Feeding characteristics and growth among children with prenatal exposure to Zika virus with and without microcephaly in the microcephaly epidemic research group pediatric cohort.

OBJECTIVE: To describe the feeding characteristics and growth of children with prenatal exposure to Zika virus (ZIKV) from birth to 48 months. DESIGN: Using data from the prospective Microcephaly Epidemic Research Group Pediatric Cohort (MERG-PC), children without microcephaly born to mothers with evidence of ZIKV infection during pregnancy (ZIKV-exposed children without microcephaly) and children with Zika-related microcephaly were compared using repeated cross-sectional analyses within the following age strata: birth; 1 to 12; 13 to 24; 25 to 36; and 37 to 48 months. The groups were compared in relation to prematurity, birth weight, breastfeeding, alternative feeding routes, dysphagia and anthropometric profiles based on the World Health Organization Anthro z-scores (weight-length/height, weight-age, length/height-age and BMI-age). RESULTS: The first assessment included 248 children, 77 (31.05%) with microcephaly and 171 (68.95%) without microcephaly. The final assessment was performed on 86 children. Prematurity was 2.35 times higher and low birth weight was 3.49 times higher in children with microcephaly. The frequency of breastfeeding was high (> 80%) in both groups. On discharge from the maternity hospital, the frequency of children requiring alternative feeding route in both groups was less than 5%. After 12 months of age, children with microcephaly required alternative feeding route more often than children without microcephaly. In children with microcephaly, the z-score of all growth indicators was lower than in children without microcephaly. CONCLUSIONS: Children with Zika-related microcephaly were more frequently premature and low birth weight and remained with nutritional parameters, i.e., weight-for-age, weight-for-length/height and length/height-for-age below those of the children without microcephaly.

Population-based surveillance for birth defects potentially related to Zika virus infection including 3-year mortality and developmental outcomes, and Early Intervention Program service use-New York City, 2016 birth cohort.

BACKGROUND: In response to the 2015-2017 Zika virus outbreak, New York City (NYC) identified and monitored infants with birth defects potentially related to congenital Zika virus. METHODS: Administrative data matches were used to describe the birth characteristics of children born in 2016 meeting screening criteria for birth defects potentially related to congenital Zika virus infection relative to other NYC births and to monitor mortality and Early Intervention Program use through age 2. RESULTS: Among 120,367 children born in NYC in 2016, 463 met screening criteria and 155 met the Centers for Disease Control and Prevention's case definition for birth defects potentially related to congenital Zika virus infection (1.3 per 1000; 95% confidence interval [CI], 1.1-1.5). Post-neonatal deaths occurred among 7.7% of cases (12) and 5.2% of non-cases (8). Odds of referral to the Early intervention Program among children who met screening criteria were lower among children of mothers who were married (OR, 0.60; 95% CI, 0.37-0.97) and among children not classified as cases whose mothers were born in Latin America and the Caribbean (OR, 0.59; 95% CI, 0.37-1.09). DISCUSSION: Prevalence of birth defects potentially related to congenital Zika virus infection was similar to that seen in other jurisdictions without local transmission. Birth defects attributable to congenital Zika virus infection may also have been present among screened children who did not meet the case definition.

A Zika virus protein expression screen in Drosophila to investigate targeted host pathways during development.

In the past decade, Zika virus (ZIKV) emerged as a global public health concern. Although adult infections are typically mild, maternal infection can lead to adverse fetal outcomes. Understanding how ZIKV proteins disrupt development can provide insights into the molecular mechanisms of disease caused by this virus, which includes microcephaly. In this study, we generated a toolkit to ectopically express ZIKV proteins in vivo in Drosophila melanogaster in a tissue-specific manner using the GAL4/UAS system. We used this toolkit to identify phenotypes and potential host pathways targeted by the virus. Our work identified that expression of most ZIKV proteins caused scorable phenotypes, such as overall lethality, gross morphological defects, reduced brain size and neuronal function defects. We further used this system to identify strain-dependent phenotypes that may have contributed to the increased pathogenesis associated with the outbreak of ZIKV in the Americas in 2015. Our work demonstrates the use of Drosophila as an efficient in vivo model to rapidly decipher how pathogens cause disease and lays the groundwork for further molecular study of ZIKV pathogenesis in flies.

Outcomes up to age 36 months after congenital Zika virus infection-U.S. states.

BACKGROUND: To characterize neurodevelopmental abnormalities in children up to 36 months of age with congenital Zika virus exposure. METHODS: From the U.S. Zika Pregnancy and Infant Registry, a national surveillance system to monitor pregnancies with laboratory evidence of Zika virus infection, pregnancy outcomes and presence of Zika associated birth defects (ZBD) were reported among infants with available information. Neurologic sequelae and developmental delay were reported among children with ≥1 follow-up exam after 14 days of age or with ≥1 visit with development reported, respectively. RESULTS: Among 2248 infants, 10.1% were born preterm, and 10.5% were small-for-gestational age. Overall, 122 (5.4%) had any ZBD; 91.8% of infants had brain abnormalities or microcephaly, 23.0% had eye abnormalities, and 14.8% had both. Of 1881 children ≥1 follow-up exam reported, neurologic sequelae were more common among children with ZBD (44.6%) vs. without ZBD (1.5%). Of children with ≥1 visit with development reported, 46.8% (51/109) of children with ZBD and 7.4% (129/1739) of children without ZBD had confirmed or possible developmental delay. CONCLUSION: Understanding the prevalence of developmental delays and healthcare needs of children with congenital Zika virus exposure can inform health systems and planning to ensure services are available for affected families. IMPACT: We characterize pregnancy and infant outcomes and describe neurodevelopmental abnormalities up to 36 months of age by presence of Zika associated birth defects (ZBD). Neurologic sequelae and developmental delays were common among children with ZBD. Children with ZBD had increased frequency of neurologic sequelae and developmental delay compared to children without ZBD. Longitudinal follow-up of infants with Zika virus exposure in utero is important to characterize neurodevelopmental delay not apparent in early infancy, but logistically challenging in surveillance models.

Low CCL2 and CXCL8 Production and High Prevalence of Allergies in Children with Microcephaly Due to Congenital Zika Syndrome.

Congenital Zika Syndrome (CZS) is associated with an increased risk of microcephaly in affected children. This study investigated the peripheral dysregulation of immune mediators in children with microcephaly due to CZS. Gene expression quantified by qPCR in whole blood samples showed an increase in IFNγ and IL-13 transcripts in children affected with microcephaly compared to the control group. The microcephaly group exhibited significantly decreased CCL2 and CXCL8 levels in serum, quantified by CBA assay. An allergic profile questionnaire revealed a high prevalence of allergies in the microcephaly group. In accordance, elevated serum IgE level measured by the Proquantum Immunoassay was observed in children affected with microcephaly compared to the control group. Altogether, these findings show a persistent systemic inflammation in children with microcephaly due to CZS and suggest a possible impairment in leukocyte migration caused by low production of CCL2 and CXCL8, in addition to high levels of IgE associated with high prevalence of allergies. The dysregulation of inflammatory genes and chemokines underscores the importance of understanding the immunological characteristics of CZS. Further investigation into the long-term consequences of systemic inflammation in these children is crucial for developing appropriate therapeutic strategies and tailored vaccination protocols.

Evaluation and monitoring of eye findings in children exposed to Zika virus during gestation: 3 years of follow-up.

INTRODUCTION: Congenital Zika syndrome (CZS) is a recently described disease. Our main objective was to evaluate and monitor, over 3 years, the ophthalmoscopic findings in children exposed to zika virus (ZIKV) during gestation. METHODS: This prospective observational study was conducted in Rio de Janeiro, Brazil, between April 2016 and May 2019. We evaluated two groups with exanthema serving as a proxy for viremia: (i) children whose mothers had exanthema during pregnancy and (ii) children who had microcephaly without maternal exanthema during pregnancy. We performed indirect ophthalmoscopy at recruitment and every 6 months thereafter. We also tested the association between ocular findings with maternal exanthema, microcephaly, CZS and maternal infection confirmed by reverse transcriptase quantitative polymerase chain reaction and gender. RESULTS: Of the 72 children included, 16 (22.2%) had optic nerve and/or retinal lesions. All 16 had CZS and 15 (93.7%) had microcephaly (14 at birth and 1 postnatally). The child with postnatally acquired microcephaly was born to a mother without exanthema during pregnancy. Fifty-six (77.8%) of the 72 children were followed for a median time of 24 months and none exhibited differences between admission and follow-up examinations. After logistic regression, only microcephaly at birth was associated with eye abnormalities (odds ratio, 77.015; 95% confidence interval, 8.85-670.38; p < 0.001). CONCLUSION: We observed that there was no progression of the lesions over the follow-up period. We also showed that the eye findings were associated only with microcephaly at birth. Attention should be paid to all children born during a ZIKV epidemic, regardless of maternal exanthema and/or microcephaly at birth.

Sociodemographic and Clinical Factors for Microcephaly Secondary to Teratogenic Infections in Brazil: An Ecological Study.

Microcephaly is a neurological condition characterized by anomalies in the growth of the cranial circumference. This study aims to examine the association between sociodemographic and clinical variables and the occurrence of secondary microcephaly in newborns in Brazil. It also aims to investigate the association between this congenital anomaly and teratogenic infections. This research adopts an observational approach with an ecological, descriptive, and analytical design. The sample includes infants aged ≤28 days and registered in the country's Live Births Information System from January 2015 to December 2021. Newborns were categorized into G1, consisting of newborns with one of the three infections (Zika, toxoplasmosis, or syphilis), and G2, consisting of newborns with two of the three infections. A total of 1513 samples were analyzed and divided into two groups: one infection (syphilis n = 423; toxoplasmosis n = 295; or Zika n = 739) and two infections (n = 56). The northeastern region of Brazil has the highest prevalence of microcephaly. Regarding the population profile, the Zika virus infection is more common among white mothers, while the syphilis infection is more common among black mothers. Among newborns with microcephaly, boys have a lower prevalence of toxoplasmosis infection, while girls have a lower prevalence of Zika virus infection. This study provides pertinent information on each infection and contributes to the epidemiologic understanding of the association between teratogenic infections and microcephaly.

Seroprevalence of Dengue, Chikungunya and Zika at the epicenter of the congenital microcephaly epidemic in Northeast Brazil: A population-based survey.

BACKGROUND: The four Dengue viruses (DENV) serotypes were re-introduced in Brazil's Northeast region in a couple of decades, between 1980's and 2010's, where the DENV1 was the first detected serotype and DENV4 the latest. Zika (ZIKV) and Chikungunya (CHIKV) viruses were introduced in Recife around 2014 and led to large outbreaks in 2015 and 2016, respectively. However, the true extent of the ZIKV and CHIKV outbreaks, as well as the risk factors associated with exposure to these viruses remain vague. METHODS: We conducted a stratified multistage household serosurvey among residents aged between 5 and 65 years in the city of Recife, Northeast Brazil, from August 2018 to February 2019. The city neighborhoods were stratified and divided into high, intermediate, and low socioeconomic strata (SES). Previous ZIKV, DENV and CHIKV infections were detected by IgG-based enzyme linked immunosorbent assays (ELISA). Recent ZIKV and CHIKV infections were assessed through IgG3 and IgM ELISA, respectively. Design-adjusted seroprevalence were estimated by age group, sex, and SES. The ZIKV seroprevalence was adjusted to account for the cross-reactivity with dengue. Individual and household-related risk factors were analyzed through regression models to calculate the force of infection. Odds Ratio (OR) were estimated as measure of effect. PRINCIPAL FINDINGS: A total of 2,070 residents' samples were collected and analyzed. The force of viral infection for high SES were lower as compared to low and intermediate SES. DENV seroprevalence was 88.7% (CI95%:87.0-90.4), and ranged from 81.2% (CI95%:76.9-85.6) in the high SES to 90.7% (CI95%:88.3-93.2) in the low SES. The overall adjusted ZIKV seroprevalence was 34.6% (CI95%:20.0-50.9), and ranged from 47.4% (CI95%:31.8-61.5) in the low SES to 23.4% (CI95%:12.2-33.8) in the high SES. The overall CHIKV seroprevalence was 35.7% (CI95%:32.6-38.9), and ranged from 38.6% (CI95%:33.6-43.6) in the low SES to 22.3% (CI95%:15.8-28.8) in the high SES. Surprisingly, ZIKV seroprevalence rapidly increased with age in the low and intermediate SES, while exhibited only a small increase with age in high SES. CHIKV seroprevalence according to age was stable in all SES. The prevalence of serological markers of ZIKV and CHIKV recent infections were 1.5% (CI95%:0.1-3.7) and 3.5% (CI95%:2.7-4.2), respectively. CONCLUSIONS: Our results confirmed continued DENV transmission and intense ZIKV and CHIKV transmission during the 2015/2016 epidemics followed by ongoing low-level transmission. The study also highlights that a significant proportion of the population is still susceptible to be infected by ZIKV and CHIKV. The reasons underlying a ceasing of the ZIKV epidemic in 2017/18 and the impact of antibody decay in susceptibility to future DENV and ZIKV infections may be related to the interplay between disease transmission mechanism and actual exposure in the different SES.

Brain MRI segmentation of Zika-Exposed normocephalic infants shows smaller amygdala volumes.

BACKGROUND: Infants with congenital Zika syndrome (CZS) are known to exhibit characteristic brain abnormalities. However, the brain anatomy of Zika virus (ZIKV)-exposed infants, born to ZIKV-positive pregnant mothers, who have normal-appearing head characteristics at birth, has not been evaluated in detail. The aim of this prospective study is, therefore, to compare the cortical and subcortical brain structural volume measures of ZIKV-exposed normocephalic infants to age-matched healthy controls. METHODS AND FINDINGS: We acquired T2-MRI of the whole brain of 18 ZIKV-exposed infants and 8 normal controls on a 3T MRI scanner. The MR images were auto-segmented into eight tissue types and anatomical regions including the white matter, cortical grey matter, deep nuclear grey matter, corticospinal fluid, amygdala, hippocampus, cerebellum, and brainstem. We determined the volumes of these regions and calculated the total intracranial volume (TICV) and head circumference (HC). We compared these measurements between the two groups, controlling for infant age at scan, by first comparing results for all subjects in each group and secondly performing a subgroup analysis for subjects below 8 weeks of postnatal age at scan. ZIKV-exposed infants demonstrated a significant decrease in amygdala volume compared to the control group in both the group and subgroup comparisons (p<0.05, corrected for multiple comparisons using FDR). No significant volume differences were observed in TICV, HC, or any specific brain tissue structures or regions. Study limitations include small sample size, which was due to abrupt cessation of extramural funding as the ZIKV epidemic waned. CONCLUSION: ZIKV-exposed infants exhibited smaller volumes in the amygdala, a brain region primarily involved in emotional and behavioral processing. This brain MRI finding may lead to poorer behavioral outcomes and warrants long-term monitoring of pediatric cases of infants with gestational exposure to Zika virus as well as other neurotropic viruses.

Insights into the structure, functional perspective, and pathogenesis of ZIKV: an updated review.

Zika virus (ZIKV) poses a serious threat to the entire world. The rapid spread of ZIKV and recent outbreaks since 2007 have caused worldwide concern about the virus. Diagnosis is complicated because of the cross-reactivity of the virus with other viral antibodies. Currently, the virus is diagnosed by molecular techniques such as RT-PCR and IgM-linked enzyme immunoassays (MAC-ELISA). Recently, outbreaks and epidemics have been caused by ZIKV, and severe clinical symptoms and congenital malformations have also been associated with the virus. Although most ZIKV infections present with a subclinical or moderate flu-like course of illness, severe symptoms such as Guillain-Barre syndrome in adults and microcephaly in children of infected mothers have also been reported. Because there is no reliable cure for ZIKV and no vaccine is available, the public health response has focused primarily on preventing infection, particularly in pregnant women. A comprehensive approach is urgently needed to combat this infection and stop its spread and imminent threat. In view of this, this review aims to present the current structural and functional viewpoints, structure, etiology, clinical prognosis, and measures to prevent this transmission based on the literature and current knowledge. Moreover, we provide thorough description of the current understanding about ZIKV interaction with receptors, and a comparative examination of its similarities and differences with other viruses.

Does Intra-Uterine Exposure to the Zika Virus Increase Risks of Cognitive Delay at Preschool Ages? Findings from a Zika-Exposed Cohort from Grenada, West Indies.

Maternal infection with Zika virus (ZIKV) is associated with a distinct pattern of birth defects, known as congenital Zika syndrome (CZS). In ZIKV-exposed children without CZS, it is often unclear whether they were protected from in utero infection and neurotropism. Early neurodevelopmental assessment is essential for detecting neurodevelopmental delays (NDDs) and prioritizing at-risk children for early intervention. We compared neurodevelopmental outcomes between ZIKV-exposed and unexposed children at 1, 3 and 4 years to assess exposure-associated NDD risk. A total of 384 mother-child dyads were enrolled during a period of active ZIKV transmission (2016-2017) in Grenada, West Indies. Exposure status was based on laboratory assessment of prenatal and postnatal maternal serum. Neurodevelopment was assessed using the Oxford Neurodevelopment Assessment, the NEPSY® Second Edition and Cardiff Vision Tests, at 12 (n = 66), 36 (n = 58) and 48 (n = 59) months, respectively. There were no differences in NDD rates or vision scores between ZIKV-exposed and unexposed children. Rates of microcephaly at birth (0.88% vs. 0.83%, p = 0.81), and childhood stunting and wasting did not differ between groups. Our results show that Grenadian ZIKV-exposed children, the majority of whom were without microcephaly, had similar neurodevelopmental outcomes to unexposed controls up to at least an age of 4 years.

Risk of adverse pregnancy and infant outcomes associated with prenatal Zika virus infection: a post-epidemic cohort in Central-West Brazil.

This study aimed to estimate the risks of adverse infant outcomes in the first year of life related to prenatal Zika virus (ZIKV) exposure. A prospective cohort of pregnant women with rash was recruited in Central-West Brazil in a post-epidemic period (January 2017 to April 2019). We evaluated participants' medical histories and performed ZIKV diagnostic testing using molecular (reverse transcription polymerase chain reaction [RT-PCR]) and serologic (immunoglobulin [Ig]M and plaque reduction neutralization tests [PRNT90]) assays. The ZIKV-positive group included both RT-PCR-confirmed cases as well as IgM and/or PRNT90-positive probable cases. Children were evaluated at birth and in the first 12 months of life. Transfontanellar ultrasound, central nervous system computed tomography, eye fundoscopy and retinography were performed. We estimated the absolute risk and 95% confidence interval (95% CI) of adverse infant outcomes among confirmed prenatally ZIKV-exposed children. Among 81 pregnant women with rash, 43 (53.1%) were ZIKV infected. The absolute risk of microcephaly among offspring of ZIKV-infected pregnant women was 7.0% (95% CI: 1.5-19.1), including the two cases of microcephaly detected prenatally and one detected postnatally. In total, 54.5% (95% CI: 39.8-68.7) of children in the ZIKV-exposed group had at least one ophthalmic abnormality, with the most frequent abnormalities being focal pigmentary mottling and chorioretinal atrophy or scarring. Our findings reinforce the importance of long-term monitoring of prenatally ZIKV-exposed children born apparently asymptomatic for Congenital Zika Syndrome.

Serological survey on bovine viral diarrhea virus in man and evaluation of relation with Zika virus-associated microcephaly.

Background: In 2015, an unprecedented epidemic of microcephaly occurred in Brazil. Preliminary observations suggested the involvement of cofactors in the etiopathology of Zika virus-associated microcephaly. Bovine viral diarrhea virus (BVDV) was identified in fetal samples with microcephaly, originating in the state of Paraíba, and two virus sequences, obtained from the amniotic fluid collected from mothers with babies affected by Zika and microcephaly, have been characterized as two different species of BVDV, types 1 and 2. Aim: The involvement of BVDV as a co-factor in the etiopathogenesis of Zika virus-associated microcephaly was explored. Methods: A serological screening using an ELISA test was undertaken to detect antibodies against BVDV among patients referred to the Central Laboratory of Natal, Rio Grande do Norte, encompassing microcephalic babies and their mothers, mothers and pregnants not associated with microcephaly and general patients as a control group. Results: Two samples were positive out of 382 tested (0.52%). No specific relation with birth defects could be established. Conclusions: The study might suggest serological evidence of BVDV in humans. Further studies and the application of improved diagnostic tests adapted to humans are necessary to clarify the epidemiological extent and impact of BVDV.

Congenital zika syndrome and family impacts: an integrative review. / Síndrome congênita do zika e impactos para as famílias: uma revisão integrativa.

In 2015, a range of congenital anomalies resulting from mother-to-child transmission of the zika virus emerged. Later called congenital zika syndrome (CZS), the condition includes microcephaly. Since then, around 4,000 children have been affected in 27 countries, with Brazil accounting for the largest proportion of cases. Family caregivers have also been affected. This study analyzes the literature on caregivers of children with CZS and how the disease has affected their everyday lives. We conducted an integrative review using the PubMed, Virtual Health Library, and Embase databases. Thirty-one articles were identified for analysis after screening. The findings were grouped into four categories: a) social impacts - changes in family relationships, life projects, and social life; b) subjective impacts - feelings of resilience, loneliness, grief, overburdening, fear, uncertainty, and spirituality and religion; c) economic and material impacts - loss of income, increased household expenses, change of residence, and unemployment; and d) health impacts - service unpreparedness, selflessness, self-care, changes in nutritional and sleep patterns, and mental health problems, including stress, anxiety and depression.

Em 2015, um espectro de anomalias congênitas, incluindo microcefalia, acometeu recém-nascidos como resultado da transmissão vertical pelo vírus zika, posteriormente denominada síndrome congênita do zika (SCZ). Desde então, cerca de 4 mil crianças foram afetadas em 27 países, sendo o Brasil o mais atingido. Cuidadores familiares também têm sido impactados. Esse estudo analisa publicações científicas que investigam as maneiras como a doença afetou as dinâmicas de vida de cuidadores familiares de crianças com SCZ. Realizou-se uma revisão integrativa de literatura consultando as bases de dados PubMed, Biblioteca Virtual em Saúde e Embase. Após as etapas de triagem, foram identificados 31 artigos. Os principais resultados foram agrupados em quatro categorias: a) impactos sociais que evidenciaram mudanças nas relações familiares, nos projetos de vida e no convívio social; b) impactos subjetivos - sentimentos de resiliência, solidão, luto, sobrecarga, medo, incerteza e relação com a espiritualidade; c) impactos econômicos e materiais - perda de renda, aumento de despesas, mudança de moradia e desemprego e d) impactos na saúde - despreparo dos serviços, renúncia do cuidado de si, modificações dos padrões nutricionais e de sono, repercussão para a saúde mental e níveis de estresse, ansiedade e depressão.

Relationship between microcephaly and indicators of social inequality in the state of Paraíba, Brazil.

OBJECTIVE: • Seventy-four (33.18%) municipalities in the state of Paraíba registered live births with microcephaly. • The highest proportion of cases (23.03%) was concentrated in the capital, João Pessoa. • Number of inhabitants, number of cases of Zika virus, water supply, and average household income were associated with a higher proportion of new cases. To analyze the relationship between microcephaly and social inequality indicators in the state of Paraíba during the biennium January 2015 and December 2016. METHODS: Ecological study with data from newborn microcephaly records and municipal socioeconomic, environmental, and demographic indicators was conducted using two health information systems from the Brazilian Ministry of Health (SINASC and SINAN) and the Brazilian Institute of Geography and Statistics. A Poisson multiple regression model was applied with a significance level of 5%. RESULTS: Among 223 municipalities in Paraíba, 74 registered new cases of microcephaly. The number of Zika virus cases, number of inhabitants, number of households without adequate water supply, and household income were predictor variables of the number of new cases of microcephaly in Paraíba. CONCLUSION: Microcephaly is associated with indicators of social inequality in Paraíba. Zika virus cases, water supply, and family income are the indicators that best explain the increase in microcephaly cases. Therefore, these variables must be monitored by health professionals and authorities.

Unravelling the epidemiological diversity of Zika virus by analyzing key protein variations.

The consequences of Zika virus (ZIKV) infections were limited to sporadic mild diseases until almost a decade ago, when epidemic outbreaks took place, with quick spread into the Americas. Simultaneously, novel severe neurological manifestations of ZIKV infections were identified, including congenital microcephaly. However, why the epidemic strains behave differently is not yet completely understood, and many questions remain about the actual significance of genetic variations in the epidemiology and biology of ZIKV. In this study, we analysed a large number of viral sequences to identify genes with different levels of variability and patterns of genomic variations that could be associated with ZIKV diversity. We compared numerous epidemic strains with pre-epidemic strains, using the BWA-mem algorithm, and we also examined specific variations among the epidemic ZIKV strains derived from microcephaly cases. We identified several viral genes with dissimilar mutation rates among the ZIKV strain groups and novel protein variation profiles that might be associated with epidemiological particularities. Finally, we assessed the impact of the detected changes on the structure and stability of the NS1, NS5, and E proteins using the I-TASSER, trRosetta, and RaptorX modelling algorithms, and we found some interesting variations that might help to explain the heterogeneous features of the diverse ZIKA strains. This work contributes to the identification of genetic differences in the ZIKV genome that might have a phenotypic impact, providing a basis for future experimental analysis to elucidate the genetic causes of the recent ZIKV emergency.

World variation in head circumference for children from birth to 5 years and a comparison with the WHO standards.

OBJECTIVE: A recent review reported that the WHO 2006 growth standards reflect a smaller head circumference at 24 months than seen in 18 countries. Whether this happens in early infancy and to what extent populations differ is not clear. This scooping review aimed to estimate the rates of children in different populations identified as macrocephalic or microcephalic by WHO standards. METHODS: We reviewed population-representative head circumference-for-age references. For each reference, we calculated the percentages of head circumferences that would be classified as microcephalic (<3rd WHO centile) or macrocephalic (>97th WHO centile) at selected ages. RESULTS: Twelve references from 11 countries/regions (Belgium, China, Ethiopia, Germany, Hong Kong, India, Japan, Norway, Saudi Arabia, UK and USA) were included. Median head circumference was larger than that for the Multicentre Growth Reference Study populations in both sexes in all these populations except for Japanese and Chinese children aged 1 month and Indians. Overall, at 12/24 months, 8%-9% children would be classified as macrocephalic and 2% would be classified as microcephalic, compared with the expected 3%. However at 1 month, there were geographic differences in the rate of macrocephaly (6%-10% in Europe vs 1%-2% in Japan and China) and microcephaly (1%-3% vs 6%-14%, respectively). CONCLUSIONS: Except for Indians and some Asian neonates, adopting the WHO head circumference standards would overdiagnose macrocephaly and underdiagnose microcephaly. Local population-specific cut-offs or references are more appropriate for many populations. There is a need to educate healthcare professionals about the limitations of the WHO head circumference standards.