scholarly journals Rare alternative second line injectable drug resistance markers identified by gene-wise genome wide association in M. tuberculosis with unexplained resistance

2021 ◽  
Author(s):  
Derek Vanian Conkle-Gutierrez ◽  
Calvin Kim ◽  
Sarah M Ramirez-Busby ◽  
Samuel J Modlin ◽  
Mikael Mansjö ◽  
...  
Keyword(s):  
Statistical Power ◽  
Point Mutations ◽  
Kanamycin Resistance ◽  
The Novel ◽  
Second Line ◽  
Mechanisms Of Resistance ◽  
Phenotypic Resistance ◽  
Genomic Markers ◽  
Novel Association ◽  
Promoter Mutations

Point mutations in the rrs gene and eis promoter are known to confer resistance to second-line injectable drugs (SLIDs) amikacin (AMK), capreomycin (CAP), and kanamycin (KAN). While mutations in these canonical genes confer a majority of SLID-resistance, alternative mechanisms of resistance are not uncommon and threaten effective treatment decisions when using conventional molecular diagnostics. In total, 1184 clinical M. tuberculosis isolates from 7 countries were studied for genomic markers associated with phenotypic resistance. The markers rrs:A1401G and rrs:G1484T were associated with resistance to all three SLIDs, and three known markers in the eis promoter (eis:G-10A, eis:C-12T, and eis:C-14T) were similarly associated with kanamycin resistance (KAN-R). Among 325, 324, 270 AMK-R, CAP-R, and KAN-R isolates, 264 (81.2%), 250 (77.2%), and 249 (92.3%) harbored canonical mutations, respectively. Thirteen isolates harbored more than one canonical mutation. Canonical mutations did not account for 111 of the phenotypically resistant isolates. A gene-wise method identified three genes and promoters with mutations that, on aggregate, associated with unexplained resistance to at least one SLID. Our analysis associated whiB7 promoter mutations with KAN resistance, supporting clinical relevance for the previously demonstrated role of whiB7 overexpression in KAN resistance. We also provide evidence for the novel association of ppe51 (a gene previously associated with various antimicrobial compounds) with AMK resistance, and for the novel association of thrB with AMK and CAP resistance. The use of gene-wise association can provide additional insight, and therefore is recommended for identification of rare mechanisms of resistance when individual mutations carry insufficient statistical power.

scholarly journals Molecular Characterization and Antimicrobial Susceptibility of C. jejuni Isolates from Italian Wild Bird Populations

Pathogens ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 304 ◽  
Author(s):  
Francesca Marotta ◽  
Anna Janowicz ◽  
Lisa Di Marcantonio ◽  
Claudia Ercole ◽  
Guido Di Donato ◽  
...  
Keyword(s):  
Nalidixic Acid ◽  
Point Mutations ◽  
Bird Species ◽  
Acid Resistance ◽  
Wild Birds ◽  
23S Rrna ◽  
The Novel ◽  
Phenotypic Resistance ◽  
Bird Populations ◽  
Sequence Types

Poultry is considered a major reservoir of human campylobacteriosis. It also been reported that not only poultry, but also wild birds, are capable of carrying C. jejuni, thus demonstrating to be a risk of spreading the bacteria in the environment. To gain insight into the population structure and investigate the antimicrobial resistance genotypes and phenotypes, we analyzed a collection of 135 C. jejuni from 15 species of wild birds in Italy. MLST revealed the presence of 41 sequence types (STs) and 13 clonal complexes (CCs). ST-179 complex and the generalist ST-45 complex were the most prevalent. Core genome MLST revealed that C. jejuni from ST-45 complex clustered according to the bird species, unlike the ST-179 complex which featured 3 different species in the same cluster. Overall we found a moderate prevalence of resistance to tetracycline (12.5%), ciprofloxacin and nalidixic acid (10%). The novel ST isolated from one pigeon showed resistance to all the antibiotics tested. The ST-179 complex (33.3%) was identified with significantly higher nalidixic acid resistance relative to other tested STs. Nine AMR genes (tet(O), cmeA, cmeB, cmeC, cmeR, aad, blaOXA-61, blaOXA-184 and erm(B)) and 23S rRNA and gyrA-associated point mutations were also described, indicating a concordance level between genotypic and phenotypic resistance of 23.3%, 23.4% and of 37.5% for streptomycin, tetracycline and quinolones/fluoroquinolones, respectively. We recommend that particular attention should be given to wild birds as key sentinel animals for the ecosystem contamination surveillance.

scholarly journals Rett syndrome: Novel correlations linking >96% genotype, disease severity, and seizures

2020 ◽  
pp. 1-11
Author(s):  
Lourdes M. Rodriguez ◽  
Alan K. Percy ◽  
Gary R. Cutter
Keyword(s):  
Disease Severity ◽  
Rett Syndrome ◽  
Seizure Frequency ◽  
Neurodevelopmental Disorder ◽  
Point Mutations ◽  
Clinical Severity ◽  
Seizure Type ◽  
The Novel ◽  
Generalized Seizures ◽  
Novel Association

BACKGROUND: Rett Syndrome (RTT), an incurable neurodevelopmental disorder associated in >96% with the X-linked gene, MECP2 includes seizures, among its most difficult issues, impacting many features and increasing morbidity and mortality. Linking these seizures with clinical severity in RTT is critical for estimating risk and guiding therapy. OBJECTIVE: Our primary purpose was to identify associations between type and frequency of seizures, disease severity, and specific MECP2 mutations to address the hypothesis that seizure frequency correlates with specific mutations and directly impacts clinical severity. METHODS: Mutation, seizure type and frequency, and clinical severity assessed by the Clinical Severity Scale (CSS) were extracted from the 5211 Natural History Study of Rett Syndrome and Related Disorders [1]. This involved observations from 222 Persons with classic or variant RTT and MECP2 mutation positive non-Rett diagnoses. Descriptive analyses were assessed utilizing SPSS software. Mutations include R106W, R133C, R168X, R294X, R306C, other point mutations, and early truncations. RESULTS: Greater frequency of generalized seizures and seizures of any type were associated with R106W mutations; R168X mutations had the highest disease severity, and R133C mutations had the lowest disease severity. CONCLUSION: Important correlations exist across several common MECP2 mutations, including the novel association between generalized seizure frequency and mild CSS.

scholarly journals Candida auris: A Quick Review on Identification, Current Treatments, and Challenges

2021 ◽  
Vol 22 (9) ◽  
pp. 4470
Author(s):  
Lucia Černáková ◽  
Maryam Roudbary ◽  
Susana Brás ◽  
Silva Tafaj ◽  
Célia F. Rodrigues
Keyword(s):  
Multidrug Resistance ◽  
Alternative Treatment ◽  
Fungal Pathogen ◽  
Fungal Diseases ◽  
High Rate ◽  
The Novel ◽  
Mechanisms Of Resistance ◽  
Candida Auris ◽  
Natural And Synthetic

Candida auris is a novel and major fungal pathogen that has triggered several outbreaks in the last decade. The few drugs available to treat fungal diseases, the fact that this yeast has a high rate of multidrug resistance and the occurrence of misleading identifications, and the ability of forming biofilms (naturally more resistant to drugs) has made treatments of C. auris infections highly difficult. This review intends to quickly illustrate the main issues in C. auris identification, available treatments and the associated mechanisms of resistance, and the novel and alternative treatment and drugs (natural and synthetic) that have been recently reported.

scholarly journals Ventilatory defects and treatable traits in very elderly patients

2021 ◽  
Vol 104 (2) ◽  
pp. 003685042110131
Author(s):  
João Gaspar-Marques ◽  
Teresa Palmeiro ◽  
Iolanda Caires ◽  
Paula Leiria Pinto ◽  
Nuno Neuparth ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Elderly Patients ◽  
Elderly Care ◽  
Airflow Limitation ◽  
The Novel ◽  
Z Score ◽  
Very Elderly ◽  
Chronic Respiratory Diseases ◽  
Novel Association ◽  
Peripheral Pulse

Though the approach used to classify chronic respiratory diseases is changing to a treatable-traits (TT) approach, data regarding very elderly patients is lacking. The objectives of this study were to assess TT frequency in very elderly patients and to study the link between extrapulmonary TT and ventilatory defects. Individuals (≥75 years) residing in elderly care centres answered a standardised questionnaire, underwent spirometry, atopy and fractional exhaled nitric oxide assessments and had their blood pressure and peripheral pulse oximetry measured. Pulmonary, extrapulmonary and behavioural TT were evaluated. Outcome variables were an airflow limitation (post-bronchodilator z-score FEV1/FVC<−1.64) and a restrictive spirometry pattern (z-score FEV1/FVC ≥ +1.64 and z-score FVC<−1.64). Seventy-two percent of the individuals who took part in the study ( n = 234) were women, and the median age of participants was 86 (IQR: 7.4). At least one pulmonary TT was identified in 105 (44.9%) individuals. The most frequent extrapulmonary TTs were: persistent systemic inflammation (47.0%), anaemia (34.4%), depression (32.5%) and obesity (27.4). Airflow limitation was exclusively associated with smoking (OR 5.03; 95% CI 1.56–16.22). A restrictive spirometry pattern was associated with cognitive impairment (OR: 3.89; 95% CI: 1.55–9.79). A high frequency of various TTs was found. The novel association between a restrictive spirometry pattern and cognitive impairment highlights the urgency of clinical research on this vulnerable age group.

scholarly journals Genomic Analysis of Antimicrobial Resistance Genotype-to-Phenotype Agreement in Helicobacter pylori

2020 ◽  
Vol 9 (1) ◽  
pp. 2
Author(s):  
Tal Domanovich-Asor ◽  
Yair Motro ◽  
Boris Khalfin ◽  
Hillary A. Craddock ◽  
Avi Peretz ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Antimicrobial Resistance ◽  
Point Mutations ◽  
Genomic Analysis ◽  
23S Rrna ◽  
Phenotype Correlation ◽  
Bioinformatics Pipeline ◽  
Phenotypic Resistance ◽  
Commercial Kits ◽  
H Pylori

Antimicrobial resistance (AMR) in Helicobacter pylori is increasing and can result in treatment failure and inappropriate antibiotic usage. This study used whole genome sequencing (WGS) to comprehensively analyze the H. pylori resistome and phylogeny in order to characterize Israeli H. pylori. Israeli H. pylori isolates (n = 48) underwent antimicrobial susceptibility testing (AST) against five antimicrobials and WGS analysis. Literature review identified 111 mutations reported to correlate with phenotypic resistance to these antimicrobials. Analysis was conducted via our in-house bioinformatics pipeline targeting point mutations in the relevant genes (pbp1A, 23S rRNA, gyrA, rdxA, frxA, and rpoB) in order to assess genotype-to-phenotype correlation. Resistance rates of study isolates were as follows: clarithromycin 54%, metronidazole 31%, amoxicillin 10%, rifampicin 4%, and levofloxacin 2%. Genotype-to-phenotype correlation was inconsistent; for every analyzed gene at least one phenotypically susceptible isolate was found to have a mutation previously associated with resistance. This was also observed regarding mutations commonly used in commercial kits to diagnose AMR in H. pylori cases. Furthermore, 11 novel point mutations associated with a resistant phenotype were detected. Analysis of a unique set of H. pylori isolates demonstrates that inferring resistance phenotypes from WGS in H. pylori remains challenging and should be optimized further.

scholarly journals Mutational Analysis of Quinolone-Resistant Determining Region gyrA and parC Genes in Quinolone-Resistant ESBL-Producing E. Coli

2021 ◽  
Vol 20 (3) ◽  
Author(s):  
Hairul Aini Hamzah ◽  
Rahmatullah Sirat ◽  
Mohammed Imad A. Mustafa Mahmud ◽  
Roesnita Baharudin
Keyword(s):  
Mutational Analysis ◽  
Single Point ◽  
Point Mutations ◽  
Multidrug Resistant ◽  
Quinolone Resistance ◽  
Resistant Bacteria ◽  
Single Point Mutation ◽  
Phenotypic Resistance ◽  
Drug Effectiveness ◽  
E Coli

 Introduction: Co-resistance to quinolones among extended spectrum β[1]lactamase (ESBL)-producing E. coli commonly occurs in clinical settings. Quinolones act on DNA gyrase and DNA topoisomerase enzymes, which are coded by gyrA and parC genes, thus any mutation to the genes may affect the drug effectiveness. The objective of the study was to characterize gyrA and parC genes in quinolone-resistant E. coli isolates and correlated the mutations with their phenotypic resistance. Materials and Methods: Thirty-two quinolone-resistant (QR) and six quinolone-sensitive (QS) ESBL-E. coli isolates were identified by antibiotic susceptibility and minimum inhibitory concentration tests. Bioinformatics analysis were conducted to study any mutations occurred in the genes and generate their codon compositions. Results: All the QR ESBL-E. coli isolates were identified as multidrug-resistant bacteria. A single point mutation in the quinolone resistance-determining region (QRDR) of gyrA, at codon 83, caused the substitution amino acid Ser83Leu. It is associated with a high level of resistance to nalidixic acid. However, double mutations Ser83Leu and Asp87Asn in the same region were significantly linked to higher levels of resistance to ciprofloxacin. Cumulative point mutations in gyrA and/or in parC were also correlated significantly (p<0.05) to increased resistance to ciprofloxacin. Conclusion: Together, the findings showed that the mutations in gyrA and parC genes handled the institution of intrinsic quinolone resistance in the ESBL-E. coli isolates. Thus, vigilant monitoring for emergence of new mutation in resistance genes may give an insight into dissemination of QR ESBL-E. coli in a particular region.

scholarly journals Fungal Endophyte Colonization Patterns Alter Over Time in the Novel Association Between Lolium perenne and Epichloë Endophyte AR37

2020 ◽  
Vol 11 ◽  
Author(s):  
Flavia Pilar Forte ◽  
Jan Schmid ◽  
Paul P. Dijkwel ◽  
Istvan Nagy ◽  
David E. Hume ◽  
...  
Keyword(s):  
Lolium Perenne ◽  
Fungal Endophyte ◽  
The Novel ◽  
Novel Association ◽  
Colonization Patterns ◽  
Over Time ◽  
Epichloë Endophyte

scholarly journals Suppressor Mutations in the Study of Photosystem I Biogenesis: sll0088 Is a Previously Unidentified Gene Involved in Reaction Center Accumulation in Synechocystis sp. Strain PCC 6803

2003 ◽  
Vol 185 (13) ◽  
pp. 3878-3887 ◽  
Author(s):  
Jianping Yu ◽  
Gaozhong Shen ◽  
Tao Wang ◽  
Donald A. Bryant ◽  
John H. Golbeck ◽  
...  
Keyword(s):  
Photosystem I ◽  
Point Mutations ◽  
Kanamycin Resistance ◽  
Negative Regulator ◽  
Binding Motif ◽  
Wild Type ◽  
Photoautotrophic Growth ◽  
Suppressor Mutations ◽  
Mutant Strains ◽  
Pcc 6803

ABSTRACT In previous work, some members of our group isolated mutant strains of Synechocystis sp. strain PCC 6803 in which point mutations had been inserted into the psaC gene to alter the cysteine residues to the FA and FB iron-sulfur clusters in the PsaC subunit of photosystem I (J. P. Yu, I. R. Vassiliev, Y. S. Jung, J. H. Golbeck, and L. McIntosh, J. Biol. Chem. 272:8032-8039, 1997). These mutant strains did not grow photoautotrophically due to suppressed levels of chlorophyll a and photosystem I. In the results described here, we show that suppressor mutations produced strains that are capable of photoautotrophic growth at moderate light intensity (20 μmol m−2 s−1). Two separate suppressor strains of C14SPsaC, termed C14SPsaC-R62 and C14SPsaC-R18, were studied and found to have mutations in a previously uncharacterized open reading frame of the Synechocystis sp. strain PCC 6803 genome named sll0088. C14SPsaC-R62 was found to substitute Pro for Arg at residue 161 as the result of a G482→C change in sll0088, and C14SPsaC-R18 was found to have a three-amino-acid insertion of Gly-Tyr-Phe following Cys231 as the result of a TGGTTATTT duplication at T690 in sll0088. These suppressor strains showed near-wild-type levels of chlorophyll a and photosystem I, yet the serine oxygen ligand to FB was retained as shown by the retention of the S ≥ 3/2 spin state of the [4Fe-4S] cluster. The inactivation of sll0088 by insertion of a kanamycin resistance cartridge in the primary C14SPsaC mutant produced an engineered suppressor strain capable of photoautotrophic growth. There was no difference in psaC gene expression or in the amount of PsaC protein assembled in thylakoids between the wild type and an sll0088 deletion mutant. The sll0088 gene encodes a protein predicted to be a transcriptional regulator with sequence similarities to transcription factors in other prokaryotic and eukaryotic organisms, including Arabidopsis thaliana. The protein contains a typical helix-turn-helix DNA-binding motif and can be classified as a negative regulator by phylogenetic analysis. This suggests that the product of sll0088 has a role in regulating the biogenesis of photosystem I.

scholarly journals New frontiers in the medical management of gastrointestinal stromal tumours

2019 ◽  
Vol 11 ◽  
pp. 175883591984194 ◽  
Author(s):  
Alessandro Mazzocca ◽  
Andrea Napolitano ◽  
Marianna Silletta ◽  
Mariella Spalato Ceruso ◽  
Daniele Santini ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Novel Therapies ◽  
Second Line ◽  
Clinical Testing ◽  
Mechanisms Of Resistance ◽  
Gastrointestinal Stromal Tumours ◽  
Molecular Events ◽  
Therapeutic Algorithm ◽  
History Of ◽  
Third Line

The tyrosine kinase inhibitor (TKI) imatinib has radically changed the natural history of KIT-driven gastrointestinal stromal tumours (GISTs). Approved second-line and third-line medical therapies are represented by the TKIs sunitinib and regorafenib, respectively. While imatinib remains the cardinal drug for patients with GISTs, novel therapies are being developed and clinically tested to overcome the mechanisms of resistance after treatments with the approved TKI, or to treat subsets of GISTs driven by rarer molecular events. Here, we review the therapy of GISTs, with a particular focus on the newest drugs in advanced phases of clinical testing that might soon change the current therapeutic algorithm.

scholarly journals Adaptations to the current ECCO/ESPGHAN guidelines on the management of paediatric acute severe colitis in the context of the COVID-19 pandemic: a RAND appropriateness panel

Gut ◽  
2020 ◽  
pp. gutjnl-2020-322449 ◽  
Author(s):  
Richard Hansen ◽  
Susanna Meade ◽  
R Mark Beattie ◽  
Marcus KH Auth ◽  
Nick Croft ◽  
...  
Keyword(s):  
The Novel ◽  
Second Line ◽  
Second Line Therapy ◽  
Nutrition Guidelines ◽  
Line Therapy ◽  
Asymptomatic Patients ◽  
Espghan Guidelines ◽  
Acute Severe Colitis ◽  
Prophylactic Anticoagulation ◽  
Severe Colitis

ObjectivePaediatric acute severe colitis (ASC) management during the novel SARS-CoV-2/COVID-19 pandemic is challenging due to reliance on immunosuppression and the potential for surgery. We aimed to provide COVID-19-specific guidance using the European Crohn’s and Colitis Organisation/European Society for Paediatric Gastroenterology, Hepatology and Nutrition guidelines for comparison.DesignWe convened a RAND appropriateness panel comprising 14 paediatric gastroenterologists and paediatric experts in surgery, rheumatology, respiratory and infectious diseases. Panellists rated the appropriateness of interventions for ASC in the context of the COVID-19 pandemic. Results were discussed at a moderated meeting prior to a second survey.ResultsPanellists recommended patients with ASC have a SARS-CoV-2 swab and expedited biological screening on admission and should be isolated. A positive swab should trigger discussion with a COVID-19 specialist. Sigmoidoscopy was recommended prior to escalation to second-line therapy or colectomy. Methylprednisolone was considered appropriate first-line management in all, including those with symptomatic COVID-19. Thromboprophylaxis was also recommended in all. In patients requiring second-line therapy, infliximab was considered appropriate irrespective of SARS-CoV-2 status. Delaying colectomy due to SARS-CoV-2 infection was considered inappropriate. Corticosteroid tapering over 8–10 weeks was deemed appropriate for all. After successful corticosteroid rescue, thiopurine maintenance was rated appropriate in patients with negative SARS-CoV-2 swab and asymptomatic patients with positive swab but uncertain in symptomatic COVID-19.ConclusionOur COVID-19-specific adaptations to paediatric ASC guidelines using a RAND panel generally support existing recommendations, particularly the use of corticosteroids and escalation to infliximab, irrespective of SARS-CoV-2 status. Consideration of routine prophylactic anticoagulation was recommended.

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