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Biomolecules Jun 2024Incidences of drug-resistant tuberculosis have become common and are rising at an alarming rate. Aminoacyl t-RNA synthetase has been validated as a newer target against...
Incidences of drug-resistant tuberculosis have become common and are rising at an alarming rate. Aminoacyl t-RNA synthetase has been validated as a newer target against . Leucyl t-RNA synthetase (LeuRS) is ubiquitously found in all organisms and regulates transcription, protein synthesis, mitochondrial RNA cleavage, and proofreading of matured t-RNA. Leucyl t-RNA synthetase promotes growth and development and is the key enzyme needed for biofilm formation in Mycobacterium. Inhibition of this enzyme could restrict the growth and development of the mycobacterial population. A database consisting of 2734 drug-like molecules was screened against leucyl t-RNA synthetase enzymes through virtual screening. Based on the docking scores and MMGBSA energy values, the top three compounds were selected for molecular dynamics simulation. The druggable nature of the top three hits was confirmed by predicting their pharmacokinetic parameters. The top three hits-compounds (ZINC000001543916), (ZINC000001554197), and (ZINC000008214483)-were evaluated for their binding affinity toward leucyl t-RNA synthetase by an isothermal titration calorimetry study. The inhibitory activity of these compounds was tested against antimycobacterial activity, biofilm formation, and LeuRS gene expression potential. Compound (Macimorelin) was found to be the most potent molecule, with better antimycobacterial activity, enzyme binding affinity, and significant inhibition of biofilm formation, as well as inhibition of the LeuRS gene expression. Compound , the top hit compound, has the potential to be used as a lead to develop successful leucyl t-RNA synthetase inhibitors.
Topics: Mycobacterium tuberculosis; Ligands; Antitubercular Agents; Leucine-tRNA Ligase; Molecular Docking Simulation; Enzyme Inhibitors; Calorimetry; Molecular Dynamics Simulation; Tuberculosis; Computer Simulation; Protein Binding; Humans
PubMed: 38927114
DOI: 10.3390/biom14060711 -
Scientific Reports Jun 2024Dental calculus is a microbial biofilm that contains biomolecules from oral commensals and pathogens, including those potentially related to cause of death (CoD). To...
Dental calculus is a microbial biofilm that contains biomolecules from oral commensals and pathogens, including those potentially related to cause of death (CoD). To assess the utility of calculus as a diagnostically informative substrate, in conjunction with paleopathological analysis, calculus samples from 39 individuals in the Smithsonian Institution's Robert J. Terry Collection with CoDs of either syphilis or tuberculosis were assessed via shotgun metagenomic sequencing for the presence of Treponema pallidum subsp. pallidum and Mycobacterium tuberculosis complex (MTBC) DNA. Paleopathological analysis revealed that frequencies of skeletal lesions associated with these diseases were partially inconsistent with diagnostic criteria. Although recovery of T. p. pallidum DNA from individuals with a syphilis CoD was elusive, MTBC DNA was identified in at least one individual with a tuberculosis CoD. The authenticity of MTBC DNA was confirmed using targeted quantitative PCR assays, MTBC genome enrichment, and in silico bioinformatic analyses; however, the lineage of the MTBC strain present could not be determined. Overall, our study highlights the utility of dental calculus for molecular detection of tuberculosis in the archaeological record and underscores the effect of museum preparation techniques and extensive handling on pathogen DNA preservation in skeletal collections.
Topics: Dental Calculus; Humans; Metagenomics; Paleopathology; Tuberculosis; Mycobacterium tuberculosis; DNA, Bacterial; Male; Treponema pallidum; Syphilis; Female; Adult; Metagenome; Middle Aged
PubMed: 38926415
DOI: 10.1038/s41598-024-64818-7 -
JMIR Public Health and Surveillance Jun 2024Finding individuals with drug-resistant tuberculosis (DR-TB) is important to control the pandemic and improve patient clinical outcomes. To our knowledge, systematic... (Review)
Review
BACKGROUND
Finding individuals with drug-resistant tuberculosis (DR-TB) is important to control the pandemic and improve patient clinical outcomes. To our knowledge, systematic reviews assessing the effectiveness, cost-effectiveness, acceptability, and feasibility of different DR-TB case-finding strategies to inform research, policy, and practice, have not been conducted and the scope of primary research is unknown.
OBJECTIVE
We therefore assessed the available literature on DR-TB case-finding strategies.
METHODS
We looked at systematic reviews, trials, qualitative studies, diagnostic test accuracy studies, and other primary research that sought to improve DR-TB case detection specifically. We excluded studies that included patients seeking care for tuberculosis (TB) symptoms, patients already diagnosed with TB, or were laboratory-based. We searched the academic databases of MEDLINE, Embase, The Cochrane Library, Africa-Wide Information, CINAHL (Cumulated Index to Nursing and Allied Health Literature), Epistemonikos, and PROSPERO (The International Prospective Register of Systematic Reviews) using no language or date restrictions. We screened titles, abstracts, and full-text articles in duplicate. Data extraction and analyses were carried out in Excel (Microsoft Corp).
RESULTS
We screened 3646 titles and abstracts and 236 full-text articles. We identified 6 systematic reviews and 61 primary studies. Five reviews described the yield of contact investigation and focused on household contacts, airline contacts, comparison between drug-susceptible tuberculosis and DR-TB contacts, and concordance of DR-TB profiles between index cases and contacts. One review compared universal versus selective drug resistance testing. Primary studies described (1) 34 contact investigations, (2) 17 outbreak investigations, (3) 3 airline contact investigations, (4) 5 epidemiological analyses, (5) 1 public-private partnership program, and (6) an e-registry program. Primary studies were all descriptive and included cross-sectional and retrospective reviews of program data. No trials were identified. Data extraction from contact investigations was difficult due to incomplete reporting of relevant information.
CONCLUSIONS
Existing descriptive reviews can be updated, but there is a dearth of knowledge on the effectiveness, cost-effectiveness, acceptability, and feasibility of DR-TB case-finding strategies to inform policy and practice. There is also a need for standardization of terminology, design, and reporting of DR-TB case-finding studies.
Topics: Humans; Tuberculosis, Multidrug-Resistant
PubMed: 38924777
DOI: 10.2196/46137 -
ELife Jun 2024During tuberculosis (TB), migration of dendritic cells (DCs) from the site of infection to the draining lymph nodes is known to be impaired, hindering the rapid...
During tuberculosis (TB), migration of dendritic cells (DCs) from the site of infection to the draining lymph nodes is known to be impaired, hindering the rapid development of protective T-cell-mediated immunity. However, the mechanisms involved in the delayed migration of DCs during TB are still poorly defined. Here, we found that infection of DCs with (Mtb) triggers HIF1A-mediated aerobic glycolysis in a TLR2-dependent manner, and that this metabolic profile is essential for DC migration. In particular, the lactate dehydrogenase inhibitor oxamate and the HIF1A inhibitor PX-478 abrogated Mtb-induced DC migration in vitro to the lymphoid tissue-specific chemokine CCL21, and in vivo to lymph nodes in mice. Strikingly, we found that although monocytes from TB patients are inherently biased toward glycolysis metabolism, they differentiate into poorly glycolytic and poorly migratory DCs compared with healthy subjects. Taken together, these data suggest that because of their preexisting glycolytic state, circulating monocytes from TB patients are refractory to differentiation into migratory DCs, which may explain the delayed migration of these cells during the disease and opens avenues for host-directed therapies for TB.
Topics: Dendritic Cells; Glycolysis; Monocytes; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Mycobacterium tuberculosis; Cell Movement; Animals; Tuberculosis; Mice; Toll-Like Receptor 2; Mice, Inbred C57BL; Female
PubMed: 38922679
DOI: 10.7554/eLife.89319 -
Toxins May 2024Diphtheria toxin (DT) is the main virulence factor of and Moreover, new species with the potential to produce diphtheria toxin have also been described. Therefore,... (Review)
Review
Diphtheria toxin (DT) is the main virulence factor of and Moreover, new species with the potential to produce diphtheria toxin have also been described. Therefore, the detection of the toxin is the most important test in the microbiological diagnosis of diphtheria and other corynebacteria infections. Since the first demonstration in 1888 that DT is a major virulence factor of , responsible for the systemic manifestation of the disease, various methods for DT detection have been developed, but the diagnostic usefulness of most of them has not been confirmed on a sufficiently large group of samples. Despite substantial progress in the science and diagnostics of infectious diseases, the Elek test is still the basic recommended diagnostic test for DT detection. The challenge here is the poor availability of an antitoxin and declining experience even in reference laboratories due to the low prevalence of diphtheria in developed countries. However, recent and very promising assays have been developed with the potential for use as rapid point-of-care testing (POCT), such as ICS and LFIA for toxin detection, LAMP for gene detection, and biosensors for both.
Topics: Diphtheria Toxin; Humans; Diphtheria; Corynebacterium; Corynebacterium diphtheriae
PubMed: 38922140
DOI: 10.3390/toxins16060245 -
Globalization and Health Jun 2024The Global Drug Facility (GDF) of the Stop TB Partnership was launched in 2001 with the goal of increasing access to quality-assured tuberculosis (TB) drugs and...
BACKGROUND
The Global Drug Facility (GDF) of the Stop TB Partnership was launched in 2001 with the goal of increasing access to quality-assured tuberculosis (TB) drugs and products. We aimed to describe the TB drugs and prices available from the GDF over time and to assess trends.
METHODS
We searched the internet, including an internet archive, for past and recent GDF Product Catalogs and extracted the listed TB drugs and prices. We calculated the lowest price for the most common drug formulations assuming drugs with similar active pharmaceutical ingredients (APIs) are substitutes for each other. We assessed time trends in the TB drugs and prices offered by the GDF in univariable regressions over the longest possible period.
RESULTS
We identified 43 different GDF Product Catalogs published between November 2001 and May 2024. These product catalogs included 122 single medicines (31 APIs), 28 fixed-dose combinations (9 API combinations), and 8 patient kits (8 API regimens and other materials). The number of TB drugs listed in the GDF Product Catalog increased from 9 (8 APIs) to 55 (32 APIs). The price decreased for 17, increased for 19, and showed no trend for 12 APIs. The price of 15 (53.6%) of 28 APIs used against drug-resistant TB decreased, including the price of drugs used in new treatment regimens. The decreasing price trend was strongest for linezolid (-16.60 [95% CI: -26.35 to -6.85] percentage points [pp] per year), bedaquiline (-12.61 [95% CI: -18.00 to -7.22] pp per year), cycloserine (-11.20 [95% CI: -17.40 to -4.99] pp per year), pretomanid (-10.47 [95% CI: -15.06 to -5.89] pp per year), and rifapentine (-10.46 [95% CI: -12.86 to -8.06] pp per year). The prices of 16 (61.5%) of 23 APIs for standard drug-susceptible TB treatment increased, including rifampicin (23.70 [95% CI: 18.48 to 28.92] pp per year), isoniazid (20.95 [95% CI: 18.96 to 22.95] pp per year), ethambutol (9.85 [95% CI: 8.83 to 10.88] pp per year), and fixed-dose combinations thereof.
CONCLUSIONS
The number of TB drugs available from the GDF has substantially increased during its first 23 years of operation. The prices of most APIs for new TB treatments decreased or remained stable. The prices of most APIs for standard drug-sensitive TB treatment increased.
Topics: Humans; Antitubercular Agents; Drug Costs; Tuberculosis; Global Health
PubMed: 38918859
DOI: 10.1186/s12992-024-01047-7 -
Journal of Orthopaedic Surgery and... Jun 2024Tuberculosis (TB) is one of the top ten causes of death worldwide, with approximately 10 million cases annually. Focus has been on pulmonary TB, while extrapulmonary TB... (Comparative Study)
Comparative Study
Comparing gene expression profiles of adults with isolated spinal tuberculosis to disseminated spinal tuberculosis identified by FDG-PET/CT at time of diagnosis, 6- and 12-months follow-up: classifying clinical stages of spinal tuberculosis and monitoring treatment response (Spinal TB X cohort...
BACKGROUND
Tuberculosis (TB) is one of the top ten causes of death worldwide, with approximately 10 million cases annually. Focus has been on pulmonary TB, while extrapulmonary TB (EPTB) has received little attention. Diagnosis of EPTB remains challenging due to the invasive procedures required for sample collection. Spinal TB (STB) accounts for 10% of EPTB and often leads to lifelong debilitating disease due to devastating spinal deformation and compression of neural structures. Little is known about the extent of disease, although both isolated STB and a disseminated form of STB have been described. In our Spinal TB X cohort study, we aim to describe the clinical phenotype of STB using whole-body FDG-PET/CT, identify a specific gene expression profile for different stages of dissemination and compare findings to previously described gene expression signatures for latent and active pulmonary TB.
METHODS
A single-centre, prospective cohort study will be established to describe the distributional pattern of STB detected by whole-body FDG-PET/CT and gene expression profile of patients with suspected STB on magnetic resonance imaging (MRI) at point of diagnosis, six months, and 12 months. Blood biobanking will be performed at these time points. Specimens for microbiology will be obtained from sputum/urine, from easily accessible sites of disease (e.g., lymph nodes, abscess) identified in the first FDG-PET/CT, from CT-guided biopsy and/or surgery. Clinical parameters and functional scores will be collected at every physical visit. Data will be entered into RedCap® database; data cleaning, validation and analysis will be performed by the study team. The University of Cape Town Ethics Committee approved the protocol (243/2022).
DISCUSSION
The Spinal TB X cohort study is the first prospective cohort study using whole-body 18FDG-PET/CT scans in patients with microbiologically confirmed spinal tuberculosis. Dual imaging techniques of the spine using FDG-PET/CT and magnetic resonance imaging as well as tissue diagnosis (microbiology and histopathology) will allow us to develop a virtual biopsy model. If successful, a distinct gene-expression profile will aid in blood-based diagnosis (point of care testing) as well as treatment monitoring and would lead to earlier diagnosis of this devastating disease.
TRIAL REGISTRATION
The study has been registered on ClinicalTrials.gov (NCT05610098).
Topics: Humans; Tuberculosis, Spinal; Positron Emission Tomography Computed Tomography; Fluorodeoxyglucose F18; Prospective Studies; Adult; Follow-Up Studies; Cohort Studies; Transcriptome; Time Factors; Treatment Outcome; Male; Radiopharmaceuticals; Gene Expression Profiling; Female
PubMed: 38918806
DOI: 10.1186/s13018-024-04840-7 -
AIDS Research and Therapy Jun 2024Tuberculosis preventive therapy is vital in caring for HIV-positive individuals, as it prevents the progression from latent tuberculosis infection to tuberculosis...
Completion of tuberculosis preventive therapy and associated factors among clients on antiretroviral therapy at Debre Berhan town health facilities, North Shoa Zone, Ethiopia.
BACKGROUND
Tuberculosis preventive therapy is vital in caring for HIV-positive individuals, as it prevents the progression from latent tuberculosis infection to tuberculosis disease. The aim of the study is to assess the completion of tuberculosis preventive therapy and associated factors among clients receiving antiretroviral therapy in Debre Berhan town, Ethiopia, in 2022.
METHOD
Institutional based cross sectional study was conducted. Random sampling methods were used to select both study participants and health facilities. Both bivariate and multivariate logistic regression analyses were performed. P-values less than 0.05 were statistically significant.
RESULT
The study found that, 83% of participants were completed tuberculosis preventive therapy. Completed tuberculosis preventive therapy was associated with no adverse drug events, taking first-line ART, and good ART adherence.
CONCLUSION
According to the Ethiopian ART guidelines, the study found a low completion rate of tuberculosis preventive therapy among HIV-positive clients on antiretroviral therapy. Factors like no adverse drug events, first-line antiretroviral regimen, and good adherence were significantly associated with completing tuberculosis preventive therapy.
Topics: Humans; Ethiopia; Male; Female; Cross-Sectional Studies; Adult; HIV Infections; Tuberculosis; Middle Aged; Medication Adherence; Antitubercular Agents; Young Adult; Anti-HIV Agents; Health Facilities; Adolescent
PubMed: 38918790
DOI: 10.1186/s12981-024-00629-0 -
BMC Public Health Jun 2024Undernutrition increases the risk of TB infection to be active TB, death and relapse of the disease. Undernutrition also disturbs the management process of tuberculosis.... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Undernutrition increases the risk of TB infection to be active TB, death and relapse of the disease. Undernutrition also disturbs the management process of tuberculosis. Therefore, this study aimed to estimate the pooled magnitude and determinants of undernutrition among TB patients in Ethiopia.
METHODS
From August 20, 2022 to January 6, 2023, the research articles were identified via the search engines Google Scholar, Medline, Pub Med, Cochrane Library, and Web of Science. Stata version 14 was used for analysis, along with a standardized data extraction checklist. The Cochrane Q test statistic and I2 statistics were used to determine heterogeneity. A random-effect model was used to assess the extent of undernutrition among TB patients. OR with a 95% CI was used to report the relationship between undernutrition and independent factors. A funnel plot and Egger's test were used to examine publication bias.
RESULTS
A total of 720 research articles were identified via several databases and 21 studies were included in the systematic review and meta-analysis. The pooled magnitude of undernutrition among TB patients was 48.23% (95% CI 42.84, 53.62). The current meta-analysis revealed that patients who had no formal education (OR = 2.11(95%CI: 1.09, 4.06), average monthly income < 1800 ETB (OR = 2.32 (95CI: 1.33, 4.04), unable to work (OR = 2.61(95CI:1.99, 3.43), patients who had eating disorder (OR = 2.73 (95CI: 2.09, 3.56), patients who had intestinal parasite (OR = 3.77 (95CI: 2.39, 5.94), patients of > 5 family size (OR = 3.79 (95CI: 1.06, 14.93), and patients who drank alcohol (OR = 1.47(95CI: 1.06, 2.05) were significantly associated with undernutrition.
CONCLUSION
This meta-analysis examined the high magnitude of undernutrition among TB patients in Ethiopia. Strategic and police-oriented intervention to prevent factors contributing to the problem is mandatory.
Topics: Humans; Ethiopia; Malnutrition; Tuberculosis; Risk Factors
PubMed: 38918733
DOI: 10.1186/s12889-024-19220-3 -
BMC Women's Health Jun 2024Underdiagnosis of female genital tuberculosis (FGTB) often leads to infertility. In this study, we aimed to determine the site and histopathologic patterns of FGTB and...
OBJECTIVE
Underdiagnosis of female genital tuberculosis (FGTB) often leads to infertility. In this study, we aimed to determine the site and histopathologic patterns of FGTB and its correlation with clinical presentation and acid-fast bacilli (AFB) status.
METHODS
A retrospective cross-sectional study was conducted on 122 patients with a histopathological diagnosis of FGTB at the Department of Pathology, College of Health Sciences (CHS), Tikur Anbessa Specialized Hospital (TASH), Addis Ababa University (AAU), from January 1, 2013, to August 30, 2022.
RESULTS
Female genital tuberculosis was found in 0.94% of the gynecology specimens examined. The most common presentations were menstrual disturbance, abdominopelvic pain, and infertility. Among patients with FGTB, 4.6% exhibited misleading clinical and radiologic findings, leading to suspicion of malignancy and subsequent aggressive surgical management. The endometrium was the most frequently affected organ, followed by the fallopian tube, ovary, cervix, and vulva. In the majority of tuberculous endometritis cases (53.3%), histopathology revealed early-stage granulomas. Acid-fast bacilli were found in a significant proportion (42.6%) of FGTB tissues with TB histopathology. The ovary had the highest rate of AFB detection, followed by the fallopian tube, endometrium, and cervix.
CONCLUSION
Female genital tuberculosis should be considered in reproductive-age women presenting with menstrual irregularities, abdominopelvic pain, infertility, or an abdominopelvic mass. The endometrium is commonly affected, displaying early granulomas with low AFB positivity.
Topics: Humans; Female; Tuberculosis, Female Genital; Cross-Sectional Studies; Retrospective Studies; Adult; Ethiopia; Young Adult; Middle Aged; Menstruation Disturbances; Infertility, Female; Endometrium; Adolescent; Cervix Uteri; Pelvic Pain; Fallopian Tubes; Ovary; Abdominal Pain; Vulva; Endometritis
PubMed: 38918726
DOI: 10.1186/s12905-024-03207-8