Publications by authors named "Charles D Mackenzie"

65 Publications

A framework for scabies control.

PLoS Negl Trop Dis 2021 Sep 2;15(9):e0009661. Epub 2021 Sep 2.

Division of Parasitic Diseases and Malaria, US Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America.

Scabies is a neglected tropical disease (NTD) that causes a significant health burden, particularly in disadvantaged communities and where there is overcrowding. There is emerging evidence that ivermectin-based mass drug administration (MDA) can reduce the prevalence of scabies in some settings, but evidence remains limited, and there are no formal guidelines to inform control efforts. An informal World Health Organization (WHO) consultation was organized to find agreement on strategies for global control. The consultation resulted in a framework for scabies control and recommendations for mapping of disease burden, delivery of interventions, and establishing monitoring and evaluation. Key operational research priorities were identified. This framework will allow countries to set control targets for scabies as part of national NTD strategic plans and develop control strategies using MDA for high-prevalence regions and outbreak situations. As further evidence and experience are collected and strategies are refined over time, formal guidelines can be developed. The control of scabies and the reduction of the health burden of scabies and associated conditions will be vital to achieving the targets set in WHO Roadmap for NTDs for 2021 to 2030 and the Sustainable Development Goals.
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http://dx.doi.org/10.1371/journal.pntd.0009661DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8412357PMC
September 2021

Alternative approaches to lymphoedema care in lymphatic filariasis.

PLoS Negl Trop Dis 2021 04 29;15(4):e0009293. Epub 2021 Apr 29.

Neglected Tropical Diseases Support Center, Task Force for Global Health, Atlanta, Georgia, United States of America.

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http://dx.doi.org/10.1371/journal.pntd.0009293DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8084153PMC
April 2021

Control of felinine-derived malodor in cat litter.

J Feline Med Surg 2021 Apr 28:1098612X211009136. Epub 2021 Apr 28.

Neglected Tropical Diseases Center, Task Force for Global Health, Decatur, GA, USA.

Objectives: Malodors stemming from soiled cat litter are a major frustration for cat owners, despite the widespread use of absorbent litters with claims of odor control. Technologies for effective litter odor control have not been rigorously evaluated. Here, we report on the effectiveness of a novel litter formulation of 1-monochlorodimethylhydantoin (MCDMH)-modified clinoptilolite zeolite (MCDMH-Z) to control the odors of 3-mercapto-3-methylbutanol (3M3MB) and ammonia, the principal products generated by the enzymatic breakdown of felinine and urea, respectively.

Methods: The efficacy of MCDMH-Z for the odor control of 3M3MB was determined by solid-phase microextraction and gas chromatography mass spectrometry analysis, colorimetric analysis and a sensory panel. Enzyme inhibition was monitored by a colorimetric coupled assay for ammonia. The antimicrobial properties were measured by a reduction in colony-forming units (CFUs).

Results: 3M3MB proved highly susceptible to modification by MCDMH-Z granules. Headspace above litter exposed to MCDMH-Z showed no detectable 3M3MB; levels >59 ng were detected in commercially available products. Urease activity decreased by >97% after incubation with MCDMH-Z to 0.14 mg/ml. Cat litter F showed comparable inhibition (0.13 mg/ml); others showed less inhibition, producing up to 4.8 mg/ml of ammonia. MCDMH-Z reduced the CFUs of by six log reduction values in 30 mins; in the same amount of time, no reduction was seen with commercial products tested. The odor control capability of the MCDMH-Z granules was further supported by a sensory panel scoring 3M3MB-spiked litters.

Conclusions And Relevance: Samples of commercially available litter products showed an effect on malodor, or inhibition of urease, or contained antimicrobial activity; no samples were capable of accomplishing these concurrently. In contrast, MCDMH-Z granules were effective in all three test categories. Control of felinine-derived odors, in particular, has the potential to improve cat owner satisfaction, and may beneficially affect cat behaviors provoked by pheromonally active sulfurous metabolites deposited in the litter.
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http://dx.doi.org/10.1177/1098612X211009136DOI Listing
April 2021

Caring for patients in the global programme to eliminate lymphatic filariasis.

Int Health 2020 12;13(Suppl 1):S48-S54

African Filariasis Morbidity Project, Korle BU, Accra, Ghana.

Clinical lymphatic filariasis (LF) is a debilitating, disfiguring medical condition with severe psychosocial consequences for patients and their families. Addressing these patients' medical needs is a major component of the global programme to eliminate lymphatic filariasis (GPELF). In the 20 y of providing a minimal package of care many thousands of surgical operations to correct LF hydrocoeles been performed and national programmes in >90% of LF endemic countries have received the training needed to care for their patients. The creation of educational materials detailing appropriate patient care, together with increased funding, have been key catalysts in increasing awareness of clinical LF in recent years. Nevertheless, the implementation of care for these patients has often faced challenges that have led to delays in fully implementing the patient care component of GPELF; these include locating these often stigmatised individuals, maintaining provision of the necessary consumables (e.g. soaps and creams) and maintaining programme support within already overstretched national LF teams. As the LF global programme moves to achieve success by 2030 it will be vital to continue to focus efforts on the care and rehabilitation of those suffering from lymphoedema and hydrocoeles, learning from the experiences of the past 20 y.
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http://dx.doi.org/10.1093/inthealth/ihaa080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7753172PMC
December 2020

Feasibility of Onchocerciasis Elimination Using a "Test-and-not-treat" Strategy in Loa loa Co-endemic Areas.

Clin Infect Dis 2021 06;72(12):e1047-e1055

Department of Public Health, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.

Background: Mass drug administration (MDA) with ivermectin is the main strategy for onchocerciasis elimination. Ivermectin is generally safe, but is associated with serious adverse events in individuals with high Loa loa microfilarial densities (MFD). Therefore, ivermectin MDA is not recommended in areas where onchocerciasis is hypo-endemic and L loa is co-endemic. To eliminate onchocerciasis in those areas, a test-and-not-treat (TaNT) strategy has been proposed. We investigated whether onchocerciasis elimination can be achieved using TaNT and the required duration.

Methods: We used the individual-based model ONCHOSIM to predict the impact of TaNT on onchocerciasis microfilarial (mf) prevalence. We simulated precontrol mf prevalence levels from 2% to 40%. The impact of TaNT was simulated under varying levels of participation, systematic nonparticipation, and exclusion from ivermectin resulting from high L loa MFD. For each scenario, we assessed the time to elimination, defined as bringing onchocerciasis mf prevalence below 1.4%.

Results: In areas with 30% to 40% precontrol mf prevalence, the model predicted that it would take between 14 and 16 years to bring the mf prevalence below 1.4% using conventional MDA, assuming 65% participation. TaNT would increase the time to elimination by up to 1.5 years, depending on the level of systematic nonparticipation and the exclusion rate. At lower exclusion rates (≤2.5%), the delay would be less than 6 months.

Conclusions: Our model predicts that onchocerciasis can be eliminated using TaNT in L loa co-endemic areas. The required treatment duration using TaNT would be only slightly longer than in areas with conventional MDA, provided that participation is good.
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http://dx.doi.org/10.1093/cid/ciaa1829DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8204788PMC
June 2021

Podoconiosis: key priorities for research and implementation.

Trans R Soc Trop Med Hyg 2020 12;114(12):889-895

Brighton and Sussex Centre for Global Health Research, Department of Global Health and Infection, Brighton and Sussex Medical School, Brighton BN1 9PX, UK.

Podoconiosis is a non-infectious tropical lymphoedema causing swelling of the lower legs. Podoconiosis is associated with stigma, depression and reduced productivity, resulting in significant socio-economic impacts for affected individuals, families and communities. It is caused by barefoot exposure to soils and affects disadvantaged populations. Evidence from the past 5 y suggests that podoconiosis is amenable to public health interventions, e.g. footwear and hygiene-based morbidity management, which reduce acute clinical episodes. Although much has been learned in recent years, advances in care for these patients and worldwide control requires further reliable and relevant research. To develop a comprehensive global control strategy, the following key research priorities are important: better understanding of the global burden of podoconiosis through extended worldwide mapping, development of new point-of-care diagnostic methods and approaches to define the presence of the environmental characteristics that contribute to the development of the condition, improving treatment through an increased understanding of the pathogenesis of dermal changes over time, improved understanding of optimal ways of providing patient care at the national level, including research to optimize behavioural change strategies, determine the optimum package of care and integrate approaches to deliver robust surveillance, monitoring and evaluation of control programmes.
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http://dx.doi.org/10.1093/trstmh/traa094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7738650PMC
December 2020

Community-based door to door census of suspected people living with epilepsy: empowering community drug distributors to improve the provision of care to rural communities in Cameroon.

BMC Public Health 2020 Jun 5;20(1):871. Epub 2020 Jun 5.

Institut de Recherche pour le Développement (IRD), UMI233/ INSERM U1175/ Université de Montpellier, 911 Avenue Agropolis, 34394, Montpellier Cedex 5, France.

Background: Epilepsy is a severe neurological disorder with huge psychological, social, and economic consequences, including premature deaths and loss of productivity. Sub-Saharan Africa carries the highest burden of epilepsy. The management of epilepsy in Cameroon remains unsatisfactory due to poor identification of cases and a limited knowledge of the distribution of the disease. The objective of this study was to determine whether community drug distributors (CDDs) - volunteers selected by their communities to distribute ivermectin against onchocerciasis and who have been proven efficient to deliver other health interventions such as insecticide-treated bed nets to prevent malaria, vitamin A tablets, and albendazole to treat soil transmitted helminthiasis - can be used to reliably identify people living with epilepsy to promote better management of cases.

Methods: This study was carried out in three health Districts in Cameroon. An exhaustive house to house census was carried out by trained CDDs under the supervision of local nurses. In each household, all suspected cases of epilepsy were identified. In each health district, five communities were randomly selected for a second census by trained health personnel (research team). The results of the two censuses were compared for verification purposes.

Results: A total of 53,005 people was registered in the 190 communities surveyed with 794 (1.4%) individuals identified as suspected cases of epilepsy (SCE) by the CDDs. In the 15 communities where the SCE census was verified, the average ratio between the number of suspected cases of epilepsy reported in a community by the research team and that reported by the CDDs was 1.1; this ratio was < 0.8 and > 1.2 in 6 communities.

Conclusions: The results of this study suggest that CDDs, who are present in about 200,000 communities in 31 Sub Saharan African countries where onchocerciasis is endemic, can be successfully used to assess epilepsy prevalence, and therefore map epilepsy in many African countries.
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http://dx.doi.org/10.1186/s12889-020-08997-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7275343PMC
June 2020

Elimination of onchocerciasis in Africa by 2025: an ambitious target requires ambitious interventions.

Infect Dis Poverty 2019 Oct 3;8(1):83. Epub 2019 Oct 3.

Neglected and Disabling Diseases of Poverty Consultant, Gravesend, Kent, UK.

To achieve the elimination of onchocerciasis transmission in all African countries will entail enormous challenges, as has been highlighted by the active discussion around onchocerciasis intervention strategies and evaluation procedures in this journal.Serological thresholds for onchocerciasis elimination, adapted for the African setting, need to be established. The Onchocerciasis Technical Advisory Subgroup of the World Health Organization is currently developing improved guidelines to allow country elimination committees to make evidence-based decisions. Importantly, onchocerciasis-related morbidity should not be forgotten when debating elimination prospects. A morbidity management and disease prevention (MMDP) strategy similar to that for lymphatic filariasis will need to be developed. This will require collaboration between the onchocerciasis elimination program, the community and other partners including primary health and mental health programs.In order to reach the goal of onchocerciasis elimination in most African countries by 2025, we should prioritize community participation and advocate for tailored interventions which are scientifically proven to be effective, but currently considered to be too expensive.
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http://dx.doi.org/10.1186/s40249-019-0593-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6775645PMC
October 2019

A Much-Needed Advance in the Diagnosis of River Blindness.

J Infect Dis 2020 05;221(11):1746-1748

Neglected Tropical Diseases Support Center, Task Force for Global Health, Atlanta, Georgia.

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http://dx.doi.org/10.1093/infdis/jiz309DOI Listing
May 2020

The public health control of scabies: priorities for research and action.

Lancet 2019 Jul 6;394(10192):81-92. Epub 2019 Jun 6.

Tropical Diseases Group, Murdoch Children's Research Institute, Melbourne, VIC, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia; Department of General Medicine, Royal Children's Hospital, Melbourne, VIC, Australia.

Scabies is a parasitic disease of the skin that disproportionately affects disadvantaged populations. The disease causes considerable morbidity and leads to severe bacterial infection and immune-mediated disease. Scientific advances from the past 5 years suggest that scabies is amenable to population-level control, particularly through mass drug administration. In recognition of these issues, WHO added scabies to the list of neglected tropical diseases in 2017. To develop a global control programme, key operational research questions must now be addressed. Standardised approaches to diagnosis and methods for mapping are required to further understand the burden of disease. The safety of treatments for young children, including with ivermectin and moxidectin, should be investigated. Studies are needed to inform optimum implementation of mass treatment, including the threshold for intervention, target, dosing, and frequency. Frameworks for surveillance, monitoring, and evaluation of control strategies are also necessary.
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http://dx.doi.org/10.1016/S0140-6736(19)31136-5DOI Listing
July 2019

Loa loa Microfilariae in Skin Snips: Consequences for Onchocerciasis Monitoring and Evaluation in L. loa-Endemic Areas.

Clin Infect Dis 2019 10;69(9):1628-1630

Centre for Research on Filariasis and Other Tropical Diseases, Yaounde, Cameroon.

The specificity of skin snips for onchocerciasis diagnoses is considered to be almost 100%. Our molecular methods revealed that microfilariae emerging from skin snips collected from highly microfilaremic Loa loa-infected individuals were largely misidentified as Onchocerca volvulus. This has important implications for onchocerciasis diagnostic testing in Loa-endemic areas.
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http://dx.doi.org/10.1093/cid/ciz172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6792118PMC
October 2019

Flubendazole as a macrofilaricide: History and background.

PLoS Negl Trop Dis 2019 01 16;13(1):e0006436. Epub 2019 Jan 16.

Johnson & Johnson Global Public Health, Janssen Research and Development, LLC., New Brunswick, New Jersey, United States of America.

Benzimidazole anthelmintics have long been employed for the control of soil-transmitted helminth infections. Flubendazole (FBZ) was approved in 1980 for the treatment of gastrointestinal nematode infections in both veterinary and human medicine. It has also long been known that parenteral administration of FBZ can lead to high macrofilaricidal efficacy in a variety of preclinical models and in humans. As part of an effort to stimulate the discovery and development of new macrofilaricides, particularly for onchocerciasis, research has recently been devoted to the development of new formulations that would afford high oral bioavailability of FBZ, paving the way for potential clinical development of this repurposed drug for the treatment of human filariases. This review summarizes the background information that led to this program and summarizes some of the lessons learned from it.
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http://dx.doi.org/10.1371/journal.pntd.0006436DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6334891PMC
January 2019

Macrofilaricidal efficacy of single and repeated oral and subcutaneous doses of flubendazole in Litomosoides sigmodontis infected jirds.

PLoS Negl Trop Dis 2019 01 16;13(1):e0006320. Epub 2019 Jan 16.

Institute for Medical Microbiology, Immunology and Parasitology, University Hospital of Bonn, Bonn, Germany.

Flubendazole (FBZ) is highly efficacious against filarial nematodes after parenteral administration and presents a promising macrofilaricidal drug candidate for the elimination of onchocerciasis and other filariae. In the present study the efficacy of a newly developed bioavailable amorphous solid dispersion (ASD) oral formulation of FBZ was investigated in the Litomosoides sigmodontis jird model. FBZ was administered to chronically infected, microfilariae-positive jirds by single (40mg/kg), repeated (2, 6 or 15mg/kg for 5 or 10 days) oral (OR) doses or single subcutaneous (SC) injections (2 or 10mg/kg). Jirds treated with 5 SC injections at 10mg/kg served as positive controls, with untreated animals used as negative controls. After OR doses, FBZ is rapidly absorbed and cleared and the exposures increased dose proportionally. SC administered FBZ was slowly released from the injection site and plasma levels remained constant up to necropsy eight weeks after treatment end. Increasing single SC doses caused less than dose-proportional exposures. At necropsy, all animals receiving 1x or 5x 10mg/kg SC FBZ had cleared all adult worms and the 1x 2mg/kg SC treatment had reduced the adult worm burden by 98%. 10x 15mg/kg OR FBZ reduced the adult worm burden by 95%, whereas 1x 40mg/kg and 5x 15mg/kg OR reduced the worm burden by 85 and 84%, respectively. Microfilaremia was completely cleared at necropsy in all animals of the SC treatment regimens, while all oral FBZ treatment regimens reduced the microfilaremia by >90% in a dose and duration dependent manner. In accordance, embryograms from female worms revealed a FBZ dose and duration dependent inhibition of embryogenesis. Histological analysis of the remaining female adult worms showed that FBZ had damaged the body wall, intestine and most prominently the uterus and uterine content. Results of this study demonstrate that single and repeated SC injections and repeated oral administrations of FBZ have an excellent macrofilaricidal effect.
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http://dx.doi.org/10.1371/journal.pntd.0006320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6334906PMC
January 2019

Effect of flubendazole on developing stages of Loa loa in vitro and in vivo: a new approach for screening filaricidal agents.

Parasit Vectors 2019 Jan 8;12(1):14. Epub 2019 Jan 8.

Parasites and Vectors Biology Research Unit (PAVBRU), Department of Microbiology and Parasitology, Faculty of Science, University of Buea, Buea, Cameroon.

Background: Loiasis, an often-neglected tropical disease, is a threat to the success of lymphatic filariasis and onchocerciasis elimination programmes in rainforest areas of the central and western Africa. Its control and even its elimination might be possible through the use of a safe macrofilaricide, a prophylactic drug, or perhaps a vaccine. This present study evaluated the effect of flubendazole (FLBZ) on the development of Loa loa L3 in vitro and in vivo.

Methods: Infective stages of L. loa were isolated and co-cultured in Dulbecco's Modified Eagle's Medium in the presence of monkey kidney epithelial cells (LLC-MK2) feeder cells. FLBZ and its principal metabolites, reduced flubendazole (RFLBZ) and hydrolyzed flubendazole (HFLBZ), were screened in vitro at concentrations 0.05, 0.1, 0.5, 1 and 10 μg/ml. The viability of the parasites was assessed microscopically daily for 15 days. For in vivo study, a total of 48 CcR3 KO mice were infected subcutaneously with 200 L. loa L3 and treated with 10 mg/kg FLBZ once daily for 5 consecutive days. Twenty-four animals were used as control and received L3 and vehicle. They were dissected at 5, 10, 15 and 20 days post-treatment for worm recovery.

Results: The motility of L3 larvae in vitro was reduced from the second day of incubation with drugs at in vivo plasma concentration levels, with a strong correlation found between reduced motility and increased drug concentration (Spearman's rho = -0.9, P < 0.0001). Except for HFLBZ (0.05 μg/ml and 0.01 μg/ml), all concentrations of FLBZ, HFLBZ and RFLBZ interrupted the moulting of L. loa infective larvae to L4. In vivo, regardless of the experimental group, there was a decrease in parasite recovery with time. However, at each time point this reduction was more pronounced in the group of animals treated with FLBZ compared to equivalent control. Parasites were recovered from the flubendazole-treated groups only on day 5 post-inoculation at an average rate of 2.1%, a value significantly lower (Mann-Whitney U-test, U = 28, P = 0.0156) than the average of 31.1% recovered from the control group.

Conclusions: This study reveals the ability of flubendazole to inhibit the development of L. loa L3 both in vitro and in vivo, and in addition validates the importance of in vitro and animal models of L. loa as tools for the development of drugs against loiasis.
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http://dx.doi.org/10.1186/s13071-018-3282-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6323797PMC
January 2019

A comparison between paper-based and m-Health tools for collating and reporting clinical cases of lymphatic filariasis and podoconiosis in Ethiopia.

Mhealth 2018 26;4:49. Epub 2018 Oct 26.

Centre for Neglected Tropical Diseases, Department of Parasitology, Liverpool School of Tropical Medicine, Liverpool, UK.

Background: Lymphatic filariasis (LF) and podoconiosis are disabling diseases, endemic in Ethiopia. The main clinical manifestations include lymphoedema from LF and podoconiosis, and hydrocoele from LF. To ensure access to morbidity management and disability prevention (MMDP) services, data on patient numbers in each implementation unit (IU) is required. House-to-house census is considered the gold standard for determining patient numbers, and data are usually collated and reported using paper-based methods. However, often there are delays in data reaching the regional and central level, which leads to subsequent delays in rolling out and prioritising MMDP services. The increase in mobile phone mHealth tools offers an alternative, potentially more rapid and cost-effective approach.

Methods: As part of an LF and podoconiosis burden assessment conducted in Hawella Tula and Bensa districts in Ethiopia, this study compared the standard paper-based methods with the new MeasureSMS-Morbidity tool for clinical cases data collation and reporting. Health extension workers (HEWs) were trained on both methods. Comparisons were made on patient information; age, gender, location (i.e., kebele), condition, severity of condition and acute attacks. Data were analysed for trends, including the differences in ranking the villages in each district based on the highest to lowest number of cases. In addition, financial and human resource requirements were compared.

Results: In total, 59 HEWs (19 from Hawella Tula; 40 from Bensa) collated and reported a similar number of cases by paper-based (n=2,377) and SMS (n=2,372) methods. Significant correlations were found between the two methods for all cases and lymphoedema cases in both districts, and for hydrocoele cases in Bensa district only. The total cost of paper-based reporting was 13.7% more expensive than SMS reporting due to costs associated with data collection and entry.

Conclusions: The rank correlation showed the same villages would be prioritised for delivery of MMDP services, with time and cost-savings observed using SMS reporting, suggesting it is an effective and efficient alternative tool to help facilitate care to those who need it most.
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http://dx.doi.org/10.21037/mhealth.2018.09.12DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6232075PMC
October 2018

A Serological Survey of Human Onchocerciasis in Yemen.

Am J Trop Med Hyg 2018 10;99(4):1049-1052

Parasitology Laboratory, National Institutes of Health/National Institute of Allergy and Infectious Diseases, Bethesda, Maryland.

Yemen is a country that has been treating severe cases of oncho-dermatitis since 1992 and is now moving to a program aimed at the elimination of the transmission of . It is important to ensure that the currently acceptable tools used in epidemiological assessment of onchocerciasis in Africa and Latin America also apply to Yemen. Five hundred and ten blood samples from three known -endemic areas, locations that have never been under a mass treatment program, were tested for the presence of antibodies against a panel of -specific antigens using enzyme-linked immunosorbent assay (Ov16) and luciferase immunoprecipitation system (Ov-FAR-1 and Ov-MSA-1) assays. Overall, 31.4% of the samples tested were positive, with positivity increasing with age. Positivity was seen in 76.5% of those presenting with clinical onchocerciasis but importantly also in more than 28.5% of those defined as free of oncho-dermatitis; these latter individuals are likely to be serving as a source for persistent reinfection. This study supports the use of the current -specific serologic methodology in Yemen.
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http://dx.doi.org/10.4269/ajtmh.18-0051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6159578PMC
October 2018

Integrated morbidity mapping of lymphatic filariasis and podoconiosis cases in 20 co-endemic districts of Ethiopia.

PLoS Negl Trop Dis 2018 07 2;12(7):e0006491. Epub 2018 Jul 2.

Centre for Neglected Tropical Diseases, Department of Parasitology, Liverpool School of Tropical Medicine, Liverpool, United Kingdom.

Background: Lymphatic filariasis (LF) and podoconiosis are neglected tropical diseases (NTDs) that pose a significant physical, social and economic burden to endemic communities. Patients affected by the clinical conditions of LF (lymphoedema and hydrocoele) and podoconiosis (lymphoedema) need access to morbidity management and disability prevention (MMDP) services. Clear estimates of the number and location of these patients are essential to the efficient and equitable implementation of MMDP services for both diseases.

Methodology/principle Findings: A community-based cross-sectional study was conducted in Ethiopia using the Health Extension Worker (HEW) network to identify all cases of lymphoedema and hydrocoele in 20 woredas (districts) co-endemic for LF and podoconiosis. A total of 612 trained HEWs and 40 supervisors from 20 districts identified 26,123 cases of clinical morbidity. Of these, 24,908 (95.3%) reported cases had leg lymphoedema only, 751 (2.9%) had hydrocoele, 387 (1.5%) had both leg lymphoedema and hydrocoele, and 77 (0.3%) cases had breast lymphoedema. Of those reporting leg lymphoedema, 89.3% reported bilateral lymphoedema. Older age groups were more likely to have a severe stage of disease, have bilateral lymphoedema and to have experienced an acute attack in the last six months.

Conclusions/significance: This study represents the first community-wide, integrated clinical case mapping of both LF and podoconiosis in Ethiopia. It highlights the high number of cases, particularly of leg lymphoedema that could be attributed to either of these diseases. This key clinical information will assist and guide the allocation of resources to where they are needed most.
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http://dx.doi.org/10.1371/journal.pntd.0006491DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6044548PMC
July 2018

Characterization of Divalent Metal Transporter 1 (DMT1) in Brugia malayi suggests an intestinal-associated pathway for iron absorption.

Int J Parasitol Drugs Drug Resist 2018 08 20;8(2):341-349. Epub 2018 Jun 20.

Institute of Parasitology, McGill University, 21111 Lakeshore Road, Sainte-Anne-de-Bellevue, Quebec, H9X 3V9, Canada. Electronic address:

Lymphatic filariasis and onchocerciasis are neglected parasitic diseases which pose a threat to public health in tropical and sub-tropical regions. Strategies for control and elimination of these diseases by mass drug administration (MDA) campaigns are designed to reduce symptoms of onchocerciasis and transmission of both parasites to eventually eliminate the burden on public health. Drugs used for MDA are predominantly microfilaricidal, and prolonged rounds of treatment are required for eradication. Understanding parasite biology is crucial to unravelling the complex processes involved in host-parasite interactions, disease transmission, parasite immune evasion, and the emergence of drug resistance. In nematode biology, large gaps still exist in our understanding of iron metabolism, iron-dependent processes and their regulation. The acquisition of iron from the host is a crucial determinant of the success of a parasitic infection. Here we identify a filarial ortholog of Divalent Metal Transporter 1 (DMT1), a member of a highly conserved family of NRAMP proteins that play an essential role in the transport of ferrous iron in many species. We cloned and expressed the B. malayi NRAMP ortholog in the iron-deficient fet3fet4 strain of Saccharomyces cerevisiae, performed qPCR to estimate stage-specific expression, and localized expression of this gene by immunohistochemistry. Results from functional iron uptake assays showed that expression of this gene in the iron transport-deficient yeast strain significantly rescued growth in low-iron medium. DMT1 was highly expressed in adult female and male B. malayi and Onchocerca volvulus. Immunolocalization revealed that DMT1 is expressed in the intestinal brush border, lateral chords, and reproductive tissues of males and females, areas also inhabited by Wolbachia. We hypothesize based on our results that DMT1 in B. malayi functions as an iron transporter. The presence of this transporter in the intestine supports the hypothesis that iron acquisition by adult females requires oral ingestion and suggests that the intestine plays a functional role in at least some aspects of nutrient uptake.
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http://dx.doi.org/10.1016/j.ijpddr.2018.06.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6038845PMC
August 2018

Heterogeneity in the in vitro susceptibility of Loa loa microfilariae to drugs commonly used in parasitological infections.

Parasit Vectors 2018 04 4;11(1):223. Epub 2018 Apr 4.

Parasites and Vectors Biology Research Unit (PAVBRU), Department of Microbiology and Parasitology, Faculty of Science, University of Buea, Buea, Cameroon.

Background: Co-infection with loiasis remains a potential problem in control programs targeting filarial infections. The effects of many anti-parasitic drugs often administered to Loa loa infected people are not well documented. This study compared the in vitro activity of several of these drugs on the viability of L. loa microfilariae (mf).

Methods: Human strain L. loa mf were isolated from baboon blood using iso-osmotic Percoll gradient, and cultured in RPMI 1640/10% FBS with antimalarial drugs (mefloquine, amodiaquine, artesunate, chloroquine and quinine), anthelmintics (ivermectin, praziquantel, flubendazole and its reduced and hydrolyzed metabolites), two potential trypanocidal agents (fexinidazole and Scynexis-7158) and the anticancer drug imatinib. The drug concentrations used varied between 0.156 μg/ml and 10 μg/ml. Mf motility (CR = 50% immotility) and a metabolic viability assay (MTT) were used to assess the effects of these drugs on the parasites.

Results: Mf in control cultures showed only a slight reduction in motility after 5 days of culture. Active inhibition of Loa loa motility was seen with mefloquine and amodiaquine (CR values of 3.87 and 4.05 μg/ml, respectively), immobilizing > 90% mf within the first 24 hours: mefloquine killed the mf after 24 hours of culture at concentrations ≥ 5 μg/ml. SCYX-7158 also induced a concentration-dependent reduction in mf motility, with > 50% reduction in mf motility seen after 5 days at 10 μg/ml. The anticancer drug imatinib reduced mf motility at 10 μg/ml from the first day of incubation to 55% by day 5, and the reduction in motility was concentration-dependent. Praziquantel and fexinidazole were inactive, and FLBZ and its metabolites, as well as ivermectin at concentrations > 5 μg/ml, had very minimal effects on mf motility over the first 4 days of culture.

Conclusions: The considerable action of the anti-malarial drugs mefloquine and amodiaquine on Loa mf in vitro highlights the possibility of repurposing the existing anti-infectious agents for the development of drugs against loiasis. The heterogeneity in the activity of anti-parasitic agents on Loa loa mf supports the need for further investigation using animal models of loiasis.
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http://dx.doi.org/10.1186/s13071-018-2799-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5883330PMC
April 2018

Establishing quality assured (QA) laboratory support for onchocerciasis elimination in Africa.

Int Health 2018 03;10(suppl_1):i33-i39

Task Force for Global Health, Atlanta, GA, USA.

An essential component in achieving accepted successful elimination of a disease or a pathogen involves the acquisition of quality-assured (QA) data that ultimately define the absence of infection or transmission in previously endemic areas. The acquisition of these essential data, in the case of onchocerciasis elimination, requires strong laboratory support for both testing and continuing evaluation/validation of the tools used for the required diagnostic and epidemiology procedures. There is also a need for standardization of the laboratory-based and field-based assays used across the onchocerciasis-endemic countries as well as continuing technical, fiscal and logistical support for laboratory activities. To achieve these needs, it is proposed to build on the existing onchocerciasis programme laboratory activities in the endemic areas by expanding these to include additional laboratories as referral services organized on a regional basis to support the needs of endemic countries. Included in these plans are the development of quality assurance mechanisms, supply chain procedures and standardization of protocols for the basic assays needed for both national onchocerciasis elimination programme surveys and supporting research activities. Such an entity could then include quality-assured testing for other neglected tropical diseases.
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http://dx.doi.org/10.1093/inthealth/ihx059DOI Listing
March 2018

Cross-border issues: an important component of onchocerciasis elimination programmes.

Int Health 2018 03;10(suppl_1):i54-i59

Mectizan Donation Programme, 325 Swanton Way, Decatur, GA 30030, USA.

Endemic areas that involve national or local borders present an important challenge to the success of elimination of onchocerciasis; such cross-border endemic foci require special attention to ensure that programme activities are unified. It is vital that national programmes and the committees responsible for the oversight of progress towards elimination are aware and address such issues in their current planning and programmatic activities. Although international borders that intersect endemic zones present the biggest challenge, intracountry borders (such as between administrative districts or loiasis endemic and non-loiasis areas) can also pose problems. The recent change in the onchocerciasis programme from disease control to transmission interruption, given the historical lack of treatment in hypo-endemic areas, may have increased the already relatively high number of cross-national scenarios in Africa. It is vital that all national programmes address the issue of any cross-border endemic areas as a matter of urgency and include this important issue in their elimination plans.
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http://dx.doi.org/10.1093/inthealth/ihx058DOI Listing
March 2018

Onchocerciasis in Yemen: moving forward towards an elimination program.

Int Health 2018 03;10(suppl_1):i89-i96

Mectizan Donation Program, Task Force for Global Health, Atlanta, GA, USA.

The onchocerciasis focus in Yemen has been known for many years as an endemic area with unique characteristics, notably the atypical and most severe form of onchodermatitis, known as sowda or reactive onchodermatitis (ROD). The national effort to control the disease began in 1992 as an individual case treatment program by administering ivermectin to those presenting with ROD. The challenging geography of the endemic area and the current political and military unrest both underscore a need for special approaches when attempting to eliminate onchocerciasis from this country. An assessment of the national situation regarding this disease was carried out in 2011-2013 aimed at defining the best approach for moving from individual clinical case treatment to elimination of transmission. The history of the control efforts and the current status of the disease are reviewed and the essential changes needed to a mass drug administration (MDA) approach are identified as the national program addresses elimination. Yemen, despite the current troubles, has shown that it can successfully implement MDA programs despite many difficulties and therefore should be supported in its efforts towards countrywide elimination of this infection; however, success will need renewed national and international efforts.
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http://dx.doi.org/10.1093/inthealth/ihx055DOI Listing
March 2018

Operationalization of the test and not treat strategy to accelerate the elimination of onchocerciasis and lymphatic filariasis in Central Africa.

Int Health 2018 03;10(suppl_1):i49-i53

IRD UMI 233-INSERM U1175-Montpellier University, Montpellier, France.

After 30 years of treatment with Mectizan (ivermectin), cutaneous and ocular complications of Onchocerca volvulus infection are now scarce in endemic communities. Indeed, transmission has been interrupted and the O. volvulus- associated disease has disappeared in some African foci. Despite this success, onchocerciasis elimination in Loa loa co-endemic areas is still constrained by severe adverse events (SAEs) occurring after ivermectin treatment in some individuals harbouring very high L. loa microfilaremia. One approach towards the prevention of these SAEs is to identify individuals with high L. loa microfilaremia and exclude them from ivermectin treatment. The development of the LoaScope has provided the tool that underlies this test and not treat (TaNT) strategy. The first successful TaNT campaign was conducted in a L. loa highly endemic focus in Cameroon in 2015 without any SAEs. To accomplish this within a research setting, 60 people were deployed for this campaign, making this 'research' strategy not sustainable from a cost perspective. We describe here a way of reducing the cost of the TaNT strategy with a smaller team (three people) selected within affected communities. We also suggest the organization of a TaNT campaign in affected countries.
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http://dx.doi.org/10.1093/inthealth/ihx051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6282645PMC
March 2018

Assessing the feasibility of integration of self-care for filarial lymphoedema into existing community leprosy self-help groups in Nepal.

BMC Public Health 2018 01 30;18(1):201. Epub 2018 Jan 30.

American Leprosy Missions, Greenville, USA.

Background: Lymphatic filariasis (LF) and leprosy are disabling infectious diseases endemic in Nepal. LF infection can lead to lymphoedema and hydrocoele, while secondary effects of leprosy infection include impairments to hands, eyes and feet. The disabling effects of both conditions can be managed through self-care and the supportive effects of self-help groups (SHGs). A network of SHGs exists for people affected by leprosy in four districts in Nepal's Central Development Region, however no such service exists for people affected by LF. The aim of this study was to determine the feasibility of integrating LF affected people into existing leprosy SHGs in this area.

Methods: A survey was conducted using a semi-structured questionnaire to elicit information on: (i) participant characteristics, clinical manifestation and disease burden; (ii) participants' knowledge of management of their condition and access to services; and (iii) participants' knowledge and perceptions of the alternate condition (LF affected participants' knowledge of leprosy and vice versa) and attitudes towards integration.

Results: A total of 52 LF affected and 53 leprosy affected participants were interviewed from 14 SHGs. On average, leprosy affected participants were shown to have 1.8 times greater knowledge of self-care techniques, and practiced 2.5 times more frequently than LF affected participants. Only a quarter of LF affected participants had accessed a health service for their condition, compared with 94.3% of leprosy affected people accessing a service (including SHGs), at least once a week. High levels of stigma were perceived by both groups towards the alternate condition, however, the majority of LF (79%) and leprosy (94.3%) affected participants stated that they would consider attending an integrated SHG.

Conclusions: LF affected participants need to increase their knowledge of self-care and access to health services. Despite stigma being a potential barrier, attitudes towards integration were positive, suggesting that the SHGs may be a good platform for LF affected people to start self-care in this area.

Trial Registration: This is not a registered trial.
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http://dx.doi.org/10.1186/s12889-018-5099-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5791211PMC
January 2018

Potential Role for Flubendazole in Limiting Filariasis Transmission: Observations of Microfilarial Sensitivity.

Am J Trop Med Hyg 2018 Jan;98(1):21-26

Institute of Parasitology, McGill University, Montreal, Quebec, Canada.

Flubendazole (FLBZ) is a potent and efficacious macrofilaricide after parenteral administration. Studies in animal models and one trial in patients infected with revealed that FLBZ elicits minimal effects on microfilariae (mf). Severe complications after ivermectin (IVM) treatment of patients with high microfilaraemia are of great concern. We examined the potential of FLBZ to rapidly kill mf, the phenomenon proposed to underlie the complications. Mf of were exposed to FLBZ, its reduced metabolite, albendazole, or IVM in vitro. Viability of mf was unaffected by FLBZ (10 μM, 72 hours); similar results were obtained with mf of We also measured the effects of FLBZ on transmission of mf. were fed FLBZ-exposed mf and dissected 24 hours or 14 days postfeeding to count mf that crossed the midgut and developed to infective L. FLBZ impaired the ability of mf to cross the midgut, regardless of duration of exposure (≥ 2 hours). FLBZ also prevented the development of mf to Ls, irrespective of duration of exposure or concentration. FLBZ is not microfilaricidal under these conditions; however, it blocks transmission. These results support the possibility that FLBZ may be a useful macrofilaricide in loiasis regions and may limit transmission from treated individuals.
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http://dx.doi.org/10.4269/ajtmh.17-0390DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5928712PMC
January 2018

A Test-and-Not-Treat Strategy for Onchocerciasis in Loa loa-Endemic Areas.

N Engl J Med 2017 11 8;377(21):2044-2052. Epub 2017 Nov 8.

From the Center for Research on Filariasis and other Tropical Diseases (J.K., H.C.N.-D., R.G.-K., G.-R.N., P.N., J.B.T.-M.) and the Faculty of Medicine and Biomedical Sciences, University of Yaounde I (J.K.), Yaounde, and the Faculty of Health Sciences, Department of Microbiology and Parasitology, University of Buea, and Research Foundation for Tropical Diseases and Environment (REFOTDE), Buea (S.W.) - all in Cameroon; Institut de Recherche pour le Développement Unité Mixte Internationale 233-INSERM Unité 1175, Montpellier University, Montpellier, France (S.D.P., C.B.C., M.B.); the Department of Bioengineering and the Biophysics Program, University of California, Berkeley, Berkeley (M.H.B., M.V.D., D.A.F.); the Department of Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing (C.D.M.); the Department of Public Health, Erasmus MC, University Medical Center, Rotterdam, the Netherlands (W.A.S.); the Chan Zuckerberg Biohub, San Francisco (D.A.F.); and the Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, MD (A.D.K., T.B.N.).

Background: Implementation of an ivermectin-based community treatment strategy for the elimination of onchocerciasis or lymphatic filariasis has been delayed in Central Africa because of the occurrence of serious adverse events, including death, in persons with high levels of circulating Loa loa microfilariae. The LoaScope, a field-friendly diagnostic tool to quantify L. loa microfilariae in peripheral blood, enables rapid, point-of-care identification of persons at risk for serious adverse events.

Methods: A test-and-not-treat strategy was used in the approach to ivermectin treatment in the Okola health district in Cameroon, where the distribution of ivermectin was halted in 1999 after the occurrence of fatal events related to L. loa infection. The LoaScope was used to identify persons with an L. loa microfilarial density greater than 20,000 microfilariae per milliliter of blood, who were considered to be at risk for serious adverse events, and exclude them from ivermectin distribution. Active surveillance for posttreatment adverse events was performed daily for 6 days.

Results: From August through October 2015, a total of 16,259 of 22,842 persons 5 years of age or older (71.2% of the target population) were tested for L. loa microfilaremia. Among the participants who underwent testing, a total of 15,522 (95.5%) received ivermectin, 340 (2.1%) were excluded from ivermectin distribution because of an L. loa microfilarial density above the risk threshold, and 397 (2.4%) were excluded because of pregnancy or illness. No serious adverse events were observed. Nonserious adverse events were recorded in 934 participants, most of whom (67.5%) had no detectable L. loa microfilariae.

Conclusions: The LoaScope-based test-and-not-treat strategy enabled the reimplementation of community-wide ivermectin distribution in a heretofore "off limits" health district in Cameroon and is a potentially practical approach to larger-scale ivermectin treatment for lymphatic filariasis and onchocerciasis in areas where L. loa infection is endemic. (Funded by the Bill and Melinda Gates Foundation and others.).
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http://dx.doi.org/10.1056/NEJMoa1705026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5629452PMC
November 2017

Lymphatic filariasis patient identification in a large urban area of Tanzania: An application of a community-led mHealth system.

PLoS Negl Trop Dis 2017 Jul 14;11(7):e0005748. Epub 2017 Jul 14.

Centre for Neglected Tropical Diseases (CNTD), Department of Parasitology, Liverpool School of Tropical Medicine, Liverpool, United Kingdom.

Background: Lymphatic filariasis (LF) is best known for the disabling and disfiguring clinical conditions that infected patients can develop; providing care for these individuals is a major goal of the Global Programme to Eliminate LF. Methods of locating these patients, knowing their true number and thus providing care for them, remains a challenge for national medical systems, particularly when the endemic zone is a large urban area.

Methodology/principle Findings: A health community-led door-to-door survey approach using the SMS reporting tool MeasureSMS-Morbidity was used to rapidly collate and monitor data on LF patients in real-time (location, sex, age, clinical condition) in Dar es Salaam, Tanzania. Each stage of the phased study carried out in the three urban districts of city consisted of a training period, a patient identification and reporting period, and a data verification period, with refinements to the system being made after each phase. A total of 6889 patients were reported (133.6 per 100,000 population), of which 4169 were reported to have hydrocoele (80.9 per 100,000), 2251 lymphoedema-elephantiasis (LE) (43.7 per 100,000) and 469 with both conditions (9.1 per 100,000). Kinondoni had the highest number of reported patients in absolute terms (2846, 138.9 per 100,000), followed by Temeke (2550, 157.3 per 100,000) and Ilala (1493, 100.5 per 100,000). The number of hydrocoele patients was almost twice that of LE in all three districts. Severe LE patients accounted for approximately a quarter (26.9%) of those reported, with the number of acute attacks increasing with reported LE severity (1.34 in mild cases, 1.78 in moderate cases, 2.52 in severe). Verification checks supported these findings.

Conclusions/significance: This system of identifying, recording and mapping patients affected by LF greatly assists in planning, locating and prioritising, as well as initiating, appropriate morbidity management and disability prevention (MMDP) activities. The approach is a feasible framework that could be used in other large urban environments in the LF endemic areas.
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http://dx.doi.org/10.1371/journal.pntd.0005748DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5529014PMC
July 2017

Ivermectin treatment of Loa loa hyper-microfilaraemic baboons (Papio anubis): Assessment of microfilarial load reduction, haematological and biochemical parameters and histopathological changes following treatment.

PLoS Negl Trop Dis 2017 Jul 7;11(7):e0005576. Epub 2017 Jul 7.

Filarial Programmes Support Unit, Liverpool School of Tropical Medicine, Liverpool, United Kingdom.

Background: Individuals with high intensity of Loa loa are at risk of developing serious adverse events (SAEs) post treatment with ivermectin. These SAEs have remained unclear and a programmatic impediment to the advancement of community directed treatment with ivermectin. The pathogenesis of these SAEs following ivermectin has never been investigated experimentally. The Loa/baboon (Papio anubis) model can be used to investigate the pathogenesis of Loa-associated encephalopathy following ivermectin treatment in humans.

Methods: 12 baboons with microfilarial loads > 8,000mf/mL of blood were randomised into four groups: Group 1 (control group receiving no drug), Group 2 receiving ivermectin (IVM) alone, Group 3 receiving ivermectin plus aspirin (IVM + ASA), and Group 4 receiving ivermectin plus prednisone (IVM + PSE). Blood samples collected before treatment and at Day 5, 7 or 10 post treatment, were analysed for parasitological, hematological and biochemical parameters using standard techniques. Clinical monitoring of animals for side effects took place every 6 hours post treatment until autopsy. At autopsy free fluids and a large number of standard organs were collected, examined and tissues fixed in 10% buffered formalin and processed for standard haematoxylin-eosin staining and specific immunocytochemical staining.

Results: Mf counts dropped significantly (p<0.05) in all animals following ivermectin treatment with reductions as high as (89.9%) recorded; while no significant drop was observed in the control animals. Apart from haemoglobin (Hb) levels which recorded a significant (p = 0.028) drop post treatment, all other haematological and biochemical parameters did not show any significant changes (p>0.05). All animals became withdrawn 48 hours after IVM administration. All treated animals recorded clinical manifestations including rashes, itching, diarrhoea, conjunctival haemorrhages, lymph node enlargement, pinkish ears, swollen face and restlessness; one animal died 5 hours after IVM administration. Macroscopic changes in post-mortem tissues observed comprised haemorrhages in the brain, lungs, heart, which seen in all groups given ivermectin but not in the untreated animals. Microscopically, the major cellular changes seen, which were present in all the ivermectin treated animals included microfilariae in varying degrees of degeneration in small vessels. These were frequently associated with fibrin deposition, endothelial changes including damage to the integrity of the blood vessel and the presence of extravascular erythrocytes (haemorrhages). There was an increased presence of eosinophils and other chronic inflammatory types in certain tissues and organs, often in large numbers and associated with microfilarial destruction. Highly vascularized organs like the brain, heart, lungs and kidneys were observed to have more microfilariae in tissue sections. The number of mf seen in the brain and kidneys of animals administered IVM alone tripled that of control animals. Co-administration of IVM + PSE caused a greater increase in mf in the brain and kidneys while the reverse was noticed with the co-administration of IVM + ASA.

Conclusions: The treatment of Loa hyper-microfilaraemic individuals with ivermectin produces a clinical spectrum that parallels that seen in Loa hyper-microfilaraemic humans treated with ivermectin. The utilization of this experimental model can contribute to the improved management of the adverse responses in humans.
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http://dx.doi.org/10.1371/journal.pntd.0005576DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5533442PMC
July 2017

Oncolytic Tanapoxvirus Expressing Interleukin-2 is Capable of Inducing the Regression of Human Melanoma Tumors in the Absence of T Cells.

Curr Cancer Drug Targets 2018 ;18(6):577-591

Laboratory of Virology, Department of Biological Sciences, Western Michigan University, Kalamazoo, MI, 49008, United States.

Background: Oncolytic viruses (OVs), which preferentially infect cancer cells and induce host anti-tumor immune responses, have emerged as an effective melanoma therapy. Tanapoxvirus (TANV), which possesses a large genome and causes mild self-limiting disease in humans, is potentially an ideal OV candidate. Interleukin-2 (IL-2), a T-cell growth factor, plays a critical role in activating T cells, natural killer (NK) cells and macrophages in both the innate and adaptive immune system.

Objective: We aimed to develop a recombinant TANV expressing mouse IL-2 (TANVΔ66R/mIL- 2), replacing the viral thymidine kinase (TK) gene (66R) with the mouse (m) mIL-2 transgene resulting in TANVΔ66R/mIL-2.

Methods: Human melanoma tumors were induced in female athymic nude mice by injecting SKMEL- 3 cells subcutaneously. Mice were treated with an intratumoral injection of viruses when the tumor volumes reached 45 ± 4.5 mm3.

Results: In cell culture, expression of IL-2 attenuated virus replication of not only TANVΔ66R/ mIL-2, but also TANVGFP. It was demonstrated that IL-2 inhibited virus replication through intracellular components and without activating the interferon-signaling pathway. Introduction of mIL-2 into TANV remarkably increased its anti-tumor activity, resulting in a more significant regression than with wild-type (wt) TANV and TANVΔ66R. Histopathological studies showed that extensive cell degeneration with a significantly increased peri-tumor accumulation of mononuclear cells in the tumors treated with TANVΔ66R/mIL-2, compared to wtTANV or TANVΔ66R.

Conclusion: We conclude that TANVΔ66R/mIL-2 is potentially therapeutic for human melanomas in the absence of T cells, and IL-2 expression resulted in an overall increase of therapeutic efficacy.
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http://dx.doi.org/10.2174/1568009617666170630143931DOI Listing
September 2019

The significant scale up and success of Transmission Assessment Surveys 'TAS' for endgame surveillance of lymphatic filariasis in Bangladesh: One step closer to the elimination goal of 2020.

PLoS Negl Trop Dis 2017 01 31;11(1):e0005340. Epub 2017 Jan 31.

Department of Parasitology, Liverpool School of Tropical Medicine, Liverpool, United Kingdom.

Background: Bangladesh had one of the highest burdens of lymphatic filariasis (LF) at the start of the Global Programme to Eliminate Lymphatic Filariasis (GPELF) with an estimated 70 million people at risk of infection across 34 districts. In total 19 districts required mass drug administration (MDA) to interrupt transmission, and 15 districts were considered low endemic. Since 2001, the National LF Programme has implemented MDA, reduced prevalence, and been able to scale up the WHO standard Transmission Assessment Survey (TAS) across all endemic districts as part of its endgame surveillance strategy. This paper presents TAS results, highlighting the momentous geographical reduction in risk of LF and its contribution to the global elimination target of 2020.

Methodology/principal Findings: The TAS assessed primary school children for the presence of LF antigenaemia in each district (known as an evaluation unit-EU), using a defined critical cut-off threshold (or 'pass') that indicates interruption of transmission. Since 2011, a total of 59 TAS have been conducted in 26 EUs across the 19 endemic MDA districts (99,148 students tested from 1,801 schools), and 22 TAS in the 15 low endemic non-MDA districts (36,932 students tested from 663 schools). All endemic MDA districts passed TAS, except in Rangpur which required two further rounds of MDA. In total 112 students (male n = 59; female n = 53), predominately from the northern region of the country were found to be antigenaemia positive, indicating a recent or current infection. However, the distribution was geographically sparse, with only two small focal areas showing potential evidence of persistent transmission.

Conclusions/significance: This is the largest scale up of TAS surveillance activities reported in any of the 73 LF endemic countries in the world. Bangladesh is now considered to have very low or no risk of LF infection after 15 years of programmatic activities, and is on track to meet elimination targets. However, it will be essential that the LF Programme continues to develop and maintain a comprehensive surveillance strategy that is integrated into the health infrastructure and ongoing programmes to ensure cost-effectiveness and sustainability.
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http://dx.doi.org/10.1371/journal.pntd.0005340DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5302837PMC
January 2017
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