Use of a Cholera Rapid Diagnostic Test during a Mass Vaccination Campaign in Response to an Epidemic in Guinea, 2012

Background

During the 2012 cholera outbreak in the Republic of Guinea, the Ministry of Health, supported by Médecins Sans Frontières - Operational Center Geneva, used the oral cholera vaccine Shanchol as a part of the emergency response. The rapid diagnostic test (RDT) Crystal VC, widely used during outbreaks, detects lipopolysaccharide antigens of Vibrio cholerae O1 and O139, both included in Shanchol. In the context of reactive use of a whole-cell cholera vaccine in a region where cholera cases have been reported, it is essential to know what proportion of vaccinated individuals would be reactive to the RDT and for how long after vaccination.

Methodology/Principal Findings

A total of 108 vaccinated individuals, selected systematically among all persons older than one year, were included at vaccination sites and 106 were included in the analysis. Stools samples of this cohort of vaccinated participants were collected and tested with the RDT every day until the test was negative for two consecutive visits or for a maximum of 7 days. A total of 94.3% of cholera vaccine recipients had a positive test after vaccination; all except one of these positive results were reactive only with the O139 antigen. The mean time to become negative in those with an initial positive result after vaccination was 3.8 days, standard deviation 1.1 days.

Conclusions/Significance

The RDT Crystal VC becomes positive in persons recently vaccinated against cholera, although almost exclusively to the O139 antigen. This reactivity largely disappeared within five days after vaccination. These results suggest that the test can be used normally as soon as 24 hours after vaccination in a context of O1 epidemics, which represent the vast majority of cases, and after a period of five days in areas where V. cholerae O139 is present. The reason why only O139 test line became positive remains to be investigated.     

The 2012 Madeira Dengue Outbreak: Epidemiological Determinants and Future Epidemic Potential

Dengue, a vector-borne viral disease of increasing global importance, is classically associated with tropical and sub-tropical regions around the world. Urbanisation, globalisation and climate trends, however, are facilitating the geographic spread of its mosquito vectors, thereby increasing the risk of the virus establishing itself in previously unaffected areas and causing large-scale epidemics. On 3 October 2012, two autochthonous dengue infections were reported within the Autonomous Region of Madeira, Portugal. During the following seven months, this first ‘European’ dengue outbreak caused more than 2000 local cases and 81 exported cases to mainland Europe. Here, using an ento-epidemiological mathematical framework, we estimate that the introduction of dengue to Madeira occurred around a month before the first official cases, during the period of maximum influx of airline travel, and that the naturally declining temperatures of autumn were the determining factor for the outbreak''s demise in early December 2012. Using key estimates, together with local climate data, we further propose that there is little support for dengue endemicity on this island, but a high potential for future epidemic outbreaks when seeded between May and August—a period when detection of imported cases is crucial for Madeira''s public health planning.     

The Evolution and Origin of Animal Toll-Like Receptor Signaling Pathway Revealed by Network-Level Molecular Evolutionary Analyses

Genes carry out their biological functions through pathways in complex networks consisting of many interacting molecules. Studies on the effect of network architecture on the evolution of individual proteins will provide valuable information for understanding the origin and evolution as well as functional conservation of signaling pathways. However, the relationship between the network architecture and the individual protein sequence evolution is yet little known. In current study, we carried out network-level molecular evolution analysis on TLR (Toll-like receptor ) signaling pathway, which plays an important role in innate immunity in insects and mammals, and we found that: 1) The selection constraint of genes was negatively correlated with its position along TLR signaling pathway; 2) all genes in TLR signaling pathway were highly conserved and underwent strong purifying selection; 3) the distribution of selective pressure along the pathway was driven by differential nonsynonymous substitution levels; 4) The TLR signaling pathway might present in a common ancestor of sponges and eumetazoa, and evolve via the TLR, IKK, IκB and NF-κB genes underwent duplication events as well as adaptor molecular enlargement, and gene structure and conservation motif of NF-κB genes shifted in their evolutionary history. Our results will improve our understanding on the evolutionary history of animal TLR signaling pathway as well as the relationship between the network architecture and the sequences evolution of individual protein.     

玉米骨干自交系黄早四的来源探究

玉米骨干自交系黄早四育成于20世纪70年代,具有适应性强、配合力高、株型紧凑、生育期短、灌浆速度快等优点.以其为基础材料选育衍生出数以百计的黄改系,形成我国特有的黄改群(或称塘四平头群)核心种质群.利用黄早四及其衍生系组配的杂交种已累计推广应用数十亿亩,包括目前的主导大品种郑单958、京科968等.该系在我国玉米育种史...     

Prediction of Aquaporin Function by Integrating Evolutionary and Functional Analyses

Aquaporins (AQPs) are a family of channel proteins, which transport water and/or small solutes across cell membranes. AQPs are present in Bacteria, Eukarya, and Archaea. The classical AQP evolution paradigm explains the inconsistent phylogenetic trees by multiple transfer events and emphasizes that the assignment of orthologous AQPs is not possible, making it difficult to integrate functional information. Recently, a novel phylogenetic framework of eukaryotic AQP evolution showed congruence between eukaryotic AQPs and organismal trees identifying 32 orthologous clusters in plants and animals (Soto et al. Gene 503:165–176, 2012). In this article, we discuss in depth the methodological strength, the ability to predict functionality and the AQP community perception about the different paradigms of AQP evolution. Moreover, we show an updated review of AQPs transport functions in association with phylogenetic analyses. Finally, we discuss the possible effect of AQP data integration in the understanding of water and solute transport in eukaryotic cells.     

Spatio-Temporal Dynamics of Cholera during the First Year of the Epidemic in Haiti

Background

In October 2010, cholera importation in Haiti triggered an epidemic that rapidly proved to be the world''s largest epidemic of the seventh cholera pandemic. To establish effective control and elimination policies, strategies rely on the analysis of cholera dynamics. In this report, we describe the spatio-temporal dynamics of cholera and the associated environmental factors.

Methodology/Principal findings

Cholera-associated morbidity and mortality data were prospectively collected at the commune level according to the World Health Organization standard definition. Attack and mortality rates were estimated and mapped to assess epidemic clusters and trends. The relationships between environmental factors were assessed at the commune level using multivariate analysis. The global attack and mortality rates were 488.9 cases/10,000 inhabitants and 6.24 deaths/10,000 inhabitants, respectively. Attack rates displayed a significantly high level of spatial heterogeneity (varying from 64.7 to 3070.9 per 10,000 inhabitants), thereby suggesting disparate outbreak processes. The epidemic course exhibited two principal outbreaks. The first outbreak (October 16, 2010–January 30, 2011) displayed a centrifugal spread of a damping wave that suddenly emerged from Mirebalais. The second outbreak began at the end of May 2011, concomitant with the onset of the rainy season, and displayed a highly fragmented epidemic pattern. Environmental factors (river and rice fields: p<0.003) played a role in disease dynamics exclusively during the early phases of the epidemic.

Conclusion

Our findings demonstrate that the epidemic is still evolving, with a changing transmission pattern as time passes. Such an evolution could have hardly been anticipated, especially in a country struck by cholera for the first time. These results argue for the need for control measures involving intense efforts in rapid and exhaustive case tracking.     

First Outbreak Response Using an Oral Cholera Vaccine in Africa: Vaccine Coverage,Acceptability and Surveillance of Adverse Events,Guinea, 2012

Background

Despite World Health Organization (WHO) prequalification of two safe and effective oral cholera vaccines (OCV), concerns about the acceptability, potential diversion of resources, cost and feasibility of implementing timely campaigns has discouraged their use. In 2012, the Ministry of Health of Guinea, with the support of Médecins Sans Frontières organized the first mass vaccination campaign using a two-dose OCV (Shanchol) as an additional control measure to respond to the on-going nationwide epidemic. Overall, 316,250 vaccines were delivered. Here, we present the results of vaccination coverage, acceptability and surveillance of adverse events.

Methodology/Principal Findings

We performed a cross-sectional cluster survey and implemented adverse event surveillance. The study population included individuals older than 12 months, eligible for vaccination, and residing in the areas targeted for vaccination (Forécariah and Boffa, Guinea). Data sources were household interviews with verification by vaccination card and notifications of adverse events from surveillance at vaccination posts and health centres. In total 5,248 people were included in the survey, 3,993 in Boffa and 1,255 in Forécariah. Overall, 89.4% [95%CI:86.4–91.8%] and 87.7% [95%CI:84.2–90.6%] were vaccinated during the first round and 79.8% [95%CI:75.6–83.4%] and 82.9% [95%CI:76.6–87.7%] during the second round in Boffa and Forécariah respectively. The two dose vaccine coverage (including card and oral reporting) was 75.8% [95%CI: 71.2–75.9%] in Boffa and 75.9% [95%CI: 69.8–80.9%] in Forécariah respectively. Vaccination coverage was higher in children. The main reason for non-vaccination was absence. No severe adverse events were notified.

Conclusions/Significance

The well-accepted mass vaccination campaign reached high coverage in a remote area with a mobile population. Although OCV should not be foreseen as the long-term solution for global cholera control, they should be integrated as an additional tool into the response.     

Cholera Transmission in Ouest Department of Haiti: Dynamic Modeling and the Future of the Epidemic

In the current study, a comprehensive, data driven, mathematical model for cholera transmission in Haiti is presented. Along with the inclusion of short cycle human-to-human transmission and long cycle human-to-environment and environment-to-human transmission, this novel dynamic model incorporates both the reported cholera incidence and remote sensing data from the Ouest Department of Haiti between 2010 to 2014. The model has separate compartments for infectious individuals that include different levels of infectivity to reflect the distribution of symptomatic and asymptomatic cases in the population. The environmental compartment, which serves as a source of exposure to toxigenic V. cholerae, is also modeled separately based on the biology of causative bacterium, the shedding of V. cholerae O1 by humans into the environment, as well as the effects of precipitation and water temperature on the concentration and survival of V. cholerae in aquatic reservoirs. Although the number of reported cholera cases has declined compared to the initial outbreak in 2010, the increase in the number of susceptible population members and the presence of toxigenic V. cholerae in the environment estimated by the model indicate that without further improvements to drinking water and sanitation infrastructures, intermittent cholera outbreaks are likely to continue in Haiti.     

Disialogangliosides and Their Interaction with Cholera Toxin—Investigation by Molecular Modeling,Molecular Mechanics and Molecular Dynamics

Abstract

Molecular mechanics and molecular dynamics studies are performed to investigate the conformational preference of cell surface disialogangliosides (GD1A, GD1B and GD3) in aqueous environment. The molecular mechanics calculation reveals that water mediated hydrogen bonding network plays a significant role in the structural stabilization of GD1A, GD1B and GD3. These water mediated hydrogen bonds not only exist between neighboring residues but also exist between residues that are separated by 2 to 3 residues in between. The conformational energy difference between different conformational states of gangliosides correlates very well with the number of water mediated and direct hydrogen bonds. The spatial flexibility of NeuNAc of gangliosides at the binding site of cholera toxin is worked out. The NeuNAc has a limited allowed eulerian space at the binding site of Cholera Toxin (2.4%). The molecular modeling, molecular mechanics and molecular dynamics of disialo- ganglioside-cholera toxin complex reveal that cholera toxin can accommodate the disialo- ganglioside GD1A in three different modes. A single mode of binding is permissible for GD1B and GD3. Direct and water mediated hydrogen bonding interactions stabilizes these binding modes and play an essential role in defining the order of specificity for different disialogangliosides towards cholera toxin. This study not only provides models for the disialoganglioside-cholera toxin complexes but also identifies the NeuNAc binding site as a site for design of inhibitors that can restrict the pathogenic activity of cholera toxin.     

2011至2012年石家庄地区沙门菌食物中毒分离株分子流行病学特征

研究沙门菌食物中毒分离株invA基因、血清型和基因型的分子流行病学特征。收集2011至2012年发生于石家庄地区6起食物中毒分离出的16株沙门菌,参照GB 4789.4-2010方法确定其血清型;用实时荧光PCR法检测分离株侵袭蛋白A(invA)基因;应用中国细菌性传染病分子分型实验室监测网络(PulseNet China)推荐的脉冲场凝胶电泳技术对分离株进行基因型研究。16株沙门菌食物中毒分离株共分为5种血清型,分别为都柏林沙门菌2株、鼠伤寒沙门菌2株、肠炎沙门菌8株、圣保罗沙门菌3株、依麦克沙门菌1株;所有分离株invA基因均为阳性;血清型不同的分离株基因型也不相同,其中2起食物中毒分离株的基因型相同,相似性系数为100%,符合同一起暴发的一般规律。石家庄地区沙门菌食物中毒分离株致病性较强,某些血清型存在暴发的风险,应加强措施进行防范。     

Epidemiological and Molecular Characterization of Invasive Meningococcal Disease in Italy, 2008/09-2012/13

BackgroundFollowing the introduction of meningococcal serogroup C conjugate vaccine in Italy in 2005, changes in the epidemiology of Invasive Meningococcal Disease (IMD) were expected. The study aims were to describe the epidemiological trend and to characterize the isolates collected during the period 2008/09-2012/13 by multilocus sequence typing (MLST). Data on laboratory confirmed meningococcal diseases from National Surveillance System of IMD were reported.MethodsPoisson regression models were used to estimate the incidence rate over time. Serogrouping and MLST were performed following published methods.ResultsThe incidence rate of laboratory confirmed meningococcal disease decreased from 0.33 per 100,000 population in 2008/09 to 0.25 per 100,000 population in 2012/13. The serogroup B incidence rate was significantly higher (p<0.01) than that of other serogroups, among all age groups. The significant decrease of the IMD incidence rate (p = 0.01) reflects the decrease of serogroup B and C, in particular among individuals aged 15–24 years old (p<0.01). On the other hand, serogroup Y incidence increased during the period (from 0.01/100,000 in 2008/09 to 0.02/100,000 in 2012/13, p = 0.05). Molecular characterizations revealed that ST–41/44 cc and ST–11 cc were the main clonal complexes identified among serogroup B and C isolates, respectively. In particular, ST–41/44 cc was predominant in all age groups, whereas ST–11 cc was not identified in infants less than 1 year of age.ConclusionsIMD incidence declined in Italy and serogroup B caused most of the IMD cases, with infants having the highest risk of disease. Continued surveillance is needed to provide information concerning further changes in circulating meningococci with special regard to serogroup distribution. Moreover, knowledge of meningococcal genotypes is essential to detect hyper-invasive strains.     

Deciphering the Dynamical Origin of Mixed Population during Neural Stem Cell Development

Neural stem cells (NSCs) often give rise to a mixed population of cells during differentiation. However, the dynamical origin of these mixed states is poorly understood. In this article, our mathematical modeling study demonstrates that the bone morphogenetic protein 2 (BMP2) mediated disparate differentiation dynamics of NSCs in central and peripheral nervous systems essentially function through two distinct bistable switches that are mutually interconnected via a mushroom-like bifurcation. Stochastic simulations of the model reveal that the mixed population originates due to the existence of these bistable switching regulations and that the maintenance of such mixed states depends on the level of stochastic fluctuations of the system. It further demonstrates that due to extrinsic variability, cells in an NSC population can dynamically transit from mushroom to a unique isola kind of bifurcation state, which essentially extends the range of the BMP2-driven mixed population state during differentiation. Importantly, the model predicts that by individually altering the expression level of key regulatory proteins, the NSCs can be converted entirely to a preferred phenotype for BMP2 doses that previously resulted in a mixed population. Our findings show that efficient neuronal regeneration can be achieved by systematically maneuvering the differentiation dynamics.     

Deciphering the Glycan Preference of Bacterial Lectins by Glycan Array and Molecular Docking with Validation by Microcalorimetry and Crystallography

Recent advances in glycobiology revealed the essential role of lectins for deciphering the glycocode by specific recognition of carbohydrates. Integrated multiscale approaches are needed for characterizing lectin specificity: combining on one hand high-throughput analysis by glycan array experiments and systematic molecular docking of oligosaccharide libraries and on the other hand detailed analysis of the lectin/oligosaccharide interaction by x-ray crystallography, microcalorimetry and free energy calculations. The lectins LecB from Pseudomonas aeruginosa and BambL from Burkholderia ambifaria are part of the virulence factors used by the pathogenic bacteria to invade the targeted host. These two lectins are not related but both recognize fucosylated oligosaccharides such as the histo-blood group oligosaccharides of the ABH(O) and Lewis epitopes. The specificities were characterized using semi-quantitative data from glycan array and analyzed by molecular docking with the Glide software. Reliable prediction of protein/oligosaccharide structures could be obtained as validated by existing crystal structures of complexes. Additionally, the crystal structure of BambL/Lewis x was determined at 1.6 Å resolution, which confirms that Lewis x has to adopt a high-energy conformation so as to bind to this lectin. Free energies of binding were calculated using a procedure combining the Glide docking protocol followed by free energy rescoring with the Prime/Molecular Mechanics Generalized Born Surface Area (MM-GBSA) method. The calculated data were in reasonable agreement with experimental free energies of binding obtained by titration microcalorimetry. The established predictive protocol is proposed to rationalize large sets of data such as glycan arrays and to help in lead discovery projects based on such high throughput technology.