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Aim\ud Our aim was to analyse 12-month outcomes of children who were prenatally exposed to the Zika virus and asymptomatic at birth.\ud Methods\ud This was an observational, exploratory study of infants exposed to the Zika virus during gestation and born between March 2016 and April 2017 without congenital Zika syndrome. They were followed until the age of 22 months. The outcome measure was neurodevelopment at 12 months of life, which was evaluated with the Bayley Scales of Infant and Toddler Development, Third edition (Bayley-III). The scores were adjusted for maternal education and prematurity.\ud Results\ud A total of 96 infants were included in the study and 35.4% scored below the normal range in at least one Bayley-III domain. The majority (91.2%) of the infants with delayed scores presented with language delay, which was not associated with the gestational age at exposure. Receptive language was more affected by exposure than expressive language (27.0% vs 19.8%). There was a direct, and significant, association between the head circumference Z-score at birth and language delay.\ud Conclusion\ud Language delay was associated with a smaller head circumference at birth in infants prenatally exposed to the Zika virus and born asymptomatic. This may indicate future learning difficulties.

Leprosy is a neglected tropical disease predominately affecting poor and marginalized populations. To test the hypothesis that poverty-alleviating policies might be associated with reduced leprosy incidence, we evaluated the association between the Brazilian Bolsa Familia (BFP) conditional cash transfer program and new leprosy case detection using linked records from 12,949,730 families in the 100 Million Brazilian Cohort (2007–2014). After propensity score matching BFP beneficiary to nonbeneficiary families, we used Mantel-Haenszel tests and Poisson regressions to estimate incidence rate ratios for new leprosy case detection and secondary endpoints related to operational classification and leprosy-associated disabilities at diagnosis. Overall, cumulative leprosy incidence was 17.4/100,000 person-years at risk (95% CI: 17.1, 17.7) and markedly higher in “priority” (high-burden) versus “nonpriority” (low-burden) municipalities (22.8/100,000 person-years at risk, 95% confidence interval (CI): 22.2, 23.3, compared with 14.3/100,000 person-years at risk, 95% CI: 14.0, 14.7). After matching, BFP participation was not associated with leprosy incidence overall (incidence rate ratio (IRR)Poisson = 0.97, 95% CI: 0.90, 1.04) but was associated with lower leprosy incidence when restricted to families living in high-burden municipalities (IRRPoisson = 0.86, 95% CI: 0.77, 0.96). In high-burden municipalities, the association was particularly pronounced for paucibacillary cases (IRRPoisson = 0.82, 95% CI: 0.68, 0.98) and cases with leprosy-associated disabilities (IRRPoisson = 0.79, 95% CI: 0.65, 0.97). These findings provide policy-relevant evidence that social policies might contribute to ongoing leprosy control efforts in high-burden communities.

Objective To estimate the incidence of epilepsy in children with Zika‐related microcephaly in the first 24 months of life; to characterize the associated clinical and electrographic findings; and to summarize the treatment responses. Methods We followed a cohort of children, born during the 2015‐2016 Zika virus (ZIKV) epidemic in Brazil, with congenital microcephaly and evidence of congenital ZIKV infection on neuroimaging and/or laboratory testing. Neurological assessments were performed at ≤3, 6, 12, 15, 18, 21, and 24 months of life. Serial electroencephalograms were performed over the first 24 months. Results We evaluated 91 children, of whom 48 were female. In this study sample, the cumulative incidence of epilepsy was 71.4% in the first 24 months, and the main type of seizure was infantile spasms (83.1%). The highest incidence of seizures occurred between 3 and 9 months of age, and the risk remained high until 15 months of age. The incidence of infantile spasms peaked between 4 and 7 months and was followed by an increased incidence of focal epilepsy cases after 12 months of age. Neuroimaging results were available for all children, and 100% were abnormal. Cortical abnormalities were identified in 78.4% of the 74 children evaluated by computed tomography and 100% of the 53 children evaluated by magnetic resonance imaging. Overall, only 46.1% of the 65 children with epilepsy responded to treatment. The most commonly used medication was sodium valproate with or without benzodiazepines, levetiracetam, phenobarbital, and vigabatrin. Significance Zika‐related microcephaly was associated with high risk of early epilepsy. Seizures typically began after the third month of life, usually as infantile spasms, with atypical electroencephalographic abnormalities. The seizure control rate was low. The onset of seizures in the second year was less frequent and, when it occurred, presented as focal epilepsy.

Background There is an increasing use of cesarean delivery (CD) based on preference rather than on medical indication. However, the extent to which nonmedically indicated CD benefits or harms child survival remains unclear. Our hypothesis was that in groups with a low indication for CD, this procedure would be associated with higher child mortality and in groups with a clear medical indication CD would be associated with improved child survival chances. Methods and findings We conducted a population-based cohort study in Brazil by linking routine data on live births between January 1, 2012 and December 31, 2018 and assessing mortality up to 5 years of age. Women with a live birth who contributed records during this period were classified into one of 10 Robson groups based on their pregnancy and delivery characteristics. We used propensity scores to match CD with vaginal deliveries (1:1) and prelabor CD with unscheduled CD (1:1) and estimated associations with child mortality using Cox regressions. A total of 17,838,115 live births were analyzed. After propensity score matching (PSM), we found that live births to women in groups with low expected frequencies of CD (Robson groups 1 to 4) had a higher death rate up to age 5 years if they were born via CD compared with vaginal deliveries (HR = 1.25, 95% CI: 1.22 to 1.28; p < 0.001). The relative rate was greatest in the neonatal period (HR = 1.39, 95% CI: 1.34 to 1.45; p < 0.001). There was no difference in mortality rate when comparing offspring born by a prelabor CD to those born by unscheduled CD. For the live births to women with a CD in a prior pregnancy (Robson group 5), the relative rates for child mortality were similar for those born by CD compared with vaginal deliveries (HR = 1.05, 95% CI: 1.00 to 1.10; p = 0.024). In contrast, for live births to women in groups with high expected rates of CD (Robson groups 6 to 10), the child mortality rate was lower for CD than for vaginal deliveries (HR = 0.90, 95% CI: 0.89 to 0.91; p < 0.001), particularly in the neonatal period (HR = 0.84, 95% CI: 0.83 to 0.85; p < 0.001). Our results should be interpreted with caution in clinical practice, since relevant clinical data on CD indication were not available. Conclusions In this study, we observed that in Robson groups with low expected frequencies of CD, this procedure was associated with a 25% increase in child mortality. However, in groups with high expected frequencies of CD, the findings suggest that clinically indicated CD is associated with a reduction in child mortality.

Background Leprosy remains concentrated among the poorest communities in low-and middle-income countries and it is one of the primary infectious causes of disability. Although there have been increasing advances in leprosy surveillance worldwide, leprosy underreporting is still common and can hinder decision-making regarding the distribution of financial and health resources and thereby limit the effectiveness of interventions. In this study, we estimated the proportion of unreported cases of leprosy in Brazilian microregions. Methodology/Principal findings Using data collected between 2007 to 2015 from each of the 557 Brazilian microregions, we applied a Bayesian hierarchical model that used the presence of grade 2 leprosy-related physical disabilities as a direct indicator of delayed diagnosis and a proxy for the effectiveness of local leprosy surveillance program. We also analyzed some relevant factors that influence spatial variability in the observed mean incidence rate in the Brazilian microregions, highlighting the importance of socioeconomic factors and how they affect the levels of underreporting. We corrected leprosy incidence rates for each Brazilian microregion and estimated that, on average, 33,252 (9.6%) new leprosy cases went unreported in the country between 2007 to 2015, with this proportion varying from 8.4% to 14.1% across the Brazilian States. Conclusions/Significance The magnitude and distribution of leprosy underreporting were adequately explained by a model using Grade 2 disability as a marker for the ability of the system to detect new missing cases. The percentage of missed cases was significant, and efforts are warranted to improve leprosy case detection. Our estimates in Brazilian microregions can be used to guide effective interventions, efficient resource allocation, and target actions to mitigate transmission., Author summary Leprosy remains an important public health problem that affects vulnerable populations in low- and middle-income countries. In this study, we estimated how many cases were not detected in each Brazilian microregion by the surveillance system during the period of 2007 until 2015. Using a mathematical model, we found out that around 10% of the estimated number of cases occurring in the country in the study period were missed by the health system, and this represented over 33 thousand cases overall. These findings are important as undetected and therefore untreated cases can progress and lead to lifelong disabilities. In addition, missing cases prevents the health system from evaluating exposed contacts, which could lead to further delays in diagnosis. Describing the magnitude, location and correlates of leprosy underreporting at the microregional level will inform the efforts of policymakers and program managers in designing interventions and allocating resources to achieve leprosy control targets.

A cornerstone of the global initiative to eradicate polio is the widespread use of live and inactivated poliovirus vaccines in extensive public health campaigns designed to prevent the development of paralytic disease and interrupt transmission of the virus. Central to these efforts is the goal of inducing mucosal immunity able to limit virus replication in the intestine. Recent clinical trials have evaluated new combined regimens of poliovirus vaccines, and demonstrated clear differences in their ability to restrict virus shedding in stool after oral challenge with live virus. Analyses of mucosal immunity accompanying these trials support a critical role for enteric neutralizing IgA in limiting the magnitude and duration of virus shedding. This review summarizes key findings in vaccine-induced intestinal immunity to poliovirus in infants, older children, and adults. The impact of immunization on development and maintenance of protective immunity to poliovirus and the implications for global eradication are discussed.

This cohort profile aims to describe the ongoing follow-up of children in the Microcephaly Epidemic Research Group Paediatric Cohort (MERG–PC). The profile details the context and aims of the study, study population, methodology including assessments, and key results and publications to date. The children that make up MERG–PC were born in Recife or within 120 km of the city, in Pernambuco/Brazil, the epicentre of the microcephaly epidemic. MERG–PC includes children from four groups recruited at different stages of the ZIKV microcephaly epidemic in Pernambuco, i.e., the Outpatient Group (OG/n = 195), the Microcephaly Case–Control Study (MCCS/n = 80), the MERG Pregnant Women Cohort (MERG-PWC/n = 336), and the Control Group (CG/n = 100). We developed a comprehensive array of clinical, laboratory, and imaging assessments that were undertaken by a ‘task force’ of clinical specialists in a single day at 3, 6, 12, 18 months of age, and annually from 24 months. Children from MCCS and CG had their baseline assessment at birth and children from the other groups, at the first evaluation by the task force. The baseline cohort includes 711 children born between February 2015 and February 2019. Children’s characteristics at baseline, excluding CG, were as follows: 32.6% (184/565) had microcephaly, 47% (263/559) had at least one physical abnormality, 29.5% (160/543) had at least one neurological abnormality, and 46.2% (257/556) had at least one ophthalmological abnormality. This ongoing cohort has contributed to the understanding of the congenital Zika syndrome (CZS) spectrum. The cohort has provided descriptions of paediatric neurodevelopment and early epilepsy, including EEG patterns and treatment response, and information on the frequency and characteristics of oropharyngeal dysphagia, cryptorchidism and its surgical findings, endocrine dysfunction, and adenoid hypertrophy in children with Zika-related microcephaly. The study protocols and questionnaires were shared across Brazilian states to enable harmonization across the different studies investigating microcephaly and CZS, providing the opportunity for the Zika Brazilian Cohorts Consortium to be formed, uniting all the ZIKV clinical cohorts in Brazil.

Congenital Zika Syndrome (CZS) is characterized by many impairments especially in the central nervous system, potentially compromising neurodevelopment and causing significant morbidity in affected children. The aim was to assess gross motor function in children with CZS. This was a cross-sectional investigation nested within a prospective cohort study of children with CZS based in a Brazilian referral hospital in Rio de Janeiro. Between March/2017 and February/2018, we performed gross motor function assessments using the Gross Motor Function Classification (GMFCS) and the Gross Motor Function Measure (GMFM), estimating the mean and standard deviation of GMFM scores among GMFCS groups. The study sample included 72 children, with a median age of 13 months (7–25). Of these, 63 (87.5%) had severe motor impairment, 3 (4%) had moderate impairment, and 6 (8%) had mild impairment. The mean GMFM score for each group was respectively 11.6, 26.1, and 81.6, with statistically significant differences (p-value Conclusion: Most children with CZS have major motor disabilities and a poor prognosis. Better understanding of limitations and functionality in children with CZS can serve as a prognostic guide in their management. What is Known:• Severe motor impairment was present in 63 (87.5%) children with CZS.• The degree of neurological impairment was inversely associated with motor performance. What is New:• Microcephaly was more frequent among children with severe gross motor function impairment.• Children with CZS have major motor disabilities and a poor prognosis.

Upper respiratory obstruction is a common sequela in children with Zika-related microcephaly (ZRM). As a cross-sectional analysis nested in a cohort study, this study aims to investigate the prevalence of adenoid hypertrophy (AH) in children with ZRM and symptoms of respiratory obstruction. The data were collected in the first three years of life from children with ZRM who were followed in two reference centers for otorhinolaryngological care of patients with congenital Zika syndrome. Out of 92 children with confirmed ZRM, 57 were evaluated by nasopharyngoscopy after presenting with upper respiratory obstruction symptoms. In this study, 31 of the 57 (54%) children with ZRM who were evaluated had obstructive AH. Thirteen children with obstructive AH were submitted to surgery, which resulted in the complete resolution of symptoms for 11, partial resolution in 1, and no improvement in 1. No evidence of direct involvement by Zika virus (ZIKV) infection in the adenoid tissues was demonstrated by histology or immunohistochemistry. Our results suggest that there is a high prevalence and early presentation of AH in children with ZRM, with consequent upper airway obstruction causing upper airway obstructive disorder, secretory otitis media, and dysphagia.

IntroductionZika virus (ZIKV) infection in pregnancy has been associated with microcephaly and severe neurological damage to the fetus. Our aim is to document the risks of adverse pregnancy and birth outcomes and the prevalence of laboratory markers of congenital infection in deliveries to women experiencing ZIKV infection during pregnancy, using data from European Commission-funded prospective cohort studies in 20 centres in 11 countries across Latin America and the Caribbean.Methods and analysisWe will carry out a centre-by-centre analysis of the risks of adverse pregnancy and birth outcomes, comparing women with confirmed and suspected ZIKV infection in pregnancy to those with no evidence of infection in pregnancy. We will document the proportion of deliveries in which laboratory markers of congenital infection were present. Finally, we will investigate the associations of trimester of maternal infection in pregnancy, presence or absence of maternal symptoms of acute ZIKV infection and previous flavivirus infections with adverse outcomes and with markers of congenital infection. Centre-specific estimates will be pooled using a two-stage approach.Ethics and disseminationEthical approval was obtained at each centre. Findings will be presented at international conferences and published in peer-reviewed open access journals and discussed with local public health officials and representatives of the national Ministries of Health, Pan American Health Organization and WHO involved with ZIKV prevention and control activities.

Background Complications in the urinary tract related to congenital Zika syndrome have recently been reported. One complication, cryptorchidism, has been reported by the Microcephaly Epidemic Research Group/MERG, in Pernambuco/Brazil. The present article describes for the first time the surgical findings in a case series of boys with Zika-related microcephaly and cryptorchidism, who underwent surgical testicular exploration as a contribution to better understand the possible mechanisms involved in gonads formation and descent. Methods A total of 7 children (11 testicular units), aged 3 to 4 years, were submitted to inguinal or scrotal orchidopexy for the treatment of palpable cryptorchidism between August 2019 and January 2020. Characteristics of the gonads and its annexes related to appendixes, testis-epididymis dissociation, gubernacular insertion, and associated hydroceles and/or hernias were described. Measures in centimetres were taken for volume calculate. Results We found a low prevalence of testicular and epididymal appendix (66.7%), a high prevalence of testis-epididymis dissociation (55.6%), low mean testicular volume for their ages (lower for older boys) and ectopic gubernacular insertion in all cases. There was no evidence of associated hydroceles and/or hernias in any case. No surgical complication was registered or reported, and all explored gonads were properly placed in the scrotal sac. Conclusions We herein describe the surgical findings of these children's orchidopexies and discuss the possible mechanisms of viral action in embryogenesis and postnatal growth and development of the testes and annexes. These children need to be followed over time due to the higher risk of testicular atrophy and malignancy. Surgical timing seems to be relevant to avoid loss of testicular volume.

Zika virus (ZIKV) infection in pregnancy is associated with congenital neurological abnormalities. Our understanding of the full clinical spectrum of ZIKV infection is incomplete. Using data from this prospective cohort study consisting of 650 women attending a high-risk pregnancy clinic during the Zika virus outbreak in Brazil, we investigated the extent to which specific symptoms can be utilized to differentiate ZIKV-infected pregnant women from those with other pregnancy-related problems. All were tested for ZIKV in urine by RT–qPCR. Demographic and clinical data including physical symptoms during follow-up were recorded and analyzed with respect to Zika virus exposure status. Forty-eight (7.4%) women were positive for ZIKV by RT–qPCR. The majority (70.8%) were asymptomatic, and only four ZIKV-positive women (8.3%) reported symptoms during pregnancy that met the WHO case definition. Zika-positive and -negative women reported similar frequencies of ZIKV-like symptoms (as per the WHO definition): fever (16.7% vs. 13.6%), arthralgia/arthritis (10.4% vs. 11.3%), rash (4.2% vs. 5.3%), and conjunctivitis (2.1% vs. 3.2%). Most pregnant women positive for ZIKV in urine are asymptomatic and do not deliver a baby with microcephaly. Physical symptoms alone did not differentiate between high-risk pregnant women positive or negative for ZIKV.

Testing of symptomatic persons for infection with severe acute respiratory syndrome coronavirus-2 is occurring worldwide. We propose two types of case–control studies that can be carried out jointly in test settings for symptomatic persons. The first, the test-negative case–control design (TND) is the easiest to implement; it only requires collecting information about potential risk factors for Coronavirus Disease 2019 (COVID-19) from the tested symptomatic persons. The second, standard case–control studies with population controls, requires the collection of data on one or more population controls for each person who is tested in the test facilities, so that test-positives and test-negatives can each be compared with population controls. The TND will detect differences in risk factors between symptomatic persons who have COVID-19 (test-positives) and those who have other respiratory infections (test-negatives). However, risk factors with effect sizes of equal magnitude for both COVID-19 and other respiratory infections will not be identified by the TND. Therefore, we discuss how to add population controls to compare with the test-positives and the test-negatives, yielding two additional case–control studies. We describe two options for population control groups: one composed of accompanying persons to the test facilities, the other drawn from existing country-wide healthcare databases. We also describe other possibilities for population controls. Combining the TND with population controls yields a triangulation approach that distinguishes between exposures that are risk factors for both COVID-19 and other respiratory infections, and exposures that are risk factors for just COVID-19. This combined design can be applied to future epidemics, but also to study causes of nonepidemic disease.

BackgroundThe urbanisation process has been associated with increases in asthma prevalence, an observation supported largely by studies comparing urban with rural populations. The nature of this association remains poorly understood, likely because of the limitations of the urban–rural approach to understand what a multidimensional process is.ObjectiveThis study explored the relationship between the urbanisation process and asthma prevalence using a multidimensional and quantitative measure of urbanicity.MethodsA cross-sectional analysis was conducted in 1843 children living in areas with diverse levels of urbanisation in the district of Quinindé, Ecuador in 2013–2015. Categorical principal components analysis was used to generate an urbanicity score derived from 18 indicators measured at census ward level based on data from the national census in 2010. Indicators represent demographic, socioeconomic, built environment and geographical dimensions of the urbanisation process. Geographical information system analysis was used to allocate observations and urban characteristics to census wards. Logistic random effects regression models were used to identify associations between urbanicity score, urban indicators and three widely used definitions for asthma.ResultsThe prevalence of wheeze ever, current wheeze and doctor diagnosis of asthma was 33.3%, 13% and 6.9%, respectively. The urbanicity score ranged 0–10. Positive significant associations were observed between the urbanicity score and wheeze ever (adjusted OR=1.033, 95% CI 1.01 to 1.07, p=0.05) and doctor diagnosis (adjusted OR=1.06, 95% CI 1.02 to 1.1, p=0.001). For each point of increase in urbanicity score, the prevalence of wheeze ever and doctor diagnosis of asthma increased by 3.3% and 6%, respectively. Variables related to socioeconomic and geographical dimensions of the urbanisation process were associated with greater prevalence of wheeze/asthma outcomes.ConclusionsEven small increases in urbanicity are associated with a higher prevalence of asthma in an area undergoing the urban transition. The use of a multidimensional urbanicity indicator has greater explanatory power than the widely used urban–rural dichotomy to improve our understanding of how the process of urbanisation affects the risk of asthma.

Increased rates of Zika virus have been identified in economically deprived areas in Brazil at the population level, yet, the implications of the interaction between socioeconomic position and prenatal Zika virus exposure on adverse neurodevelopmental outcomes remains insufficiently evaluated at the individual level. Using data collected between September 2015 and September 2019 from 163 children with qRT-PCR and/or IgM-confirmed prenatal exposure to Zika virus participating in a prospective cohort study in Rio de Janeiro, Brazil (NCT03255369), this study evaluated the relationships of socioeconomic indicators with microcephaly at birth and Bayley-III neurodevelopmental scores during the early life course. Adjusted logistic regression models indicated increased odds of microcephaly in children born to families with lower household income (OR, 95% CI: 3.85, 1.43 to 10.37) and higher household crowding (OR, 95% CI: 1.83, 1.16 to 2.91), while maternal secondary and higher education appeared to have a protective effect for microcephaly compared to primary education (OR, 95% CI: 0.33, 0.11 to 0.98 and 0.10, 0.03 to 0.36, respectively). Consistent with these findings, adjusted linear regression models indicated lower composite language (&minus, 10.78, 95% CI: &minus, 19.87 to &minus, 1.69), motor (&minus, 10.45, 95% CI: &minus, 19.22 to &minus, 1.69), and cognitive (&minus, 17.20, 95% CI: &minus, 26.13 to &minus, 8.28) scores in children whose families participated in the Bolsa Fam&iacute, lia social protection programme. As such, the results from this investigation further emphasise the detrimental effects of childhood disadvantage on human health and development by providing novel evidence on the link between individual level socioeconomic indicators and microcephaly and delayed early life neurodevelopment following prenatal Zika virus exposure.

Background The implications of congenital Zika Virus (ZIKV) infections for pediatric neurodevelopment and behavior remain inadequately studied. The aim of this study is to investigate patterns of neurodevelopment and behavior in groups of children with differening severities of ZIKV-related microcephaly and children with prenatal ZIKV exposure in the absence of microcephaly. Methods We conducted a cross-sectional study, nested in a cohort, of 274 children (aged 10–45 months) who were born during the peak and decline of the microcephaly epidemic in Northeast Brazil. Participants were evaluated between February 2017 and August 2019 at two tertiary care hospitals in Recife, Pernambuco, Brazil. We analyzed the children in four groups assigned based on clinical and laboratory criteria: Group 1 had severe microcephaly; Group 2 had moderate microcephaly; Group 3 had prenatal ZIKVexposure confirmed by maternal RT-PCR testing but no microcephaly; and Group 4 was a neurotypical control group. Groups were evaluated clinically for neurological abnormalities and compared using the Survey of Wellbeing of Young Children (SWYC), a neurodevelopment and behavior screening instrument validated for use in Brazil. Children with severe delays underwent further evaluation with an adapted version of the SWYC. Results Based on the SWYC screening, we observed differences between the groups for developmental milestones but not behavior. Among the 114 children with severe microcephaly of whom 98.2% presented with neurological abnormalities, 99.1% were ‘at risk of development delay’ according to the SWYC instrument. Among the 20 children with moderate microcephaly of whom 60% presented with neurological abnormalities, 65% were ‘at risk of development delay’. For children without microcephaly, the percentages found to be ‘at risk of developmental delay’ were markedly lower and did not differ by prenatal ZIKV exposure status: Group 3 (N = 94), 13.8%; Group 4 (N = 46), 21.7%. Conclusions Among children with prenatal ZIKV exposure, we found a gradient of risk of development delay according to head circumference. Children with severe microcephaly were at highest risk for delays, while normocephalic ZIKV-exposed children had similar risks to unexposed control children. We propose that ZIKV-exposed children should undergo first-line screening for neurodevelopment and behavior using the SWYC instrument. Early assessment and follow-up will enable at-risk children to be referred to a more comprehensive developmental evaluation and to multidisciplinary care management.

Background Recent Zika virus (ZIKV) outbreaks in the Pacific and the Americas have highlighted clinically significant congenital neurological abnormalities resulting from ZIKV infection in pregnancy. However, little is known about ZIKV infections in children and adolescents, a group that is potentially vulnerable to ZIKV neurovirulence. Methods We conducted a systematic review on the clinical presentation and complications of children and adolescents aged 0 to 18 years with a robust diagnosis of ZIKV infection. We searched PubMed, Web of Science, LILACs, and EMBASE until 13 February 2020 and screened reference lists of eligible articles. We assessed the studies’ risk of bias using pre-specified criteria. Findings Our review collated the evidence from 2543 pediatric ZIKV cases representing 17 countries and territories, identified in 1 cohort study, 9 case series and 22 case reports. The most commonly observed signs and symptoms of ZIKV infection in children and adolescents were mild and included fever, rash, conjunctivitis and arthralgia. The frequency of neurological complications was reported only in the largest case series (identified in 1.0% of cases) and in an additional 14 children identified from hospital-based surveillance studies and case reports. ZIKV-related mortality was primarily accompanied by co-morbidity and was reported in one case series (, Author summary Although the number of Zika virus (ZIKV) cases has declined following the 2015–2016 outbreak in the Americas, ZIKV remains a public health concern due to the potentially severe consequences of in utero exposure to the virus. While there is an increasing understanding of the effects of prenatal congenital ZIKV infection, less is known regarding the potential consequences of postnatal non-congenital ZIKV infection in children and adolescents. As this age group may also be vulnerable to the adverse effects of ZIKV on the nervous system, a better understanding of ZIKV infection in this population is needed. This knowledge may help to inform the case definition for ZIKV disease in children and elucidate whether children and adolescents should be included in strategies and measures for prevention of ZIKV infection, which are currently aimed primarily at pregnant women. After a review of the existing literature, the authors found that ZIKV infection in children and adolescents appears to be similar to adults and primarily mild, with little evidence of severe neurological consequences. Further research using prospective methods and neurodevelopmental assessments is warranted.

Severe brain damage associated with Zika-related microcephaly (ZRM) have been reported to result in oropharyngeal dysphagia (OPD); however, it is unknown if OPD presents in children with prenatal Zika virus (ZIKV) exposure but only mild or undetectable abnormalities. The aims of this study were: to compare the frequency and characteristics of OPD in children with ZRM and in children without microcephaly born to mothers who tested polymerase chain reaction positive (PCR+) for ZIKV during pregnancy; and to investigate the concordance of caregiver reports of OPD with the diagnosis from the clinical swallowing assessment (CSA). Between Mar/2017 and May/2018, we evaluated 116 children (n = 58 with microcephaly, n = 58 children without microcephaly born to ZIKV PCR + mothers) participating in the Microcephaly Epidemic Research Group (MERG) cohort of children born during the 2015–2016 ZIKV epidemic in Pernambuco, Brazil. To assess OPD we used: a CSA; a clinical assessment of the stomatognathic system; and a questionnaire administered to caregivers. The frequency of OPD was markedly higher in children with ZRM (79.3%) than in the exposed but normocephalic group (8.6%). The children with microcephaly also presented more frequently with anatomic and functional abnormalities in the stomatognathic system. There was a high degree of agreement between the caregiver reports of OPD and the CSA (κ = 0.92). In conclusion, our findings confirm that OPD is a feature of Congenital Zika Syndrome that primarily occurs in children with microcephaly and provide support for policies in which children are referred for rehabilitation with an OPD diagnosis based on caregiver report.

Background Although leprosy is largely curable with multidrug therapy, incomplete treatment limits therapeutic effectiveness and is an important obstacle to disease control. To inform efforts to improve treatment completion rates, we aimed to identify the geographic and socioeconomic factors associated with leprosy treatment default in Brazil. Methodology/Principal findings Using individual participant data collected in the Brazilian national registries for social programs and notifiable diseases and linked as part of the 100 Million Brazilian Cohort, we evaluated the odds of treatment default among 20,063 leprosy cases diagnosed and followed up between 2007 and 2014. We investigated geographic and socioeconomic risk factors using a multivariate hierarchical analysis and carried out additional stratified analyses by leprosy subtype and geographic region. Over the duration of follow-up, 1,011 (5.0%) leprosy cases were observed to default from treatment. Treatment default was markedly increased among leprosy cases residing in the North (OR = 1.57; 95%CI 1.25–1.97) and Northeast (OR = 1.44; 95%CI 1.17–1.78) regions of Brazil. The odds of default were also higher among cases with black ethnicity (OR = 1.29; 95%CI 1.01–1.69), no income (OR = 1.41; 95%CI 1.07–1.86), familial income ≤ 0.25 times Brazilian minimum wage (OR = 1.42; 95%CI 1.13–1.77), informal home lighting/no electricity supply (OR = 1.53; 95%CI 1.28–1.82), and household density of > 1 individual per room (OR = 1.35; 95%CI 1.10–1.66). Conclusions The findings of the study indicate that the frequency of leprosy treatment default varies regionally in Brazil and provide new evidence that adverse socioeconomic conditions may represent important barriers to leprosy treatment completion. These findings suggest that interventions to address socioeconomic deprivation, along with continued efforts to improve access to care, have the potential to improve leprosy treatment outcomes and disease control., Author summary While the leprosy new case detection has been decreasing worldwide since the introduction of multidrug therapy (MDT) in the 1980s, treatment default remains an important risk factor for leprosy-associated disability and an obstacle to disease control and elimination. Treatment default occurs when an individual with leprosy does not take the prescribed number of doses required for treatment with MDT. We hypothesized that the frequency of defaulting may be influenced by geographic factors, especially as related to access to care, and socioeconomic factors, such as income, education, and household living conditions. To test this hypothesis, we investigated geographic and socioeconomic factors associated with leprosy treatment default among 20,063 new leprosy cases followed as part of the 100 Million Brazilian Cohort between 2007 and 2014. In total, 5.0% of the leprosy patients defaulted from MDT. Among the associated factors, we found that having residency in the North and Northeast of Brazil, black ethnicity, low familial income, lack of formal electricity, and a high household density were associated with higher odds of leprosy treatment default. Overall, these findings highlight the need for tailoring MDT strategies for vulnerable populations in high-burden communities and suggest that social policies aiming to alleviate poverty should be investigated as potential tools for improving leprosy treatment completion.

Robust epidemiological and biological evidence supports a causal link between prenatal Zika Virus (ZIKV) infection and congenital brain abnormalities including microcephaly. However, it remains uncertain if ZIKV infection in pregnancy also increases the risk for other adverse fetal and birth outcomes. In a prospective cohort study we investigated the influence of ZIKV on the prevalence of prematurity, low birth weight, small-for-gestational-age, and fetal death as well as microcephaly (i.e., overall and disproportionate) in the offspring of women attending a high-risk pregnancy clinic during the recent ZIKV outbreak in Brazil. During the recruitment period (01 March 2016–23 August 2017), urine samples were tested for ZIKV by RT-PCR from all women attending the high-risk pregnancy clinic at Jundiaí University Hospital and from the neonates after delivery. Of the 574 women evaluated, 44 (7.7%) were ZIKV RT-PCR positive during pregnancy. Of the 409 neonates tested, 19 (4.6%) were ZIKV RT-PCR positive in the first 10 days of life. In this cohort, maternal ZIKV exposure was not associated with increased risks of prematurity, low birth weight, small-for-gestational-age, or fetal death. However, relative to ZIKV-negative neonates, ZIKV-positive infants had a five-fold increased risk of microcephaly overall (RR 5.1, 95% CI 1.2–22.5) and a ten-fold increased risk of disproportionate microcephaly (RR 10.3, 95% CI 2.0–52.6). Our findings provide new evidence that, in a high-risk pregnancy cohort, ZIKV RT-PCR positivity in the neonate at birth is strongly associated with microcephaly. However, ZIKV infection during pregnancy does not appear to influence the risks of prematurity, low birth weight, small-for-gestational-age or fetal death in women who already have gestational comorbidities. The results suggest disproportion between neonatal head circumference and weight may be a useful screening indicator for the detection of congenital microcephaly associated with ZIKV infection.

Our study aims to describe trends in new case detection rate (NCDR) of leprosy in Brazil from 2006 to 2017 overall and in subgroups, and to analyze the evolution of clinical and treatment characteristics of patients, with emphasis on cases diagnosed with grade 2 physical disabilities. We conducted a descriptive study to analyze new cases of leprosy registered in the Brazilian Information System for Notificable Diseases (SINAN), from 2006-2017. We calculated the leprosy NCDR per 100,000 inhabitants (overall and for individuals aged < 15 and ≥ 15 years) by sex, age, race/ethnicity, urban/rural areas, and Brazilian regions, and estimated the trends using the Mann-Kendall non-parametric test. We analyzed the distributions of cases according to relevant clinical characteristics over time. In Brazil, there was a sharp decrease in the overall NCDR from 23.4/100,000 in 2006 to 10.3/100,000 in 2017; among children < 15 years, from 6.94 to 3.20/100,000. The decline was consistent in all Brazilian regions and race/ethnicity categories. By 2017, 70.2% of the cases were multibacillary, 30.5% had grade 1 (G1D) or 2 (G2D) physical disabilities at diagnosis and 42.8% were not evaluated at treatment completion/discharge; cases with G2D at diagnosis were mostly detected in urban areas (80%) and 5% of cases died during the treatment (leprosy or other causes). Although the frequency of leprosy NCDR decreased in Brazil from 2006 to 2017 across all evaluated population groups, the large number of cases with multibacillary leprosy, physical disabilities or without adequate evaluation, and among children suggest the need to reinforce timely diagnosis and treatment to control leprosy in Brazil. Resumo: O estudo teve com objetivos descrever as tendências na taxa de detecção de casos novos (TDCN) de hanseníase no Brasil em 2006-2017, global e por subgrupos, e analisar a evolução das características clínicas e terapêuticas dos pacientes, com ênfase nos casos diagnosticados com incapacidade física grau 2. Realizamos um estudo descritivo par analisar casos novos de hanseníase registrados no Sistema de Informação de Agravos de Notificação (SINAN), 2006-2017. Calculamos a TDCN de hanseníase por 100.000 habitantes (global e para indivíduos < 15 e ≥ 15 anos de idade) por sexo, idade, raça/etnicidade, área urbana/rural e macrorregião do Brasil e estimamos as tendências com o teste não paramétrico de Mann-Kendall. Analisamos as distribuições de casos de acordo com características clínicas relevantes ao longo do tempo. No Brasil, houve uma queda marcante na TDCN global, de 23,4/100.000 em 2006 para 10,3/100.000 em 2017; entre crianças < 15 anos, de 6,94 para 3,20/100.000. A queda foi consistente em todas a regiões brasileiras e em todas as categorias de raça/etnicidade. Até 2017, 70,2% dos casos eram multibacilares, 30,5% apresentavam incapacidades físicas grau 1 (G1D) ou grau 2 (G2D) ao diagnóstico e 42,8% não foram avaliados ao encerramento do tratamento ou alta; os casos com G2D ao diagnóstico foram detectados majoritariamente nas áreas urbanas (80%), e 5% dos casos faleceram durante o tratamento (devido à hanseníase ou por outras causas). Embora a frequência da TDCN da hanseníase tenha diminuído no Brasil entre 2006 e 2017 em todos os grupos avaliados, o número grande de casos com hanseníase multibacilar, incapacidades físicas ou sem avaliação adequada e entre crianças sugere a necessidade de reforçar o diagnóstico e tratamento oportunos para controlar a hanseníase no Brasil. Resumen: Se realizó este trabajo con el fin de describir la tendencia general y en subgrupos de la tasa de detección de nuevos casos de lepra (NCDR por sus siglas en inglés) en Brasil, entre 2006-2017, así como para analizar la evolución de las características clínicas y de tratamiento de los pacientes, con énfasis en los casos diagnosticados con un grado 2 de discapacidad física. Realizamos un estudio descriptivo para analizar los nuevos casos de lepra registrados en el Sistema Brasileño de Información de Enfermedades de Notificación (SINAN), 2006-2017. Calculamos la NCDR de lepra por cada 100.000 habitantes (general e individuos con una edad < 15 y ≥ 15 años) por sexo, edad, raza/etnicidad, áreas urbanas/rurales y regiones brasileñas, y estimamos las tendencias usando el test no paramétrico de Mann-Kendall. Analizamos las distribuciones de casos según las características clínicas relevantes a lo largo del tiempo. En Brasil, hubo una drástica disminución en general de NCDR de los 23,4/100.000 en 2006, a los 10,3/100.000 en 2017; entre niños < 15 años, desde los 6,94 a los 3,20/100.000. El decremento fue consistente en todas las regiones brasileñas y categorías de raza/etnicidad. En 2017, un 70,2% de los casos fueron multibacilares, un 30,5% tenían grado 1 (G1D) o 2 (G2D) discapacidad física en el diagnóstico y un 42,8% no fueron evaluados al completar el tratamiento/ser dados de alta; casos con G2D en el diagnóstico fueron en su mayoría detectados en áreas urbanas (80%) y un 5% de los casos murieron durante el tratamiento (lepra u otras causas). A pesar de la frecuencia de lepra los NCDR decrecieron en Brasil de 2006 a 2017, a través de todos los grupos de población evaluados, el elevado número de casos con lepra multibacilar, discapacidad física o sin una adecuada evaluación, y entre niños sugiere la necesidad de reforzar a tiempo el diagnóstico y tratamiento para controlar la lepra en Brasil.

Summary 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 Familia (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–Doencas Negligenciadas, the UK Medical Research Council, the Wellcome Trust, and Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior–Brazil (CAPES).

BackgroundThere is limited knowledge on the influence of concurrent coinfections on the clinical presentation of Zika virus (ZIKV) disease.MethodsTo better understand the types, frequencies and clinical manifestations of ZIKV coinfections, we did a systematic review of four databases (PubMed, Embase, Web of Science, LILACS) without restrictions for studies on ZIKV coinfections confirmed by nucleic acid (quantitative real-time-PCR) testing of ZIKV and coinfecting pathogens. The review aimed to identify cohort, cross-sectional, case series and case report studies that described frequencies and/or clinical signs and symptoms of ZIKV coinfections. Conference abstracts, reviews, commentaries and studies with imprecise pathogen diagnoses and/or no clinical evaluations were excluded.ResultsThe search identified 34 articles from 10 countries, comprising 2 cohort, 10 cross-sectional, 8 case series and 14 case report studies. Coinfections were most frequently reported to have occurred with other arthropod-borne viruses (arboviruses); out of the 213 coinfections described, ZIKV infections co-occurred with chikungunya in 115 cases, with dengue in 68 cases and with both viruses in 19 cases. Other coinfecting agents included human immunodeficiency, Epstein-Barr, human herpes and Mayaro viruses, Leptospira spp, Toxoplasma gondii and Schistosoma mansoni. ZIKV-coinfected cases primarily presented with mild clinical features, typical of ZIKV monoinfection; however, 9% of cases in cohort and cross-sectional studies were reported to experience complications.ConclusionBased on the evidence collated in this review, coinfections do not appear to strongly influence the clinical manifestations of uncomplicated ZIKV infections. Further research is needed to confirm whether risk of severe complications is altered when ZIKV infection co-occurs with other infections.PROSPERO registration numberCRD42018111023.

The genitourinary tract was recently identified as a potential site of complications related to the congenital Zika syndrome (CZS). We provide the first report of a series of cryptorchidism cases in 3-year-old children with Zika-related microcephaly who underwent consultations between October 2018 and April 2019 as part of the follow-up of the children cohort of the Microcephaly Epidemic Research Group, Pernambuco, Brazil. Of the 22 males examined, eight (36.4%) presented with cryptorchidism. Among 14 undescended testis cases, 11 (78.6%) could be palpated in the inguinal region. Seven of the eight children had severe microcephaly. Conventional risk factors for cryptorchidism were relatively infrequent in these children. We hypothesize that cryptorchidism is an additional manifestation of CZS present in children with severe microcephaly. As in our cases, for most of the children, the testes were located in the inguinal region, and the possible mechanisms for cryptorchidism were gubernaculum disturbance or cremasteric abnormality.

Importance Despite progress toward reducing global incidence, leprosy control remains a challenge in low- and middle-income countries. Objective To estimate new case detection rates of leprosy among household contacts of patients with previously diagnosed leprosy and to investigate its associated risk factors. Design, Setting, and Participants This population-based cohort study included families registered in the 100 Million Brazilian Cohort linked with nationwide registries of leprosy; data were collected from January 1, 2007, through December 31, 2014. Household contacts of patients with a previous diagnosis of leprosy from each household unit were followed up from the time of detection of the primary case to the time of detection of a subsequent case or until December 31, 2014. Data analysis was performed from May to December 2018. Exposures Clinical characteristics of the primary case and sociodemographic factors of the household contact. Main Outcomes and Measures Incidence of leprosy, estimated as the new case detection rate of leprosy per 100 000 household contacts at risk (person-years at risk). The association between occurrence of a subsequent leprosy case and the exposure risk factors was assessed using multilevel mixed-effects logistic regressions allowing for state- and household-specific random effects. Results Among 42 725 household contacts (22 449 [52.5%] female; mean [SD] age, 22.4 [18.5] years) of 17 876 patients detected with leprosy, the new case detection rate of leprosy was 636.3 (95% CI, 594.4-681.1) per 100 000 person-years at risk overall and 521.9 (95% CI, 466.3-584.1) per 100 000 person-years at risk among children younger than 15 years. Household contacts of patients with multibacillary leprosy had higher odds of developing leprosy (adjusted odds ratio [OR],1.48; 95% CI, 1.17-1.88), and the odds increased among contacts aged 50 years or older (adjusted OR, 3.11; 95% CI, 2.03-4.76). Leprosy detection was negatively associated with illiterate or preschool educational level (adjusted OR, 0.59; 95% CI, 0.38-0.92). For children, the odds were increased among boys (adjusted OR, 1.70; 95% CI, 1.20-2.42). Conclusions and Relevance The findings in this Brazilian population-based cohort study suggest that the household contacts of patients with leprosy may have increased risk of leprosy, especially in households with existing multibacillary cases and older contacts. Public health interventions, such as contact screening, that specifically target this population appear to be needed.

Background Understanding immunogenicity and safety of monovalent type 2 oral poliovirus vaccine (mOPV2) in inactivated poliovirus vaccine (IPV)–immunized children is of major importance in informing global policy to control circulating vaccine-derived poliovirus outbreaks. Methods In this open-label, phase 4 study (NCT02582255) in 100 IPV-vaccinated Lithuanian 1–5-year-olds, we measured humoral and intestinal type 2 polio neutralizing antibodies before and 28 days after 1 or 2 mOPV2 doses given 28 days apart and measured stool viral shedding after each dose. Parents recorded solicited adverse events (AEs) for 7 days after each dose and unsolicited AEs for 6 weeks after vaccination. Results After 1 mOPV2 challenge, the type 2 seroprotection rate increased from 98% to 100%. Approximately 28 days after mOPV2 challenge 34 of 68 children (50%; 95% confidence interval, 38%–62%) were shedding virus; 9 of 37 (24%; 12%–41%) were shedding 28 days after a second challenge. Before challenge, type 2 intestinal immunity was undetectable in IPV-primed children, but 28 of 87 (32%) had intestinal neutralizing titers ≥32 after 1 mOPV2 dose. No vaccine-related serious or severe AEs were reported. Conclusions High viral excretion after mOPV2 among exclusively IPV-vaccinated children was substantially lower after a subsequent dose, indicating induction of intestinal immunity against type 2 poliovirus.

GeoSentinel, initiated in 1995 by the International Society of Travel Medicine, is a global network of 70 travel and tropical medicine centers in 31 countries initially created to track emerging infections at their point of entry, but now expanded to include monitoring of global disease trends among travellers and determining individual-level and destination-related risk factors [5] [ ]travellers and locals may have differing age distributions and underlying risk factors that could modify the clinical severity or complications of the resulting disease [ ]travellers may display more health-seeking behaviour traits, be more likely to seek testing for minor symptoms, and have better access to testing laboratories

We report Zika virus (ZIKV) vertical transmission in 130 infants born to PCR+ mothers at the time of the Rio de Janeiro epidemic of 2015–2016. Serum and urine collected from birth through the first year of life were tested by quantitative reverse transcriptase polymerase chain reaction (PCR) and/or IgM Zika MAC-ELISA. Four hundred and seven specimens are evaluated; 161 sera tested by PCR and IgM assays, 85 urines by PCR. Sixty-five percent of children (N = 84) are positive in at least one assay. Of 94 children tested within 3 months of age, 70% are positive. Positivity declines to 33% after 3 months. Five children are PCR+ beyond 200 days of life. Concordance between IgM and PCR results is 52%, sensitivity 65%, specificity 40% (positive PCR results as gold standard). IgM and serum PCR are 61% concordant; serum and urine PCR 55%. Most children (65%) are clinically normal. Equal numbers of children with abnormal findings (29 of 45, 64%) and normal findings (55 of 85, 65%) have positive results, p = 0.98. Earlier maternal trimester of infection is associated with positive results (p = 0.04) but not clinical disease (p = 0.98). ZIKV vertical transmission is frequent but laboratory confirmed infection is not necessarily associated with infant abnormalities., Here, Brasil et al. investigate mother to child Zika virus (ZIKV) transmission rates in a large longitudinal cohort of pregnant ZIKV-positive women with their infants followed from the time of maternal infection through birth and onwards, finding high in utero transmission rates that do not predict clinical outcomes, suggesting follow-up of children with antenatal ZIKV exposure is necessary.

The main goal of this manuscript was to investigate the neurodevelopment of children exposed by Zika virus in the intrauterine period who are asymptomatic at birth. Newborns with documented Zika virus exposure during the intrauterine period who were asymptomatic at birth were followed in the first two years of life for neurodevelopment using Bayley III test. Children were classified as having normal or delayed neurodevelopment for age based on most recent Bayley III evaluation results. Eighty-four infants were included in the study. The first Bayley III evaluation was performed at a mean chronological age of 9.7±3.1 month; 13 children (15%) had a delay in one of the three domains, distributed as follow: 10 (12%) in the language domain and 3 (3.5%) in the motor domain. The most recent Bayley III evaluation was performed at a mean age 15.3±3.1 months; 42 children (50%) had a delay in one of the three domains: 4 (5%) in cognition, 31 (37%) in language, and 20 (24%) in motor performance. There were no statistical differences in Gender, Gestational Age, Birth Weight and Head Circurference at birth between children with normal and delayed neurodevelopment for age. A very high proportion of children exposed ZIKV during pregnancy who were asymptomatic at birth demonstrated a delay in neurodevelopment, mainly in the language domain, the first two years of life.

The implications of Zika Virus exposure in pregnancy for early infant growth remains poorly described. The main goal of this study is to compare the growth, body composition, and feeding modality of infants in the first three months of life by prenatal Zika Virus exposure status. We selected an analytical cohort of 115 infants born without microcephaly, comprising 56 infants with qRT-PCR confirmed exposure to ZIKV during gestation and 59 infants born to women with presumptively no evidence of ZIKV in pregnancy. Infants were evaluated at birth, 1 and 3 months of age in terms of anthropometrics, body composition All the results were adjusted by maternal age, maternal BMI and gestational age. We observe no differences between anthropometric measurements at birth. Mothers in exposed group showed higher BMI. At 1 month and 3 months of age there were differences in mid arm circumference, arm muscle circumference and fat free mass. Weight and length was less in the ZIKV exposed in pregnancy infants and statistically different at 3 month of age. The findings of this investigation provide new evidence that ZIKV exposure in pregnancy may be associated with differences in body composition.

Severe malarial anaemia (SMA) is the most common life-threatening complication of Plasmodium falciparum infection in African children. SMA is characterised by haemolysis and inadequate erythropoiesis, and is associated with dysregulated inflammatory responses and reduced complement regulatory protein levels (including CD35). However, a deeper mechanistic understanding of the pathogenesis requires improved animal models. In this comparative study of two closely related macaque species, we interrogated potential causal factors for their differential and temporal relationships to onset of SMA. We found that rhesus macaques inoculated with blood-stage Plasmodium coatneyi developed SMA within 2 weeks, with no other severe outcomes, whereas infected cynomolgus macaques experienced only mild/ moderate anaemia. The abrupt drop in haematocrit in rhesus was accompanied by consumption of haptoglobin (haemolysis) and poor reticulocyte production. Rhesus developed a greater inflammatory response than cynomolgus macaques, and had lower baseline levels of CD35 on red blood cells (RBCs) leading to a significant reduction in the proportion of CD35+ RBCs during infection. Overall, severe anaemia in rhesus macaques infected with P. coatneyi has similar features to SMA in children. Our comparisons are consistent with an association of low baseline CD35 levels on RBCs and of early inflammatory responses with the pathogenesis of SMA.

Background There are limited data on the natural history of antenatal Zika virus (ZIKV) exposure in twin pregnancies, especially regarding intertwin concordance of prenatal, placental, and infant outcomes. Methods This prospective cohort study included twin pregnancies referred to a single institution from September 2015 to June 2016 with maternal ZIKV. Polymerase chain reaction (PCR) testing of maternal, placental, and neonatal samples was performed. Prenatal ultrasounds were completed for each twin, and histomorphologic analysis was performed for each placenta. Abnormal neonatal outcome was defined as abnormal exam and/or abnormal imaging. Two- to three-year follow-up of infants included physical exams, neuroimaging, and Bayley-III developmental assessment. Results Among 244 pregnancies, 4 twin gestations without coinfection were identified. Zika virus infection occurred at 16–33 weeks gestation. Zika virus PCR testing revealed discordance between dichorionic twins, between placentas in a dichorionic pair, between portions of a monochorionic placenta, and between a neonate and its associated placenta. Of the 8 infants, 3 (38%) had an abnormal neonatal outcome. Of 6 infants with long-term follow-up, 3 (50%) have demonstrated ZIKV-related abnormalities. Conclusions Neonatal PCR testing, placental findings, and infant outcomes can be discordant between co-twins with antenatal ZIKV exposure. These findings demonstrate that each twin should be evaluated independently for vertical transmission.

Whole-sporozoite vaccines confer sterilizing immunity to malaria-naive individuals by unknown mechanisms. In the first PfSPZ Vaccine trial ever in a malaria-endemic population, Vδ2 γδ T cells were significantly elevated and Vγ9/Vδ2 transcripts ranked as the most upregulated in vaccinees who were protected from Plasmodium falciparum infection. In a mouse model, absence of γδ T cells during vaccination impaired protective CD8 T cell responses and ablated sterile protection. γδ T cells were not required for circumsporozoite protein–specific Ab responses, and γδ T cell depletion before infectious challenge did not ablate protection. γδ T cells alone were insufficient to induce protection and required the presence of CD8α+ dendritic cells. In the absence of γδ T cells, CD8α+ dendritic cells did not accumulate in the livers of vaccinated mice. Altogether, our results show that γδ T cells were essential for the induction of sterile immunity during whole-organism vaccination.

Zika virus (ZIKV) is a vectorborne infectious agent of global public health significance due to its potential to cause severe teratogenic outcomes. The question of whether health systems should consider adopting screening programmes for ZIKV infections during pregnancy warrants consideration. In this analysis, we apply the Wilson-Jungner framework to appraise the potential utility of a prenatal ZIKV screening programme, outline potential screening strategies within the case-finding pathway, and consider other epidemiological factors that may influence the planning of such a screening programme. Our evaluation of a potential prenatal ZIKV screening programme highlights factors affirming its usefulness, including the importance of Congenital Zika Syndrome as a public health problem and the existence of analogous congenital prenatal screening programmes for STORCH agents (syphilis, toxoplasmosis, others (eg, human immunodeficiency virus, varicella-zoster virus, parvovirus B19), rubella, cytomegalovirus, and herpes simplex virus). However, our assessment also reveals key barriers to implementation, such as the need for more accurate diagnostic tests, effective antiviral treatments, increased social service capacity, and surveillance. Given that the reemergence of ZIKV is likely, we provide a guiding framework for policymakers and public health leaders that can be further elaborated and adapted to different contexts in order to reduce the burden of adverse ZIKV-related birth outcomes during future outbreaks.

There are important differences in the risk of SARS-CoV-2 infection and death depending on occupation. Infections in healthcare workers have received the most attention, and there are clearly increased risks for intensive care unit workers who are caring for COVID-19 patients. However, a number of other occupations may also be at an increased risk, particularly those which involve social care or contact with the public. A large number of data sets are available with the potential to assess occupational risks of COVID-19 incidence, severity, or mortality. We are reviewing these data sets as part of the Partnership for Research in Occupational, Transport, Environmental COVID Transmission (PROTECT) initiative, which is part of the National COVID-19 Core Studies. In this report, we review the data sets available (including the key variables on occupation and potential confounders) for examining occupational differences in SARS-CoV-2 infection and COVID-19 incidence, severity and mortality. We also discuss the possible types of analyses of these data sets and the definitions of (occupational) exposure and outcomes. We conclude that none of these data sets are ideal, and all have various strengths and weaknesses. For example, mortality data suffer from problems of coding of COVID-19 deaths, and the deaths (in England and Wales) that have been referred to the coroner are unavailable. On the other hand, testing data is heavily biased in some periods (particularly the first wave) because some occupations (e.g. healthcare workers) were tested more often than the general population. Random population surveys are, in principle, ideal for estimating population prevalence and incidence, but are also affected by non-response. Thus, any analysis of the risks in a particular occupation or sector (e.g. transport), will require a careful analysis and triangulation of findings across the various available data sets.

Shifting the malaria priorities from a paradigm of control and elimination to a goal of global eradication calls for renewed attention to the interruption of malaria transmission. Sustained progress toward eradication will require both improved understanding of infectious reservoirs and efficient development of novel transmission-blocking interventions, such as rapidly acting and highly efficacious therapeutics and vaccines. Here, we review the direct skin feeding assay (DSF), which has been proposed as a valuable tool for measuring the in natura transmission of malaria parasites from human hosts to mosquito vectors across heterogeneous populations. To capture the methodological breadth of this assay’s use, we first systematically review and qualitatively synthesize previously published investigations using DSFs to study malaria transmission in humans. Then, using a recent Phase 1 trial in Mali of the Pfs25H-EPA/Alhydrogel® vaccine candidate (NCT01867463) designed to interrupt Plasmodium falciparum transmission as a case study, we describe the potential opportunities and current limitations of utilizing the endpoints measured by DSF in making early clinical decisions for individually randomized transmission-interrupting intervention candidates. Using simulations based on the data collected in the clinical trial, we demonstrate that the capacity of the DSF to serve as an evaluative tool is limited by the statistical power constraints of the “effective sample size” (i.e. the number of subjects that are capable of transmitting at the time of feeding). Altogether, our findings suggest DSFs have great potential utility for assessing the public health impacts of emerging antimalarial tools, but additional research is needed to address issues of scalability and to establish correlation with community-wide clinical endpoints as well as complementary in vitro measures, such as standard membrane feeding assays.

Summary: Background: Although leprosy is recognised as a disease of poverty, there is little evidence on the specific socioeconomic factors associated with disease risk. To inform targeted strategies for disease elimination, we investigated socioeconomic markers of leprosy risk in Brazil. Methods: Socioeconomic data from the 100 Million Brazilian Cohort were linked to the Brazilian national disease registry (Sistema de Informação de Agravos de Notificação) for leprosy from Jan 1, 2007, to Dec 31, 2014. Using Poisson regression, we assessed the association of socioeconomic factors with risk of incident leprosy in the full cohort and in children (aged 0–15 years), by leprosy subtype and region of residence. Findings: In an analysis of 23 899 942 individuals including 18 518 patients with leprosy, increased levels of deprivation were associated with an increased risk of leprosy in Brazil. Directions of effect were consistent in children younger than 15 years and across disease subtypes. Individuals residing in regions with the highest poverty in the country (central-west, north, and northeast regions) had a risk of leprosy incidence five-to-eight times greater than did other individuals. Decreased levels of income and education and factors reflecting unfavourable living conditions were associated with an up to two-times increase in leprosy incidence (incidence rate ratio 1·46, 95% CI 1·32–1·62, for lowest vs highest quartile of income per capita; 2·09, 95% CI 1·62–2·72, for lowest vs highest level of education). Interpretation: Within the poorest half of the Brazilian population, the most deprived individuals have the greatest risk of leprosy. Strategies focusing on early detection and treatment in the poorest populations could contribute substantially to global disease control. Funding: Medical Research Council, Wellcome Trust, Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (Brazil), the Conselho Nacional das Fundações Estaduais de Amparo à Pesquisa, Economic and Social Research Council, Biotechnology and Biological Sciences Research Council, Conselho Nacional de Desenvolvimento Científico e Tecnológico, and Fundação de Apoio à Pesquisa do Distrito Federal.

PurposeThe Jundiaí Zika Cohort (JZC) is a prospective pregnancy and birth cohort setup in the State of São Paulo, Brazil, to investigate the epidemic of cases of microcephaly and other neurological disorders, presumed to be associated with Zika virus (ZIKV) infection.ParticipantsA total of 748 women with high-risk pregnancies were recruited in the period of March 2016 to August 2017.Findings to dateBaseline sociodemographic and medical data were collected at recruitment from 737 pregnant women. Biological samples (ie, blood, saliva and urine) were collected from 695 of the pregnant women (94.3%), of whom 53 (7.6%) were ZIKV-positive on subsequent testing by reverse transcription polymerase chain reaction (RT-PCR) in urine. Biological sample (ie, blood, saliva, urine and cerebrospinal fluid) were collected within 10 days of birth from 409 (57.4%) of the liveborn infants, of whom 19 (4.6%) were ZIKV-positive on subsequent testing by RT-PCR in urine. All remaining biological specimens, as well as colostrum, umbilical cord and placental samples, have been stored in a secure biorepository. Antenatal and postnatal imaging studies and neonatal anthropometry were carried out.Future plansThe JZC provides a unique data set which will continue to be explored to study the effects of pregnancy comorbidities on Zika virus infection during pregnancy, the long-term outcomes of children with congenital Zika infection and how physiotherapy and group interventions can improve outcomes for congenitally-infected children. All women in the cohort have reached the end of their pregnancy and currently the oldest children are 2 years old. The study will continue until all the children reach their third birthday (April 2021).

IntroductionZika virus (ZIKV) infection during pregnancy is a known cause of microcephaly and other congenital and developmental anomalies. In the absence of a ZIKV vaccine or prophylactics, principal investigators (PIs) and international leaders in ZIKV research have formed the ZIKV Individual Participant Data (IPD) Consortium to identify, collect and synthesise IPD from longitudinal studies of pregnant women that measure ZIKV infection during pregnancy and fetal, infant or child outcomes.Methods and analysisWe will identify eligible studies through the ZIKV IPD Consortium membership and a systematic review and invite study PIs to participate in the IPD meta-analysis (IPD-MA). We will use the combined dataset to estimate the relative and absolute risk of congenital Zika syndrome (CZS), including microcephaly and late symptomatic congenital infections; identify and explore sources of heterogeneity in those estimates and develop and validate a risk prediction model to identify the pregnancies at the highest risk of CZS or adverse developmental outcomes. The variable accuracy of diagnostic assays and differences in exposure and outcome definitions means that included studies will have a higher level of systematic variability, a component of measurement error, than an IPD-MA of studies of an established pathogen. We will use expert testimony, existing internal and external diagnostic accuracy validation studies and laboratory external quality assessments to inform the distribution of measurement error in our models. We will apply both Bayesian and frequentist methods to directly account for these and other sources of uncertainty.Ethics and disseminationThe IPD-MA was deemed exempt from ethical review. We will convene a group of patient advocates to evaluate the ethical implications and utility of the risk stratification tool. Findings from these analyses will be shared via national and international conferences and through publication in open access, peer-reviewed journals.Trial registration numberPROSPERO International prospective register of systematic reviews (CRD42017068915).

Objective To quantify total sialic acid in milk from HIV-positive Tanzanian mothers and to determine the impact of maternal diet on milk sialic acid levels. Design Milk samples were analyzed from 74 HIV-positive, Tanzanian women enrolled in a randomized, controlled clinical study of a dietary macronutrient supplement. Women were provided with a daily protein-calorie supplement and a micronutrient supplement or micronutrient supplement only during the last trimester of pregnancy and up to the first 6 months of breastfeeding. Methods Milk samples were collected at approximately 2 weeks and at least 3 months postpartum and assayed for total sialic acid. Milk sialic acid was assessed relative to maternal macronutrient intake, age, BMI, CD4+ cell count and infant birth weight. Results The mean concentration of milk sialic acid was highest in the first 2 weeks postpartum (6.89 ± 2.79 mmol/l) and declined rapidly by 3 months (2.49 ± 0.60 mmol/l). Sialic acid content in milk was similar between both treatment arms of the study, and did not correlate with maternal macronutrient intake. No correlation was found between maternal age, BMI, CD4+ cell count or infant birth weight and total milk sialic acid concentration. Conclusion Milk sialic acid levels in HIV-positive, Tanzanian women without malnutrition are comparable with reported values for women of European descent and show a similar temporal decline during early lactation. These findings suggest that total milk sialic acid is maintained despite macronutrient deficiencies in maternal diet and support a conserved role for milk sialic acid in neonatal development.

National Council for Scientific and Technological Development (Conselho Nacional de Desenvolvimento Cient?fico e Tecnol?gico? CNPq) (grant number 404861/2018-0); Wellcome Trust and the United Kingdom?s Department for International Development (grant numbers: 205377/Z/16/Z; 201870/Z/16/Z). European Union?s Horizon 2020 research and innovation programme under ZikaPLAN (grant number 734584). Wellcome Trust - Research Enrichment in Epidemic Situation (grant number 107779/Z/15/Z; with ER1505 & ER1601). Medical Research Council on behalf of the Newton Fund and Wellcome Trust (grant number MC_PC_15088). National Institutes of Health/National Institute of Allergy and Infectious Diseases (grant number RO1/AI140718). Fondation Christophe et Rodolphe M?rieux. National Council for Scientific and Technological Development (Conselho Nacional de Desenvolvimento Cient?fico e Tecnol?gico?CNPq) (grant numbers 443875/2018-9; 440573/2016-5; 441098/2016-9; 305090/2016-0; 307282/2017-1; 304476/2018- 8; 465549/2014-4; 440763/2016-9; 309722/2017-9; 306708/2014-0; 440577/2016-0). Coordination for the improvement of Higher Education Personnel (Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior-Capes) (grant numbers 88881.130813/2016-01; 88887.116627/2016-01; 88887.136366/2017-00). Ministry of Health of Brazil-Emergency Response in Public Health-Zika virus and Microcephaly (Minist?rio da Sa?de de Brasil-Resposta ? Emerg?ncia em Sa?de P?blica?Zika v?rus e Microcefalia) (grant number 837058/2016). Department of Science and Technology (Departamento de Ci?ncia e TecnologiaDECIT) (grant numbers 25000.072811/2016-19; 440839/2016-5). Foundation of Research Support of the State of S?o Paulo (Funda??o de Amparo ? Pesquisa do Estado de S?o Paulo?FAPESP) (grant numbers 2016/08578-0; 2017/21688-1; 2013/21719-3; 2016/15021-1; 2015/12295-0; 2016/05115-9). Foundation of Research Support of the State of Rio de Janeiro (Funda??o de Amparo ? Pesquisa do Estado do Rio de Janeiro ?FAPERJ) (grant numbers E-26/201.351/2016; E-18/2015TXB; E-26/202.862/2018; E-26/010.002477/2016). Foundation of Support for Research and Scientific and Technological Development of Maranh?o (Funda??o de Amparo ? Pesquisa e ao Desenvolvimento Cient?fico e Tecnol?gico do Maranh?o?FAPEMA) (grant number 008/2016). Brazilian Ministry of Health (Minist?rio da Sa?de?MS) (grant number 929698560001160-02). Evandro Chagas Institute/Brazilian Ministry of Health (Instituto Evandro Chagas/Minist?rio da Sa?de). Foundation of Research Support of the State of Goi?s (Funda??o de Amparo ? Pesquisa do Estado de Goi?s?FAPEG) (number grant 2017/10267000531). Foundation of Research Support of the State of Rio Grande do Sul (Funda??o de Amparo ? Pesquisa do Estado do Rio Grande do Sul?FAPERGS) (grant number 17/2551-0000521-0). Foundation to Support Teaching, Research and Assistance at Hospital das Cl?nicas, Faculty of Medicine of Ribeir?o Preto (Funda??o de Apoio ao Ensino, Pesquisa e Assist?ncia do Hospital das Cl?nicas da Faculdade de Medicina de Ribeir?o Preto) and S?o Paulo State Department of Health (Secretaria de Sa?de do Estado de S?o Paulo). Support Foundation of Pernambuco Science and Technology (Funda??o de Amparo ? Ci?ncia e Tecnologia de Pernambuco?FACEPE) (grant numbers APQ-0172-4.01/16; APQ-0192-4.01/17; APQ-0793-4.01/17). Funda??o de Medicina Tropical Doutor Heitor Vieira Dourado. Manaus, AM, Brasil. Universidade Federal de Campina Grande. Campina Grande, PB, Brasil / Instituto de Medicina Integral Professor Fernando Figueira. Recife, PE, Brazil. Universidade Federal de Pernambuco. Departamento de Medicina Social. Recife, PE, Brazil. Funda??o Oswaldo Cruz. Instituto Nacional de Infectologia Evandro Chagas. Rio de Janeiro, RJ, Brazil. London School of Hygiene & Tropical Medicine. London, UK. Funda??o de Medicina Tropical Doutor Heitor Vieira Dourado. Manaus, AM, Brasil. Universidade Federal de Pernambuco. Centro de Ci?ncias da Sa?de. Recife, PE, Brazil. Universidade Federal do Rio de Janeiro. Departamento de Pediatria. Rio de Janeiro, RJ, Brazil. Universidade de S?o Paulo, Ribeir?o Preto. Faculdade de Medicina de Ribeir?o Preto. Ribeir?o Preto, SP, Brasil. Universidade Federal de Sergipe. Aracaju, SE, Brazil. Secretaria Municipal de Tangar? da Serra. Tangar? da Serra, MT, Brazil. Universidade Federal do Rio de Janeiro. Departamento de Pediatria. Rio de Janeiro, RJ, Brazil. Universidade Federal de Sergipe. Aracaju, SE, Brazil. Funda??o Oswaldo Cruz. Instituto Aggeu Magalh?es. Recife, PE, Brazil. Universidade Federal de Campina Grande. Campina Grande, PB, Brasil / Instituto Paraibano de Diagn?stico. Campina Grande, PB, Brazil. Universidade de Pernambuco. Faculdade de Ci?ncias M?dicas. Recife, PE, Brazil. Universidade de Pernambuco. Instituto de Ci?ncias Biol?gicas. Recife, PE, Brazil. Funda??o Oswaldo Cruz. Instituto Fernandes Figueira. Rio de Janeiro, RJ, Brasil. Universidade de S?o Paulo. Faculdade de Medicina de Ribeir?o Preto. Ribeir?o Preto, SP, Brazil. Minist?rio da Sa?de. Secretaria de Vigil?ncia em Sa?de. Instituto Evandro Chagas. Ananindeua, PA, Brasil Faculdade de Medicina de Jundia?. Jundia?, SP, Brasil. Instituto D?Or de Pesquisa e Ensino. Rio de Janeiro, RJ, Brazil. Universidade Federal da Bahia. Instituto Sa?de Coletiva. Salvador, BA, Brazil. Universidade Federal do Rio Grande do Sul. Porto Alegre, RS, Brazil. Universidade Federal do Maranh?o. Departamento de Sa?de P?blica. S?o Lu?s, MA, Brazil. Centro de Pesquisas Gon?alo Moniz. Salvador, BA, Brazil. Secretaria de Sa?de do Estado do Maranh?o. Assist?ncia e Reabilita??o de Crian?as. Centro de Refer?ncia em Neurodesenvolvimento. S?o Lu?s, MA, Brazil. Universidade Federal de Goi?s. Departamento de Saude Coletiva. Goi?nia, GO, Brazil. Faculdade de Medicina de S?o Jos? do Rio Preto. S?o Jos? do Rio Preto, SP, Brasil. Despite great advances in our knowledge of the consequences of Zika virus to human health, many questions remain unanswered, and results are often inconsistent. The small sample size of individual studies has limited inference about the spectrum of congenital Zika manifestations and the prognosis of affected children. The Brazilian Zika Cohorts Consortium addresses these limitations by bringing together and harmonizing epidemiological data from a series of prospective cohort studies of pregnant women with rash and of children with microcephaly and/or other manifestations of congenital Zika. The objective is to estimate the absolute risk of congenital Zika manifestations and to characterize the full spectrum and natural history of the manifestations of congenital Zika in children with and without microcephaly. This protocol describes the assembly of the Consortium and protocol for the Individual Participant Data Meta-analyses (IPD Meta-analyses). The findings will address knowledge gaps and inform public policies related to Zika virus. The large harmonized dataset and joint analyses will facilitate more precise estimates of the absolute risk of congenital Zika manifestations among Zika virus-infected pregnancies and more complete descriptions of its full spectrum, including rare manifestations. It will enable sensitivity analyses using different definitions of exposure and outcomes, and the investigation of the sources of heterogeneity between studies and regions.

Background While Zika virus (ZIKV) is now widely recognized as a teratogen, the frequency and full spectrum of adverse outcomes of congenital ZIKV infection remains incompletely understood. Methods Participants in the MERG cohort of pregnant women with rash, recruited from the surveillance system from December/2015-June/2017. Exposure definition was based on a combination of longitudinal data from molecular, serologic (IgM and IgG3) and plaque reduction neutralization tests for ZIKV. Children were evaluated by a team of clinical specialists and by transfontanelle ultrasound and were classified as having microcephaly and/or other signs/symptoms consistent with congenital Zika syndrome (CZS). Risks of adverse outcomes were quantified according to the relative evidence of a ZIKV infection in pregnancy. Findings 376 women had confirmed and suspected exposure to ZIKV. Among evaluable children born to these mothers, 20% presented with an adverse outcome compatible with exposure to ZIKV during pregnancy. The absolute risk of microcephaly was 2.9% (11/376), of calcifications and/or ventriculomegaly was 7.2% (13/180), of additional neurologic alterations was 5.3% (13/245), of ophthalmologic abnormalities was 7% (15/214), and of dysphagia was 1.8% (4/226). Less than 1% of the children experienced abnormalities across all of the domains simultaneously. Interpretation: Although approximately one-fifth of children with confirmed and suspected exposure to ZIKV in pregnancy presented with at least one abnormality compatible with CZS, the manifestations presented more frequently in isolation than in combination. Due to the rare nature of some outcomes and the possibility of later manifestations, large scale individual participant data meta-analysis and the long-term evaluation of children are imperative to identify the full spectrum of this syndrome and to plan actions to reduce damages., Author summary The ability to meaningfully quantify the absolute and relative risks of Congenital Zika Syndrome is contingent on the accurate identification of ZIKV infections in pregnant women and the long-term follow-up of children at risk. This study builds on the evidence base on ZIKV in pregnancy by not only examining pregnancy and birth outcomes, but also considering later onset manifestations of Congenital Zika Syndrome, conducting a deep and standardized investigation of infant outcomes. In addition, it used unprecedented repeated testing and the use of multiple diagnostic platforms, including qRT-PCR, IgM and IgG3 ELISAs, and PRNTs to identify ZIKV cases. The absolute risk of microcephaly was 2.9%, of calcifications and/or ventriculomegaly was 7.2%, of additional neurologic alterations was 5.3%, of ophthalmologic abnormalities was 7% and of dysphagia was 1.8%. The manifestations presented more frequently in isolation than in combination (i.e., less than 1% of the children experienced abnormalities across all of the domains simultaneously). Although approximately one-fifth of children with confirmed and suspected exposure to ZIKV in pregnancy presented with at least one abnormality compatible with CZS, the manifestations presented more frequently in isolation than in combination

Congenital viral infections and the occurrence of septo-optic dysplasia, which is a combination of optic nerve hypoplasia, abnormal formation of structures along the midline of the brain, and pituitary hypofunction, support the biological plausibility of endocrine dysfunction in Zika-related microcephaly. In this case series we ascertained the presence and describe endocrine dysfunction in 30 children with severe Zika-related microcephaly from the MERG Pediatric Cohort, referred for endocrinological evaluation between February and August 2019. Of the 30 children, 97% had severe microcephaly. The average age at the endocrinological consultation was 41 months and 53% were female. The most frequently observed endocrine dysfunctions comprised short stature, hypothyroidism, obesity and variants early puberty. These dysfunctions occurred alone 57% or in combination 43%. We found optic nerve hypoplasia (6/21) and corpus callosum hypoplasia (20/21). Seizure crises were reported in 86% of the children. The most common&mdash, and clinically important&mdash, endocrine dysfunctions were pubertal dysfunctions, thyroid disease, growth impairment, and obesity. These dysfunctions require careful monitoring and signal the need for endocrinological evaluation in children with Zika-related microcephaly, in order to make early diagnoses and implement appropriate treatment when necessary.

Recent outbreaks of influenza, Ebola, and Zika viruses have taught us that pregnant women are uniquely vulnerable to emerging infectious threats. Let’s not fail pregnant frontline workers during the covid-19 pandemic, say Elizabeth B Brickley and Enny S Paixao

Background Identifying polio vaccine regimens that can elicit robust intestinal mucosal immunity and interrupt viral transmission is a key priority of the polio endgame. Methods In a 2013 Chilean clinical trial (NCT01841671) of trivalent inactivated polio vaccine (IPV) and bivalent oral polio vaccine (bOPV; targeting types 1 and 3), infants were randomized to receive IPV-bOPV-bOPV, IPV-IPV-bOPV, or IPV-IPV-IPV at 8, 16, and 24 weeks of age and challenged with monovalent oral polio vaccine type 2 (mOPV2) at 28 weeks. Using fecal samples collected from 152 participants, we investigated the extent to which IPV-bOPV and IPV-only immunization schedules induced intestinal neutralizing activity and immunoglobulin A against polio types 1 and 2. Results Overall, 37% of infants in the IPV-bOPV groups and 26% in the IPV-only arm had detectable type 2–specific stool neutralization after the primary vaccine series. In contrast, 1 challenge dose of mOPV2 induced brisk intestinal immune responses in all vaccine groups, and significant rises in type 2–specific stool neutralization titers (P < .0001) and immunoglobulin A concentrations (P < 0.0001) were measured 2 weeks after the challenge. In subsidiary analyses, duration of breastfeeding also appeared to be associated with the magnitude of polio-specific mucosal immune parameters measured in infant fecal samples. Conclusions Taken together, these results underscore the concept that mucosal and systemic immune responses to polio are separate in their induction, functionality, and potential impacts on transmission and, specifically, provide evidence that primary vaccine regimens lacking homologous live vaccine components are likely to induce only modest, type-specific intestinal immunity.

Summary Background The use of abdominal tissue in post-mastectomy autologous breast reconstruction is a popular choice among reconstructive surgeons. This is the first study to evaluate donor complications comparing unilateral, bilateral, and bipedicled DIEP breast reconstructions. Methods A retrospective chart review was conducted of all women undergoing rib-preserving DIEP free flap breast reconstruction at a University Hospital between 2008 and 2015 by the senior surgeon (CMM). Results A total of 130 patients were included in this study and were divided into three groups: unipedicled unilateral ( n = 93), unipedicled bilateral ( n = 19), and bipedicled unilateral ( n = 18). Relative to the unipedicled unilateral group, the age and BMI-adjusted odds of complication were almost two-fold higher in the bilateral group [Odds ratio (95% CI): 1.97 (0.63, 6.19)] and approximately halved in the bipedicled group [Odds ratio (95% CI): 0.59 (0.22, 1.61)]; however, these associations were not statistically significant. Overall, 75% of complications were managed conservatively. The majority of Clavien–Dindo grade 3 complications were observed in participants from the unipedicled unilateral group (84%), whereas no patients in the bipedicled group developed morbidity that required recourse to surgery or readmission to hospital. Conclusions Although further research with greater statistical power will be valuable, the results of this investigation provide evidence that donor site morbidity of bipedicled DIEP free flap breast reconstructions does not increase when compared with those of unipedicled unilateral and unipedicled bilateral surgical procedure types.

BackgroundOur understanding of the acquisition of intestinal mucosal immunity and the control of poliovirus replication and transmission in later life is still emerging.MethodsAs part of a 2011 randomised, blinded, placebo-controlled clinical trial of the experimental antiviral agent pocapavir (EudraCT 2011-004804-38), Swedish adults, aged 18–50 years, who had previously received four doses of inactivated polio vaccine (IPV) in childhood were challenged with a single dose of monovalent oral polio vaccine type 1 (mOPV1). Using faecal samples collected before and serially, over the course of 45 days, after mOPV1 challenge from a subset of placebo-arm participants who did not receive pocapavir (N=12), we investigated the kinetics of the intestinal antibody response to challenge virus by measuring poliovirus type 1-specific neutralising activity and IgA concentrations.ResultsIn faecal samples collected prior to mOPV1 challenge, we found no evidence of pre-existing intestinal neutralising antibodies to any of the three poliovirus serotypes. Despite persistent high-titered vaccine virus shedding and rising serum neutralisation responses after mOPV1 challenge, intestinal poliovirus type 1-specific neutralisation remained low with a titer of ≤18.4 across all time points and individuals. Poliovirus types 1-specific, 2-specific and 3-specific IgA remained below the limit of detection for all specimens collected postchallenge.InterpretationIn contrast to recent studies demonstrating brisk intestinal antibody responses to oral polio vaccine challenge in young children previously vaccinated with IPV, this investigation finds that adults previously vaccinated with IPV have only modest intestinal poliovirus type 1-specific neutralisation and no IgA responses that are measurable in stool samples following documented mOPV1 infection.

The 2017 Stanley A. Plotkin Lecture in Vaccinology was delivered by Professor Peter F. Wright at the Pediatric Academic Societies Annual Meeting in San Francisco, California, in May 2017. The presentation provided an overview of the mucosal immune system as it applies to vaccinology. Specifically, Professor Wright’s lecture highlighted the remarkable opportunities for mucosal immunity research afforded by having both topically administered live vaccines and systemically administered inactivated vaccines available for the same pathogen. Using influenza and poliovirus case studies, Professor Wright described the use of live attenuated vaccines for human challenges and discussed how recent technological advancements in immunological assays have ushered in a new era for investigating the correlates of immune protection against wild-type infections at mucosal sites.

As a pilot study to investigate whether personalized medicine approaches could have value for the reduction of malaria-related mortality in young children, we evaluated questionnaire and biomarker data collected from the Mother Offspring Malaria Study Project birth cohort (Muheza, Tanzania, 2002–2006) at the time of delivery as potential prognostic markers for pediatric severe malarial anemia. Severe malarial anemia, defined here as aPlasmodium falciparuminfection accompanied by hemoglobin levels below 50 g/L, is a key manifestation of life-threatening malaria in high transmission regions. For this study sample, a prediction model incorporating cord blood levels of interleukin-1β provided the strongest discrimination of severe malarial anemia risk with a C-index of 0.77 (95% CI 0.70–0.84), whereas a pragmatic model based on sex, gravidity, transmission season at delivery, and bed net possession yielded a more modest C-index of 0.63 (95% CI 0.54–0.71). Although additional studies, ideally incorporating larger sample sizes and higher event per predictor ratios, are needed to externally validate these prediction models, the findings provide proof of concept that risk score-based screening programs could be developed to avert severe malaria cases in early childhood.