Is Africa part of the partnership?

This essay presents an African perspective on medical research partnerships done in Africa. While African institutions have a long history of establishing research partnerships with Western institutions it is important to assess how they have been contributing to this relationship. After describing how partnerships are established and how they currently function for many institutions, I discuss how mutual and antagonistic interests can affect those global health relationships that finish in ‘divorce’. I end with defining the place of Africa in its partnerships with Western institutions in medical research, and argue for a new mind-set that would bolster African ownership and funding of research done in Africa

Evaluation of the modified colorimetric resazurin microtiter plate-based antibacterial assay for rapid and reliable tuberculosis drug susceptibility testing

Background: The resazurin microtiter assay (classic REMA), a colorimetric liquid culture-based drug susceptibility assay for Mycobacterium tuberculosis (MTB), has been endorsed by the World Health Organization. The assay requires 8-16 days to obtain results, delaying management of drug resistant tuberculosis patients. A modified REMA which allows results in as little as 24 hours for bacterial strains, has been developed and validated using Staphylococcus aureus, but has not yet been evaluated for MTB. Therefore we assessed the performance of the modified REMA for rifampicin (RIF) and isoniazid (INH) susceptibility, using the classic REMA as the reference standard. We also compared simplicity (from the technicians’ point of view), time taken to obtain results (rank-sum testing), specificity and Kappa statistics of the two methods. Results: The modified REMA, which is a one-step procedure, was found to be simpler to perform and results were obtained in a significantly shorter time (5 versus 9 days, p < 0.0001) compared to the classic REMA due to addition of indicator and strain at the same time. The specificity of the modified REMA was low {46.8% (35.5% - 58.4%) for RIF and 13.9% (7.2% - 23.5%) for INH}. Kappa statistics were 16.0% for RIF and 2.0% for INH. Low specificity and kappa statistics are due to indicator reduction by the strains before complete drug activity. Conclusion: Although modified REMA is faster and simpler compared to classic REMA, it is not reliable for MTB drug susceptibility testing

Antibiotic-Resistant Profiles of Bacteria Isolated from Cesarean and Surgical Patients from Kasese District Hospitals Western Uganda

Surgical site infections (SSIs) are challenging to treat and often associated with much higher extended stays, morbidity, and mortality, higher treatment costs, especially when the causative agent is multidrug resistance (MDR). This study was designed to determine the prevalence of nosocomial infections and susceptibility profiles of bacteria isolated from Cesarean section (C-section) and surgical patients from Kasese District Hospitals in Western Uganda. A descriptive cross-sectional study was conducted from January to September 2016 involving 303 patients with SSIs in obstetrics &amp; gynecology; and general surgery wards in three health facilities. Clinical-demographic characteristics of patients were obtained using structured questionnaires before surgery. Bacterial analysis of the air and floor of the theatre room was done using the standard culture method. Of the 303 patients enrolled with SSIs (median age 34 years), 71.6% were female, and 28.4% were males. Only 14.5% developed SSIs, with predominant isolates being Staphylococcus aureus&nbsp;33.33% and Escherichia coli 24%. The majority of recruited participants underwent a C-section of 58% and the least amputations of 0.3%. Duration of operation or surgery, p-value 0.002 (95% CI 1.599-7.667) was significantly associated with SSIs. Gram-negative bacteria were found resistant (50-100%) to ampicillin, gentamycin, and ciprofloxacin, the commonly used post-operative drugs of choice. Hospital-acquired infections were common with emerging antibiotic-resistant strains isolated in most SSIs at Kasese hospitals. The development of resistance to commonly used antibiotics such as ampicillin, gentamycin, and ciprofloxacin than previously reported calls for laboratory-guided SSIs therapy and strengthening infection control policies

Evaluation of the SD Bioline TB Ag MPT64 test for identification of <i>Mycobacterium tuberculosis</i> complex from liquid cultures in Southwestern Uganda

Background: To confirm presence of Mycobacterium tuberculosis complex, some tuberculosis culture laboratories still rely on para-nitrobenzoic acid (PNB), a traditional technique that requires sub-culturing of clinical isolates and two to three weeks to give results. Rapid identification tests have improved turnaround times for mycobacterial culture results. Considering the challenges of the PNB method, we assessed the performance of the SD Bioline TB Ag MPT64 assay by using PNB as gold standard to detect M. tuberculosis complex from acid-fast bacilli (AFB) positive cultures. Objectives: The aim of this study was to determine the sensitivity, specificity and turnaround time of the SD MPT64 assay for identification of M. tuberculosis complex, in a setting with high prevalence of tuberculosis and HIV. Methods: A convenience sample of 690 patients, with tuberculosis symptoms, was enrolled at Epicentre Mbarara Research Centre between April 2010 and June 2011. The samples were decontaminated using NALC-NaOH and re-suspended sediments inoculated in Mycobacterium Growth Indicator Tubes (MGIT) media, then incubated at 37 °C for a maximum of eight weeks. A random sample of 50 known negative cultures and 50 non-tuberculous mycobacteria isolates were tested for specificity, while sensitivity was based on AFB positivity. The time required from positive culture to reporting of results was also assessed with PNB used as the gold standard. Results: Of the 138 cultures that were AFB-positive, the sensitivity of the SD MPT64 assay was 100.0% [95% CI: 97.3 – 100] and specificity was 100.0% (95% CI, 96.4 – 100). The median time from a specimen receipt to confirmation of strain was 10 days [IQR: 8–12] with SD MPT64 and 24 days [IQR: 22–26] with PNB. Conclusion: The SD MPT64 assay is comparable to PNB for identification of M. tuberculosis complex and reduces the time to detection

Sociocultural and Structural Factors Contributing to Delays in Treatment for Children with Severe Malaria: A Qualitative Study in Southwestern Uganda

Malaria is a leading cause of pediatric mortality, and Uganda has among the highest incidences in the world. Increased morbidity and mortality are associated with delays to care. This qualitative study sought to characterize barriers to prompt allopathic care for children hospitalized with severe malaria in the endemic region of southwestern Uganda. Minimally structured, qualitative interviews were conducted with guardians of children admitted to a regional hospital with severe malaria. Using an inductive and content analytic approach, transcripts were analyzed to identify and define categories that explain delayed care. These categories represented two broad themes: sociocultural and structural factors. Sociocultural factors were 1) interviewee's distinctions of “traditional” versus “hospital” illnesses, which were mutually exclusive and 2) generational conflict, where deference to one's elders, who recommended traditional medicine, was expected. Structural factors were 1) inadequate distribution of health-care resources, 2) impoverishment limiting escalation of care, and 3) financial impact of illness on household economies. These factors perpetuate a cycle of illness, debt, and poverty consistent with a model of structural violence. Our findings inform a number of potential interventions that could alleviate the burden of this preventable, but often fatal, illness. Such interventions could be beneficial in similarly endemic, low-resource settings

Low Resistance to First and Second Line Anti-Tuberculosis Drugs among Treatment Naive Pulmonary Tuberculosis Patients in Southwestern Uganda

Background: There are limited data on region-specific drug susceptibility of tuberculosis (TB) in Uganda. We performed resistance testing on specimens collected from treatment-naive patients with pulmonary TB in Southwestern Uganda for first and second line anti-TB drugs. We sought to provide data to guide regional recommendations for empiric TB therapy. Methods: Archived isolates, obtained from patients at Mbarara Regional Referral Hospital from February 2009 to February 2013, were tested for resistance to isoniazid and rifampicin using the MTBDRplus and Xpert MTB/RIF assays. A subset of randomly selected isolates was tested for second line agents, including fluoroquinolones (FQs), aminoglycosides, cyclic peptides, and ethambutol using the MTBDRsl assay. We performed confirmatory testing for FQ resistance using repeated MTBDRsl, the Mycobacteria growth indicator tube (MGIT) assay, and sequencing of the gyrA and gyrB genes. Results: We tested isolates from 190 patients. The cohort had a median age of 33 years (IQR 26-43), 69% (131/190) were male, and the HIV prevalence was 42% (80/190). No isolates (0/190) were rifampicin-resistant and only 1/190 (0.5%) was isoniazid-resistant. Among 92 isolates tested for second-line drug resistance, 71 (77%) had interpretable results, of which none were resistant to aminoglycosides, cyclic peptides or ethambutol. Although 7 (10%) initially tested as resistant to FQs by the MTBDRsl assay, they were confirmed as susceptible by repeat MTBDRsl testing as well as by MGIT and gyrase gene sequencing Conclusion: We found no MDR-TB and no resistance to ethambutol, FQs, or injectable anti-TB drugs in treatment naïve patients with pulmonary TB in Southwestern Uganda. Standard treatment guidelines for susceptible TB should be adequate for most patients with TB in this population. Where possible, molecular susceptibility testing methods should be routinely validated by culture methods

CD4 Count at ART Initiation and Economic Restoration in Rural Uganda

To determine whether earlier initiation of antiretroviral therapy (ART) is associated with better economic outcomes

Inhaled Nitric Oxide as an Adjunctive Treatment for Cerebral Malaria in Children: A Phase II Randomized Open-Label Clinical Trial

Background. Children with cerebral malaria (CM) have high rates of mortality and neurologic sequelae. Nitric oxide (NO) metabolite levels in plasma and urine are reduced in CM. Methods. This randomized trial assessed the efficacy of inhaled NO versus nitrogen (N2) as an adjunctive treatment for CM patients receiving intravenous artesunate.We hypothesized that patients treated with NO would have a greater increase of the malaria biomarker, plasma angiopoietin-1 (Ang-1) after 48 hours of treatment. Results. Ninety-two children with CM were randomized to receive either inhaled 80 part per million NO or N2 for 48 or more hours. Plasma Ang-1 levels increased in both treatment groups, but there was no difference between the groups at 48 hours (P = not significant [NS]). Plasma Ang-2 and cytokine levels (tumor necrosis factor-α, interferon- γ, interleukin [IL]-1β, IL-6, IL-10, and monocyte chemoattractant protein-1) decreased between inclusion and 48 hours in both treatment groups, but there was no difference between the groups (P = NS). Nitric oxide metabolite levels—blood methemoglobin and plasma nitrate—increased in patients treated with NO (both P \u3c .05). Seven patients in the N2 group and 4 patients in the NO group died. Five patients in the N2 group and 6 in the NO group had neurological sequelae at hospital discharge. Conclusions. Breathing NO as an adjunctive treatment for CM for a minimum of 48 hours was safe, increased blood methemoglobin and plasma nitrate levels, but did not result in a greater increase of plasma Ang-1 levels at 48 hours

Étudedu mécanisme catalytique de la thymidylate synthase ThyX de Chlamydia trachomatis et découverte d'inhibiteurs des ThyX par criblage aléatoire de banques de petites molécules

Les thymidylates synthases ThyA et ThyX sont responsables de la formation du thymidylate (dTMP), un précurseur essentiel à la synthèse de l ADN. Ces deux enzymes diffèrent au niveau de leur séquence, de leur structure et de leur mécanisme. ThyX est absente chez l Homme mais présente chez un grand nombre de bactéries pathogènes pour l Homme telles que, Helicobacter pylori, Mycobacterium tuberculosis et Chlamydia trachomatis. Ces différences ont fait de ThyX une cible thérapeutique prioritaire, validée par l OMS dans la recherche de nouveaux antimicrobiens pour la lutte contre la tuberculose. ThyA est active sous la forme de dimère, tandis que ThyX est proposée comme étant active sous la forme de tétramère. Elles diffèrent également au niveau de leur mécanisme réactionnel, ThyX est une flavoprotéine et utilise le NADPH comme cofacteur. Bien que le modèle de mécanisme catalytique de type séquentiel soit proposé pour les deux familles d enzyme, le modèle de type ping-pong est proposé pour ThyX de C. trachomatis. L objectif de mon travail était d étudier le mécanisme catalytique de ThyX de C. trachomatis, d évaluer le rôle des résidus conservés dans la famille des ThyX sur l activité catalytique de ThyX de M. tuberculosis, et de découvrir de nouveaux inhibiteurs des ThyX. Les résultats de mes travaux me permettent de proposer que la ThyX de C. trachomatis suit un modèle catalytique de type séquentiel, tel qu il est proposé pour les autres membres de la famille des Thyx. Les analyses réalisées par diffusion de rayon X aux petits angles (SAXS), m ont permis d observer un équilibre en solution entre les formes dimériques, tétramériques et hexamériques de ThyX de C. trachomatis. Ces résultats montrent que ThyX est également active sous la forme de dimère, comme peut l être ThyA. J ai confirmé le rôle essentiel des résidus très conservés du motif thyX dans l activité catalytique de ThyX de M. tuberculosis. Les résultats obtenus ont contribué à l extension de ce motif à la séquence (Y/W)X19-40RHRX7-8SXR(Y/F)X68-114R. L optimisation et la validation des tests permettant de mesurer l activité de ThyX, m ont permis de cribler quatre banques de 2610 molécules sur les ThyX de Paramecium bursaria chlorella virus 1, d H. pylory, de M. tuberculosis, de Borellia hermsei et de C. trachomatis. J ai identifié six molécules qui ont un effet inhibiteur sur la ThyX de ces cinq espèces bactériennes, et n ont aucun effet sur la ThyA humaine. Ces six molécules ont également un effet antimicrobien sur un organisme possédant ThyX (H. pylori), sur un organisme possédant à la fois ThyX et ThyA (M. smegmatis), et n ont aucun effet sur un organisme ne possédant que ThyA (E. coli).Thymidylate synthases, ThyA and ThyX, are enzymes responsible for the formation of the thymidylate (dTMP), an essential precursor in the synthesis of DNA. These two enzymes are different in their sequence, their structure and their mechanism. ThyX is absent in human but present in a large number of human pathogenic bacteria such as: Helicobacter pylory, Microbacterium tuberculosis, C. trachomatis and many others. The differences of mechanism, structure and distribution of these enzymes, made the World Health Organization define the ThyX as a priority therapeutic target in the discovery of new antimicrobial agent against tuberculosis. ThyA is functionally active as a dimer, whereas ThyX is proposed to be a tetramer in its active form. They also differ mechanistically; ThyX is a flavindependent protein and use NADPH as a cofactor, while ThyA de not. Although sequential mechanism model is proposed for both families of enzyme, the ping-pong type model is proposed for Chlamydia trachomatis ThyX. The aim of my work was to study the mechanism of C. trachomatis ThyX, to evaluate the role of residues conserved among this family on the catalytic activity of M. tuberculosis ThyX, and to discover new inhibitors of ThyX. The outcome of my work allows me to propose that ThyX of C. trachomatis follows a catalytic sequential type model, such as the other members of ThyX family. Small angle x-ray scattering (SAXS) analyses allowed me to observe equilibrium in solution between the dimer, tetramer and hexamer form of C. trachomatis ThyX. These results show that ThyX is also active as dimer form like ThyA. I have confirmed the essential role of residues of the ThyX motif in the catalytic activity of tha ThyX of M. tuberculosis. The obtained results contributed to the extension of this ThyX motif to the sequence (Y/W)X19-40RHRX7-8SXR(Y/F)X68-114R. The optimization and validation of the oxidation test and deprotonation test which allow the measurement of ThyX activity, led me to screen four libraries for a total of 2610 compounds against ThyX of Paramecium bursaria chlorella virus 1, M. tuberculosis, Borellia hermsei, and C. trachomatis. I have identified six inhibitors of ThyX activity from these five organisms which also de not inhibit human ThyA. These six molacules also have an antimicrobial effect on a bacteria species possessing ThyX (e.g. H. pylori MIC~1,25-2,5 g/ml), on a bacteria species possessing both ThyX and ThyA (M. smegmatis), and have no effect on a bacteria species possessing ThyA (E. coli).ORSAY-PARIS 11-BU Sciences (914712101) / SudocSudocFranceF