A global assessment of Echinococcus multilocularis infections in domestic dogs: proposing a framework to overcome past methodological heterogeneity

Echinococcus multilocularis, the aetiological agent of human Alveolar Echinococcosis, is transmitted between small mammals and wild or domestic canids. Dogs infected with E. multilocularis as dead-end hosts. Whereas E. multilocularis infections in wild hosts and humans have been well-studied in recent decades, infections in domestic dogs are sparsely reported. This literature review and meta-analysis highlighted gaps in the available data and provided a re-assessment of the global distribution of domestic dog E. multilocularis infections. We found 46 published articles documenting the prevalence of E. multilocularis in domestic dogs from 21 countries across Europe, Asia and North America. Apparent prevalence estimates ranged from 0.00% (0.00–0.33%) in Germany to 55.50% (26.67–81.12%) in China. Most studies were conducted in areas of high human Alveolar Echinococcosis. By accounting for reassessed diagnostic sensitivity and specificity, we estimated true prevalence in a subset of studies, which varied between 0.00% (0.00–12.42%) and 41.09% (21.12–65.81%), as these true prevalence estimates were seldom reported in the articles themselves. Articles also showed a heavy emphasis on rural dogs, dismissing urban ones, which is concerning due to the role urbanisation plays in the transmission of zoonotic diseases, especially those utilising pets as definitive hosts. Lastly, population studies on canine Alveolar Echinococcosis were absent, highlighting the relative focus on human rather than animal health. We thus developed a framework for investigating domestic dog E. multilocularis infections and performing risk assessment of dog-associated transmission to fill the gaps found in the literature

Total coliform and Escherichia coli contamination in rural well water: Analysis for passive surveillance

With increasing stress on our water resources and recent waterborne disease outbreaks, understanding the epidemiology of waterborne pathogens is crucial to build surveillance systems. The purpose of this study was to explore techniques for describing microbial water quality in rural drinking water wells, based on spatiotemporal analysis, time series analysis and relative risk mapping. Tests results for Escherichia coli and coliforms from private and small public well water samples, collected between 2004 and 2012 in Alberta, Canada, were used for the analysis. Overall, 14.6 and 1.5% of the wells were total coliform and E. coli-positive, respectively. Private well samples were more often total coliform or E. coli-positive compared with untreated public well samples. Using relative risk mapping we were able to identify areas of higher risk for bacterial contamination of groundwater in the province not previously identified. Incorporation of time series analysis demonstrated peak contamination occurring for E. coli in July and a later peak for total coliforms in September, suggesting a temporal dissociation between these indicators in terms of groundwater quality, and highlighting the potential need to increase monitoring during certain periods of the year

Study of arc-jet propulsion devices Final report, 20 Nov. 1964 - 19 Dec. 1965

Energy transfer mechanisms in radiation, water, and regeneratively cooled, and MPD arc jet propulsion device

Antimicrobial resistance in fecal generic Escherichia coli in 90 Alberta swine finishing farms: prevalence and risk factors for resistance

The objective of this retrospective study was to determine the prevalence of antimicrobial resistance (AMR) in generic Escherichia coli isolates obtained from 90 Alberta finisher swine farms, and to evaluate the potential associations between on-farm antimicrobial use (AMU) practices and observed AMR. The farms were visited three times, approximately one month apart (n=269 farm visits). In total, 5 pen fecal samples were collected per each visit and mixed into one pool per visit. Conventional culture and susceptibility testing were employed. Reported AMU practices through feed, water and injection in different phases of pig production, were collected using a questionnaire

Predicting Functional and Regulatory Divergence of a Drug Resistance Transporter Gene in the Human Malaria Parasite

Background: The paradigm of resistance evolution to chemotherapeutic agents is that a key coding mutation in a specific gene drives resistance to a particular drug. In the case of resistance to the anti-malarial drug chloroquine (CQ), a specific mutation in the transporter pfcrt is associated with resistance. Here, we apply a series of analytical steps to gene expression data from our lab and leverage 3 independent datasets to identify pfcrt-interacting genes. Resulting networks provide insights into pfcrt’s biological functions and regulation, as well as the divergent phenotypic effects of its allelic variants in different genetic backgrounds. Results: To identify pfcrt-interacting genes, we analyze pfcrt co-expression networks in 2 phenotypic states - CQ-resistant (CQR) and CQ-sensitive (CQS) recombinant progeny clones - using a computational approach that prioritizes gene interactions into functional and regulatory relationships. For both phenotypic states, pfcrt co-expressed gene sets are associated with hemoglobin metabolism, consistent with CQ’s expected mode of action. To predict the drivers of co-expression divergence, we integrate topological relationships in the co-expression networks with available high confidence protein-protein interaction data. This analysis identifies 3 transcriptional regulators from the ApiAP2 family and histone acetylation as potential mediators of these divergences. We validate the predicted divergences in DNA mismatch repair and histone acetylation by measuring the effects of small molecule inhibitors in recombinant progeny clones combined with quantitative trait locus (QTL) mapping. Conclusions: This work demonstrates the utility of differential co-expression viewed in a network framework to uncover functional and regulatory divergence in phenotypically distinct parasites. pfcrt-associated co-expression in the CQ resistant progeny highlights CQR-specific gene relationships and possible targeted intervention strategies. The approaches outlined here can be readily generalized to other parasite populations and drug resistances

Identification of Antigens Specific to Non-Tuberculous Mycobacteria: The Mce Family of Proteins as a Target of T Cell Immune Responses

The lack of an effective TB vaccine hinders current efforts in combating the TB pandemic. One theory as to why BCG is less protective in tropical countries is that exposure to non-tuberculous mycobacteria (NTM) reduces BCG efficacy. There are currently several new TB vaccines in clinical trials, and NTM exposure may also be relevant in this context. NTM exposure cannot be accurately evaluated in the absence of specific antigens; those which are known to be present in NTM and absent from M. tuberculosis and BCG. We therefore used a bioinformatic pipeline to define proteins which are present in common NTM and absent from the M. tuberculosis complex, using protein BLAST, TBLASTN and a short sequence protein BLAST to ensure the specificity of this process. We then assessed immune responses to these proteins, in healthy South Africans and in patients from the United Kingdom and United States with documented exposure to NTM. Low level responses were detected to a cluster of proteins from the mammalian cell entry family, and to a cluster of hypothetical proteins, using ex vivo ELISpot and a 6 day proliferation assay. These early findings may provide a basis for characterising exposure to NTM at a population level, which has applications in the field of TB vaccine design as well as in the development of diagnostic tests

Open defecation and childhood stunting in India: an ecological analysis of new data from 112 districts.

Poor sanitation remains a major public health concern linked to several important health outcomes; emerging evidence indicates a link to childhood stunting. In India over half of the population defecates in the open; the prevalence of stunting remains very high. Recently published data on levels of stunting in 112 districts of India provide an opportunity to explore the relationship between levels of open defecation and stunting within this population. We conducted an ecological regression analysis to assess the association between the prevalence of open defecation and stunting after adjustment for potential confounding factors. Data from the 2011 HUNGaMA survey was used for the outcome of interest, stunting; data from the 2011 Indian Census for the same districts was used for the exposure of interest, open defecation. After adjustment for various potential confounding factors--including socio-economic status, maternal education and calorie availability--a 10 percent increase in open defecation was associated with a 0.7 percentage point increase in both stunting and severe stunting. Differences in open defecation can statistically account for 35 to 55 percent of the average difference in stunting between districts identified as low-performing and high-performing in the HUNGaMA data. In addition, using a Monte Carlo simulation, we explored the effect on statistical power of the common practice of dichotomizing continuous height data into binary stunting indicators. Our simulation showed that dichotomization of height sacrifices statistical power, suggesting that our estimate of the association between open defecation and stunting may be a lower bound. Whilst our analysis is ecological and therefore vulnerable to residual confounding, these findings use the most recently collected large-scale data from India to add to a growing body of suggestive evidence for an effect of poor sanitation on human growth. New intervention studies, currently underway, may shed more light on this important issue

Cryptosporidium Priming Is More Effective than Vaccine for Protection against Cryptosporidiosis in a Murine Protein Malnutrition Model

Cryptosporidium is a major cause of severe diarrhea, especially in malnourished children. Using a murine model of C. parvum oocyst challenge that recapitulates clinical features of severe cryptosporidiosis during malnutrition, we interrogated the effect of protein malnutrition (PM) on primary and secondary responses to C. parvum challenge, and tested the differential ability of mucosal priming strategies to overcome the PM-induced susceptibility. We determined that while PM fundamentally alters systemic and mucosal primary immune responses to Cryptosporidium, priming with C. parvum (106 oocysts) provides robust protective immunity against re-challenge despite ongoing PM. C. parvum priming restores mucosal Th1-type effectors (CD3+CD8+CD103+ T-cells) and cytokines (IFNγ, and IL12p40) that otherwise decrease with ongoing PM. Vaccination strategies with Cryptosporidium antigens expressed in the S. Typhi vector 908htr, however, do not enhance Th1-type responses to C. parvum challenge during PM, even though vaccination strongly boosts immunity in challenged fully nourished hosts. Remote non-specific exposures to the attenuated S. Typhi vector alone or the TLR9 agonist CpG ODN-1668 can partially attenuate C. parvum severity during PM, but neither as effectively as viable C. parvum priming. We conclude that although PM interferes with basal and vaccine-boosted immune responses to C. parvum, sustained reductions in disease severity are possible through mucosal activators of host defenses, and specifically C. parvum priming can elicit impressively robust Th1-type protective immunity despite ongoing protein malnutrition. These findings add insight into potential correlates of Cryptosporidium immunity and future vaccine strategies in malnourished children

Adrenocortical, autonomic, and inflammatory causes of the metabolic syndrome: nested case-control study.

BACKGROUND: The causes of metabolic syndrome (MS), which may be a precursor of coronary disease, are uncertain. We hypothesize that disturbances in neuroendocrine and cardiac autonomic activity (CAA) contribute to development of MS. We examine reversibility and the power of psychosocial and behavioral factors to explain the neuroendocrine adaptations that accompany MS. METHODS AND RESULTS: This was a double-blind case-control study of working men aged 45 to 63 years drawn from the Whitehall II cohort. MS cases (n=30) were compared with healthy controls (n=153). Cortisol secretion, sensitivity, and 24-hour cortisol metabolite and catecholamine output were measured over 2 days. CAA was obtained from power spectral analysis of heart rate variability (HRV) recordings. Twenty-four-hour cortisol metabolite and normetanephrine (3-methoxynorepinephrine) outputs were higher among cases than controls (+ 0.49, +0.45 SD, respectively). HRV and total power were lower among cases (both -0.72 SD). Serum interleukin-6, plasma C-reactive protein, and viscosity were higher among cases (+0.89, +0.51, and +0.72 SD). Lower HRV was associated with higher normetanephrine output (r=-0.19; P=0.03). Among former cases (MS 5 years previously, n=23), cortisol output, heart rate, and interleukin-6 were at the level of controls. Psychosocial factors accounted for 37% of the link between MS and normetanephrine output, and 7% to 19% for CAA. Health-related behaviors accounted for 5% to 18% of neuroendocrine differences. CONCLUSIONS: Neuroendocrine stress axes are activated in MS. There is relative cardiac sympathetic predominance. The neuroendocrine changes may be reversible. This case-control study provides the first evidence that chronic stress may be a cause of MS. Confirmatory prospective studies are required

Anti-vortex state in cross-like nanomagnets

We report on results of computer micromodelling of anti-vortex states in asymmetrical cross-like ferromagnetic nanostructures and their practical realization. The arrays of cobalt crosses with 1 mkm branches, 100 nm widths of the branches and 40 nm thicknesses were fabricated using e-beam lithography and ion etching. Each branch of the cross was tapered at one end and bulbous at the other. The stable formation of anti-vortex magnetic states in these nanostructures during magnetization reversal was demonstrated experimentally using magnetic force microscopy.Comment: 19 pages, 9 figure