THE IMPORTANCE OF MOSQUITO BEHAVIOURAL ADAPTATIONS TO MALARIA CONTROL IN AFRICA

Over the past decade the use of long‐lasting insecticidal nets (LLINs), in combination with improved drug therapies, indoor residual spraying (IRS), and better health infrastructure, has helped reduce malaria in many African countries for the first time in a generation. However, insecticide resistance in the vector is an evolving threat to these gains. We review emerging and historical data on behavioral resistance in response to LLINs and IRS. Overall the current literature suggests behavioral and species changes may be emerging, but the data are sparse and, at times unconvincing. However, preliminary modeling has demonstrated that behavioral resistance could have significant impacts on the effectiveness of malaria control. We propose seven recommendations to improve understanding of resistance in malaria vectors. Determining the public health impact of physiological and behavioral insecticide resistance is an urgent priority if we are to maintain the significant gains made in reducing malaria morbidity and mortality.     

Epidemic management and control through risk-dependent individual contact interventions

Testing, contact tracing, and isolation (TTI) is an epidemic management and control approach that is difficult to implement at scale because it relies on manual tracing of contacts. Exposure notification apps have been developed to digitally scale up TTI by harnessing contact data obtained from mobile devices; however, exposure notification apps provide users only with limited binary information when they have been directly exposed to a known infection source. Here we demonstrate a scalable improvement to TTI and exposure notification apps that uses data assimilation (DA) on a contact network. Network DA exploits diverse sources of health data together with the proximity data from mobile devices that exposure notification apps rely upon. It provides users with continuously assessed individual risks of exposure and infection, which can form the basis for targeting individual contact interventions. Simulations of the early COVID-19 epidemic in New York City are used to establish proof-of-concept. In the simulations, network DA identifies up to a factor 2 more infections than contact tracing when both harness the same contact data and diagnostic test data. This remains true even when only a relatively small fraction of the population uses network DA. When a sufficiently large fraction of the population (≳ 75%) uses network DA and complies with individual contact interventions, targeting contact interventions with network DA reduces deaths by up to a factor 4 relative to TTI. Network DA can be implemented by expanding the computational backend of existing exposure notification apps, thus greatly enhancing their capabilities. Implemented at scale, it has the potential to precisely and effectively control future epidemics while minimizing economic disruption.     

Synthesising 30 Years of Mathematical Modelling of Echinococcus Transmission

Background

Echinococcosis is a complex zoonosis that has domestic and sylvatic lifecycles, and a range of different intermediate and definitive host species. The complexities of its transmission and the sparse evidence on the effectiveness of control strategies in diverse settings provide significant challenges for the design of effective public health policy against this disease. Mathematical modelling is a useful tool for simulating control packages under locally specific transmission conditions to inform optimal timing and frequency of phased interventions for cost-effective control of echinococcosis. The aims of this review of 30 years of Echinococcus modelling were to discern the epidemiological mechanisms underpinning models of Echinococcus granulosus and E. multilocularis transmission and to establish the need to include a human transmission component in such models.

Methodology/Principal Findings

A search was conducted of all relevant articles published up until July 2012, identified from the PubMED, Web of Knowledge and Medline databases and review of bibliographies of selected papers. Papers eligible for inclusion were those describing the design of a new model, or modification of an existing mathematical model of E. granulosus or E. multilocularis transmission. A total of 13 eligible papers were identified, five of which described mathematical models of E. granulosus and eight that described E. multilocularis transmission. These models varied primarily on the basis of six key mechanisms that all have the capacity to modulate model dynamics, qualitatively affecting projections. These are: 1) the inclusion of a ‘latent’ class and/or time delay from host exposure to infectiousness; 2) an age structure for animal hosts; 3) the presence of density-dependent constraints; 4) accounting for seasonality; 5) stochastic parameters; and 6) inclusion of spatial and risk structures.

Conclusions/Significance

This review discusses the conditions under which these mechanisms may be important for inclusion in models of Echinococcus transmission and proposes recommendations for the design of dynamic human models of transmission. Accounting for the dynamic behaviour of the Echinococcus parasites in humans will be key to predicting changes in the disease burden over time and to simulate control strategies that optimise public health impact.     

An Apparent Lack of Epidemiologic Association between Hepatitis C Virus Knowledge and the Prevalence of Hepatitis C Infection in a National Survey in Egypt

Background

Egypt has by far the largest hepatitis C virus (HCV) prevalence in the world with 14.7% of the population being antibody positive for HCV. The aim of this study was to examine the association between knowledge of HCV and HCV antibody positivity among the Egyptian population.

Methods

We characterized different measures of HCV knowledge and examined their associations with HCV prevalence, by analyzing a nationally representative database using standard epidemiologic methods. The database, the 2008 Egyptian Demographic and Health Survey, included demographic, health, and HCV biomarker information for a sample of over 12,000 individuals.

Results

Basic knowledge of HCV was found to be high, but multiple gaps were identified in the specific knowledge of HCV and its modes of transmission. There was no statistically significant difference in HCV prevalence between those who have heard of HCV infection and those who have not (14.4% vs. 15.9%, p>.05). Similar results were found for the other HCV knowledge measures including those specific to HCV modes of transmission and to the sources of information for HCV awareness. Logistic regression analyses did not demonstrate an association between HCV knowledge and HCV prevalence.

Conclusions

Our results do not provide support for an effect of awareness on reducing the risk of HCV infection in Egypt. Public health messages directed at the lay public may not provide sufficient empowerment for individuals to avoid HCV infection, and should be complemented with prevention programs to promote and strengthen infection control in the settings of exposure, particularly in health care facilities.     

Systematic Identification of H274Y Compensatory Mutations in Influenza A Virus Neuraminidase by High-Throughput Screening

Compensatory mutations contribute to the appearance of the oseltamivir resistance substitution H274Y in the neuraminidase (NA) gene of H1N1 influenza viruses. Here, we describe a high-throughput screening method utilizing error-prone PCR and next-generation sequencing to comprehensively screen NA genes for H274Y compensatory mutations. We found four mutations that can either fully (R194G, E214D) or partially (L250P, F239Y) compensate for the fitness deficiency of the H274Y mutant. The compensatory effect of E214D is applicable in both seasonal influenza virus strain A/New Caledonia/20/1999 and 2009 pandemic swine influenza virus strain A/California/04/2009. The technique described here has the potential to profile a gene at the single-nucleotide level to comprehend the dynamics of mutation space and fitness and thus offers prediction power for emerging mutant species.     

Understanding the Potential Impact of a Combination HIV Prevention Intervention in a Hyper-Endemic Community

Objectives

Despite demonstrating only partial efficacy in preventing new infections, available HIV prevention interventions could offer a powerful strategy when combined. In anticipation of combination HIV prevention programs and research studies we estimated the population-level impact of combining effective scalable interventions at high population coverage, determined the factors that influence this impact, and estimated the synergy between the components.

Methods

We used a mathematical model to investigate the effect on HIV incidence of a combination HIV prevention intervention comprised of high coverage of HIV testing and counselling, risk reduction following HIV diagnosis, male circumcision for HIV-uninfected men, and antiretroviral therapy (ART) for HIV-infected persons. The model was calibrated to data for KwaZulu-Natal, South Africa, where adult HIV prevalence is approximately 23%.

Results

Compared to current levels of HIV testing, circumcision, and ART, the combined intervention with ART initiation according to current guidelines could reduce HIV incidence by 47%, from 2.3 new infections per 100 person-years (pyar) to 1.2 per 100 pyar within 4 years and by almost 60%, to 1 per 100 pyar, after 25 years. Short-term impact is driven primarily by uptake of testing and reductions in risk behaviour following testing while long-term effects are driven by periodic HIV testing and retention in ART programs. If the combination prevention program incorporated HIV treatment upon diagnosis, incidence could be reduced by 63% after 4 years and by 76% (to about 0.5 per 100 pyar) after 15 years. The full impact of the combination interventions accrues over 10–15 years. Synergy is demonstrated between the intervention components.

Conclusion

High coverage combination of evidence-based strategies could generate substantial reductions in population HIV incidence in an African generalized HIV epidemic setting. The full impact could be underestimated by the short assessment duration of typical evaluations.     

Role for nucleolin/Nsr1 in the cellular localization of topoisomerase I

Nucleolin functions in ribosome biogenesis and contains an acidic N terminus that binds nuclear localization sequences. In previous work we showed that human nucleolin associates with the N-terminal region of human topoisomerase I (Top1). We have now mapped the topoisomerase I interaction domain of nucleolin to the N-terminal 225 amino acids. We also show that the Saccharomyces cerevisiae nucleolin ortholog, Nsr1p, physically interacts with yeast topoisomerase I, yTop1p. Studies of isogenic NSR1(+) and Deltansr1 strains indicate that NSR1 is important in determining the cellular localization of yTop1p. Moreover, deletion of NSR1 reduces sensitivity to camptothecin, an antineoplastic topoisomerase I inhibitor. By contrast, Deltansr1 cells are hypersensitive to the topoisomerase II-targeting drug amsacrine. These findings indicate that nucleolin/Nsr1 is involved in the cellular localization of Top1 and that this localization may be important in determining sensitivity to drugs that target topoisomerases.     

The Epidemiology of Hepatitis C Virus in the Fertile Crescent: Systematic Review and Meta-Analysis

Objective

To characterize hepatitis C virus (HCV) epidemiology in countries of the Fertile Crescent region of the Middle East and North Africa (MENA), namely Iraq, Jordan, Lebanon, Palestine, and Syria.

Methods

We systematically reviewed and synthesized available records of HCV incidence and prevalence following PRISMA guidelines. Meta-analyses were implemented using a DerSimonian-Laird random effects model with inverse weighting to estimate the country-specific HCV prevalence among the various at risk population groups.

Results

We identified eight HCV incidence and 240 HCV prevalence measures in the Fertile Crescent. HCV sero-conversion risk among hemodialysis patients was 9.2% in Jordan and 40.3% in Iraq, and ranged between 0% and 3.5% among other populations in Iraq over different follow-up times. Our meta-analyses estimated HCV prevalence among the general population at 0.2% in Iraq (range: 0–7.2%; 95% CI: 0.1–0.3%), 0.3% in Jordan (range: 0–2.0%; 95% CI: 0.1–0.5%), 0.2% in Lebanon (range: 0–3.4%; 95% CI: 0.1–0.3%), 0.2% in Palestine (range: 0–9.0%; 95% CI: 0.2–0.3%), and 0.4% in Syria (range: 0.3–0.9%; 95% CI: 0.4–0.5%). Among populations at high risk, HCV prevalence was estimated at 19.5% in Iraq (range: 0–67.3%; 95% CI: 14.9–24.5%), 37.0% in Jordan (range: 21–59.5%; 95% CI: 29.3–45.0%), 14.5% in Lebanon (range: 0–52.8%; 95% CI: 5.6–26.5%), and 47.4% in Syria (range: 21.0–75.0%; 95% CI: 32.5–62.5%). Genotypes 4 and 1 appear to be the dominant circulating strains.

Conclusions

HCV prevalence in the population at large appears to be below 1%, lower than that in other MENA sub-regions, and tending towards the lower end of the global range. However, there is evidence for ongoing HCV transmission within medical facilities and among people who inject drugs (PWID). Migration dynamics appear to have played a role in determining the circulating genotypes. HCV prevention efforts should be targeted, and focus on infection control in clinical settings and harm reduction among PWID.     

Mapping the Risk of Soil-Transmitted Helminthic Infections in the Philippines

BackgroundIn order to increase the efficient allocation of soil-transmitted helminth (STH) disease control resources in the Philippines, we aimed to describe for the first time the spatial variation in the prevalence of A. lumbricoides, T. trichiura and hookworm across the country, quantify the association between the physical environment and spatial variation of STH infection and develop predictive risk maps for each infection.Conclusions/SignificanceThis analysis revealed significant spatial variation in STH infection prevalence within provinces of the Philippines. This suggests that a spatially targeted approach to STH interventions, including mass drug administration, is warranted. When financially possible, additional STH surveys should be prioritized to high-risk areas identified by our study in Luzon.     

Modelling parasite aggregation: disentangling statistical and ecological approaches

The overdispersion in macroparasite infection intensity among host populations is commonly simulated using a constant negative binomial aggregation parameter. We describe an alternative to utilising the negative binomial approach and demonstrate important disparities in intervention efficacy projections that can come about from opting for pattern-fitting models that are not process-explicit. We present model output in the context of the epidemiology and control of soil-transmitted helminths due to the significant public health burden imposed by these parasites, but our methods are applicable to other infections with demonstrable aggregation in parasite numbers among hosts.