Browsing by Author "Leja, Marcis"

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    Abundance and prevalence of ESBL coding genes in patients undergoing first line eradication therapy for Helicobacter pylori
    (2023-08) Gudra, Dita; Silamikelis, Ivars; Pjalkovskis, Janis; Danenberga, Ilva; Pupola, Darta; Skenders, Girts; Ustinova, Maija; Megnis, Kaspars; Leja, Marcis; Vangravs, Reinis; Fridmanis, Davids
    The spread of extended-spectrum beta-lactamases (ESBLs) in nosocomial and community-acquired enterobacteria is an important challenge for clinicians due to the limited therapeutic options for infections that are caused by these organisms. Here, we developed a panel of ESBL coding genes, evaluated the abundance and prevalence of ESBL encoding genes in patients undergoing H. pylori eradication therapy, and summarized the effects of eradication therapy on functional profiles of the gut microbiome. To assess the repertoire of known beta lactamase (BL) genes, they were divided into clusters according to their evolutionary relation. Primers were designed for amplification of cluster marker regions, and the efficiency of this amplification panel was assessed in 120 fecal samples acquired from 60 patients undergoing H. pylori eradication therapy. In addition, fecal samples from an additional 30 patients were used to validate the detection efficiency of the developed ESBL panel. The presence for majority of targeted clusters was confirmed by NGS of amplification products. Metagenomic sequencing revealed that the abundance of ESBL genes within the pool of microorganisms was very low. The global relative abundances of the ESBL-coding gene clusters did not differ significantly among treatment states. However, at the level of each cluster, classical ESBL producers such as Klebsiella sp. for blaOXY (p = 0.0076), Acinetobacter sp. for blaADC (p = 0.02297) and others, differed significantly with a tendency to decrease compared to the pre- and post-eradication states. Only 13 clusters were common across all three datasets, suggesting a patient-specific distribution profile of ESBL-coding genes. The number of AMR genes detected in the post-eradication state was higher than that in the pre-eradication state, which could be attributed, at least in part, to the therapy. This study demonstrated that the ESBL screening panel was effective in targeting ESBL-coding gene clusters from bacterial DNA and that minor differences exist in the abundance and prevalence of ESBL-coding gene levels before and after eradication therapy.
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    Assessment of Serum Pepsinogens with and without Co-Testing with Gastrin-17 in Gastric Cancer Risk Assessment—Results from the GISTAR Pilot Study
    (2022-07) Robles, Claudia; Rudzite, Dace; Polaka, Inese; Sjomina, Olga; Tzivian, Lilian; Kikuste, Ilze; Tolmanis, Ivars; Vanags, Aigars; Isajevs, Sergejs; Liepniece-Karele, Inta; Razuka-Ebela, Danute; Parshutin, Sergej; Murillo, Raul; Herrero, Rolando; Young Park, Jin; Leja, Marcis
    Introduction––Serum pepsinogen tests for gastric cancer screening have been debated for decades. We assessed the performance of two pepsinogen assays with or without gastrin-17 for the detection of different precancerous lesions alone or as a composite endpoint in a Latvian cohort. Methods––Within the intervention arm of the GISTAR population-based study, participants with abnormal pepsinogen values by ELISA or latex-agglutination tests, or abnormal gastrin-17 by ELISA and a subset of subjects with all normal biomarker values were referred for upper endoscopy with biopsies. Performance of biomarkers, corrected by verification bias, to detect five composite outcomes based on atrophy, intestinal metaplasia, dysplasia or cancer was explored. Results––Data from 1045 subjects were analysed, of those 273 with normal biomarker results. Both pepsinogen assays showed high specificity (>93%) but poor sensitivity (range: 18.4–31.1%) that slightly improved when lesions were restricted to corpus location (40.5%) but decreased when dysplasia and prevalent cancer cases were included (23.8%). Adding gastrin-17 detection, sensitivity reached 33–45% while specificity decreased (range: 61.1–62%) and referral rate for upper endoscopy increased to 38.6%. Conclusions––Low sensitivity of pepsinogen assays is a limiting factor for their use in population-based primary gastric cancer screening, however their high specificity could be useful for triage.
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    Biopsy Sampling in Upper Gastrointestinal Endoscopy : A Survey from 10 Tertiary Referral Centres across Europe
    (2021-05) Bornschein, Jan; Tran-Nguyen, Terry; Fernandez-Esparrach, Gloria; Ash, Stephen; Balaguer, Francesc; Bird-Lieberman, Elisabeth L.; Córdova, Henry; Dzerve, Zane; Fassan, Matteo; Leja, Marcis; Lyutakov, Ivan; Middelburg, Tim; Moreira, Leticia; Nakov, Radislav; Nieuwenburg, Stella A.V.; O'Connor, Anthony; Realdon, Stefano; De Schepper, Heiko; Smet, Annemieke; Spaander, M. C.W.; Tolmanis, Ivars; Urbonas, Tadas; Weigt, Jochen; Hold, Georgina L.; Link, Alexander; Kupcinskas, Juozas
    Background: Guidelines give robust recommendations on which biopsies should be taken when there is endoscopic suggestion of gastric inflammation. Adherence to these guidelines often seems arbitrary. This study aimed to give an overview on current practice in tertiary referral centres across Europe. Methods: Data were collected at 10 tertiary referral centres. Demographic data, the indication for each procedure, endoscopic findings, and the number and sampling site of biopsies were recorded. Findings were compared between centres, and factors influencing the decision to take biopsies were explored. Results: Biopsies were taken in 56.6% of 9,425 procedures, with significant variation between centres (p < 0.001). Gastric biopsies were taken in 43.8% of all procedures. Sampling location varied with the procedure indication (p < 0.001) without consistent pattern across the centres. Fewer biopsies were taken in centres which routinely applied the updated Sydney classification for gastritis assessment (46.0%), compared to centres where this was done only upon request (75.3%, p < 0.001). This was the same for centres stratifying patients according to the OLGA system (51.8 vs. 73.0%, p < 0.001). More biopsies were taken in centres following the MAPS guidelines on stomach surveillance (68.1 vs. 37.1%, p < 0.001). Biopsy sampling was more likely in younger patients in 8 centres (p < 0.05), but this was not true for the whole cohort (p = 0.537). The percentage of procedures with biopsies correlated directly with additional costs charged in case of biopsies (r = 0.709, p = 0.022). Conclusion: Adherence to guideline recommendations for biopsy sampling at gastroscopy was inconsistent across the participating centres. Our data suggest that centre-specific policies are applied instead.
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    Lack of Association between Rs2067474 Polymorphism in the Histamine Receptor H2 Gene and Gastric Cancer in Latvian Population
    (2018-12-01) Moisejevs, Georgijs; Gailite, Linda; Isajevs, Sergejs; Nikitina-Zaķe, Liene; Kempa, Inga; Jančiauskas, Dainius; Kikuste, Ilze; Siviņš, Armands; Ancans, Guntis; Leja, Marcis; Scientific Laboratory of Molecular Genetics
    Histamine has an important role in the process of the gastric mucosa inflammation acting via histamine receptor H2 (encoded by the gene HRH2). Single nucleotide polymorphism of the enhancer element of HRH2 gene promoter rs2067474 (1018G>A)may be associated with changes of expression of the receptor. We attempted to clarify the association of this polymorphism with gastric cancer and/or atrophic gastritis in the Latvian (Caucasian) population. The study group consisted of 121 gastric cancer patients and 650 patients with no evidence of gastric neoplasia on upper gastrointestinal endoscopy. Genotyping for rs2067474 was performed with the TaqMan probe-based system using a commercially available probe for RT-PCR. The frequency of the A allele in the gastric cancer group was 0.41% and in the control group - 1.54% (p = 0.231). No significant differences were found comparing genotypes between gastric cancer versus control patients (OR = 0.236, CI95% = 0.030-1.896), patients with (n = 165) versus without (n = 485) gastric metaplastic lesions (OR = 0.854, CI95% = 0.288-2.540) and patients with (n = 297) and without (n = 353) gastric atrophic lesions (OR = 1.145, CI95% = 0.451-2.906). Our findings suggest that the HRH2 -1018G>A polymorphism (rs2067474) is neither associated with gastric cancer nor the grade of atrophic gastritis in the Latvian (Caucasian) population.
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    Modular Point-of-Care Breath Analyzer and Shape Taxonomy-Based Machine Learning for Gastric Cancer Detection
    (2022-02) Polaka, Inese; Bhandari, Manohar Prasad; Mezmale, Linda; Anarkulova, Linda; Veliks, Viktors; Sivins, Armands; Lescinska, Anna Marija; Tolmanis, Ivars; Vilkoite, Ilona; Ivanovs, Igors; Padilla, Marta; Mitrovics, Jan; Shani, Gidi; Haick, Hossam; Leja, Marcis; Department of Internal Diseases; Department of Doctoral Studies
    Background: Gastric cancer is one of the deadliest malignant diseases, and the non-invasive screening and diagnostics options for it are limited. In this article, we present a multi-modular device for breath analysis coupled with a machine learning approach for the detection of cancer-specific breath from the shapes of sensor response curves (taxonomies of clusters). Methods: We analyzed the breaths of 54 gastric cancer patients and 85 control group participants. The analysis was carried out using a breath analyzer with gold nanoparticle and metal oxide sensors. The response of the sensors was analyzed on the basis of the curve shapes and other features commonly used for comparison. These features were then used to train machine learning models using Naïve Bayes classifiers, Support Vector Machines and Random Forests. Results: The accuracy of the trained models reached 77.8% (sensitivity: up to 66.54%; specificity: up to 92.39%). The use of the proposed shape-based features improved the accuracy in most cases, especially the overall accuracy and sensitivity. Conclusions: The results show that this point-of-care breath analyzer and data analysis approach constitute a promising combination for the detection of gastric cancer-specific breath. The cluster taxonomy-based sensor reaction curve representation improved the results, and could be used in other similar applications.
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    Non-invasive diagnosis of gastroesophageal reflux disease using gastrin- and pepsinogen-based tests
    (2018) Moisejevs, Georgijs; Daugule, Ilva; Isajevs, Sergejs; Rudzite, Dace; Janciauskas, Dainius; Tolmanis, Ivars; Leja, Marcis; Scientific Laboratory of Molecular Genetics; Department of Internal Diseases
    Gastrin-17 (G-17), pepsinogen-1 (Pg1) and pepsinogen-2 (Pg2) reflect the functional state of gas-tric mucosa and are used for non-invasive diagnosis and screening of atrophic gastritis. The aimof the study was to clarify if erosive reflux disease (ERD) or non-ERD (NERD) can be distin-guished from other dyspeptic conditions in patients, in a non-invasive manner using specificbiomarkers. Levels of G-17, Pg1, and Pg2 were measured in 141 ERD patients (median age 48years, males — 68), 122 NERD patients (median age 45 years, males — 32) and 410 control pa-tients (median age 50 years, males — 97). Levels of biomarkers in ERD and NERD groups werecompared to controls. Median levels of G-17 (1.94 vs 2.92 pmol/L, p = 0.036) and Pg2 (6.70 vs7.79 μg/l,p= 0.046) were lower in the ERD group compared to control patients; no differencewith respect to the control was found for the NERD group. After exclusion of the patients havingat least one potential condition that might modify the levels of the biomarkers (gastric mucosa at-rophy, Helicobacter pylori colonisation), no difference in levels of biomarkers was observed withrespect to the control for both the ERD and NERD groups. G-17, Pg1, and Pg2 based tests can-not be used to distinguish ERD or NERD from other dyspeptic conditions in patients.
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    Pepsinogen testing for evaluation of the success of Helicobacter pylori eradication at 4 weeks after completion of therapy
    (2014) Leja, Marcis; Lapina, Sanita; Polaka, Inese; Rudzite, Dace; Vilkoite, Ilona; Daugule, Ilva; Belkovets, Anna; Pimanov, Sergey; Makarenko, Jelena; Tolmanis, Ivars; Lejnieks, Aivars; Boka, Viesturs; Rumba-Rozenfelde, Ingrida; Vikmanis, Uldis; Rīga Stradiņš University
    Background and objective: Pepsinogen levels in plasma are increased by inflammation in the gastric mucosa, including inflammation resulting from Helicobacter pylori infection. A decrease in pepsinogen II level has been suggested as a reliable marker to confirm the successful eradication of infection. The aim of our study was to evaluate the potential role of pepsinogens I and II, gastrin-17 and H. pylori antibodies in confirming successful eradication. Material and methods: Altogether 42 patients (25 women, 17 men), mean age 45 years (range 23-74), were enrolled. Pepsinogens I and II, gastrin-17 and H. pylori IgG antibodies were measured in plasma samples using an ELISA test (Biohit, Oyj., Finland) before the eradication and 4 weeks after completing the treatment. The success of eradication was determined by a urea breath test. Results: Eradication was successful in 31 patients (74%) and unsuccessful in 11 patients (26%). Pepsinogen II decreased significantly in both the successful (P = 0.029) and unsuccessful (P = 0.042) eradication groups. Pepsinogen I decreased significantly in the successful (P = 0.025) but not the unsuccessful (P = 0.29) eradication group. The pepsinogen I/II ratio increased in the successful eradication group (P = 0.0018) but not in the group in which treatment failed (P = 0.12). There were no differences in gastrin-17 or H. pylori antibody values. Conclusions: A decrease in pepsinogen II levels cannot be used as a reliable marker for the successful eradication of H. pylori 4 weeks after the completion of treatment. The increase in pepsinogen I/II ratio reflects differences in pepsinogen production following the eradication irrespective of improvement in atrophy.
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    Replication study of ulcerative colitis risk loci in a Lithuanian-Latvian case control sample
    (2013-10) Skieceviciene, Jurgita; Kiudelis, Gediminas; Ellinghaus, Eva; Balschun, Tobias; Jonaitis, Laimas V.; Zvirbliene, Aida; Denapiene, Goda; Leja, Marcis; Pranculiene, Gitana; Kalibatas, Vytenis; Saadati, Hamidreza; Ellinghaus, David; Andersen, Vibeke; Valantinas, Jonas; Irnius, Algimantas; Derovs, Aleksejs; Tamelis, Algimantas; Schreiber, Stefan; Kupcinskas, Limas; Franke, Andre; Department of Internal Diseases
    Background: Differences between populations might be reflected in their different genetic risk maps to complex diseases, for example, inflammatory bowel disease. We here investigated the role of known inflammatory bowel disease associated single nucleotide polymorphisms (SNPs) in a subset of patients with ulcerative colitis (UC) from the Northeastern European countries Lithuania and Latvia and evaluated possible epistatic interactions between these genetic variants. Methods: We investigated 77 SNPs derived from 5 previously published genome-wide association studies for Crohn's disease and UC. Our study panel comprised 444 Lithuanian and Latvian patients with UC and 1154 healthy controls. Single marker case control association and SNP-SNP epistasis analyses were performed. Results: We found 14 SNPs tagging 9 loci, including 21q21.1, NKX2-3, MST1, the HLA region, 1p36.13, IL10, JAK2, ORMDL3, and IL23R, to be associated with UC. Interestingly, the association of UC with previously identified variants in the HLA region was not the strongest association in our study (P = 4.34 × 1023, odds ratio [OR] = 1.25), which is in contrast to all previously published studies. No association with any disease subphenotype was found. SNP-SNP interaction analysis showed significant epistasis between SNPs in the PTPN22 (rs2476601) and C13orf31 (rs3764147) genes and increased risk for UC (P = 1.64 × 1026, OR = 2.44). The association has been confirmed in the Danish study group (P = 0.04, OR = 3.25). Conclusions: We confirmed the association of the 9 loci (21q21.1, 1p36.13, NKX2-3, MST1, the HLA region, IL10, JAK2, ORMDL3, and IL23R) with UC in the Lithuanian Latvian population. SNP-SNP interaction analyses showed that the combination of SNPs in the PTPN22 (rs2476601) and C13orf31 (rs3764147) genes increase the risk for UC.
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    The Role of an Artificial Intelligence Method of Improving the Diagnosis of Neoplasms by Colonoscopy
    (2023-02-13) Vilkoite, Ilona; Tolmanis, Ivars; Meri, Hosams Abu; Polaka, Inese; Mezmale, Linda; Anarkulova, Linda; Leja, Marcis; Lejnieks, Aivars; Department of Doctoral Studies; Department of Internal Diseases
    BACKGROUND: Colorectal cancer (CRC) is the third most common cancer worldwide. Colonoscopy is the gold standard examination that reduces the morbidity and mortality of CRC. Artificial intelligence (AI) could be useful in reducing the errors of the specialist and in drawing attention to the suspicious area. METHODS: A prospective single-center randomized controlled study was conducted in an outpatient endoscopy unit with the aim of evaluating the usefulness of AI-assisted colonoscopy in PDR and ADR during the day time. It is important to understand how already available CADe systems improve the detection of polyps and adenomas in order to make a decision about their routine use in practice. In the period from October 2021 to February 2022, 400 examinations (patients) were included in the study. One hundred and ninety-four patients were examined using the ENDO-AID CADe artificial intelligence device (study group), and 206 patients were examined without the artificial intelligence (control group). RESULTS: None of the analyzed indicators (PDR and ADR during morning and afternoon colonoscopies) showed differences between the study and control groups. There was an increase in PDR during afternoon colonoscopies, as well as ADR during morning and afternoon colonoscopies. CONCLUSIONS: Based on our results, the use of AI systems in colonoscopies is recommended, especially in circumstances of an increase of examinations. Additional studies with larger groups of patients at night are needed to confirm the already available data.
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    Toll-Like Receptor 1 Locus Re-examined in a Genome-Wide Association Study Update on Anti–Helicobacter pylori IgG Titers
    (2022-05) Lam, Suk Yee; Mommersteeg, Michiel C.; Yu, Bingting; Broer, Linda; Spaander, Manon C.W.; Frost, Fabian; Weiss, Stefan; Völzke, Henry; Lerch, Markus M.; Schöttker, Ben; Zhang, Yan; Stocker, Hannah; Brenner, Hermann; Levy, Daniel; Hwang, Shih Jen; Wood, Alexis C.; Rich, Stephen S.; Rotter, Jerome I.; Taylor, Kent D.; Tracy, Russell P.; Kabagambe, Edmond K.; Leja, Marcis; Klovins, Janis; Peculis, Raitis; Rudzite, Dace; Nikitina-Zake, Liene; Skenders, Girts; Rovite, Vita; Uitterlinden, André; Kuipers, Ernst J.; Fuhler, Gwenny M.; Homuth, Georg; Peppelenbosch, Maikel P.; Rīga Stradiņš University
    Background & Aims: A genome-wide significant association between anti–Helicobacter pylori (H pylori) IgG titers and Toll-like receptor (TLR1/6/10) locus on 4p14 was demonstrated for individuals of European ancestry, but not uniformly replicated. We re-investigated this association in an updated genome-wide association study (GWAS) meta-analysis for populations with low gastric cancer incidence, address potential causes of cohort heterogeneity, and explore functional implications of genetic variation at the TLR1/6/10 locus. Methods: The dichotomous GWAS (25% individuals exhibiting highest anti–H pylori IgG titers vs remaining 75%) included discovery and replication sampls of, respectively, n = 15,685 and n = 9676, all of European ancestry. Longitudinal analysis of serologic data was performed on H pylori–eradicated subjects (n = 132) and patients under surveillance for premalignant gastric lesions (n = 107). TLR1/6/10 surface expression, TLR1 mRNA, and cytokine levels were measured in leukocyte subsets of healthy subjects (n = 26) genotyped for TLR1/6/10 variants. Results: The association of the TLR1/6/10 locus with anti–H pylori IgG titers (rs12233670; β = −0.267 ± SE 0.034; P = 4.42 × 10−15) presented with high heterogeneity and failed replication. Anti–H pylori IgG titers declined within 2–4 years after eradication treatment (P = 0.004), and decreased over time in patients with premalignant gastric lesions (P < 0.001). Variation at the TLR1/6/10 locus affected TLR1-mediated cytokine production and TLR1 surface expression on monocytes (P = 0.016) and neutrophils (P = 0.030), but not mRNA levels. Conclusions: The association between anti–H pylori IgG titers and TLR1/6/10 locus was not replicated across cohorts, possibly owing to dependency of anti–H pylori IgG titers on therapy, clearance, and antibody decay. H pylori–mediated immune cell activation is partly mediated via TLR1 signaling, which in turn is affected by genetic variation.
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    Who Could Be Blamed in the Case of Discrepant Histology and Serology Results for Helicobacter pylori Detection?
    (2022-01) Skrebinska, Sabine; Megraud, Francis; Daugule, Ilva; Santare, Daiga; Isajevs, Sergejs; Liepniece-Karele, Inta; Bogdanova, Inga; Rudzite, Dace; Vangravs, Reinis; Kikuste, Ilze; Vanags, Aigars; Tolmanis, Ivars; Savcenko, Selga; Alix, Chloé; Herrero, Rolando; Park, Jin Young; Leja, Marcis
    Background. Discrepancies between histology and serology results for Helicobacter pylori detection could be caused by a variety of factors, including a biopsy sampling error, expertise of the pathologist, natural loss of infection due to advanced atrophy, or a false-positive serology in the case of a previous infection, since antibodies may be present in blood following recovery from the infection. Aims. To identify true H. pylori-positive individuals in discrepant cases by serology and histology using real time polymerase chain reaction (RT-PCR) as a gold standard. Methods. Study subjects with discrepant histology and serology results were selected from the GISTAR pilot study data base in Latvia. Subjects having received previous H. pylori eradication therapy or reporting use of proton pump inhibitors, antibacterial medications, or bismuth containing drugs one month prior to upper endoscopy were excluded. We compared the discrepant cases to the corresponding results of RT-PCR performed on gastric biopsies. Results. In total, 97 individuals with discrepant results were identified: 81 subjects were serology-positive/histology-negative, while 16 were serologynegative/histology-positive. Among the serology-positive/histology-negative cases, 64/81 (79.0%) were false-positives by serology and, for the majority, inflammation was absent in all biopsies, while, in the serology-negative/histology-positive group, only 6.2% were proven false-positives by histology. Conclusions. Among this high H. pylori prevalent, middle-aged population, the majority of discrepant cases between serology and histology were due to false positive-serology, rather than false-negative histology. This confirms the available evidence that the choice of treatment should not be based solely on the serological results, but also after excluding previous, self-reported eradication therapy.
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    A widely used sampling device in colorectal cancer screening programmes allows for large-scale microbiome studies
    (2019-09-01) Gudra, Dita; Shoaie, Saeed; Fridmanis, Davids; Klovins, Janis; Wefer, Hugo; Silamikelis, Ivars; Peculis, Raitis; Kalnina, Ineta; Elbere, Ilze; Radovica-Spalvina, Ilze; Hultcrantz, Rolf; Škenders, Girts; Leja, Marcis; Engstrand, Lars