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      Access to prompt diagnosis: The missing link in preventing mental health disorders associated with neglected tropical diseases

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          Abstract

          Introduction Globally, there are an estimated 1 billion people suffering from at least one of the 20 neglected tropical diseases (NTDs) prioritized by the World Health Organization (WHO). Prevalent in tropical and subtropical regions, this group of NTDs comprises diverse diseases, including vector-borne parasitic diseases (such as human African trypanosomiasis [HAT], Chagas disease, and leishmaniasis), skin diseases caused by environmental bacteria (such as Buruli ulcer [BU]), foodborne parasitic diseases (such as taeniasis/cysticercosis) or snake bite envenoming, which—together with scabies and other ectoparasites, mycetoma, and deep mycoses—were recently added to the list [1]. Despite their differences, NTDs are synonymous with poverty, life-long disability, stigma, and discrimination, not to mention the lack of effective control tools such as vaccines, diagnostics, and drugs. The majority of NTDs have been shown to worsen a patient’s mental health [2,3] in different ways: (i) neurological—infection directly affects the brain, causing mental disorders, such as in HAT, Chagas disease, and neurocysticercosis [4]; (ii) pain or physical impairment—large skin ulcers in BU, blindness in onchocerciasis, and scrotal swelling in lymphatic filariasis, all of which reduce the quality of life and increase the risk of depression [5]; and (iii) stigma and social discrimination—NTDs are stigmatizing due to their symptoms, e.g., skin lesions and disfigurement in BU, cutaneous leishmaniasis (CL), or leprosy, as well as their association with poverty. All these factors are related to impaired quality of life and have psychological consequences [6]. New initiatives, such as the Mental Wellbeing and Stigma (MWS) Task Group from the Neglected Tropical Disease Non-Governmental Organization Network, are working to raise awareness of psychosocial morbidity in patients and communities affected by NTDs [7]. The ultimate objective of the MWS group is to improve the care of both NTD patients and their caregivers who are suffering or are at risk of suffering from mental health issues. This line of action is crucial but would be considerably more effective if complemented by preventive measures. Preventing NTDs in the first place will reduce the risk of suffering from the mental health consequences associated with them. Alone or in combination, the following interventions should be encouraged to control NTDs, mitigate their impact, and promote well-being for affected communities [8]: (i) preventive chemotherapy through mass drug administration campaigns (for soil-transmitted helminthiasis and schistosomiasis); (ii) vector control (for Chagas disease, HAT, dengue, and chikungunya virus); or (iii) providing safe water, sanitation, and hygiene (WASH) to control trachoma, soil-transmitted helminths, and lymphatic filariasis. In this Viewpoint, we suggest a complementary strategy to reduce the potential onset of mental health disorders among NTD patients by advocating for early diagnosis and therefore prompt treatment of these diseases. In NTDs, the development of neuropsychiatric manifestations is usually associated with chronicity and late-stage disease. The parasites causing HAT or Chagas disease only invade the central nervous system (CNS) in the so-called second and chronic stages of the disease. Skin NTDs, such as BU, CL, or yaws, often start as painless swelling or small nodules that eventually develop into disfiguring and disabling ulcers if they are not treated early. Similarly, long-term infections are associated with disability and chronic pain as experienced by patients suffering from leprosy, lymphatic filariasis, and mycetoma or blindness in the case of nontreated eye infections with bacteria (trachoma) and parasites (onchocerciasis). The latter has also been associated with nodding syndrome, a neurological condition causing progressive neurological deterioration and epilepsy in children. We argue that treating NTDs as soon as possible after infection will reduce the risk of developing neuropsychiatric disorders. Treatment in the early stage of disease requires prompt access to correct diagnosis. In this paper, we present three examples showing that developing and implementing better tools and strategies to diagnose NTDs could significantly reduce their adverse impact on mental health. HAT HAT, or sleeping sickness, is a parasitic disease caused by protozoans belonging to the species Trypanosoma brucei. The large majority of cases are caused by T. b. gambiense. The disease has 2 consecutive stages: the first a hemolymphatic stage and the second a meningo-encephalitic stage. In the first stage, trypanosomes invade the hemolymphatic system, causing clinical signs and symptoms that are not specific to the disease (e.g., headaches or fever). If the patient is not treated, the trypanosomes invade the CNS (stage 2), where they cause damage resulting in neuropsychiatric disorders (e.g., sleep disorders, derangement, or deep sensory disturbances). These syndromes are associated with a strong stigma, which affects patients and impacts their health-seeking behavior [9]. Diagnosing and treating HAT patients in stage 1 precludes the development of mental health problems associated with stage 2. However, diagnosing HAT can be challenging because the clinical signs and symptoms in stage 1 are not specific to the disease. Until recently, diagnosis was conducted by specialized teams, often as part of large active screening campaigns (teams of 10 to 15 people) or in a limited number of health facilities, because case confirmation (usually compulsory to start treatment) requires trained laboratory personnel. The development of rapid diagnostic tests (RDTs) to screen for T. b. gambiense HAT [10,11] has enabled implementation of new control strategies. First, RDTs can be deployed in primary healthcare facilities, enhancing the capacity for passive screening for HAT [12]. Reducing the distance that a sick person has to travel to get screened for HAT reduces the time from onset of symptoms to treatment and allows diagnosing a significant number of HAT cases in the first stage of the disease. In Kongo Central province (Democratic Republic of the Congo), for example, 65.4% of the HAT cases diagnosed in health facilities using RDTs were in the early stage of the disease [13]. Second, RDTs allow implementing targeted active screening using smaller teams (e.g., 1 to 2 people using motorcycles [14] to easily cover distances). These new active screening strategies (door-to-door) are more efficient than active mass screening in low-prevalence settings [15] and are currently being implemented using RDTs in Guinea, Côte d’Ivoire, and Chad. Clearly, diagnosing HAT patients earlier improves the outcome of their treatment and contributes to the control and elimination of the disease in endemic countries. CL CL is one of the clinical forms of leishmaniasis, a group of diseases caused by a protozoan of the Leishmania genus. Although CL is not lethal, it causes chronic and disfiguring skin lesions, leading to well-documented psychosocial morbidity in affected individuals [2,3]. The impact of CL on the mental health of the patients depends largely on the type and location of the lesions [16], particularly for women and young girls if the lesions occur on the face [17]. Early treatment prevents the enlargement of the scars and disfigurement, as well as the risk of developing mucocutaneous leishmaniasis, a secondary form of CL that causes significant tissue destruction. This form is endemic in some areas, such as South America. Because treatment for CL is toxic and painful, it should only be initiated after a confirmatory diagnosis has been made. However, CL diagnosis is still based on demonstrating the presence of Leishmania parasites by direct microscopy of Giemsa-stained smears made using skin scrapings or fine needle aspirates obtained from lesions. This approach reduces access to diagnosis and treatment at reference health facilities, such as district hospitals in endemic countries. In Afghanistan, for example, where almost 30,000 CL cases were reported in 2015, CL patients from rural areas had to travel to the reference leishmaniasis clinic in Kabul for diagnosis and treatment. The lack of diagnostic capacity in peripheral health facilities severely delays or precludes access to care for patients, leading to chronic skin lesions, reduced function, disability, stigma, and mental health problems. An RDT for the detection of Leishmania in CL skin lesions is now available: the CL Detect Rapid Test (InBios International, Seattle, WA). This RDT allows diagnosing CL in primary healthcare facilities as it only requires obtaining a sample from the lesion using a small dental broach; the results are available in less than an hour and can be interpreted the same way as results from a malaria RDT. As shown in different studies, the specificity of the CL Detect RDT is good, but its sensitivity is low [18–20]. Nevertheless, the CL Detect can significantly improve access to CL diagnosis in endemic regions. Based on its performance, people showing signs of having CL and who then test positive using the RDT in peripheral health facilities should start treatment without delay. Those who test negative still need to be referred for confirmation of either being positive or negative [19]. Better diagnostic tests for CL should be developed [21], but we must maximize the use of the tools already available, in particular, the CL Detect RDT, to improve access to CL care and reduce the mental health sequelae associated with CL in endemic countries such as Afghanistan. BU BU is an important public health problem among rural communities in several countries in sub-Saharan Africa, where it mainly affects children under 15 years of age. As with several other NTDs, BU initially presents as small, nonspecific, painless swellings that, without treatment, eventually ulcerate and enlarge into disfiguring sores that cause long-term functional disability in up to 25% of cases. With the majority of cases impacting children, patients typically have to be accompanied by family members during several weeks of hospitalization, which has a negative effect on household earnings and leads to many patients being abandoned in hospitals or withdrawn from treatment. Patients with large ulcers or cured people with disfigurement often become socially excluded through negative attitudes in the community and end up dropping out of school or from the workforce [22]. Early and accurate diagnosis and antibiotic treatment are highly effective and therefore minimize the suffering, disability, and socioeconomic burden of the disease. Thus, it is crucial to have a radically improved diagnostic test that can make decentralized early diagnosis possible [23]. Although current diagnostics for BU are expensive and inappropriate for poor, rural settings, significant progress has been made in recent years. Simple molecular amplification methods, such as the loop-mediated isothermal amplification (LAMP), are now available for BU diagnosis [24]. However, even if these tests are easier to perform than PCR, they still require basic laboratory infrastructure. To allow BU diagnosis at primary healthcare facilities in endemic regions, efforts have been concentrated in developing an RDT to detect mycolactone, an exotoxin produced by Mycobacterium ulcerans in BU lesions [23]. Promising preliminary results of a prototype RDT to detect mycolactone were presented at the WHO meeting on “BU and skin NTDs” held in Geneva from 25–27 March 2019. This point-of-care test will enable the identification of the disease in its early stages at community or primary healthcare facilities where the at-risk populations live. As for CL, early diagnosis and treatment of BU patients will limit the extent of the skin lesions, disability, and stigma, thus significantly reducing the adverse impact on mental health. Conclusion The links between poverty, mental health, and NTDs are well established (Fig 1). Preventing NTDs, ensuring prompt access to diagnosis and treatment of NTDs, and improving care of those suffering from the psychological consequences of these diseases should be part of a holistic approach to break the existing vicious cycle of disease—lack of diagnosis, lack of treatment, and deterioration. As illustrated by the previous examples, the efforts to improve diagnosis of NTDs should be made at different levels: research and development (e.g., RDT for BU), evaluation (e.g., RDT for CL), and implementation (e.g., RDT for HAT). The burden of neuropsychiatric disorders, particularly for NTDs, is sadly underestimated [2]. Thus, even if the impact of prompt diagnosis of NTDs in preventing mental health disorders remains to be evaluated, we can foresee that it is significant. 10.1371/journal.pntd.0007679.g001 Fig 1 Poverty, NTDs, and mental health cycle, plus areas of intervention. 1MWS group objectives: “(i) to support and develop resources for advocacy of affected individuals and to promote their empowerment; (ii) to ensure NTD programmes include interventions which promote positive attitudes and behaviour of communities to those affected and address structural discrimination; (iii) to promote self-advocacy and expression of the needs of those affected; and (iv) to increase the awareness of the rights and responsibilities of those affected and those who provide services to them, including their caregivers” [3]. MDA, mass drug administration; MWS, Mental Wellbeing and Stigma; NTD, neglected tropical disease; WASH, water, sanitation, and hygiene.

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          Most cited references 21

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          Neglected tropical diseases and mental health: a perspective on comorbidity.

          Mental health conditions will be the largest contributor to the global health burden by 2030. Our review suggests that neglected tropical diseases (NTDs) predispose individuals to poor mental health. Factors predisposing to poor mental health include stigma and discrimination, exclusion from participating fully in society, reduced access to health and social services, lack of educational opportunities, exclusion from income-generation and employment opportunities, and restrictions in exercising civil and political rights. These characteristics are all features of NTDs, but the mental health of these sufferers has been ignored. This review raises an issue of concern and highlights the opportunities for research by psychiatrists and psychologists on NTDs. Copyright © 2012 Elsevier Ltd. All rights reserved.
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            Social stigma towards neglected tropical diseases: a systematic review.

            People affected by neglected tropical diseases (NTDs) are frequently the target of social stigmatization. To date not much attention has been given to stigma in relation to NTDs. The objective of this review is to identify the extent of social stigma and the similarities and differences in the causes, manifestations, impact of stigma and interventions used between the NTDs.
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              Accuracy of Individual Rapid Tests for Serodiagnosis of Gambiense Sleeping Sickness in West Africa

              Introduction Human African trypanosomiasis (HAT) or sleeping sickness is a fatal parasitic infection affecting rural populations in sub-Saharan Africa. During the last decade, active case finding by specialized mobile teams has considerably contributed to the reduction of the prevalence of HAT caused by Trypanosoma brucei (T.b.) gambiense. Since 2009, the number of cases reported annually has dropped below ten thousand. At low prevalence, cost-effectiveness of active screening decreases and passive case finding becomes increasingly important [1]. This shift from the mobile team to the fixed health system for HAT detection requires an adapted diagnostic approach. Detection of trypanosome specific antibodies in blood with the card agglutination test for trypanosomiasis (CATT), [2] is routinely applied for large scale active population screening. CATT is however ill-adapted to the conditions encountered in health-care centers. The limited shelf-life of the reconstituted CATT reagent at ambient temperature leads to considerable reagent loss when only few tests are performed per day. Another limitation of the CATT is the need of an agitator and a cold chain and therefore electric power, which are not always available in rural health-care centers. The venue of individual rapid tests for serodiagnosis of HAT that are stable at ambient temperature and can be performed without additional material [3–5], is a key event in the development of an effective passive screening and HAT surveillance system [6]. Two rapid diagnostic tests (RDT) have been evaluated in phase 2 diagnostic trials [5, 7], show sufficient diagnostic accuracy and have been commercialized. So far, all RDT diagnostic evaluations have been performed on samples originating from Central-Africa, and no large scale evaluation has been performed for diagnosis of gambiense HAT in West Africa, while geographic variation in the accuracy of HAT serodiagnostic tests may occur [8]. The objective of this study was therefore to assess the diagnostic accuracy of 2 RDTs on stored plasma samples collected from HAT cases, negative controls, and serological suspects originating from Guinea and Côte d’Ivoire, two countries where HAT transmission is still active [9, 10]. Materials and Methods Ethical statement Samples were collected during medical surveys conducted by the national HAT control programs. All participants were informed about the study objectives in their own language and gave written informed consent. Children less than 12 years old were excluded. For participants between 12 and 18 years old, informed consent was obtained from the parents. Approval for this study was obtained from the consultative committee for deontology and ethics (Comité Consultatif de Déontologie et d’Ethique) of the Institut de Recherche pour le Développement. In Côte d’Ivoire, the protocol was approved by the national ethical committee (N°0308/MSLS/CNER-P). Origin of test samples Plasma samples originated from subjects identified during active screening campaigns in the Dubreka, Boffa and Forecariah coastal mangrove HAT foci, situated north of Conakry in the Republic of Guinea and in the HAT foci of Oumé, Bouaflé, Sinfra, and Bonon in western central Côte d’Ivoire. All subjects underwent CATT/T.b. gambiense performed on whole blood (CATT-WB). Blood was collected in heparinised tubes and for CATT WB-positive persons, the plasma end titre was determined. All CATT-pl ≥1/4 positive persons underwent parasitological examination by direct microscopic examination of the lymph node aspirate if swollen lymph nodes were present and/or mini-anion exchange centrifugation technique on buffy coat (mAECT-BC) [11]. Based on the CATT and parasitological result, four categories of study participants (n = 722) were defined: 1° HAT: Parasitologically confirmed HAT patients with positive CATT-WB and CATT-pl end titer ≥1/4 (n = 229 from Guinea, n = 2 from Côte d’Ivoire); 2°Control: CATT-WB negative individuals for whom there was no suspicion for sleeping sickness infection (n = 101 from Guinea and n = 156 from Côte d’Ivoire); 3° SERO: Individuals with positive CATT-WB and CATT-pl end titer ≥1/4 (Seropositives) but no parasites detected (n = 123 from Guinea, n = 42 from Côte d’Ivoire); 4° SUSP: Individuals with positive CATT-WB but CATT-pl 0.16). Sensitivity and specificity of immune trypanolysis were respectively 100% (CI 98.4–100) and 95.7% (CI 92.5–97.8). Immune trypanolysis was significantly more specific than SD Bioline HAT and HAT Sero-K-Set (p 0.2). Specificities in controls were respectively 98.8% (CI 96.6–99.8) for the combination SD Bioline HAT and trypanolysis, 98.1% (CI 95.5–99.4) for HAT Sero-K-Set combined with trypanolysis, and 99.2% (CI 97.2–99.9) for the combination of the 2 RDTs with trypanolysis. No significant differences were observed between the specificities of the different test combinations (p>0.08). However, the combination of one or 2 RDTs with immune trypanolysis was more specific than one or 2 RDTs without immune trypanolysis (p<0.005). 10.1371/journal.pntd.0003480.t004 Table 4 Number of positive test results combining RDTs with trypanolysis, by type of study participant. Category SD Bioline HAT + TL HAT Sero-K-Set + TL SD Bioline HAT + HAT Sero-K-Set + TL HAT (n = 231) 230 (99.6%) 229 (99.1%) 228 (98.7%) Control (n = 257) 3 (1.2%) 5 (1.9%) 2 (0.8%) SERO (n = 165) 66 (40.0%) 68 (41.2%) 63 (38.2%) SUSP (n = 69) 2 (2.9%) 2 (2.9%) 2 (2.9%) Total (n = 722) 301 (41.9%) 304 (42.1%) 295 (40.9%) The combination of one or two RDTs with trypanolysis was positive in 38.2–41.2% of SERO, 2.9% of SUSP (Table 4). Again, significantly more SERO tested positive than SUSP (p≤0.001), while a similar proportion of SUSP and controls were positive (p≥0.6). Discussion This is the first study to report on HAT diagnostic accuracy on a large number of samples originating from West Africa, and also the first to perform both commercially available RDTs for serodiagnosis of HAT on the same sample set. Although sensitivity of the two tested RDTs for serodiagnosis of HAT in West Africa was high, specificity remained limited to 88%. Specificity significantly increased to 93% considering combined seropositivity in both RDTs. Using a combination of one or two RDTs with trypanolysis further improved specificity to 99% while maintaining sensitivity at 99%. For interpretation of the results, a selection bias caused by routine screening of the population at risk using the CATT test should be taken into account. This could result in an overestimation of test sensitivity and specificity, as CATT consists of whole fixed and stained trypanosomes of the LiTat 1.3 variable antigen type and the corresponding purified native VSG is one of the two antigens used in both RDTs as well. Furthermore the evaluation was done on stored plasma samples and not on fresh whole blood. We cannot exclude that this could influence the test results, although antibodies are well conserved after freezing. Subjectivity of scoring of the RDT test result was largely eliminated by the use of 3 independent readers. Absence of a consensus intensity or the occurrence of large differences between scores, were not frequent but can be explained by a non-uniform coloration of the test line. The RDT specificities around 88% observed in this study are close to the 87% specificity mentioned in the SD Bioline HAT test instructions (version 53FK10–04-En-0) but below the previously observed specificities of 98.6% for HAT-Sero-K-Set [7] and of 94.6% for a SD Bioline HAT prototype [5]. Specificity of both RDTs was also below the 98.7% specificity of CATT on whole blood previously reported in West Africa [15]. Possible explanations could be regional differences [8], cross reaction with other infections or superior challenge by animal trypanosomes to cause false positive reactions [15], or other. Although immune trypanolysis has been considered 100% specific for HAT [15], 4.3% of controls tested positive. It is not clear if this is due to false positivity, if previously treated HAT cases who did not declare themselves were included as controls, or if they were trypanotolerant individuals who became negative in CATT but remained immune trypanolysis positive [17]. The phenomenon of immune trypanolysis positive, CATT negative healthy controls requires further examination. Taking into account the high number of false positive test results observed, we examined the possible performance of combined positivity in both RDTs for diagnosis of HAT, taking the example of the strategy of serial testing applied with RDTs for diagnosis of HIV [18]. Although both RDTs actually available for serodiagnosis of HAT are based on identical antigens, considering combined positivity significantly increased specificity and reduced the number of false positives by almost half. Serial application of SD Bioline HAT and HAT Sero-K-Set could therefore be considered as an option for passive case finding, as long as no second generation RDTs for serodiagnosis of HAT are available based on different antigens. However, as the combined specificity of 93.4% is still suboptimal, the local context, on-site availability of parasitological confirmation tests and the relative cost should be taken into account when deciding on test algorithms. For surveillance of HAT, RDTs are actually being implemented in fixed health centres. In case of clinical suspicion and a positive RDT, and depending on the experience of the health centres in HAT diagnosis, local prevalence, and availability of sensitive confirmation diagnostic tests, blood on filter paper is sampled and sent to a reference centre for immune trypanolysis, either directly, or after unsuccessful parasitological examination. Those persons with a trypanolysis positive result are considered at high suspicion for infection, should be (re-)examined parasitologically and followed-up closely. Although in this study stored plasma samples were used for immune trypanolysis instead of filter paper, our results show the potential high diagnostic accuracy of a combined RDT-trypanolysis approach. In the final result no difference in accuracy occurred when combining one or two RDTs followed by trypanolysis. However, the serial application of two RDTs may present considerable advantages. The number of unnecessary parasitological examinations may be significantly reduced as well as the number of filter papers to be dispatched and tested in trypanolysis. Use of filter paper instead of plasma for immune trypanolysis, may further decrease of the number of trypanolysis positive SERO and SUSP individuals [19] thus further decrease the number of people to be followed up. Our data suggest that the specificity of actual RDTs for serodiagnosis of HAT might be lower than expected. Care should therefore be taken in interpretation of the result, especially since the future use of RDTs alone, without parasitological confirmation, for patient management has already been suggested [20]. Serological screening using serial application of SD Bioline HAT and HAT Sero-K-Set might offer superior specificity compared to a single RDT, maintaining high sensitivity. The combination of one or two RDTs with trypanolysis seems promising for HAT surveillance. However, the diagnostic accuracy and especially the specificity of applying a combination of RDTs on fresh blood for HAT diagnosis, without prior CATT selection, remains to be determined as well as their combination with trypanolysis on filter paper, not only in West Africa but also in Central Africa. Supporting Information S1 Checklist STARD checklist. (DOCX) Click here for additional data file.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Negl Trop Dis
                PLoS Negl Trop Dis
                plos
                plosntds
                PLoS Neglected Tropical Diseases
                Public Library of Science (San Francisco, CA USA )
                1935-2727
                1935-2735
                17 October 2019
                October 2019
                : 13
                : 10
                Affiliations
                [1 ] Foundation for Innovative New Diagnostics (FIND), Geneva, Switzerland
                [2 ] National School of Public Health, Instituto de Salud Carlos III, Madrid, Spain
                Universiteit Antwerpen, BELGIUM
                Author notes

                The authors have declared that no competing interests exist.

                Article
                PNTD-D-19-00882
                10.1371/journal.pntd.0007679
                6797081
                31622340
                © 2019 Picado et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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                There was no specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors. FIND is grateful to its donors, public and private, who have helped bring innovative new diagnostics for diseases of poverty. A full list of FIND donors can be found at: https://www.finddx.org/partners-donors/. FIND donors were not involved in the study design; in the collection, analysis and interpretation of the data; in the writing of the report; nor in the decision to submit the paper for publication.
                Categories
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                Medicine and Health Sciences
                Mental Health and Psychiatry
                Medicine and Health Sciences
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                African Trypanosomiasis
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                Medicine and Health Sciences
                Infectious Diseases
                Zoonoses
                Trypanosomiasis
                African Trypanosomiasis
                Medicine and Health Sciences
                Infectious Diseases
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                Buruli Ulcer
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