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Background The Global Programme to Eliminate Lymphatic Filariasis (GPELF) was launched in 2000 with the goal of eliminating lymphatic filariasis (LF) as a public health problem by 2020. Despite considerable progress, the current prevalence is around 60% of the 2000 figure, with the deadline looming a year away. Consequently, there is a continued need for investment in both the mass drug administration (MDA) and morbidity management programs, and this paper aims to demonstrate that need by estimating the health and economic burdens of LF prior to MDA programs starting in GPELF areas. Methods A previously developed model was used to estimate the numbers of individuals infected and individuals with symptomatic disease, along with the attributable number of disability-adjusted life years (DALYs). The economic burden was calculated by quantifying the costs incurred by the health-care system in managing clinical cases, the patients’ out-of-pocket costs, and their productivity costs. Results Prior to the MDA program, approximately 129 million people were infected with LF, of which 43 million had clinical disease, corresponding to a DALY burden of 5.25 million. The average annual economic burden per chronic case was US $115, the majority of which resulted from productivity costs. The total economic burden of LF was estimated at US $5.8 billion annually. Conclusions These results demonstrate the magnitude of the LF burden and highlight the continued need to support the GPELF. Patients with clinical disease bore the majority of the economic burden, but will not benefit much from the current MDA program, which is aimed at reducing transmission. This assessment further highlights the need to scale up morbidity management programs.

Background\ud Vanuatu was formerly highly endemic for lymphatic filariasis (LF), caused by Wuchereria bancrofti and transmitted by Anopheles mosquitoes. After a baseline survey showing 4.8% antigen prevalence in 1998, the country conducted nationwide (in one implementation unit) annual mass drug administration (MDA) with albendazole and diethylcarbamazine citrate from 2000 to 2004 and achieved prevalence of 0.2% by 2006 in a representative nationwide cluster survey among all age groups.\ud \ud Methods\ud Post MDA surveillance was conducted from 2006 to 2012. After MDA, the country was divided for surveillance into three evaluation units (EUs) formed by grouping provinces according to baseline prevalence: EU1: Torba, Sanma and Malampa; EU2: Penama; EU3: Shefa and Tafea. The study compiled all past data and information on surveys in Vanuatu from the country programme. This paper reviews the surveillance activities done after stopping MDA to validate the interruption of transmission and elimination of LF as a public health problem.\ud \ud Results\ud Post-MDA surveillance consisting of at least three transmission assessment surveys (TAS) in each of the three EUs was conducted between 2006 and 2012. Sentinel and spot check surveys identified a few villages with persistent high prevalence; all antigen positive cases in these sites were treated and additional targeted MDA conducted for 3 years in 13 villages in one area of concern. All three EUs passed all TAS in 2007, 2010 and 2012 respectively, with no positives found except in EU2 (Penama province) in 2012 when 2 children tested positive for circulating filariasis antigen. Assessment of the burden of chronic filariasis morbidity found 95 cases in 2003 and 32 remaining cases in 2007, all aged over 60 years.\ud \ud Conclusions\ud Vanuatu has achieved validation of elimination of LF as a public health problem. Post-validation surveillance is still recommended especially in formerly highly endemic areas.

Purpose: We sought to estimate the prevalence of trachoma at sufficiently fine resolution to allow elimination interventions to begin, where required, in the Southern Nations, Nationalities, and Peoples’ Region (SNNPR) of Ethiopia. Methods: We carried out cross-sectional population-based surveys in 14 rural zones. A 2-stage cluster randomized sampling technique was used. A total of 40 evaluation units (EUs) covering 110 districts (“woredas”) were surveyed from February 2013 to May 2014 as part of the Global Trachoma Mapping Project (GTMP), using the standardized GTMP training package and methodology. Results: A total of 30,187 households were visited in 1047 kebeles (clusters). A total of 131,926 people were enumerated, with 121,397 (92.0%) consenting to examination. Of these, 65,903 (54.3%) were female. In 38 EUs (108 woredas), TF prevalence was above the 10% threshold at which the World Health Organization recommends mass drug administration with azithromycin annually for at least 3 years. The region-level age- and sex-adjusted trichiasis prevalence was 1.5%, with the highest prevalence of 6.1% found in Cheha woreda in Gurage zone. The region-level age-adjusted TF prevalence was 25.9%. The highest TF prevalence found was 48.5% in Amaro and Burji woredas. In children aged 1–9 years, TF was associated with being a younger child, living at an altitude 15°C, and the use of open defecation by household members. Conclusion: Active trachoma and trichiasis are significant public health problems in SNNPR, requiring full implementation of the SAFE strategy (surgery, antibiotics, facial cleanliness, and environmental improvement).

Purpose: We sought to complete the baseline trachoma map of the Solomon Islands by establishing prevalences of active trachoma and trichiasis in the provinces of Choiseul, Western, Rennell-Bellona, and Temotu. Methods: Using the standardized methodology developed for the Global Trachoma Mapping Project, we conducted cross-sectional community-based surveys from September to November 2013. Choiseul and Western provinces were each mapped as separate evaluation units (EUs); Rennell-Bellona and Temotu were combined to form a third EU. Results: A total of 9819 individuals were sampled for inclusion, with 9224 (93.3%) consenting to examination, of whom 4587 (46.3%) were female. Survey teams visited 82 villages, and surveyed 2448 households. Two EUs had prevalences of trachomatous inflammation – follicular (TF) in 1–9-year-olds over the 10% threshold at which WHO recommends mass distribution of azithromycin for at least 3 years (Western 20.4%, 95% confidence interval, CI 15.6–26.3%; Rennell-Bellona/Temotu 22.0%, 95% CI 18.5–26.0%). Choiseul had a TF prevalence of 6.1% (95% CI 4.1–8.6%), and met the criterion for a single round of mass antibiotic distribution before re-survey. The adjusted prevalences of trichiasis in those aged 15+ years were 0.0% (95% CI 0.0–0.2%) in Choiseul, 0.16% (95% CI 0.0–0.5%) in Western, and 0.10% (95% CI 0–0.3%) in Rennell-Bellona/Temotu provinces. All three EUs require implementation of the facial cleanliness and environmental improvement components of the trachoma elimination strategy. Conclusion: Active trachoma is prevalent in the Solomon Islands. However, there is little evidence of the blinding complications of trachoma being a public health problem there. Further research into the explanation for this phenomenon is warranted.

PURPOSE: To complete the baseline trachoma map in Oromia, Ethiopia, by determining prevalences of trichiasis and trachomatous inflammation - follicular (TF) at evaluation unit (EU) level, covering all districts (woredas) without current prevalence data or active control programs, and to identify factors associated with disease. METHODS: Using standardized methodologies and training developed for the Global Trachoma Mapping Project, we conducted cross-sectional community-based surveys from December 2012 to July 2014. RESULTS: Teams visited 46,244 households in 2037 clusters from 252 woredas (79 EUs). A total of 127,357 individuals were examined. The overall age- and sex-adjusted prevalence of trichiasis in adults was 0.82% (95% confidence interval, CI, 0.70-0.94%), with 72 EUs covering 240 woredas having trichiasis prevalences above the elimination threshold of 0.2% in those aged ≥15 years. The overall age-adjusted TF prevalence in 1-9-year-olds was 23.4%, with 56 EUs covering 218 woredas shown to need implementation of the A, F and E components of the SAFE strategy (surgery, antibiotics, facial cleanliness and environmental improvement) for 3 years before impact surveys. Younger age, female sex, increased time to the main source of water for face-washing, household use of open defecation, low mean precipitation, low mean annual temperature, and lower altitude, were independently associated with TF in children. The 232 woredas in 64 EUs in which TF prevalence was ≥5% require implementation of the F and E components of the SAFE strategy. CONCLUSION: Both active trachoma and trichiasis are highly prevalent in much of Oromia, constituting a significant public health problem for the region.

Purpose: To complete the baseline trachoma map of Sudan by estimating the prevalence of trachoma and associated risk factors in the five Darfur States and Khartoum State. Methods: Using a standardized methodology developed for the Global Trachoma Mapping Project, we undertook a cross sectional, community-based survey in each of 32 evaluation units (EUs) covering all accessible districts. Results: We enumerated a total of 84,568 individuals, with 73,489 people (86.9%) examined from 20,242 households in 908 villages. The highest prevalence of trachomatous inflammation – follicular (TF) in children was found in El Fashir district (18.7%), and the lowest in El Malha district (0.0%). Five districts (El Fashir, Zalinji, Azoom, Maleet, and El Koma) were in the three EUs that had TF prevalences above the 10% threshold at which the World Health Organization recommends mass treatment with azithromycin, together with facial clean3liness and environmental improvement interventions, for at least 3 years. The highest trachomatous trichiasis prevalence in adults was found in the EU composed of Forbranga and Habillah (1.2%), and the lowest in the EU composed of As-salam and Belale districts in South Darfur (0.0%). TF in children was independently associated with younger age, unimproved sanitation in the household, having ≥5 children in the household, outside annual maximum temperatures

Purpose: To determine the local government area (LGA)-level prevalence of trachoma in all 34 LGAs of Katsina State. Methods: A population-based prevalence survey was conducted in each LGA of Katsina State, using the Global Trachoma Mapping Project methodology. We used a 3-stage cluster random sampling strategy to select 25 households from each of 25 clusters. We examined all residents of selected households aged 1 year and older for the clinical signs of trachomatous inflammation–follicular (TF), trachomatous inflammation–intense and trichiasis, using the World Health Organization (WHO) simplified grading scheme. Results: We examined 129,281 persons. Six LGAs had a TF prevalence ≥10%, and another six LGAs had a TF prevalence between 5% and 9.9%; all 12 require mass drug administration with azithromycin plus other interventions. The prevalence of trichiasis was ≥1.0% in 13 LGAs, and there is a need to perform trichiasis surgery in over 26,000 persons to reach targets set by the WHO for elimination of trichiasis. Conclusion: The prevalence of TF is generally low in Katsina state, but urgent steps must be taken to implement the full SAFE strategy (surgery, antibiotics, facial cleanliness, environmental improvement) in at least 12 LGAs while also stepping up efforts to provide community-based trichiasis surgery throughout the whole state, in order to make trachoma elimination by 2020 a reality.

PURPOSE: To determine the need or otherwise for establishment of a trachoma elimination program in Gombe State, Nigeria, by estimating the population-based prevalence of trachoma in each Local Government Area (LGA) of Gombe. METHODS: Using a multi-stage, systematic, random, and quasi-random sampling approach and Global Trachoma Mapping Project support, we selected 25 clusters in each LGA. In each cluster, we selected 25 households and all consenting residents aged 1 year and older were examined for trachomatous inflammation-follicular (TF) and trichiasis, using the World Health Organization simplified grading scheme. RESULTS: No LGA in Gombe State had a TF prevalence ≥5% in 1-9-year-olds. All LGAs had trichiasis prevalences above the elimination threshold and should be targeted for community-based delivery of trichiasis surgery. Only three LGAs had household-level improved wash water access of greater than 80%. Access to improved sanitation facilities was also poor as household access to improved sanitation facilities was above 80% in only one LGA. CONCLUSION: A trachoma program focused on delivery of trichiasis surgery is required in Gombe. Improvements in water and sanitation, through engagement with other sectors, are necessary.

Author(s): Hiep, Nguyen Xuan; Ngondi, Jeremiah M; Anh, Vu Tuan; Dat, Tran Minh; An, Tran Van; Dung, Nguyen Chi; Thang, Nguyen Duy; Chu, Brian K; Willis, Rebecca; Bakhtiari, Ana; Pavluck, Alexandre L; Johnson, James; Sidwell, Joshua; Brady, Molly; Henry, Rob; Mosher, Aryc; Porco, Travis C; Lietman, Thomas M; Rotondo, Lisa A; Lewallen, Susan; Courtright, Paul; Solomon, Anthony W; Global Trachoma Mapping Project | Abstract: PurposeFollowing interventions against trachoma in Viet Nam, impact surveys conducted in 2003-2011 suggested that trachoma was no longer a public health problem. In 2014, we undertook surveillance surveys to estimate prevalence of trachomatous inflammation-follicular (TF) and trichiasis.MethodsA population-based prevalence survey was undertaken in 11 evaluation units (EUs) encompassing 24 districts, using Global Trachoma Mapping Project methods. A two-stage cluster sampling design was used in each EU, whereby 20 clusters and 60 children per cluster were sampled. Consenting eligible participants (children aged 1-9nyears and adults aged ≥50nyears) were examined for trachoma.ResultsA total of 9391 households were surveyed, and 20,185 participants (98.8% of those enumerated) were examined for trachoma. EU-level TF prevalence in 1-9-year-olds ranged from 0% to 1.6%. In one cluster (in Ha Giang Province), the percentage of children with TF was 10.3%. The overall pattern of cluster-level percentages of children with TF, however, was consistent with an exponential distribution, which would be consistent with trachoma disappearing. Among people aged ≥50nyears, prevalence of trichiasis by EU ranged from 0% to 0.75%; these estimates are equivalent to 0-0.13% in all ages. The prevalence of trichiasis unknown to the health system among people aged ≥50nyears, by EU, ranged from 0% to 0.17%, which is equivalent to 0-0.03% in all ages.ConclusionFindings suggest that trachoma is no longer a public health problem in any of the 11 EUs surveyed. However, given the high proportion of children with TF in one cluster in Ha Giang Province, further investigations will be undertaken.

Author(s): Muhammad, Nasiru; Mpyet, Caleb; Adamu, Mohammed Dantani; William, Adamani; Umar, Murtala Muhammad; Muazu, Habila; Onyebuchi, Uwazoeke; Isiyaku, Sunday; Flueckiger, Rebecca M; Chu, Brian K; Willis, Rebecca; Pavluck, Alex; Dalhatu, Abbas; Ogoshi, Chris; Olobio, Nicholas; Gordon, Bruce A; Solomon, Anthony W; For The Global Trachoma Mapping Project | Abstract: PurposeThe World Health Organization's (WHO's) global trachoma elimination programme recommends mapping of trachoma at district level for planning of elimination activities in affected populations. This study aimed to provide data on trachoma prevalence for the Area Councils of Nigeria's Federal Capital Territory (FCT).MethodsUsing the Global Trachoma Mapping Project (GTMP) protocols, in March and April 2014, we conducted a population-based cross-sectional survey in each of the six Area Councils of FCT. Signs were defined based on the WHO simplified grading scheme.Results98% to 100% of the targeted households were enrolled in each Area Council. The number of children aged 1-9 years examined per Area Council ranged from 867 to 1248. The number of persons aged ≥15 years examined ranged from 1302 to 1836. The age-adjusted prevalence of trachomatous inflammation-follicular in 1-9-year-olds was l5% in each Area Council. The age- and gender-adjusted prevalence of trichiasis in those aged ≥15 years ranged from 0.0% to 0.3%; two Area Councils (Gwagwalada and Kwali) had prevalences above the 0.2% elimination threshold. The proportion of households with access to improved latrines and water sources ranged from 17 to 90% and 39 to 85% respectively.ConclusionsGwagwalada and Kwali Area Councils need to perform more trichiasis surgeries to attain the trichiasis elimination prevalence target of 0.2% in persons aged ≥15 years. No Area Council requires mass antibiotic administration for the purposes of trachoma's elimination as a public health problem. All Area Councils need to accelerate provision of access to improved water sources and latrine facilities, to achieve universal coverage.

Author(s): Negash, Kassahun; Macleod, Colin; Adamu, Yilikal; Ahmed, Mohammed; Ibrahim, Mohamed; Ali, Mussa; Haileselassie, Tesfaye; Willis, Rebecca; Chu, Brian K; Dejene, Michael; Asrat, Atsbeha; Flueckiger, Rebecca M; Pavluck, Alexandre L; Solomon, Anthony W; Global Trachoma Mapping Project | Abstract: PurposeTrachoma is to be eliminated as a public health problem by 2020. To help the process of planning interventions where needed, and to provide a baseline for later comparison, we set out to complete the map of trachoma in Afar, Ethiopia, by estimating trachoma prevalence in evaluation units (EUs) of grouped districts ("woredas").MethodsWe conducted seven community-based surveys from August to October 2013, using standardised Global Trachoma Mapping Project (GTMP) survey methodologies.ResultsWe enumerated 5065 households and 18,177 individuals in seven EUs covering 19 of Afar's 29 woredas; the other ten were not accessible. 16,905 individuals (93.0%) were examined, of whom 9410 (55.7%) were female. One EU incorporating four woredas (Telalak, Dalefage, Dewe, Hadele Ele) was shown to require full implementation of the SAFE strategy for three years before impact survey, with a trachomatous inflammation-follicular (TF) prevalence in 1-9-year-olds of 17.1% (95%CI 9.4-25.5), and a trichiasis prevalence in adults aged ≥15 years of 1.2% (95%CI 0.6-2.0). Five EUs, covering 13 woredas (Berahle, Aba'ala, Dupti, Kurri, Elidihare, Ayesayeta, Afamboo, Bure Mudaitu, Gewane, Amibara, Dulecho, Dalolo, and Konebo), had TF prevalences in children of 5-9.9% and need one round of azithromycin mass treatment and implementation of the F and E components of SAFE before re-survey; three of these EUs had trichiasis prevalences in adults ≥0.2%. The final EU (Mile, Ada'ar) had a sub-threshold TF prevalence and a trichiasis prevalence in adults just g0.2%.ConclusionTrachoma is a public health problem in Afar, and implementation of the SAFE strategy is required.

Stochastic simulation has been a powerful tool for studying the dynamics of gene regulatory networks, particularly in terms of understanding how cell-phenotype stability and fate-transitions are impacted by noisy gene expression. However, gene networks often have dynamics characterized by multiple attractors. Stochastic simulation is often inefficient for such systems, because most of the simulation time is spent waiting for rare, barrier-crossing events to occur. We present a rare-event simulation-based method for computing epigenetic landscapes and phenotype-transitions in metastable gene networks. Our computational pipeline was inspired by studies of metastability and barrier-crossing in protein folding, and provides an automated means of computing and visualizing essential stationary and dynamic information that is generally inaccessible to conventional simulation. Applied to a network model of pluripotency in Embryonic Stem Cells, our simulations revealed rare phenotypes and approximately Markovian transitions among phenotype-states, occurring with a broad range of timescales. The relative probabilities of phenotypes and the transition paths linking pluripotency and differentiation are sensitive to global kinetic parameters governing transcription factor-DNA binding kinetics. Our approach significantly expands the capability of stochastic simulation to investigate gene regulatory network dynamics, which may help guide rational cell reprogramming strategies. Our approach is also generalizable to other types of molecular networks and stochastic dynamics frameworks., Author summary Cell phenotypes are controlled by complex interactions between genes, proteins, and other molecules within a cell, along with signals from the cell’s environment. Gene regulatory networks (GRNs) describe these interactions mathematically. In principle, a GRN model can produce a map of possible cell phenotypes and phenotype-transitions, potentially informing experimental strategies for controlling cell phenotypes. Such a map could have a profound impact on many medical fields, ranging from stem cell therapies to wound healing. However, analytical solution of GRN models is virtually impossible, except for the smallest networks. Instead, time course trajectories of GRN dynamics can be simulated using specialized algorithms. However, these methods suffer from the difficulty of studying rare events, such as the spontaneous transitions between cell phenotypes that can occur in Embryonic Stem Cells or cancer cells. In this paper, we present a method to expand current stochastic simulation algorithms for the sampling of rare phenotypes and phenotype-transitions. The output of the computational pipeline is a simplified network of a few stable phenotypes, linked by potential transitions with quantified probabilities. This simplified network gives an intuitive representation of cell phenotype-transition dynamics, which could be useful for understanding how molecular processes impact cellular responses and aid interpretation of experimental data.

In many biological settings, two or more cells come into physical contact to form a cell-cell interface. In some cases, the cell-cell contact must be transient, forming on timescales of seconds. One example is offered by the T cell, an immune cell which must attach to the surface of other cells in order to decipher information about disease. The aspect ratio of these interfaces (tens of nanometers thick and tens of micrometers in diameter) puts them into the thin-layer limit, or “lubrication limit”, of fluid dynamics. A key question is how the receptors and ligands on opposing cells come into contact. What are the relative roles of thermal undulations of the plasma membrane and deterministic forces from active filopodia? We use a computational fluid dynamics algorithm capable of simulating 10-nanometer-scale fluid-structure interactions with thermal fluctuations up to seconds- and microns-scales. We use this to simulate two opposing membranes, variously including thermal fluctuations, active forces, and membrane permeability. In some regimes dominated by thermal fluctuations, proximity is a rare event, which we capture by computing mean first-passage times using a Weighted Ensemble rare-event computational method. Our results demonstrate a parameter regime in which the time it takes for an active force to drive local contact actually increases if the cells are being held closer together (e.g., by nonspecific adhesion), a phenomenon we attribute to the thin-layer effect. This leads to an optimal initial cell-cell separation for fastest receptor-ligand binding, which could have relevance for the role of cellular protrusions like microvilli. We reproduce a previous experimental observation that fluctuation spatial scales are largely unaffected, but timescales are dramatically slowed, by the thin-layer effect. We also find that membrane permeability would need to be above physiological levels to abrogate the thin-layer effect., Author summary The elastohydrodynamics of water in and around cells is playing an increasingly recognized role in biology. In this work, we investigate the flow of extracellular fluid in between cells during the formation of a cell-cell contact, to determine whether its necessary evacuation as the cells approach is a rate-limiting step before molecules on either cell can interact. To overcome the computational challenges associated with simulating fluid in this mechanically soft, stochastic and high-aspect-ratio environment, we extend a computational framework where the cell plasma membranes are treated as immersed boundaries in the fluid, and combine this with computational methods for simulating stochastic rare events in which an ensemble of simulations are given weights according to their probability. We find that the membranes fluctuate independently with a characteristic timescale of approximately microseconds, but that as the cells approach, a new, slower timescale of approximately milliseconds is introduced. Thermal undulations nor typical amounts of membrane permeability can overcome the timescale, but active forces, e.g., from the cytoskeleton, can. Our results suggest an explanation for differences in molecular interactions in live cells compared to in vitro reconstitution experiments.

Background The monitoring and evaluation of lymphatic filariasis (LF) has largely relied on the detection of antigenemia and antibodies in human populations. Molecular xenomonitoring (MX), the detection of parasite DNA/RNA in mosquitoes, may be an effective complementary method, particularly for detecting signals in low-level prevalence areas where Culex is the primary mosquito vector. This paper investigated the application of a household-based sampling method for MX in Tamil Nadu, India. Methods MX surveys were conducted in 2010 in two evaluation units (EUs): 1) a hotspot area, defined as sites with community microfilaria prevalence ≥1%, and 2) a larger area that also encompassed the hotspots. Households were systematically selected using a sampling interval proportional to the number of households in the EU. Mosquito pools were collected and analyzed by real-time polymerase chain reaction (qPCR). Two independent samples were taken in each EU to assess reproducibility of results. Follow-up surveys were conducted in 2012. Results In 2010, the proportion of positive pools in the hotspot EU was 49.3% compared to 23.4% in the overall EU. In 2012, pool positivity was significantly reduced to 24.3% and 6.5%, respectively (p, Author summary Lymphatic filariasis (LF) is one of the world’s foremost debilitating infectious diseases with nearly 800 million people at risk of infection. Given that LF is a mosquito-borne disease, the use of molecular xenomonitoring (MX) to detect parasite DNA/RNA in mosquitoes can serve as a valuable tool for LF monitoring and evaluation, particularly in Culex vector areas. We investigated using MX in a low-level prevalence district of Tamil Nadu, India by applying a household-based sampling strategy to determine trap location sites. Two independent mosquito samples were collected in each of a higher human infection hotspot area (sites with community microfilaria prevalence ≥1%) and across a larger evaluation area that also encompassed the hotspots. Pooled results showed mostly reproducible outcomes in both settings and a significant higher pool positivity in the hotspot area. A follow-up survey conducted two years later reconfirmed these findings while also showing a reduction in pool positivity and estimated prevalence of infection in mosquitoes in both settings. The utilization of a household-based sampling strategy for MX proved effective and should be further validated in wider epidemiological settings.

When the U.S. Agency for International Development (USAID) began to support national programs integrating their neglected tropical disease (NTD) program activities, the expected impact on individual disease-specific programs was unclear, particularly with respect to program financing and coverage. To assess this impact, data were collected by NTD program managers and their non-governmental organization (NGO) partners in Burkina Faso, Mali, and Uganda from 2 years prior and 2 years after their individual programs received funding for an integrated NTD program. Findings show that these countries experienced some increases in overall funding available for integrated NTD programs, an expansion of geographical coverage and of the number of persons treated, and the addition of treatments targeted at new diseases. What is not clear is whether these achievements can be sustained if there are decreases in external support in the future. Seeking increased government commitment or sustained external donor support should be a top priority.

Smart biomaterials that are self-assembled from peptide amphiphiles (PA) are known to undergo morphological transitions in response to specific physiological stimuli. The design of such customizable hydrogels is of significant interest due to their potential applications in tissue engineering, biomedical imaging, and drug delivery. Using a novel coarse-grained peptide/polymer model, which has been validated by comparison of equilibrium conformations from atomistic simulations, large-scale molecular dynamics simulations are performed to examine the spontaneous self-assembly process. Starting from initial random configurations, these simulations result in the formation of nanostructures of various sizes and shapes as a function of the electrostatics and temperature. At optimal conditions, the self-assembly mechanism for the formation of cylindrical nanofibers is deciphered involving a series of steps: (1) PA molecules quickly undergo micellization whose driving force is the hydrophobic interactions between alkyl tails; (2) neighboring peptide residues within a micelle engage in a slow ordering process that leads to the formation of β-sheets exposing the hydrophobic core; (3) spherical micelles merge together through an end-to-end mechanism to form cylindrical nanofibers that exhibit high structural fidelity to the proposed structure based on experimental data. As the temperature and electrostatics vary, PA molecules undergo alternative kinetic mechanisms, resulting in the formation of a wide spectrum of nanostructures. A phase diagram in the electrostatics-temperature plane is constructed delineating regions of morphological transitions in response to external stimuli.

Yaws and trachoma are targeted for eradication and elimination as public health problems. In trachoma-endemic populations mass administration of azithromycin can simultaneously treat yaws. We conducted a population-based prevalence survey in the five northernmost provinces of Vanuatu, where trachoma and yaws are suspected to be co-endemic. Clinical signs of trachoma were evaluated using the WHO simplified grading system, and skin examination with a serological rapid diagnostic test used to identify yaws. We enrolled 1004 households in 59 villages over 16 islands, and examined 3650 individuals of all ages for trachoma. The overall adjusted prevalence of trachomatous inflammation-follicular (TF) in 1-9 year-olds was 12.0% (95% Confidence Interval: 8.1-16.7%), and the overall adjusted prevalence of TT in those aged 15 years and greater was 0.04% (95% CI 0-0.14%). In multivariate analysis, the odds of children having TF was 2.6 (95% CI = 1.5-4.4) times higher in households with unimproved latrines, and independently associated with the number of children in the household (OR 1.3, 95% CI = 1.0-1.6 for each additional child). We examined the skin of 821 children aged 5-14 years. Two children had yaws, giving an estimated prevalence of active yaws in those aged 5-14 years of 0.2% (95% CI = 0.03-0.9%). Mass treatment with azithromycin is recommended in these provinces. Given the apparent low burden of yaws, integration of yaws and trachoma control programmes is likely to be useful and cost-effective to national programmes.

Summary We found that both the preventive chemotherapy and hydrocele surgery provided under the Global Programme to Eliminate Lymphatic Filariasis (GPELF) are cost-effective and offer a very good investment in public health. These results clearly demonstrate the value and importance of continued investment in the GPELF and show that continued funding is justified and highly cost-effective., Background. It has been estimated that $154 million per year will be required during 2015–2020 to continue the Global Programme to Eliminate Lymphatic Filariasis (GPELF). In light of this, it is important to understand the program’s current value. Here, we evaluate the cost-effectiveness and cost-benefit of the preventive chemotherapy that was provided under the GPELF between 2000 and 2014. In addition, we also investigate the potential cost-effectiveness of hydrocele surgery. Methods. Our economic evaluation of preventive chemotherapy was based on previously published health and economic impact estimates (between 2000 and 2014). The delivery costs of treatment were estimated using a model developed by the World Health Organization. We also developed a model to investigate the number of disability-adjusted life years (DALYs) averted by a hydrocelectomy and identified the cost threshold under which it would be considered cost-effective. Results. The projected cost-effectiveness and cost-benefit of preventive chemotherapy were very promising, and this was robust over a wide range of costs and assumptions. When the economic value of the donated drugs was not included, the GPELF would be classed as highly cost-effective. We projected that a typical hydrocelectomy would be classed as highly cost-effective if the surgery cost less than $66 and cost-effective if less than $398 (based on the World Bank’s cost-effectiveness thresholds for low income countries). Conclusions. Both the preventive chemotherapy and hydrocele surgeries provided under the GPELF are incredibly cost-effective and offer a very good investment in public health.

Purpose: Trachoma is a major cause of blindness in Ethiopia, and targeted for elimination as a public health problem by the year 2020. Prevalence data are needed to plan interventions. We set out to estimate the prevalence of trachoma in each evaluation unit of grouped districts (“woredas”) in Benishangul Gumuz region, Ethiopia. Methods: We conducted seven cross-sectional community-based surveys, covering 20 woredas, between December 2013 and January 2014, as part of the Global Trachoma Mapping Project (GTMP). The standardized GTMP training package and methodologies were used. Results: A total of 5828 households and 21,919 individuals were enumerated in the surveys. 19,583 people (89.3%) were present when survey teams visited. A total of 19,530 (99.7%) consented to examination, 11,063 (56.6%) of whom were female. The region-wide age- and sex-adjusted trichiasis prevalence in adults aged ≥15 years was 1.3%. Two evaluation units covering four woredas (Pawe, Mandura, Bulen and Dibate) with a combined rural population of 166,959 require implementation of the A, F and E components of the SAFE strategy (surgery, antibiotics, facial cleanliness and environmental improvement) for at least three years before re-survey, and intervention planning should begin for these woredas as soon as possible. Conclusion: Both active trachoma and trichiasis are public health problems in Benishangul Gumuz, which needs implementation of the full SAFE strategy.

Introduction: To prepare for global elimination of trachoma by 2020, the World Health Organization (WHO) recommends mapping of trachoma at district-level to enable planning of elimination activities in affected populations. The aim of our study was to provide data on trachoma for each local government area (LGA) of Kaduna State, Nigeria, as such data were previously unavailable. Method: As part of the Global Trachoma Mapping Project (GTMP), a population-based cross-sectional trachoma survey was conducted in each of the 23 LGAs of Kaduna State, between May and June 2013. The protocols of the GTMP were used. Results: The prevalence of trachomatous inflammation – follicular (TF) in children aged 1–9 years was between 0.03% and 8% across the LGAs, with only one LGA (Igabi) having a TF prevalence ≥5%. The LGA-level prevalences of trichiasis in persons aged 15 years and older were between 0.00% and 0.78%. Eleven LGAs had trichiasis prevalences of 0.2% and over in adults; a threshold equivalent to 1 case per 1000 total population. The LGA-level proportion of households with access to improved water sources ranged from 9% to 96%, while household access to latrines ranged from 5% to 99%. Conclusion: Kaduna State has generally hypoendemic trachoma, but a few trichiasis surgeries are still required to attain the WHO elimination targets. Better access to improved water and sanitation is needed.

Purpose: To determine the prevalence of trachoma in each of the 25 local government areas (LGAs) of Niger State, Nigeria. Methods: A population-based cross-sectional survey was conducted in each Niger State LGA between March and April 2014, as part of the Global Trachoma Mapping Project (GTMP). GTMP protocols were used in planning and conduct of the surveys. Using probability proportional to size, 25 clusters were selected; in each of these clusters, 25 households were enrolled for the survey. All residents aged 1 year and older were examined by GTMP-certified graders for trachomatous inflammation – follicular (TF) and trichiasis using the World Health Organization simplified grading scheme. Additionally, we collected data on household water and sanitation facilities. Results: Only one LGA (Kontagora) had TF prevalence in 1–9-year-olds above 10%; one other LGA (Rafi) had TF prevalence between 5.0 and 9.9%. Six LGAs need trichiasis surgical services provided to achieve a prevalence of

Purpose: To determine the prevalence of trachomatous inflammation – follicular (TF) and trichiasis in each of the 20 local government areas (LGAs) of Bauchi State, Nigeria. Methods: We undertook a population-based prevalence survey in each LGA in Bauchi State, employing the Global Trachoma Mapping Project methodology. We used a 2-stage, systematic and quasi-random sampling strategy. Using probability proportional to size, we selected 25 clusters, in each of which 25 households were selected by random walk. All residents of selected households 1 year and older were examined for TF, trachomatous inflammation – intense, and trichiasis, using the World Health Organization simplified grading scheme. Results: Only two LGAs in Bauchi State had TF prevalences in 1–9-year-olds over 5%, with none having TF prevalences of 10% or greater. Only one LGA had a trichiasis prevalence in adults below the elimination threshold; all the others had trichiasis at levels suggestive of public health significance. In all 20 LGAs, more than 60% of households were within 1 km of an improved source of water for hygiene. Conclusion: Efforts need to be made in Bauchi State to provide trichiasis surgery in order to avert trachomatous blindness. Water supplies needs to be sustained and good personal hygiene practices assured so that elimination of trachoma as a public health problem will be achieved and sustained.

Background Since 2001, Haiti’s National Program for the Elimination of Lymphatic Filariasis (NPELF) has worked to reduce the transmission of lymphatic filariasis (LF) through annual mass drug administration (MDA) with diethylcarbamazine and albendazole. The NPELF reached full national coverage with MDA for LF in 2012, and by 2014, a total of 14 evaluation units (48 communes) had met WHO eligibility criteria to conduct LF transmission assessment surveys (TAS) to determine whether prevalence had been reduced to below a threshold, such that transmission is assumed to be no longer sustainable. Haiti is also endemic for malaria and many communities suffer a high burden of soil transmitted helminths (STH). Heeding the call from WHO for integration of neglected tropical diseases (NTD) activities, Haiti’s NPELF worked with the national malaria control program (NMCP) and with partners to develop an integrated TAS (LF-STH-malaria) to include assessments for malaria and STH. Methodology/Principle findings The aim of this study was to evaluate the feasibility of using TAS surveys for LF as a platform to collect information about STH and malaria. Between November 2014 and June 2015, TAS were conducted in 14 evaluation units (EUs) including 1 TAS (LF-only), 1 TAS-STH-malaria, and 12 TAS-malaria, with a total of 16,655 children tested for LF, 14,795 tested for malaria, and 298 tested for STH. In all, 12 of the 14 EUs passed the LF TAS, allowing the program to stop MDA for LF in 44 communes. The EU where children were also tested for STH will require annual school-based treatment with albendazole to maintain reduced STH levels. Finally, only 12 of 14,795 children tested positive for malaria by RDT in 38 communes. Conclusions/Significance Haiti’s 2014–2015 Integrated TAS surveys provide evidence of the feasibility of using the LF TAS as a platform for integration of assessments for STH and or malaria., Author summary Lymphatic filariasis and malaria are mosquito-borne parasitic infections that are endemic in Haiti. Soil-transmitted helminths are also present in Haiti, infecting large numbers of people every year. Since 2001, Haiti’s National Program for the Elimination of Lymphatic Filariasis (NPELF) has worked to reduce the transmission of LF through annual mass drug administration with the aim of reducing LF prevalence in the population below a threshold, such that transmission is assumed to be no longer sustainable. By treating the entire population of Haiti with a combination of drugs, the elimination program has made tremendous progress towards eliminating the disease. By 2014, Haiti’s NPELF had met the World Health Organization eligibility criteria to conduct LF transmission assessment surveys (TAS) and decided to use the LF TAS as a platform to collect information about STH and malaria. The WHO has called for the integration of program activities in the field, and the TAS is a platform that allows for such integration. In Haiti the integrated TAS reduced the burden of repeated surveys on communities by minimizing site visits and benefited all three disease programs by sharing the responsibilities of field data collection.

Gene regulatory networks are multistable dynamical systems in which attractor states represent cell phenotypes. Spontaneous, noise-induced transitions between these states are thought to underlie critical cellular processes, including cell developmental fate decisions, phenotypic plasticity in fluctuating environments, and carcinogenesis. As such, there is increasing interest in the development of theoretical and computational approaches that can shed light on the dynamics of these stochastic state transitions in multistable gene networks. We applied a numerical rare-event sampling algorithm to study transition paths of spontaneous noise-induced switching for a ubiquitous gene regulatory network motif, the bistable toggle switch, in which two mutually repressive genes compete for dominant expression. We find that the method can efficiently uncover detailed switching mechanisms that involve fluctuations both in occupancies of DNA regulatory sites and copy numbers of protein products. In addition, we show that the rate parameters governing binding and unbinding of regulatory proteins to DNA strongly influence the switching mechanism. In a regime of slow DNA-binding/unbinding kinetics, spontaneous switching occurs relatively frequently and is driven primarily by fluctuations in DNA-site occupancies. In contrast, in a regime of fast DNA-binding/unbinding kinetics, switching occurs rarely and is driven by fluctuations in levels of expressed protein. Our results demonstrate how spontaneous cell phenotype transitions involve collective behavior of both regulatory proteins and DNA. Computational approaches capable of simulating dynamics over many system variables are thus well suited to exploring dynamic mechanisms in gene networks.

Purpose: To complete the baseline trachoma map worldwide by conducting population-based surveys in an estimated 1238 suspected endemic districts of 34 countries. Methods: A series of national and sub-national projects owned, managed and staffed by ministries of health, conduct house-to-house cluster random sample surveys in evaluation units, which generally correspond to “health district” size: populations of 100,000–250,000 people. In each evaluation unit, we invite all residents aged 1 year and older from h households in each of c clusters to be examined for clinical signs of trachoma, where h is the number of households that can be seen by 1 team in 1 day, and the product h × c is calculated to facilitate recruitment of 1019 children aged 1–9 years. In addition to individual-level demographic and clinical data, household-level water, sanitation and hygiene data are entered into the purpose-built LINKS application on Android smartphones, transmitted to the Cloud, and cleaned, analyzed and ministry-of-health-approved via a secure web-based portal. The main outcome measures are the evaluation unit-level prevalence of follicular trachoma in children aged 1–9 years, prevalence of trachomatous trichiasis in adults aged 15 + years, percentage of households using safe methods for disposal of human feces, and percentage of households with proximate access to water for personal hygiene purposes. Results: In the first year of fieldwork, 347 field teams commenced work in 21 projects in 7 countries. Conclusion: With an approach that is innovative in design and scale, we aim to complete baseline mapping of trachoma throughout the world in 2015.

Peptide amphiphiles (PA) offer the potential of incorporating biological function into synthetic materials for tissue engineering in regenerative medicine. These hybrid conjugates are known to undergo self-assembly starting from single molecules to nanofibers before turning into hydrogel scaffolds-such a process involves conformational changes in secondary structures of peptides. Therefore, insights on the ability of peptide amphiphiles to form secondary structure as single molecules are useful for understanding self-assembly behavior. We report here a molecular simulation study of peptide folding by two PA sequences, each contains an alkyl tail and short peptide segment. The alkyl tail is observed to play two opposing roles in modulating sequence-dependent folding kinetics and thermodynamics. On one hand, it restricts conformational freedom reducing the entropic cost of folding, which is thus promoted. On the other hand, it acts as an interaction site with nonpolar peptide residues, blocking the peptide from helix nucleation, which reduces folding.

Using a novel coarse-grained model, large-scale molecular dynamics simulations were performed to examine self-assembly of 800 peptide amphiphiles (sequence palmitoyl-V3A3E3). Under suitable physiological conditions, these molecules readily assemble into nanofibers leading to hydrogel construction as observed in experiments. Our simulations capture this spontaneous self-assembly process, including formation of secondary structure, to identify morphological transitions of distinctive nanostructures. As the hydrophobic interaction is increased, progression from open networks of secondary structures toward closed cylindrical nanostructures containing either β-sheets or random coils are observed. Moreover, temperature effects are also determined to play an important role in regulating formation of secondary structures within those nanostructures. These understandings of the molecular interactions involved and the role of environmental factors on hydrogel formation provide useful insight for development of innovative smart biomaterials for biomedical applications.

Background Lymphatic filariasis (LF) is targeted for global elimination through treatment of entire at-risk populations with repeated annual mass drug administration (MDA). Essential for program success is defining and confirming the appropriate endpoint for MDA when transmission is presumed to have reached a level low enough that it cannot be sustained even in the absence of drug intervention. Guidelines advanced by WHO call for a transmission assessment survey (TAS) to determine if MDA can be stopped within an LF evaluation unit (EU) after at least five effective rounds of annual treatment. To test the value and practicality of these guidelines, a multicenter operational research trial was undertaken in 11 countries covering various geographic and epidemiological settings. Methodology The TAS was conducted twice in each EU with TAS-1 and TAS-2 approximately 24 months apart. Lot quality assurance sampling (LQAS) formed the basis of the TAS survey design but specific EU characteristics defined the survey site (school or community), eligible population (6–7 year olds or 1st–2nd graders), survey type (systematic or cluster-sampling), target sample size, and critical cutoff (a statistically powered threshold below which transmission is expected to be no longer sustainable). The primary diagnostic tools were the immunochromatographic (ICT) test for W. bancrofti EUs and the BmR1 test (Brugia Rapid or PanLF) for Brugia spp. EUs. Principal Findings/Conclusions In 10 of 11 EUs, the number of TAS-1 positive cases was below the critical cutoff, indicating that MDA could be stopped. The same results were found in the follow-up TAS-2, therefore, confirming the previous decision outcome. Sample sizes were highly sex and age-representative and closely matched the target value after factoring in estimates of non-participation. The TAS was determined to be a practical and effective evaluation tool for stopping MDA although its validity for longer-term post-MDA surveillance requires further investigation., Author Summary Lymphatic filariasis (LF) is targeted for global elimination through a strategy of repeated annual mass drug administration (MDA) to entire at-risk populations. A transmission assessment survey (TAS) is designed to evaluate whether transmission of LF is presumed to have reached a level low enough that it cannot be sustained in the absence of drug intervention and, therefore, MDA can be stopped. This multicenter operational research trial examines the value and practicality of the TAS guidelines through its implementation in 11 countries of diverse geographical and epidemiologic profiles. The field experiences support the TAS survey design methodology with particular respect to school and cluster-based sampling strategies. We found that sample sizes were age and sex representative and met the target values after factoring in estimates of non-participation rates. In 10 of 11 countries, the TAS found the number of positive cases in the evaluation unit to be no more than the statistically powered critical threshold. These results were corroborated in a follow-up TAS approximately 24 months later. We conclude the TAS is a valuable and effective tool for stopping MDA but its utility for longer-term post-MDA surveillance needs further empirical evidence and may be best supported with complementary tools and methods.

Background Mass drug administration (MDA) for lymphatic filariasis (LF) programs has delivered more than 2 billion treatments of albendazole, in combination with either ivermectin or diethylcarbamazine, to communities co-endemic for soil-transmitted helminthiasis (STH), reducing the prevalence of both diseases. A transmission assessment survey (TAS) is recommended to determine if MDA for LF can be stopped within an evaluation unit (EU) after at least five rounds of annual treatment. The TAS also provides an opportunity to simultaneously assess the impact of these MDAs on STH and to determine the frequency of school-based MDA for STH after community-wide MDA is no longer needed for LF. Methodology/Principal Findings Pilot studies conducted in Benin and Tonga assessed the feasibility of a coordinated approach. Of the schools (clusters) selected for a TAS in each EU, a subset of 5 schools per STH ecological zone was randomly selected, according to World Health Organization (WHO) guidelines, for the coordinated survey. In Benin, 519 children were sampled in 5 schools and 22 (4.2%) had STH infection (A. lumbricoides, T. trichiura, or hookworm) detected using the Kato-Katz method. All infections were classified as light intensity under WHO criteria. In Tonga, 10 schools were chosen for the coordinated TAS and STH survey covering two ecological zones; 32 of 232 (13.8%) children were infected in Tongatapu and 82 of 320 (25.6%) in Vava'u and Ha'apai. All infections were light-intensity with the exception of one with moderate-intensity T. trichiura. Conclusions Synchronous assessment of STH with TAS is feasible and provides a well-timed evaluation of infection prevalence to guide ongoing treatment decisions at a time when MDA for LF may be stopped. The coordinated field experiences in both countries also suggest potential time and cost savings. Refinement of a coordinated TAS and STH sampling methodology should be pursued, along with further validation of alternative quantitative diagnostic tests for STH that can be used with preserved stool specimens., Author Summary Since 2000, some 2 billion preventive chemotherapy treatments have been delivered for lymphatic filariasis (LF), many in areas co-endemic for soil-transmitted helminthiasis (STH). A transmission assessment survey (TAS) is recommended to determine if such ‘mass drug administration (MDA)’ for LF can be stopped in a specified evaluation unit. The TAS also provides an opportune platform to simultaneously conduct STH assessments and make informed programmatic decisions about STH control. Through piloting this coordinated TAS and STH survey approach in Benin and Tonga, we found that after 5–6 rounds of annual MDA, STH prevalence was 4.2% in Benin and 13.8–25.6% in Tonga. All infections were light intensity except one moderate A. lumbricoides case in Tonga. Our study highlights that a coordinated strategy is operationally feasible, programmatically relevant, and potentially cost-effective. A more robust sampling methodology for coordinated TAS and STH surveys should be further explored, as well as alternative diagnostic tests for STH.

Background Lymphatic filariasis (LF), also known as elephantiasis, is a neglected tropical disease (NTD) targeted for elimination through a Global Programme to Eliminate LF (GPELF). Between 2000 and 2014, the GPELF has delivered 5.6 billion treatments to over 763 million people. Updating the estimated health and economic benefits of this significant achievement is important in justifying the resources and investment needed for eliminating LF. Method We combined previously established models to estimate the number of clinical manifestations and disability-adjusted life years (DALYs) averted from three benefit cohorts (those protected from acquiring infection, those with subclinical morbidity prevented from progressing and those with clinical disease alleviated). The economic savings associated with this disease prevention was then analysed in the context of prevented medical expenses incurred by LF clinical patients, potential income loss through lost-labour, and prevented costs to the health system to care for affected individuals. The indirect cost estimates were calculated using the human capital approach. A combination of four wage sources was used to estimate the fair market value of time for an agricultural worker with LF infection (to ensure a conservative estimate, the lowest wage value was used). Results We projected that due to the first 15 years of the GPELF 36 million clinical cases and 175 (116–250) million DALYs will potentially be averted. It was estimated that due to this notable health impact, US$100.5 billion will potentially be saved over the lifetimes of the benefit cohorts. This total amount results from summing the medical expenses incurred by LF patients (US$3 billion), potential income loss (US$94 billion), and costs to the health system (US$3.5 billion) that were projected to be prevented. The results were subjected to sensitivity analysis and were most sensitive to the assumed percentage of work hours lost for those suffering from chronic disease (changing the total economic benefit between US$69.30–150.7 billion). Conclusions Despite the limitations of any such analysis, this study identifies substantial health and economic benefits that have resulted from the first 15 years of the GPELF, and it highlights the value and importance of continued investment in the GPELF. Electronic supplementary material The online version of this article (doi:10.1186/s40249-016-0147-4) contains supplementary material, which is available to authorized users.

Purpose: We aimed to estimate the prevalence of trachoma in each district (“woreda”) of Tigray Region, Ethiopia. Methods: We conducted 11 cross-sectional community-based surveys in evaluation units covering 34 rural woredas from January to March 2013 using the standardized methodology developed for the Global Trachoma Mapping Project. Results: Teams visited 8034 households in 275 villages. A total of 28,581 consenting individuals were examined, 16,163 (56.7%) of whom were female. The region-wide adjusted trichiasis prevalence was 1.7% in those aged 15 years and older. All evaluation units mapped had a trichiasis prevalence over the World Health Organization elimination threshold of 0.2% in people aged 15 years and older. The region-wide adjusted prevalence of the clinical sign trachomatous inflammation – follicular (TF) in children aged 1–9 years was 26.1%. A total 10 evaluation units, covering 31 woredas, with a combined rural population of 4.3 million inhabitants, had a prevalence of TF ≥10%, and require full implementation of the SAFE strategy (surgery, antibiotics, facial cleanliness, and environmental improvement) for at least 3 years before impact surveys are undertaken. Of these, four evaluation units, covering 12 woredas, with a combined rural population of 1.7 million inhabitants, had a TF prevalence ≥30%. Conclusion: Both active trachoma and trichiasis are public health problems in Tigray, which needs urgent implementation of the full SAFE strategy.