FROM AUTHOR]

Background: Chemotherapy for leishmaniasis, a disease caused by Leishmania parasites, is expensive and causes side effects. Furthermore, parasite resistance constitutes an increasing problem, and new drugs against this disease are needed. In this study, we examine the effect of the compound 8,10,18-trihydroxy-2,6-dolabelladiene (Dolabelladienetriol), on Leishmania growth in macrophages. The ability of this compound to modulate macrophage function is also described. Methodology/Principal Findings: Leishmania-infected macrophages were treated with Dolabelladienetriol, and parasite growth was measured using an infectivity index. Nitric oxide (NO), TNF-α and TGF-β production were assayed in macrophages using specific assays. NF-kB nuclear translocation was analyzed by western blot. Dolabelladienetriol inhibited Leishmania in a dose-dependent manner; the IC50 was 44 µM. Dolabelladienetriol diminished NO, TNF-α and TGF-β production in uninfected and Leishmania-infected macrophages and reduced NF-kB nuclear translocation. Dolabelladienetriol inhibited Leishmania infection even when the parasite growth was exacerbated by either IL-10 or TGF-β. In addition, Dolabelladienetriol inhibited Leishmania growth in HIV-1-co-infected human macrophages. Conclusion: Our results indicate that Dolabelladienetriol significantly inhibits Leishmania in macrophages even in the presence of factors that exacerbate parasite growth, such as IL-10, TGF-β and HIV-1 co-infection. Our results suggest that Dolabelladienetriol is a promising candidate for future studies regarding treatment of leishmaniasis, associated or not with HIV-1 infection. Author Summary: Leishmaniasis is a global disease, which is treated with expensive compounds. Anti-leishmaniasis therapy causes severe side effects, and parasite resistance is often observed, which highlights the importance of discovering new drugs against its causal agent, the protozoan parasite Leishmania. Recently, the geographical overlapping distribution of leishmaniasis and the infection by the human immunodeficiency virus type 1 (HIV-1) has contributed to a dramatic increase in the number of individuals infected with Leishmania. The dolabellene diterpene Dolabelladienetriol, purified from the marine algae Dictyota pfaffii collected along the northeast coast of Brazil, presents anti-HIV-1 activity. In this paper, we report that Dolabelladienetriol reduces the number of Leishmania amazonensis in host cells. We found that Dolabelladienetriol decreased the Leishmania load even in the presence of factors that exacerbate parasite growth, such as cytokines and HIV-1 co-infection. Our data may call attention to Dolabelladienetriol as a promising candidate for future studies regarding the treatment of leishmaniasis alone or in association with HIV-1 coinfection. [ABSTRACT FROM AUTHOR]

Background: Dengue virus (DENV) was reintroduced into Brazil in 1986 and by 1995 it had spread throughout the country. In 2007 the number of dengue hemorrhagic fever (DHF) cases more than doubled and a shift in the age distribution was reported. While previously the majority of DHF cases occurred among adults, in 2007 53% of cases occurred in children under 15 years old. The reasons for this shift have not been determined. Methods and Findings: Age stratified cross-sectional seroepidemiologic survey conducted in Recife, Brazil in 2006. Serostatus was determined by ELISA based detection of Dengue IgG. We estimated time-constant and time-varying forces of infection of DENV between 1986 and 2006. We used discrete-time simulation to estimate the accumulation of monotypic and multitypic immunity over time in a population previously completely susceptible to DENV. We projected the age distribution of population immunity to dengue assuming similar hazards of infection in future years. The overall prevalence of DENV IgG was 0.80 (n = 1427). The time-constant force of infection for the period was estimated to be 0.052 (95% CI 0.041, 0.063), corresponding to 5.2% of susceptible individuals becoming infected each year by each serotype. Simulations show that as time since re-emergence of dengue goes by, multitypic immunity accumulates in adults while an increasing proportion of susceptible individuals and those with monotypic immunity are among young age groups. The median age of those monotypically immune can be expected to shift from 24 years, 10 years after introduction, to 13 years, 50 years after introduction. Of those monotypically immune, the proportion under 15 years old shifts from 27% to 58%. These results are consistent with the dengue notification records from the same region since 1995. Interpretation: Assuming that persons who have been monotypically exposed are at highest risk for severe dengue, the shift towards younger patient ages observed in Brazil can be partially explained by the accumulation of multitypic immunity against DENV-1, 2, and 3 in older age groups, 22 years after the re-introduction of these viruses. Serotype specific seroepidemiologic studies are necessary to accurately estimate the serotype specific forces of infection. Author Summary: The spread of dengue virus is a major public health problem. Though the burden of dengue has historically been concentrated in Southeast Asian countries, Brazil has become the country that reports the largest number of cases in the world. While prior to 2007 the disease affected mostly adults, during the 2007 epidemic the number of dengue hemorrhagic fever cases more than doubled, and over 53% of cases were in children under 15 years of age. In this paper, we propose that the conditions for the shift were being set gradually since the re-introduction of dengue in 1986 and that they represent the transition from re-emergence to hyperendemicity. Using data from an age stratified seroprevalence study conducted in Recife, we estimated the force of infection (a measure of transmission intensity) between 1986–2006 and used these estimates to simulate the accumulation of immunity since the re-emergence. As the length of time that dengue has circulated increases, adults have a lower probability of remaining susceptible to primary or secondary infection and thus, cases become on average younger. If in fact the shift represents the transition from re-emergence to hyperendemicity, similar shifts are likely to be observed in the rest of Brazil, the American continent and other regions where transmission emerges. [ABSTRACT FROM AUTHOR]

Background: Trachoma is the commonest infectious cause of blindness worldwide. Efforts are being made to eliminate trachoma as a public health problem globally. However, as prevalence decreases, it becomes more challenging to precisely predict prevalence. We demonstrate how model-based geostatistics (MBG) can be used as a reliable, efficient, and widely applicable tool to assess the elimination status of trachoma. Methods: We analysed trachoma surveillance data from Brazil, Malawi, and Niger. We developed geostatistical Binomial models to predict trachomatous inflammation—follicular (TF) and trachomatous trichiasis (TT) prevalence. We proposed a general framework to incorporate age and gender in the geostatistical models, whilst accounting for residual spatial and non-spatial variation in prevalence through the use of random effects. We also used predictive probabilities generated by the geostatistical models to quantify the likelihood of having achieved the elimination target in each evaluation unit (EU). Results: TF and TT prevalence varied considerably by country, with Brazil showing the lowest prevalence and Niger the highest. Brazil and Malawi are highly likely to have met the elimination criteria for TF in each EU, but, for some EUs, there was high uncertainty in relation to the elimination of TT according to the model alone. In Niger, the predicted prevalence varied significantly across EUs, with the probability of having achieved the elimination target ranging from values close to 0% to 100%, for both TF and TT. Conclusions: We demonstrated the wide applicability of MBG for trachoma programmes, using data from different epidemiological settings. Unlike the standard trachoma prevalence survey approach, MBG provides a more statistically rigorous way of quantifying uncertainty around the achievement of elimination prevalence targets, through the use of spatial correlation. In addition to the analysis of existing survey data, MBG also provides an approach to identify areas in which more sampling effort is needed to improve EU classification. We advocate MBG as the new standard method for analysing trachoma survey outputs. Author summary: Trachoma is the most common infectious cause of blindness worldwide. Achieving elimination in resource-limited settings requires pragmatic strategies, including determining the likelihood that the elimination prevalence targets have been reached. Model-based geostatistics (MBG) is a branch of spatial statistics that can underpin highly efficient methods for designing surveys and analysing surveillance data for NTD programmes. Here, we illustrate the application of the MBG framework to analyse trachoma surveillance data from Brazil, Malawi, and Niger. Using the elimination criteria set by WHO, we predict the likelihood of elimination thresholds for trachomatous inflammation—follicular (TF) and trachomatous trichiasis (TT) having been achieved in each evaluation unit in each of the three countries. MBG is a statistically rigorous approach to quantify the likelihood around the exceedance of elimination prevalence thresholds. By providing a way to identify areas where there is more uncertainty about the achievement of elimination, MBG could be used to select areas in which more intensive sampling efforts should be undertaken. [ABSTRACT FROM AUTHOR]

Opportunistic scorpion species can colonize urban environments, establishing high-density communities that enhance the chances of human accidents. This scenario has been taking place in Brazil, in which some Tityus species have taken city centers, causing an explosion in the number of scorpion envenoming cases. The characteristics of this scorpionism epidemic in Brazil is discussed in the present work. The number of Brazilian scorpion stings has surpassed 120,000 cases in 2017, and has been maintained above this number ever since, representing a more than 3-fold increase in 10 years, which was higher than the number of cases for most of the neglected tropical diseases in the country. The escalation in scorpionism cases is even higher in some regions of Brazil. Fortunately, the proportion of mild cases has also increased in the analyzed period, as well as the number of victims seeking for medical attention within the first hour after the accident. The species Tityus serrulatus, Tityus stigmurus, Tityus bahiensis, and Tityus obscurus are traditionally accountable for most of the scorpion accidents in different regions of Brazil, but other species deserve to be closely watched. Despite scorpionism being a notable health problem in Brazil, accident prevention and pest control regarding this venomous animal have not been properly addressed by the scientific community nor by policy makers. Therefore, this review also aims to point possible fields of research that could help to contain the aggravation of the current scorpionism landscape in Brazil. Author summary: The presence of scorpions in Brazilian urban centers has been increasing over the last decade and has led to an important augmentation in the number of human accidents in this country. This review aimed to better understand this scorpionism epidemic in Brazil, analyzing the evolution and dynamics of the accidents per region, the victim's profile, and the outcomes of the resulting reported cases. The main scorpion species related to these accidents were reviewed, but emerging threatening species are also pointed and discussed. Considering this current medical emergency, it would be expected to have more preventive measures being proposed by the political and scientific community, but this has not been observed. Therefore, this work also suggests different fields that could be important points of action to reduce and contain problems related to scorpionism. These recommendations ranges from improvements in housing and education in all levels to chemical, biological, and genetic forms of control of scorpion populations. The effort made in this review intended to call attention to the scorpion problem in Brazil and to be part of the solution. [ABSTRACT FROM AUTHOR]

Background: Mucosal or mucocutaneous leishmaniasis is the most severe form of tegumentary leishmaniasis due to its destructive character and potential damage to respiratory and digestive tracts. The current treatment recommendations are based on low or very low-quality evidence, and pentavalent antimonial derivatives remain strongly recommended. The aim of this review was to update the evidence and estimate the cure rate and safety profile of the therapeutic options available for mucosal leishmaniasis (ML) in the Americas. Methodology: A systematic review was conducted in four different databases and by different reviewers, independently, to evaluate the therapeutic efficacy and toxicity associated with different treatments for ML. All original studies reporting cure rates in more than 10 patients from American regions were included, without restriction of design, language, or publication date. The risk of bias was assessed by two reviewers, using different tools according to the study design. The pooled cure rate based on the latest cure assessment reported in the original studies was calculated grouping all study arms addressing the same intervention. The protocol for this review was registered at the International Prospective Register of Systematic Reviews, PROSPERO: CRD42019130708. Principal findings: Twenty-seven original studies from four databases fulfilled the selection criteria. A total of 1,666 patients with ML were treated predominantly with pentavalent antimonials in Brazil. Other interventions, such as pentamidine, miltefosine, imidazoles, aminosidine sulfate, deoxycholate and lipidic formulations of amphotericin B (liposomal, lipid complex, colloidal dispersion), in addition to combinations with pentoxifylline, allopurinol or sulfa were also considered. In general, at least one domain with a high risk of bias was identified in the included studies, suggesting low methodological quality. The pooled cure rate based on the latest cure assessment reported in the original studies was calculated grouping all study arms addressing the same intervention. It was confirmed that antimony is still the most used treatment for ML, with only moderate efficacy (possibly increased by combining with pentoxifylline). There is already evidence for the use of miltefosine for ML, with a cure rate similar to antimony, as observed in the only direct meta-analysis including 57 patients (OR: 1.2; 0.43–3.49, I2 = 0). It was possible to gather all descriptions available about adverse events reported during ML treatment, and the toxicity reflected the pattern informed in the manufacturers' technical information. Conclusions: This study provides an overview of the clinical experience in the Americas related to ML treatment and points out interventions and possible combinations that are eligible to be explored in future well-designed studies. Author summary: Mucosal leishmaniasis (ML) is a deforming leishmaniasis clinical form related to functional damage and stigmatization. This disease is caused mainly by L. braziliensis and predominates in neglected populations in the Americas, where approximately 2000 cases occur per year. There are few ML clinical trials, which makes the current treatment supported by fragile scientific evidence. In this study, we carried out an extensive literature search to gather the accumulated evidence for ML treatment. Twenty-seven studies with different designs were included with a total of 1,666 patients with ML treated. The results confirmed that antimony is still the main drug used for ML treatment, with only a moderate cure rate, an efficacy possibly increased by pentoxifylline combination. Miltefosine was found to be an alternative, with a cure rate similar to antimonials standard doses. In turn, the high toxicity of amphotericin B deoxycholate was clearly demonstrated, generating low cure rates due to early interruption of treatment. Other alternatives such as pentamidine, imidazoles, and aminosidine, were evaluated in a small number of cases and presented variable cure rates. The quality of the studies is low, and there is great heterogeneity in the definitions of cure, which limits a global analysis of the data. More and well-designed studies are needed to guide ML treatment recommendations. [ABSTRACT FROM AUTHOR]

This study aimed to assess the prevalence of non-use of health services in the last year by people with Chagas disease (CD) in an endemic area in Brazil and the contextual and individual factors associated with this non-use. This is a multilevel study that considered contextual and individual data. Contextual data were collected from official publicly accessible databases of the Brazilian government, at the municipal level. The individual data came from the first follow-up of a Brazilian cohort that assessed patients with CD in 21 municipalities in endemic area for the disease. The sample consisted of 1,160 individuals with CD. The dependent variable "use of health services in the last year" was categorized as yes vs. no. The analysis was performed using Poisson regression with robust variance. The prevalence of non-use of health services in the last year was 23.5% (IC95%: 21.1–25.9). The contextual factor "larger population" (PR: 1.6; 95% CI = 1.2–2.0) and individual factors related to the lower severity of the disease as a functional class without limitations (PR: 1.6; 95% CI = 1.2–2.1) and unaltered N-terminal pro b-type natriuretic peptide levels (PR: 2.2; 95% CI = 1.3–3.6) increased the prevalence of non-use of the health service in the last year by people with CD. The results of this study showed that individual determinants are not isolated protagonists of the non-use of health services in the last year by people with CD, which reinforces the need for public policies that consider the contextual determinants of the use of health services by populations affected by the disease. Author summary: Chagas disease (CD) is a parasitic infection caused by Trypanosoma cruzi (T. cruzi) that predominantly affects poor and vulnerable populations. It is estimated that around six million people are infected with T. cruzi, most of them in endemic areas of Latin American countries. It is recommended that individuals with CD be followed up by health services through one to two medical consultations per year. Identifying groups of people with CD who are more vulnerable in relation to their health status, whether due to the unavailability of health services or the types of behavior that lead to the non-use of available services, can contribute to reducing morbidity and mortality from the disease. Our study evaluated the prevalence of non-use of health services in the last year by 1,160 people with CD in an endemic area in Brazil and the contextual and individual factors associated with this non-use. The study results showed that almost a quarter of these patients had not had a medical appointment in the last year. "Living in cities with a larger population" and "having a lower severity of the disease" influenced the non-use of the health service in the last year by these patients. These results reinforce the need for public policies that consider the contextual determinants of the use of health services by populations affected by the disease. [ABSTRACT FROM AUTHOR]

The dengue virus affects millions of people every year worldwide, causing large epidemic outbreaks that disrupt people's lives and severely strain healthcare systems. In the absence of a reliable vaccine against dengue or an effective treatment to manage the illness in humans, most efforts to combat dengue infections have focused on preventing its vectors, mainly the Aedes aegypti mosquito, from flourishing across the world. These mosquito-control strategies need reliable disease activity surveillance systems to be deployed. Despite significant efforts to estimate dengue incidence using a variety of data sources and methods, little work has been done to understand the relative contribution of the different data sources to improved prediction. Additionally, scholarship on the topic had initially focused on prediction systems at the national- and state-levels, and much remains to be done at the finer spatial resolutions at which health policy interventions often occur. We develop a methodological framework to assess and compare dengue incidence estimates at the city level, and evaluate the performance of a collection of models on 20 different cities in Brazil. The data sources we use towards this end are weekly incidence counts from prior years (seasonal autoregressive terms), weekly-aggregated weather variables, and real-time internet search data. We find that both random forest-based models and LASSO regression-based models effectively leverage these multiple data sources to produce accurate predictions, and that while the performance between them is comparable on average, the former method produces fewer extreme outliers, and can thus be considered more robust. For real-time predictions that assume long delays (6–8 weeks) in the availability of epidemiological data, we find that real-time internet search data are the strongest predictors of dengue incidence, whereas for predictions that assume short delays (1–3 weeks), in which the error rate is halved (as measured by relative RMSE), short-term and seasonal autocorrelation are the dominant predictors. Despite the difficulties inherent to city-level prediction, our framework achieves meaningful and actionable estimates across cities with different demographic, geographic and epidemic characteristics. Author summary: As the incidence of infectious diseases like dengue continues to increase throughout the world, tracking their spread in real time poses a significant challenge to local and national health authorities. Accurate incidence data are often difficult to obtain as outbreaks emerge and unfold, both due the partial reach of serological surveillance (especially in rural areas), and due to delays in reporting, which result in post-hoc adjustments to what should have been real-time data. Thus, a range of 'nowcasting' tools have been developed to estimate disease trends, using different mathematical and statistical methodologies to fill the temporal data gap. Over the past several years, researchers have investigated how to best incorporate internet search data into predictive models, since these can be obtained in real-time. Still, most such models have been regression-based, and have tended to underperform in cases when epidemiological data are only available after long reporting delays. Moreover, in tropical countries, attention has increasingly turned from testing and applying models at the national level to models at higher spatial resolutions, such as states and cities. Here, we develop machine learning models based on both LASSO regression and on random forest ensembles, and proceed to apply and compare them across 20 cities in Brazil. We find that our methodology produces meaningful and actionable disease estimates at the city level with both underlying model classes, and that the two perform comparably across most metrics, although the ensemble method produces fewer outliers. We also compare model performance and the relative contribution of different data sources across diverse geographic, demographic and epidemic conditions. [ABSTRACT FROM AUTHOR]

Background: Yellow fever (YF) is an arboviral disease which is endemic to Brazil due to a sylvatic transmission cycle maintained by infected mosquito vectors, non-human primate (NHP) hosts, and humans. Despite the existence of an effective vaccine, recent sporadic YF epidemics have underscored concerns about sylvatic vector surveillance, as very little is known about their spatial distribution. Here, we model and map the environmental suitability of YF's main vectors in Brazil, Haemagogus spp. and Sabethes spp., and use human population and NHP data to identify locations prone to transmission and spillover risk. Methodology/Principal findings: We compiled a comprehensive set of occurrence records on Hg. janthinomys, Hg. leucocelaenus, and Sabethes spp. from 1991–2019 using primary and secondary data sources. Linking these data with selected environmental and land-cover variables, we adopted a stacked regression ensemble modelling approach (elastic-net regularized GLM, extreme gradient boosted regression trees, and random forest) to predict the environmental suitability of these species across Brazil at a 1x1 km resolution. We show that while suitability for each species varies spatially, high suitability for all species was predicted in the Southeastern region where recent outbreaks have occurred. By integrating data on NHP host reservoirs and human populations, our risk maps further highlight municipalities within the region that are prone to transmission and spillover. Conclusions/Significance: Our maps of sylvatic vector suitability can help elucidate potential locations of sylvatic reservoirs and be used as a tool to help mitigate risk of future YF outbreaks and assist in vector surveillance. Furthermore, at-risk regions identified from our work could help disease control and elucidate gaps in vaccination coverage and NHP host surveillance. Author summary: Yellow fever virus (YFV) is an arbovirus transmitted to humans from mosquitoes and can lead to severe disease and death. Recent sporadic outbreaks coupled with low vaccination coverage have highlighted the importance of mosquito surveillance for preventing future outbreaks and potential virus spillover into dense urban areas. Yet, very little is known about the spatial distribution of mosquitoes known to transmit YFV and the factors that contribute to their environmental suitability in Brazil. We compiled an occurrence database of primary and secondary mosquito vectors belonging to Haemagogus and Sabethes species' collected between 1991–2019 and integrated this data with environmental and land-use data to predict their spatial suitability at 1x1km resolution. Using this information, we identified suitable regions for their co-existence. We overlaid this information with human population density and locations of non-human primate host reservoirs to identify areas at risk of transmission and spillover. Our study provides high-resolution mapping tools to assist with mosquito and arbovirus surveillance which is especially useful in low-resource settings. [ABSTRACT FROM AUTHOR]

Background: Brazil faced a yellow fever(YF) outbreak in 2016–2018 and vaccination was considered for autoimmune rheumatic disease patients(ARD) with low immunosuppression due to YF high mortality. Objective: This study aimed to evaluate, prospectively for the first time, the short-term immunogenicity of the fractional YF vaccine(YFV) immunization in ARD patients with low immunossupression. Objective: Methodology and principal findings: A total of 318 participants(159 ARD and 159 age- and sex-matched healthy controls) were vaccinated with the fractional-dose(one fifth) of 17DD-YFV. All subjects were evaluated at entry(D0), D5, D10, and D30 post-vaccination for clinical/laboratory and disease activity parameters for ARD patients. Post-vaccination seroconversion rate(83.7%vs.96.6%, p = 0.0006) and geometric mean titers(GMT) of neutralizing antibodies[1143.7 (95%CI 1012.3–1292.2) vs.731 (95%CI 593.6–900.2), p<0.001] were significantly lower in ARD compared to controls. A lower positivity rate of viremia was also identified for ARD patients compared to controls at D5 (53%vs.70%, p = 0.005) and the levels persisted in D10 for patients and reduced for controls(51%vs.19%, p = 0.0001). The viremia was the only variable associated with seroconvertion. No serious adverse events were reported. ARD disease activity parameters remained stable at D30(p>0.05). Objective: Conclusion: Fractional-dose 17DD-YF vaccine in ARD patients resulted in a high rate of seroconversion rate(>80%) but lower than controls, with a longer but less intense viremia. This vaccine was immunogenic, safe and did not induce flares in ARD under low immunosuppression and may be indicated in YF outbreak situations and for patients who live or travel to endemic areas. Trial registration: This clinical trial was registered with Clinicaltrials.gov (#NCT03430388). Author summary: Yellow fever is a viral hemorragic fever with high mortality rate and the vaccine is a remarkably successful way of preventing it. As a live attenuated virus vaccine, it isnot recommended for rheumatic and other immunossupressed patients in general. However, in an outbreak scenario, the risk of dying of the disease can be higher than the risk of a vaccine serious adverse event. In 2018, the fractional-dose yellow fever vaccine was offered to the hospital employees and to the rheumatic patients without or with low immunossupression therapy in Hospital das Clinicas of University of São Paulo, during the yellow fever outbreak in São Paulo, Brazil. In order to optimize the yellow fever vaccine (YFV) supply, the fractional-dose (corresponding to one fifth) was adopted in the public vaccine campaign. This is the first study evaluating the primary vaccination with fractional-dose YFV in autoimmune rheumatic diseases(ARD) patients (n = 159) under low immunosuppression. Most vaccinated participants were able to produce enough neutralizing antibodies to be protected against yellow fever (seroconversion rate of 84% versus 96% in healthy controls). Neither activity of the rheumatic disease or serious adverse event was identified during the 30 days of followup after the vaccination. [ABSTRACT FROM AUTHOR]

Background: Leishmania (Viannia) braziliensis is a parasite recognized as the most important etiologic agent of mucosal leishmaniasis (ML) in the New World. In Amazonia, seven different species of Leishmania, etiologic agents of human Cutaneous Leishmaniasis, have been described. Isolated cases of ML have been described for several different species of Leishmania: L. (V.) panamensis, L. (V.) guyanensis and L. (L.) amazonensis. Methodology: Leishmania species were characterized by polymerase chain reaction (PCR) of tissues taken from mucosal biopsies of Amazonian patients who were diagnosed with ML and treated at the Tropical Medicine Foundation of Amazonas (FMTAM) in Manaus, Amazonas state, Brazil. Samples were obtained retrospectively from the pathology laboratory and prospectively from patients attending the aforementioned tertiary care unit. Results: This study reports 46 cases of ML along with their geographical origin, 30 cases caused by L. (V.) braziliensis and 16 cases by L. (V.) guyanensis. This is the first record of ML cases in 16 different municipalities in the state of Amazonas and of simultaneous detection of both species in 4 municipalities of this state. It is also the first record of ML caused by L. (V.) guyanensis in the states of Pará, Acre, and Rondônia and cases of ML caused by L. (V.) braziliensis in the state of Rondônia. Conclusions/Significance: L. (V.) braziliensis is the predominant species that causes ML in the Amazon region. However, contrary to previous studies, L. (V.) guyanensis is also a significant causative agent of ML within the region. The clinical and epidemiological expression of ML in the Manaus region is similar to the rest of the country, although the majority of ML cases are found south of the Amazon River. [ABSTRACT FROM AUTHOR]

Objective: Chagas disease (CD) globalization facilitated the co-infection with Human Immunodeficiency Virus (HIV) in endemic and non-endemic areas. Considering the underestimation of Trypanosoma cruzi (T. cruzi)-HIV co-infection and the risk of life-threatening Chagas Disease Reactivation (CDR), this study aimed to analyze the major co-infection clinical characteristics and its mortality rates. Methods: This is a cross-sectional retrospective multicenter study of patients with CD confirmed by two serological or one parasitological tests, and HIV infection confirmed by immunoblot. CDR was diagnosed by direct microscopy with detection of trypomastigote forms in the blood or other biological fluids and/or amastigote forms in inflammatory lesions. Results: Out of 241 patients with co-infection, 86.7% were from Brazil, 47.5% had <200 CD4+ T cells/μL and median viral load was 17,000 copies/μL. Sixty CDR cases were observed. Death was more frequent in patients with reactivation and was mainly caused by CDR. Other causes of death unrelated to CDR were the manifestation of opportunistic infections in those with Acquired Immunodeficiency Syndrome. The time between the co-infection diagnosis to death was shorter in patients with CDR. Lower CD4+ cells count at co-infection diagnosis was independently associated with reactivation. Similarly, lower CD4+ cells numbers at co-infection diagnosis and male sex were associated with higher lethality in CDR. Additionally, CD4+ cells were lower in meningoencephalitis than in myocarditis and milder forms. Conclusion: This study showed major features on T. cruzi-HIV co-infection and highlighted the prognostic role of CD4+ cells for reactivation and mortality. Since lethality was high in meningoencephalitis and all untreated patients died shortly after the diagnosis, early diagnosis, immediate antiparasitic treatment, patient follow-up and epidemiological surveillance are essentials in T. cruzi/HIV co-infection and CDR managements. Author summary: Chagas disease (CD) is a chronic infectious disease caused by the parasite T. cruzi that accounts for a major burden due to its life-lasting morbidity in endemic and non-endemic areas. Globalization facilitated the meeting of CD and Human Immunodeficiency Virus (HIV) infection (T. cruzi/HIV co-infection). Patients with this co-infection are at risk of life-threatening CDR. This study aimed to analyze the clinical characteristics and mortality rates of patients with T. cruzi/HIV co-infection. This retrospective multicenter study included 241 patients with co-infection, of those 60 with CDR. Death was more frequent in patients with reactivation and was mainly caused by CDR. Our data showed that co-infection diagnosis is close to the reactivation diagnosis and characterized by poor immune response associated to CDR, higher lethality and more severe forms of CDR (meningoencephalitis). This study emphasizes the prognostic role of CD4+ cells on reactivation and mortality and the need of epidemiological surveillance for co-infection and CDR. [ABSTRACT FROM AUTHOR]

Human T-cell lymphotropic viruses 1 and 2 (HTLV-1/2) are relatively common in Brazil but remain silent and neglected infections. HTLV-1 is associated with a range of diseases with high morbidity and mortality. There is no curative treatment for this lifelong infection, so measures to prevent transmission are essential. This narrative review discusses HTLV-1/2 transmission routes and measures to prevent its continuous dissemination. The public health policies that are currently implemented in Brazil to avoid HTLV-1/2 transmission are addressed, and further strategies are proposed. [ABSTRACT FROM AUTHOR]

Background: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a common enzyme deficiency, prevalent in many malaria-endemic countries. G6PD-deficient individuals are susceptible to hemolysis during oxidative stress, which can occur from exposure to certain medications, including 8-aminoquinolines used to treat Plasmodium vivax malaria. Accordingly, access to point-of-care (POC) G6PD testing in Brazil is critical for safe treatment of P. vivax malaria. Methodology/Principal findings: This study evaluated the performance of the semi-quantitative, POC STANDARD G6PD Test (SD Biosensor, Republic of Korea). Participants were recruited at clinics and through an enriched sample in Manaus and Porto Velho, Brazil. G6PD and hemoglobin measurements were obtained from capillary samples at the POC using the STANDARD and HemoCue 201+ (HemoCue AB, Sweden) tests. A thick blood slide was prepared for malaria microscopy. At the laboratories, the STANDARD and HemoCue tests were repeated on venous samples and a quantitative spectrophotometric G6PD reference assay was performed (Pointe Scientific, Canton, MI). G6PD was also assessed by fluorescent spot test. In Manaus, a complete blood count was performed. Samples were analyzed from 1,736 participants. In comparison to spectrophotometry, the STANDARD G6PD Test performed equivalently in determining G6PD status in venous and capillary specimens under varied operating temperatures. Using the manufacturer-recommended reference value thresholds, the test's sensitivity at the <30% threshold on both specimen types was 100% (95% confidence interval [CI] venous 93.6%–100.0%; capillary 93.8%–100.0%). Specificity was 98.6% on venous specimens (95% CI 97.9%–99.1%) and 97.8% on capillary (95% CI 97.0%–98.5%). At the 70% threshold, the test's sensitivity was 96.9% on venous specimens (95% CI 83.8%–99.9%) and 94.3% on capillary (95% CI 80.8%–99.3%). Specificity was 96.5% (95% CI 95.0%–97.6%) and 92.3% (95% CI 90.3%–94.0%) on venous and capillary specimens, respectively. Conclusion/Significance: The STANDARD G6PD Test is a promising tool to aid in POC detection of G6PD deficiency in Brazil. Trial registration: This study was registered with ClinicalTrials.gov (identifier: NCT04033640). Author summary: G6PD deficiency affects an estimated 500 million people worldwide and is prevalent in many malaria-endemic settings. People with G6PD deficiency are at risk of hemolysis when exposed to certain medications, including 8-aminoquinoline drugs used to treat Plasmodium vivax malaria. Increased access to testing for G6PD deficiency at or near the point of care is critical for expanding the safe treatment of P. vivax malaria. In this study, we aimed to evaluate the performance of a point-of-care, semi-quantitative test for G6PD deficiency, the STANDARD G6PD Test, in a malaria-endemic setting in Brazil. The test was evaluated on both capillary and venous blood samples across a broad range of operating temperatures. The findings show that the STANDARD G6PD Test performed equivalently to the reference test in its ability to diagnose G6PD deficiency at the point of care. The STANDARD G6PD Test is a promising tool to aid in detecting G6PD deficiency at the point of care in Brazil. [ABSTRACT FROM AUTHOR]

Visceral leishmaniasis (VL) is one of the most prevalent parasitic diseases worldwide. In 2019, 97% of the total numbers of cases in Latin America were reported in Brazil. In São Paulo state, currently 17.6% of infected individuals live in the western region. To study this neglected disease on a regional scale, we describe the spread of VL in 45 municipalities of the Regional Network for Health Assistance11(RNHA11). Environmental, human VL (HVL), and canine VL (CVL) cases, Human Development Index, and Lutzomyia longipalpis databases were obtained from public agencies. Global Moran's I index and local indicators of spatial association (LISA) statistics were used to identify spatial autocorrelation and to generate maps for the identification of VL clusters. On a local scale, we determined the spread of VL in the city of Teodoro Sampaio, part of the Pontal of Paranapanema. In Teodoro Sampaio, monthly peri-domicile sand fly collection; ELISA, IFAT and Rapid Test serological CVL; and ELISA HVL serum surveys were carried out. In RNHA11 from 2000 to 2018, Lu. longipalpis was found in 77.8%, CVL in 69%, and HVL in 42.2% of the 45 municipalities, and 537 individuals were notified with HVL. Dispersion occurred from the epicenter in the north to Teodoro Sampaio, in the south, where Lu. longipalpis and CVL were found in 2010, HVL in 2018, and critical hotspots of CVL were found in the periphery. Moran's Global Index showed a weak but statistically significant spatial autocorrelation related to cases of CVL (I = 0.2572), and 11 municipalities were identified as priority areas for implementing surveillance and control actions. In RNHA11, a complex array of socioeconomic and environmental factors may be fueling the epidemic and sustaining endemic transmission of VL, adding to the study of a neglected disease in a region of São Paulo, Brazil. Author summary: Visceral leishmaniasis (VL) is considered the second most important disease caused by a protozoan worldwide. Currently, 97% of the cases in Latin America are in Brazil. In São Paulo state, since 1997, the disease has been found in an increasing number of municipalities, mainly in the western region. The reasons why VL is spreading in a crescent shape in this region is not well understood, however, socioeconomic and environmental risk factors that increase vulnerability to the disease may be involved. From 2000 to 2018, vectors of Lutzomyia longipalpis were found in 77.8%, canine VL in 69%, and human VL in 44.4% of the 45 municipalities of the western region. Dispersion occurred from the epicenter in the north and followed central and radial highways, reaching Teodoro Sampaio in the south. Among the 45 municipalities, 11 were identified as priority areas for implementing surveillance and control actions. Considered the last frontier and one of the poorest regions of São Paulo, our findings are relevant for planning interventions aimed at reducing the cases of VL in the region. [ABSTRACT FROM AUTHOR]

The World Health Organization has raised concerns about the increasing number of Hansen disease (HD) relapses worldwide, especially in Brazil, India, and Indonesia that report the highest number of recurrent cases. Relapses are an indicator of MDT effectiveness and can reflect Mycobacterium leprae persistence or re-infection. Relapse is also a potential marker for the development or progression of disability. In this research, we studied a large cohort of persons affected by HD treated with full fixed-dose multibacillary (MB) multidrug therapy (MDT) followed for up to 20 years and observed that relapses are a rare event. We estimated the incidence density of relapse in a cohort of patients classified to receive MB regime (bacillary index (BI) > 0), diagnosed between September 1997 and June 2017, and treated with twelve-dose MB-MDT at a HD reference center in Rio de Janeiro, Brazil. We obtained the data from the data management system of the clinic routine service. We linked the selected cases to the dataset of relapses of the national HD data to confirm possible relapse cases diagnosed elsewhere. We diagnosed ten cases of relapse in a cohort of 713 patients followed-up for a mean of 12.1 years. This resulted in an incidence rate of 1.16 relapse cases per 1000 person-year (95% CI = 0.5915–2.076). The accumulated risk was 0.025 in 20 years. The very low risk observed in this cohort of twelve-dose-treated MB patients reinforces the success of the current MDT scheme. Author summary: People affected by Hansen disease that have many skin patches or lumps receive twelve-dose multibacillary multidrug therapy. After the fixed-dose regime, they are released from treatment and are considered cured. However, some of these people may have a recurrence of skin lesions or peripheral nerve problems after several years. Clinicians, scientists, and the World Health Organization are concerned about this problem, known as relapse, which seems to be increasing in countries where Hansen disease is common, especially in Brazil, India, and Indonesia. It is important to demonstrate regular proof that the therapy remains effective to treat people affected by Hansen disease. In this study, we showed that the recurrence of signs and symptoms of Hansen disease after the twelve-dose multibacillary treatment is rare. These findings are good evidence of the success of the current multibacillary scheme. [ABSTRACT FROM AUTHOR]

Background: Serological diagnosis of Zika virus (ZIKV) infection is challenging because of the antibody cross-reactivity among flaviviruses. At the same time, the role of Nucleic Acid Testing (NAT) is limited by the low proportion of symptomatic infections and the low average viral load. Here, we compared the diagnostic performance of commercially available IgM, IgAM, and IgG ELISAs in sequential samples during the ZIKV and chikungunya (CHIKV) epidemics and co-circulation of dengue virus (DENV) in Brazil and Venezuela. Methodology/Principal findings: Acute (day of illness 1–5) and follow-up (day of illness ≥ 6) blood samples were collected from nine hundred and seven symptomatic patients enrolled in a prospective multicenter study of symptomatic patients recruited between June 2012 and August 2016. Acute samples were tested by RT-PCR for ZIKV, DENV, and CHIKV. Acute and follow-up samples were tested for IgM, IgAM, and IgG antibodies to ZIKV using commercially available ELISAs. Among follow-up samples with a RT-PCR confirmed ZIKV infection, anti-ZIKV IgAM sensitivity was 93.5% (43/48), while IgM and IgG exhibited sensitivities of 30.3% (10/35) and 72% (18/25), respectively. An additional 24% (26/109) of ZIKV infections were detected via IgAM seroconversion in ZIKV/DENV/CHIKV RT-PCR negative patients. The specificity of anti-ZIKV IgM was estimated at 93% and that of IgAM at 85%. Conclusions/Significance: Our findings exemplify the challenges of the assessment of test performance for ZIKV serological tests in the real-world setting, during co-circulation of DENV, ZIKV, and CHIKV. However, we can also demonstrate that the IgAM immunoassay exhibits superior sensitivity to detect ZIKV RT-PCR confirmed infections compared to IgG and IgM immunoassays. The IgAM assay also proves to be promising for detection of anti-ZIKV seroconversions in sequential samples, both in ZIKV PCR-positive as well as PCR-negative patients, making this a candidate assay for serological monitoring of pregnant women in future ZIKV outbreaks. Author summary: Zika virus (ZIKV) is transmitted through the bite of infected Aedes mosquitos but can also be transmitted sexually or vertically from mother-to-child. The same mosquitoes transmit dengue virus (DENV) and chikungunya virus (CHIKV), which cause similar clinical syndromes. The ZIKV epidemics in the Pacific and the Americas that occurred between 2015 and 2017 were linked to congenital abnormalities, most prominently microcephaly, in newborns. Because most infections are asymptomatic, diagnosis via indirect serological assays is an important strategy. On the other hand, many serological assays are affected by cross-reactivity resulting from prior infections by closely related viruses, such as DENV. This study evaluated three commercially available and widely used immunoassays that detect IgG, IgM or IgA and M (IgAM) antibodies to ZIKV. Our results suggest that the IgAM test performs best by detecting around 90% of RT-PCR confirmed infections. We also detected additional infections that were not detected by RT-PCR. The strength of this study is that it was carried out in two different countries of the American region where several arboviruses are endemic and that sequential blood samples from individual patients were available to evaluate the performance of the tests over time. [ABSTRACT FROM AUTHOR]

Background: Antibody responses as serological markers of Plasmodium vivax infection have been shown to correlate with exposure, but little is known about the other factors that affect antibody responses in naturally infected people from endemic settings. To address this question, we studied IgG responses to novel serological exposure markers (SEMs) of P. vivax in three settings with different transmission intensity. Methodology: We validated a panel of 34 SEMs in a Peruvian cohort with up to three years' longitudinal follow-up using a multiplex platform and compared results to data from cohorts in Thailand and Brazil. Linear regression models were used to characterize the association between antibody responses and age, the number of detected blood-stage infections during follow-up, and time since previous infection. Receiver Operating Characteristic (ROC) analysis was used to test the performance of SEMs to identify P. vivax infections in the previous 9 months. Principal findings: Antibody titers were associated with age, the number of blood-stage infections, and time since previous P. vivax infection in all three study sites. The association between antibody titers and time since previous P. vivax infection was stronger in the low transmission settings of Thailand and Brazil compared to the higher transmission setting in Peru. Of the SEMs tested, antibody responses to RBP2b had the highest performance for classifying recent exposure in all sites, with area under the ROC curve (AUC) = 0.83 in Thailand, AUC = 0.79 in Brazil, and AUC = 0.68 in Peru. Conclusions: In low transmission settings, P. vivax SEMs can accurately identify individuals with recent blood-stage infections. In higher transmission settings, the accuracy of this approach diminishes substantially. We recommend using P. vivax SEMs in low transmission settings pursuing malaria elimination, but they are likely to be less effective in high transmission settings focused on malaria control. Author summary: Plasmodium vivax still poses a threat in many countries due to its ability to cause recurrent infections. Key to achieving the goal of malaria elimination is the ability to quickly detect and treat carriers of relapsing parasites. Failing to identify this transmission reservoir will hinder progress towards malaria elimination. Recently, novel serological markers of recent exposure to P. vivax (SEM) have been developed and validated in low transmission settings. It is still poorly understood what factors affect the antibody response to these markers when evaluated in contrasting endemic contexts. To determine the factors that influence the antibody response to SEM, we compared the antibody levels in three sites with different transmission intensity: Thailand (low), Brazil (moderate) and Peru (high). In this study, we found that transmission intensity plays a key role in the acquisition of the antibody repertoire to P. vivax. In highly endemic sites, it is likely that immunological memory resulting from a constant and sustained exposure will impact the performance of SEMs to detect individuals with recent exposure to P. vivax. In summary, SEMs that perform well in low transmission sites do not perform as well in high transmission regions. [ABSTRACT FROM AUTHOR]

Transmission foci of autochthonous malaria caused by Plasmodium vivax-like parasites have frequently been reported in the Atlantic Forest in Southeastern and Southern Brazil. Evidence suggests that malaria is a zoonosis in these areas as human infections by simian Plasmodium species have been detected, and the main vector of malaria in the Atlantic Forest, Anopheles (Kerteszia) cruzii, can blood feed on human and simian hosts. In view of the lack of models that seek to predict the dynamics of zoonotic transmission in this part of the Atlantic Forest, the present study proposes a new deterministic mathematical model that includes a transmission compartment for non-human primates and parameters that take into account vector displacement between the upper and lower forest strata. The effects of variations in the abundance and acrodendrophily of An. cruzii on the prevalence of infected humans in the study area and the basic reproduction number (R0) for malaria were analyzed. The model parameters are based on the literature and fitting of the empirical data. Simulations performed with the model indicate that (1) an increase in the abundance of the vector in relation to the total number of blood-seeking mosquitoes leads to an asymptotic increase in both the proportion of infected individuals at steady state and R0; (2) the proportion of infected humans at steady state is higher when displacement of the vector mosquito between the forest strata increases; and (3) in most scenarios, Plasmodium transmission cannot be sustained only between mosquitoes and humans, which implies that non-human primates play an important role in maintaining the transmission cycle. The proposed model contributes to a better understanding of the dynamics of malaria transmission in the Atlantic Forest. Author summary: The etiological agents of malaria are protozoa of the genus Plasmodium that are transmitted to humans and other vertebrate hosts by mosquitoes. In the Atlantic Forest in Southeastern and Southern Brazil, human infections by simian Plasmodium species have been detected, showing that in certain situations malaria can be transmitted zoonotically in this region. Anopheles cruzii, a sylvatic mosquito, is considered the main vector of malaria parasites in the Atlantic Forest. The fact that this species can feed on humans and monkeys reinforces the hypothesis of zoonotic transmission. Here we present a new mathematical model to explain the dynamics of zoonotic transmission of malaria in the Atlantic Forest. Simulations performed with the model showed that the prevalence of human cases and the basic reproduction number for malaria can be strongly influenced by variations in the abundance of An. cruzii and the frequency with which these mosquitoes move between the ground and the forest canopy to feed on humans and monkeys, respectively. The proposed model contributes to a better understanding of the dynamics of malaria transmission in the Atlantic Forest. [ABSTRACT FROM AUTHOR]

Vector control largely relies on neurotoxic chemicals, and insecticide resistance (IR) directly threatens their effectiveness. In some cases, specific alleles cause IR, and knowledge of the genetic diversity and gene flow among mosquito populations is crucial to track their arrival, rise, and spread. Here we evaluated Aedes aegypti populations' susceptibility status, collected in 2016 from six different municipalities of Rio de Janeiro state (RJ), to temephos, pyriproxyfen, malathion, and deltamethrin. We collected eggs of Ae. aegypti in Campos dos Goytacazes (Cgy), Itaperuna (Ipn), Iguaba Grande (Igg), Itaboraí (Ibr), Mangaratiba (Mgr), and Vassouras (Vsr). We followed the World Health Organization (WHO) guidelines and investigated the degree of susceptibility/resistance of mosquitoes to these insecticides. We used the Rockefeller strain as a susceptible positive control. We genotyped the V1016I and F1534C knockdown resistance (kdr) alleles using qPCR TaqMan SNP genotyping assay. Besides, with the use of Ae. aegypti SNP-chip, we performed genomic population analyses by genotyping more than 15,000 biallelic SNPs in mosquitoes from each population. We added previous data from populations from other countries to evaluate the ancestry of RJ populations. All RJ Ae. aegypti populations were susceptible to pyriproxyfen and malathion and highly resistant to deltamethrin. The resistance ratios for temephos was below 3,0 in Cgy, Ibr, and Igg populations, representing the lowest rates since IR monitoring started in this Brazilian region. We found the kdr alleles in high frequencies in all populations, partially justifying the observed resistance to pyrethroid. Population genetics analysis showed that Ae. aegypti revealed potential higher migration among some RJ localities and low genetic structure for most of them. Future population genetic studies, together with IR data in Ae aegypti on a broader scale, can help us predict the gene flow within and among the Brazilian States, allowing us to track the dynamics of arrival and changes in the frequency of IR alleles, providing critical information to improving vector control program. Author summary: Monitoring of insecticide resistance (IR) is mandatory for the effectiveness of vector control programs. We investigate six populations of Aedes aegypti regarding their IR status towards insecticides previously or currently in use, their frequency of IR alleles and resistance ratio, their genetic ancestry and structure, and the gene flow. We observed that Ae. aegypti populations from RJ are becoming susceptible to the larvicide organophosphate temephos. The resistance ratios of temephos are lower among populations where gene flow might be occurring. All RJ populations are highly resistant to deltamethrin, partially explained by the high frequency of kdr alleles. Besides, all populations are susceptible to pyriproxyfen's insect growth regulator and the organophosphate malathion. Population genomic analyses using more than 15,000 SNPs identified three potential genetic clusters within RJ populations, with higher gene flow to and out of the touristic region called Região dos Lagos. IR data, together with knowledge of the genetic structure and gene flow among different mosquito populations, can help with vector control program decisions. [ABSTRACT FROM AUTHOR]

Background: The rising incidence of visceral leishmaniasis due to Leishmania infantum requires novel methods to control transmission by the sand fly vector. Indoor residual spraying of insecticide (IRS) against these largely exophilic / exophagic vectors may not be the most effective method. A synthetic copy of the male sex-aggregation pheromone of the key vector species Lutzomyia longipalpis in the Americas, was co-located with residual pyrethroid insecticide, and tested for its effects on vector abundance, hence potential transmission, in a Brazilian community study. Methods: Houses within eight defined semi-urban blocks in an endemic municipality in Brazil were randomised to synthetic pheromone + insecticide or to placebo treatments. A similar number of houses located >100m from each block were placebo treated and considered as "True Controls" (thus, analysed as three trial arms). Insecticide was sprayed on a 2.6m2 surface area of the property boundary or outbuilding wall, co-located within one metre of 50mg synthetic pheromone in controlled-release dispensers. Vector numbers captured in nearby CDC light traps were recorded at monthly intervals over 3 months post intervention. Recruited sentinel houses under True Control and pheromone + insecticide treatments were similarly monitored at 7–9 day intervals. The intervention effects were estimated by mixed effects negative binomial models compared to the True Control group. Results: Dose-response field assays using 50mg of the synthetic pheromone captured a mean 4.8 (95% C.L.: 3.91, 5.80) to 6.3 (95% C.L.: 3.24, 12.11) times more vectors (female Lu. longipalpis) than using 10mg of synthetic pheromone. The intervention reduced household female vector abundance by 59% (C.L.: 48.7, 66.7%) (IRR = 0.41) estimated by the cross-sectional community study, and by 70% (C.L.: 56.7%, 78.8%) estimated by the longitudinal sentinel study. Similar reductions in male Lu. longipalpis were observed. Beneficial spill-over intervention effects were also observed at nearby untreated households with a mean reduction of 24% (95% C.L.: 0.050%, 39.8%) in female vectors. The spill-over effect in untreated houses was 44% (95% C.L.: 29.7%, 56.1%) as effective as the intervention in pheromone-treated houses. Ownership of chickens increased the intervention effects in both treated and untreated houses, attributed to the suspected synergistic attraction of the synthetic pheromone and chicken kairomones. The variation in IRR between study blocks was not associated with inter-household distances, household densities, or coverage (proportion of total households treated). Conclusions: The study confirms the entomological efficacy of the lure-and-kill method to reduce the abundance of this important sand fly vector in treated and untreated homesteads. The outcomes were achieved by low coverage and using only 1–2% of the quantity of insecticide as normally required for IRS, indicating the potential cost-effectiveness of this method. Implications for programmatic deployment of this vector control method are discussed. Author summary: The predominant sand fly vector of the intracellular parasite Leishmania infantum, that causes human and canine visceral leishmaniasis in the Americas, is Lutzomyia longipalpis. Vector control tools to reduce transmission are needed. A sex-aggregation pheromone released by male Lu. longipalpis attracts female conspecifics which facilitates blood-feeding and transmission. This study, conducted in Brazil, quantifies the effects of community deployment of a synthetic version of the sex-aggregation pheromone, in a controlled-release dispenser, and co-located with lethal insecticide applied to a small area of the household compound or outbuilding wall. 50mg synthetic pheromone dispensers were used since they attracted substantially more vectors than 10mg dispensers. Deploying this novel lure-and-kill method to houses in eight replicate study blocks in two suburban endemic areas, demonstrated that it reduces vector numbers at both pheromone + insecticide treated houses, and neighbouring untreated houses. The presence of chickens (a known additional attraction to blood-seeking female Lu. longipalpis) increased the beneficial effects of the intervention. The method used only 1–2% of the quantity of insecticide necessary for IRS for an average sized house. The results demonstrate the efficacy and potential cost-effectiveness of this novel lure-and-kill control method. [ABSTRACT FROM AUTHOR]