https://hdl.handle.net/20.500.14178/901 2026-05-03T13:23:46Z 2026-05-03T13:23:46Z Chudějová, Kateřina Mattioni Marchetti, Vittoria Zaccaria, Vita Kanova, Stepanka Šrámková, Anna Krůtová, Marcela Ryšková, Lenka Kroneislová, Gabriela Horvathova, Beata Tejkalova, Renata Krejci, Eva Vagnerova, Iva Zemanova, Zuzana Bitar, Ibrahim https://hdl.handle.net/20.500.14178/3743 2026-04-28T01:00:32Z 2026-01-01T00:00:00Z

One-year multicenter surveillance of Fosfomycin resistance Enterobacterales: the rise of FosA3-producing P. mirabilis Chudějová, Kateřina; Mattioni Marchetti, Vittoria; Zaccaria, Vita; Kanova, Stepanka; Šrámková, Anna; Krůtová, Marcela; Ryšková, Lenka; Kroneislová, Gabriela; Horvathova, Beata; Tejkalova, Renata; Krejci, Eva; Vagnerova, Iva; Zemanova, Zuzana; Bitar, Ibrahim The global rise of antimicrobial resistance has renewed interest in fosfomycin (FOS), an old antibiotic with activity against multidrug-resistant Enterobacterales . However, resistance to FOS is increasing, driven by impaired drug uptake, target modification, and by fosA -encoded enzymatic inactivation. This study assessed the prevalence and molecular basis of FOS resistance among Enterobacterales collected in Czech tertiary care hospitals in 2024. A total of 211 preliminary FOS-resistant isolates were obtained from nine hospitals across the Czech Republic, predominantly Proteus mirabilis (n=149) and Escherichia coli (n=57). All isolates showed elevated FOS MICs, and the PPF test identified FosA activity in 34/211 isolates. Carbon-source growth testing demonstrated widespread impairment of GlpT and UhpT transporters (93.8 % affecting both). PCR confirmed fosA genes in 14 isolates (9 P. mirabilis , 5 E. coli ). WGS revealed fosA3 as the dominant variant (85.7 %), followed by fosA4 (14.3 %). P. mirabilis isolates primarily belonged to ST185 and ST135, forming two Czech-specific fosA3 clusters with limited relatedness to international genomes. FosA-producing E. coli displayed broader diversity (ST69, ST58, ST550, ST1308). FosA4 was detected exclusively in E. coli . Most fosA -positive strains co-harbored ESBL genes, predominantly bla <inf>CTX-M-65</inf>. SNP-based phylogenies indicated local clonal circulation of fosA3 -positive P. mirabilis ST185, whereas E. coli isolates showed heterogeneous international linkages. Analysis of GlpT/UhpT/MurA identified numerous amino acid substitutions, though only a minority were predicted to affect protein function. This study documents the first broader emergence of plasmid-mediated FOS resistance in Czech Enterobacterales and underscores the importance of continuous genomic surveillance of fosA -mediated resistance.

2026-01-01T00:00:00Z Steiner Mrázová, Lenka Vrbacká, Alena Majer, Filip Stránecký, Viktor Nosková, Lenka Záhoráková, Daniela Májovská, Jitka Bitar, Ibrahim Klempíř, Jiří Šaligová, Jana Majlingová, Stella Giertlová, Mária Drenčáková, Petra Harvanová, Denisa Solařová, Pavla Brůha, Radan Dušek, Petr Kmoch, Stanislav Sikora, Jakub Jedličková, Ivana https://hdl.handle.net/20.500.14178/3741 2026-04-22T01:00:16Z 2026-01-01T00:00:00Z

Analyses of ATP7B mRNA in Nasopharyngeal Swab Samples Increase Yields of Wilson Disease Molecular Genetic Diagnostics Steiner Mrázová, Lenka; Vrbacká, Alena; Majer, Filip; Stránecký, Viktor; Nosková, Lenka; Záhoráková, Daniela; Májovská, Jitka; Bitar, Ibrahim; Klempíř, Jiří; Šaligová, Jana; Majlingová, Stella; Giertlová, Mária; Drenčáková, Petra; Harvanová, Denisa; Solařová, Pavla; Brůha, Radan; Dušek, Petr; Kmoch, Stanislav; Sikora, Jakub; Jedličková, Ivana Wilson disease (WD) is an autosomal recessive disorder of copper transport caused by bi-allelic pathogenic variants in the ATPase copper transporting beta gene (ATP7B). Results of standard genetic diagnostics remain inconclusive in 3%-20% of WD patients in part due to problematic assessment of variants of unknown or conflicting pathogenicity (synonymous variants included). Correct interpretation of potential effects of such variants can be substantially enhanced by RNA analyses. This strategy is, however, of limited utility in WD patients because of predominant liver expression of ATP7B. To avoid invasive bioptic liver collection and increase WD diagnostic yields, we searched for a surrogate tissue sample and identified profiles of ATP7B transcripts in nasopharyngeal swabs that were comparable to liver. Amplicons spanning ATP7B Exons 3-21 were prepared from the swab material and analysed by long-read nanopore sequencing to enable the detection of splicing changes and variant phasing. Diagnostic utility of this novel in vivo methodology was demonstrated by characterization of mRNA splicing abnormalities caused by synonymous ATP7B variants c.1488C>T (p.(Gly496=)), c.2241C>T (p.(Ile747=)), c.2292C>T (p.(Phe764=)), and a nonsense variant c.2336G>A (p.(Trp779Ter)) in four WD patients, who were not genetically resolved by standard techniques. Nasopharyngeal swab sampling is minimally invasive and allows effective analyses of mRNA to detect and/or validate effects of ATP7B variants in WD patients. Conclusive genetic diagnosis attained by this novel technique may facilitate family counselling and substantiate initiation of copper-chelation therapy in presymptomatic individuals.

2026-01-01T00:00:00Z Gil-Korilis, Adrián Ergui-Arbizu, Jorge Hanák, Petr Danešová, Natálie Tomášová, Kristýna Valíčková, Anna Horák, Josef Gentiluomo, Manuel Levý, Miroslav Křivonosková, Soňa Král, Jan Jungwirth, Jiří Vodičková, Ľudmila Vymetálková, Veronika Azqueta, Amaya Campa, Daniele Vodička, Pavel Vodenková, Soňa https://hdl.handle.net/20.500.14178/3733 2026-04-14T01:00:14Z 2026-01-01T00:00:00Z

Unraveling the telomere-mitochondrial axis in colorectal cancer: Results from a prospectively followed cohort Gil-Korilis, Adrián; Ergui-Arbizu, Jorge; Hanák, Petr; Danešová, Natálie; Tomášová, Kristýna; Valíčková, Anna; Horák, Josef; Gentiluomo, Manuel; Levý, Miroslav; Křivonosková, Soňa; Král, Jan; Jungwirth, Jiří; Vodičková, Ľudmila; Vymetálková, Veronika; Azqueta, Amaya; Campa, Daniele; Vodička, Pavel; Vodenková, Soňa Background Telomere shortening and mitochondrial dysfunction are well-known independent contributors to many diseases, but emerging evidence suggests a reciprocal relationship between the two processes. The role of the so-called telomere-mitochondrial axis in colorectal cancer (CRC) remains largely unknown. Methods This prospective cohort study screened CRC patients who underwent surgery, from whom peripheral blood, intestinal mucosa, and tumor samples were collected. Colonoscopically confirmed cancer- and adenoma-free healthy individuals were screened as controls, from whom peripheral blood and intestinal mucosa samples were obtained. Relative mitochondrial DNA copy number (mtDNA-CN) and relative telomere length (RTL) were measured in all samples by real-time quantitative polymerase chain reaction and were further compared and correlated considering clinical data. Relative mtDNA-CN was quantified using both TaqMan probes and SYBR Green to compare both methods. Finally, multivariable analyses were conducted to investigate the association between both biomarkers and the risk of tumor recurrence and mortality. Results A total of 166 CRC patients and 61 healthy individuals were included in the study. In TNM stage I patients, relative mtDNA-CN and RTL were negatively correlated with each other in intestinal mucosa (ρ = -0.77, p < 0.0001), tumor tissue (ρ = -0.41, p = 0.032), and the tumor-to-intestinal mucosa ratio (ρ = -0.39, p = 0.046). However, these associations disappeared with increasing TNM stage, suggesting a dysregulation of the telomere-mitochondrial axis in advanced disease. Higher relative mtDNA-CN in blood was associated with a lower risk of disease recurrence even after adjusting for multiple covariates (HR = 0.43, 95% CI 0.20-0.97, p = 0.041), highlighting its potential use as a prognostic tool. The quantification of mtDNA-CN performed by both methods -TaqMan probes and SYBR Green- was shown to be positively correlated (p < 0.01). Relative mtDNA-CN and RTL were found to be tissue-dependent in both CRC patients and healthy controls. Conclusions This study provides a novel contribution to the understanding of the almost unexplored telomere-mitochondrial axis in CRC, highlighting its potential role in disease progression and prognosis.

2026-01-01T00:00:00Z Surcinelli, Andrea Kalincik, Tomas Roos, Izanne D'amico, Emanuele Lechner-Scott, Jeannette Ozakbas, Serkan Hradilek, Pavel Horáková, Dana Vachová, Marta Panzera, Ivan Ruzza, Stefano Piscaglia, Maria Grazia Gerlach, Oliver Meca-Lallana, Jose Eustasio Valero-Lopez, Gabriel Kermode, Allan G. Fabis-Pedrini, Marzena J. Prevost, Julie Ampapa, Radek Hodgkinson, Suzanne Grand'maison, Francois Khoury, Samia J. John, Nevin A. Peterka, Marek Houskova, Jana Recmanova, Eva Rous, Zuzana Shaygannejad, Vahid Alroughani, Raed Kuhle, Jens Jakob, Gregor Brecl Grammond, Pierre Patti, Francesco Van Der Walt, Anneke Butzkueven, Helmut Foschi, Matteo https://hdl.handle.net/20.500.14178/3728 2026-04-10T01:00:12Z 2026-01-01T00:00:00Z

Comparative effectiveness of anti-CD20 therapies and S1P receptor modulators in late-onset multiple sclerosis: real-world evidence from the MSBase registry Surcinelli, Andrea; Kalincik, Tomas; Roos, Izanne; D'amico, Emanuele; Lechner-Scott, Jeannette; Ozakbas, Serkan; Hradilek, Pavel; Horáková, Dana; Vachová, Marta; Panzera, Ivan; Ruzza, Stefano; Piscaglia, Maria Grazia; Gerlach, Oliver; Meca-Lallana, Jose Eustasio; Valero-Lopez, Gabriel; Kermode, Allan G.; Fabis-Pedrini, Marzena J.; Prevost, Julie; Ampapa, Radek; Hodgkinson, Suzanne; Grand'maison, Francois; Khoury, Samia J.; John, Nevin A.; Peterka, Marek; Houskova, Jana; Recmanova, Eva; Rous, Zuzana; Shaygannejad, Vahid; Alroughani, Raed; Kuhle, Jens; Jakob, Gregor Brecl; Grammond, Pierre; Patti, Francesco; Van Der Walt, Anneke; Butzkueven, Helmut; Foschi, Matteo Background: Late-onset multiple sclerosis (LOMS), defined by symptom onset after age 50, is increasingly recognised as a distinct clinical entity. Evidence comparing disease-modifying therapies (DMTs) in this subgroup remains limited. Objectives: To compare clinical outcomes of anti-CD20 monoclonal antibodies and sphingosine-1-phosphate receptor modulators (S1PRMs) in LOMS. Design: Multicentre, observational cohort study based on real-world data from an international multiple sclerosis registry. Methods: We analysed data from the MSBase registry, including relapsing-remitting LOMS patients treated with anti-CD20 therapies (ocrelizumab, ofatumumab, rituximab) or S1PRMs (fingolimod, ozanimod, siponimod, ponesimod) for >= 6 months. Primary outcomes were annualised relapse rate (ARR), Expanded Disability Status Scale (EDSS) change, confirmed disability worsening (CDW), progression independent of relapse activity (PIRA), and PIRA without MRI activity (PIRMA). Analyses used inverse probability of treatment weighting (IPTW). Causal forest and best linear projector (BLP) models explored effect modification. Results: After weighting, 347 patients (median age 53.7 years; 69% female; median follow-up 6.9 years) were included. No significant differences were found for ARR, EDSS change, CDW, PIRA, or PIRMA. Exploratory analyses suggested greater anti-CD20 benefit in patients with earlier onset (<= 55 years), shorter disease duration (<= 2 years from diagnosis), and lower disability (EDSS < 3). Conclusions: In this real-world LOMS cohort, no statistically significant differences were observed between anti-CD20 and S1PRM therapies. Exploratory analyses suggested anti-CD20 may be associated with better outcomes in selected subgroups; these findings are hypothesis-generating.

2026-01-01T00:00:00Z