Assessing density dependence in the transmission of lymphatic filariasis: uptake and development of Wuchereria bancrofti microfilariae in the vector mosquitoes

Understanding density dependence in the transmission of lymphatic filariasis is essential for assessing the prospects of elimination. This study seeks to quantify the relationship between microfilaria (Mf) density in human blood and the number of third stage (L3) larvae developing in the mosquito vectors Aedes polynesiensis Marks and Culex quinquefasciatus Say (Diptera: Culicidae) after blood-feeding. Two types of curves are fitted to previously published data. Fitting a linearized power curve through the data allows for correction for measurement error in human Mf counts. Ignoring measurement error leads to overestimation of the strength of density dependence; the degree of overestimation depends on the accuracy of measurement of Mf density. For use in mathematical models of transmission of lymphatic filariasis, a hyperbolic saturating function is preferable. This curve explicitly estimates the Mf uptake and development at lowest Mf densities and the average maximum number of L3 that can develop in mosquitoes. This maximum was estimated at 23 and 4 for Ae. polynesiensis and Cx. quinquefasciatus, respectively.     

Short-term variability of biomarkers of proteinase activity in patients with emphysema associated with type Z alpha-1-antitrypsin deficiency

Background

The burden of proteinases from inflammatory cells in the lung of subjects with type Pi ZZ of alpha-1-antitrypsin deficiency is higher than in those without the deficiency. Cross-sectional studies have shown increased levels of biomarkers of extracellular matrix degradation in vivo. Longitudinal variability of these biomarkers is unknown but desirable for clinical studies with proteinase inhibitors.

Methods

We measured three different types of biomarkers, including desmosines, elastase-formed fibrinogen fragments and heparan sulfate epitope JM403, in plasma and urine for a period of 7 weeks in a group of 12 patients who participated in a placebo-controlled study to assess the safety of a single inhalation of hyaluronic acid.

Results

Effect of study medication on any of the biomarkers was not seen. Baseline desmosines in plasma and urine correlated with baseline CO diffusion capacity (R = 0.81, p = 0.01 and R = 0.65, p = 0.05). Mean coefficient of variation within patients (CVi) for plasma and urine desmosines was 18.7 to 13.5%, respectively. Change in urinary desmosine levels correlated significantly with change in plasma desmosine levels (R = 0.84, p < 0.01). Mean CVi for fibrinogen fragments in plasma was 20.5% and for JM403 in urine was 27.8%. No correlations were found between fibrinogen fragments or JM403 epitope and desmosines.

Conclusion

We found acceptable variability in our study parameters, indicating the feasibility of their use in an evaluation of biochemical efficacy of alpha-1-antitrypsin augmentation therapy in Pi Z subjects.     

Genome-Wide Association Study in an Admixed Case Series Reveals IL12A as a New Candidate in Beh?et Disease

Introduction

The etiology of Behçet’s disease (BD) is unknown, but widely considered an excessive T-cell mediated inflammatory response in a genetically susceptible host. Recent genome-wide association studies (GWAS) have shown limited number of novel loci-associations. The rarity and unequal distribution of the disease prevalence amongst different ethnic backgrounds have hampered the use of GWAS in cohorts of mixed ethnicity and sufficient sample size. However, novel statistical approaches have now enabled GWAS in admixed cohorts.

Methods

We ran a GWAS on 336 BD cases and 5,843 controls. The cases consisted of Western Europeans, Middle Eastern and Turkish individuals. Participants from the Generation R study, a multiethnic birth cohort in Rotterdam, The Netherlands were used as controls. All samples were genotyped and data was combined. Linear regression models were corrected for population stratification using Genomic Principal Components and Linear Mixed Modelling. Meta-analysis was performed on selected results previously published.

Results

We identified SNPs associated at genome-wide significant level mapping to the 6p21.33 (HLA) region. In addition to this known signal two potential novel associations on chromosomes 6 and 18 were identified, yet with low minor allele frequencies. Extended meta-analysis reveal a GWS association with the IL12A variant rs17810546 on chromosome 3.

Discussion

We demonstrate that new statistical techniques enable GWAS analyses in a limited sized cohort of mixed ethnicity. After implementation, we confirmed the central role of the HLA region in the disease and identified new regions of interest. Moreover, we validated the association of a variant in the IL2A gene by meta-analysis with previous work. These findings enhance our knowledge of genetic associations and BD, and provide further justification for pursuing collective initiatives in genetic studies given the low prevalence of this and other rare diseases.     

Control,Elimination, and Eradication of River Blindness: Scenarios,Timelines, and Ivermectin Treatment Needs in Africa

River blindness (onchocerciasis) causes severe itching, skin lesions, and vision impairment including blindness. More than 99% of all current cases are found in sub-Saharan Africa. Fortunately, vector control and community-directed treatment with ivermectin have significantly reduced morbidity. Studies in Mali and Senegal proved the feasibility of elimination with ivermectin administration. The treatment goal is shifting from control to elimination in endemic African regions. Given limited resources, national and global policymakers need a rigorous analysis comparing investment options. For this, we developed scenarios for alternative treatment goals and compared treatment timelines and drug needs between the scenarios. Control, elimination, and eradication scenarios were developed with reference to current standard practices, large-scale studies, and historical data. For each scenario, the timeline when treatment is expected to stop at country level was predicted using a dynamical transmission model, and ivermectin treatment needs were predicted based on population in endemic areas, treatment coverage data, and the frequency of community-directed treatment. The control scenario requires community-directed treatment with ivermectin beyond 2045 with around 2.63 billion treatments over 2013–2045; the elimination scenario, until 2028 in areas where feasible, but beyond 2045 in countries with operational challenges, around 1.15 billion treatments; and the eradication scenario, lasting until 2040, around 1.30 billion treatments. The eradication scenario is the most favorable in terms of the timeline of the intervention phase and treatment needs. For its realization, strong health systems and political will are required to overcome epidemiological and political challenges.     

The impact of mass drug administration expansion to low onchocerciasis prevalence settings in case of connected villages

BackgroundThe existence of locations with low but stable onchocerciasis prevalence is not well understood. An often suggested yet poorly investigated explanation is that the infection spills over from neighbouring locations with higher infection densities.MethodologyWe adapted the stochastic individual based model ONCHOSIM to enable the simulation of multiple villages, with separate blackfly (intermediate host) and human populations, which are connected through the regular movement of the villagers and/or the flies. With this model we explore the impact of the type, direction and degree of connectedness, and of the impact of localized or full-area mass drug administration (MDA) over a range of connected village settings.Principal findingsIn settings with annual fly biting rates (ABR) below the threshold needed for stable local transmission, persistence of onchocerciasis prevalence can well be explained by regular human traffic and/or fly movement from locations with higher ABR. Elimination of onchocerciasis will then theoretically be reached by only implementing MDA in the higher prevalence area, although lingering infection in the low prevalence location can trigger resurgence of transmission in the total region when MDA is stopped too soon. Expanding MDA implementation to the lower ABR location can therefore shorten the duration of MDA needed. For example, when prevalence spill-over is due to human traffic, and both locations have about equal populations, then the MDA duration can be shortened by up to three years. If the lower ABR location has twice as many inhabitants, the reduction can even be up to six years, but if spill-over is due to fly movement, the expected reduction is less than a year.Conclusions/SignificanceAlthough MDA implementation might not always be necessary in locations with stable low onchocerciasis prevalence, in many circumstances it is recommended to accelerate achieving elimination in the wider area.     

Fnr (EtrA) acts as a fine-tuning regulator of anaerobic metabolism in <Emphasis Type="Italic">Shewanella oneidensis</Emphasis>MR-1

Background  

EtrA in Shewanella oneidensis MR-1, a model organism for study of adaptation to varied redox niches, shares 73.6% and 50.8% amino acid sequence identity with the oxygen-sensing regulators Fnr in E. coli and Anr in Pseudomonas aeruginosa, respectively; however, its regulatory role of anaerobic metabolism in Shewanella spp. is complex and not well understood.     

Alternative communication systems for people with severe motor disabilities: a survey

We have now sufficient evidence that using electrical biosignals in the field of Alternative and Augmented Communication is feasible. Additionally, they are particularly suitable in the case of people with severe motor impairment, e.g. people with high-level spinal cord injury or with locked-up syndrome. Developing solutions for them implies that we find ways to use sensors that fit the user's needs and limitations, which in turn impacts the specifications of the system translating the user's intentions into commands. After devising solutions for a given user or profile, the system should be evaluated with an appropriate method, allowing a comparison with other solutions. This paper submits a review of the way three bioelectrical signals - electromyographic, electrooculographic and electroencephalographic - have been utilised in alternative communication with patients suffering severe motor restrictions. It also offers a comparative study of the various methods applied to measure the performance of AAC systems.     

Validation of ultrasound estimates of visceral fat in black South African adolescents

Accurate quantification of visceral adipose tissue (VAT) is needed to understand ethnic variations and their implications for metabolic disease risk. The use of reference methods such as computed tomography (CT) and magnetic resonance imaging (MRI) is limited in large epidemiological studies. Surrogate measures such as anthropometry and dual-energy X-ray absorptiometry (DXA) do not differentiate between VAT and subcutaneous abdominal adipose tissue (SCAT). Ultrasound provides a validated estimate of VAT and SCAT in white populations. This study aimed to validate the use of ultrasound-based assessment of VAT in black South African adolescents. One hundred healthy adolescents (boys = 48, girls = 52) aged 18-19 years participating in the birth to twenty cohort study had VAT and SCAT measured by single slice MRI at L4. These MRI "criterion measures" were related to ultrasound VAT and SCAT thickness, anthropometry (BMI, waist and hip circumferences), and DXA android region fat. Ultrasound VAT thickness showed the strongest correlations with MRI VAT (Spearman's correlation coefficients: r = 0.72 and r = 0.64; in boys and girls, respectively), and substantially improved the estimation of MRI VAT compared to anthropometry and DXA alone; in regression models the addition of ultrasound VAT thickness to models containing BMI, waist, and DXA android fat improved the explained variance in VAT from 39% to 60% in boys, and from 31% to 52% in girls. In conclusion, ultrasound substantially increased the precision of estimating VAT beyond anthropometry and DXA alone. Black South African adolescents have relatively little VAT compared to elderly whites, and we therefore provide new ultrasound-based prediction equations for VAT specific to this group.     

African Programme for Onchocerciasis Control 1995–2015: Model-Estimated Health Impact and Cost

Background

Onchocerciasis causes a considerable disease burden in Africa, mainly through skin and eye disease. Since 1995, the African Programme for Onchocerciasis Control (APOC) has coordinated annual mass treatment with ivermectin in 16 countries. In this study, we estimate the health impact of APOC and the associated costs from a program perspective up to 2010 and provide expected trends up to 2015.

Methods and Findings

With data on pre-control prevalence of infection and population coverage of mass treatment, we simulated trends in infection, blindness, visual impairment, and severe itch using the micro-simulation model ONCHOSIM, and estimated disability-adjusted life years (DALYs) lost due to onchocerciasis. We assessed financial costs for APOC, beneficiary governments, and non-governmental development organizations, excluding cost of donated drugs. We estimated that between 1995 and 2010, mass treatment with ivermectin averted 8.2 million DALYs due to onchocerciasis in APOC areas, at a nominal cost of about US$257 million. We expect that APOC will avert another 9.2 million DALYs between 2011 and 2015, at a nominal cost of US$221 million.

Conclusions

Our simulations suggest that APOC has had a remarkable impact on population health in Africa between 1995 and 2010. This health impact is predicted to double during the subsequent five years of the program, through to 2015. APOC is a highly cost-effective public health program. Given the anticipated elimination of onchocerciasis from some APOC areas, we expect even more health gains and a more favorable cost-effectiveness of mass treatment with ivermectin in the near future.