Insights into pneumococcal pneumonia using lung aspirates and nasopharyngeal swabs collected from pneumonia patients in The Gambia.

We investigated the pathogenesis of pneumococcal pneumonia using clinical specimens collected for pneumonia surveillance in The Gambia. Lung aspirates and nasopharyngeal swabs from 31 patients were examined by culture, qPCR, whole genome sequencing, serotyping, and reverse transcription qPCR. Five lung aspirates cultured pneumococci, with a matching strain identified in the nasopharynx. Three virulence genes including ply (pneumolysin) were upregulated >20-fold in the lung compared with the nasopharynx. Nasopharyngeal pneumococcal density was higher in pediatric pneumonia patients compared with controls (p <0.0001). Findings suggest that changes in pneumococcal gene expression occurring in the lung environment may be important in pathogenesis

Human eosinophils modulate peripheral blood mononuclear cell response to Schistosoma mansoni adult worm antigen in vitro.

High numbers of eosinophils are observed in parasitic infections and allergic diseases, where they are proposed to be terminally differentiated effector cells that play beneficial role in host defence, or cause harmful inflammatory response. Eosinophils have been associated with killing of schistosomulae in vitro, but there is growing evidence that eosinophils can play additional immuno-regulatory role. Here, we report results of a study that examines peripheral blood mononuclear cell (PBMC) cytokine responses to Schistosoma mansoni adult worm antigen (SWA) when stimulated alone or enriched with autologous eosinophils. Production of the Th-2 type cytokines interleukin (IL)-4, IL-5 and IL-13 was lower (P = 0·017, 0·018 and <0·001, respectively) in PBMC + eosinophil cultures than in PBMC-only cultures stimulated with SWA. Substantial levels of IL-13, IL-10, interferon gamma and tumour necrosis factor alpha were recorded in cultures of eosinophils, but none of these cytokines showed significant association with the observed eosinophil-induced drop in cytokine responses of PBMC. Transwell experiments suggested that the observed effect is due to soluble mediators that downmodulate production of Th-2 type cytokines. This study shows that eosinophils may down-modulate schistosome-specific Th-2 type cytokine responses in S. mansoni-infected individuals. The mechanism of this immune modulation remains to be elucidated.The study was a fellowship funded by Wellcome Trust, Makerere-UVRI Research Training Programme in Infection and Immunity (grant number 084344) and European Foundations Initiative for NTDs ‘EFINTD’ (grant ref 86 529). The study was carried out under co-infection studies programme lead by AME funded by Wellcome Trust (grant number 095778)

Characterization of 19A-like 19F pneumococcal isolates from Papua New Guinea and Fiji.

Molecular identification of Streptococcus pneumoniae serotype 19F is routinely performed by PCR targeting the wzy gene of the capsular biosynthetic locus. However, 19F isolates with genetic similarity to 19A have been reported in the United States and Brazil. We screened 78 pneumococcal carriage isolates and found six 19F wzy variants that originated from children in Papua New Guinea and Fiji. Isolates were characterized using multilocus sequence typing and opsonophagocytic assays. The 19F wzy variants displayed similar susceptibility to anti-19F IgG antibodies compared to standard 19F isolates. Our findings indicate that these 19F variants may be more common than previously believed

Diffusion of treatment in social networks and mass drug administration

Information, behaviours, and technologies spread when people interact. Understanding these interactions is critical for achieving the greatest diffusion of public interventions. Yet, little is known about the performance of starting points (seed nodes) for diffusion. We track routine mass drug administration—the large-scale distribution of deworming drugs—in Uganda. We collect friendship networks, socioeconomic factors, and treatment delivery outcomes for 16,357 individuals in 3,491 households of 17 rural villages. Each village has two community medicine distributors (CMDs), who are the seed nodes and responsible for administering treatments. Here we show that CMDs with tightly-knit (clustered) friendship connections achieve the greatest reach and speed of treatment coverage. Importantly, we demonstrate that clustering predicts diffusion through social networks when spreading relies on contact with seed nodes whilst centrality is unrelated to diffusion. Clustering should be considered when selecting seed nodes for large-scale treatment campaigns.Financially supported by the Vice Chancellor’s Fund of the University of Cambridge, the Schistosomiasis Control Initiative, the Wellcome Trust (Programme grant 083931/Z/07/Z to D.W.D), and the Netherlands Organization for Scientific Research (N.W.O. grant 452-04-333 to E.B.)

Community-directed mass drug administration is undermined by status seeking in friendship networks and inadequate trust in health advice networks

Over 1.9 billion individuals require preventive chemotherapy through mass drug administration (MDA). Community-directed MDA relies on volunteer community medicine distributors (CMDs) and their achievement of high coverage and compliance. Yet, it is unknown if village social networks influence effective MDA implementation by CMDs. In Mayuge District, Uganda, census-style surveys were conducted for 16,357 individuals from 3,491 households in 17 villages. Praziquantel, albendazole, and ivermectin were administered for one month in community-directed MDA to treat Schistosoma mansoni, hookworm, and lymphatic filariasis. Self-reported treatment outcomes, socioeconomic characteristics, friendship networks, and health advice networks were collected. We investigated systematically missed coverage and noncompliance. Coverage was defined as an eligible person being offered at least one drug by CMDs; compliance included ingesting at least one of the offered drugs. These outcomes were analyzed as a two-stage process using a Heckman selection model. To further assess if MDA through CMDs was working as intended, we examined the probability of accurate drug administration of 1) praziquantel, 2) both albendazole and ivermectin, and 3) all drugs. This analysis was conducted using bivariate Probit regression. Four indicators from each social network were examined: degree, betweenness centrality, closeness centrality, and the presence of a direct connection to CMDs. All models accounted for nested household and village standard errors. CMDs were more likely to offer medicines, and to accurately administer the drugs as trained by the national control programme, to individuals with high friendship degree (many connections) and high friendship closeness centrality (households that were only a short number of steps away from all other households in the network). Though high (88.59%), additional compliance was associated with directly trusting CMDs for health advice. Effective treatment provision requires addressing CMD biases towards influential, well-embedded individuals in friendship networks and utilizing health advice networks to increase village trust in CMDs.The authors acknowledge financial support from the Vice Chancellor’s Fund of the University of Cambridge, the Schistosomiasis Control Initiative, the Wellcome Trust Programme grant 083931/Z/07/Z to David W. Dunne, the Netherlands Organization for Scientific Research grant 452-04- 333 to Erwin Bulte, and the Isaac Newton Trust and King’s College, Cambridge fellowships to Goylette F. Chami

Carriage of Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, and Staphylococcus aureus in Indonesian children: A cross-sectional study.

Streptococcus pneumoniae is an important cause of infection and commonly colonizes the nasopharynx of young children, along with other potentially pathogenic bacteria. The objectives of this study were to estimate the carriage prevalence of S. pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, and Staphylococcus aureus in young children in Indonesia, and to examine interactions between these bacterial species. 302 healthy children aged 12-24 months were enrolled in community health centers in the Bandung, Central Lombok, and Padang regions. Nasopharyngeal swabs were collected and stored according to World Health Organization recommendations, and bacterial species detected by qPCR. Pneumococcal serotyping was conducted by microarray and latex agglutination/Quellung. Overall carriage prevalence was 49.5% for S. pneumoniae, 27.5% for H. influenzae, 42.7% for M. catarrhalis, and 7.3% for S. aureus. Prevalence of M. catarrhalis and S. pneumoniae, as well as pneumococcal serotype distribution, varied by region. Positive associations were observed for S. pneumoniae and M. catarrhalis (OR 3.07 [95%CI 1.91-4.94]), and H. influenzae and M. catarrhalis (OR 2.34 [95%CI 1.40-3.91]), and a negative association was found between M. catarrhalis and S. aureus (OR 0.06 [95%CI 0.01-0.43]). Densities of S. pneumoniae, H. influenzae, and M. catarrhalis were positively correlated when two of these species were present. Prior to pneumococcal vaccine introduction, pneumococcal carriage prevalence and serotype distribution varies among children living in different regions of Indonesia. Positive associations in both carriage and density identified among S. pneumoniae, H. influenzae, and M. catarrhalis suggest a synergistic relationship among these species with potential clinical implications

Pneumococcal carriage in vaccine-eligible children and unvaccinated infants in Lao PDR two years following the introduction of the 13-valent pneumococcal conjugate vaccine.

Pneumococcal carriage is a prerequisite for disease, and underpins herd protection provided by pneumococcal conjugate vaccines (PCVs). There are few data on the impact of PCVs in lower income settings, particularly in Asia. In 2013, the Lao People's Democratic Republic (Lao PDR) introduced 13-valent PCV (PCV13) as a 3 + 0 schedule (doses at 6, 10 and 14 weeks of age) with limited catch-up vaccination. We conducted two cross-sectional carriage surveys (pre- and two years post-PCV) to assess the impact of PCV13 on nasopharyngeal pneumococcal carriage in 5-8 week old infants (n = 1000) and 12-23 month old children (n = 1010). Pneumococci were detected by quantitative real-time PCR, and molecular serotyping was performed using DNA microarray. Post PCV13, there was a 23% relative reduction in PCV13-type carriage in children aged 12-23 months (adjusted prevalence ratio [aPR] 0.77 [0.61-0.96]), and no significant change in non-PCV13 serotype carriage (aPR 1.11 [0.89-1.38]). In infants too young to be vaccinated, there was no significant change in carriage of PCV13 serotypes (aPR 0.74 [0.43-1.27]) or non-PCV13 serotypes (aPR 1.29 [0.85-1.96]), although trends were suggestive of indirect effects. Over 70% of pneumococcal-positive samples contained at least one antimicrobial resistance gene, which were more common in PCV13 serotypes (p < 0.001). In 12-23 month old children, pneumococcal density of both PCV13 serotypes and non-PCV13 serotypes was higher in PCV13-vaccinated compared with undervaccinated children (p = 0.004 and p < 0.001, respectively). This study provides evidence of PCV13 impact on carriage in a population without prior PCV7 utilisation, and provides important data from a lower-middle income setting in Asia. The reductions in PCV13 serotype carriage in vaccine-eligible children are likely to result in reductions in pneumococcal transmission and disease in Lao PDR

Functional imaging of the developing brain with wearable high-density diffuse optical tomography: a new benchmark for infant neuroimaging outside the scanner environment

Studies of cortical function in the awake infant are extremely challenging to undertake with traditional neuroimaging approaches. Partly in response to this challenge, functional near-infrared spectroscopy (fNIRS) has become increasingly common in developmental neuroscience, but has significant limitations including resolution, spatial specificity and ergonomics. In adults, high-density arrays of near-infrared sources and detectors have recently been shown to yield dramatic improvements in spatial resolution and specificity when compared to typical fNIRS approaches. However, most existing fNIRS devices only permit the acquisition of ∼20-100 sparsely distributed fNIRS channels, and increasing the number of optodes presents significant mechanical challenges, particularly for infant applications. A new generation of wearable, modular, high-density diffuse optical tomography (HD-DOT) technologies has recently emerged that overcomes many of the limitations of traditional, fibre-based and low-density fNIRS measurements. Driven by the development of this new technology, we have undertaken the first study of the infant brain using wearable HD-DOT. Using a well-established social stimulus paradigm, and combining this new imaging technology with advances in cap design and spatial registration, we show that it is now possible to obtain high-quality, functional images of the infant brain with minimal constraints on either the environment or on the infant participants. Our results are consistent with prior low-density fNIRS measures based on similar paradigms, but demonstrate superior spatial localization, improved depth specificity, higher SNR and a dramatic improvement in the consistency of the responses across participants. Our data retention rates also demonstrate that this new generation of wearable technology is well tolerated by the infant population

Pneumococcal carriage in children in Ulaanbaatar, Mongolia before and one year after the introduction of the 13-valent pneumococcal conjugate vaccine.

BACKGROUND: Nasopharyngeal carriage of Streptococcus pneumoniae precedes disease, is the source of pneumococcal community spread, and the mechanism for herd protection provided by pneumococcal conjugate vaccines (PCVs). There are few PCV impact studies in low- and middle-income countries, particularly in Asia. In 2016, Mongolia introduced the 13-valent PCV (PCV13) in a phased manner using a 2 + 1 schedule, with catch-up. We aimed to assess the impact of PCV13 introduction on nasopharyngeal pneumococcal carriage and density in children in Mongolia. METHODS: We conducted two cross-sectional carriage surveys (pre- and one year post-PCV) at community health clinics in two districts of the capital city, Ulaanbaatar in both May-July 2015 and 2017. The study analysis included 961 children too young to be vaccinated (5-8 weeks old) and 989 children eligible for vaccination (12-23 months old). Pneumococci were detected by quantitative real-time PCR and molecular serotyping performed using DNA microarray. FINDINGS: One year post-PCV introduction, PCV13 serotype carriage reduced by 52% in 12-23 month olds (adjusted prevalence ratio [aPR] 0.48 [95% confidence interval [CI] 0.39-0.59]), with evidence of non-PCV13 serotype replacement (aPR 1.55 [95% CI 1.30-1.85]), compared with the pre-PCV period. In 5-8 week olds, PCV13 serotype carriage reduced by 51% (aPR 0.49 [95% CI 0.33-0.73]) with no significant change in non-PCV13 serotype carriage (aPR 1.10 [95% CI 0.83-1.46]). An increase was observed in both PCV13 and non-PCV13 pneumococcal density post-PCV introduction. Antimicrobial resistance (AMR) genes were common, with 82.3% of samples containing at least one of the 10 AMR genes assessed. CONCLUSION: This study demonstrates substantive PCV13 impact on pneumococcal carriage one year post-vaccine introduction in Mongolia. The reductions in PCV13 serotype carriage are likely to result in reductions in pneumococcal disease including indirect effects. Increases in non-PCV13 serotypes require further monitoring

The interplay of microscopic and mesoscopic structure in complex networks

Not all nodes in a network are created equal. Differences and similarities exist at both individual node and group levels. Disentangling single node from group properties is crucial for network modeling and structural inference. Based on unbiased generative probabilistic exponential random graph models and employing distributive message passing techniques, we present an efficient algorithm that allows one to separate the contributions of individual nodes and groups of nodes to the network structure. This leads to improved detection accuracy of latent class structure in real world data sets compared to models that focus on group structure alone. Furthermore, the inclusion of hitherto neglected group specific effects in models used to assess the statistical significance of small subgraph (motif) distributions in networks may be sufficient to explain most of the observed statistics. We show the predictive power of such generative models in forecasting putative gene-disease associations in the Online Mendelian Inheritance in Man (OMIM) database. The approach is suitable for both directed and undirected uni-partite as well as for bipartite networks