Advancing Health Security and Disease Eradication Through Peace and Health: A Mali Case Study.

Conflict and violence constitute threats to public health. As levels of conflict increase within and between countries, it is important to explore how conflict resolution initiatives can be adapted to meet the health needs of communities, and how addressing the health needs of communities can assist in conflict resolution and contribute to health security. In conflict-affected central Mali, a Peace through Health Initiative, piloted between 2018 and 2022, used conflict resolution trainings, facilitated community meetings, and human and animal health interventions to negotiate "periods of tranquility" to achieve public health goals. Project activities resulted in improved health, improved livelihoods, reduced violence, improved trust among stakeholders, and greater inclusion of community members in peace and health decisionmaking. The Peace-Health Initiative generated several lessons learned related to 3 phases of peace-health programming: preintervention, program development, and implementation. These lessons can be applied to support expanded Peace through Health Initiatives within Mali, may be adaptable to other conflict-afflicted contexts, and should be considered in relation to the implementation of global health security.

[Relationship between occupational exposure of waste manipulators of electrical and electronic equipment and respiratory problems in Bamako in 2019]. / Relation entre exposition professionnelle des manipulateurs de dechets d'equipements electriques et electroniques et problemes respiratoires a Bamako en 2019.

INTRODUCTION: waste electrical and electronic equipment (WEEE), with its health and environmental issues, has become a public health problem exposing workers to toxic compounds causing respiratory problems. OBJECTIVE: To study the relationship between professional exposure to WEEE and the occurrence of respiratory problems in Bamako in 2019. MATERIAL AND METHODS: This was a 6-month cross-sectional, analytical study carried out in the city of Bamako in 2019 and involved 159 WEEE manipulators. Data were collected using a tablet (2). Univariate and multivariate analyzes were performed using SPSS version 22 with the significance level of 0.05. Odds Ratio (OR) were presented with their 95% confident interval (OR[95%CI]). RESULTS: The overall prevalence of respiratory disorders was 67.3% among WEEE handlers. It was noted that the removal of the coating of electronic wires (OR[95%CI]=25.93[2.30;291.53]), recent weight loss outside of a diet (OR[95% CI]=7,43[1.68;32.85]) and the infrequent hand washing with soap after the toilet (OR[95% CI]=11.50[2.07; 63.89]) represented a higher risk of (2) breathing problems. CONCLUSION: These results show that D3E handlers have a lot of risky behavior for respiratory problems. This study could be used to implement strategies to reduce the impact of D3E.

INTRODUCTION: les déchets d'équipements électriques et électroniques (D3E), avec leurs enjeux sanitaires et environnementaux, sont devenus un problème de santé publique exposant les travailleurs aux composés d'éléments toxiques responsables de (2ème expertise) troubles respiratoires. OBJECTIF: Etudier la relation entre l'exposition professionnelle aux D3E et la survenue des problèmes respiratoires à Bamako en 2019. MATÉRIEL ET MÉTHODES: Il s'agissait d'une étude transversale, analytique de 6 mois, menée dans la ville de Bamako en 2019 et concernait 159 manipulateurs de D3E. Les données ont été collectées sur tablette et les analyses univariées et multivariées réalisées sur SPSS version 22 au seuil de significativité de 0,05 avec présentation des Odds Ratio (OR) et leurs intervalles de confiance à 95% (OR[IC95%]). RÉSULTATS: La prévalence en général des troubles respiratoires était de 67,3% chez les manipulateurs des D3E. On notait que le retrait du revêtement des fils électroniques (OR[IC95%]=25,93[2,30;291,53]), la perte de poids récente en dehors d'un régime (OR[IC95%]=7,43[1,68;32,85]) et la rareté de lavage des mains avec du savon après les toilettes (OR[IC95%]=11,50[2,07;63,89]) représentaient un risque plus élevé de problèmes respiratoires. CONCLUSION: Ces résultats montrent que les manipulateurs de D3E ont beaucoup de comportement à risque des problèmes respiratoires. Cette étude pourrait servir à la mise en œuvre de stratégies visant à réduire l'impact des D3E.

Relation entre exposition professionnelle des manipulateurs de déchets d'équipements électriques et électroniques et problèmes respiratoires à Bamako en 2019 / Relationship between occupational exposure of waste electrical and electronic equipment handlers and respiratory problems in Bamako in 2019

Introduction: les déchets d'équipements électriques et électroniques (D3E), avec leurs enjeux sanitaires et environnementaux, sont devenus un problème de santé publique exposant les travailleurs aux composés d'éléments toxiques responsables de (2ème expertise) troubles respiratoires. Objectif: Etudier la relation entre l'exposition professionnelle aux D3E et la survenue des problèmes respiratoires à Bamako en 2019. Matériel et Méthodes : Il s'agissait d'une étude transversale, analytique de 6 mois, menée dans la ville de Bamako en 2019 et concernait 159 manipulateurs de D3E. Les données ont été collectées sur tablette et les analyses univariées et multivariées réalisées sur SPSS version 22 au seuil de significativité de 0,05 avec présentation des Odds Ratio (OR) et leurs intervalles de confiance à 95% (OR[IC95%]). Résultats : La prévalence en général des troubles respiratoires était de 67,3% chez les manipulateurs des D3E. On notait que le retrait du revêtement des fils électroniques (OR[IC95%] =25,93[2,30;291,53]), la perte de poids récente en dehors d'un régime (OR[IC95%] =7,43[1,68;32,85]) et la rareté de lavage des mains avec du savon après les toilettes (OR[IC95%] =11,50[2,07;63,89]) représentaient un risque plus élevé de problèmes respiratoires. Conclusion :Ces résultats montrent que les manipulateurs de D3E ont beaucoup de comportement à risque des problèmes respiratoires. Cette étude pourrait servir à la mise en œuvre de stratégies visant à réduire l'impact des D3E

Introduction: waste electrical and electronic equipment (WEEE), with its health and environmental issues, has become a public health problem exposing workers to toxic compounds causing respiratory problems. Objective: To study the relationship between professional exposure to WEEE and the occurrence of respiratory problems in Bamako in 2019. Material and Methods: This was a 6-month cross-sectional, analytical study carried out in the city of Bamako in 2019 and involved 159 WEEE manipulators. Data were collected using a tablet (2). Univariate and multivariate analyzes were performed using SPSS version 22 with the significance level of 0.05. Odds Ratio (OR) were presented with their 95% confident interval (OR [95%CI]). Results: The overall prevalence of respiratory disorders was 67.3% among WEEE handlers. It was noted that the removal of the coating of electronic wires (OR [95%CI] =25.93[2.30;291.53]), recent weight loss outside of a diet (OR [95% CI] =7,43[1.68;32.85]) and the infrequent hand washing with soap after the toilet (OR [95% CI] =11.50[2.07; 63.89]) represented a higher risk of (2) breathing problems. Conclusion: These results show that D3E handlers have a lot of risky behavior for respiratory problems. This study could be used to implement strategies to reduce the impact of D3E

Concordance of vaccination status and associated factors with incomplete vaccination: a household survey in the health district of Segou, Mali, 2019.

INTRODUCTION: the region of Segou recorded 36.8% of children were incompletely vaccinated in 2018. In 2019, the district of Segou was one of the districts with the lowest vaccination coverage in the region, with 85.1% coverage for the three doses of the pentavalent vaccine and 85.4% for the measles vaccine. This study was initiated to better understand this low vaccination coverage, in the absence of specific studies on vaccination coverage in the district of Segou. METHODS: a prospective cross-sectional study was conducted from May to August 2020 with 30 clusters. We performed Kappa coefficient, bivariate, and multiple logistic regression analysis. RESULTS: findings showed that 18.46% (101/547) [15.44-21.93] of children were incompletely vaccinated. Mothers correctly reported the vaccination status of their children in 67.30% of cases (Kappa coefficient). Uneducated (OR[IC95%]=2.13[1.30-3.50]), living in rural area (OR[IC95%]=2.07[1.23-3.47]), lack of knowledge of Expanded Program on Immunization (EPI) target diseases (OR[IC95%]=2.37[1.52-3.68]), lack of knowledge of vaccination schedule (OR[IC95%]=3.33[1.90-5.81]) and lack of knowledge of the importance of vaccination (OR[IC95%]=3.6[2.35-6.32]) were associated with incomplete vaccination. In multivariate analysis, uneducated (ORa[IC95%>]=1.68[1.004-2.810]) and lack of knowledge of the importance of vaccination were associated with incomplete vaccination (ORa[IC95%]=3.40[2.049-5.649]). CONCLUSION: findings showed a good concordance of the vaccination status. Living in a rural area, no education, lack of the knowledge of EPI target diseases, lack of the knowledge of vaccination schedule and lack of knowledge of the importance of vaccination were associated with incomplete vaccination.

[Factors associated to the implementation of compulsory health insurance at the CHC level in Kalaban Coro, Kati, Mali]. / Lies a la mise en œuvre de l'assurance maladie obligatoire au niveau des cscoms a Kalaban Coro, Kati, Mali.

OBJECTIVE: To identify the factors influencing the implementation of compulsory health insurance in two community health centers (CHC) in the health district of Kalaban Coro in Kati. MATERIAL METHODS: It was a cross-sectional descriptive study from July 1, 2017 to October 31, 2018 in both CHC of Koulouba and Kalaban Coro central. We conducted a literature review and in-depth interviews with 20 people. A content analysis was done manually using deductive and inductive logic. RESULTS: Out of all the services in 2017, those insured by the compulsory health insurance benefited from 5% of deliveries, 7% of the first antenatal cares and 8% of curative cares at the CHC of Koulouba against 0.1%, 0,3% and 3% respectively in CHC of Kalaban Coro central. The implementation of the compulsory health insurance and the reimbursement mechanisms have been facilitated through the establishment of information and communication channels, the training of members of the Federations of Community Health Associations at national, regional and local levels and other forms of support for CHC. The reimbursement period was 1-3 months in Koulouba against an absence since 2017 in Kalaban Coro central. Governance, monitoring and evaluation and staff motivation systems were weak or nonexistent. They resulted in financial and drug supply difficulties. CONCLUSION: Among the factors identified, the reimbursement mechanism posed the most problem for CHC and delegated management organizations.

OBJECTIF: Identifier les facteurs influençant la mise en œuvre de l'assurance maladie obligatoire dans deux centres de santé communautaire du district sanitaire de Kalaban Coro dans le Cercle de Kati. MATÉRIEL MÉTHODES: il s'agissait d'une étude transversale descriptive couvrant la période du 1er juillet 2017 au 31 octobre 2018 dans les CSComs de Koulouba et Kalaban Coro central. Nous avons réalisé une analyse documentaire et des entrevues individuelles approfondies de 20 personnes. Une analyse de contenu a été faite manuellement selon les logiques déductive et inductive. RÉSULTATS: Sur l'ensemble des prestations en 2017, les assurés de l'AMO ont bénéficié de 5% des accouchements, 7% des premières consultations prénatales et 8% des consultations curatives au niveau du CSCom de Koulouba contre respectivement 0,1%, 0,3% et 3% à Kalaban Coro central. La mise en œuvre de l'AMO et les mécanismes de remboursement ont été facilités grâce à la mise en place des canaux d'informations et de communications, à la formation des membres des Fédérations des ASACO au niveau national, régional et local et à d'autres formes d'appuis aux CSComs. Le délai de remboursement était de 1-3mois à Koulouba contre une absence depuis 2017 à Kalaban Coro central. Les systèmes de gouvernance, de suivi et évaluation et de motivations du personnel étaient insuffisants, voire inexistant. Ils avaient pour conséquences, des difficultés financières et d'approvisionnement en médicaments. CONCLUSION: Parmi les facteurs identifiés, le mécanisme de remboursement des prestations posait le plus de problème aux CSComs et organismes gestionnaires délégués.

[Epidemiological profile of COVID-19 in Tombouctou region in Mali]. / Profil epidemiologique de la COVID-19 dans la region de Tombouctou au Mali.

INTRODUCTION: The objective of our study was to establish the epidemiological profile of COVID-19 in Tombouctou. MATERIAL AND METHODS: This was a descriptive cross-sectional study of COVID-19 surveillance data from Tombouctou from April 3 to October 1, 2020. Our variables of interest were extracted from the surveillance database and analyzed with Excel 2013. The frequencies, rate, and ratio were computed. RESULTS: Overall, 1851 suspects from all districts of the region were screened by RT-PCR, including 572 confirmed, which indicate a positivity rate of 30.90%. The 15-34 age group was the most represented with 48% of the confirmed cases. The sex ratio (male / female) of confirmed cases was 2.67. The city of Tombouctou was the epicenter of COVID-19. The Tombouctou region had a detection rate of around 2‰ (1851/928,000) and peaked between weeks 22 and 23 with a case fatality of 2.8%. CONCLUSION: Young people and men were most likely to be infected with COVID-19. We recommend increasing awareness of compliance with barrier measures.

INTRODUCTION: L'objectif de notre étude était d'établir le profil épidémiologique de la COVID-19 à Tombouctou. MATÉRIEL ET MÉTHODES: Il s'agissait d'une étude transversale descriptive des données de surveillance de la COVID-19 de la Région de Tombouctou du 3 avril au 1er octobre 2020. Nos variables d'intérêts ont été extraites de la base de données de surveillance et analysées sur Excel 2013. Les fréquences, taux et ratio ont été calculés. RÉSULTATS: Au total 1851 cas suspects en provenance de tous les districts de la région ont été testés à la RT-PCR dont 572 confirmés soit un taux de positivité de 30,90%. La tranche d'âge de 15-34 ans était la plus représentée avec une proportion de 48% de l'effectif des confirmés. Le sex ratio (homme/femme) des cas confirmés était de 2,67. La ville de Tombouctou était l'épicentre de la COVID-19. La région de Tombouctou avait un taux de dépistage d'environ 2‰ (1851/928.000) et a connu son pic entre les semaines 22 et 23 avec une létalité de 2,8%. CONCLUSION: Les jeunes et les hommes seraient les plus susceptibles d'être infectés par la COVID-19. Nous recommandons le renforcement de la sensibilisation pour le respect des mesures barrières.

[Management of addictions at the University Hospital Center Point G, Bamako-Mali]. / Prise en charge des addictions au Centre Hospitalier Universitaire du Point G, Bamako-Mali.

OBJECTIVE: To evaluate the health impact of drug use among patients in care in the psychiatric unit of the University Hospital Center Point G. METHOD: This was a prospect in description study of drug users admitted to the G-UHC for care. From January to July 2018. It was performed in the Psychiatry Department of the University Hospital Center Point G in Bamako, which is the only structure in Mali that deals with addiction. RESULTS: Our results show that young people in the 20-30 year group were the most affected. Cannabis was the most consumed, followed by Alcohol, and Tramadol Hydrochloride. There were cases of poly-drug abuse as well as new forms of consumption. Drug use has multiple negative consequences on health and social life: addiction, psychopathological disorders. CONCLUSION: Substance abuse of drugs is a reality that is gaining momentum in Mali. Our study have demonstrated its sanitary impact among patients with adduction. The fight against the use of drugs requires the combined efforts of all the actors involved.

OBJECTIF: Evaluer l'impact sanitaire de la consommation des drogues chez les patients pris en charge au service de psychiatrie du Centre Hospitalier universitaire du Point G. MÉTHODE: Il s'agissait d'une étude prospective descriptive chez les patients consommateurs de drogues admis au CHU du Point G pour des soins. Elle a été réalisée de janvier à juillet 2018. Elle a été réalisée dans le service de Psychiatrie du Centre Hospitalier Universitaire du Point G à Bamako, Mali, l'unique structure au Mali qui fait la prise en charge de l'addiction. RÉSULTATS: Nos résultats ont montré que les jeunes de la tranche 20-30 ans étaient les plus touchés. Le Cannabis était le plus consommé, suivi la de l'Alcool, et du Chlorhydrate de Tramadol. La polytoxicomanie ainsi que des nouvelles formes de consommation avait été notée. La consommation de drogues avait généré de multiples conséquences néfastes sur la santé et la vie sociale : la dépendance, les troubles psychopathologiques. CONCLUSION: L'abus de substances psychoactives, est une réalité qui prend de l'ampleur au Mali. Notre étude a démontré son impact sur la santé des consommateurs. La lutte contre l'usage des drogues nécessite la conjugaison des efforts de tous les acteurs impliqués.

Performance of Xpert MTB/RIF in comparison with light-emitting diode-fluorescence microscopy and culture for detecting tuberculosis in pulmonary and extrapulmonary specimens in Bamako, Mali.

Background: The diagnosis of tuberculosis (TB) has mostly been relied on a long-used method called sputum smear microscopy. In 2010, Xpert MTB/RIF assay was approved by the World Health Organization for simultaneous TB diagnosis and detection of resistance. Our current study was undertaken to compare the diagnostic performance of Xpert MTB/RIF assay to auramine staining-based light-emitting diode-Fluorescence Microscopy (LED-FM) considering culture as the gold standard method for pulmonary and extrapulmonary TB. Method: Pulmonary and extrapulmonary specimens of suspected TB patients were examined in this study. From January 2016 to June 2019, sputum, urine, superficial swabs, gastric aspirates, and pleural infusion specimens were collected from new and previously treated TB individuals. Specimens were examined using Xpert MTB/RIF, LED-FM, and Mycobacterium culture techniques to evaluate their performance. Results: A total of 697 suspected TB samples were included in this analysis, and of these, 469 (67.29%) were positive for all three used methods. The overall sensitivities, specificities, and positive and negative predictive values were 99.6%, 62.0%, 88.4%, and 98.2% for Xpert MTB/RIF and 88.0%, 95.6%, 99.0%, and 60.7% for LED-FM, respectively, compared to culture method. Conclusion: The sensitivity of Xpert MTB/RIF assay was observed to be higher than the LED-FM method, thus suggesting this molecular technique as a promising tool for the diagnosis of pulmonary and extrapulmonary TB, which will help in the management of TB infections in developing countries such as Mali.

Population genomic evidence that human and animal infections in Africa come from the same populations of Dracunculus medinensis.

BACKGROUND: Guinea worm-Dracunculus medinensis-was historically one of the major parasites of humans and has been known since antiquity. Now, Guinea worm is on the brink of eradication, as efforts to interrupt transmission have reduced the annual burden of disease from millions of infections per year in the 1980s to only 54 human cases reported globally in 2019. Despite the enormous success of eradication efforts to date, one complication has arisen. Over the last few years, hundreds of dogs have been found infected with this previously apparently anthroponotic parasite, almost all in Chad. Moreover, the relative numbers of infections in humans and dogs suggests that dogs are currently the principal reservoir on infection and key to maintaining transmission in that country. PRINCIPAL FINDINGS: In an effort to shed light on this peculiar epidemiology of Guinea worm in Chad, we have sequenced and compared the genomes of worms from dog, human and other animal infections. Confirming previous work with other molecular markers, we show that all of these worms are D. medinensis, and that the same population of worms are causing both infections, can confirm the suspected transmission between host species and detect signs of a population bottleneck due to the eradication efforts. The diversity of worms in Chad appears to exclude the possibility that there were no, or very few, worms present in the country during a 10-year absence of reported cases. CONCLUSIONS: This work reinforces the importance of adequate surveillance of both human and dog populations in the Guinea worm eradication campaign and suggests that control programs aiming to interrupt disease transmission should stay aware of the possible emergence of unusual epidemiology as pathogens approach elimination.

[Determinants of home delivery in two neighborhoods in Commune V of Bamako]. / Comparaison des determinants de l'accouchement a domicile dans deux quartiers en Commune V de Bamako.

OBJECTIVE: The objective was to study the determinants of home delivery in the Commune V Health District of Bamako. MATERIALS AND METHODS: We conducted an analytical cross-sectional study among women who delivered at home, in two neighborhoodsofSabalibougou and Badalabougou, from March 2015 to February 2016, and who were admitted at the Maternity of the Commune V Referral Health Center during the same period. Two groups of women from two neighborhoods were compared. The data were entered and analyzed using EpiInfo 3.5.3. We presented the Odds Ratios and confident intervals. RESULTS: The frequency of home delivery was 16.18%. The age group 35 years and over were the most represented in both Sabalibougou with 80.75% and Badalabougou with 19.42%.In Sabalibougou, compared to Badalabougou, we found 0.49 times fewer women in school (p = 0.01); 8.92 times more women with gainful occupation (p = 10-8); 3.5 times more partners with non-gainful occupation (p = 10-6); 4.59 times more risk to give birth at home (p = 10-8); 3 times more risk not to perform antenatal care (p = 0.0002); 3.26 times more appreciation of the high cost of delivery care (p = 10-4) and 3.03 times more lack of financial support (p=3*10-4). CONCLUSION: The frequency of home delivery was higher in Sabalibougou. The determinants of this phenomenon were: the low level of schooling, the low socioeconomic level, the non-use of antenatal care, theperceived high cost of delivery care.

OBJECTIF: L'objectif était d'étudierles déterminants de l'accouchement à domicile en Commune V de Bamako. MATÉRIELS ET MÉTHODES: Nous avons mené une étude transversale analytique chez les femmes qui ont accouchées à domicile, dans les quartiers de Sabalibougou et Badalabougou, de Mars 2015 en Février 2016 et reçues à la maternité du Centre de Santé de Référence de la Commune V pendant la même période. Les deux quartiers ont été comparés. Les données ont été saisies et analysées sur EpiInfo 3.5.3, avec présentation des Odds Ratios et intervalles de confiance. RÉSULTATS: La fréquence de l'accouchement à domicile était de 16,18%.La tranche d'âge 35 ans et plus était la plus représentée à Sabalibougou (80,75%) et à Badalabougou (19,42%). Nous avons trouvéà Sabalibougou, comparé à Badalabougou, 0,49 fois moins de femmes scolarisées (p=0,01) ;8,92 fois plus de femmes avec activité rémunératrice (p=10-8) ;3,5 fois plus de partenaires avec activité non rémunératrice (p=10-6) ; 4,59 fois plus de risque d'accoucher à domicile (p=10-8) ; 3 fois plus de risque de ne pas réaliser de consultation prénatale (p=0,0002) ;3,26 fois plus d'appréciation du coût de l'accouchement élevé (p=10-4) et3,03 fois plus de manque de moyens (p=3*10-4). CONCLUSION: La fréquence de l'accouchement à domicile était plus élevée à Sabalibougou.Les déterminants étaient : l'absence de scolarisation, lemanque de moyens financiers, l'absence de réalisation de consultation prénatale, le coût jugé élevé de l'accouchement.

Impact of insecticide-treated bednets and indoor residual spraying in controlling populations of Phlebotomus duboscqi, the vector of Leishmania major in Central Mali.

BACKGROUND: Cutaneous leishmaniasis (CL) is an endemic neglected tropical disease prevalent in several areas where seasonal malaria transmission is active. We assessed the effect of indoor residual spraying (IRS) and the mass distribution of long-lasting insecticide-treated bednets (LLINs) for malaria control on sand fly population diversity and abundance, and its impact on the risk of Leishmania transmission in the district of Baroueli, endemic for CL in Mali. METHODS: Kemena and Sougoula, two villages in the district of Baroueli, were selected for entomology surveys from March to September 2016 to evaluate sand fly species composition and density, and Leishmania infection rates in the vector Phlebotomus duboscqi. The surveys followed an annual indoor residual spraying and mass distribution of long-lasting insecticide-treated bednets (IRS/LLINs) that began in 2011 for malaria vector control. We also carried out a leishmanin skin test (LST) survey in the two villages to determine the incidence of Leishmania infection in humans living in the endemic area. RESULTS: A total of 2936 sand fly specimens, 1013 males and 1923 females, were collected and identified from the two villages throughout the study period. Fourteen species, 2 belonging to the genus Phlebotomus and 12 to the genus Sergentomyia, were documented. The genus Sergentomyia constituted 91% of collected sand flies versus 9% for the genus Phlebotomus (P. duboscqi and P. rodhaini). Of those, P. duboscqi was the most abundant, representing 99.6% of the collected Phlebotomus species. In both villages, P. duboscqi was most abundant during the end of dry season (June). The prevalence of Leishmania infection in individual females of P. duboscqi by PCR was 3.5%. After 5 years of the IRS/LLINs, the incidence of Leishmania infection in the human population as measured by LST was 4.2%. CONCLUSIONS: Compared to historical data collected from 2005-2008, a considerable reduction was observed in both sand fly density and prevalence of human Leishmania infection in the villages of Kemena and Sougoula, Baroueli District, following IRS/LLINs. This suggests that IRS/LLINs used for mosquito control also impacts sand fly vectors reducing the incidence of leishmaniasis. TRIAL REGISTRATION: NCT00344084 . Registered: 23 June 2006.

Correction: Prevalence of Cutaneous Leishmaniasis in Districts of High and Low Endemicity in Mali.

[This corrects the article DOI: 10.1371/journal.pntd.0005141.].

Prevalence of Cutaneous Leishmaniasis in Districts of High and Low Endemicity in Mali.

Historically the western sahelian dry regions of Mali are known to be highly endemic for cutaneous leishmaniasis (CL) caused by Leishmania major, while cases are rarely reported from the Southern savanna forest of the country. Here, we report baseline prevalence of CL infection in 3 ecologically distinct districts of Mali (dry sahelian, north savanna and southern savanna forest areas). We screened 195 to 250 subjects from 50 to 60 randomly selected households in each of the 6 villages (four from the western sahelian district of Diema in Kayes region, one from the central district of Kolokani and one from the southern savanna district of Kolodieba, region of Sikasso). The screening consisted of: 1] A Leishmanin Skin Test (LST) for detection of exposure to Leishmania parasites; 2] clinical examination of suspected lesions, followed by validation with PCR and 3] finger prick blood sample to determine antibody levels to sand fly saliva. LST positivity was higher in the western district of Diema (49.9%) than in Kolokani (24.9%) and was much lower in Kolondieba (2.6%). LST positivity increased with age rising from 13.8% to 88% in Diema for age groups 2-5 years and 41-65 years, respectively. All eight PCR-confirmed L. major CL cases were diagnosed in subjects below 18 years of age and all were residents of the district of Diema. Exposure to sand fly bites, measured by anti-saliva antibody titers, was comparable in individuals living in all three districts. However, antibody titers were significantly higher in LST positive individuals (P<0.0001). In conclusion, CL transmission remains active in the western region of Mali where lesions were mainly prevalent among children under 18 years old. LST positivity correlated to higher levels of antibodies to sand fly salivary proteins, suggesting their potential as a risk marker for CL acquisition in Mali.

In Vivo Efficacy and Parasite Clearance of Artesunate + Sulfadoxine-Pyrimethamine Versus Artemether-Lumefantrine in Mali.

Although artemisinin resistance has yet to be reported in Africa, surveillance of the efficacy of artemisinin-based combination therapies (ACTs) is warranted. Here, the efficacy of artesunate + sulfadoxine-pyrimethamine (AS + SP) and artemether-lumefantrine (AL) was evaluated in Mali. Randomized open-label comparative in vivo assay of AS + SP versus AL were carried out using the 28-day follow-up World Health Organization protocol. Patients with uncomplicated falciparum malaria and at least 6 months of age were recruited between October 2010 and January 2014. A subset of these patients was selected to measure Plasmodium falciparum clearance time. Polymerase chain reaction-corrected adequate clinical and parasitological responses were 100% for AS + SP and 98.2% for AL with no significant difference (P = 0.06). The reinfection rates were comparable (P = 0.63) with 8.0% for AS + SP and 12.6% for AL. Individuals under 8 years were more susceptible to treatment failure (relative risk = 1.9; 95% confidence interval = 1.2, 3.3). Median parasite clearance half-life was 1.7 hours (interquartile range [IQR] = 1.3-2.2) for AS + SP and 1.9 hours (IQR = 1.5-2.5) for AL with no statistically significant difference (P = 0.24). Efficacy of AS + SP and AL was high. This study provides baseline information on parasite clearance half-lives after ACT treatment, particularly AS + SP, in Mali.

Suppressing active replication of a live attenuated simian immunodeficiency virus vaccine does not abrogate protection from challenge.

Although safety concerns preclude the use of live attenuated HIV vaccines in humans, they provide a useful system for identifying the elusive correlates of protective immunity in the SIV/macaque animal model. However, a number of pieces of evidence suggest that protection may result from prior occupancy of susceptible target cells by the vaccine virus rather than the immune response. To address this, we developed a Nef-deletion variant of an RT-SHIV whose active replication could be shut off by treatment with RT-inhibitors. Groups of macaques were inoculated with the ∆Nef-RT-SHIV and immune responses allowed to develop before antiretroviral treatment and subsequent challenge with wild-type SIVmac239. Vaccinated animals either resisted infection fully or significantly controlled the subsequent viremia. However, there was no difference between animals undergoing replication of the vaccine virus and those without. This strongly suggests that competition for available target cells does not play a role in protection.

Exclusive Transduction of Human CD4+ T Cells upon Systemic Delivery of CD4-Targeted Lentiviral Vectors.

Playing a central role in both innate and adaptive immunity, CD4(+) T cells are a key target for genetic modifications in basic research and immunotherapy. In this article, we describe novel lentiviral vectors (CD4-LV) that have been rendered selective for human or simian CD4(+) cells by surface engineering. When applied to PBMCs, CD4-LV transduced CD4(+) but not CD4(-) cells. Notably, also unstimulated T cells were stably genetically modified. Upon systemic or intrasplenic administration into mice reconstituted with human PBMCs or hematopoietic stem cells, reporter gene expression was predominantly detected in lymphoid organs. Evaluation of GFP expression in organ-derived cells and blood by flow cytometry demonstrated exclusive gene transfer into CD4(+) human lymphocytes. In bone marrow and spleen, memory T cells were preferentially hit. Toward therapeutic applications, we also show that CD4-LV can be used for HIV gene therapy, as well as for tumor therapy, by delivering chimeric Ag receptors. The potential for in vivo delivery of the FOXP3 gene was also demonstrated, making CD4-LV a powerful tool for inducible regulatory T cell generation. In summary, our work demonstrates the exclusive gene transfer into a T cell subset upon systemic vector administration opening an avenue toward novel strategies in immunotherapy.

A novel small animal model to study the replication of simian foamy virus in vivo.

Preclinical evaluation in a small animal model would help the development of gene therapies and vaccines based on foamy virus vectors. The establishment of persistent, non-pathogenic infection with the prototype foamy virus in mice and rabbits has been described previously. To extend this spectrum of available animal models, hamsters were inoculated with infectious cell supernatant or bioballistically with a foamy virus plasmid. In addition, a novel foamy virus from a rhesus macaque was isolated and characterised genetically. Hamsters and mice were infected with this new SFVmac isolate to evaluate whether hamsters are also susceptible to infection. Both hamsters and mice developed humoral responses to either virus subtype. Virus integration and replication in different animal tissues were analysed by PCR and co-cultivation. The results strongly indicate establishment of a persistent infection in hamsters. These studies provide a further small animal model for studying FV-based vectors in addition to the established models.

Intrahepatic application of suicide gene-armed measles virotherapeutics: a safety study in transgenic mice and rhesus macaques.

Abstract Oncolytic viruses such as measles virus (MV) represent a new class of therapeutic agents that might help to overcome current limitations in cancer therapy. Although MV-based virotherapeutics already have entered clinical testing for various tumor entities, the preclinical safety of MV virotherapeutics so far has not been elucidated for particular regimens with high medical need, such as (1) direct injection into hepatic tumor sites, (2) employing high doses ibidem, and (3) concurrent usage of arming with cytotoxic genes required to further enhance oncolytic efficiency. Here, we assessed the safety and pharmacokinetics of suicide gene-armed vector MV-SCD when administered intrahepatically in two animal models, IFNAR(tm)-CD46(Ge) (interferon-α receptor deficient and CD46 MV receptor knock-in) transgenic mice and rhesus macaques (Macaca mulatta). Clinically, singular direct intrahepatic applications of MV-SCD were found to be well tolerated. Quantitative RT-PCR demonstrated the transient presence of viral RNA in various organs, whereas no shedding of infectious virus particles was observed at any time point. Histological analyses of organs did not exhibit adverse effects attributable to the test article. Blood parameters including liver enzymes revealed no deviations from normal. In both species an antiviral humoral immune response was mounted shortly after virus administration. Surprisingly, daily repeated systemic applications of MV-SCD under concomitant prodrug administration resulted in side effects in IFNAR(tm)-CD46(Ge) mice, but were less pronounced than in a 5-fluorouracil standard therapy control cohort. Taken together, these data indicate that "single shot" direct intrahepatic injections of MV-SCD in conjunction with systemic prodrug administration are safe and could be used in future virotherapeutic treatments of liver cancers.

Delayed-type hypersensitivity to sand fly saliva in humans from a leishmaniasis-endemic area of Mali is Th1-mediated and persists to midlife.

Immunity to sand fly saliva in rodents induces a T(H)1 delayed-type hypersensitivity (DTH) response conferring protection against leishmaniasis. The relevance of DTH to sand fly bites in humans living in a leishmaniasis-endemic area remains unknown. Here, we describe the duration and nature of DTH to sand fly saliva in humans from an endemic area of Mali. DTH was assessed at 24, 48, 72, and 96 hours post bite in volunteers exposed to colony-bred sand flies. Dermal biopsies were obtained 48 hours post bite; cytokines were quantified from peripheral blood mononuclear cells (PBMCs) stimulated with sand fly saliva in vitro. A DTH response to bites was observed in 75% of individuals aged 1-15 years, decreasing gradually to 48% by age 45, and dropping to 21% thereafter. Dermal biopsies were dominated by T lymphocytes and macrophages. Abundant expression of IFN-γ and absence of T(H)2 cytokines establishes the T(H)1 nature of this DTH response. PBMCs from 98% of individuals responded to sand fly saliva. Of these, 23% were polarized to a T(H)1 and 25% to a T(H)2 response. We demonstrate the durability and T(H)1 nature of DTH to sand fly bites in humans living in a cutaneous leishmaniasis-endemic area. A systemic T(H)2 response may explain why some individuals remain susceptible to disease.

Seasonality and prevalence of Leishmania major infection in Phlebotomus duboscqi Neveu-Lemaire from two neighboring villages in central Mali.

Phlebotomus duboscqi is the principle vector of Leishmania major, the causative agent of cutaneous leishmaniasis (CL), in West Africa and is the suspected vector in Mali. Although found throughout the country the seasonality and infection prevalence of P. duboscqi has not been established in Mali. We conducted a three year study in two neighboring villages, Kemena and Sougoula, in Central Mali, an area with a leishmanin skin test positivity of up to 45%. During the first year, we evaluated the overall diversity of sand flies. Of 18,595 flies collected, 12,952 (69%) belonged to 12 species of Sergentomyia and 5,643 (31%) to two species of the genus Phlebotomus, P. duboscqi and P. rodhaini. Of those, P. duboscqi was the most abundant, representing 99% of the collected Phlebotomus species. P. duboscqi was the primary sand fly collected inside dwellings, mostly by resting site collection. The seasonality and infection prevalence of P. duboscqi was monitored over two consecutive years. P. dubsocqi were collected throughout the year. Using a quasi-Poisson model we observed a significant annual (year 1 to year 2), seasonal (monthly) and village effect (Kemena versus Sougoula) on the number of collected P. duboscqi. The significant seasonal effect of the quasi-Poisson model reflects two seasonal collection peaks in May-July and October-November. The infection status of pooled P. duboscqi females was determined by PCR. The infection prevalence of pooled females, estimated using the maximum likelihood estimate of prevalence, was 2.7% in Kemena and Sougoula. Based on the PCR product size, L. major was identified as the only species found in flies from the two villages. This was confirmed by sequence alignment of a subset of PCR products from infected flies to known Leishmania species, incriminating P. duboscqi as the vector of CL in Mali.