scholarly journals Within-Host Selection of Drug Resistance in a Mouse Model Reveals Dose-Dependent Selection of Atovaquone Resistance Mutations

2017 ◽  
Vol 61 (5) ◽  
Author(s):  
Suci Nuralitha ◽  
Lydia S. Murdiyarso ◽  
Josephine E. Siregar ◽  
Din Syafruddin ◽  
Jessica Roelands ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Body Weight ◽  
Host Selection ◽  
Therapeutic Dose ◽  
Critical Role ◽  
Malaria Treatment ◽  
Resistance Mutations ◽  
Content Type ◽  
Number Of Treatment ◽  
Selection Of

ABSTRACT The evolutionary selection of malaria parasites within an individual host plays a critical role in the emergence of drug resistance. We have compared the selection of atovaquone resistance mutants in mouse models reflecting two different causes of failure of malaria treatment, an inadequate subtherapeutic dose and an incomplete therapeutic dose. The two models are based on cycles of insufficient treatment of Plasmodium berghei-infected mice: repeated inadequate treatment associated with a subtherapeutic dose (RIaT) (0.1 mg kg−1 of body weight) and repeated incomplete treatment with a therapeutic dose (RIcT) (14.4 mg kg−1 of body weight). The number of treatment cycles for the development of a stable resistance phenotype during RIaT was 2.00 ± 0.00 cycles (n = 9), which is not statistically different from that during RIcT (2.57 ± 0.85 cycles; combined n = 14; P = 0.0591). All mutations underlying atovaquone resistance selected by RIaT (M133I, T142N, and L144S) were found to be in the Qo1 (quinone binding 1) domain of the mitochondrial cytochrome b gene, in contrast to those selected by RIcT (Y268N/C, L271V, K272R, and V284F) in the Qo2 domain or its neighboring sixth transmembrane region. Exposure of mixed populations of resistant parasites from RIaT to the higher therapeutic dose of RIcT revealed further insights into the dynamics of within-host selection of resistance to antimalarial drugs. These results suggest that both inadequate subtherapeutic doses and incomplete therapeutic doses in malaria treatment pose similar threats to the emergence of drug resistance. RIcT and RIaT could be developed as useful tools to predict the potential emergence of resistance to newly introduced and less-understood antimalarials.

scholarly journals Within-Host Selection of Drug Resistance in a Mouse Model of Repeated Incomplete Malaria Treatment: Comparison between Atovaquone and Pyrimethamine

2015 ◽  
Vol 60 (1) ◽  
pp. 258-263 ◽  
Author(s):  
Suci Nuralitha ◽  
Josephine E. Siregar ◽  
Din Syafruddin ◽  
Jessica Roelands ◽  
Jan Verhoef ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Dihydrofolate Reductase ◽  
Selection Process ◽  
Rare Event ◽  
Mitochondrial Dna Mutation ◽  
Content Type ◽  
Dna Mutation ◽  
Treatment Comparison ◽  
Number Of Treatment ◽  
Selection Of

ABSTRACTThe evolutionary selection of malaria parasites within individual hosts is an important factor in the emergence of drug resistance but is still not well understood. We have examined the selection process for drug resistance in the mouse malaria agentPlasmodium bergheiand compared the dynamics of the selection for atovaquone and pyrimethamine. Resistance to these drugs has been shown to be associated with genetic lesions in the dihydrofolate reductase gene in the case of pyrimethamine and in the mitochondrial cytochromebgene for atovaquone. A mouse malaria model for the selection of drug resistance, based on repeated incomplete treatment (RICT) with a therapeutic dose of antimalarial drugs, was established. The number of treatment cycles for the development of stable resistance to atovaquone (2.47 ± 0.70;n= 19) was found to be significantly lower than for pyrimethamine (5.44 ± 1.46;n= 16;P< 0.0001), even when the parentalP. bergheiLeiden strain was cloned prior to the resistance selection. Similar results were obtained withP. bergheiEdinburgh. Mutational changes underlying the resistance were identified to be S110N in dihydrofolate reductase for pyrimethamine and Y268N, Y268C, Y268S, L271V-K272R, and G280D in cytochromebfor atovaquone. These results are consistent with the rate of mitochondrial DNA mutation being higher than that in the nucleus and suggest that mutation leading to pyrimethamine resistance is not a rare event.

scholarly journals Whole-Genome Sequencing for Drug Resistance Profile Prediction inMycobacterium tuberculosis

2019 ◽  
Vol 63 (4) ◽  
Author(s):  
Sebastian M. Gygli ◽  
Peter M. Keller ◽  
Marie Ballif ◽  
Nicolas Blöchliger ◽  
Rico Hömke ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Critical Concentration ◽  
Drug Susceptibility Testing ◽  
Quality Data ◽  
Whole Genome ◽  
Resistance Mutations ◽  
Content Type ◽  
Agar Dilution

ABSTRACTWhole-genome sequencing allows rapid detection of drug-resistantMycobacterium tuberculosisisolates. However, the availability of high-quality data linking quantitative phenotypic drug susceptibility testing (DST) and genomic data have thus far been limited. We determined drug resistance profiles of 176 genetically diverse clinicalM. tuberculosisisolates from the Democratic Republic of the Congo, Ivory Coast, Peru, Thailand, and Switzerland by quantitative phenotypic DST for 11 antituberculous drugs using the BD Bactec MGIT 960 system and 7H10 agar dilution to generate a cross-validated phenotypic DST readout. We compared DST results with predicted drug resistance profiles inferred by whole-genome sequencing. Classification of strains by the two phenotypic DST methods into resistotype/wild-type populations was concordant in 73 to 99% of cases, depending on the drug. Our data suggest that the established critical concentration (5 mg/liter) for ethambutol resistance (MGIT 960 system) is too high and misclassifies strains as susceptible, unlike 7H10 agar dilution. Increased minimal inhibitory concentrations were explained by mutations identified by whole-genome sequencing. Using whole-genome sequences, we were able to predict quantitative drug resistance levels for the majority of drug resistance mutations. Predicting quantitative levels of drug resistance by whole-genome sequencing was partially limited due to incompletely understood drug resistance mechanisms. The overall sensitivity and specificity of whole-genome-based DST were 86.8% and 94.5%, respectively. Despite some limitations, whole-genome sequencing has the potential to infer resistance profiles without the need for time-consuming phenotypic methods.

scholarly journals Molecular Drug Susceptibility Testing and Genotyping of Mycobacterium leprae Strains from South America

2011 ◽  
Vol 55 (6) ◽  
pp. 2971-2973 ◽  
Author(s):  
Pushpendra Singh ◽  
Philippe Busso ◽  
Alberto Paniz-Mondolfi ◽  
Nacarid Aranzazu ◽  
Marc Monot ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Resistance Mutation ◽  
Mycobacterium Leprae ◽  
Drug Susceptibility ◽  
Drug Susceptibility Testing ◽  
Polymorphism Analysis ◽  
South American ◽  
Resistance Mutations ◽  
Single Nucleotide ◽  
Content Type

ABSTRACTPossible drug resistance inMycobacterium lepraestrains from Venezuela and three other South American countries was surveyed by molecular methods. None of the 230 strains from new leprosy cases exhibited drug resistance-associated mutations. However, two of the three strains from relapsed cases contained dapsone resistance mutations, and one strain also harbored a rifampin resistance mutation. Single nucleotide polymorphism analysis of these strains revealed five subtypes: 3I (73.8%), 4P (11.6%), 1D (6.9%), 4N (6%), and 4O (1.7%).

An examination of ecopreneurs’ incentives through a combination between institutional and resource-based approach

2018 ◽  
Vol 29 (2) ◽  
pp. 195-215 ◽  
Author(s):  
Ioannis E. Nikolaou ◽  
Konstantinos P. Tsagarakis ◽  
Kyriaki Tasopoulou
Keyword(s):  
Environmental Sustainability ◽  
Service Sector ◽  
Research Question ◽  
Critical Role ◽  
Sample Selection ◽  
Future Research ◽  
Key Factors ◽  
Policy Makers ◽  
Content Type ◽  
Selection Of

Purpose The purpose of this paper is to address two research questions: which are the key factors that stimulate entrepreneurs to invest in ecopreneurship, and how ecopreneurhsip contributes to environmental sustainability. Design/methodology/approach To answer these questions, a framework has been developed to identify the incentives that lead entrepreneurs to invest in firms in the ecopreneurship through institutional and resource-based thinking. Findings From a survey of 91 Greek firms from the green service sector, it is shown that some specific institutional and resource-based view factors play a critical role in green entrepreneurs’ decisions, as well as some certain environmental practices that are frequently used by entrepreneurs to address environmental issues. Research limitations/implications First, the answer of the second research question through data collected by a questionnaire survey may be faced with skepticism by some authors, as it could be seen that entrepreneurs and managers of firms could have overstated their company's environmental activities. Second, although the sample selection of 91 firms is a representative sample (response rate 12.35 percent) of the total population of Greek green firms (761) and equal to other relative studies, a higher number of firms and a wider variety of green entrepreneurship ventures is necessary in future research. Practical implications The findings are useful for scholars, practitioners and policy makers since it provide information regarding the behavior of green entrepreneurs. Originality/value The paper analyze the types of green entrepreneurs in relation to the different features and strategies which are emerged from two theories, such as institutional and resource-based theory.

scholarly journals Stochastic investigation of HIV infection and the emergence of drug resistance

2021 ◽  
Vol 19 (2) ◽  
pp. 1174-1194
Author(s):  
Damilola Olabode ◽  
◽  
Libin Rong ◽  
Xueying Wang ◽  
Keyword(s):  
Drug Resistance ◽  
Antiretroviral Therapy ◽  
Hiv Infection ◽  
Stochastic Models ◽  
Early Stage ◽  
Critical Role ◽  
Resistance Mutations ◽  
Multitype Branching Process ◽  
Increased Risk ◽  
Hiv 1

<abstract><p>Drug-resistant HIV-1 has caused a growing concern in clinic and public health. Although combination antiretroviral therapy can contribute massively to the suppression of viral loads in patients with HIV-1, it cannot lead to viral eradication. Continuing viral replication during sub-optimal therapy (due to poor adherence or other reasons) may lead to the accumulation of drug resistance mutations, resulting in an increased risk of disease progression. Many studies also suggest that events occurring during the early stage of HIV-1 infection (i.e., the first few hours to days following HIV exposure) may determine whether the infection can be successfully established. However, the numbers of infected cells and viruses during the early stage are extremely low and stochasticity may play a critical role in dictating the fate of infection. In this paper, we use stochastic models to investigate viral infection and the emergence of drug resistance of HIV-1. The stochastic model is formulated by a continuous-time Markov chain (CTMC), which is derived based on an ordinary differential equation model proposed by Kitayimbwa et al. that includes both forward and backward mutations. An analytic estimate of the probability of the clearance of HIV infection of the CTMC model near the infection-free equilibrium is obtained by a multitype branching process approximation. The analytical predictions are validated by numerical simulations. Unlike the deterministic dynamics where the basic reproduction number $ \mathcal{R}_0 $ serves as a sharp threshold parameter (i.e., the disease dies out if $ \mathcal{R}_0 &lt; 1 $ and persists if $ \mathcal{R}_0 &gt; 1 $), the stochastic models indicate that there is always a positive probability for HIV infection to be eradicated in patients. In the presence of antiretroviral therapy, our results show that the chance of clearance of the infection tends to increase although drug resistance is likely to emerge.</p></abstract>

Metaphors we manage and develop quality by

2020 ◽  
Vol 12 (4) ◽  
pp. 405-416
Author(s):  
Johan Lilja ◽  
Pernilla Ingelsson ◽  
Kristen Snyder ◽  
Ingela Bäckström ◽  
Christer Hedlund
Keyword(s):  
Quality Management ◽  
Literature Review ◽  
Design Methodology ◽  
Dynamic Properties ◽  
Critical Role ◽  
Critical Discussion ◽  
Future Research ◽  
Content Type ◽  
Selection Of

Purpose Metaphors are a powerful and human way of understanding and experiencing one kind of thing in terms of another. In quality management (QM), several metaphors are used to describe and bring to life the often-abstract QM concepts and systems. These metaphors are of great importance for how QM is understood, communicated and practiced. However, the metaphors of QM have seldom been systematically screened or put in focus, neither the topic of a critical discussion. The purpose of this paper is hence to contribute with a screening of the metaphors currently used, within QM literature and in practice among QM leaders, and then elaborate on their potential for improvement and development. Design/methodology/approach The paper is based on a literature review combined with interviews of QM leaders. Findings The paper highlights that the current QM metaphors provide intuitive associations to properties such as stability, shelter, and structure, but not to the important dynamic properties of QM, such as learning, or to the critical role of people in QM. What can be seen as core properties of QM are communicated by texts or labels added on to metaphors with properties that often are in sharp contrast to them. The paper also provides suggestions for further improvements and development. Originality/value The paper highlights the area of metaphors within QM as an important area for future research. It also provides insights concerning the successful use and selection of metaphors in future QM practice.

scholarly journals Factors influencing tourist’s satisfaction, loyalty and word of mouth in selection of local foods in Pakistan

2019 ◽  
Vol 122 (6) ◽  
pp. 2021-2043
Author(s):  
Muhammad Ali ◽  
Chin-Hong Puah ◽  
Norazirah Ayob ◽  
Syed Ali Raza
Keyword(s):  
Factor Analysis ◽  
Conceptual Framework ◽  
Structural Equation ◽  
Word Of Mouth ◽  
Critical Role ◽  
Economic Benefits ◽  
Equation Modeling ◽  
Local Foods ◽  
Content Type ◽  
Selection Of

Purpose Local foods from the perspective of tourism play a significant role to attract tourists. Surprisingly, empirical evidence on food tourism is quite scarce. The purpose of this paper is to develop and investigate a conceptual framework on tourist satisfaction, loyalty and word of mouth (WOM) to select local foods in Pakistan. Design/methodology/approach The study uses a quantitative approach while convenience (non-probability) sampling is used to collect a sample of 286 final responses using a survey-based questionnaire. The study employed exploratory factor analysis and confirmatory factor analysis to stabilize the factor structure. The conceptual model is then tested under the assumptions of structural equation modeling. Findings The findings indicate that food quality, perceived environmental quality, perceived value and service quality has a significant impact on the tourist’s satisfaction. However, interpersonal interaction quality shows an insignificant influence on satisfaction. Moreover, satisfaction has a significant impact on loyalty while loyalty further shows a significant effect on tourist WOM. Overall, the authors found satisfaction and loyalty are the major contributors to the hypothesized model. Practical implications The conceptual framework and study findings will support practitioners and researchers to understand the factors that influence a tourist’s selection of local foods. Additionally, the study provides a useful policy to gain long-term economic benefits for the tourism sector in Pakistan. Originality/value To the authors’ best knowledge, this study is the first attempt to explore WOM behavior in tourism research focusing on the critical role of satisfaction and loyalty. The authors are certain that the findings will contribute significantly to the existing body of knowledge.

scholarly journals Nitrotriazole-Based Compounds as Antichagasic Agents in a Long-Treatment In Vivo Assay

2017 ◽  
Vol 61 (5) ◽  
Author(s):  
Maria V. Papadopoulou ◽  
William D. Bloomer ◽  
Howard S. Rosenzweig ◽  
Ana Lia Mazzeti ◽  
Karolina Ribeiro Gonçalves ◽  
...  
Keyword(s):  
Body Weight ◽  
Weight Gain ◽  
Adverse Effects ◽  
Myocardial Inflammation ◽  
Reference Drug ◽  
Content Type ◽  
Number Of Treatment ◽  
Better Than

ABSTRACT 3-Nitrotriazole-based compounds belonging to various chemical subclasses were found to be very effective against Chagas disease both in vitro and in vivo after a short administration schedule. In this study, five compounds with specific characteristics were selected to be administered for longer periods of time to mice infected with the virulent Trypanosoma cruzi Y strain to further evaluate their effectiveness as antichagasic agents and whether or not potential adverse effects occur. Benznidazole was included for comparison purposes. Complete parasitemia depletion, weight gain, 100% survival, and a lack of myocardial inflammation were observed with four of the compounds and benznidazole administered intraperitoneally at 15 or 20 mg/kg of body weight/day for 40 days. There was a significant reduction in the number of treatment days (number of doses) necessary to induce parasitemia suppression with all four compounds compared to that required with benznidazole. Partial cures were obtained with only one compound tested at 15 mg/kg/day and on the schedule mentioned above but not with benznidazole. Taken together, our data suggest that these compounds demonstrate potent trypanocidal activity comparable to or better than that of the reference drug, benznidazole, when they are administered at the same dose and on the same schedule.

scholarly journals Detection of Isoniazid-, Fluoroquinolone-, Amikacin-, and Kanamycin-Resistant Tuberculosis in an Automated, Multiplexed 10-Color Assay Suitable for Point-of-Care Use

2016 ◽  
Vol 55 (1) ◽  
pp. 183-198 ◽  
Author(s):  
Soumitesh Chakravorty ◽  
Sandy S. Roh ◽  
Jennifer Glass ◽  
Laura E. Smith ◽  
Ann Marie Simmons ◽  
...  
Keyword(s):  
Point Of Care ◽  
Stokes Shift ◽  
Drug Resistant ◽  
Wild Type ◽  
Resistance Mutations ◽  
Content Type ◽  
Automated Assay ◽  
Resistant Tuberculosis ◽  
Three Phase ◽  
Selection Of

ABSTRACTExtensively drug-resistant (XDR) tuberculosis (TB) cannot be easily or quickly diagnosed. We developed a rapid, automated assay for the detection of XDR-TB plus resistance to the drug isoniazid (INH) for point-of-care use. Using a simple filter-based cartridge with an integrated sample processing function, the assay identified a wide selection of wild-type and mutant sequences associated with XDR-TB directly from sputum. Four new large-Stokes-shift fluorophores were developed. When these four Stokes-shift fluorophores were combined with six conventional fluorophores, 10-color probe detection in a single PCR tube was enabled. A new three-phase, double-nested PCR approach allowed robust melting temperature analysis with enhanced limits of detection (LODs). Finally, newly designed sloppy molecular beacons identified many different mutations using a small number of probes. The assay correctly distinguished wild-type sequences from 32 commonly occurring mutant sequences tested ingyrA,gyrB,katG, andrrsgenes and the promoters ofinhAandeisgenes responsible for resistance to INH, the fluoroquinolone (FQ) drugs, amikacin (AMK), and kanamycin (KAN). The LOD was 300 CFU ofMycobacterium tuberculosisin 1 ml sputum. The rate of detection of heteroresistance by the assay was equivalent to that by Sanger sequencing. In a blind study of 24 clinical sputum samples, resistance mutations were detected in all targets with 100% sensitivity, with the specificity being 93.7 to 100%. Compared to the results of phenotypic susceptibility testing, the sensitivity of the assay was 75% for FQs and 100% each for INH, AMK, and KAN and the specificity was 100% for INH and FQ and 94% for AMK and KAN. Our approach could enable testing for XDR-TB in point-of-care settings, potentially identifying highly drug-resistant TB more quickly and simply than currently available methods.

scholarly journals Evolution of Fluconazole-ResistantCandida albicansStrains by Drug-Induced Mating Competence and Parasexual Recombination

mBio ◽  
2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Christina Popp ◽  
Bernardo Ramírez-Zavala ◽  
Sonja Schwanfelder ◽  
Ines Krüger ◽  
Joachim Morschhäuser
Keyword(s):  
Drug Resistance ◽  
Mating Type ◽  
Acquired Resistance ◽  
Resistance Mechanisms ◽  
Drug Resistant ◽  
Resistance Mutations ◽  
Type Locus ◽  
Content Type ◽  
Mating Type Locus ◽  
Resistant Progeny

ABSTRACTThe clonal population structure ofCandida albicanssuggests that (para)sexual recombination does not play an important role in the lifestyle of this opportunistic fungal pathogen, an assumption that is strengthened by the fact that mostC. albicansstrains are heterozygous at the mating type locus (MTL) and therefore mating-incompetent. On the other hand, mating might occur within clonal populations and allow the combination of advantageous traits that were acquired by individual cells to adapt to adverse conditions. We have investigated if parasexual recombination may be involved in the evolution of highly drug-resistant strains exhibiting multiple resistance mechanisms against fluconazole, an antifungal drug that is commonly used to treat infections byC. albicans. Growth of strains that were heterozygous forMTLand different fluconazole resistance mutations in the presence of the drug resulted in the emergence of derivatives that had become homozygous for the mutated allele and the mating type locus and exhibited increased drug resistance. WhenMTLa/aandMTLα/α cells of these strains were mixed in all possible combinations, we could isolate mating products containing the genetic material from both parents. The initial mating products did not exhibit higher drug resistance than their parental strains, but further propagation under selective pressure resulted in the loss of the wild-type alleles and increased fluconazole resistance. Therefore, fluconazole treatment not only selects for resistance mutations but also promotes genomic alterations that confer mating competence, which allows cells in an originally clonal population to exchange individually acquired resistance mechanisms and generate highly drug-resistant progeny.IMPORTANCESexual reproduction is an important mechanism in the evolution of species, since it allows the combination of advantageous traits of individual members in a population. The pathogenic yeastCandida albicansis a diploid organism that normally propagates in a clonal fashion, because heterozygosity at the mating type locus (MTL) inhibits mating between cells. Here we show thatC. albicanscells that have acquired drug resistance mutations during treatment with the commonly used antifungal agent fluconazole rapidly develop further increased resistance by genome rearrangements that result in simultaneous loss of heterozygosity for the mutated allele and the mating type locus. This enables the drug-resistant cells of a population to switch to the mating-competent opaque morphology and mate with each other to combine different individually acquired resistance mechanisms. The tetraploid mating products reassort their merged genomes and, under selective pressure by the drug, generate highly resistant progeny that have retained the advantageous mutated alleles. Parasexual propagation, promoted by stress-induced genome rearrangements that result in the acquisition of mating competence in cells with adaptive mutations, may therefore be an important mechanism in the evolution ofC. albicanspopulations.

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