Anne G. Hoen

The global distribution and burden of dengue

Dengue is a systemic viral infection transmitted between humans by Aedes mosquitoes. For some patients, dengue is a life-threatening illness. There are currently no licensed vaccines or specific therapeutics, and substantial vector control efforts have not stopped its rapid emergence and global spread. The contemporary worldwide distribution of the risk of dengue virus infection and its public health burden are poorly known. Here we undertake an exhaustive assembly of known records of dengue occurrence worldwide, and use a formal modelling framework to map the global distribution of dengue risk. We then pair the resulting risk map with detailed longitudinal information from dengue cohort studies and population surfaces to infer the public health burden of dengue in 2010. We predict dengue to be ubiquitous throughout the tropics, with local spatial variations in risk influenced strongly by rainfall, temperature and the degree of urbanization. Using cartographic approaches, we estimate there to be 390 million (95% credible interval 284–528) dengue infections per year, of which 96 million (67–136) manifest apparently (any level of disease severity). This infection total is more than three times the dengue burden estimate of the World Health Organization. Stratification of our estimates by country allows comparison with national dengue reporting, after taking into account the probability of an apparent infection being formally reported. The most notable differences are discussed. These new risk maps and infection estimates provide novel insights into the global, regional and national public health burden imposed by dengue. We anticipate that they will provide a starting point for a wider discussion about the global impact of this disease and will help to guide improvements in disease control strategies using vaccine, drug and vector control methods, and in their economic evaluation.

Refining the Global Spatial Limits of Dengue Virus Transmission by Evidence-Based Consensus

Background Dengue is a growing problem both in its geographical spread and in its intensity, and yet current global distribution remains highly uncertain. Challenges in diagnosis and diagnostic methods as well as highly variable national health systems mean no single data source can reliably estimate the distribution of this disease. As such, there is a lack of agreement on national dengue status among international health organisations. Here we bring together all available information on dengue occurrence using a novel approach to produce an evidence consensus map of the disease range that highlights nations with an uncertain dengue status. Methods/Principal Findings A baseline methodology was used to assess a range of evidence for each country. In regions where dengue status was uncertain, additional evidence types were included to either clarify dengue status or confirm that it is unknown at this time. An algorithm was developed that assesses evidence quality and consistency, giving each country an evidence consensus score. Using this approach, we were able to generate a contemporary global map of national-level dengue status that assigns a relative measure of certainty and identifies gaps in the available evidence. Conclusion The map produced here provides a list of 128 countries for which there is good evidence of dengue occurrence, including 36 countries that have previously been classified as dengue-free by the World Health Organization and/or the US Centers for Disease Control. It also identifies disease surveillance needs, which we list in full. The disease extents and limits determined here using evidence consensus, marks the beginning of a five-year study to advance the mapping of dengue virus transmission and disease risk. Completion of this first step has allowed us to produce a preliminary estimate of population at risk with an upper bound of 3.97 billion people. This figure will be refined in future work.

Human risk of infection with Borrelia burgdorferi, the Lyme disease agent, in eastern United States.

The geographic pattern of human risk for infection with Borrelia burgdorferi sensu stricto, the tick-borne pathogen that causes Lyme disease, was mapped for the eastern United States. The map is based on standardized field sampling in 304 sites of the density of Ixodes scapularis host-seeking nymphs infected with B. burgdorferi, which is closely associated with human infection risk. Risk factors for the presence and density of infected nymphs were used to model a continuous 8 km×8 km resolution predictive surface of human risk, including confidence intervals for each pixel. Discontinuous Lyme disease risk foci were identified in the Northeast and upper Midwest, with a transitional zone including sites with uninfected I. scapularis populations. Given frequent under- and over-diagnoses of Lyme disease, this map could act as a tool to guide surveillance, control, and prevention efforts and act as a baseline for studies tracking the spread of infection.

Geographic Variation in the Relationship between Human Lyme Disease Incidence and Density of Infected Host-Seeking Ixodes scapularis Nymphs in the Eastern United States

Prevention and control of Lyme disease is difficult because of the complex biology of the pathogens (Borrelia burgdorferi) vector (Ixodes scapularis) and multiple reservoir hosts with varying degrees of competence. Cost-effective implementation of tick- and host-targeted control methods requires an understanding of the relationship between pathogen prevalence in nymphs, nymph abundance, and incidence of human cases of Lyme disease. We quantified the relationship between estimated acarological risk and human incidence using county-level human case data and nymphal prevalence data from field-derived estimates in 36 eastern states. The estimated density of infected nymphs (mDIN) was significantly correlated with human incidence (r = 0.69). The relationship was strongest in high-prevalence areas, but it varied by region and state, partly because of the distribution of B. burgdorferi genotypes. More information is needed in several high-prevalence states before DIN can be used for cost-effectiveness analyses.

Association of Cesarean Delivery and Formula Supplementation With the Intestinal Microbiome of 6-Week-Old Infants

IMPORTANCE The intestinal microbiome plays a critical role in infant development, and delivery mode and feeding method (breast milk vs formula) are determinants of its composition. However, the importance of delivery mode beyond the first days of life is unknown, and studies of associations between infant feeding and microbiome composition have been generally limited to comparisons between exclusively breastfed and formula-fed infants, with little consideration given to combination feeding of both breast milk and formula. OBJECTIVE To examine the associations of delivery mode and feeding method with infant intestinal microbiome composition at approximately 6 weeks of life. DESIGN, SETTING, AND PARTICIPANTS Prospective observational study of 102 infants followed up as part of a US pregnancy cohort study. EXPOSURES Delivery mode was abstracted from delivery medical records, and feeding method prior to the time of stool collection was ascertained through detailed questionnaires. MAIN OUTCOMES AND MEASURES Stool microbiome composition was characterized using next-generation sequencing of the 16S rRNA gene. RESULTS There were 102 infants (mean gestational age, 39.7 weeks; range, 37.1-41.9 weeks) included in this study, of whom 70 were delivered vaginally and 32 by cesarean delivery. In the first 6 weeks of life, 70 were exclusively breastfed, 26 received combination feeding, and 6 were exclusively formula fed. We identified independent associations between microbial community composition and both delivery mode (P< .001; Q < .001) and feeding method (P = .01; Q < .001). Differences in microbial community composition between vaginally delivered infants and infants delivered by cesarean birth were equivalent to or significantly larger than those between feeding groups (P = .003). Bacterial communities associated with combination feeding were more similar to those associated with exclusive formula feeding than exclusive breastfeeding (P = .002). We identified 6 individual bacterial genera that were differentially abundant between delivery mode and feeding groups. CONCLUSIONS AND RELEVANCE The infant intestinal microbiome at approximately 6 weeks of age is significantly associated with both delivery mode and feeding method, and the supplementation of breast milk feeding with formula is associated with a microbiome composition that resembles that of infants who are exclusively formula fed. These results may inform feeding choices and shed light on the mechanisms behind the lifelong health consequences of delivery and infant feeding modalities.

Associations between Gut Microbial Colonization in Early Life and Respiratory Outcomes in Cystic Fibrosis

OBJECTIVE To examine patterns of microbial colonization of the respiratory and intestinal tracts in early life in infants with cystic fibrosis (CF) and their associations with breastfeeding and clinical outcomes. STUDY DESIGN A comprehensive, prospective longitudinal analysis of the upper respiratory and intestinal microbiota in a cohort of infants and young children with CF followed from birth was performed. Genus-level microbial community composition was characterized using 16S-targeted pyrosequencing, and relationships with exposures and outcomes were assessed using linear mixed-effects models, time-to-event analysis, and principal components analysis. RESULTS Sequencing of 120 samples from 13 subjects collected from birth to 34 months revealed relationships between breastfeeding, microbial diversity in the respiratory and intestinal tracts, and the timing of onset of respiratory complications, including exacerbations and colonization with Pseudomonas aeruginosa. Fluctuations in the abundance of specific bacterial taxa preceded clinical outcomes, including a significant decrease in bacteria of the genus Parabacteroides within the intestinal tract prior to the onset of chronic P aeruginosa colonization. Specific assemblages of bacteria in intestinal samples, but not respiratory samples, were associated with CF exacerbation in early life, indicating that the intestinal microbiome may play a role in lung health. CONCLUSIONS Our findings relating breastfeeding to respiratory outcomes, gut diversity to prolonged periods of health, and specific bacterial communities in the gut prior to respiratory complications in CF highlight a connection between the intestinal microbiome and health and point to potential opportunities for antibiotic or probiotic interventions. Further studies in larger cohorts validating these findings are needed.

Seroepidemiology of Human Polyomaviruses in a US Population

Polyomaviruses (PyV) are potentially tumorigenic in humans. However, limited data exist on the population seroprevalence of PyVs and individual characteristics that relate to seropositivity. Using multiplex serology, we determined the seroprevalence of 10 human PyVs (BK, JC, KI, WU, MCV, HPyV6, HPyV7, TSV, HPyV9, and HPyV10) among controls from a population-based skin cancer case-control study (n = 460) conducted in New Hampshire between 1993 and 1995. On a subset of participants (n = 194), methylation at CpG dinucleotides across the genome was measured in peripheral blood using the Illumina Infinium HumanMethylation27 BeadChip array (Illumina Inc., San Diego, California), from which lymphocyte subtype proportions were inferred. All participants were seropositive for at least 1 PyV, with seroprevalences ranging from 17.6% (HPyV9) to 99.1% (HPyV10). Seropositivity to JC, MCV, and HPyV7 increased with age. JC and TSV seropositivity were more common among men than among women. Smokers were more likely to be HPyV9-seropositive but MCV-seronegative, and HPyV7 seropositivity was associated with prolonged glucocorticoid use. Based on DNA methylation profiles, differences were observed in CD8-positive T- and B-cell proportions by BK, JC, and HPyV9 seropositivity. Our findings suggest that PyV seropositivity is common in the United States and varies by sociodemographic and biological characteristics, including those related to immune function.

Two boundaries separate Borrelia burgdorferi populations in North America

ABSTRACT Understanding the spread of infectious diseases is crucial for implementing effective control measures. For this, it is important to obtain information on the contemporary population structure of a disease agent and to infer the evolutionary processes that may have shaped it. Here, we investigate on a continental scale the population structure of Borrelia burgdorferi, the causative agent of Lyme borreliosis (LB), a tick-borne disease, in North America. We test the hypothesis that the observed population structure is congruent with recent population expansions and that these were preceded by bottlenecks mostly likely caused by the near extirpation in the 1900s of hosts required for sustaining tick populations. Multilocus sequence typing and complementary population analytical tools were used to evaluate B. burgdorferi samples collected in the Northeastern, Upper Midwestern, and Far-Western United States and Canada. The spatial distribution of sequence types (STs) and inferred population boundaries suggest that the current populations are geographically separated. One major population boundary separated western B. burgdorferi populations transmitted by Ixodes pacificus in California from Eastern populations transmitted by I. scapularis; the other divided Midwestern and Northeastern populations. However, populations from all three regions were genetically closely related. Together, our findings suggest that although the contemporary populations of North American B. burgdorferi now comprise three geographically separated subpopulations with no or limited gene flow among them, they arose from a common ancestral population. A comparative analysis of the B. burgdorferi outer surface protein C (ospC) gene revealed novel linkages and provides additional insights into the genetic characteristics of strains.

Evidence-based tool for triggering school closures during influenza outbreaks, Japan.

In this letter, we report the first infrared spectrum of C(76)(2-). This multiply charged anion has been studied in an electrodynamic ion trap held at room temperature using tunable infrared radiation from a free-electron laser. Resonant vibrational excitation is found to cause electron detachment and the resulting singly negatively charged as well as the remaining doubly charged parent ion are monitored as a function of IR wavelength in an experimental scheme that we term infrared multiphoton electron detachment spectroscopy. The obtained IR spectra are contrasted to computed vibrational spectra using density functional theory. The dianionic molecule retains its overall symmetry (i.e., D(2) point group) with a (1)A(1) ground state with respect to the neutral fullerene. Spectral shifts of characteristic tangential modes relative to the neutral cage are shown to originate from the excess charge density.

Live Attenuated and Inactivated Influenza Vaccines in Children

BACKGROUND Live attenuated influenza vaccine (LAIV) and inactivated influenza vaccine (IIV) are available for children. Local and systemic immunity induced by LAIV followed a month later by LAIV and IIV followed by LAIV were investigated with virus recovery after LAIV doses as surrogates for protection against influenza on natural exposure. METHODS Fifteen children received IIV followed by LAIV, 13 an initial dose of LAIV, and 11 a second dose of LAIV. The studies were done during autumn 2009 and autumn 2010 with the same seasonal vaccine (A/California/07/09 [H1N1], A/Perth/16/09 [H3N2], B/Brisbane/60/08). RESULTS Twenty-eight of 39 possible influenza viral strains were recovered after the initial dose of LAIV. When LAIV followed IIV, 21 of 45 viral strains were identified. When compared to primary LAIV infection, the decreased frequency of shedding with the IIV-LAIV schedule was significant (P = .023). With LAIV-LAIV, the fewest viral strains were recovered (3/33)--numbers significantly lower (P < .001) than shedding after initial LAIV and after IIV-LAIV (P < .001). Serum hemagglutination inhibition antibody responses were more frequent after IIV than LAIV (P = .02). In contrast, more mucosal immunoglobulin A responses were seen with LAIV. CONCLUSIONS LAIV priming induces greater inhibition of virus recovery on LAIV challenge than IIV priming. The correlate(s) of protection are the subject of ongoing analysis. CLINICAL TRIALS REGISTRATION NCT01246999.