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Background: We investigated perinatal outcomes among live births from international migrant and local-born mothers in a cohort of low-income individuals in Brazil., Methods: We linked nationwide birth registries to mortality records and socioeconomic data from the CIDACS Birth Cohort and studied singleton live births of women aged 10-49 years from 1 st January 2011 to 31 st December 2018. We used logistic regressions to investigate differences in antenatal care, adverse pregnancy outcomes, and neonatal (i.e., ≤28 days) mortality among international migrants compared to non-migrants in Brazil; and explored the interaction between migration, race/ethnicity and living in international border municipalities., Results: We studied 10,279,011 live births, of which 9469 (0.1 %) were born to international migrants. Migrant women were more likely than their Brazilian-born counterparts to have a previous foetal loss (ORadj: 1.16, 1.11-1.22), a delayed start of antenatal care (i.e., beyond 1st trimester) (1.22, 95%CI:1.16-1.28), a newborn who is large for gestational age (1.29, 1.22-1.36), or a newborn with congenital anomalies (1.37, 1.14-1.65). Conversely, migrant women were less likely to deliver prematurely (0.89, 0.82-0.95) or have a low birth weight infant (0.74, 0.68-0.81). There were no differences in neonatal mortality rates between migrants and non-migrants. Our analyses also showed that, when disparities in perinatal outcomes were present, disparities were mostly concentrated among indigenous mothers in international borders and among live births of Black mothers in non-borders., Conclusion: Although live births of international migrants generally have lower rates of adverse birth outcomes, our results suggest that indigenous and Black migrant mothers may face disproportionate barriers to accessing antenatal care., Competing Interests: Declaration of competing interest We declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Pneumonia is a major cause of morbidity and mortality in children, with pneumococcus as the main etiologic agent. In Brazil, the 10-valent pneumococcal conjugate vaccine (PCV-10) was introduced into the childhood immunization schedule in 2010. The aim of this study was to assess the impact caused by implementing PCV-10 on the hospitalizations of children with pneumonia, between 2005 and 2015, in the state of Pernambuco, Brazil. An ecological time series study and a forecasting analysis were conducted. A comparison was made between the hospitalizations of children aged between seven months and four years due to pneumonia in the Brazilian Unified Health System, in the 5 years before (2005-2009) and after (2011-2015) implementation of PCV-10. Descriptive analysis included absolute and relative values, means and rates of hospitalization. The chi-square test was used to compare the annual incidence of hospitalizations and the t-Student test to compare the five-year mean values. For the temporal modeling of hospitalizations, an autoregressive integrated moving average was used, adjusted with seasonal-SARIMA (Box-Jenkins methodology), with a prediction of the monthly number of hospitalizations for 2011-2015. The predicted and observed values for 2011-2015 were then compared. The number of hospitalizations after implementing PCV-10 was reduced by 24.5 %. The monthly average of hospitalizations dropped from 681 (2005-2009) to 514 (2011-2015). The hospitalization rate dropped from 56.1 per thousand live births in the five-year period prior to PCV-10 to 43.4 in the following five-year period (a 22.7% reduction). Comparing the values predicted by the SARIMA model for a scenario without PCV-10 in the second five-year period, with those reported after implementing PCV-10, the estimated number of prevented hospitalizations was 8,682 in the five years following the introduction of the vaccine. In conclusion, in the five years following implementation of PCV-10, hospitalizations of children with pneumonia in Pernambuco decrease by 22%., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The combined allergic rhinitis and asthma syndrome (CARAS) is a chronic airway inflammation of allergic individuals, with a type 2 immune response. Pharmacotherapy is based on drugs with relevant side effects. Thus, the goal of this study was to evaluate the synthetic alkaloid, MHTP in the experimental model of CARAS. Therefore, BALB/c mice were ovalbumin (OVA) -sensitized and -challenged and treated with MHTP by intranasal or oral routes. Treated animals showed a decrease (p < 0.05) of sneezing, nasal rubbings, and histamine nasal hyperactivity. Besides, MHTP presented binding energy and favorable interaction for adequate anchoring in the histamine H1 receptor. MHTP treatment inhibited the eosinophil migration into the nasal (NALF) and the bronchoalveolar (BALF) fluids. Histological analysis showed that the alkaloid decreased the inflammatory cells in the subepithelial and perivascular regions of nasal tissue and in the peribronchiolar and perivascular regions of lung tissue. The MHTP treatment also reduced the pulmonary hyperactivity by decreasing the smooth muscle layer hypertrophy and the collagen fiber deposition in the extracellular matrix. The immunomodulatory effect of the alkaloid was due to the decrease of cytokines like IL-5 and IL-17A (type 2 and 3), TSLP (epithelial), and the immunoregulatory cytokine, TGF-β. These MHTP effects on granulocytes were dependent on the p38/ERK1/2 MAP kinase signaling pathway axis. Indeed, the synthetic alkaloid reduced the frequency of activation of both kinases independent of the NF-κB (p65) pathway indicating that the molecule shut down the intracellular transduction signals underlie the cytokine gene transcription., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The abuse of stimulants such as amphetamine, methamphetamine, ecstasy (MDMA), and their analogues (MDEA and MDA) has been increasing considerably worldwide since 2009. In this work, an analytical method using dispersive liquid-liquid microextraction (DLLME) to determine amphetamine and derivatives in oral fluid samples by liquid chromatography-tandem mass spectrometry (LC-MS/MS) was developed and validated. Linearity was achieved between 20 to 5000 ng/mL (r>0.992, 1/x² weighted linear regression), with a limit of quantification (LOQ) of 20 ng/mL. Imprecision (%relative standard deviation) and bias (%) were not higher than 9.1 and -12.3%, respectively. The matrix effect was lower than 14.6%, with no carryover observed up to 5000 ng/mL and no interference with 10 different oral fluid matrix sources and against 14 pharmaceuticals and other common drugs of abuse. MDMA, MDA, and MDEA in processed samples were stable up to 24 h at autosampler (10°C); and amphetamine and methamphetamine up to 18 h. The developed method was successfully applied to authentic oral fluid analyses (n = 140). The proposed method is an example of the Green Analytical Toxicology, since it reduces both the amount of solvent required in samples preparation and the quantity of solvents and reagents used in analytical-instrumental stage, as well as requires a minimal sample volume, being a cheaper, quicker and more ecological alternative to conventional methods. Obtained results showed that DLLME extraction combined with LC-MS/MS is a fast and simple method to quantify amphetamine derivatives in oral fluid samples., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Indirect financial costs and barriers to health-care access might contribute to leprosy treatment non-adherence. We estimated the association of the Brazilian conditional cash transfer programme, the Programa Bolsa Família (PBF), on leprosy treatment adherence and cure in patients in Brazil., Methods: In this quasi-experimental study, we linked baseline demographic and socioeconomic information for individuals who entered the 100 Million Brazilian Cohort between Jan 1, 2007, and Dec 31, 2014, with the PBF payroll database and the Information System for Notifiable Diseases, which includes nationwide leprosy registries. Individuals were eligible for inclusion if they had a household member older than 15 years and had not received PBF aid or been diagnosed with leprosy before entering the 100 Million Brazilian Cohort; they were excluded if they were partial receivers of PBF benefits, had missing data, or had a monthly per-capita income greater than BRL200 (US$50). Individuals who were PBF beneficiaries before leprosy diagnosis were matched to those who were not beneficiaries through propensity-score matching (1:1) with replacement on the basis of baseline covariates, including sex, age, race or ethnicity, education, work, income, place of residence, and household characteristics. We used logistic regression to assess the average treatment effect on the treated of receipt of PBF benefits on leprosy treatment adherence (six or more multidrug therapy doses for paucibacillary cases or 12 or more doses for multibacillary cases) and cure in individuals of all ages. We stratified our analysis according to operational disease classification (paucibacillary or multibacillary). We also did a subgroup analysis of paediatric leprosy restricted to children aged up to 15 years., Findings: We included 11 456 new leprosy cases, of whom 8750 (76·3%) had received PBF before diagnosis and 2706 (23·6%) had not. Overall, 9508 (83·0%) patients adhered to treatment and 10 077 (88·0%) were cured. After propensity score matching, receiving PBF before diagnosis was associated with adherence to treatment (OR 1·22, 95% CI 1·01-1·48) and cure (1·26, 1·01-1·58). PBF receipt did not significantly improve treatment adherence (1·37, 0·98-1·91) or cure (1·12, 0·75-1·67) in patients with paucibacillary leprosy. For patients with multibacillary disease, PBF beneficiaries had better treatment adherence (1·37, 1·08-1·74) and cure (1·43, 1·09-1·90) than non-beneficiaries. In the propensity score-matched analysis in 2654 children younger than 15 years with leprosy, PBF exposure was not associated with leprosy treatment adherence (1·55, 0·89-2·68) or cure (1·57, 0·83-2·97)., Interpretation: Our results suggest that being a beneficiary of the PBF, which facilitates cash transfers and improved access to health care, is associated with greater leprosy multidrug therapy adherence and cure in multibacillary cases. These results are especially relevant for patients with multibacillary disease, who are treated for a longer period and have lower cure rates than those with paucibacillary disease., Funding: CONFAP/ESRC/MRC/BBSRC/CNPq/FAPDF-Doenças Negligenciadas, the UK Medical Research Council, the Wellcome Trust, and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior-Brazil (CAPES)., (Copyright © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Long-term survival and cause-specific mortality of patients who start tuberculosis treatment is rarely described. We aimed to assess the long-term survival of these patients and evaluate the association between vulnerable conditions (social, health behaviours, and comorbidities) and cause-specific mortality in a country with a high burden of tuberculosis., Methods: In this population-based, longitudinal study in São Paulo state, Brazil, we described the 5-year survival of patients who were newly diagnosed with tuberculosis in 2010. We included patients with newly-diagnosed tuberculosis, aged 15 years or older, and notified to the São Paulo State Tuberculosis Program in 2010. We excluded patients whose diagnosis had changed during follow-up (ie, they did not have tuberculosis) and patients who had multidrug-resistant (MDR) tuberculosis. We selected our population with tuberculosis from the dedicated electronic system TBweb. Our primary objective was to estimate the excess mortality over 5 years and within the group who survived the first year, compared with the general São Paulo state population. We also estimated the association between social vulnerability (imprisonment and homelessness), health behaviours (alcohol and drug use), and comorbidities (diabetes and mental disorders) with all-cause and cause-specific mortality. We used the competing risk analysis framework, estimating cause-specific hazard ratios (HRs) adjusted for potential confounding factors., Findings: In 2010, there were 19 252 notifications of tuberculosis cases. We excluded 550 cases as patients were younger than 15 years, 556 cases that were not tuberculosis, 2597 retreatments, and 48 cases of MDR tuberculosis, resulting in a final cohort of 15 501 patients with tuberculosis. Over a period of 5 years from tuberculosis diagnosis, 2660 (17%) of 15 501 patients died. Compared with the source population, matched by age, sex, and calendar year, the standardised mortality ratio was 6·47 (95% CI 6·22-6·73) over 5 years and 3·93 (3·71-4·17) among those who survived the first year. 1197 (45%) of 2660 deaths were due to infection. Homelessness and alcohol and drug use were associated with death from infection (adjusted cause-specific HR 1·60, 95% CI 1·39-1·85), cardiovascular (1·43, 1·06-1·95), and external or ill-defined causes of death (1·80, 1·37-2·36). Diabetes was associated with deaths from cardiovascular causes (1·70, 1·23-2·35)., Interpretation: Patients newly diagnosed with tuberculosis were at a higher risk of death than were the source population, even after tuberculosis treatment. Post-tuberculosis sequelae and vulnerability are associated with excess mortality and must be addressed to mitigate the tuberculosis burden worldwide., Funding: Wellcome Trust., (Copyright © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: A Zika virus epidemic emerged in northeast Brazil in 2015 and was followed by a striking increase in congenital microcephaly cases, triggering a declaration of an international public health emergency. This is the final report of the first case-control study evaluating the potential causes of microcephaly: congenital Zika virus infection, vaccines, and larvicides. The published preliminary report suggested a strong association between microcephaly and congenital Zika virus infection., Methods: We did a case-control study in eight public maternity hospitals in Recife, Brazil. Cases were neonates born with microcephaly, defined as a head circumference of 2 SD below the mean. Two controls without microcephaly were matched to each case by expected date of delivery and area of residence. We tested the serum of cases and controls and the CSF of cases for detection of Zika virus genomes with quantitative RT-PCR and for detection of IgM antibodies with capture-IgM ELISA. We also tested maternal serum with plaque reduction neutralisation assays for Zika and dengue viruses. We estimated matched crude and adjusted odds ratios with exact conditional logistic regression to determine the association between microcephaly and Zika virus infection., Findings: We screened neonates born between Jan 15 and Nov 30, 2016, and prospectively recruited 91 cases and 173 controls. In 32 (35%) cases, congenital Zika virus infection was confirmed by laboratory tests and no controls had confirmed Zika virus infections. 69 (83%) of 83 cases with known birthweight were small for gestational age, compared with eight (5%) of 173 controls. The overall matched odds ratio was 73·1 (95% CI 13·0-∞) for microcephaly and Zika virus infection after adjustments. Neither vaccination during pregnancy or use of the larvicide pyriproxyfen was associated with microcephaly. Results of laboratory tests for Zika virus and brain imaging results were available for 79 (87%) cases; within these cases, ten were positive for Zika virus and had cerebral abnormalities, 13 were positive for Zika infection but had no cerebral abnormalities, and 11 were negative for Zika virus but had cerebral abnormalities., Interpretation: The association between microcephaly and congenital Zika virus infection was confirmed. We provide evidence of the absence of an effect of other potential factors, such as exposure to pyriproxyfen or vaccines (tetanus, diphtheria, and acellular pertussis, measles and rubella, or measles, mumps, and rubella) during pregnancy, confirming the findings of an ecological study of pyriproxyfen in Pernambuco and previous studies on the safety of Tdap vaccine administration during pregnancy., Funding: Brazilian Ministry of Health, Pan American Health Organization, and Enhancing Research Activity in Epidemic Situations., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Microcephaly is an important sign of neurological malformation and a predictor of future disability. The 2015-16 outbreak of Zika virus and congenital Zika infection brought the world's attention to links between Zika infection and microcephaly. However, Zika virus is only one of the infectious causes of microcephaly and, although the contexts in which they occur vary greatly, all are of concern. In this Review, we summarise important aspects of major congenital infections that can cause microcephaly, and describe the epidemiology, transmission, clinical features, pathogenesis, management, and long-term consequences of these infections. We include infections that cause substantial impairment: cytomegalovirus, herpes simplex virus, rubella virus, Toxoplasma gondii, and Zika virus. We highlight potential issues with classification of microcephaly and show how some infants affected by congenital infection might be missed or incorrectly diagnosed. Although Zika virus has brought the attention of the world to the problem of microcephaly, prevention of all infectious causes of microcephaly and appropriately managing its consequences remain important global public health priorities., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Maternal infections during pregnancy can increase the risk of fetal death. Dengue infection is common, but little is known about its role in fetal mortality. We aimed to investigate the association between symptomatic dengue infection during pregnancy and fetal death., Methods: We did a nested case-control study using obstetrician-collected data from the Brazilian livebirth information system (SINASC), the mortality information system (SIM), and the national reportable disease information system (SINAN). We identified all pregnancies ending in stillbirth and a random sample of livebirths between Jan 1, 2006, and Dec 31, 2012. We did linkage to determine which mothers were diagnosed with dengue infection during pregnancy. By use of stillbirths as cases and a sample of matched livebirths as a control, we calculated matched odds ratios (mORs) using conditional logistic regression adjusted for maternal age and education., Findings: 275 (0·2%) of 162 188 women who had stillbirths and 1507 (0·1%) of 1 586 105 women who had livebirths were diagnosed with dengue infection during pregnancy. Symptomatic dengue infection during pregnancy almost doubled the odds of fetal death (mOR 1·9, 95% CI 1·6-2·2). The increase in risk was similar when analyses were restricted to laboratory-confirmed cases of dengue infection (1·8, 1·4-2·4). Severe dengue infection increased the risk of fetal death by about five times (4·9, 2·3-10·2)., Interpretation: Symptomatic dengue infection during pregnancy is associated with an increased risk of fetal death. We recommend further epidemiological and biological studies of the association between dengue and poor birth outcomes to measure the burden of subclinical infections and elucidate pathological mechanisms., Funding: Brazilian National Council for Scientific and Technological Development, Horizon 2020., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

The case-control methodology is frequently used to evaluate vaccine effectiveness post-licensure. The results of such studies provide important insight into the level of protection afforded by vaccines in a 'real world' context, and are commonly used to guide vaccine policy decisions. However, the potential for bias and confounding are important limitations to this method, and the results of a poorly conducted or incorrectly interpreted case-control study can mislead policies. In 2012, a group of experts met to review recent experience with case-control studies evaluating vaccine effectiveness; we summarize the recommendations of that group regarding best practices for data collection, analysis, and presentation of the results of case-control vaccine effectiveness studies. Vaccination status is the primary exposure of interest, but can be challenging to assess accurately and with minimal bias. Investigators should understand factors associated with vaccination as well as the availability of documented vaccination status in the study context; case-control studies may not be a valid method for evaluating vaccine effectiveness in settings where many children lack a documented immunization history. To avoid bias, it is essential to use the same methods and effort gathering vaccination data from cases and controls. Variables that may confound the association between illness and vaccination are also important to capture as completely as possible, and where relevant, adjust for in the analysis according to the analytic plan. In presenting results from case-control vaccine effectiveness studies, investigators should describe enrollment among eligible cases and controls as well as the proportion with no documented vaccine history. Emphasis should be placed on confidence intervals, rather than point estimates, of vaccine effectiveness. Case-control studies are a useful approach for evaluating vaccine effectiveness; however careful attention must be paid to the collection, analysis and presentation of the data in order to best inform evidence-based vaccine policies., (Published by Elsevier Ltd.)

Case-control studies are commonly used to evaluate effectiveness of licensed vaccines after deployment in public health programs. Such studies can provide policy-relevant data on vaccine performance under 'real world' conditions, contributing to the evidence base to support and sustain introduction of new vaccines. However, case-control studies do not measure the impact of vaccine introduction on disease at a population level, and are subject to bias and confounding, which may lead to inaccurate results that can misinform policy decisions. In 2012, a group of experts met to review recent experience with case-control studies evaluating the effectiveness of several vaccines; here we summarize the recommendations of that group regarding best practices for planning, design and enrollment of cases and controls. Rigorous planning and preparation should focus on understanding the study context including healthcare-seeking and vaccination practices. Case-control vaccine effectiveness studies are best carried out soon after vaccine introduction because high coverage creates strong potential for confounding. Endpoints specific to the vaccine target are preferable to non-specific clinical syndromes since the proportion of non-specific outcomes preventable through vaccination may vary over time and place, leading to potentially confusing results. Controls should be representative of the source population from which cases arise, and are generally recruited from the community or health facilities where cases are enrolled. Matching of controls to cases for potential confounding factors is commonly used, although should be reserved for a limited number of key variables believed to be linked to both vaccination and disease. Case-control vaccine effectiveness studies can provide information useful to guide policy decisions and vaccine development, however rigorous preparation and design is essential., (Published by Elsevier Ltd.)

Background: The microcephaly epidemic, which started in Brazil in 2015, was declared a Public Health Emergency of International Concern by WHO in 2016. We report the preliminary results of a case-control study investigating the association between microcephaly and Zika virus infection during pregnancy., Methods: We did this case-control study in eight public hospitals in Recife, Brazil. Cases were neonates with microcephaly. Two controls (neonates without microcephaly), matched by expected date of delivery and area of residence, were selected for each case. Serum samples of cases and controls and cerebrospinal fluid samples of cases were tested for Zika virus-specific IgM and by quantitative RT-PCR. Laboratory-confirmed Zika virus infection during pregnancy was defined as detection of Zika virus-specific IgM or a positive RT-PCR result in neonates. Maternal serum samples were tested by plaque reduction neutralisation assay for Zika virus and dengue virus. We estimated crude odds ratios (ORs) and 95% CIs using a median unbiased estimator for binary data in an unconditional logistic regression model. We estimated ORs separately for cases with and without radiological evidence of brain abnormalities., Findings: Between Jan 15, 2016, and May 2, 2016, we prospectively recruited 32 cases and 62 controls. 24 (80%) of 30 mothers of cases had Zika virus infection compared with 39 (64%) of 61 mothers of controls (p=0·12). 13 (41%) of 32 cases and none of 62 controls had laboratory-confirmed Zika virus infection; crude overall OR 55·5 (95% CI 8·6-∞); OR 113·3 (95% CI 14·5-∞) for seven cases with brain abnormalities; and OR 24·7 (95% CI 2·9-∞) for four cases without brain abnormalities., Interpretation: Our data suggest that the microcephaly epidemic is a result of congenital Zika virus infection. We await further data from this ongoing study to assess other potential risk factors and to confirm the strength of association in a larger sample size., Funding: Brazilian Ministry of Health, Pan American Health Organization, and Enhancing Research Activity in Epidemic Situations., (Copyright This is an Open Access article published under the CC BY 3.0 IGO license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. In any use of this article, there should be no suggestion that WHO endorses any specific organisation, products or services. The use of the WHO logo is not permitted. This notice should be preserved along with the article's original URL.)

Background: Little is known about the possible adverse effects of dengue infection during pregnancy on fetal outcomes. In this systematic review and meta-analysis we aimed to estimate the increase in risk of four adverse fetal outcomes in women who had dengue infection during pregnancy., Methods: For this systematic review and meta-analysis, we searched Medline, Embase, Global Health Library, and Scopus for articles published before Aug 1, 2015. We included original studies that reported any fetal outcomes for pregnant women who had dengue infection during the gestational period. Case-control, cohort, and cross-sectional studies and unselected case series were eligible for inclusion. We excluded case reports, ecological studies, reviews, in-vitro studies, and studies without data for pregnancy outcomes. We independently screened titles and abstracts to select papers for inclusion and scored the quality of those included in meta-analyses. For each study, we recorded study design, year of publication, study location, period of study, and authors and we extracted data for population characteristics such as the number of pregnancies, dengue diagnostic information, and the frequency of outcomes. We investigated four adverse fetal outcomes: stillbirth, miscarriage, preterm birth, and low birthweight. We estimated the increase in risk of these adverse fetal outcomes by use of Mantel-Haenszel methods. We assessed heterogeneity of odds ratios (OR) with the I(2) statistic., Findings: We identified 278 non-duplicate records, of which 107 full-text articles were screened for eligibility. 16 studies were eligible for inclusion in the systematic review and eight were eligible for the meta-analyses, which included 6071 pregnant women, 292 of whom were exposed to dengue during pregnancy. For miscarriage, the OR was 3·51 (95% CI 1·15-10·77, I(2)=0·0%, p=0·765) for women with dengue infection during pregnancy compared with those without. We did not do a meta-analysis for stillbirth because this outcome was investigated in only one study with a comparison group; we calculated the crude relative risk to be 6·7 (95% CI 2·1-21·3) in women with symptomatic dengue compared with women without dengue. Preterm birth and low birthweight were the most common adverse pregnancy outcomes. The OR for the association with dengue was 1·71 (95% CI 1·06-2·76, I(2)=56·1%, p=0·058) for preterm birth and 1·41 (95% CI 0·90-2·21, I(2)=0·0%, p=0·543) for low birthweight., Interpretation: Evidence suggests that symptomatic dengue during pregnancy might be associated with fetal adverse outcomes. If confirmed, it would be important to monitor pregnancies during which dengue is diagnosed and to consider pregnant women in dengue control policies., Funding: National Council for Scientific and Technological Development (CNPq)., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Little is known about how long the BCG vaccine protects against tuberculosis. We assessed the long-term vaccine effectiveness (VE) in Norwegian-born individuals., Methods: In this retrospective population-based cohort study, we studied Norwegian-born individuals aged 12-50 years who were tuberculin skin test (TST) negative and eligible for BCG vaccination as part of the last round of Norway's mandatory mass tuberculosis screening and BCG vaccination programme between 1962 and 1975. We excluded individuals who had tuberculosis before or in the year of screening and those with unknown TST and BCG status. We obtained TST and BCG information and linked it to the National Tuberculosis Register, population and housing censuses, and the population register for emigrations and deaths. We followed individuals up to their first tuberculosis episode, emigration, death, or Dec 31, 2011. We used Cox regressions to estimate VE against all tuberculosis and just pulmonary tuberculosis by time since vaccination, adjusted for age, time, county-level tuberculosis rates, and demographic and socioeconomic indicators., Findings: Median follow-up was 41 years (IQR 32-49) for 83 421 BCG-unvaccinated and 44 years (41-46) for 297 905 vaccinated individuals, with 260 tuberculosis episodes. Tuberculosis rates were 3·3 per 100 000 person-years in unvaccinated and 1·3 per 100 000 person-years in vaccinated individuals. The adjusted average VE during 40 year follow-up was 49% (95% CI 26-65), although after 20 years, the VE was not significant (up to 9 years VE [excluding tuberculosis episodes in the first 2 years] 61% [95% CI 24-80]; 10-19 years 58% [27-76]; 20-29 years 38% [-32 to 71]; 30-40 years 42% [-24 to 73]). VE against pulmonary tuberculosis up to 9 years (excluding tuberculosis episodes in the first 2 years) was 67% (95% CI 27-85), 10-19 years was 63% (32-80), 20-29 years was 50% (-19 to 79), and 30-40 years was 40% (-46 to 76)., Interpretation: Findings are consistent with long-lasting BCG protection, but waning of VE with time. The vaccine could be more cost effective than has been previously estimated, Funding: Norwegian Institute of Public Health and London School of Hygiene & Tropical Medicine., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

BCG protection varies and in some places (nearest the equator) is low or absent. Understanding this variation can inform the efforts to develop new vaccines against tuberculosis. Two main hypotheses are used to explain this variation: under masking, new vaccines are unlikely to increase protection; under blocking new vaccines have a greater potential to be effective when BCG is not. We conducted a cluster randomized trial to explored the masking and blocking hypotheses by studying BCG vaccine efficacy of neonatal vaccination and when administered for the first or a second (revaccination) time at school age in two sites (Manaus close and Salvador further south from the equator). Seven hundred and sixty three state schools were matched on socio economic characteristics of the neighborhood and 239,934 children were randomized to vaccine (BCG vaccination at school age) or control group. Protection by first BCG vaccination at school age was high in Salvador (34%, 95% CI 7-53%, p=0.017) but low in Manaus (8%, 95% CI t0 39-40%, p=0.686). For revaccination at school age, protection was modest in Salvador (19%, 95% CI 3-33%, p=0.022) and absent in Manaus (1%, 95% CI to 27-23%, p=0.932). Vaccine efficacy for neonatal vaccination was similar in Salvador (40%, 95% CI 22-54%, p<0.001) and Manaus (36%, 95% CI 11-53%, p=0.008). Variation in BCG efficacy was marked when vaccine was given at school age but absent at birth, which points towards blocking as the dominant mechanism. New tuberculosis vaccines that overcome or by pass this blocking effect could confer protection in situations where BCG is not protective., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Rotavirus is one of the leading cause of hospitalization and outpatients visits among children under five years. This study evaluated overall and genotype-specific vaccine effectiveness of oral monovalent rotavirus vaccine (G1P[8] strain) in preventing hospital admission of Brazilian children with rotavirus acute diarrhea. A hospital based case-control study was conducted in five Regions of Brazil using the National Rotavirus Acute Diarrhea Surveillance System from July 2008 to August 2011. A total of 215 cases (aged 4-24 months) admitted with confirmed rotavirus diarrhea were recruited and 1961 controls hospitalized without diarrhea were frequency matched by sex and age group to cases. Two-dose adjusted vaccine effectiveness (adjusted by year of birth and the frequency matching variables) was 76% (95%CI: 58-86) lasting for two years. Effectiveness controlled by the available potential confounders was 72% (95%CI: 44-85), suggesting no appreciable confounding by those factors for which adjustment was made. In a half of the cases the rotavirus genotype was G2P[4] and in 15% G1P[8]. Genotype-specific VE (two doses) was 89% (95%CI: 78-95), for G1P[8] and 76% (95%CI: 64-84) for G2P[4]. For all G1, it was 74% (95%CI: 35-90), for all G2, 76% (95%CI: 63-84), and for all non G1/G2 genotypes, 63% (95%CI: -27-99). Effectiveness for one dose was 62% (95%CI: 39-97). Effectiveness of two-dose monovalent rotavirus vaccine in preventing hospital admission with rotavirus diarrhea was high, lasted for two years and it was similar against both G1P[8] and G2P[4]. Based on the findings of the study we recommend the continued use of rotavirus in the Brazilian National Immunization Program and the monitoring of the early emergence of unusual and novel rotavirus genotypes., (Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Neonatal BCG vaccination is part of routine vaccination schedules in many developing countries; vaccination at school age has not been assessed in trials in low-income and middle-income countries. Catch-up BCG vaccination of school-age children who missed neonatal BCG vaccination could be indicated if it confers protection and is cost-effective. We did a cluster-randomised trial (BCG REVAC) to estimate the effectiveness (efficacy given in routine settings) of school-age vaccination., Methods: We assessed the effectiveness of BCG vaccination in school-age children (aged 7-14 years) with unknown tuberculin status who did not receive neonatal BCG vaccination (subpopulation of the BCG REVAC cluster-randomised trial), between July, 1997, and June, 2006, in Salvador, Brazil, and between January, 1999, and December, 2007, in Manaus, Brazil. 763 schools were randomly assigned into BCG vaccination group or a not-vaccinated control group. Neither allocation nor intervention was concealed. Incidence of tuberculosis was the primary outcome. Cases were identified via the Brazilian Tuberculosis Control Programme. Study staff were masked to vaccination status when identified cases were linked to the study population. We estimated cost-effectiveness in Salvador by comparison of the cost for vaccination to prevent one case of tuberculosis (censored at 9 years) with the average cost of treating one case of tuberculosis. Analysis of all included children was by intention to treat. For calculation of the incidence rate we used generalised estimating equations and correlated observations over time., Findings: We randomly assigned 20,622 children from 385 schools to the BCG vaccination group and 18,507 children from 365 schools to the control group. The crude incidence of tuberculosis was 54·9 (95% CI 45·3-66·7) per 100,000 person-years in the BCG vaccination group and 72·7 (62·8-86·8) per 100,000 person-years in the control group. The overall vaccine effectiveness of a first BCG vaccination at school age was 25% (3-43%). In Salvador, where vaccine effectiveness was 34% (8-53%), vaccination of 381 children would prevent one case of tuberculosis and was cheaper than treatment. The frequency of adverse events was very low with only one axillary lymphadenitis and one ulcer greater than 1 cm in 11,980 BCG vaccinations., Interpretation: Vaccination of school-age children without previous tuberculin testing can reduce the incidence of tuberculosis and could reduce the costs of tuberculosis control. Restriction of BCG vaccination to the first year of life is not in the best interests of the public nor of programmes for tuberculosis control., Funding: UK Department for International Development, National Health Foundation., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

To estimate the proportion of children in day-care centres with incomplete vaccination and to identify associated risk factors, we conducted a cross-sectional study among 258 children less than 18 months of age attending public and philanthropic day-care centres in the city of Sao Paulo, Brazil. Interviews, blood collection and anthropometry were performed. Unconditional logistic regression was adjusted for incomplete vaccination risk factors. 10.9% of children had incomplete vaccination. Children who were born prematurely (OR=4.27; p=0.004), or were malnourished (OR=4.99; p=0.049), or lived in inadequate housing (OR=2.88; p=0.039), or whose mothers had had poor prenatal care (OR=4.98; p=0.040) were more likely to have incomplete vaccination. Opportunities are being missed to identify children with incomplete vaccination; strategies to enhance vaccination coverage should pay special attention to the needs of families living in inadequate housing; and health promotion actions in primary health facilities and day-care centres should be performed as concomitant activities., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

BCG revaccination is still used in some tuberculosis endemic countries. Until now, the little evidence available suggested that BCG revaccination confers very limited additional protection, although there was no information on whether protection depends on the setting and age of revaccination, or if protection increases with time since vaccination. Here we report on an extended follow up of the BCG-REVAC trial, a cluster randomised trial conducted in the Brazilian cities Salvador and Manaus including over 200,000 children aged 7-14 years aimed to evaluate the efficacy of BCG revaccination in children who had received neonatal BCG vaccination. With the extended follow-up (9 years) and the additional cases accrued we now have enough power to report vaccine efficacy separately for the two cities (with different distances from Equator and presumably different prevalence of non-tuberculosis mycobacteria), and by age at vaccination and clinical form. The overall vaccine efficacy was 12% (-2 to 24%) as compared to 9% (-16 to 29%) for the 5-year follow up. Vaccine efficacy was higher in Salvador (19%, 3 to 33%) than in Manaus (1%, -27 to 27%) with the highest vaccine efficacy in children from Salvador aged <11 years at revaccination (33%, 3 to 54%). The findings are in line with the hypothesis that BCG vaccination offers higher efficacy in low NTMb prevalence, and show that revaccination with BCG can offer weak protection in selected subgroups., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Leprosy continues to be a challenge to health worldwide, with about 250,000 new cases being detected every year. Despite widespread implementation of effective multidrug therapy, leprosy has not been eliminated. A third of newly diagnosed patients have nerve damage and might develop disabilities, although the proportion varies according to several factors, including level of self-care. Women who develop leprosy continue to be especially disadvantaged, with rates of late diagnosis and disability remaining high in this subgroup. Leprosy was not a specified disease in the Millennium Development Goals, but improvements in the other areas they cover, such as education and levels of poverty, will help leprosy patients and services. We review data and make recommendations for research on diagnosis, treatment, and prevention, such as further use of molecular analysis of the Mycobacterium leprae genome, implementation of BCG vaccination, and administration of chemoprophylaxis to household contacts. We also suggest development of tools for early diagnosis and detection of infection and nerve damage, and formulation of strategies to manage the chronic complications of leprosy, such as immune-mediated reactions and neuropathy., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Vaccines against human helminths are being developed but the choice of optimal parasitological endpoints and effect measures to assess their efficacy has received little attention. Assuming negative binomial distributions for the parasite counts, we rank the statistical power of three measures of efficacy: ratio of mean parasite intensity at the end of the trial, the odds ratio of infection at the end of the trial, and the rate ratio of incidence of infection during the trial. We also use a modelling approach to estimate the likely impact of trial interventions on the force of infection, and hence statistical power. We conclude that (1) final mean parasite intensity is a suitable endpoint for later phase vaccine trials, and (2) mass effects of trial interventions are unlikely to appreciably reduce the force of infection in the community - and hence statistical power - unless there is a combination of high vaccine efficacy and a large proportion of the population enrolled., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

BCG scar has been used as an indicator of vaccination with BCG in the past, but the validity of scar among HIV-positive children is still unknown. The validity of BCG scar reading among such children was estimated, using three different gold standards. The sensitivity ranged from 81.3% (95%-CI: 78.0-84.2) to 91.6% (95%-CI: 88.4-94.0), when the gold standards were, respectively, information from the adult responsible for the child and the vaccination card. The specificity ranged from 90.5% (95% CI: 81.6-95.5) to 94.1% (95% CI: 87.7-97.4), when the gold standards were, respectively, the vaccination card and information from the adult responsible for the child. Reading of BCG scar was shown to be a good indicator for vaccination in the past, among HIV-infected children., (Copyright 2009 Elsevier Ltd. All rights reserved.)

Background: BCG vaccine protects against leprosy., Objectives: Estimate BCG protection against leprosy by age by age., Methods: A case control study with 226 cases of leprosy and 857 controls. BCG vaccination was ascertained via examination of BCG scars. Protection is presented for three age groups., Results: BCG protection against leprosy was 86% (95% CI: 77-92%) in the age group 18-29; 54% (95% CI: -37% to 85%) in the age group 30-39 and 32% (95% CI: -3% to 56%) in those aged 40 or more., Conclusions: BCG efficacy against leprosy may well last for three decades and possibly even longer. BCG vaccination must have contributed to worldwide reduction in leprosy incidence.

Tuberculin skin test (TST) response and cytokine production in finger stab-derived whole blood cultures from 136 BCG scar-positive school-age children were evaluated before and after BCG revaccination. Fifty-four percent of the children increased in vitro production of IFN-gamma after revaccination, and this increase was highly significant for previously unresponsive children (P<0.0001). No correlation was found between TST response and cytokine production. Our data suggest that the in vitro IFN-gamma response to mycobacterial antigens can be boosted by BCG revaccination and may contribute to the search of correlates of protection to be used for the evaluation of new mycobacterial vaccines.

When the hypothesis of a link between vaccination and a possible adverse outcome arises, further investigation is required to confirm or refute the suspicion. Given the rarity of most serious adverse effects, a case-control approach will often be chosen. This paper discusses aspects of the design, analysis and interpretation of case-control studies to evaluate vaccine adverse effects. Potential biases (and how to minimise such biases) in the selection of cases and assessment of vaccine exposure and the potential for confounding are discussed. Finally the increasing use of electronic databases in the evaluation of vaccine adverse effects is considered.

Data from routine surveillance during two mass immunisation campaigns (MIC) with Measles-mumps-rubella (MMR)vaccine using Leningrad-Zagreb mumps strain in two states in Brazil were analysed to estimate the risk of vaccine-related meningitis and mumps. Increase in the incidence of the two diseases was observed in both states, 3 weeks after the vaccination campaigns. The estimated number of doses applied per one case of vaccine-related meningitis ranged from 6199 (95% CI: 4854-8058) to 19,247 (95% CI: 12,648-29,513) depending on the diagnostic criteria used and state. It was 300 doses (95% CI: 286-317) for each case of mumps. The implications for vaccination policy are discussed.