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Background In Brazil, many individuals with tuberculosis (TB) do not receive appropriate care due to delayed or missed diagnosis, ineffective treatment regimens, or loss-to-follow-up. This study aimed to estimate the health losses and TB program costs attributable to each gap in the care cascade for TB disease in Brazil. Methods and findings We constructed a Markov model simulating the TB care cascade and lifetime health outcomes (e.g., death, cure, postinfectious sequelae) for individuals developing TB disease in Brazil. We stratified the model by age, human immunodeficiency virus (HIV) status, drug resistance, state of residence, and disease severity, and developed a parallel model for individuals without TB that receive a false-positive TB diagnosis. Models were fit to data (adult and pediatric) from Brazil's Notifiable Diseases Information System (SINAN) and Mortality Information System (SIM) for 2018. Using these models, we assessed current program performance and simulated hypothetical scenarios that eliminated specific gaps in the care cascade, in order to quantify incremental health losses and TB diagnosis and treatment costs along the care cascade. TB-attributable disability-adjusted life years (DALYs) were calculated by comparing changes in survival and nonfatal disability to a no-TB counterfactual scenario. We estimated that 90.0% (95% uncertainty interval [UI]: 85.2 to 93.4) of individuals with TB disease initiated treatment and 10.0% (95% UI: 7.6 to 12.5) died with TB. The average number of TB-attributable DALYs per incident TB case varied across Brazil, ranging from 2.9 (95% UI: 2.3 to 3.6) DALYs in Acre to 4.0 (95% UI: 3.3 to 4.7) DALYs in Rio Grande do Sul (national average 3.5 [95% UI: 2.8 to 4.1]). Delayed diagnosis contributed the largest health losses along the care cascade, followed by post-TB sequelae and loss to follow up from TB treatment, with TB DALYs reduced by 71% (95% UI: 65 to 76), 41% (95% UI: 36 to 49), and 10% (95% UI: 7 to 16), respectively, when these factors were eliminated. Total health system costs were largely unaffected by improvements in the care cascade, with elimination of treatment failure reducing attributable costs by 3.1% (95% UI: 1.5 to 5.4). TB diagnosis and treatment of false-positive individuals accounted for 10.2% (95% UI: 3.9 to 21.7) of total programmatic costs but contributed minimally to health losses. Several assumptions were required to interpret programmatic data for the analysis, and we were unable to estimate the contribution of social factors to care cascade outcomes. Conclusions In this study, we observed that delays to diagnosis, post-disease sequelae and treatment loss to follow-up were primary contributors to the TB burden of disease in Brazil. Reducing delays to diagnosis, improving healthcare after TB cure, and reducing treatment loss to follow-up should be prioritized to improve the burden of TB disease in Brazil., Author(s): Sivaram Emani 1,*, Kleydson Alves 2, Layana Costa Alves 2, Daiane Alves da Silva 2, Patricia Bartholomay Oliveira 3, Marcia C. Castro 4, Ted Cohen 5, Rodrigo de Macedo [...]

Among the emerging and reemerging arboviral diseases, Zika, dengue and chikungunya deserve special attention due to their wide geographical distribution and clinical severity. The three arboviruses are transmitted by the same vector and can present similar clinical syndromes, bringing challenges to their identification and register. Demographic characteristics and individual and contextual social factors have been associated with the three arboviral diseases. However, little is known about such associations among adolescents, whose relationships with the social environment are different from those of adult populations, implying potentially different places, types, and degrees of exposure to the vector, particularly in the school context. This study aims to identify sociodemographic and environmental risk factors for the occurrence of Zika, dengue, and chikungunya in a cohort of adolescents from the Study of Cardiovascular Risks in Adolescents—ERICA—in the cities of Rio de Janeiro/RJ and Fortaleza/CE, from January 2015 to March 2019. Cases were defined as adolescents with laboratory or clinical-epidemiological diagnosis of Zika, dengue, or chikungunya, notified and registered in the Information System for Notifiable Diseases (SINAN). The cases were identified by linkage between the databases of the ERICA cohort and of SINAN. Multilevel Cox regression was employed to estimate hazard ratios (HR) as measures of association and respective 95% confidence intervals (95%CI). In comparison with adolescents living in lower socioeconomic conditions, the risk of becoming ill due to any of the three studied arboviral diseases was lower among those living in better socioeconomic conditions (HR = 0.43; 95%CI: 0.19–0.99; p = 0.047) and in the adolescents who attended school in the afternoon period (HR = 0.17; 95%CI: 0.06–0.47; p<0.001). When compared to areas whose Building Infestation Index (BII) for Aedes aegypti was considered satisfactory, a BII in the school region classified as "alert" and "risk" was associated with a higher risk of arboviral diseases (HR = 1.62, 95%CI: 0.98–2.70; p = 0.062; HR = 3.72, 95%CI: 1.27–10.9; p = 0.017, respectively). These findings indicate that living in less favored socioeconomic conditions, attending school in the morning, and having a high BII for Ae. aegypti in school's region can contribute to an increased risk of infection by Zika, dengue, or chikungunya in adolescents. The identification of residential or school areas based on those variables can contribute to the implementation of control measures in population groups and priority locations. Author summary: Zika, dengue, and chikungunya are arbovirus with a wide geographic distribution that can cause serious diseases. The three pathogens are transmitted by the same vector and can present similar symptoms, hindering their identification and register. Despite the great efforts to control arboviruses diseases, Brazil still registers frequently epidemics. Scientific evidence of the association of the environment, vectors, humans, and their behaviors in the arbovirus transmission is vast, but little in know about those association in adolescents. This study focused on adolescents, a part of the population whose relationships with the social environment are different from those of adult and child populations, implying different types, and degrees of exposure to the vector, particularly in the school context. For this reason, this study aims to identify sociodemographic and environmental factors associated with Zika, dengue, and chikungunya disease in adolescents in Rio de Janeiro and Fortaleza municipalities in Brazil from 2015 to 2019. The results obtained in this study highlight factors that may be influencing the transmission of Zika, dengue and Chikungunya, enabling effective measures to be implemented in the school context to control these arboviruses. [ABSTRACT FROM AUTHOR]

Background: The epidemiology of childhood SARS-CoV-2 infection and COVID-19-related illness remains little studied in high-transmission tropical settings, partly due to the less severe clinical manifestations typically developed by children and the limited availability of diagnostic tests. To address this knowledge gap, we investigate the prevalence and predictors of SARS-CoV-2 infection (either symptomatic or not) and disease in 5 years-old Amazonian children. Methodology/Principal findings: We retrospectively estimated SARS-CoV-2 attack rates and the proportion of infections leading to COVID-19-related illness among 660 participants in a population-based birth cohort study in the Juruá Valley, Amazonian Brazil. Children were physically examined, tested for SARS-CoV-2 IgG and IgM antibodies, and had a comprehensive health questionnaire administered during a follow-up visit at the age of 5 years carried out in January or June-July 2021. We found serological evidence of past SARS-CoV-2 infection in 297 (45.0%; 95% confidence interval [CI], 41.2–48.9%) of 660 cohort participants, but only 15 (5.1%; 95% CI, 2.9–8.2%) seropositive children had a prior medical diagnosis of COVID-19 reported by their mothers or guardians. The period prevalence of clinically apparent COVID-19, defined as the presence of specific antibodies plus one or more clinical symptoms suggestive of COVID-19 (cough, shortness of breath, and loss of taste or smell) reported by their mothers or guardians since the pandemic onset, was estimated at 7.3% (95% CI, 5.4–9.5%). Importantly, children from the poorest households and those with less educated mothers were significantly more likely to be seropositive, after controlling for potential confounders by mixed-effects multiple Poisson regression analysis. Likewise, the period prevalence of COVID-19 was 1.8-fold (95%, CI 1.2–2.6-fold) higher among cohort participants exposed to food insecurity and 3.0-fold (95% CI, 2.8–3.5-fold) higher among those born to non-White mothers. Finally, children exposed to household and family contacts who had COVID-19 were at an increased risk of being SARS-CoV-2 seropositive and–even more markedly–of having had clinically apparent COVID-19 by the age of 5 years. Conclusions/Significance: Childhood SARS-CoV-2 infection and COVID-19-associated illness are substantially underdiagnosed and underreported in the Amazon. Children in the most socioeconomically vulnerable households are disproportionately affected by SARS-CoV-2 infection and disease. Author summary: The epidemiology of childhood COVID-19 in the tropics remains a relatively neglected research topic, in part because SARS-CoV-2 typically causes fewer severe illnesses, hospitalizations, and deaths in children than in adults. Here we show that 45% of 660 participants in a birth cohort study in the Brazilian Amazon had SARS-CoV-2 antibodies at the age of 5 years, although only 5% of them reported previously diagnosed COVID-19 episodes–implying that as many as 8 in 9 SARS-CoV-2 infections had remained undiagnosed in these young children. Only 16% of the seropositive children had reportedly experienced cough, shortness of breath, and/or loss of taste or smell. The most socioeconomically vulnerable participants were more likely to have experienced SARS-CoV-2 infection and overt COVID-19 by the age of 5 years. Importantly, children exposed to household food insecurity, which affects 54% of our study participants, had their COVID-19 risk increased by 76%. [ABSTRACT FROM AUTHOR]

Compelling evidence supports the current international recommendation of at least 150 min/week of leisure-time physical activity (LTPA) during pregnancy. However, the potential relationship between LTPA and birth weight (BW) remains unclear in low- and middle-income countries. The purpose of this study was to examine the association between LTPA during pregnancy and offspring BW in an Amazonian population. Prospective cohort study was carried-out with 500 pregnant women and their offspring followed-up in the MINA-Brazil study, which was conducted in Cruzeiro do Sul, Western Brazilian Amazon. LTPA was assessed in the second (mean 19.6, SD 2.4 weeks) and third (mean 27.8, SD 1.6 weeks) gestational trimesters by a standardised interview and categorised according to the recommended cut-off of at least 150 min/week. We calculated offspring BW z-scores by sex and gestational age. We then explored the effect of LTPA during pregnancy on offspring BW, the association between LTPA and small-for-gestational-age (SGA) or large-for-gestational-age (LGA) births, and the mediating role of excessive and insufficient gestational weight gain (GWG). At least 150 min/week of LTPA during the third gestational trimester was associated with an offspring BW decrease of -0.35 z-score (95% CI: -0.65, -0.05) or -147.9 grams (95% CI: -260.9, -14.8), without increasing the frequency of SGA foetuses either in the second or third gestational trimester (p > 0.05). Excessive GWG mediated the effect of LTPA on the offspring BW (indirect effect = -0.05 z-score [95% CI: -0.10, -0.00] or -34.7 grams (95% CI: -66.1, -3.3]). This mediation effect was not observed for insufficient GWG. LTPA in the third, but not in the second, trimester of pregnancy was inversely associated with offspring BW without increasing the frequency of SGA, an effect that was partly mediated by excessive GWG. [ABSTRACT FROM AUTHOR]

Background Under-five mortality is declining in Ghana and many other countries. Very few studies have measured under-five mortality-and its social and environmental risk factors-at fine spatial resolutions, which is relevant for policy purposes. Our aim was to estimate under-five mortality and its social and environmental risk factors at the district level in Ghana. Methods and Findings We used 10% random samples of Ghana's 2000 and 2010 National Population and Housing Censuses. We applied indirect demographic methods and a Bayesian spatial model to the information on total number of children ever born and children surviving to estimate under-five mortality (probability of dying by 5 y of age, 5q0) for each of Ghana's 110 districts. We also used the census data to estimate the distributions of households or persons in each district in terms of fuel used for cooking, sanitation facility, drinking water source, and parental education. Median district 5q0 declined from 99 deaths per 1,000 live births in 2000 to 70 in 2010. The decline ranged from 40% in southern districts, where it had been lower in 2000, exacerbating existing inequalities. Primary education increased in men and women, and more households had access to improved water and sanitation and cleaner cooking fuels. Higher use of liquefied petroleum gas for cooking was associated with lower 5q0 in multivariate analysis. Conclusions Under-five mortality has declined in all of Ghana's districts, but the cross-district inequality in mortality has increased. There is a need for additional data, including on healthcare, and additional environmental and socioeconomic measurements, to understand the reasons for the variations in mortality levels and trends., Author(s): Raphael E. Arku 1, James E. Bennett 2,3, Marcia C. Castro 4, Kofi Agyeman-Duah 5, Samilia E. Mintah 5, James H. Ware 6, Philomena Nyarko 5, John D. Spengler [...]

Background: Malaria causes significant morbidity and mortality in children under 5 years of age in sub-Saharan Africa and the Asia-Pacific region. Neonates and young infants remain relatively protected from clinical disease and the transplacental transfer of maternal antibodies is hypothesized as one of the protective factors. The adverse health effects of Plasmodium vivax malaria in early childhood–traditionally viewed as a benign infection–remain largely neglected in relatively low-endemicity settings across the Amazon. Methodology/Principal findings: Overall, 1,539 children participating in a birth cohort study in the main transmission hotspot of Amazonian Brazil had a questionnaire administered, and blood sampled at the two-year follow-up visit. Only 7.1% of them experienced malaria confirmed by microscopy during their first 2 years of life– 89.1% of the infections were caused by P. vivax. Young infants appear to be little exposed to, or largely protected from infection, but children >12 months of age become as vulnerable to vivax malaria as their mothers. Few (1.4%) children experienced ≥4 infections during the 2-year follow-up, accounting for 43.4% of the overall malaria burden among study participants. Antenatal malaria diagnosed by microscopy during pregnancy or by PCR at delivery emerged as a significant correlate of subsequent risk of P. vivax infection in the offspring (incidence rate ratio, 2.58; P = 0.002), after adjusting for local transmission intensity. Anti-P. vivax antibodies measured at delivery do not protect mothers from subsequent malaria; whether maternal antibodies transferred to the fetus reduce early malaria risk in children remains undetermined. Finally, recent and repeated vivax malaria episodes in early childhood are associated with increased risk of anemia at the age of 2 years in this relatively low-endemicity setting. Conclusions/Significance: Antenatal infection increases the risk of vivax malaria in the offspring and repeated childhood P. vivax infections are associated with anemia at the age of 2 years. Author summary: Plasmodium vivax malaria causes frequent hospital admissions of infants and toddlers in areas of intense transmission in the Asia-Pacific region, often due to severe anemia, but its epidemiology and burden have been understudied in children from other endemic settings. Here we characterize the cumulative impact of P. vivax infections in infants and toddlers exposed to relatively low levels of malaria transmission in the Brazilian Amazon. We have previously shown that vivax malaria in pregnancy is associated with increased risk of maternal anemia and impaired fetal growth in this population. Now we show that the adverse effects of malaria extend to early childhood. Children born to mothers who had one or more infections during pregnancy are at an elevated risk of P. vivax malaria in their early life, although the transfer of maternal antibodies to the fetus may provide some short-term protection. Children who are repeatedly infected with P. vivax since birth are more likely to be anemic at the age of 2 years. These findings further challenge the traditional view of vivax malaria as a relatively benign infection in pregnancy and early childhood in the Amazon. [ABSTRACT FROM AUTHOR]

The mosquito-borne viruses dengue (DENV), Zika (ZIKV), and chikungunya (CHIKV), now co-endemic in the Americas, pose growing threats to health worldwide. However, it remains unclear whether there exist interactions between these viruses that could shape their epidemiology. This study advances knowledge by assessing the transmission dynamics of co-circulating DENV, ZIKV, and CHIKV in the city of Fortaleza, Brazil. Spatiotemporal transmission dynamics of DENV, ZIKV, and CHIKV were analyzed using georeferenced data on over 210,000 reported cases from 2011 to 2017 in Fortaleza, Brazil. Local spatial clustering tests and space-time scan statistics were used to compare transmission dynamics across all years. The transmission of co-circulating viruses in 2016 and 2017 was evaluated at fine spatial and temporal scales using a measure of spatiotemporal dependence, the τ-statistic. Results revealed differences in the diffusion of CHIKV compared to previous DENV epidemics and spatially distinct transmission of DENV/ZIKV and CHIKV during the period of their co-circulation. Significant spatial clustering of viruses of the same type was observed within 14-day time intervals at distances of up to 6.8 km (p<0.05). These results suggest that arbovirus risk is not uniformly distributed within cities during co-circulation. Findings may guide outbreak preparedness and response efforts by highlighting the clustered nature of transmission of co-circulating arboviruses at the neighborhood level. The potential for competitive interactions between the arboviruses should be further investigated. Author summary: Most of the global population is at risk of infection with dengue, Zika, and chikungunya viruses, all transmitted by the Aedes mosquitoes. Although these viruses now circulate together in the Americas, it is not known how, if at all, they might interact inside co-infected vectors or hosts. Such interactions could serve as important determinants of transmission in the context of co-circulation. We used seven years of surveillance data from Fortaleza, the fifth largest city in Brazil, to investigate the potential effects of co-circulation on the transmission dynamics of the three Aedes-borne viruses. We found that, during years with co-circulation, different families of viruses (dengue/Zika and chikungunya) clustered in distinct areas of the city. This spatial clustering of viruses of the same type was maintained even within narrow time intervals. Transmission patterns in epidemic years with co-circulation deviated from patterns in previous epidemic years. Our findings suggest that co-circulation may alter the transmission dynamics of these mosquito-borne viruses. Further research is needed to confirm any competitive interactions between the viruses and to establish evidence-based public health recommendations for concurrent outbreaks. [ABSTRACT FROM AUTHOR]

The Amazon is Brazil's greatest natural resource and invaluable to the rest of the world as a buffer against climate change. The recent election of Brazil's president brought disputes over development plans for the region back into the spotlight. Historically, the development model for the Amazon has focused on exploitation of natural resources, resulting in environmental degradation, particularly deforestation. Although considerable attention has focused on the long-term global cost of "losing the Amazon," too little attention has focused on the emergence and reemergence of vector-borne diseases that directly impact the local population, with spillover effects to other neighboring areas. We discuss the impact of Amazon development models on human health, with a focus on vector-borne disease risk. We outline policy actions that could mitigate these negative impacts while creating opportunities for environmentally sensitive economic activities. This Perspective article maintains that a development model for the Amazon must be bold, creative, carefully planned, and sustainable, explicitly acknowledging the importance of public health in reinforcing economic development, environmental protection, and land use change. [ABSTRACT FROM AUTHOR]

Symptomatic acute CHIKV infection is mainly characterized by high fever and severe joint pain (arthralgia) that can compromise daily life activities [[2]]. CHIKV infection and its complications can be the underlying cause of death or trigger a decompensation of preexisting medical conditions leading to a fatal outcome. Atypical Chikungunya virus infections: clinical manifestations, mortality and risk factors for severe disease during the 2005-2006 outbreak on Reunion. A major epidemic of chikungunya virus infection on Reunion Island, France, 2005-2006. [Extracted from the article]

Early life feeding practices can directly affect the growth, development, and survival of a child. This study aimed to estimate the frequency of and factors associated with exclusive breastfeeding (EBF) in the first month of life among Amazonian infants. We used data of 1,523 mother-child pairs of the MINA-Brazil birth cohort study. Mothers were interviewed soon after delivery at baseline and by telephone at 30–45 days postpartum (n = 962, 63.2% of those eligible). Kaplan-Meier survival analysis and accelerated failure-time (AFT) models were used to estimate the probability of EBF and the factors associated with EBF duration in the first month. At 30 days of age, 36.7% of the studied population (95% confidence interval [CI] 33.6–39.8) were exclusively breastfed, with a median duration of 16 days. Considering all eligible children for follow-up, the probability of EBF in the first month was 43.7% (95% CI 40.4–46.8), and the median duration was 30 days. The duration of EBF (time-ratio, TR) was 28% longer among multiparous mothers (TR 1.28; 95% CI 1.11–1.48). The use of a pacifier and the occurrence of wheezing were associated with a reduced EBF duration by 33% (TR 0.67; 95% CI 0.58–0.77) and 19% (TR 0.80; 95% CI 0.70–0.93), respectively. These results highlight that EBF among children in the Brazilian Amazon is considerably below international recommendations, and indicate the immediate need to plan and implement actions to promote and support breastfeeding early in life. [ABSTRACT FROM AUTHOR]

Nutrition during pregnancy is one of the key elements to good maternal and child health, as well as to lifetime landmarks. However, many pregnant women go undernourished in less developed settings. The purpose of this study was to estimate the prevalence and factors associated with gestational night blindness (GXN) and maternal anemia in a cross-sectional population-based study in Cruzeiro do Sul, Acre State, Western Brazilian Amazon. All women living in the municipality admitted at the only maternity-hospital in the city to delivery of a singleton infant were eligible to this study (n = 1,525). Recruitment of participants took place between July 2015 to June 2016. GXN was assessed in the postpartum period by WHO standardized interview. Maternal anemia was defined as hemoglobin at delivery < 110.0 g/L. We estimated prevalence rates and adjusted prevalence ratios (aPR), alongside 95% confidence intervals (95% CI), of the factors associated with the outcomes through multiple Poisson regression models with robust variance. Alarming prevalence of GXN (11.5%; 95% CI, 9.97–13.25) and maternal anemia (39.4%; 95% CI, 36.84–41.95) were found. Factors associated with GXN were (aPR; 95% CI): ≥ 5 residents in the household (2.06; 1.24–3.41), smoking during pregnancy (1.78; 1.15–2.78), and attending < 6 antenatal care visits (1.61; 1.08–2.40). Factors associated with maternal anemia were (aPR; 95% CI): maternal age < 19 years (1.18; 1.01–1.38), gestational malaria (1.22; 1.01–1.49), not taking micronutrient supplements during pregnancy (1.27; 1.01–1.62), and attending < 6 antenatal care visits (1.40; 1.15–1.70). High prevalence rates of GXN and maternal anemia in these postpartum women may reflect poor assistance during antenatal care, underlying the importance of rethinking current protocols related to nutrition in pregnancy. [ABSTRACT FROM AUTHOR]

Background: After being eliminated during the 1950s, dengue reemerged in Brazil in the 1980s. Since then, incidence of the disease has increased, as serotypes move within and between cities. The co-circulation of multiple serotypes contributes to cycles of epidemic and interepidemic years, and a seasonal pattern of transmission is observed annually. Little is known regarding possible differences in the epidemiology of dengue under epidemic and interepidemic scenarios. This study addresses this gap and aims to assess the epidemiological characteristics and determinants of epidemic and interepidemic dengue transmission, utilizing data from the 5th largest city in Brazil (Fortaleza), at fine spatial and temporal scales. Methods/Principal findings: Longitudinal models of monthly rates of confirmed dengue cases were used to estimate the differential contribution of contextual factors to dengue transmission in Fortaleza between 2011 and 2015. Models were stratified by annual climatological schedules and periods of interepidemic and epidemic transmission, controlling for social, economic, structural, entomological, and environmental factors. Results revealed distinct seasonal patterns between interepidemic and epidemic years, with persistent transmission after June in interepidemic years. Dengue was strongly associated with violence across strata, and with poverty and irregular garbage collection during periods of low transmission, but not with other indicators of public service provision or structural deprivation. Scrapyards and sites associated with tire storage were linked to incidence differentially between seasons, with the strongest associations during transitional precipitation periods. Hierarchical clustering analysis suggests that the dengue burden concentrates in the southern periphery of the city, particularly during periods of minimal transmission. Conclusions/Significance: Our findings have direct programmatic implications. Vector control operations must be sustained after June even in non-epidemic years. More specifically, scrapyards and sites associated with tires (strongly associated with incidence during periods of minimal transmission), require sustained entomological surveillance, particularly during interepidemic intervals and in the urban periphery. Intersectoral collaborations that address urban violence are critical for facilitating the regular activities of vector control agents. [ABSTRACT FROM AUTHOR]

Family Health Strategy, the primary health care program in Brazil, has been scaled up throughout the country, but its expansion has been heterogeneous across municipalities. We investigate if there are unique municipal characteristics that can explain the timing of uptake and the pattern of expansion of the Family Health Strategy from years 1998 to 2012. We categorized municipalities in six groups based on the relative speed of the Family Health Strategy uptake and the pattern of Family Health Strategy coverage expansion. We assembled data for 11 indicators for years 2000 and 2010, for 5,507 municipalities, and assessed differences in indicators across the six groups, which we mapped to examine spatial heterogeneities. Important factors differentiating early and late adopters of the Family Health Strategy were supply of doctors and population density. Sustained coverage expansion was related mainly to population size, marginal benefits of the program and doctors’ supply. The uptake was widespread nationwide with no distinct patterns among regions, but highly heterogeneous at the state and municipal level. The Brazilian experience of expanding primary health care offers three lessons in relation to factors influencing diffusion of primary health care. First, the funding mechanism is critical for program implementation, and must be accompanied by ways to support the supply of primary care physicians in low density areas. Second, in more developed and bigger areas the main challenge is lack of incentives to pursue universal coverage, especially due to the availability of private insurance. Third, population size is a crucial element to guarantee coverage sustainability over time. [ABSTRACT FROM AUTHOR]

Methodology to estimate malaria incidence rates from a commonly occurring form of interval-censored longitudinal parasitological data—specifically, 2-wave panel data—was first proposed 40 years ago based on the theory of continuous-time homogeneous Markov Chains. Assumptions of the methodology were suitable for settings with high malaria transmission in the absence of control measures, but are violated in areas experiencing fast decline or that have achieved very low transmission. No further developments that can accommodate such violations have been put forth since then. We extend previous work and propose a new methodology to estimate malaria incidence rates from 2-wave panel data, utilizing the class of 2-component mixtures of continuous-time Markov chains, representing two sub-populations with distinct behavior/attitude towards malaria prevention and treatment. Model identification, or even partial identification, requires context-specific a priori constraints on parameters. The method can be applied to scenarios of any transmission intensity. We provide an application utilizing data from Dar es Salaam, an area that experienced steady decline in malaria over almost five years after a larviciding intervention. We conducted sensitivity analysis to account for possible sampling variation in input data and model assumptions/parameters, and we considered differences in estimates due to submicroscopic infections. Results showed that, assuming defensible a priori constraints on model parameters, most of the uncertainty in the estimated incidence rates was due to sampling variation, not to partial identifiability of the mixture model for the case at hand. Differences between microscopy- and PCR-based rates depend on the transmission intensity. Leveraging on a method to estimate incidence rates from 2-wave panel data under any transmission intensity, and from the increasing availability of such data, there is an opportunity to foster further methodological developments, particularly focused on partial identifiability and the diversity of a priori parameter constraints associated with different human-ecosystem interfaces. As a consequence there can be more nuanced planning and evaluation of malaria control programs than heretofore. [ABSTRACT FROM AUTHOR]

Background: To evaluate the effect of insecticide spraying for vector control and elimination of infected dogs on the incidence of human infection with L. infantum, a randomized community intervention trial was carried out in the city of Teresina, Brazil. Methods/Principal Findings: Within each of ten localities in the city, four blocks were selected and randomized to 4 interventions: 1) spraying houses and animal pens with insecticide; 2) eliminating infected dogs; 3) combination of spraying and eliminating dogs, and 4) nothing. The main outcome is the incidence of infection assessed by the conversion of the Montenegro skin test (MST) after 18 months of follow-up in residents aged ≥1 year with no previous history of visceral leishmaniasis (VL). Reactions were measured at 48–72 h, induration of ≥5 mm considered positive. Interventions were executed after the baseline interview and repeated 6 and 12 months later. The effects of each type of intervention scheme on the incidence of infection were assessed by calculating relative risks and 95% confidence intervals using Poisson population-averaged regression models with robust variance. Among the 1105 participants, 408 (37%) were MST positive at baseline. Of the 697 negatives, only 423 (61%) were reexamined at the end of the follow-up; 151 (36%) of them converted to a positive MST. Only dog culling had some statistically significant effect on reducing the incidence of infection, with estimates of effectiveness varying between 27% and 52%, depending on the type of analysis performed. Conclusions/Significance: In light of the continuous spread of VL in Brazil despite the large scale deployment of insecticide spraying and dog culling, the relatively low to moderate effectiveness of dog culling and the non-significant effect of insecticide spraying on the incidence of human infection, we conclude that there is an urgent need for revision of the Brazilian VL control program. Author Summary: Zoonotic visceral leishmaniasis (VL) constitutes a serious public health problem in the Americas, particularly in Brazil. The disease is caused by the protozoan parasite Leishmania infantum, which is transmitted by the bite of female sand flies, and dogs are the main source of infection. To decrease the risk of transmission, the Brazilian VL control program recommends residual insecticide spraying and environmental management for vector control, and culling of seropositive dogs in areas with moderate to high levels of transmission. Because there is a lack of scientific evidence supporting such interventions, we designed a study to assess the effectiveness of dog culling and residual insecticide spraying in the reduction of incidence of human VL infection. The results show that only dog culling had some statistically significant effect on reducing the incidence of infection, with estimates of effectiveness varying between 27% and 52%. In light of the continuous spread of VL in Brazil despite the large scale deployment of insecticide spraying and dog culling, the relatively low to moderate effectiveness of dog culling and the non-significant effect of insecticide spraying on the incidence of human infection, we conclude that there is an urgent need for revision of the Brazilian VL control program. [ABSTRACT FROM AUTHOR]

Background: All four serotypes of dengue virus are endemic in Indonesia, where the population at risk for infection exceeds 200 million people. Despite continuous control efforts that were initiated more than four decades ago, Indonesia still suffers from multi-annual cycles of dengue outbreak and dengue remains as a major public health problem. Dengue vaccines have been viewed as a promising solution for controlling dengue in Indonesia, but thus far its potential acceptability has not been assessed. Methodology/Principal Findings: We conducted a household survey in the city of Bandung, Indonesia by administering a questionnaire to examine (i) acceptance of a hypothetical pediatric dengue vaccine; (ii) participant's willingness-to-pay (WTP) for the vaccine, had it not been provided for free; and (iii) whether people think vector control would be unnecessary if the vaccine was available. A proportional odds model and an interval regression model were employed to identify determinants of acceptance and WTP, respectively. We demonstrated that out of 500 heads of household being interviewed, 94.2% would agree to vaccinate their children with the vaccine. Of all participants, 94.6% were willing to pay for the vaccine with a median WTP of US$1.94. In addition, 7.2% stated that vector control would not be necessary had there been a dengue vaccination program. Conclusions/Significance: Our results suggest that future dengue vaccines can have a very high uptake even when delivered through the private market. This, however, can be influenced by vaccine characteristics and price. In addition, reduction in community vector control efforts may be observed following vaccine introduction but its potential impact in the transmission of dengue and other vector-borne diseases requires further study. Author Summary: While methods for vector control such as mosquito breeding source reduction and focal insecticide spraying that have been practiced to reduce dengue transmission in Indonesia have had limited success, dengue vaccines are expected to be an effective control method. However, even if an efficacious vaccine is developed, public acceptance and viable financing mechanisms are crucial for a successful introduction and sustainability of a new vaccination program. In this paper, we report public acceptance and willingness-to-pay for a hypothetical dengue vaccine for children that would be made available in the future. We found a very high proportion of surveyed participants, more than ninety-four percent, were willing to accept and pay for the vaccine. These findings provide a strong support for a dengue vaccination program. On the other hand, we also found a small possibility of reduction in vector control efforts if a dengue vaccination program is put in place. This could have a potential to increase the transmission of other vector-borne diseases and should be taken into account when introducing a dengue vaccination program. [ABSTRACT FROM AUTHOR]

Background: Malaria burden in Brazil has reached its lowest levels in 35 years and Plasmodium vivax now accounts for 84% of cases countrywide. Targeting residual malaria transmission entrenched in the Amazon is the next major challenge for ongoing elimination efforts. Better strategies are urgently needed to address the vast reservoir of asymptomatic P. vivax carriers in this and other areas approaching malaria elimination. Methods: We evaluated a reactive case detection (RCD) strategy tailored for P. vivax transmission in farming settlements in the Amazon Basin of Brazil. Over six months, 41 cases detected by passive surveillance triggered four rounds of RCD (0, 30, 60, and 180 days after index case enrollment), using microscopy- and quantitative real-time polymerase chain reaction (qPCR)-based diagnosis, comprising subjects sharing the household (HH) with the index case (n = 163), those living in the 5 nearest HHs within 3 km (n = 878), and individuals from 5 randomly chosen control HHs located > 5 km away from index cases (n = 841). Correlates of infection were identified with mixed-effects logistic regression models. Molecular genotyping was used to infer local parasite transmission networks. Principal findings/Conclusions Subjects in index and neighbor HHs were significantly more likely to be parasitemic than control HH members, after adjusting for potential confounders, and together harbored > 90% of the P. vivax biomass in study subjects. Clustering patterns were temporally stable. Four rounds of microscopy-based RCD would identify only 49.5% of the infections diagnosed by qPCR, but 76.8% of the total parasite biomass circulating in the proximity of index HHs. However, control HHs accounted for 27.6% of qPCR-positive samples, 92.6% of them from asymptomatic carriers beyond the reach of RCD. Molecular genotyping revealed high P. vivax diversity, consistent with complex transmission networks and multiple sources of infection within clusters, potentially complicating malaria elimination efforts.

Background: The use of larval source management is not prioritized by contemporary malaria control programs in sub-Saharan Africa despite historical success. Larviciding, in particular, could be effective in urban areas where transmission is focal and accessibility to Anopheles breeding habitats is generally easier than in rural settings. The objective of this study is to assess the effectiveness of a community-based microbial larviciding intervention to reduce the prevalence of malaria infection in Dar es Salaam, United Republic of Tanzania. Methods and Findings: Larviciding was implemented in 3 out of 15 targeted wards of Dar es Salaam in 2006 after two years of baseline data collection. This intervention was subsequently scaled up to 9 wards a year later, and to all 15 targeted wards in 2008. Continuous randomized cluster sampling of malaria prevalence and socio-demographic characteristics was carried out during 6 survey rounds (2004–2008), which included both cross-sectional and longitudinal data (N = 64,537). Bayesian random effects logistic regression models were used to quantify the effect of the intervention on malaria prevalence at the individual level. Effect size estimates suggest a significant protective effect of the larviciding intervention. After adjustment for confounders, the odds of individuals living in areas treated with larviciding being infected with malaria were 21% lower (Odds Ratio = 0.79; 95% Credible Intervals: 0.66–0.93) than those who lived in areas not treated. The larviciding intervention was most effective during dry seasons and had synergistic effects with other protective measures such as use of insecticide-treated bed nets and house proofing (i.e., complete ceiling or window screens). Conclusion: A large-scale community-based larviciding intervention significantly reduced the prevalence of malaria infection in urban Dar es Salaam. [ABSTRACT FROM AUTHOR]

Background: Dar es Salaam has an extensive drain network, mostly with inadequate water flow, blocked by waste, causing flooding after rainfall. The presence of Anopheles and Culex larvae is common, which is likely to impact the transmission of lymphatic filariasis and malaria by the resulting adult mosquito populations. However, the importance of drains as larval habitats remains unknown. Methodology: Data on mosquito larval habitats routinely collected by the Urban Malaria Control Program (UMCP) and a special drain survey conducted in 2006 were used to obtain a typology of habitats. Focusing on drains, logistic regression was used to evaluate potential factors impacting the presence of mosquito larvae. Spatial variation in the proportion of habitats that contained larvae was assessed through the local Moran's I indicator of spatial association. Principal Findings: More than 70% of larval habitats in Dar es Salaam were human-made. Aquatic habitats associated with agriculture had the highest proportion of Anopheles larvae presence and the second highest of Culex larvae presence. However, the majority of aquatic habitats were drains (42%), and therefore, 43% (1,364/3,149) of all culicine and 33% (320/976) of all anopheline positive habitats were drains. Compared with drains where water was flowing at normal velocity, the odds of finding Anopheles and Culex larvae were 8.8 and 6.3 (p<0.001) times larger, respectively, in drains with stagnant water. There was a positive association between vegetation and the presence of mosquito larvae (p<0.001). The proportion of habitats with mosquito larvae was spatially correlated. Conclusion: Restoring and maintaining drains in Dar es Salaam has the potential to eliminate more than 40% of all potential mosquito larval habitats that are currently treated with larvicides by the UMCP. The importance of human-made larval habitats for both lymphatic filariasis and malaria vectors underscores the need for a synergy between on-going control efforts of those diseases. Author Summary: Lymphatic filariasis and malaria are endemic in Dar es Salaam and partially share common vectors, but no synergy exists between their control programs. The vast majority of mosquito breeding habitats in the city is human-made, and therefore could be mitigated through the implementation of a community-based vector control program accompanied by an educational campaign to sensitize the population and promote behavior change. Of particular importance are clogged drains and ditches with stagnant water, which are the most common larval habitat in the city. This problem could be addressed by an environmental management intervention in order to restore and maintain the functionality of drains. Such intervention can potentially contribute to reduce vector-borne disease transmission, but also promote an overall healthier environment, particularly improving the situation of those living under slum conditions, as proposed by the Millennium Development Goal 7. A synergy between efforts to control lymphatic filariasis and malaria, identifying common strategies, combining monitoring activities, optimizing the use of limited financial resources, and carefully evaluating the cost-effectiveness of the joint venture would not only contribute to current goals of lymphatic filariasis and malaria elimination, but also provide important lessons for future integrated control efforts. [ABSTRACT FROM AUTHOR]

Background: New frontier settlements across the Amazon Basin pose a major challenge for malaria elimination in Brazil. Here we describe the epidemiology of malaria during the early phases of occupation of farming settlements in Remansinho area, Brazilian Amazonia. We examine the relative contribution of low-density and asymptomatic parasitemias to the overall Plasmodium vivax burden over a period of declining transmission and discuss potential hurdles for malaria elimination in Remansinho and similar settings. Methods: Eight community-wide cross-sectional surveys, involving 584 subjects, were carried out in Remansinho over 3 years and complemented by active and passive surveillance of febrile illnesses between the surveys. We used quantitative PCR to detect low-density asexual parasitemias and gametocytemias missed by conventional microscopy. Mixed-effects multiple logistic regression models were used to characterize independent risk factors for P. vivax infection and disease. Principal Findings/Conclusions P. vivax prevalence decreased from 23.8% (March–April 2010) to 3.0% (April–May 2013), with no P. falciparum infections diagnosed after March–April 2011. Although migrants from malaria-free areas were at increased risk of malaria, their odds of having P. vivax infection and disease decreased by 2–3% with each year of residence in Amazonia. Several findings indicate that low-density and asymptomatic P. vivax parasitemias may complicate residual malaria elimination in Remansinho: (a) the proportion of subpatent infections (i.e. missed by microscopy) increased from 43.8% to 73.1% as P. vivax transmission declined; (b) most (56.6%) P. vivax infections were asymptomatic and 32.8% of them were both subpatent and asymptomatic; (c) asymptomatic parasite carriers accounted for 54.4% of the total P. vivax biomass in the host population; (d) over 90% subpatent and asymptomatic P. vivax had PCR-detectable gametocytemias; and (e) few (17.0%) asymptomatic and subpatent P. vivax infections that were left untreated progressed to clinical disease over 6 weeks of follow-up and became detectable by routine malaria surveillance.

Background: As a result of poor economic opportunities and an increasing shortage of affordable housing, much of the spatial growth in many of the world's fastest-growing cities is a result of the expansion of informal settlements where residents live without security of tenure and with limited access to basic infrastructure. Although inadequate water and sanitation facilities, crowding and other poor living conditions can have a significant impact on the spread of infectious diseases, analyses relating these diseases to ongoing global urbanization, especially at the neighborhood and household level in informal settlements, have been infrequent. To begin to address this deficiency, we analyzed urban environmental data and the burden of cholera in Dar es Salaam, Tanzania. Methodology/Principal Findings: Cholera incidence was examined in relation to the percentage of a ward's residents who were informal, the percentage of a ward's informal residents without an improved water source, the percentage of a ward's informal residents without improved sanitation, distance to the nearest cholera treatment facility, population density, median asset index score in informal areas, and presence or absence of major roads. We found that cholera incidence was most closely associated with informal housing, population density, and the income level of informal residents. Using data available in this study, our model would suggest nearly a one percent increase in cholera incidence for every percentage point increase in informal residents, approximately a two percent increase in cholera incidence for every increase in population density of 1000 people per km2 in Dar es Salaam in 2006, and close to a fifty percent decrease in cholera incidence in wards where informal residents had minimally improved income levels, as measured by ownership of a radio or CD player on average, in comparison to wards where informal residents did not own any items about which they were asked. In this study, the range of access to improved sanitation and improved water sources was quite narrow at the ward level, limiting our ability to discern relationships between these variables and cholera incidence. Analysis at the individual household level for these variables would be of interest. Conclusions/Significance: Our results suggest that ongoing global urbanization coupled with urban poverty will be associated with increased risks for certain infectious diseases, such as cholera, underscoring the need for improved infrastructure and planning as the world's urban population continues to expand.

Human mobility has challenged malaria elimination efforts and remains difficult to routinely track. In Brazil, administrative records from the Ministry of Health allow monitoring of mobility locally and internationally. Although most imported malaria cases are between municipalities in Brazil, detailed knowledge of patterns of mobility is limited. Here, we address this gap by quantifying and describing patterns of malaria-infected individuals across the Amazon. We used network analysis, spatial clustering, and linear models to quantify and characterize the movement of malaria cases in Brazil between 2004 and 2022. We identified sources and sinks of malaria within and between states. We found that between-state movement of cases has become proportionally more important than within-state, that source clusters persisted longer than sink clusters, that movement of cases into sinks was seasonal while movement out of sources was not, and that importation is an impediment for subnational elimination in many municipalities. We elucidate the vast travel networks of malaria infected individuals that characterize the Amazon region. Uncovering patterns of malaria case mobility is vital for effective microstratification within Brazil. Our results have implications for intervention stratification across Brazil in line with the country's goal of malaria elimination by 2035., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Arisco et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Congenital syphilis (CS) is a significant public health problem in Brazil. Despite efforts to increase syphilis testing and treatment among pregnant women, rates of CS in the country remain high. We conducted a retrospective case-control study to identify potential associations between the mothers' sociodemographic characteristics, clinical factors related to the current and previous pregnancies, and the occurrence of CS among newborns in Fortaleza, a populous city with one of the highest incidences of CS in Brazil. Data from newborns diagnosed with CS between 2017 and 2020 were extracted from SINAN, the national database for notifiable diseases. Data from women who had delivered an infant with CS were extracted from SINASC, the national database for registration of live births, and linked with their infant's data. CS cases and non-CS controls were matched by year of birth at a ratio of 1:3 respectively. Potential associations were estimated using a multivariate regression model accounting for sociodemographic, obstetric, and antenatal care-related factors. Epidemiological data from 8,744 live births were included in the analysis, including 2,186 cases and 6,588 controls. The final multivariate regression model identified increased odds of delivering an infant with CS among pregnant women and girls aged below 20 years (OR 1.29), single women (OR 1.48), women who had less than 8 years of formal education (OR 2.42), women who delivered in a public hospital (OR 6.92), women who had more than 4 previous pregnancies (OR 1.60), and women who had one or more prior fetal loss (OR 1.19). The odds of delivering an infant with CS also increased as the number of antenatal visits decreased. Women who did not attend any antenatal visits had 3.94 times the odds of delivering an infant with CS compared to women who attended 7 or more visits. Our study found that increased odds of delivering an infant with CS were highly associated with factors related to socioeconomic vulnerability. These determinants not only affect the access to essential antenatal care services, but also the continuity and quality of such preventive measures. Future policies aimed at reducing the incidence of CS should not only target those pregnant women and adolescents with identifiable risk factors for testing, but also assure high quality care, treatment and follow-up for this group., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Etti et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Reliable subnational estimates of TB incidence would allow national policy makers to focus disease control resources in areas of highest need. We developed an approach for generating small area estimates of TB incidence, and the fraction of individuals missed by routine case detection, based on available notification and mortality data. We demonstrate the feasibility of this approach by creating municipality-level burden estimates for Brazil. We developed a mathematical model describing the relationship between TB incidence and TB case notifications and deaths, allowing for known biases in each of these data sources. We embedded this model in a regression framework with spatial dependencies between local areas, and fitted the model to municipality-level case notifications and death records for Brazil during 2016-2018. We estimated outcomes for 5568 municipalities. Incidence rate ranged from 8.6 to 57.2 per 100,000 persons/year for 90% of municipalities, compared to 44.8 (95% UI: 43.3, 46.8) per 100,000 persons/year nationally. Incidence was concentrated geographically, with 1% of municipalities accounting for 50% of incident TB. The estimated fraction of incident TB cases receiving diagnosis and treatment ranged from 0.73 to 0.95 across municipalities (compared to 0.86 (0.82, 0.89) nationally), and the rate of untreated TB ranged from 0.8 to 72 cases per 100,000 persons/year (compared to 6.3 (4.8, 8.3) per 100,000 persons/year nationally). Granular disease burden estimates can be generated using routine data. These results reveal substantial subnational differences in disease burden and other metrics useful for designing high-impact TB control strategies., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 Chitwood et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

After a longstanding global presence, malaria is now largely non-existent or suppressed in most parts of the world. Today, cases and deaths are primarily concentrated in sub-Saharan Africa. According to many experts, this persistence on the African continent reflects factors such as resistance to insecticides and drugs as well as insufficient access to essential commodities such as insecticide-treated nets and effective drugs. Crucially, however, this narrative ignores many central weaknesses in the fight against malaria and instead reinforces a narrow, commodity-driven vision of disease control. This paper therefore describes the core challenges hindering malaria programs in Africa and highlights key opportunities to rethink current strategies for sustainable control and elimination. The epidemiology of malaria in Africa presents far greater challenges than elsewhere and requires context-specific initiatives tailored to national and sub-national targets. To sustain progress, African countries must systematically address key weaknesses in its health systems, improve the quality and use of data for surveillance-responses, improve both technical and leadership competencies for malaria control, and gradually reduce overreliance on commodities while expanding multisectoral initiatives such as improved housing and environmental sanitation. They must also leverage increased funding from both domestic and international sources, and support pivotal research and development efforts locally. Effective vaccines and drugs, or other potentially transformative technologies such as genedrive modified mosquitoes, could further accelerate malaria control by complementing current tools. However, our underlying strategies remain insufficient and must be expanded to include more holistic and context-specific approaches critical to achieve and sustain effective malaria control., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 Okumu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Despite considerable success in controlling malaria worldwide, progress toward achieving malaria elimination has largely stalled. In particular, strategies to overcome roadblocks in malaria control and elimination in Africa are critical to achieving worldwide malaria elimination goals-this continent carries 94% of the global malaria case burden. To identify key areas for targeted efforts, we combined a comprehensive review of current literature with direct feedback gathered from frontline malaria workers, leaders, and scholars from Africa. Our analysis identified deficiencies in human resources, training, and capacity building at all levels, from research and development to community involvement. Addressing these needs will require active and coordinated engagement of stakeholders as well as implementation of effective strategies, with malaria-endemic countries owning the relevant processes. This paper reports those valuable identified needs and their concomitant opportunities to accelerate progress toward the goals of the World Health Organization's Global Technical Strategy for Malaria 2016-2030. Ultimately, we underscore the critical need to re-think current approaches and expand concerted efforts toward increasing relevant human resources for health and capacity building at all levels if we are to develop the relevant competencies necessary to maintain current gains while accelerating momentum toward malaria control and elimination., Competing Interests: No competing interests., (Copyright: © 2022 Mwenesi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Family Health Strategy, the primary health care program in Brazil, has been scaled up throughout the country, but its expansion has been heterogeneous across municipalities. We investigate if there are unique municipal characteristics that can explain the timing of uptake and the pattern of expansion of the Family Health Strategy from years 1998 to 2012. We categorized municipalities in six groups based on the relative speed of the Family Health Strategy uptake and the pattern of Family Health Strategy coverage expansion. We assembled data for 11 indicators for years 2000 and 2010, for 5,507 municipalities, and assessed differences in indicators across the six groups, which we mapped to examine spatial heterogeneities. Important factors differentiating early and late adopters of the Family Health Strategy were supply of doctors and population density. Sustained coverage expansion was related mainly to population size, marginal benefits of the program and doctors' supply. The uptake was widespread nationwide with no distinct patterns among regions, but highly heterogeneous at the state and municipal level. The Brazilian experience of expanding primary health care offers three lessons in relation to factors influencing diffusion of primary health care. First, the funding mechanism is critical for program implementation, and must be accompanied by ways to support the supply of primary care physicians in low density areas. Second, in more developed and bigger areas the main challenge is lack of incentives to pursue universal coverage, especially due to the availability of private insurance. Third, population size is a crucial element to guarantee coverage sustainability over time., Competing Interests: The authors have declared that no competing interests exist.