There is a paucity of reference early childhood development (ECD) data at community level in rural Africa. Our objective was to conduct a comprehensive assessment of ECD in rural Zimbabwe and determine the impact of stunting and schistosome infections on ECD. Using the Griffiths Scales of Child Development, we conducted a cross sectional assessment of Eye and Hand Coordination (EHC), Personal-Social-Emotional (PSE), Language and Communication (LC), Foundations of Learning (FL) and Gross Motor (GM) domains and the summary General Development (GD) in 166 children aged 6-72 months. The effects of stunting, malnutrition and Schistosoma haematobium infection on ECD was determined. The impact of praziquantel curative treatment of schistosome infection on the developmental scores was determined through a longitudinal follow up at 6 and 12 months. From an initial 166 children, 11 were found to have developmental deficits warranting further investigation. Of the remaining 155, 58.7% recorded a good (≥ average) score for the overall General Development (GD). Proportions of children scoring above the cut-off (≥ average) for each domain were GM (84.5%), PSE (80.6%), EHC (61.9%), FL (43.9%) and LC (44.5%). The prevalence of stunting was 26.8% (95% CI = 20.1%-34.8%) Scores for stunted children were significantly lower for EHC (p = 0.0042), GM (p = 0.0099), and GD (p = 0.0014) with the fraction of lower scores attributable to stunting being GM = 63.4%, GD = 46.6%, EHC = 45%, and LC = 21%. S. haematobium infection prevalence was 39.7% and mean infection intensity was 5.4 eggs/10 ml urine. Infected children had poorer cognitive performance scores for the FL (p = 0.0005) with 30.8% of poor FL attributable to the infection. Performance in all domains improved to the expected normal or above reference levels at 6 and 12 months post curative treatment of schistosome infections. Our study documented reference values for ECD in rural Zimbabwean children. The study detected deficiencies in the FL domain, which were more pronounced in children, infected with schistosomes, highlighting the need for provision of cognitive stimulation tools and access to early childhood foundation education. There is also need for improved child nutrition and treatment of schistosome infections to improve child development outcomes.

An estimated 30% of women in Sub-Saharan Africa suffer from soil-transmitted helminth infection during pregnancy (SHIP), which has been shown to increase risk of pre-term birth, low birth weight, and maternal anemia. A previous study in Benin found that SHIP was associated with impaired cognitive and gross motor development scores in 635 one-year-old children. The objective of the present study was to follow children prospectively to investigate whether the association between SHIP and child neurocognitive and behavioral development persisted at age six.

Global deworming programs aim to reach 75% of at-risk preschool-age children (pre-SAC) by 2020. The 2013 global pre-SAC deworming coverage initially published by the World Health Organization (WHO) was 23.9%, but this estimate inadequately captured deworming delivered through Child Health Day (CHD) platforms.

Shigella infections cause inflammation, which has been hypothesized to mediate the associations between Shigella and child development outcomes among children in low-resource settings. We aimed to assess whether early life inflammation and Shigella infections affect school-aged growth and cognitive outcomes from 6-8 years of age.

Poor water, sanitation and hygiene (WaSH) conditions are hypothesized to contribute to environmental enteric dysfunction (EED), a subclinical condition that may be associated with chronic undernutrition and impaired linear growth. We evaluated the effect of a combined water and sanitation intervention on biomarkers of EED, and then assessed associations of biomarkers of EED with height-for-age z-scores (HAZ), in children under five. We conducted a sub-study within a matched cohort study of a household-level water and sanitation infrastructure intervention in rural Odisha, India, in which we had observed an effect of the intervention on HAZ. We collected stool samples (N = 471) and anthropometry data (N = 209) for children under age 5. We analyzed stool samples for three biomarkers of EED: myeloperoxidase (MPO), neopterin (NEO), and α1-anti-trypsin (AAT). We used linear mixed models to estimate associations between the intervention and each biomarker of EED and between each biomarker and HAZ. The intervention was inversely associated with AAT (-0.25 log μg/ml, p = 0.025), suggesting a protective effect on EED, but was not associated with MPO or NEO. We observed an inverse association between MPO and HAZ (-0.031 per 1000 ng/ml MPO, p = 0.0090) but no association between either NEO or AAT and HAZ. Our results contribute evidence that a transformative WaSH infrastructure intervention may reduce intestinal permeability, but not intestinal inflammation and immune activation, in young children. Our study also adds to observational evidence of associations between intestinal inflammation and nutritional status, as measured by HAZ, in young children. Trial Registration: ClinicalTrials.gov (NCT02441699).

The role of the immune response in influencing leptospirosis clinical outcomes is not yet well understood. We hypothesized that acute-phase serum cytokine responses may play a role in disease progression, risk for death, and severe pulmonary hemorrhage syndrome (SPHS).

Invasive infections associated with non-typhoidal Salmonella (NTS) serovars Enteritidis (SE), Typhimurium (STm) and monophasic variant 1,4,[5],12:i:- are a major health problem in infants and young children in sub-Saharan Africa, and currently, there are no approved human NTS vaccines. NTS O-polysaccharides and flagellin proteins are protective antigens in animal models of invasive NTS infection. Conjugates of SE core and O-polysaccharide (COPS) chemically linked to SE flagellin have enhanced the anti-COPS immune response and protected mice against fatal challenge with a Malian SE blood isolate. We report herein the development of a STm glycoconjugate vaccine comprised of STm COPS conjugated to the homologous serovar phase 1 flagellin protein (FliC) with assessment of the role of COPS O-acetyls for functional immunity. Sun-type COPS conjugates linked through the polysaccharide reducing end to FliC were more immunogenic and protective in mice challenged with a Malian STm blood isolate than multipoint lattice conjugates (>95% vaccine efficacy [VE] versus 30-43% VE). Immunization with de-O-acetylated STm-COPS conjugated to CRM197 provided significant but reduced protection against STm challenge compared to mice immunized with native STm-COPS:CRM197 (63-74% VE versus 100% VE). Although OPS O-acetyls were highly immunogenic, post-vaccination sera that contained various O-acetyl epitope-specific antibody profiles displayed similar in vitro bactericidal activity when equivalent titers of anti-COPS IgG were assayed. In-silico molecular modeling further indicated that STm OPS forms a single dominant conformation, irrespective of O-acetylation, in which O-acetyls extend outward and are highly solvent exposed. These preclinical results establish important quality attributes for an STm vaccine that could be co-formulated with an SE-COPS:FliC glycoconjugate as a bivalent NTS vaccine for use in sub-Saharan Africa.

Despite the devastating impact of mosquito-borne illnesses on human health, surprisingly little is known about mosquito developmental biology, including development of the olfactory system, a tissue of vector importance. Analysis of mosquito olfactory developmental genetics has been hindered by a lack of means to target specific genes during the development of this sensory system. In this investigation, chitosan/siRNA nanoparticles were used to target semaphorin-1a (sema1a) during olfactory system development in the dengue and yellow fever vector mosquito Aedes aegypti. Immunohistochemical analyses and anterograde tracing of antennal sensory neurons, which were used to track the progression of olfactory development in this species, revealed antennal lobe defects in sema1a knockdown fourth instar larvae. These findings, which correlated with a larval odorant tracking behavioral phenotype, identified previously unreported roles for Sema1a in the developing insect larval olfactory system. Analysis of sema1a knockdown pupae also revealed a number of olfactory phenotypes, including olfactory receptor neuron targeting and projection neuron defects coincident with a collapse in the structure and shape of the antennal lobe and individual glomeruli. This study, which is to our knowledge the first functional genetic analysis of insect olfactory development outside of D. melanogaster, identified critical roles for Sema1a during Ae. aegypti larval and pupal olfactory development and advocates the use of chitosan/siRNA nanoparticles as an effective means of targeting genes during post-embryonic Ae. aegypti development. Use of siRNA nanoparticle methodology to understand sensory developmental genetics in mosquitoes will provide insight into the evolutionary conservation and divergence of key developmental genes which could be exploited in the development of both common and species-specific means for intervention.

Hundreds of millions of people in poor countries continue to suffer from disease caused by bloodfeeding hookworms. While mice and rats are not reliably permissive hosts for any human hookworm species, adult Golden Syrian hamsters are fully permissive for the human and animal pathogen Ancylostoma ceylanicum. Similar to humans, hamsters may be infected with A. ceylanicum third-stage larvae orally or percutaneously. Oral infection typically leads to consistent worm yields in hamsters but may not accurately reflect the clinical and immunological manifestations of human infection resulting from skin penetration.

Environmental enteric dysfunction (EED) may contribute to poor growth and development in young children. While validated EED biomarkers are currently lacking, multiplex assays are able to capture multiple domains of the condition. The purpose of this exploratory study was to examine the relationship between biomarkers of EED and subsequent growth and development among Tanzanian HIV-exposed uninfected (HEU) infants.

Onchocerciasis also known as river blindness is a neglected tropical disease and the world's second-leading infectious cause of blindness in humans; it is caused by Onchocerca volvulus. Current treatment with ivermectin targets microfilariae and transmission and does not kill the adult parasites, which reside within subcutaneous nodules. To support the development of macrofilaricidal drugs that target the adult worm to further support the elimination of onchocerciasis, an in-depth understanding of O. volvulus biology especially the factors that support the longevity of these worms in the human host (>10 years) is required. However, research is hampered by a lack of access to adult worms. O. volvulus is an obligatory human parasite and no small animal models that can propagate this parasite were successfully developed. The current optimized 2-dimensional (2-D) in vitro culturing method starting with O. volvulus infective larvae does not yet support the development of mature adult worms. To overcome these limitations, we have developed and applied 3-dimensional (3-D) culture systems with O. volvulus larvae that simulate the human in vivo niche using in vitro engineered skin and adipose tissue. Our proof of concept studies have shown that an optimized indirect co-culture of in vitro skin tissue supported a significant increase in growth of the fourth-stage larvae to the pre-adult stage with a median length of 816-831 μm as compared to 767 μm of 2-D cultured larvae. Notably, when larvae were co-cultured directly with adipose tissue models, a significant improvement for larval motility and thus fitness was observed; 95% compared to 26% in the 2-D system. These promising co-culture concepts are a first step to further optimize the culturing conditions and improve the long-term development of adult worms in vitro. Ultimately, it could provide the filarial research community with a valuable source of O. volvulus worms at various developmental stages, which may accelerate innovative unsolved biomedical inquiries into the parasite's biology.

Dengue is an important public health problem in the Philippines. We sought to describe the trends in dengue research in the country. We searched four databases and identified published studies on dengue research in the Philippines during the past 60 years. We reviewed 135 eligible studies, of which 33% were descriptive epidemiologic studies or case series, 16% were entomologic or vector control studies, 12% were studies on dengue virology and serologic response, 10% were socio-behavioral and economics studies, 8% were clinical trials, 7% were on burden of disease, 7% were investigations on markers of disease severity, 5% were on dengue diagnostics, and 2% were modeling studies. During the last decade, dengue research in the Philippines has increased and evolved from simple descriptive studies to those with more complex and diverse designs. We identified several key topics where more research would be useful.

Environmental enteric dysfunction (EED) may be an important modifiable cause of child stunting. We described the evolution of EED biomarkers from birth to 18 months in rural Zimbabwe and tested the independent and combined effects of improved water, sanitation, and hygiene (WASH), and improved infant and young child feeding (IYCF), on EED.

It is estimated that in Latin America and the Caribbean (LAC) at least 13.9 million preschool age and 35.4 million school age children are at risk of infections by soil-transmitted helminths (STH): Ascaris lumbricoides, Trichuris trichiura and hookworms (Necator americanus and Ancylostoma duodenale). Although infections caused by this group of parasites are associated with chronic deleterious effects on nutrition and growth, iron and vitamin A status and cognitive development in children, few countries in the LAC Region have implemented nationwide surveys on prevalence and intensity of infection. The aim of this study was to identify gaps on the mapping of prevalence and intensity of STH infections based on data published between 2000 and 2010 in LAC, and to call for including mapping as part of action plans against these infections. A total of 335 published data points for STH prevalence were found for 18 countries (11.9% data points for preschool age children, 56.7% for school age children and 31.3% for children from 1 to 14 years of age). We found that 62.7% of data points showed prevalence levels above 20%. Data on the intensity of infection were found for seven countries. The analysis also highlights that there is still an important lack of data on prevalence and intensity of infection to determine the burden of disease based on epidemiological surveys, particularly among preschool age children. This situation is a challenge for LAC given that adequate planning of interventions such as deworming requires information on prevalence to determine the frequency of needed anthelmintic drug administration and to conduct monitoring and evaluation of progress in drug coverage.

In its first 8 years, the Global Programme to Eliminate Lymphatic Filariasis (GPELF) achieved an unprecedentedly rapid scale-up: >1.9 billion treatments with anti-filarial drugs (albendazole, ivermectin, and diethylcarbamazine) were provided via yearly mass drug administration (MDA) to a minimum of 570 million individuals living in 48 of the 83 initially identified LF-endemic countries.

Despite the known burden of neglected tropical diseases (NTDs) on child health, there is limited information on current efforts to increase pediatric therapeutic options. Our objective was to quantify and characterize research activity and treatment availability for NTDs in children in order to inform the prioritization of future research efforts.

The history of Chagas disease control in Peru and many other nations is marked by scattered and poorly documented vector control campaigns. The complexities of human migration and sporadic control campaigns complicate evaluation of the burden of Chagas disease and dynamics of Trypanosoma cruzi transmission.

If a mother contracts the Zika Virus before or during pregnancy, then there is a risk of the child developing Congenital Zika Syndrome (CZS). An infant can then experience problems feeding due to the specific physical and developmental consequences of Congenital Zika Syndrome (CZS), such as microcephaly, dysphagia and an increased likelihood of choking. This qualitative evidence synthesis accesses direct and indirect evidence to inform WHO infant feeding guidelines. We conducted a qualitative evidence synthesis of the values and preferences of relevant stakeholders (e.g. pregnant women, mothers, family members and health practitioners) concerning infant (0-2 years) feeding in the presence of: 1) CZS (the'direct evidence'); 2) severe disability and nonprogressive, chronic encephalopathies ('indirect evidence'), which present with similar problems. Authors' findings were extracted, synthesised using thematic synthesis techniques, and confidence in the findings were assessed using GRADE-CERQual. Six CZS-specific studies (all from Brazil) were included in the direct evidence, with a further eight indirect studies reporting feeding difficulties in infants with severe disability and nonprogressive, chronic encephalopathies. Included studies highlighted: breast-feeding represented the preference for all mothers in the studies in both reviews, and the inability to do so affected bonding between parents and child, and generated fear and anxiety relating to feeding choices, especially around the risks of choking and swallowing; the perception that health professionals were often unable to offer appropriate advice; the potential value of training; and a strong desire to achieve individual maternal autonomy in infant feeding decisions. Confidence in most findings ranged from low to moderate. The evidence base has limitations, but consistently reported that parents of children with feeding difficulties due to Congenital Zika Syndrome, or similar, need information, advice and counselling, and substantial emotional support. Parents perceive that these needs are often neither recognised nor satisfied; optimal feeding and support strategies for this population have not yet been identified.

Brazil has at least 800,000 HTLV-1 infected individuals. HTLV-1 can be transmitted via sexual intercourse, contact with blood and from mother to child, mainly by breastfeeding. Treatments for the high morbidity/mortality associated diseases (ATL and HAM/TSP) are limited, therefore, infection prevention is of utmost importance. However, antenatal screening is not routinely performed in Brazil. A lack of data regarding the number of individuals infected via breastfeeding impairs the development of government policies. The objective is to estimate the number of HTLV-1 infections occurring annually due to mother to child transmission (MTCT) in Brazil, nationally and regionally.

Culture-independent diagnostics have revealed a larger burden of Shigella among children in low-resource settings than previously recognized. We further characterized the epidemiology of Shigella in the first two years of life in a multisite birth cohort. We tested 41,405 diarrheal and monthly non-diarrheal stools from 1,715 children for Shigella by quantitative PCR. To assess risk factors, clinical factors related to age and culture positivity, and associations with inflammatory biomarkers, we used log-binomial regression with generalized estimating equations. The prevalence of Shigella varied from 4.9%-17.8% in non-diarrheal stools across sites, and the incidence of Shigella-attributable diarrhea was 31.8 cases (95% CI: 29.6, 34.2) per 100 child-years. The sensitivity of culture compared to qPCR was 6.6% and increased to 27.8% in Shigella-attributable dysentery. Shigella diarrhea episodes were more likely to be severe and less likely to be culture positive in younger children. Older age (RR: 1.75, 95% CI: 1.70, 1.81 per 6-month increase in age), unimproved sanitation (RR: 1.15, 95% CI: 1.03, 1.29), low maternal education (<10 years, RR: 1.14, 95% CI: 1.03, 1.26), initiating complementary foods before 3 months (RR: 1.10, 95% CI: 1.01, 1.20), and malnutrition (RR: 0.91, 95% CI: 0.88, 0.95 per unit increase in weight-for-age z-score) were risk factors for Shigella. There was a linear dose-response between Shigella quantity and myeloperoxidase concentrations. The burden of Shigella varied widely across sites, but uniformly increased through the second year of life and was associated with intestinal inflammation. Culture missed most clinically relevant cases of severe diarrhea and dysentery.