Minimal resilience and insurgent conflict: qualitative analysis of the resilience process in six primary health centres in central Mali.

BACKGROUND: In the context of universal health coverage in the Sahel, the study focuses on primary health centres and the difficulties of their implementation in the context of insurgency conflicts in central Mali. METHODS: This is qualitative research through a multiple case study. We selected six health centres according to a reasoned choice to bring together contrasting situations. We conducted 96 semistructured interviews and consulted secondary quantitative data on attendance. By focusing on community health centres, the conceptual approach focuses on the process of resilience that unfolds in a dual context of chronic health system dysfunctions and armed conflict. RESULTS: The resilience strategies deployed by health professionals were relatively basic and uncoordinated. In the end, it was the individuals who showed absorption. However, their room for manoeuvre was limited. In the most isolated health centres, resilience was based on subordinate, poorly trained staff, often from the locality. Degraded working conditions and fear caused a form of resignation among health workers. CONCLUSION: The strategies and resources used showed a form of minimal resilience. This form is unfolding in a context marked by two structuring features. On the one hand, the Malian health system was relatively dysfunctional before the crisis, and on the other hand, the type of conflict was relatively low intensity that allowed health centres to remain open.

Evolution of assisted deliveries at primary healthcare centres in an unstable security context in Mali.

INTRODUCTION: In Mali, healthcare systems are severely affected by conflict. However, several studies suggest a lack of knowledge about its impact on maternal healthcare. Frequent and repeated attacks increase insecurity, limit access to maternal care, and thus represent a barrier to accessing care. The objective of this study is to understand how assisted deliveries are being reorganised at the health centre level, and how they are adapting to the security crisis. METHOD: This is a mixed sequential and explanatory study. The quantitative approaches combine a spatial scan analysis of assisted deliveries by health centres, an analysis of health centre performance using an ascending hierarchical classification, and a spatial analysis of violent events in two health districts in central Mali: Mopti and Bandiagara. The qualitative phase analyses semidirective and targeted interviews with managers (n=22) of primary healthcare centres (CsCOM) and two agents of international institutions. RESULTS: The study reveals an important territorial heterogeneity of assisted deliveries. The primary health centres with high rates of assisted deliveries have mainly high-performance levels. This high level of use can be explained by the movement of the population to areas less exposed to attacks. The centres with low rates of assisted deliveries are those where qualified health workers refused to practice, where populations had few financial resources, and where they limited their travel to reduce their exposure to insecurity. CONCLUSION: This study confirms that combining methodological approaches is essential to explain significant use in the local context. The analysis of the number of assisted deliveries in conflict zones must consider the number of procedures, the nearby security context, the number of internally displaced persons and the presence of camps in which humanitarian organisations offer programmes.

Innovations in mutuality: challenges and learnings for the Universal Health Insurance Plan in Mali.

BACKGROUND: Many Sahel countries in Africa are looking for solutions for universal health coverage (UHC). Mali is in the process of adopting the Universal Health Insurance Plan, which allows for the mutualisation of existing schemes. Its operationalisation requires numerous adjustments to the current mutualist proposal and innovations in the system. The study focuses on innovations experienced in mutuality and their conditions of scale for UHC in Mali. METHODS: This is qualitative research by multiple case studies. It is based on the collection of data by interviews (n=136), at a national and local level, on the analysis of documents (n=42) and a long field observation (7 months). The analytical framework concerns the dissemination and maintenance of health innovations (Greenhalgh et al, 2004). RESULT: The analysis of this innovation shows an interest in the technical and institutional viability that determines its performance and scale-up. The procrastination and scepticism displayed at the highest level of the state and the international level, the reluctance, both financial and ideological, to renew the old mutualist proposal, penalise this Malian experiment. CONCLUSION: This innovation is a decisive step in ensuring the health coverage of Mali's agricultural and informal sectors. The reform will need to be amplified and supported in the future to expect the scale-up of a cheaper, technically and institutionally more efficient system. Without a political intention to mobilise national resources and accept a fundamental paradigm shift in health financing, the search for the financial viability of mutuality may, again, be at the expense of the performance.

Antituberculosis Therapy and Gut Microbiota: Review of Potential Host Microbiota Directed-Therapies.

Tuberculosis (TB) remains a major public health concern with millions of deaths every year. The overlap with HIV infections, long treatment duration, and the emergence of drug resistance are significant obstacles to the control of the disease. Indeed, the standard first-line regimen TB treatment takes at least six months and even longer for the second-line therapy, resulting in relapses, drug resistance and re-infections. Many recent reports have also shown prolonged and significant damage of the gut microbial community (dysbiosis) from anti-TB drugs that can detrimentally persist several months after the cessation of treatment and could lead to the impairment of the immune response, and thus re-infections and drug resistance. A proposed strategy for shortening the treatment duration is thus to apply corrective measures to the dysbiosis for a faster bacterial clearance and a better treatment outcome. In this review, we will study the role of the gut microbiota in both TB infection and treatment, and its potential link with treatment duration. We will also discuss, the new concept of "Host Microbiota Directed-Therapies (HMDT)" as a potential adjunctive strategy to improve the treatment effectiveness, reduce its duration and or prevent relapses. These strategies include the use of probiotics, prebiotics, gut microbiota transfer, and other strategies. Application of this innovative solution could lead to HMDT as an adjunctive tool to shorten TB treatment, which will have enormous public health impacts for the End TB Strategy worldwide.

Development and clinical evaluation of a new multiplex PCR assay for a simultaneous diagnosis of tuberculous and nontuberculous mycobacteria.

BACKGROUND: The prevalence of non-tuberculous mycobacteria (NTM) has been increasing worldwide in both developed and developing countries. NTM infection is clinically indistinguishable from tuberculosis and therefore poses significant challenges in patient management, especially in patients chronically treated for pulmonary TB. In this study, we evaluated a new highly sensitive Multiplex MTB/NTM assay that can differentiate M. tuberculosis complex (MTBC) from all NTM, including the treatable and most common NTM, M. avium complex (MAC). METHODS: We developed and optimized a new open- Multiplex MTB/NTM assay with two gene-targets for MTBC (IS6110/senX3-regX3) and two targets for MAC (IS1311/DT1) with samples spiked with stored strains and testing 20 replicates. Patients with presumptive TB and NTM were enrolled at the Respiratory Disease Department of The University Teaching Hospital of Point G, in Mali. FINDINGS: In the development stage, the new assay showed a high analytic performance with 100% detections of MTBC and MAC at only 5 colony forming units (CFUs). Overall, without the treatment failure cases, the Multiplex assay and the Xpert showed a sensitivity, specificity, PPV and NPV of 83·3% [66·4-92·6], 96·6% [88·6-99·0], 92·5% [82·3-96·5] and 92·2% [82·7-96·5] and the Xpert had values of 96·7% [83·3-99·4], 80·0% [68·2-88·1], 70·7 [55·5-82·3] and 97·9% [89·3-99·6], respectively. The Multiplex assay successfully detected all (5/5) the MAC cases. INTERPRETATION: Our new Multiplex assay demonstrates better specificity than Xpert for all group studied, in addition to detecting potential NTM cases. The assay could therefore complement the widely used Xpert assay and enhance discrimination of TB and NTM infections. FUNDING: This work was supported by the National Institutes of Health (R03AI137674, U54EB027049, D43TW010350 and UM1AI069471) and Northwestern University's Institute for Global Health Catalyzer Fund.

Patients infected with Mycobacterium africanum versus Mycobacterium tuberculosis possess distinct intestinal microbiota.

BACKGROUND: Mycobacterium tuberculosis complex (MTBC), the causative agent of tuberculosis (TB), is composed of eight subspecies. TB in West Africa, in contrast to other geographical regions, is caused by Mycobacterium africanum (MAF) in addition to M. tuberculosis (MTB), with both infections presenting similar symptoms. Nevertheless, MAF is considered to be hypovirulent in comparison with MTB and less likely to progress to active disease. In this study, we asked whether MAF and MTB infected patients possess distinct intestinal microbiomes and characterized how these microbiota communities are affected by anti-tuberculosis therapy (ATT). Additionally, we assessed if the changes in microbiota composition following infection correlate with pathogen induced alterations in host blood-gene expression. METHODS: A longitudinal, clinical study of MAF infected, MTB infected patients assessed at diagnosis and two months after start of ATT, and healthy, endemic controls was conducted to compare compositions of the fecal microbiome as determined by 16S rRNA sequencing. A blood transcriptome analysis was also performed on a subset of subjects in each group by microarray and the results cross-compared with the same individual's microbiota composition. FINDINGS: MAF participants have distinct microbiomes compared with MTB patients, displaying decreased diversity and increases in Enterobacteriaceae with respect to healthy participants not observed in the latter patient group. Interestingly, this observed elevation in Enterobacteriaceae positively correlated with enhanced inflammatory gene expression in peripheral blood and was reversed after initiation of ATT. INTERPRETATION: Our findings indicate that MAF and MTB have distinct associations with the gut microbiome that may be reflective of the differential susceptibility of West Africans to these two co-endemic infections either as biomarkers or as a contributing determinant.

Association of Mycobacterium africanum Infection with Slower Disease Progression Compared with Mycobacterium tuberculosis in Malian Patients with Tuberculosis.

Mycobacterium africanum (MAF) is known to endemically cause up to 40-50% of all pulmonary TB in West Africa. The aim of this study was to compare MAF with Mycobacterium tuberculosis (MTB) with regard to time from symptom onset to TB diagnosis, and clinical and radiological characteristics. A cross-sectional study was conducted in Bamako, Mali, between August 2014 and July 2016. Seventy-seven newly diagnosed pulmonary TB patients who were naive to treatment were enrolled at Mali's University Clinical Research Center. Sputum cultures were performed to confirm the diagnosis and spoligotyping to identify the mycobacterial strain. Univariate and multivariate analyses were used to identify factors associated with disease progression. Overall, the frequency of female patients was 25% in MAF infection and only 10.0% in MTB infection (OR = 2.9), and MAF was more represented in patients aged ≥ 30 years (57.1% versus 36.7% [OR = 2.3]). More MAF- than MTB-infected patients had a history of a prior TB contact (32.1% versus 14.3% [OR = 2.8]). The mean duration between cough onset and TB diagnosis was 111 days (∼3.7 months) for MAF and 72 days (∼2.4 months) for MTB (P = 0.007). In a multivariate regression, weight loss (body mass index [BMI] < 18.5 kg/m2) and cough duration (> 4 months) were strongly associated with MAF infection (OR = 5.20 [1.49-18.26], P = 0.010, and 4.74 [1.2-18.58], P = 0.02), respectively. Our data show that MAF infection was significantly associated with lower BMI and a longer time between symptom onset and TB diagnosis than MTB. This supports the concept that MAF infection may have slower disease progression and less severe cough symptoms than MTB.

Use of sodium dodecyl sulfate to improve tuberculosis sputum smear microscopy.

Sputum smear microscopy (SSM), the most widely available tool for tuberculosis (TB) detection, has limited performance in paucibacillary patients and requires highly experienced technicians. The objective of this study was to determine whether the addition of sodium dodecyl sulfate (SDS), a detergent that thins sputum, at 4% and 10%, improves the detection of acid-fast bacilli (AFB), the clarity of slides, and the biosafety of the technique. Thirty participants with presumptive TB were enrolled. Three independent, blinded technicians examined the slides. Regular sputum concentrated AFB smear and sputum culture were used as standard control methods. Sputum culture was also performed before and after 10% SDS addition for safety analysis. We found that neither SSM with SDS 4% nor SSM with SDS 10% improved the test's performance. However, slides with 4% and 10% SDS, compared with slides prepared without SDS, had significantly better clarity scores. The 10% SDS-prepared sputum samples were all culture negative. While adding SDS detergent does not improve the performance of SSM slides, it does improve the clarity and biosafety. Where experienced technicians are scarce, especially in low resource settings, use of SDS may enhance the ease of slide reading in sputum smear microscopy.

Clinical risk factors associated with multidrug-resistant tuberculosis (MDR-TB) in Mali.

BACKGROUND: MDR-TB is a major threat to global TB control. In 2015, 580,000 were treated for MDR-TB worldwide. The worldwide roll-out of GeneXpert MTB/RIF® has improved diagnosis of MDR-TB; however, in many countries laboratories are unable to assess drug resistance and clinical predictors of MDR-TB could help target suspected patients. In this study, we aimed to determine the clinical factors associated with MDR-TB in Bamako, Mali. METHODS: We performed a cross-sectional study of 214 patients with presumed MDR-TB admitted to University of Bamako Teaching Hospital, Point-G between 2007 and 2016. We calculated crude and adjusted odds ratios for MDR-TB disease diagnosis using SPSS. RESULTS: We found that age ≤40years (OR=2.56. 95% CI: 1.44-4.55), two courses of prior TB treatment (OR=3.25, 95% CI: 1.44-7.30), TB treatment failure (OR=3.82, 95% CI 1.82-7.79), sputum microscopy with 3+ bacilli load (OR=1.98, 95% CI: 1.13-3.48) and a history of contact with a TB patient (OR=2.48, 95% CI: 1.11-5.50) were significantly associated with confirmation of MDR-TB disease. HIV was not a risk factor for MDR-TB (aOR=0.88, 95% CI: 0.34-1.94). CONCLUSION: We identified several risk factors that could be used to identify MDR-TB suspects and prioritize them for laboratory confirmation. Prospective studies are needed to understand factors associated with TB incidence and clinical outcomes of TB treatment and disease.

Diagnostic Performances of Three Rapid Diagnostic Tests for Detecting HIV Infections in Mali.

Diagnosis of HIV infections in resource-limited countries like Mali is based on Rapid Diagnostic Tests (RDTs). The RDTs are diagnostic assays designed for use at the Point-Of-Care (POC), which is quick, cost-effective and easy to perform. However, in these countries, the tests are commonly used without any initial evaluation or monitoring of their performance despite high levels of HIV strain diversity and rapid evolution of the virus. In this study, the reliability and accuracy of HIV RDTs (Determine™, Multispot™, SD Bioline™) used in Mali, where HIV-1 and HIV-2 co-exist, were evaluated from August 2004 to November 2017. A total of 1303 samples from new HIV-suspect patients in Bamako were tested for HIV-1 and HIV-2 using the RDT Determine™, followed by ELISA and Western Blot (WB). The Determine™ test showed a robust diagnostic sensitivity of 98.7% [CI 95: 97.59-99.37] and a diagnostic specificity of 99.2% [CI 95: 98.22-99.67]. The Multispot™ assay showed a diagnostic sensitivity of 98.77% [CI 95: 97.59-99.37] and a diagnostic specificity of 99.2% [CI 95: 98.22-99.67]. The diagnostic sensitivity and specificity of SD Bioline™ HIV-1/2 were 100% [CI 95:72.25-100] and 88.89% [CI 95: 56.50- 98.71], respectively. These data indicate excellent performance for HIV RDTs in Mali and we recommend the use of Determine™ HIV-1/2 for HIV screening and Multispot™ for discriminating HIV-2 from HIV-1 infections.

Differential HLA allele frequency in Mycobacterium africanum vs Mycobacterium tuberculosis in Mali.

Tuberculosis (TB) is caused by Mycobacterium tuberculosis complex (MTBC), however, the distribution and frequency of MTBC lineages and sublineages vary in different parts of the globe. Mycobacterium africanum, a member of MTBC is responsible for a large percentage of TB cases in West Africa, however, it is rarely identified outside of this part of the World. Whether or not differential HLA polymorphism (an important host factor) is contributing to the geographic restriction of M. africanum to West Africa is unknown. Here, we conducted a cohort study in Mali of newly diagnosed individuals with active pulmonary TB and normal healthy controls. The MTBC isolates were spoligotyped to determine the TB study groups (M. tuberculosis sensu stricto LAM10 and M. africanum), and HLA typing was performed on peripheral blood. Unlike previous reports on other populations, we found that HLA class-I alleles were significantly associated with active TB disease in this population. HLA-B alleles (B*07:02, B*08:01, B*14:02, B*15:03, B*15:10, B*18:01, B*42:01, B*42:02, B*51:01 and B*81:01) were significantly associated with M. africanum (40%-45%) and M. tuberculosis (75%) compared with healthy controls. Many HLA-A alleles (A*02:05, A*34:02, A*66:01 and A*68:02) were also associated with both TB groups (65%-70%). However, many class II HLA-DR variants were found to be associated with M. tuberculosis but not M. africanum with the exception of the DRB1*03:01, which was associated with both groups. The differential HLA distribution observed in this study might be at least partially responsible for the geographical restriction of M. africanum infections to West Africa.

The most frequent Mycobacterium tuberculosis complex families in mali (2006-2016) based on spoligotyping.

BACKGROUND: To identify strains of Mycobacterium tuberculosis complex (MTBc) circulating in Bamako region during the past 10 years. METHODS: From 2006 to 2016, we conducted a cross-sectional study to identify with spoligotyping, clinical isolates from tuberculosis (TB)-infected patients at different stages of their treatments in Bamako, Mali. RESULTS: Among the 904 suspected TB patients included in the study and thereafter tested in our BSL-3 laboratory, 492 (54.4%) had MTBc and therefore underwent spoligotyping. Overall, three subspecies, i.e., MTB T1 (31.9%) and MTB LAM10 (15.3%) from lineage 4 and M. africanum 2 (16.8%) from lineage 6 were the leading causes of TB in Bamako region during the past 10 years. Other spoligotypes such as MTB T3, MTB Haarlem 2, MTB EAI3, and MTB family 33 were also commonly seen from 2010 to 2016. CONCLUSION: This study showed a high genetic diversity of strains isolated in Bamako region and highlights that M. tuberculosis T1 strain was the most prevalent. Furthermore, the data indicate an increasing proportion of primary drug resistance overtime in Bamako.