-
Scientific Reports May 2024Tuberculosis (TB), caused by Mycobacterium tuberculosis, has a significant impact on global health worldwide. The development of multi-drug resistant strains that are...
Tuberculosis (TB), caused by Mycobacterium tuberculosis, has a significant impact on global health worldwide. The development of multi-drug resistant strains that are resistant to the first-line drugs isoniazid and rifampicin threatens public health security. Rifampicin and isoniazid resistance are largely underpinned by mutations in rpoB and katG respectively and are associated with fitness costs. Compensatory mutations are considered to alleviate these fitness costs and have been observed in rpoC/rpoA (rifampicin) and oxyR'-ahpC (isoniazid). We developed a framework (CompMut-TB) to detect compensatory mutations from whole genome sequences from a large dataset comprised of 18,396 M. tuberculosis samples. We performed association analysis (Fisher's exact tests) to identify pairs of mutations that are associated with drug-resistance, followed by mediation analysis to identify complementary or full mediators of drug-resistance. The analyses revealed several potential mutations in rpoC (N = 47), rpoA (N = 4), and oxyR'-ahpC (N = 7) that were considered either 'highly likely' or 'likely' to confer compensatory effects on drug-resistance, including mutations that have previously been reported and validated. Overall, we have developed the CompMut-TB framework which can assist with identifying compensatory mutations which is important for more precise genome-based profiling of drug-resistant TB strains and to further understanding of the evolutionary mechanisms that underpin drug-resistance.
Topics: Mycobacterium tuberculosis; Mutation; Genome, Bacterial; Drug Resistance, Multiple, Bacterial; Rifampin; Antitubercular Agents; Isoniazid; Tuberculosis, Multidrug-Resistant; Humans; Bacterial Proteins; Whole Genome Sequencing; Microbial Sensitivity Tests
PubMed: 38811658
DOI: 10.1038/s41598-024-62946-8 -
ESMO Open May 2024DESTINY-Breast03 is a randomized, multicenter, open-label, phase III study of trastuzumab deruxtecan (T-DXd) versus trastuzumab emtansine (T-DM1) in patients with human... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
DESTINY-Breast03 is a randomized, multicenter, open-label, phase III study of trastuzumab deruxtecan (T-DXd) versus trastuzumab emtansine (T-DM1) in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (mBC) previously treated with trastuzumab and a taxane. A statistically significant improvement in progression-free survival (PFS) versus T-DM1 was reported in the primary analysis. Here, we report exploratory efficacy data in patients with and without brain metastases (BMs) at baseline.
PATIENTS AND METHODS
Patients were randomly assigned 1 : 1 to receive T-DXd 5.4 mg/kg or T-DM1 3.6 mg/kg. Patients with clinically inactive/asymptomatic BMs were eligible. Lesions were measured as per modified RECIST, version 1.1. Outcomes included PFS by blinded independent central review (BICR), objective response rate (ORR), and intracranial ORR as per BICR.
RESULTS
As of 21 May 2021, 43/261 patients randomized to T-DXd and 39/263 patients randomized to T-DM1 had BMs at baseline, as per investigator assessment. Among patients with baseline BMs, 20/43 in the T-DXd arm and 19/39 in the T-DM1 arm had not received prior local BM treatment. For patients with BMs, median PFS was 15.0 months [95% confidence interval (CI) 12.5-22.2 months] for T-DXd versus 3.0 months (95% CI 2.8-5.8 months) for T-DM1; hazard ratio (HR) 0.25 (95% CI 0.13-0.45). For patients without BMs, median PFS was not reached (95% CI 22.4 months-not estimable) for T-DXd versus 7.1 months (95% CI 5.6-9.7 months) for T-DM1; HR 0.30 (95% CI 0.22-0.40). Confirmed systemic ORR was 67.4% for T-DXd versus 20.5% for T-DM1 and 82.1% for T-DXd versus 36.6% for T-DM1 for patients with and without BMs, respectively. Intracranial ORR was 65.7% with T-DXd versus 34.3% with T-DM1.
CONCLUSIONS
Patients with HER2-positive mBC whose disease progressed after trastuzumab and a taxane achieved a substantial benefit from treatment with T-DXd compared with T-DM1, including those with baseline BMs.
Topics: Humans; Female; Breast Neoplasms; Brain Neoplasms; Trastuzumab; Middle Aged; Ado-Trastuzumab Emtansine; Receptor, ErbB-2; Adult; Aged; Camptothecin; Antineoplastic Agents, Immunological; Immunoconjugates; Progression-Free Survival
PubMed: 38796287
DOI: 10.1016/j.esmoop.2024.102924 -
International Journal of Molecular... May 2024The main focus of in vitro toxicity assessment methods is to assess the viability of the cells, which is usually based on metabolism changes. Yet, when exposed to toxic...
The main focus of in vitro toxicity assessment methods is to assess the viability of the cells, which is usually based on metabolism changes. Yet, when exposed to toxic substances, the cell triggers multiple signals in response. With this in mind, we have developed a promising cell-based toxicity method that observes various cell responses when exposed to toxic substances (either death, division, or remain viable). Based on the collective cell response, we observed and predicted the dynamics of the cell population to determine the toxicity of the toxicant. The method was tested with two different conformations: In the first conformation, we exposed a monoculture model of blood macrophages to UV light, hydrogen peroxide, nutrient deprivation, tetrabromobisphenol A, fatty acids, and 5-fluorouracil. In the second, we exposed a coculture liver model consisting of hepatocytes, hepatic stellate cells, Kupffer cells, and liver sinusoidal endothelial cells to rifampicin, ibuprofen, and 5-fluorouracil. The method showed good accuracy compared to established toxicity assessment methods. In addition, this approach provided more representative information on the toxic effects of the compounds, as it considers the different cellular responses induced by toxic agents.
Topics: Humans; Fluorouracil; Macrophages; Hepatocytes; Toxicity Tests; Hydrogen Peroxide; Cell Survival; Animals; Coculture Techniques; Ultraviolet Rays; Endothelial Cells; Liver; Ibuprofen; Cells, Cultured; Rifampin; Hepatic Stellate Cells
PubMed: 38791172
DOI: 10.3390/ijms25105133 -
PeerJ 2024Antibiotics are commonly used for controlling microbial growth in diseased organisms. However, antibiotic treatments during early developmental stages can have negative...
BACKGROUND
Antibiotics are commonly used for controlling microbial growth in diseased organisms. However, antibiotic treatments during early developmental stages can have negative impacts on development and physiology that could offset the positive effects of reducing or eliminating pathogens. Similarly, antibiotics can shift the microbial community due to differential effectiveness on resistant and susceptible bacteria. Though antibiotic application does not typically result in mortality of marine invertebrates, little is known about the developmental and transcriptional effects. These sublethal effects could reduce the fitness of the host organism and lead to negative changes after removal of the antibiotics. Here, we quantify the impact of antibiotic treatment on development, gene expression, and the culturable bacterial community of a model cnidarian, .
METHODS
Ampicillin, streptomycin, rifampicin, and neomycin were compared individually at two concentrations, 50 and 200 µg mL, and in combination at 50 µg mL each, to assess their impact on . First, we determined the impact antibiotics have on larval development. Next Amplicon 16S rDNA gene sequencing was used to compare the culturable bacteria that persist after antibiotic treatment to determine how these treatments may differentially select against the native microbiome. Lastly, we determined how acute (3-day) and chronic (8-day) antibiotic treatments impact gene expression of adult anemones.
RESULTS
Under most exposures, the time of larval settlement extended as the concentration of antibiotics increased and had the longest delay of 3 days in the combination treatment. Culturable bacteria persisted through a majority of exposures where we identified 359 amplicon sequence variants (ASVs). The largest proportion of bacteria belonged to Gammaproteobacteria, and the most common ASVs were identified as and . The acute antibiotic exposure resulted in differential expression of genes related to epigenetic mechanisms and neural processes, while constant application resulted in upregulation of chaperones and downregulation of mitochondrial genes when compared to controls. Gene Ontology analyses identified overall depletion of terms related to development and metabolism in both antibiotic treatments.
DISCUSSION
Antibiotics resulted in a significant increase to settlement time of larvae. Culturable bacterial species after antibiotic treatments were taxonomically diverse. Additionally, the transcriptional effects of antibiotics, and after their removal result in significant differences in gene expression that may impact the physiology of the anemone, which may include removal of bacterial signaling on anemone gene expression. Our research suggests that impacts of antibiotics beyond the reduction of bacteria may be important to consider when they are applied to aquatic invertebrates including reef building corals.
Topics: Animals; Anti-Bacterial Agents; Sea Anemones; Larva; Ampicillin; Neomycin; Streptomycin; Rifampin; Gene Expression
PubMed: 38784394
DOI: 10.7717/peerj.17349 -
The European Respiratory Journal May 2024https://bit.ly/3UnWm43 (Clinical Trial)
Clinical Trial
Short oral treatment regimens for rifampicin-resistant tuberculosis are safe and effective for young children: results from a field-based, non-randomised clinical trial from Kandahar, Afghanistan.
https://bit.ly/3UnWm43
Topics: Humans; Rifampin; Afghanistan; Child, Preschool; Male; Female; Tuberculosis, Multidrug-Resistant; Antitubercular Agents; Infant; Treatment Outcome; Administration, Oral; Child; Mycobacterium tuberculosis
PubMed: 38782466
DOI: 10.1183/13993003.00436-2024 -
PloS One 2024Mutations in the non-structural protein regions of hepatitis C virus (HCV) are a cause of a non-sustained virological response (SVR) to treatment with direct-acting...
Mutations in the non-structural protein regions of hepatitis C virus (HCV) are a cause of a non-sustained virological response (SVR) to treatment with direct-acting antivirals (DAAs) for chronic hepatitis; however, there are non-SVR cases without these mutations. In this study, we examined immune cell profiles in peripheral blood before and after ombitasvir/paritaprevir/ritonavir treatment and screened for genes that could be used to predict the therapeutic effects of DAAs. Fluorescence-activated cell sorting analysis indicated that the median frequencies of programmed cell death-1-positive (PD-1+) effector regulatory T cells (eTregs), PD-1+CD8+ T cells, and PD-1+Helper T cells were decreased significantly in SVR cases, but without significant changes in non-SVR cases. The frequency of PD-1+ naïve Tregs was significantly higher in the SVR group than in the non-SVR group before and after treatment. Similar results were found in patients treated with other DAAs (e.g., daclatasvir plus asunaprevir) and supported an immune response after HCV therapy. RNA-sequencing analysis indicated a significant increase in the expression of genes associated with the immune response in the SVR group, while genes related to intracellular and extracellular signal transduction were highly expressed in the non-SVR group. Therefore, we searched for genes associated with PD-1+ eTregs and CD8+ T cells that were significantly different between the SVR and non-SVR groups and found that T-box transcription factor 21 was associated with the non-SVR state. These results indicate that PD-1-related signaling pathways are associated with a non-SVR mechanism after DAAs treatment separate from mutation-related drug resistance.
Topics: Humans; Antiviral Agents; Programmed Cell Death 1 Receptor; Male; Hepacivirus; Female; Middle Aged; Carbamates; CD8-Positive T-Lymphocytes; T-Lymphocytes, Regulatory; Sulfonamides; Hepatitis C, Chronic; Cyclopropanes; Valine; Proline; Anilides; Lactams, Macrocyclic; Macrocyclic Compounds; Aged; Ritonavir; Adult; Drug Therapy, Combination; T-Lymphocytes, Helper-Inducer; Imidazoles; Isoquinolines; Pyrrolidines
PubMed: 38781172
DOI: 10.1371/journal.pone.0299424 -
BMC Infectious Diseases May 2024This study aimed to analyze the risk factors associated with isoniazid-resistant and rifampicin-susceptible tuberculosis (Hr-TB) in adults.
INTRODUCTION
This study aimed to analyze the risk factors associated with isoniazid-resistant and rifampicin-susceptible tuberculosis (Hr-TB) in adults.
METHOD
The clinical data of 1,844 adult inpatients diagnosed with culture-positive pulmonary tuberculosis (PTB) in Nanjing Second Hospital from January 2019 and December 2021 were collected. All culture positive strain from the patient specimens underwent drug susceptibility testing (DST). Among them, 166 patients with Hr-TB were categorized as the Hr-TB group, while the remaining 1,678 patients were classified as having drug-susceptible tuberculosis (DS-TB). Hierarchical logistic regression was employed for multivariate analysis to identify variables associated with Hr-TB.
RESULTS
Multivariate logistic regression analysis revealed that individuals with diabetes mellitus (DM) (OR 1.472, 95% CI 1.037-2.088, p = 0.030) and a history of previous tuberculosis treatment (OR 2.913, 95% CI 1.971-4.306, p = 0.000) were at higher risk of developing adult Hr-TB, with this risk being more pronounced in male patients. Within the cohort, 1,640 patients were newly treated, and among them, DM (OR 1.662, 95% CI 1.123-2.461, p = 0.011) was identified as risk factors for Hr-TB.
CONCLUSIONS
Diabetes mellitus is a risk factor for Hr-TB in adults, and the contribution of diabetes as a risk factor was more pronounced in the newly treatment or male subgroup. And previous TB treatment history is also a risk factor for Hr-TB in adults.
Topics: Humans; Male; Female; Risk Factors; Isoniazid; Rifampin; Middle Aged; Adult; China; Antitubercular Agents; Mycobacterium tuberculosis; Tuberculosis, Pulmonary; Tuberculosis, Multidrug-Resistant; Microbial Sensitivity Tests; Aged; Young Adult; Retrospective Studies; Diabetes Mellitus
PubMed: 38773443
DOI: 10.1186/s12879-024-09404-y -
International Journal of... Jan 2024Rapid detection of tuberculosis (TB) and its resistance are essential for the prompt initiation of correct drug therapy and for stopping the spread of drug-resistant TB....
BACKGROUND
Rapid detection of tuberculosis (TB) and its resistance are essential for the prompt initiation of correct drug therapy and for stopping the spread of drug-resistant TB. There is an urgent need for increased use of rapid diagnostic tests to control the threat of increased TB and multidrug-resistant TB (MDR-TB).
METHODS
EMPE Diagnostics has developed a multiplex molecular diagnostic platform called mfloDx™ by combining nucleotide-specific padlock probe-dependent rolling circle amplification with sensitive lateral flow biosensors, providing visual signals, similar to a COVID-19 test. The first test kit of this platform, mfloDx™ MDR-TB can identify Mycobacterium tuberculosis (MTB) complex and its clinically significant mutations in the rpoB and katG genes and in the inhA promotor contributing resistance to rifampicin (RIF) and isoniazid (INH), causing MDR-TB.
RESULTS
We have evaluated the performance of the mfloDx™ MDR-TB test on 210 sputum samples (110 from suspected TB cases and 100 from TB-negative controls) received from a tertiary care center in India. The clinical sensitivity for detecting MTB compared to acid-fast microscopy and mycobacteria growth indicator tube (MGIT) cultures was 86.4% and 84.9%, respectively. All the 100 control samples were negative indicating excellent specificity. In smear-positive sputum samples, the mfloDx™ MDR-TB test showed a sensitivity of 92.5% and 86.4% against MGIT culture and Xpert MTB/RIF, respectively. The clinical sensitivity for the detection of RIF and INH resistance in comparison with MGIT drug susceptibility testing was 100% and 84.6%, respectively, while the clinical specificity was 100%.
CONCLUSION
From the above evaluation, we find mfloDx™ MDR-TB to be a rapid and efficient test to detect TB and its multidrug resistance in 3 h at a low cost making it suitable for resource-limited laboratories.
Topics: Rifampin; Humans; Isoniazid; Mycobacterium tuberculosis; Tuberculosis, Multidrug-Resistant; Antitubercular Agents; Sensitivity and Specificity; Microbial Sensitivity Tests; Drug Resistance, Multiple, Bacterial; Sputum; Bacterial Proteins; India; Molecular Diagnostic Techniques; Catalase; Oxidoreductases
PubMed: 38771285
DOI: 10.4103/ijmy.ijmy_21_24 -
International Journal of... Jan 2024Smear microscopy for acid-fast bacilli visualization is important to assess the infectivity rate in patients with pulmonary tuberculosis (PTB), but it has limited... (Comparative Study)
Comparative Study
Correlation of Cyclic Threshold Values Generated by GeneXpert Ultra MTB/RIF and Fluorescence Microscopy to Predict Mycobacterial Burden in Suspected Cases of Pulmonary Tuberculosis.
BACKGROUND
Smear microscopy for acid-fast bacilli visualization is important to assess the infectivity rate in patients with pulmonary tuberculosis (PTB), but it has limited sensitivity; hence, it is important to find an alternative strategy. The aim of our study was to compare the fluorescence microscopy grading by Auramine O phenol staining technique of respiratory samples with the cyclic threshold (Ct) values of GeneXpert Ultra (Mycobacterium tuberculosis/rifampicin [MTB/RIF]) and assess the diagnostic efficacy of GeneXpert Ultra (MTB/RIF) compared to microscopy in suspected cases of PTB.
METHODS
The study was conducted in the Mycobacteriology Laboratory, Department of Microbiology, in Kasturba Hospital, Manipal. The study was a prospective, single-centered, cross-sectional study. Four hundred and fifty-two respiratory samples were included in the study. An optimal Ct cutoff value for ruling smear-positivity and smear-negativity and the mean Ct cutoff value were calculated. Clinical and radiological data from the requisition forms were assessed. IBM SPSS statistics software version 22 was used. The correlation between GeneXpert Ultra (MTB/RIF) Ct values and smear status was calculated by polychoric correlation. The extended McNemar's test was used to find the association between the variables.
RESULTS
GeneXpert Ultra (MTB/RIF) yielded a higher positivity rate of 22.2% compared to smear microscopy 17.2%. Ct value and smear grading yielded a positive correlation (P = 0.8681; P < 0.05). GeneXpert Ultra (MTB/RIF) yielded nontuberculous mycobacteria in five undetected cases and speciated as Mycobacterium abscessus complex.
CONCLUSIONS
Our study confirms the GeneXpert Ultra (MTB/RIF) Ct value levels as a predictor of smear positivity.
Topics: Humans; Tuberculosis, Pulmonary; Mycobacterium tuberculosis; Cross-Sectional Studies; Prospective Studies; Microscopy, Fluorescence; Male; Female; Adult; Middle Aged; Sputum; Young Adult; Rifampin; Aged; Sensitivity and Specificity; Adolescent; Bacterial Load
PubMed: 38771279
DOI: 10.4103/ijmy.ijmy_199_23 -
International Journal of... Jan 2024Although Zimbabwe has transitioned out of the 30 high-burden countries, it still remained in the 30 high multidrug-resistant (MDR)/rifampicin-resistant tuberculosis (TB)...
Diagnostic Performance of STANDARD™ M10 Multidrug-resistant Tuberculosis Assay for Detection of Mycobacterium tuberculosis and Rifampicin and Isoniazid Resistance in Zimbabwe.
BACKGROUND
Although Zimbabwe has transitioned out of the 30 high-burden countries, it still remained in the 30 high multidrug-resistant (MDR)/rifampicin-resistant tuberculosis (TB) burden. Rapid detection of rifampicin (RIF) and isoniazid (INH) is essential for the diagnosis of MDR-TB. The World Health Organization has recommended the use of molecular WHO-recommended rapid diagnostic (mWRD) for TB and DR-TB. STANDARD™ M10 MDR-TB assay is a new molecular rapid diagnostic assay developed by SD Biosensor for the detection of Mycobacterium tuberculosis (MTB) and RIF and INF resistance. This study aims to determine the diagnostic accuracy of STANDARD™ M10 MDR-TB assay.
METHODS
The study was conducted on 214 samples with different MTB and RIF and INH resistance status. The STANDARD™ M10 MDR-TB assay was performed according to the manufacturer's instructions. Xpert MTB/RIF Ultra, MGIT culture, and phenotypic drug susceptibility testing are used as comparative methods.
RESULTS
The sensitivity and specificity of STANDARD™ M10 MDR-TB assay for the detection of MTB are 99% and 97.9%, respectively. The sensitivity and specificity of the assay for detection of MDR-TB were 97.8% and 100%, respectively.
CONCLUSION
The STANDARD™ M10 MDR-TB assay demonstrated high diagnostic accuracy in the detection of MTB and RIF and INH resistance. This molecular assay can also be used as an alternative to other mWRD assays.
Topics: Mycobacterium tuberculosis; Rifampin; Zimbabwe; Humans; Isoniazid; Tuberculosis, Multidrug-Resistant; Antitubercular Agents; Sensitivity and Specificity; Microbial Sensitivity Tests; Drug Resistance, Multiple, Bacterial; Molecular Diagnostic Techniques
PubMed: 38771275
DOI: 10.4103/ijmy.ijmy_194_23