scholarly journals Population Genetics Study of Isoniazid Resistance Mutations and Evolution of Multidrug-Resistant Mycobacterium tuberculosis

2006 ◽  
Vol 50 (8) ◽  
pp. 2640-2649 ◽  
Author(s):  
Manzour Hernando Hazbón ◽  
Michael Brimacombe ◽  
Miriam Bobadilla del Valle ◽  
Magali Cavatore ◽  
Marta Inírida Guerrero ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Large Scale ◽  
Sample Selection ◽  
Multidrug Resistant ◽  
Small Sample ◽  
Inverse Association ◽  
Resistance Mutations ◽  
Isoniazid Resistance ◽  
Large Scale Analysis ◽  
Small Sample Sizes

ABSTRACT The molecular basis for isoniazid resistance in Mycobacterium tuberculosis is complex. Putative isoniazid resistance mutations have been identified in katG, ahpC, inhA, kasA, and ndh. However, small sample sizes and related potential biases in sample selection have precluded the development of statistically valid and significant population genetic analyses of clinical isoniazid resistance. We present the first large-scale analysis of 240 alleles previously associated with isoniazid resistance in a diverse set of 608 isoniazid-susceptible and 403 isoniazid-resistant clinical M. tuberculosis isolates. We detected 12 mutant alleles in isoniazid-susceptible isolates, suggesting that these alleles are not involved in isoniazid resistance. However, mutations in katG, ahpC, and inhA were strongly associated with isoniazid resistance, while kasA mutations were associated with isoniazid susceptibility. Remarkably, the distribution of isoniazid resistance-associated mutations was different in isoniazid-monoresistant isolates from that in multidrug-resistant isolates, with significantly fewer isoniazid resistance mutations in the isoniazid-monoresistant group. Mutations in katG315 were significantly more common in the multidrug-resistant isolates. Conversely, mutations in the inhA promoter were significantly more common in isoniazid-monoresistant isolates. We tested for interactions among mutations and resistance to different drugs. Mutations in katG, ahpC, and inhA were associated with rifampin resistance, but only katG315 mutations were associated with ethambutol resistance. There was also a significant inverse association between katG315 mutations and mutations in ahpC or inhA and between mutations in kasA and mutations in ahpC. Our results suggest that isoniazid resistance and the evolution of multidrug-resistant strains are complex dynamic processes that may be influenced by interactions between genes and drug-resistant phenotypes.

scholarly journals Use of Antiplatelet Agents Decreases the Positive Predictive Value of Fecal Immunochemical Tests for Colorectal Cancer but Does Not Affect Their Sensitivity

2021 ◽  
Vol 11 (6) ◽  
pp. 497
Author(s):  
Yoonsuk Jung ◽  
Eui Im ◽  
Jinhee Lee ◽  
Hyeah Lee ◽  
Changmo Moon
Keyword(s):  
Colorectal Cancer ◽  
Large Scale ◽  
Screening Program ◽  
Antiplatelet Agents ◽  
Population Based ◽  
Small Sample ◽  
Antithrombotic Agents ◽  
Predictive Values ◽  
Prescription Rates ◽  
Small Sample Sizes

Previous studies have evaluated the effects of antithrombotic agents on the performance of fecal immunochemical tests (FITs) for the detection of colorectal cancer (CRC), but the results were inconsistent and based on small sample sizes. We studied this topic using a large-scale population-based database. Using the Korean National Cancer Screening Program Database, we compared the performance of FITs for CRC detection between users and non-users of antiplatelet agents and warfarin. Non-users were matched according to age and sex. Among 5,426,469 eligible participants, 768,733 used antiplatelet agents (mono/dual/triple therapy, n = 701,683/63,211/3839), and 19,569 used warfarin, while 4,638,167 were non-users. Among antiplatelet agents, aspirin, clopidogrel, and cilostazol ranked first, second, and third, respectively, in terms of prescription rates. Users of antiplatelet agents (3.62% vs. 4.45%; relative risk (RR): 0.83; 95% confidence interval (CI): 0.78–0.88), aspirin (3.66% vs. 4.13%; RR: 0.90; 95% CI: 0.83–0.97), and clopidogrel (3.48% vs. 4.88%; RR: 0.72; 95% CI: 0.61–0.86) had lower positive predictive values (PPVs) for CRC detection than non-users. However, there were no significant differences in PPV between cilostazol vs. non-users and warfarin users vs. non-users. For PPV, the RR (users vs. non-users) for antiplatelet monotherapy was 0.86, while the RRs for dual and triple antiplatelet therapies (excluding cilostazol) were 0.67 and 0.22, respectively. For all antithrombotic agents, the sensitivity for CRC detection was not different between users and non-users. Use of antiplatelet agents, except cilostazol, may increase the false positives without improving the sensitivity of FITs for CRC detection.

scholarly journals Detection of mutations associated with isoniazid resistance in multidrug-resistant Mycobacterium tuberculosis clinical isolates

2014 ◽  
Vol 69 (9) ◽  
pp. 2369-2375 ◽  
Author(s):  
Tomasz Jagielski ◽  
Zofia Bakuła ◽  
Katarzyna Roeske ◽  
Michał Kamiński ◽  
Agnieszka Napiórkowska ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Multidrug Resistant ◽  
Clinical Isolates ◽  
Isoniazid Resistance ◽  
Detection Of Mutations

scholarly journals Collaboration and Open Science Initiatives in Primate Research

2021 ◽  
Author(s):  
ManyPrimates ◽  
Alba Motes Rodrigo ◽  
Charlotte Canteloup ◽  
Sonja J. Ebel ◽  
Christopher I Petkov ◽  
...  
Keyword(s):  
Cognitive Abilities ◽  
Large Scale ◽  
Open Science ◽  
Small Sample ◽  
Primate Research ◽  
Research Model ◽  
Primate Cognition ◽  
History Of ◽  
Small Sample Sizes ◽  
Successful Collaboration

Traditionally, primate cognition research has been conducted by independent teams on small populations of a few species. Such limited variation and small sample sizes pose problems that prevent us from reconstructing the evolutionary history of primate cognition. In this chapter, we discuss how large-scale collaboration, a research model successfully implemented in other fields, makes it possible to obtain the large and diverse datasets needed to conduct robust comparative analysis of primate cognitive abilities. We discuss the advantages and challenges of large-scale collaborations and argue for the need for more open science practices in the field. We describe these collaborative projects in psychology and primatology and introduce ManyPrimates as the first, successful collaboration that has established an infrastructure for large-scale, inclusive research in primate cognition. Considering examples of large-scale collaborations both in primatology and psychology, we conclude that this type of research model is feasible and has the potential to address otherwise unattainable questions in primate cognition.

scholarly journals Constraints of Drug Resistance in Mycobacterium tuberculosis - Prospects for Pharmacological Reversion of Susceptibility to Antibiotics

2017 ◽  
Vol 8 (1) ◽  
pp. 33-43 ◽  
Author(s):  
Aleksandr I. Ilin ◽  
Murat E. Kulmanov ◽  
Ilya S. Korotetskiy ◽  
Marina V. Lankina ◽  
Gulshara K. Akhmetova ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Drug Resistance ◽  
Mycobacterium Tuberculosis ◽  
Genetic Heterogeneity ◽  
Multidrug Resistant ◽  
Resistance Mutations ◽  
General Increase ◽  
Drug Induced ◽  
Mdr Tb ◽  
Resistant Strains

Emergence of multidrug resistant strains ofMycobacterium tuberculosis(MDR-TB) threatens humanity. This problem was complicated by the crisis in development of new anti-tuberculosis antibiotics. Induced reversion of drug resistance seems promising to overcome the problem. Successful clinical trial of a new anti-tuberculosis nanomolecular complex FS-1 has demonstrated prospectively of this approach in combating MDR-TB. Several clinical MDR-TB cultures were isolated from sputum samples prior and in the process of the clinical trial. Every isolate was tested for susceptibility to antibiotics and then they were sequenced for comparative genomics. It was found that the treatment with FS-1 caused an increase in the number of antibiotic susceptible strains among Mtb isolates that was associated with a general increase of genetic heterogeneity of the isolates. Observed impairing of phthiocerol dimycocerosate biosynthesis by disruptive mutations inppsACDsubunits indicated a possible virulence remission for the sake of persistence. It was hypothesized that the FS-1 treatment eradicated the most drug resistant Mtb variants from the population by aggravating the fitness cost of drug resistance mutations. Analysis of distribution of these mutations in the global Mtb population revealed that many of them were incompatible with each other and dependent on allelic states of many other polymorphic loci. The latter discovery may explain the negative correlation between the genetic heterogeneity of the population and the level of drug tolerance. To the best of our knowledge, this work was the first experimental confirmation of the drug induced antibiotic resistance reversion by the induced synergy mechanism that previously was predicted theoretically.

scholarly journals Age and sex dependent variability of type 2 dopamine receptors in the human brain: A large-scale PET cohort

2021 ◽  
Author(s):  
Tuulia Malén ◽  
Tomi Karjalainen ◽  
Janne Isojärvi ◽  
Aki Vehtari ◽  
Paul-Christian Bürkner ◽  
...  
Keyword(s):  
Human Brain ◽  
Large Scale ◽  
Movement Control ◽  
Heterogeneous Data ◽  
Small Sample ◽  
Cross Sectional ◽  
Psychiatric Conditions ◽  
Small Sample Sizes ◽  
Age And Sex

BACKGROUND: The dopamine system contributes to a multitude of functions ranging from reward and motivation to learning and movement control, making it a key component in goal-directed behavior. Altered dopaminergic function is observed in neurological and psychiatric conditions. Numerous factors have been proposed to influence dopamine function, but due to small sample sizes and heterogeneous data analysis methods in previous studies their specific and joint contributions remain unresolved. METHODS: In this cross-sectional register-based study we investigated how age, sex, body mass index (BMI), as well as cerebral hemisphere and regional volume influence striatal type 2 dopamine receptor (D2R) availability in the human brain. We analyzed a large historical dataset (n=156, 120 males and 36 females) of [11C]raclopride PET scans performed between 2004 and 2018. RESULTS: Striatal D2R availability decreased through age for both sexes and was higher in females versus males throughout age. BMI and striatal D2R availability were weakly associated. There was no consistent lateralization of striatal D2R. The observed effects were independent of regional volumes. These results were validated using two different spatial normalization methods, and the age and sex effects also replicated in an independent sample (n=135). CONCLUSIONS: D2R density is dependent on age and sex, which may contribute to the vulnerability of neurological and psychiatric conditions involving altering D2R expression.

scholarly journals Genotypic Analysis of Genes Associated with Independent Resistance and Cross-Resistance to Isoniazid and Ethionamide in Mycobacterium tuberculosis Clinical Isolates

2015 ◽  
Vol 59 (12) ◽  
pp. 7805-7810 ◽  
Author(s):  
Johana Rueda ◽  
Teresa Realpe ◽  
Gloria Isabel Mejia ◽  
Elsa Zapata ◽  
Juan Carlos Rozo ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Multidrug Resistant ◽  
Cross Resistance ◽  
Resistance Mutations ◽  
Content Type ◽  
Genotypic Analysis ◽  
Mdr Tb ◽  
Proportion Method ◽  
Emergence Of Resistance ◽  
Phenotypic Susceptibility

ABSTRACTEthionamide (ETH) is an antibiotic used for the treatment of multidrug-resistant (MDR) tuberculosis (TB) (MDR-TB), and its use may be limited with the emergence of resistance in theMycobacterium tuberculosispopulation. ETH resistance inM. tuberculosisis phenomenon independent or cross related when accompanied with isoniazid (INH) resistance. In most cases, resistance to INH and ETH is explained by mutations in theinhApromoter and in the following genes:katG,ethA,ethR,mshA,ndh, andinhA. We sequenced the above genes in 64M. tuberculosisisolates (n= 57 ETH-resistant MDR-TB isolates;n= 3 ETH-susceptible MDR-TB isolates; andn= 4 fully susceptible isolates). Each isolate was tested for susceptibility to first- and second-line drugs using the agar proportion method. Mutations were observed in ETH-resistant MDR-TB isolates at the following rates: 100% inkatG, 72% inethA, 45.6% inmshA, 8.7% inndh, and 33.3% ininhAor its promoter. Of the three ETH-susceptible MDR-TB isolates, all showed mutations inkatG; one had a mutation inethA, and another, inmshAandinhA. Finally, of the four fully susceptible isolates, two showed no detectable mutation in the studied genes, and two had mutations inmshAgene unrelated to the resistance. Mutations not previously reported were found in theethA,mshA,katG, andndhgenes. The concordance between the phenotypic susceptibility testing to INH and ETH and the sequencing was 1 and 0.45, respectively. Among isolates exhibiting INH resistance, the high frequency of independent resistance and cross-resistance with ETH in theM. tuberculosisisolates suggests the need to confirm the susceptibility to ETH before considering it in the treatment of patients with MDR-TB.

scholarly journals Complete Genome Sequences of Two Multidrug-Resistant Mycobacterium tuberculosis Strains Isolated in Guiyang, China

2018 ◽  
Vol 6 (1) ◽  
Author(s):  
Zhenghong Chen ◽  
Weizheng Ou ◽  
Xiangyu Fan ◽  
Guzhen Cui ◽  
Qiong Wang ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Complete Genome ◽  
Multidrug Resistant ◽  
Dna Array ◽  
Genome Sequences ◽  
Isoniazid Resistance ◽  
Proportion Method ◽  
False Diagnosis

ABSTRACT We identified the genome sequences of two Mycobacterium tuberculosis isolates. They were resistant to rifampin and isoniazid, as determined by the agar proportion method, but were susceptible to isoniazid, as determined by the DNA array method. The genome sequences showed that a katG deletion led to the false diagnosis of isoniazid resistance by DNA array.

scholarly journals Epigenome-wide meta-analysis of blood DNA methylation and its association with subcortical volumes: findings from the ENIGMA Epigenetics Working Group

2019 ◽  
Author(s):  
Tianye Jia ◽  
Congying Chu ◽  
Yun Liu ◽  
Jenny van Dongen ◽  
Evangelos Papastergios ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Nucleus Accumbens ◽  
Large Scale ◽  
Biomarker Discovery ◽  
Association Studies ◽  
Meta Analysis ◽  
Hippocampal Volume ◽  
Small Sample ◽  
Small Sample Sizes ◽  
Meta Analyses

AbstractDNA methylation, which is modulated by both genetic factors and environmental exposures, may offer a unique opportunity to discover novel biomarkers of disease-related brain phenotypes, even when measured in other tissues than brain, such as blood. A few studies of small sample sizes have revealed associations between blood DNA methylation and neuropsychopathology, however, large-scale epigenome-wide association studies (EWAS) are needed to investigate the utility of DNA methylation profiling as a peripheral marker for the brain. Here, in an analysis of eleven international cohorts, totalling 3337 individuals, we report epigenome-wide meta-analyses of blood DNA methylation with volumes of the hippocampus, thalamus and nucleus accumbens (NAcc)—three subcortical regions selected for their associations with disease and heritability and volumetric variability. Analyses of individual CpGs revealed genome-wide significant associations with hippocampal volume at two loci. No significant associations were found for analyses of thalamus and nucleus accumbens volumes. Cluster-based analyses revealed additional differentially methylated regions (DMRs) associated with hippocampal volume. DNA methylation at these loci affected expression of proximal genes involved in learning and memory, stem cell maintenance and differentiation, fatty acid metabolism and type-2 diabetes. These DNA methylation marks, their interaction with genetic variants and their impact on gene expression offer new insights into the relationship between epigenetic variation and brain structure and may provide the basis for biomarker discovery in neurodegeneration and neuropsychiatric conditions.

Modern Clinician-initiated Clinical Trials to Determine Optimal Therapy for Multidrug-resistant Gram-negative Infections

2019 ◽  
Vol 71 (2) ◽  
pp. 433-439
Author(s):  
Adam G Stewart ◽  
Patrick N A Harris ◽  
Mark Chatfield ◽  
Scott R Evans ◽  
David van Duin ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Treatment Options ◽  
Treatment Strategies ◽  
Multidrug Resistant ◽  
Small Sample ◽  
Consensus Approach ◽  
Gram Negative ◽  
Therapeutic Trials ◽  
Clinical Trial Designs ◽  
Small Sample Sizes

Abstract Treatment options for multidrug-resistant (MDR) gram-negative infection are growing. However, postregistration, pragmatic, and clinician-led clinical trials in this field are few, recruit small sample sizes, and experience deficiencies in design and operations. MDR gram-negative therapeutic trials are often inefficient, only evaluating a single antibiotic or strategy at a time. Novel clinical trial designs offer potential solutions by attempting to obtain clinically meaningful conclusions at the end or during a trial, for many treatment strategies, simultaneously. An integrated, consensus approach to MDR gram-negative infection trial design is crucial.

scholarly journals Defining the biological bases of individual differences in musicality

2015 ◽  
Vol 370 (1664) ◽  
pp. 20140092 ◽  
Author(s):  
Bruno Gingras ◽  
Henkjan Honing ◽  
Isabelle Peretz ◽  
Laurel J. Trainor ◽  
Simon E. Fisher
Keyword(s):  
Large Scale ◽  
Twin Studies ◽  
Small Sample ◽  
Aptitude Tests ◽  
Large Scale Assessment ◽  
Genome Wide ◽  
Entry Points ◽  
High Heritability ◽  
Small Sample Sizes ◽  
Complex Human Traits

Advances in molecular technologies make it possible to pinpoint genomic factors associated with complex human traits. For cognition and behaviour, identification of underlying genes provides new entry points for deciphering the key neurobiological pathways. In the past decade, the search for genetic correlates of musicality has gained traction. Reports have documented familial clustering for different extremes of ability, including amusia and absolute pitch (AP), with twin studies demonstrating high heritability for some music-related skills, such as pitch perception. Certain chromosomal regions have been linked to AP and musical aptitude, while individual candidate genes have been investigated in relation to aptitude and creativity. Most recently, researchers in this field started performing genome-wide association scans. Thus far, studies have been hampered by relatively small sample sizes and limitations in defining components of musicality, including an emphasis on skills that can only be assessed in trained musicians. With opportunities to administer standardized aptitude tests online, systematic large-scale assessment of musical abilities is now feasible, an important step towards high-powered genome-wide screens. Here, we offer a synthesis of existing literatures and outline concrete suggestions for the development of comprehensive operational tools for the analysis of musical phenotypes.

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