Enteroaggregative Escherichia coli Subclinical Infection and Coinfections and Impaired Child Growth in the MAL-ED Cohort Study.

OBJECTIVE: We evaluated the impact of subclinical enteroaggregative Escherichia coli (EAEC) infection alone and in combination with other pathogens in the first 6 months of life on child growth. METHODS: Nondiarrheal samples from 1684 children across 8 Multisite Birth Cohort Study, Malnutrition and Enteric Diseases (MAL-ED) sites in Asia, Africa, and Latin America were tested monthly; more than 90% of children were followed-up twice weekly for the first 6 months of life. RESULTS: Children with subclinical EAEC infection did not show altered growth between enrollment and 6 months. Conversely, EAEC coinfection with any other pathogen was negatively associated with delta weight-for-length (P < 0.05) and weight-for-age (P > 0.05) z scores between 0 and 6 months. The presence of 2 or more pathogens without EAEC was not significantly associated with delta weight-for-length and weight-for-age. The most frequent EAEC coinfections included Campylobacter spp, heat-labile toxin-producing enterotoxigenic E coli, Cryptosporidium spp, and atypical enteropathogenic E coli. Myeloperoxidase levels were increased with EAEC coinfection (P < 0.05). EAEC pathogen codetection was associated with lower neopterin levels compared to those of no-pathogen control children (P < 0.05). Mothers of children with EAEC coinfections had lower levels of education, poorer hygiene and sanitation, lower socioeconomic status, and lower breast-feeding rates compared to mothers of children in whom no pathogen was detected (P < 0.05). CONCLUSIONS: These data emphasize the public health importance of subclinical EAEC infection in early infancy in association with other pathogens and the need for improved maternal and child care, hygiene, sanitation, and socioeconomic factors.

Effects of methyl and inorganic mercury exposure on genome homeostasis and mitochondrial function in Caenorhabditis elegans.

Mercury toxicity mechanisms have the potential to induce DNA damage and disrupt cellular processes, like mitochondrial function. Proper mitochondrial function is important for cellular bioenergetics and immune signaling and function. Reported impacts of mercury on the nuclear genome (nDNA) are conflicting and inconclusive, and mitochondrial DNA (mtDNA) impacts are relatively unknown. In this study, we assessed genotoxic (mtDNA and nDNA), metabolic, and innate immune impacts of inorganic and organic mercury exposure in Caenorhabditis elegans. Genotoxic outcomes measured included DNA damage, DNA damage repair (nucleotide excision repair, NER; base excision repair, BER), and genomic copy number following MeHg and HgCl2 exposure alone and in combination with known DNA damage-inducing agents ultraviolet C radiation (UVC) and hydrogen peroxide (H2O2), which cause bulky DNA lesions and oxidative DNA damage, respectively. Following exposure to both MeHg and HgCl2, low-level DNA damage (∼0.25 lesions/10kb mtDNA and nDNA) was observed. Unexpectedly, a higher MeHg concentration reduced damage in both genomes compared to controls. However, this observation was likely the result of developmental delay. In co-exposure treatments, both mercury compounds increased initial DNA damage (mtDNA and nDNA) in combination with H2O2 exposure, but had no impact in combination with UVC exposure. Mercury exposure both increased and decreased DNA damage removal via BER. DNA repair after H2O2 exposure in mercury-exposed nematodes resulted in damage levels lower than measured in controls. Impacts to NER were not detected. mtDNA copy number was significantly decreased in the MeHg-UVC and MeHg-H2O2 co-exposure treatments. Mercury exposure had metabolic impacts (steady-state ATP levels) that differed between the compounds; HgCl2 exposure decreased these levels, while MeHg slightly increased levels or had no impact. Both mercury species reduced mRNA levels for immune signaling-related genes, but had mild or no effects on survival on pathogenic bacteria. Overall, mercury exposure disrupted mitochondrial endpoints in a mercury-compound dependent fashion.

Plasma Tryptophan and the Kynurenine-Tryptophan Ratio are Associated with the Acquisition of Statural Growth Deficits and Oral Vaccine Underperformance in Populations with Environmental Enteropathy.

Early childhood enteric infections have adverse impacts on child growth and can inhibit normal mucosal responses to oral vaccines, two critical components of environmental enteropathy. To evaluate the role of indoleamine 2,3-dioxygenase 1 (IDO1) activity and its relationship with these outcomes, we measured tryptophan and the kynurenine-tryptophan ratio (KTR) in two longitudinal birth cohorts with a high prevalence of stunting. Children in rural Peru and Tanzania (N = 494) contributed 1,251 plasma samples at 3, 7, 15, and 24 months of age and monthly anthropometrics from 0 to 36 months of age. Tryptophan concentrations were directly associated with linear growth from 1 to 8 months after biomarker assessment. A 1-SD increase in tryptophan concentration was associated with a gain in length-for-age Z-score (LAZ) of 0.17 over the next 6 months in Peru (95% confidence interval [CI] = 0.11-0.23, P < 0.001) and a gain in LAZ of 0.13 Z-scores in Tanzania (95% CI = 0.03-0.22, P = 0.009). Vaccine responsiveness data were available for Peru only. An increase in kynurenine by 1 µM was associated with a 1.63 (95% CI = 1.13-2.34) increase in the odds of failure to poliovirus type 1, but there was no association with tetanus vaccine response. A KTR of 52 was 76% sensitive and 50% specific in predicting failure of response to serotype 1 of the oral polio vaccine. KTR was associated with systemic markers of inflammation, but also interleukin-10, supporting the association between IDO1 activity and immunotolerance. These results strongly suggest that the activity of IDO1 is implicated in the pathophysiology of environmental enteropathy, and demonstrates the utility of tryptophan and kynurenine as biomarkers for this syndrome, particularly in identifying those at risk for hyporesponsivity to oral vaccines.

River transport of mercury from artisanal and small-scale gold mining and risks for dietary mercury exposure in Madre de Dios, Peru.

Artisanal and small-scale gold mining (ASGM) is a major contributor to deforestation and the largest anthropogenic source of atmospheric mercury worldwide. Despite significant information on the direct health impacts of mercury to ASGM miners, the impact of mercury contamination on downstream communities has not been well characterized, particularly in Peru's Madre de Dios region. In this area, ASGM has increased significantly since 2000 and has led to substantial political and social controversy. This research examined the spatial distribution and transport of mercury through the Madre de Dios River with distance from ASGM activity. This study also characterized risks for dietary mercury exposure to local residents who depend on fish from the river. River sediment, suspended solids from the water column, and fish samples were collected in 2013 at 62 sites near 17 communities over a 560 km stretch of the Madre de Dios River and its major tributaries. In areas downstream of known ASGM activity, mercury concentrations in sediment, suspended solids, and fish within the Madre de Dios River were elevated relative to locations upstream of mining. Fish tissue mercury concentrations were observed at levels representing a public health threat, with greater than one-third of carnivorous fish exceeding the international health standard of 0.5 mg kg(-1). This study demonstrates that communities located hundreds of kilometers downstream of ASGM activity, including children and indigenous populations who may not be involved in mining, are at risk of dietary mercury exposure that exceed acceptable body burdens. This report represents the first systematic study of the region to aid policy decision-making related to ASGM activities in Peru.

Association of vaccine-related attitudes and beliefs between parents and health care providers.

OBJECTIVES: Health care providers influence parental vaccination decisions. Over 90% of parents report receiving vaccine information from their child's health care provider. The majority of parents of vaccinated children and children exempt from school immunization requirements report their child's primary provider is a good source for vaccine information. The role of health care providers in influencing parents who refuse vaccines has not been fully explored. The objective of the study was to determine the association between vaccine-related attitudes and beliefs of health care providers and parents. METHODS: We surveyed parents and primary care providers of vaccinated and unvaccinated school age children in four states in 2002-2003 and 2005. We measured key immunization beliefs including perceived risks and benefits of vaccination. Odds ratios for associations between parental and provider responses were calculated using logistic regression. RESULTS: Surveys were completed by 1367 parents (56.1% response rate) and 551 providers (84.3% response rate). Parents with high confidence in vaccine safety were more likely to have providers with similar beliefs, however viewpoints regarding disease susceptibility and severity and vaccine efficacy were not associated. Parents whose providers believed that children get more immunizations than are good for them had 4.6 higher odds of holding that same belief compared to parents whose providers did not have that belief. CONCLUSIONS: The beliefs of children's health care providers and parents, including those regarding vaccine safety, are similar. Provider beliefs may contribute to parental decisions to accept, delay or forgo vaccinations. Parents may selectively choose providers who have similar beliefs to their own.

Are Recent Medical Graduates More Skeptical of Vaccines?

Rates of delay and refusal of recommended childhood vaccines are increasing in many U.S. communities. Children's health care providers have a strong influence on parents' knowledge, attitudes, and beliefs about vaccines. Provider attitudes towards immunizations vary and affect their immunization advocacy. One factor that may contribute to this variability is their familiarity with vaccine-preventable diseases and their sequelae. The purpose of this study was to investigate the association of health care provider year of graduation with vaccines and vaccine-preventable disease beliefs. We conducted a cross sectional survey in 2005 of primary care providers identified by parents of children whose children were fully vaccinated or exempt from one or more school immunization requirements. We examined the association of provider graduation cohort (5 years) with beliefs on immunization, disease susceptibility, disease severity, vaccine safety, and vaccine efficacy. Surveys were completed by 551 providers (84.3% response rate). More recent health care provider graduates had 15% decreased odds of believing vaccines are efficacious compared to graduates from a previous 5 year period; had lower odds of believing that many commonly used childhood vaccines were safe; and 3.7% of recent graduates believed that immunizations do more harm than good. Recent health care provider graduates have a perception of the risk-benefit balance of immunization, which differs from that of their older counterparts. This change has the potential to be reflected in their immunization advocacy and affect parental attitudes.

Disparities in preschool immunization coverage associated with maternal age.

Associations between maternal age and preschool immunization coverage are unclear. This study aimed to determine if maternal age is associated with preschool immunization coverage and the importance of maternal age compared with other factors affecting vaccination coverage. Data from the 2001-2003 National Immunization Survey (NIS) were used to estimate vaccine coverage. Children were considered up-to-date (UTD) if they received > or =4 doses of DTaP, > or =3 doses of polio, > or =1 doses of MMR, > or =3 doses of Hib and > or =3 doses of Hep B. Bivariate and multivariate relationships between UTD coverage and maternal, child and household factors were evaluated. Classification tree analysis assessed complex interactions between maternal, child and household factors associated with UTD coverage and isolated the most important factors in predicting UTD coverage. UTD coverage was significantly associated with maternal age: coverage increased as maternal age increased. Coverage among children with 17 year old mothers was 64%; coverage among children of mothers 17-26 years old increased by 16.3% overall (approximately 1.8% per year). After 26 years of age, coverage did not increase significantly as maternal age increased. The relationship between maternal age and UTD coverage remained statistically significant after adjusting for a broad range of maternal, child and household factors. Classification tree analysis suggested that maternal age is the most important factor associated with vaccine coverage. More research is needed to determine the reasons for underimmunization of children born to young mothers.

Peptide YY: a gut hormone associated with anorexia during infectious diarrhea in children.

OBJECTIVE: To evaluate the effects of diarrhea on appetite among Peruvian children age 12 to 71 months and to assess whether elevated plasma levels of peptide YY, tumor necrosis factor (TNF)-alpha, and interleukin (IL)-1beta contribute to anorexia in this population. STUDY DESIGN: A total of 46 Peruvian children with diarrhea and 46 healthy controls underwent an observed feeding trial that was repeated when cases were healthy. Blood samples were obtained from 30 cases and 30 controls at the first trial and from 30 cases at the second trial and assayed for peptide YY, TNF-alpha, and IL-1beta. RESULTS: In the cases, mean consumption was less when sick than when healthy. The mean plasma level of peptide YY was higher for cases than controls and higher for cases when sick than when healthy. TNF-alpha levels were higher in cases than controls at visit 1 and also higher in cases when sick than when healthy. There were no differences in IL-1beta levels between cases and controls or between cases when sick and healthy. Peptide YY levels in children with diarrhea correlated with the likelihood of them eating less when sick than when healthy. CONCLUSIONS: Elevated serum peptide YY may be a mechanism for anorexia in children with diarrhea.

Vaccine knowledge and practices of primary care providers of exempt vs. vaccinated children.

OBJECTIVES: Compare vaccine knowledge, attitudes and practices of primary care providers for fully vaccinated children and children who are exempt from school immunization requirements. METHODS: We conducted a mailed survey of parent-identified primary care providers from four states to measure perceived risks and benefits of vaccination and other key immunization beliefs. Frequencies of responses were stratified by type of provider, identified by exempt versus vaccinated children. Logistic regression was used to calculate odds ratios for responses by provider type. RESULTS: 551 surveys were completed (84.3% response rate). Providers for exempt children had similar attitudes to providers for non-exempt children. However, there were statistically significant increased concerns among providers for exempt children regarding vaccine safety and lack of perceived individual and community benefits for vaccines compared to other providers. CONCLUSIONS: The great majority of providers for exempt children had similar attitudes about vaccine safety, effectiveness and benefits as providers of non-exempt children. Although providers for exempt children were more likely to believe that multiple vaccines weaken a child's immune system and were concerned about vaccine safety and less likely to consider vaccines were beneficial, a substantial proportion of providers of both exempt and vaccinated children have concerns about vaccine safety and believe that CDC underestimates the frequency of vaccine side effects. Effective continuing education of providers about the risks and benefits of immunization and including in vaccine recommendations more information on pre and post licensing vaccine safety evaluations may help address these concerns.

Diagnosis of cystic echinococcosis, central Peruvian Highlands.

We evaluated prevalence of cystic echinococcosis (CE) in a central Peruvian Highland district by using 4 diagnostic methods: ultrasonography for 949 persons, radiography for 829, and 2 serologic tests for 929 (2 immunoblot formats using bovine hydatid cyst fluid [IBCF] and recombinant EpC1 glutathione S-transferase [rEpC1-GST] antigens). For the IBCF and rEpC1-GST testing, prevalence of liver and pulmonary CE was 4.7% and 1.1% and seropositivity was 8.9% and 19.7%, respectively. Frequency of seropositive results for IBCF and rEpC1-GST testing was 35.7% and 16.7% (all hepatic cysts), 47.1% and 29.4% (hepatic calcifications excluded), and 22.2% and 33.3% (lung cysts), respectively. Weak immune response against lung cysts, calcified cysts, small cysts, and cysts in sites other than lung and liver might explain the poor performance of the serodiagnostic tests. We confirm that CE is highly endemic to Peru and emphasize the limited performance of available serologic assays in the field.

Nonmedical exemptions to school immunization requirements: secular trends and association of state policies with pertussis incidence.

CONTEXT: School immunization requirements have played a major role in controlling vaccine-preventable diseases in the United States. Most states offer nonmedical exemptions to school requirements (religious or personal belief). Exemptors are at increased risk of acquiring and transmitting disease. The role of exemption policies may be especially important for pertussis, which is endemic in the United States. OBJECTIVE: To determine if (1) the rates of nonmedical exemptions differ and have been increasing in states that offer only religious vs personal belief exemptions; (2) the rates of nonmedical exemptions differ and have been increasing in states that have easy vs medium and easy vs difficult processes for obtaining exemptions; and (3) pertussis incidence is associated with policies of granting personal belief exemptions, ease of obtaining exemptions, and acceptance of parental signature as sufficient proof of compliance with school immunization requirements. DESIGN, SETTING, AND PARTICIPANTS: We analyzed 1991 through 2004 state-level rates of nonmedical exemptions at school entry and 1986 through 2004 pertussis incidence data for individuals aged 18 years or younger. MAIN OUTCOME MEASURES: State-level exemption rates and pertussis incidence. RESULTS: From 2001 through 2004, states that permitted personal belief exemptions had higher nonmedical exemption rates than states that offered only religious exemptions, and states that easily granted exemptions had higher nonmedical exemption rates in 2002 through 2003 compared with states with medium and difficult exemption processes. The mean exemption rate increased an average of 6% per year, from 0.99% in 1991 to 2.54% in 2004, among states that offered personal belief exemptions. In states that easily granted exemptions, the rate increased 5% per year, from 1.26% in 1991 to 2.51% in 2004. No statistically significant change was seen in states that offered only religious exemptions or that had medium and difficult exemption processes. In multivariate analyses adjusting for demographics, easier granting of exemptions (incidence rate ratio = 1.53; 95% confidence interval, 1.10-2.14) and availability of personal belief exemptions (incidence rate ratio = 1.48; 95% confidence interval, 1.03-2.13) were associated with increased pertussis incidence. CONCLUSIONS: Permitting personal belief exemptions and easily granting exemptions are associated with higher and increasing nonmedical US exemption rates. State policies granting personal belief exemptions and states that easily grant exemptions are associated with increased pertussis incidence. States should examine their exemption policies to ensure control of pertussis and other vaccine-preventable diseases.

Support for tobacco control policies among youth in North Carolina.

BACKGROUND: The objective of this research was to examine attitudes toward tobacco control policies among middle and high school students in North Carolina. Specifically, we report data on knowledge of the harmfulness of secondhand smoke and support for restaurant and school-based smoking restrictions. METHODS: The statewide North Carolina Youth Tobacco Survey was administered to a representative sample of 3,073 middle school and 3,261 high school students in the fall of 2003. The overall response rate for the middle and high school samples was 77.0% and 77.4%, respectively. Support for tobacco policies was analyzed by smoking status and by knowledge of the harmfulness of secondhand smoke RESULTS: The vast majority of respondents in the middle school (87.6%) and high school (91.6%) reported that secondhand smoke was "definitely" or probably" harmful. However, less than half of middle school (48.6%) and high school (40.2%) students responded that smoking should be banned in restaurants. Even among the select group of students who had never smoked and who believed secondhand smoke was harmful, support for such a ban was less than 60% at both school levels. CONCLUSIONS: Youth in North Carolina are aware of the health risks of secondhand smoke, but are not convinced of the need to restrict smoking in restaurants. These results point to the need for more youth-focused advocacy and education around smoking restrictions, both to reduce youth exposure to secondhand smoke and to solidify voter support for such protections once they reach adulthood.

Measuring immunization coverage among preschool children: past, present, and future opportunities.

Control of vaccine-preventable diseases depends on maintaining high levels of immunization coverage. Immunization coverage among preschool children remains suboptimal in some areas and sociodemographic subgroups, as well as for more recently introduced vaccines, leaving susceptible young children vulnerable to complications from vaccine-preventable diseases. This paper reviews approaches historically used to measure immunization coverage among preschool children in the United States. The strengths and weaknesses of various approaches to measuring immunization coverage among preschool children are explored, with emphasis on the current means to measure national immunization coverage-the National Immunization Survey. Methods for measuring immunization coverage among preschool children at local and state levels are also evaluated. Future opportunities and challenges for measuring immunization coverage at the local, state, and national levels are explored.

Declining fertility on the frontier: the Ecuadorian Amazon.

This paper examines farm and household characteristics associated with a rapid fertility decline in a forest frontier of the Ecuadorian Amazon. The Amazon basin and other rainforests in the tropics are among the last frontiers in the ongoing global fertility transition. The pace of this transition along agricultural frontiers will likely have major implications for future forest transitions, rural development, and ultimately urbanization in frontier areas. The study here is based upon data from a probability sample of 172 women who lived on the same farm in 1990 and 1999. These data are from perhaps the first region-wide longitudinal survey of fertility in an agricultural frontier. Descriptive analyses indicate that fertility has plummeted in the region, which is surprising since it had remained high and unchanging among migrant colonists up to 1990. Thus only half of the women in our sample reported having a birth during the 1990-1999 time period, and most women report in 1999 that they do not want to have any more children. Analyses, controlling for women's age, corroborate hypotheses about land-fertility relations. For example, women from households with a legal land title had fewer than half as many children as those from households without a title. Large cattle (pasture) holdings and hiring laborers to work on the farm (which may replace household labor) are both related to socio-economic status that is traditionally associated with lower fertility. Similarly, distance to the nearest community center is positively related to fertility. Factors negatively related to fertility include increasing temporary out-migration of adult men or women from the household, asset accumulation, and access to electricity.