Search results for: pulmonary tuberculosis

Authors: Vagolu S. Krishna, Shan Zheng, Estharla M. Rekha, Luke W. Guddat, Dharmarajan Sriram

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Tuberculosis (TB) remains a major threat to human health. This due to the fact that current drug treatments are less than optimal as well as the rising occurrence of multi drug-resistant and extensively drug-resistant strains of the etiological agent, Mycobacterium tuberculosis (Mt). Given the wide-spread significance of this disease, we have undertaken a design and evaluation program to discover new anti-TB drug leads. Here, our attention is focused on ketol-acid reductoisomerase (KARI), the second enzyme in the branched-chain amino acid biosynthesis pathway. Importantly, this enzyme is present in bacteria but not in humans, making it an attractive proposition for drug discovery. In the present work, we used high-throughput virtual screening to identify seventeen potential inhibitors of KARI using the Birla Institute of Technology and Science in-house database. Compounds were selected based on high docking scores, which were assigned as the result of favourable interactions between the compound and the active site of KARI. The Ki values for two leads, compounds 14 and 16 are 3.71 and 3.06 µM, respectively for Mt KARI. To assess the mode of binding, 100 ns molecular dynamics simulations for these two compounds in association with Mt KARI were performed and showed that the complex was stable with an average RMSD of less than 2.5 Å for all atoms. Compound 16 showed an MIC of 2.06 ± 0.91 µM and a 1.9 fold logarithmic reduction in the growth of Mt in an infected macrophage model. The two compounds exhibited low toxicity against murine macrophage RAW 264.7 cell lines. Thus, both compounds are promising candidates for development as an anti-TB drug leads.

Keywords: ketol-acid reductoisomerase, macrophage, molecular docking and dynamics, tuberculosis

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Authors: Gina Leisching, Ray-Dean Pietersen, Carel Van Heerden, Paul Van Helden, Ian Wiid, Bienyameen Baker

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The distinguishing factors that characterize the host response to infection with virulent Mycobacterium tuberculosis (M.tb) are largely confounding. We present an infection study with two genetically closely related M.tb strains that have vastly different pathogenic characteristics. The early host response to infection with these detergent-free cultured strains was analyzed through RNAseq in an attempt to provide information on the subtleties which may ultimately contribute to the virulent phenotype. Murine bone marrow-derived macrophages (BMDMs) were infected with either a hyper- (R5527) or hypovirulent (R1507) Beijing M. tuberculosis clinical isolate. RNAseq revealed 69 differentially expressed host genes in BMDMs during comparison of these two transcriptomes. Pathway analysis revealed activation of the stress-induced and growth inhibitory Gadd45 signaling pathway in hypervirulent infected BMDMs. Upstream regulators of interferon activation such as and IRF3 and IRF7 were predicted to be upregulated in hypovirulent-infected BMDMs. Additional analysis of the host immune response through ELISA and qPCR included the use of human THP-1 macrophages where a robust proinflammatory response was observed after infection with the hypervirulent strain. RNAseq revealed two early-response genes (IER3 and SAA3) and two host-defence genes (OASL1 and SLPI) that were significantly upregulated by the hypervirulent strain. The role of these genes under M.tb infection conditions are largely unknown but here we provide validation of their presence with use of qPCR and Western blot. Further analysis into their biological role under infection with virulent M.tb is required.

Keywords: host-response, Mycobacterium tuberculosis, RNAseq, virulence

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Authors: M. F. Abreu, A. I. Aguiar, R. Gaio, R. Duarte

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Background: Prison establishments constitute high-risk environments for the transmission and spread of tuberculosis (TB), given their epidemiological context and the difficulty of implementing preventive and control measures. Guidelines for control and prevention of tuberculosis in prisons have been described as incomplete and heterogeneous internationally, due to several identified obstacles, for example scarcity of human resources and funding of prisoner health services. In Portugal, a protocol was created in 2014 with the aim to define and standardize procedures of detection and prevention of tuberculosis within prisons. Objective: The main objective of this study was to identify and describe barriers to tuberculosis detection in prisons of Porto and Lisbon districts in Portugal. Methods: A cross-sectional study was conducted from 2ⁿᵈ January 2018 till 30ᵗʰ June 2018. Semi-structured questionnaires were applied to health care professionals working in the prisons of the districts of Porto (n=6) and Lisbon (n=8). As inclusion criteria we considered having work experience in the area of tuberculosis (either in diagnosis, treatment, or follow up). The questionnaires were self-administered, in paper format. Descriptive analyses of the questionnaire variables were made using frequencies and median. Afterwards, a hierarchical agglomerative clusters analysis was performed. After obtaining the clusters, the chi-square test was applied to study the association between the variables collected and the clusters. The level of significance considered was 0.05. Results: From the total of 186 health professionals, 139 met the criteria of inclusion and 82 health professionals were interviewed (62,2% of participation). Most were female, nurses, with a median age of 34 years, with term employment contract. From the cluster analysis, two groups were identified with different characteristics and behaviors for the procedures of this protocol. Statistically significant results were found in: elements of cluster 1 (78% of the total participants) work in prisons for a longer time (p=0.003), 45,3% work > 4 years while 50% of the elements of cluster 2 work for less than a year, and more frequently answered they know and apply the procedures of the protocol (p=0.000). Both clusters answered frequently the need of having theoretical-practical training for TB (p=0.000), especially in the areas of diagnosis, treatment and prevention and that there is scarcity of funding to prisoner health services (p=0.000). Regarding procedures for TB screening (periodic and contact screening) and procedures for transferring a prisoner with this disease, cluster 1 also answered more frequently to perform them (p=0.000). They also referred that the material/equipment for TB screening is accessible and available (p=0.000). From this clusters we identified as barriers scarcity of human resources, the need to theoretical-practical training for tuberculosis, inexperience in working in health services prisons and limited knowledge of protocol procedures. Conclusions: The barriers found in this study are the same described internationally. This protocol is mostly being applied in portuguese prisons. The study also showed the need to invest in human and material resources. This investigation bridged gaps in knowledge that could help prison health services optimize the care provided for early detection and adherence of prisoners to treatment of tuberculosis.

Keywords: barriers, health care professionals, prisons, protocol, tuberculosis

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Authors: Helen K. Buteme, Rebecca Axelsson-Robertson, Moses L. Joloba, Henry W. Boom, Gunilla Kallenius, Markus Maeurer

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Background: The Ugandan population is heavily affected by infectious diseases and Human leukocyte antigen (HLA) diversity plays a crucial role in the host-pathogen interaction and affects the rates of disease acquisition and outcome. The identification of HLA class 1 alleles and determining which alleles are associated with tuberculosis (TB) outcomes would help in screening individuals in TB endemic areas for susceptibility to TB and to predict resistance or progression to TB which would inevitably lead to better clinical management of TB. Aims: To be able to determine the HLA class 1 phenotype distribution in a Ugandan TB cohort and to establish the relationship between these phenotypes and active and latent TB. Methods: Blood samples were drawn from 32 HIV negative individuals with active TB and 45 HIV negative individuals with latent MTB infection. DNA was extracted from the blood samples and the DNA samples HLA typed by the polymerase chain reaction-sequence specific primer method. The allelic frequencies were determined by direct count. Results: HLA-A*02, A*01, A*74, A*30, B*15, B*58, C*07, C*03 and C*04 were the dominant phenotypes in this Ugandan cohort. There were differences in the distribution of HLA types between the individuals with active TB and the individuals with LTBI with only HLA-A*03 allele showing a statistically significant difference (p=0.0136). However, after FDR computation the corresponding q-value is above the expected proportion of false discoveries (q-value 0.2176). Key findings: We identified a number of HLA class I alleles in a population from Central Uganda which will enable us to carry out a functional characterization of CD8+ T-cell mediated immune responses to MTB. Our results also suggest that there may be a positive association between the HLA-A*03 allele and TB implying that individuals with the HLA-A*03 allele are at a higher risk of developing active TB.

Keywords: HLA, phenotype, tuberculosis, Uganda

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Authors: Oleg Reva, Ilya Korotetskiy, Marina Lankina, Murat Kulmanov, Aleksandr Ilin

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Molecular docking approaches are widely used for design of new antibiotics and modeling of antibacterial activities of numerous ligands which bind specifically to active centers of indispensable enzymes and/or key signaling proteins of pathogens. Widespread drug resistance among pathogenic microorganisms calls for development of new antibiotics specifically targeting important metabolic and information pathways. A generally recognized problem is that almost all molecular targets have been identified already and it is getting more and more difficult to design innovative antibacterial compounds to combat the drug resistance. A promising way to overcome the drug resistance problem is an induction of reversion of drug resistance by supplementary medicines to improve the efficacy of the conventional antibiotics. In contrast to well established computer-based drug design, modeling of drug resistance reversion still is in its infancy. In this work, we proposed an approach to identification of compensatory genetic variants reducing the fitness cost associated with the acquisition of drug resistance by pathogenic bacteria. The approach was based on an analysis of the population genetic of Mycobacterium tuberculosis and on results of experimental modeling of the drug resistance reversion induced by a new anti-tuberculosis drug FS-1. The latter drug is an iodine-containing nanomolecular complex that passed clinical trials and was admitted as a new medicine against MDR-TB in Kazakhstan. Isolates of M. tuberculosis obtained on different stages of the clinical trials and also from laboratory animals infected with MDR-TB strain were characterized by antibiotic resistance, and their genomes were sequenced by the paired-end Illumina HiSeq 2000 technology. A steady increase in sensitivity to conventional anti-tuberculosis antibiotics in series of isolated treated with FS-1 was registered despite the fact that the canonical drug resistance mutations identified in the genomes of these isolates remained intact. It was hypothesized that the drug resistance phenotype in M. tuberculosis requires an adjustment of activities of many genes to compensate the fitness cost of the drug resistance mutations. FS-1 cased an aggravation of the fitness cost and removal of the drug-resistant variants of M. tuberculosis from the population. This process caused a significant increase in genetic heterogeneity of the Mtb population that was not observed in the positive and negative controls (infected laboratory animals left untreated and treated solely with the antibiotics). A large-scale search for linkage disequilibrium associations between the drug resistance mutations and genetic variants in other genomic loci allowed identification of target proteins, which could be influenced by supplementary drugs to increase the fitness cost of the drug resistance and deprive the drug-resistant bacterial variants of their competitiveness in the population. The approach will be used to improve the efficacy of FS-1 and also for computer-based design of new drugs to combat drug-resistant infections.

Keywords: complete genome sequencing, computational modeling, drug resistance reversion, Mycobacterium tuberculosis

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Authors: Ngabilas Salama

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Background: Indonesia has the 2nd highest number of incidents of tuberculosis (TB). It accounts for 1.020.000 new cases per year, only 30% of which has been reported. To find the lost 70%, a massive active case discovery was conducted through two programs: Ketuk Pintu Layani Dengan Hati (KPLDH) and Kader Juru Pemantau Batuk (Jumantuk cadres), who also plays a role in child TB screening. Methods: Data was collected and analyzed through Tuberculosis Integrated Online System from 2014 to 2017 involving 129 DOTS facility with 86 primary health centers in East Jakarta. Results: East Jakarta consists of 2.900.722 people. KPLDH program started in February 2016 consisting of 84 teams (310 people). Jumantuk cadres was formed 4 months later (218 orang). The number of new TB cases in East Jakarta (primary health center) from 2014 to June 2017 respectively is as follows: 6.499 (2.637), 7.438 (2.651), 8.948 (3.211), 5.701 (1.830). Meanwhile, the percentage of child TB case discovery in primary health center was 8,5%, 9,8%, 12,1% from 2014 to 2016 respectively. In 2017, child TB case discovery was 13,1% for the first 3 months and 16,5% for the next 3 months. Discussion: Increased TB incidence rate from 2014 to 2017 was 14,4%, 20,3%, and 27,4% respectively in East Jakarta, and 0,5%, 21,1%, and 14% in primary health center. This reveals the positive role of KPLDH and Jumantuk in TB detection and reporting. Likewise, these programs were responsible for the increase in child TB case discovery, especially in the first 3 months of 2017 (Ketuk Pintu TB Day program) and the next 3 months (active TB screening). Conclusion: KPLDH dan Jumantuk are actively involved in increasing TB case discovery in both adults and children.

Keywords: tuberculosis, case discovery program, primary health center, cadre

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Authors: G. Wojcik, J. Gindlhuber, A. Syarif, K. Hoetzenecker, P. Bohm, P. Vesely, V. Biasin, G. Kwapiszewska

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Pulmonary fibrosis is a rare disease where uncontrolled wound healing processes damage the lung structure. Intensive changes within the extracellular matrix (ECM) and its interaction with fibroblasts have a major role in pulmonary fibrosis development. Among others, collagen is one of the main components of the ECM, and it is important for lung structure. In IPF, constant production of collagen by fibroblast, through TGFβ1-SMAD2/3 pathways, leads to an uncontrolled deposition of matrix and hence lung remodeling. Abnormal changes in lipid production, alterations in fatty acids (FAs) metabolism, enhanced oxidative stress, and lipid peroxidation in fibrotic lung and fibrotic fibroblasts have been reported; however, the interplay between the collagen and lipids is not yet established. One of the FAs influx regulators is Angiopoietin-like 4 (ANGPTL4), which inhibits lipoprotein lipase work, decreasing the availability of FAs. We hypothesized that altered lipid composition or availability could have the capability to influence the phenotype of different fibroblast populations in the lung and hence influence lung fibrosis. To prove our hypothesis, we aim to investigate lipids and their influence on human, animal, and in vitro levels. In the bleomycin model, treatment with the well-known metabolic drugs Rosiglitazone or Metformin significantly lower collagen production. Similar results were noticed in ANGPTL4 KO animals, where the KO of ANGPTL4 leads to an increase of FAs availability and lower collagen deposition after the bleomycin challenge. Currently, we study the treatment of different FAs on human lung para fibroblasts (hPF) isolated from donors. To understand the lipid composition, we are collecting human lung tissue from donors and pulmonary fibrosis patients for Liquid chromatography-mass spectrometry. In conclusion, our results suggest the lipid influence on collagen deposition during lung fibrosis, but further research needs to be conducted to understand the matter of this relationship.

Keywords: collagen, fibroblasts, lipidomics, lung, pulmonary fibrosis

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Authors: Ishani Das, Avinash Padhi, Sitabja Mukherjee, Santosh Kar, Avinash Sonawane

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Activation of cell mediated and humoral immune responses to Mycobacterium tuberculosis (Mtb) are critical for protection. Herein, we show that mice immunized with Mtb lipid bound chitosan nanoparticles(NPs) induce secretion of prominent Th1 and Th2 cytokines in lymph node and spleen cells, and also induced significantly higher levels of IgG, IgG1, IgG2 and IgM in comparison to control mice measured by ELISA. Furthermore, significantly enhanced γδ-T cell activation was observed in lymph node cells isolated from mice immunized with Mtb lipid coated chitosan-NPs as compared to mice immunized with chitosan-NPs alone or Mtb lipid liposomes through flow cytometric analysis. Also, it was observed that in comparison to CD8+ cells, significantly higher CD4+ cells were present in both the lymph node and spleen cells isolated from mice immunized with Mtb lipid coated chitosan NP. In conclusion, this study represents a promising new strategy for efficient delivery of Mtb lipids using chitosan NPs to trigger enhanced cell mediated and antibody response against Mtb lipids.

Keywords: antibody response, chitosan nanoparticles, cytokines, mycobacterium tuberculosis lipids

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Authors: Md. Samsuddin Ansari, Ashish Arora

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Every year 10 million people fall ill with one of the oldest diseases known as tuberculosis, caused by Mycobacterium tuberculosis. The success of M. tuberculosis as a pathogen is because of its ability to persist in host tissues. Multidrug resistance (MDR) mycobacteria cases increase every day, which is associated with efflux pumps controlled at the level of transcription. The transcription regulators of MDR transporters in bacteria belong to one of the following four regulatory protein families: AraC, MarR, MerR, and TetR. Phenolic acid decarboxylase repressor (PadR), like a family of transcription regulators, is closely related to the MarR family. Phenolic acid decarboxylase repressor (PadR) was first identified as a transcription factor involved in the regulation of phenolic acid stress response in various microorganisms (including Mycobacterium tuberculosis H37Rv). Recently research has shown that the PadR family transcription factors are global, multifunction transcription regulators. Rv0047c is a PadR subfamily-1 protein. We are exploring the biophysical and structural characterization of Rv0047c. The Rv0047 gene was amplified by PCR using the primers containing EcoRI and HindIII restriction enzyme sites cloned in pET-NH6 vector and overexpressed in DH5α and BL21 (λDE3) cells of E. coli following purification with Ni2+-NTA column and size exclusion chromatography. We did DSC to know the thermal stability; the Tm (transition temperature) of protein is 55.29ºC, and ΔH (enthalpy change) of 6.92 kcal/mol. Circular dichroism to know the secondary structure and conformation and fluorescence spectroscopy for tertiary structure study of protein. To understand the effect of pH on the structure, function, and stability of Rv0047c we employed spectroscopy techniques such as circular dichroism, fluorescence, and absorbance measurements in a wide range of pH (from pH-2.0 to pH-12). At low and high pH, it shows drastic changes in the secondary and tertiary structure of the protein. EMSA studies showed the specific binding of Rv0047c with its own 30-bp promoter region. To determine the effect of complex formation on the secondary structure of Rv0047c, we examined the CD spectra of the complex of Rv0047c with promoter DNA of rv0047. The functional role of Rv0047c was characterized by over-expressing the Rv0047c gene under the control of hsp60 promoter in Mycobacterium tuberculosis H37Rv. We have predicted the three-dimensional structure of Rv0047c using the Swiss Model and Modeller, with validity checked by the Ramachandra plot. We did molecular docking of Rv0047c with dnaA, through PatchDock following refinement through FireDock. Through this, it is possible to easily identify the binding hot-stop of the receptor molecule with that of the ligand, the nature of the interface itself, and the conformational change undergone by the protein pattern. We are using X-crystallography to unravel the structure of Rv0047c. Overall the studies show that Rv0047c may have transcription regulation along with providing an insight into the activity of Rv0047c in the pH range of subcellular environment and helps to understand the protein-protein interaction, a novel target to kill dormant bacteria and potential strategy for tuberculosis control.

Keywords: mycobacterium tuberculosis, phenolic acid decarboxylase repressor, Rv0047c, Circular dichroism, fluorescence spectroscopy, docking, protein-protein interaction

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Authors: Rupali Bhatia, Deepthi Nair, Geetika Khanna, Seema Singhal

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Introduction: Genital tract tuberculosis is a chronic disease (caused by reactivation of organisms from systemic distribution of Mycobacterium tuberculosis) that often presents with low grade symptoms and non-specific complaints. Patients with genital tuberculosis are usually young women seeking workup and treatment for infertility. Infertility is the commonest presentation due to involvement of the fallopian tubes, endometrium and ovarian damage with poor ovarian volume and reserve. The diagnosis of genital tuberculosis is difficult because of the fact that it is a silent invader of genital tract. Since tissue cannot be obtained from fallopian tubes, the diagnosis is made by isolation of bacilli from endometrial tissue obtained by endometrial biopsy curettage and/or aspiration. Problems are associated with sampling technique as well as diagnostic modality due to lack of adequate sample volumes and the segregation of the sample for various diagnostic tests resulting in non-uniform distribution of microorganisms. Moreover, lack of an efficient sampling technique universally applicable for all specific diagnostic tests contributes to the diagnostic challenges. Endometrial sampling plays a key role in accurate diagnosis of female genital tuberculosis. It may be done by 2 methods viz. endometrial curettage and endometrial aspiration. Both endometrial curettage and aspirate have their own limitations as curettage picks up strip of the endometrium from one of the walls of the uterine cavity including tubal osteal areas whereas aspirate obtains total tissue with exfoliated cells present in the secretory fluid of the endometrial cavity. Further, sparse and uneven distribution of the bacilli remains a major factor contributing to the limitations of the techniques. The sample that is obtained by either technique is subjected to histopathological examination, AFB staining, culture and PCR. Aim: Comparison of the sampling techniques viz. endometrial biopsy curettage and endometrial aspiration using different laboratory methods of histopathology, cytology, microbiology and molecular biology. Method: In a hospital based observational study, 75 Indian females suspected of genital tuberculosis were selected on the basis of inclusion criteria. The women underwent endometrial tissue sampling using Novaks biopsy curette and Karmans cannula. One part of the specimen obtained was sent in formalin solution for histopathological testing and another part was sent in normal saline for acid fast bacilli smear, culture and polymerase chain reaction. The results so obtained were correlated using coefficient of correlation and chi square test. Result: Concordance of results showed moderate agreement between both the sampling techniques. Among HPE, AFB and PCR, maximum sensitivity was observed for PCR, though the specificity was not as high as other techniques. Conclusion: Statistically no significant difference was observed between the results obtained by the two sampling techniques. Therefore, one may use either EA or EB to obtain endometrial samples and avoid multiple sampling as both the techniques are equally efficient in diagnosing genital tuberculosis by HPE, AFB, culture or PCR.

Keywords: acid fast bacilli (AFB), histopatholgy examination (HPE), polymerase chain reaction (PCR), endometrial biopsy curettage

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Authors: N. Jait, M. Maamar, H. Khibri, H. Harmouche, N. Mouatssim, W. Ammouri, Z. Tazimezaelek, M. Adnaoui

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Introduction: Uveitis presents with inflammation of the uvea, intraocular, of heterogeneous etiology and presentation. The objective of our study is to describe the clinical and therapeutic characteristics of infectious uveitis in HIV+ and HIV- patients. Patients and Methods: This is a retrospective study conducted at the internal medicine department of CHU Ibn Sina in Rabat over a period of 12 years (2010–2021), collecting 42 cases of infectious uveitis. Results: 42 patients were identified. 34% (14 cases) had acquired immunosuppression (9 cases: 22% had HIV infection and 12% were on chemotherapy), and 66% were immunocompetent. The M/F sex ratio was 1.1. The average age was 39 years old. Uveitis revealed HIV in a single case; 8/9 patients have already been followed, their average viral load is 3.4 log and an average CD4 count is 356/mm³. The revealing functional signs were: ocular redness (27%), decreased visual acuity (63%), visual blurring (40%), ocular pain (18%), scotoma (13%), and headaches (4%). The uveitis was site: anterior (30%), intermediate (6%), posterior (32%), and pan-uveitis (32%); unilateral in 80% of patients and bilateral in 20%. The etiologies of uveitis in HIV+ were: 3 cases of CMV, 2 cases of toxoplasmosis, 1 case of tuberculosis, 1 case of HSV, 1 case of VZV, and 1 case of syphilis. Etiologies of immunocompetent patients: tuberculosis (41%), toxoplasmosis (18%), syphilis (15%), CMV infection (4 cases: 10%), HSV infection (4 cases: 10%) , lepromatous uveitis (1 case: 2%), VZV infection (1 case: 2%), a locoregional infectious cause such as dental abscess (1 case: 2%), and one case of borreliosis (3% ). 50% of tuberculous uveitis was of the pan-uveitis type, 75% of the uveitis by toxoplasmosis was of the posterior type. Uveitis was associated with other pathologies in 2 seropositive cases (cerebral vasculitis, multifocal tuberculosis). A specific treatment was prescribed in all patients. The initial evolution was favorable in 67%, including 12% HIV+. 11% presented relapses of the same seat during uveitis of the toxoplasmic, tuberculous and herpetic type. 47% presented complications, of which 4 patients were HIV+: 3 retinal detachments; 7 Retinal hemorrhages. 6 unilateral blindness (including 2 HIV+ patients). Conclusion: In our series, the etiologies of infectious uveitis differ between HIV+ and HIV- patients. In HIV+ patients most often had toxoplasmosis and CMV, while HIV - patients mainly presented with tuberculosis and toxoplasmosis. The association between HIV and uveitis is undetermined, but HIV infection was an independent risk factor for uveitis.

Keywords: uveitis, HIV, immunosuppression, infection

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Authors: Sonam Kumari

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Tuberculosis is the deadliest disease worldwide. Millions of people lose their lives every year due to this disease. It has turned lethal due to the erratic nature of its causative organism, Mycobacterium tuberculosis (Mtb). Mtb tends to enter into an inactive, dormant state and emerge to replicating state upon encountering favorable conditions. The mechanism by which Mtb switches from the dormant state to the replicative form is still poorly characterized. Proteome studies have given us an insight into the role of certain proteins in giving stupendous virulence to Mtb, but numerous dotsremain unconnected and unaccounted. The WhiB family of proteins is one such protein that is associated with developmental processes in actinomycetes. Mtb has seven such proteins (WhiB1 to WhiB7). WhiB proteins are transcriptional regulators; they regulate various essential genes of Mtbby binding to their promoter DNA. Biophysical parameters of the effect of DNA binding on WhiB proteins has not yet been appropriately characterized. Interaction with DNA induces conformational changes in the WhiB proteins, confirmed by steady-state fluorescence and circular dichroism spectroscopy. ITC has deduced thermodynamic parameters and the binding affinity of the interaction. Since these transcription factors are highly unstable in vitro, their stability and solubility were enhanced by the co-expression of molecular chaperones. The present study findings help determine the conditions under which the WhiB proteins interact with their interacting partner and the factors that influence their binding affinity. This is crucial in understanding their role in regulating gene expression in Mtbandin targeting WhiB proteins as a drug target to cure TB.

Keywords: mycobacterium tuberculosis, TB, whiB proteins, ITC

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Authors: Kriti Upadhyay, Ashraf Ali, Puja Sohal, Randeep Guleria

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Background: In Chronic Obstructive Pulmonary diseases (COPD) pathogenesis oxidative stress plays an important role. Hypoxia-Inducible factor (HIF-1α) is a dimeric protein complex which Functions as a master transcriptional regulator of the adaptive response to hypoxiaand is a risk factor that increases when oxidative stress triggers. The role ofHIF-1αin COPD due to smoking is lacking. Aim: This study aims to evaluate the role of HIF-1α in smoker COPD patients comparing its association with diseases severity. Method: In this cross-sectional study, we recruited 87 subjects, 57 were smokers with COPD,15 were smokers without COPD and other 15 were non-smoker healthy controls. The mean age was 54.6± 9.32 (cases 57.08±8.15; controls 50.0± 9.8). There were 62%smokers, 25% non-smokers,7% tobacco chewers and 6% ex-smokers. Enzyme-linked immune sorbent assay (ELISA) method was used for analyzing serum samples wherein HIF-1α was analyzed by Sandwich-ELISA. Results: In smoker COPD patients, a significantly higher HIF-1α level showed positive association with hypoxia, smoking status and severity of disease (p=0.03). The mean value of HIF-1α was not significantly different in smokers without COPD and healthy controls. Conclusion: It is found that HIF-1α level was increased in smoker COPD, but not in smokers without COPD. This suggests that development of COPD drive the HIF-1α pathway and it correlates with the severity of diseases.

Keywords: COPD, chronic obstructive pulmonary diseases, smokers, nonsmokers, hypoxia

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Authors: Vasundhara Arora, Anupam Jhobta, Suresh Thakur, Sanjiv Sharma

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Aims and Objectives: Intracranial tuberculosis (TB) is one of the most devastating manifestations of TB and a challenging public health issue of considerable importance and magnitude world over. This study elaborates on the imaging spectrum of neurotuberculosis on magnetic resonance imaging (MRI) in 29 clinically suspected cases from a tertiary care hospital. Materials and Methods: The prospective hospital based evaluation of MR imaging features of neuro-tuberculosis in 29 clinically suspected cases was carried out in Department of Radio-diagnosis, Indira Gandhi Medical Hospital from July 2017 to August 2018. MR Images were obtained on a 1.5 T Magnetom Avanto machine and were analyzed to identify any abnormal meningeal enhancement or parenchymal lesions. Microbiological and Biochemical CSF analysis was performed in radio-logically suspected cases and the results were compared with the imaging data. Clinical follow up of the patients started on anti-tuberculous treatment was done to evaluate the response to treatment and clinical outcome. Results: Age range of patients in the study was between 1 year to 73 years. The mean age of presentation was 11.5 years. No significant difference in the distribution of cerebral tuberculosis was noted among the two genders. Imaging findings of neuro-tuberculosis obtained were varied and non specific ranging from lepto-meningeal enhancement, cerebritis to space occupying lesions such as tuberculomas and tubercular abscesses. Complications presenting as hydrocephalus (n= 7) and infarcts (n=9) was noted in few of these patients. 29 patients showed radiological suspicion of CNS tuberculosis with meningitis alone observed in 11 cases, tuberculomas alone were observed in 4 cases, meningitis with parenchymal tuberculomas in 11 cases. Tubercular abscess and cerebritis were observed in one case each. Tuberculous arachnoiditis was noted in one patient. Gene expert positivity was obtained in 11 out of 29 radiologically suspected patients; none of the patients showed culture positivity. Meningeal form of the disease alone showed higher positivity rate of gene Xpert (n=5) followed by combination of meningeal and parenchymal forms of disease (n=4). The parenchymal manifestation of disease alone showed least positivity rates (n= 3) with gene xpert testing. All 29 patients were started on anti tubercular treatment based on radiological suspicion of the disease with clinical improvement observed in 27 treated patients. Conclusions: In our study, higher incidence of neuro- tuberculosis was noted in paediatric population with predominance of the meningeal form of the disease. Gene Xpert positivity obtained was low due to paucibacillary nature of cerebrospinal fluid (CSF) with even lower positivity of CSF samples in parenchymal form of the manifestation. MRI showed high accuracy in detecting CNS lesions in neuro-tuberculosis. Hence, it can be concluded that MRI plays a crucial role in the diagnosis because of its inherent sensitivity and specificity and is an indispensible imaging modality. It caters to the need of early diagnosis owing to poor sensitivity of microbiological tests more so in the parenchymal manifestation of the disease.

Keywords: neurotuberculosis, tubercular abscess, tuberculoma, tuberculous meningitis

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Authors: Shantanu Arya, Sachin Sakhuja, Gunjan Mehta, Sanjay Munjal

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Stuttering may be defined as a speech disorder affecting the fluency domain of speech and characterized by covert features like word substitution, omittance and circumlocution and overt features like prolongation of sound, syllables and blocks etc. Many etiologies have been postulated to explain stuttering based on various experiments and research. Moreover, Breathlessness has also been reported by many individuals with stuttering for which breathing exercises are generally advised. However, no studies reporting objective evaluation of the pulmonary capacity and further objective assessment of the efficacy of breathing exercises have been conducted. Pulmonary Function Test which evaluates parameters like Forced Vital Capacity, Peak Expiratory Flow Rate, Forced expiratory flow Rate can be used to study the pulmonary behavior of individuals with stuttering. The study aimed: a) To identify speech motor & physiologic behaviours associated with stuttering by administering PFT. b) To recognize possible reasons for an association between speech motor behaviour & stuttering severity. In this regard, PFT tests were administered on individuals who reported signs and symptoms of stuttering and showed abnormal scores on Stuttering Severity Index. Parameters like Forced Vital Capacity, Forced Expiratory Volume, Peak Expiratory Flow Rate (L/min), Forced Expiratory Flow Rate (L/min) were evaluated and correlated with scores of Stuttering Severity Index. Results showed significant decrease in the parameters (lower than normal scores) in individuals with established stuttering. Strong correlation was also found between degree of stuttering and the degree of decrease in the pulmonary volumes. Thus, it is evident that fluent speech requires strong support of lung pressure and requisite volumes. Further research in demonstrating the efficacy of abdominal breathing exercises in this regard is needed.

Keywords: forced expiratory flow rate, forced expiratory volume, forced vital capacity, peak expiratory flow rate, stuttering

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Authors: Ammar Ali Saleh Jaber, Amer Hayat Khan, Syed Azhar Syed Sulaiman

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Tuberculosis (TB) is considered as a major disease that affects daily activities and impairs health-related quality of life (HRQoL). The impact of TB on HRQoL can affect treatment outcome and may lead to treatment defaulting. Therefore, this study aims to evaluate the HRQoL of TB treatment lost to follow-up during and after treatment in Yemen. For this aim, this prospective study enrolled a total of 399 TB lost to follow-up patients between January 2011 and December 2015. By applying HRQoL criteria, only 136 fill the survey during treatment. Moreover, 96 were traced and fill out the HRQoL survey. All eight HRQol domains were categorized into the physical component score (PCS) and mental component score (MCS), which were calculated using QM scoring software. Results show that all lost to follow-up TB patients reported a score less than 47 for all eight domains, except general health (67.3) during their treatment period. Low scores of 27.9 and 29.8 were reported for emotional role limitation (RE) and mental health (MH), respectively. Moreover, the mental component score (MCS) was found to be only 28.9. The trace lost follow-up shows a significant improvement in all eight domains and a mental component score of 43.1. The low scores of 27.9 and 29.8 for role emotion and mental health, respectively, in addition to the MCS score of 28.9, show that severe emotional condition and reflect the higher depression during treatment period that can result to lost to follow-up. The low MH, RE, and MCS can be used as a clue for predicting future TB treatment lost to follow-up.

Keywords: Yemen, tuberculosis, health-related quality of life, Khat

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Authors: Tsegahun Manyazewal, Francesco Marinucci, Getachew Belay, Abraham Tesfaye, Gonfa Ayana, Amaha Kebede, Tsegahun Manyazewal, Francesco Marinucci, Getachew Belay, Abraham Tesfaye, Gonfa Ayana, Amaha Kebede, Yewondwossen Tadesse, Susan Lehman, Zelalem Temesgen

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In-service health trainings in Sub-Saharan Africa are mostly content-centered with higher disconnection with the real practice in the facility. This study intended to evaluate in-service training approach aimed to strengthen health care human resources. A combined web-based and face-to-face training was designed and piloted in Ethiopia with the diagnosis of tuberculosis. During the first part, which lasted 43 days, trainees accessed web-based material and read without leaving their work; while the second part comprised a one-day hands-on evaluation. Trainee’s competency was measured using multiple-choice questions, written-assignments, exercises and hands-on evaluation. Of 108 participants invited, 81 (75%) attended the course and 71 (88%) of them successfully completed. Of those completed, 73 (90%) scored a grade from A to C. The approach was effective to transfer knowledge and turn it into practical skills. In-service health training should transform from a passive one-time-event to a continuous behavioral change of participants and improvements on their actual work.

Keywords: Ethiopia, health care, Mycobacterium tuberculosis, training

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Authors: A. V. Alabut, V. D. Sikilinda, N. J. Nelasov, O. L. Eroshenko, M. N. Morgunov, I. V. Koroleva

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We have analyzed the results of treatment of 204 patients with knee prosthetic arthroplasty. For the purpose of active delineation of vascular pathology triplex sonography of arterial and venous vessels of low extremities was performed in all cases in the preoperative period. When it was necessary, reconstructive vascular surgery was implemented to improve peripheral circulation and reduce the hazard of thrombosis after knee replacement. The combination of specific and nonspecific methods of thromboprophylaxis was used in perioperative period. On 7-10 day and 2.5-3 month after prosthetic arthroplasty, all patients iteratively underwent triple sonography. In case of detection of floating thrombus, urgent venous ligation was performed. Active diagnostics of venous thrombosis gave the opportunity to avoid fatal pulmonary embolism.

Keywords: knee replacement, venous thrombosis, pulmonary embolism, vascular surgery

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Authors: Gehan Moubarz, Atef M. F. Mohammed, Inas A. Saleh, Heba Mahdy-Abdallah, Amal Saad-Hussein

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This study estimates the association between respiratory outcomes among employees of a secondary aluminum plant and airborne pollutants. Additionally, it looks into the relationship between pulmonary dysfunction in workers and XRCC1 gene polymorphisms. 110 exposed workers and 58 non-exposed workers participated in the study. Measurements have been conducted on SO₂, NO₂, and particulate particles. Pulmonary function was tested. Eosinophil cationic protein (ECP), C-reactive protein (CRP), matrix metalloproteinase-1 (MMP-1), interleukin 6 (IL6), GM-CSF, X-Ray Repair Cross Complementing 1 (XRCC1) protein, and genotyping of XRCC1 gene polymorphisms were examined. Results: The annual average concentrations of (PM₂.₅, PM₁₀, TSP, SO₂, and NO₂) were lower than the permissible limit. The areas around ovens, evaporators, and cold rolling mills exhibited the highest amounts. The majority of employees in these departments had impaired lung function. With longer exposure times, the exposed group's FEV1% and FVC% considerably reduced. The exposed workers had considerably higher XRCC1 levels. The evaluated inflammatory biomarkers showed no statistically significant difference. Conclusion: Aluminum workers are at risk of developing respiratory disorders. The level of serum XRCC1 may act as a biomarker that might be very useful for detecting susceptible workers.

Keywords: aluminum industry, particulate matter, SO₂, NO₂, lung function, XRCC1 gene polymorphism, XRCC1 protein, inflammatory biomarkers

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Authors: Awais Naeem, Osama Shakeel, Faizan Ullah, Abdul Wahid Anwer

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Introduction: To study the clinic-pathological factors, diagnostic factors and survival of extra-pulmonary small cell carcinoma. Methodology: From 1995 to 2017 all patients with a diagnosis of extra-pulmonary small cell carcinoma were included in the study. Demographic variables and clinic-pathological factors were collected. Management of disease was recorded. Short and long term oncological outcomes were recorded. All data was entered and analyzed in SPSS version 21. Results: A total of 14 patients were included in the study. Median age was 53.42 +/- 16.1 years. There were 5 male and 9 female patients. Most common presentation was dysphagia in 16 patient among esophageal small cell carcinoma and while other patient had pain in abdomen. Mean duration of symptoms was 4.23+/-2.91 months .Most common site is esophagus (n=6) followed by gall bladder(n=3). Almost all of the patients received chemo-radiotherapy. Majority of the patient presented with extensive disease. Five patients (35.7%) died during the follow up period, two (14.3%) were alive and rest of the patients were lost to follow up. Mean follow up period was 22.92 months and median follow up was 15 months. Conclusion: Extra-pulmonary small cell carcinoma is rare and needs to be managed aggressively. All patients should be treated with both systemic and local therapies.

Keywords: small cell carcinoma of esophagus, extrapulmonary small cell carcinoma, small cell carcinoma of gall bladder, small cell carcinoma of rectum, small cell carcinoma of stomach

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Authors: Yung-Feng Yen, Yun-Ju Lai

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Background: Animal studies have shown that alcohol exposure may cause immunosuppression and increase the susceptibility to tuberculosis (TB) infection. However, the temporality of alcohol consumption with subsequent TB development remains unclear. This nationwide population-based cohort study aimed to investigate the impact of alcohol exposure on TB development in Taiwanese adults. Methods: We included 46 196 adult participants from three rounds (2001, 2005, 2009) of the Taiwan National Health Interview Survey. Alcohol consumption was classified into heavy, regular, social, or never alcohol use. Heavy alcohol consumption was defined as intoxication at least once/week. Alcohol consumption and other covariates were collected by in-person interviews at baseline. Incident cases of active TB were identified from the National Health Insurance database. Multivariate logistic regression was used to estimate the association between alcohol consumption and active TB, with adjustment for age, sex, smoking, socioeconomic status, and other covariates. Results: A total of 279 new cases of active TB occurred during the study follow-up period. Heavy (adjusted odds ratio [AOR], 5.21; 95% confident interval [CI], 2.41-11.26) and regular alcohol use (AOR, 1.73; 95% CI, 1.26-2.38) were associated with higher risks of incident TB after adjusting for the subject demographics and comorbidities. Moreover, a strong dose-response effect was observed between increasing alcohol consumption and incident TB (AOR, 2.26; 95% CI, 1.59-3.21; P <.001). Conclusion: Heavy and regular alcohol consumption were associated with higher risks of active TB. Future TB control programs should consider strategies to lower the overall level of alcohol consumption to reduce the TB disease burden.

Keywords: alcohol consumption, tuberculosis, risk factor, cohort study

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Authors: Lista Andriyati, Nurpudji A Taslim

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The human immunodeficiency virus (HIV) patients have potential nutritional and metabolic problems. HIV is a virus that attacks cells T helper and impairs the function of immune cells. Infected individuals gradually become immunodeficient, results in increased susceptibility to a wide range of infections such as tuberculosis (TB). Malnutrition has destructive effects on the immune system and host defense mechanisms. Effective and proper nutritional therapies are important to improve medical outcomes and quality of life, which is associated with functional improvement. A case of 38-years old man admitted to hospital with loss of consciousness and was diagnosed HIV infection and relapse lung TB with severe malnutrition, fever, oral candidiasis, anemia (6.3 g/dL), severe hypoalbuminemia (1.9 g/dL), severe hypokalemia (2.2 mmol/L), immune depletion (1085 /µL) and elevated liver enzyme (ALT 1198/AST 375 U/L). Nutritional intervention by giving 2300 kcal of energy, protein 2 g/IBW/day, carbohydrate 350 g, fat 104 g through enteral and parenteral nutrition. Supplementations administered are zinc, vitamin A, vitamin B1, vitamin B6, vitamin B12, vitamin C, vitamin D, and snakehead fish extract high content of protein albumin (Pujimin®). After 46 days, there are clinical and metabolic improvement in Hb (6.3 to 11.2 g/dL), potassium (2.2 to 3.4 mmol/L), albumin (1.9 to 2.3 g/dL), ALT 1198 to 47/AST 375 to 68 U/L) and improved awareness. In conclusion, nutritional therapy in HIV infection with adequate macronutrients and micronutrients fulfillment and immunonutrition is very important to avoid cachexia and to improve nutritional status and immune disfunction.

Keywords: HIV, hypoalbuminemia, malnutrition, tuberculosis

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Authors: Alaa Badawi, Suzan Sayegh, Mohamed Sallam, Eman Sadoun, Mohamed Al-Thani, Muhammad W. Alam, Paul Arora

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Background: The dual burden of tuberculosis (TB) and diabetes mellitus (DM) has increased over the past decade with DM prevalence increasing in countries already afflicted with a high burden of TB. The coexistence of the two conditions presents a serious threat to global public health. Objective: The present study examines the global relationship between the prevalence of DM and the incidence of TB to evaluate their coexistence worldwide and their contribution to one another. Methods: This is an ecological longitudinal study covering the period between years 2000 to 2012. We utilized data from the WHO and World Bank sources and International Diabetes Federation to estimate prevalence of DM (%) and the incidence of TB (per 100,000). Measures of central tendency and dispersion as well as the harmonic mean and linear regression were used for different WHO regions. The association between DM prevalence and TB incidence was examined by quartile of DM prevalence. Results: The worldwide average (±S.D.) prevalence of DM within the study period was 6.6±3.8% whereas TB incidence was 135.0±190.5 per 100,000. DM prevalence was highest in the Eastern Mediterranean (8.3±4.1) and West Pacific (8.2±5.6) regions and lowest in the Africa (3.5±2.6). TB incidence was highest in Africa (313.1±275.9 per 100,000) and South-East Asia (216.7±124.9) and lowest in the European (46.5±68.6) and American (47.2±52.9) regions. Only countries with high DM prevalence (>7.6%) showed a significant positive association with TB incidence (r=0.17, p=0.013). Conclusion: A positive association between DM and TB may exist in some – but not all – world regions, a dual burden that necessitates identifying the nature of this coexistence to assist in developing public health approaches that curb their rising burden.

Keywords: diabetes mellitus, tuberculosis, disease burden, global association

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Authors: Akinsola Oluwatosin, Udofia Samuel, Odofin Mayowa

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The study is aimed at assessing the Geographic Information System (GIS)-based spatial analysis of Survival Pattern and Treatment Outcomes of Multi-Drug Resistant Tuberculosis (MDR-TB) cases for Lagos, Nigeria, with an objective to inform priority areas for public health planning and resource allocation. Multi-drug resistant tuberculosis (MDR-TB) develops due to problems such as irregular drug supply, poor drug quality, inappropriate prescription, and poor adherence to treatment. The shapefile(s) for this study were already georeferenced to Minna datum. The patient’s information was acquired on MS Excel and later converted to . CSV file for easy processing to ArcMap from various hospitals. To superimpose the patient’s information the spatial data, the addresses was geocoded to generate the longitude and latitude of the patients. The database was used for the SQL query to the various pattern of the treatment. To show the pattern of disease spread, spatial autocorrelation analysis was used. The result was displayed in a graphical format showing the areas of dispersing, random and clustered of patients in the study area. Hot and cold spot analysis was analyzed to show high-density areas. The distance between these patients and the closest health facility was examined using the buffer analysis. The result shows that 22% of the points were successfully matched, while 15% were tied. However, the result table shows that a greater percentage of it was unmatched; this is evident in the fact that most of the streets within the State are unnamed, and then again, most of the patients are likely to supply the wrong addresses. MDR-TB patients of all age groups are concentrated within Lagos-Mainland, Shomolu, Mushin, Surulere, Oshodi-Isolo, and Ifelodun LGAs. MDR-TB patients between the age group of 30-47 years had the highest number and were identified to be about 184 in number. The outcome of patients on ART treatment revealed that a high number of patients (300) were not ART treatment while a paltry 45 patients were on ART treatment. The result shows the Z-score of the distribution is greater than 1 (>2.58), which means that the distribution is highly clustered at a significance level of 0.01.

Keywords: tuberculosis, patients, treatment, GIS, MDR-TB

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Authors: Sihame Amakrane, Zineb Ouahdi, Mohammed Salah, Said Belaaouad

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\This research explores the efficacy of novel pyrimidine derivatives on bacterial strains such as Escherichia coli, Staphylococcus aureus, and Myccobacterium tuberculosis, utilizing bending energy calculations. Of the 25 compounds examined, 13 displayed potent activity against all the bacterial strains under study, exhibiting bending energy measurements between -7.4 and -10.7 kcal/mol. The -7.4 kcal/mol value corresponds to the bending energy of the SA12 and SA13 compounds with the 2xct protein (Staphylococcus aureus), whereas the -10.7 kcal/molis linked with the bending energy of SA6 and SA11 compounds with the 6GAV protein (Myccobacterium tuberculosis). Further research will involve a QSAR (Quantitative Structure-Activity Relationship) study aimed at constructing a reliable model to combat the aforementioned bacterial strains and a molecular dynamics study to evaluate the stability of ligand-protein complexes.

Keywords: docking, QSAR, bending energy, e. coli

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Authors: Parveen Kundu, Zile Singh, Kunika Kundu, Swaran Kaur

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Context: Tuberculous osteomyelitis is a relatively uncommon condition that can present with various clinical and radiological features, often mimicking bone tumors or tumor-like lesions. In endemic countries like India, tuberculosis should be considered as a potential differential diagnosis for lytic bone lesions. This study aimed to highlight the different presentations of tuberculosis that can mimic tumors or tumor-like lesions in bone and emphasize the successful outcome of antitubercular therapy (ATT) in treating these cases. Research Aim: The main objective of this research was to explore the varied presentations of tuberculosis that mimic bone tumors or tumor-like lesions both clinically and radiologically, focusing on different bones. The study aimed to raise awareness among clinicians about this possibility and highlight the importance of histopathological confirmation before initiating treatment for lytic bone lesions. Methodology: This study utilized a retrospective review of 22 patients with suspected lytic bone lesions, who were subsequently diagnosed with tuberculous osteomyelitis through histopathological examination. The cases were collected over a period of ten years. Eleven cases required curettage for extensive lesions with sequestrations, while all 22 patients received 12 months of antitubercular therapy. Findings: The study included 14 male and 8 female patients, ranging in age from 3 to 61 years, with an average age of 22.05. The clinical and radiological presentations varied, with examples including bone cysts in the metaphyseal area of long bones, lesions resembling chondroblastomas, giant cell tumors, and osteoid osteoma, as well as multifocal lytic lesions resembling metastasis or multiple myeloma. One patient had lesions in both the clavicle and hand. Lesions mimicking chondromas were also observed in the phalanges of the hand and foot metatarsal. All patients showed resolution of the lesions and no residual disability following ATT. Theoretical Importance: This study highlights the importance of considering tuberculosis as a potential differential diagnosis for lytic bone lesions, particularly in endemic regions. It emphasizes the need for histopathological confirmation to accurately diagnose tuberculous osteomyelitis, as this is considered the gold standard. Data Collection and Analysis Procedures: Data for this study were collected retrospectively from medical records and radiological images of the 22 patients. The cases were analyzed based on clinical presentation, radiological findings, and histopathological confirmation. The outcomes of antitubercular therapy were also assessed. The data were summarized and presented descriptively. Question Addressed: This study aimed to address the question of how tuberculosis can mimic different bone tumors and tumor-like lesions clinically and radiologically. It also aimed to assess the successful outcome of antitubercular therapy in treating these cases. Conclusion: Tuberculous osteomyelitis can present with varied clinical and radiological features, often mimicking bone tumors or tumor-like lesions. Clinicians should consider tuberculosis as a potential diagnosis for lytic bone lesions, especially in endemic areas. Histopathological confirmation is essential for accurate diagnosis. Antitubercular therapy is an effective treatment for tuberculous osteomyelitis, leading to the resolution of the lesions with no residual disability.

Keywords: tuberculosis, tumor, curettage, bone

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Authors: Gail Louw, Helena Boshoff, Taeksun Song, Clifton Barry

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Drug resistance in Mycobacterium tuberculosis is primarily attributed to mutations in target genes. These mutations incur a fitness cost and result in bacterial generations that are less fit, which subsequently acquire compensatory mutations to restore fitness. We hypothesize that mutations in specific drug target genes influence bacterial metabolism and cellular function, which affects its ability to develop subsequent resistance to additional agents. We aim to determine whether the sequential acquisition of drug resistance and specific mutations in a well-defined clinical M. tuberculosis strain promotes or limits the development of additional resistance. In vitro mutants resistant to pretomanid, linezolid, moxifloxacin, rifampicin and kanamycin were generated from a pan-susceptible clinical strain from the Beijing lineage. The resistant phenotypes to the anti-TB agents were confirmed by the broth microdilution assay and genetic mutations were identified by targeted gene sequencing. Growth of mono-resistant mutants was done in enriched medium for 14 days to assess in vitro fitness. Double resistant mutants were generated against anti-TB drug combinations at concentrations 5x and 10x the minimum inhibitory concentration. Subsequently, mutation frequencies for these anti-TB drugs in the different mono-resistant backgrounds were determined. The initial level of resistance and the mutation frequencies observed for the mono-resistant mutants were comparable to those previously reported. Targeted gene sequencing revealed the presence of known and clinically relevant mutations in the mutants resistant to linezolid, rifampicin, kanamycin and moxifloxacin. Significant growth defects were observed for mutants grown under in vitro conditions compared to the sensitive progenitor. Mutation frequencies determination in the mono-resistant mutants revealed a significant increase in mutation frequency against rifampicin and kanamycin, but a significant decrease in mutation frequency against linezolid and sutezolid. This suggests that these mono-resistant mutants are more prone to develop resistance to rifampicin and kanamycin, but less prone to develop resistance against linezolid and sutezolid. Even though kanamycin and linezolid both inhibit protein synthesis, these compounds target different subunits of the ribosome, thereby leading to different outcomes in terms of fitness in the mutants with impaired cellular function. These observations showed that oxazolidinone treatment is instrumental in limiting the development of multi-drug resistance in M. tuberculosis in vitro.

Keywords: oxazolidinones, mutations, resistance, tuberculosis

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Authors: Munirah Ismail, Joon Hock Yeo

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Babies born with Tetralogy of Fallot, a congenital heart defect, are required to undergo reconstruction surgery to create a valved conduit. As the child matures, the partially reconstructed pulmonary conduit increases in diameter, while the size of the reconstructed valve remains the same. As a result, follow up surgery is required to replace the undersized valve. Thus, in this project, we evaluated the in-vitro performance of a bi-leaflet valve design in terms of percentage regurgitation with increasing artery (conduit) diameters. Results revealed percentage regurgitations ranging from 13% to 34% for conduits tested. It was observed that percentage of regurgitation increased exponentially with increasing diameters. While the amount of regurgitation may seem severe, it is deemed acceptable, and this valve could potentially reduce the frequency of re-operation in the lifetime of pediatric patients.

Keywords: pulmonary heart valve, tetralogy of fallot, expanded polytetrafluoroethylene valve, pediatric heart valve replacement

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Authors: Selamawit Hirpa, Girmay Medhin, Belaineh Girma, Muluken Melese, Alemayehu Mekonen, Pedro Suarez, Gobena Ameni

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Worldwide, there were 650,000 multi-drug resistant tuberculosis (MDR-TB) cases in 2010. Ethiopia is 15th among the 27 MDR-TB high-burden countries. A case control study was conducted at St. Peter Hospital and five health centers in Addis Ababa. Cases were MDR-TB patients who were in treatment at St. Peter Hospital during the study period. Controls were patients who were on first-line anti-TB treatment and were registered as cured or having completed treatment in the period 9 April 2009– 28 February 2010, in five health centers. A structured interview questionnaire was used to assess factors that could potentially be associated with the occurrence of MDR-TB. Factors that were significantly associated with MDR-TB: drug side effects during first-line treatment (adjusted odds ratio (AOR): 4.5, 95% CI; 1.9 - 10.5); treatment not directly observed by a health worker (AOR = 11.7, 95% CI; 4–34.3); and retreatment with the Category II regimen (P = 0.000).

Keywords: adherence to TB treatment, MDR-TB, TB treatment, TB treatment regimens

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Authors: Ran An, Dang Wang

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Background: Mechanical ventilation has been confirmed to increase the incidence of postoperative pulmonary complications (PPCs), and several studies have shown that low tidal volumes combined with positive end-expiratory pressure (PEEP) and recruitment manoeuvres (RM) reduce the incidence of PPCs. However, the optimal lung-protective ventilatory strategy remains unclear. Methods: Multiple databases were searched for randomized controlled trials (RCTs) published prior to October 2023. The association between individual PEEP (iPEEP) or other forms of lung-protective ventilation and the incidence of PPCs was evaluated by Bayesian network meta-analysis. Results: We included 58 studies (11610 patients) in this meta-analysis. The network meta-analysis showed that low ventilation (LVt) combined with iPEEP and RM was associated with significantly lower incidences of PPCs [HVt: OR=0.38 95CrI (0.19, 0.75), LVt: OR=0.33, 95% CrI (0.12, 0.82)], postoperative atelectasis, and pneumonia than was HVt or LVt. In abdominal surgery, LVT combined with iPEEP or medium-to-high PEEP and RM were associated with significantly lower incidences of PPCs, postoperative atelectasis, and pneumonia. LVt combined with iPEEP and RM was ranked the highest, which was based on SUCRA scores. Conclusion: LVt combined with iPEEP and RM decreased the incidences of PPCs, postoperative atelectasis, and pneumonia in noncardiac surgery patients. iPEEP-guided ventilation was the optimal lung protection ventilation strategy. The quality of evidence was moderate.

Keywords: protection ventilation strategies, postoperative pulmonary complications, network meta-analysis, noncardiac surgery

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