Uruguayan Patients Research Articles

Plasma Interleukin-13 Levels Correlate With the Severity of Symptoms Induced by Functional Dyspepsia.

Functional dyspepsia (FD) is a gastrointestinal functional disorder of the upper gastrointestinal tract that affects the quality of life of patients and poses a significant economic burden. It has been proposed that the local inflammatory immune response at the duodenum is associated with an increase in intestinal permeability, favoring the recruitment of Th2 cells and granulocyte degranulation. Moreover, systemic immune response could also be related to the symptoms of FD. The objective of this study was to evaluate the systemic immune response in Uruguayan patients with FD by analyzing the cytokine levels in plasma and the frequency of circulating T cells associated with duodenal recruitment. An analytic and cross-sectional study in 30 patients with FD and 15 healthy controls (HCs) was carried out. Patients were diagnosed with FD according to the Roma IV Committee definition. Cytokine levels were measured in plasma by a specific assay. Expression of α4β7 and CC chemokine receptor9 in circulating T cells was evaluated by flow cytometry. Higher levels of interleukin (IL)-5, IL-13, and IL-8 and lower levels of IL-10 and IL-12p70 were detected in patients with FD than in HC. Furthermore, a positive linear correlation between IL-13 and the severity of FD symptoms was found. CD4 + T cells from patients with FD expressed higher levels of α4β7 and CC chemokine receptor9 than those from HC. An increase of Th2-like cytokines and a positive correlation between the levels of plasma IL-13 and the severity of symptoms in patients with FD from Uruguay were detected.

Impact of Bariatric Surgery on metabolic health in a Uruguayan cohort and the emerging predictive role of FSTL1

Obesity poses significant challenges, necessitating comprehensive strategies for effective intervention. Bariatric Surgery (BS) has emerged as a crucial therapeutic approach, demonstrating success in weight loss and comorbidity improvement. This study aimed to evaluate the outcomes of BS in a cohort of 48 Uruguayan patients and investigate the interplay between BS and clinical and metabolic features, with a specific focus on FSTL1, an emerging biomarker associated with obesity and inflammation. We quantitatively analyzed BS outcomes and constructed linear models to identify variables impacting BS success. The study revealed the effectiveness of BS in improving metabolic and clinical parameters. Importantly, variables correlating with BS success were identified, with higher pre-surgical FSTL1 levels associated with an increased effect of BS on BMI reduction. FSTL1 levels were measured from patient plasma using an ELISA kit pre-surgery and six months after. This research, despite limitations of a small sample size and limited follow-up time, contributes valuable insights into understanding and predicting the success of BS, highlighting the potential role of FSTL1 as a useful biomarker in obesity.

Relationship between hope and quality of life in patients with advanced cancer in Uruguay: An observational analysis.

e24055 Background: International research suggests a beneficial effect of hope on quality of life in advanced-stage cancer patients. Specific evidence for Latin America and Uruguay is limited, highlighting the need to explore this relationship for regional clinical strategies. Objective: To evaluate the correlation between hope and quality of life in Uruguayan patients with advanced cancer. Methods: This observational, analytical-descriptive, and cross-sectional study used the Herth Hope Index (HHI) and the Functional Assessment of Cancer Therapy - General (FACT-G) Quality of Life questionnaire. It included 59 patients aged 18 or older, diagnosed with advanced, non-curable cancer. Results: There was a positive but non-significant correlation between HHI and FACT-G scores (Pearson coefficient of 0.05). Hope significantly correlated with support from oncology services (p = 0.044), family support (p = 0.003), and spiritual beliefs (p = 0.029). Factors like bone metastases, diagnostic delay, and being accompanied at consultations significantly impacted quality of life (p = 0.041, p = 0.035, p = 0.012). Conclusions: The study observed a positive association between hope and quality of life, but the lack of statistical significance indicates the need for more research. Clinically, results highlight the importance of comprehensive care addressing spiritual and emotional needs, in addition to medical treatment. It also underscores the potential impact of supportive services on patient well-being. Future research should include larger sample sizes and consider longitudinal designs to better understand hope's effects over time in advanced cancer patients.

Relationship between Hope and Quality of Life in Patients with Advanced Cancer in Uruguay: An Observational Analysis

Introduction: International research suggests a beneficial effect of hope on quality of life in advanced-stage cancer patients. Specific evidence for Latin America and Uruguay is limited, highlighting the need to explore this relationship for regional clinical strategies.Objective: To evaluate the correlation between hope and quality of life in Uruguayan patients with advanced cancer. Materials and Methods: This observational, analytical-descriptive, and cross-sectional study used the Herth Hope Index (HHI) and the Functional Assessment of Cancer Therapy - General (FACT-G) Quality of Life questionnaire. It included 59 patients aged 18 or older, diagnosed with advanced, non-curable cancer.

Dietary Acid Load and Cancer Risk: A Review of the Uruguayan Experience.

Dietary acid load (DAL) is recognized as a risk factor for several chronic disorders, including obesity, diabetes, and osteoporosis. Recent evidence suggests that an elevated DAL, as measured by the validated potential renal acid load (PRAL) and net endogenous acid production (NEAP) scores, could also increase the risk for several cancers. This narrative review summarizes the potential role of DAL in Uruguayan cancer patients and outlines the potentially involved pathophysiological pathways that mediate the role of DAL in both cancer development and growth. Although Uruguay is a developing country, its average diet is a heavily meat-based Western one, translating into a supraphysiological acid burden from diet. In recent years, we have published epidemiologic evidence based on ten case-control studies involving 3736 cancer cases and 9534 hospital-based controls. Odds ratios and 95% confidence intervals were estimated for each interest variable to analyze the association between the exposure levels of DAL scores and cancer, calculated by unconditional logistic regression. In a majority of the cases, the highest DAL scores tended to double the cancer risk as compared to the lowest category. We also found high risks for methionine intake, an acidifying amino acid found in higher concentrations in animal-based foods, which may increase cancer risks at least by a joint action based on the pH and the proliferation enhancing properties of the amino acid itself.

Local clinical informatics investments are required for in silico biomarker generation across the globe: lessons learned from a secondary analysis of the PROP trial

Background Advances in statistical modelling and machine learning approaches, which can be deployed locally using open source programming languages, represent a unique opportunity to improve workflows and lower costs in health care across the globe through the creation of in silico biomarkers. The goal of this study was to extract meaningful data from the publicly available Prematurity and Respiratory Outcomes Program (PROP) trial data that could help generate useful clinical diagnostic aids with minimal cost for deployment in global healthcare settings. Methods A cluster analysis of the PROP dataset was conducted. We generated a simple model using an open-source software platform that generates a growth prediction of patients born less than 30 weeks. We then obtained validation data from a Uruguayan hospital to test the capacity for deployment of the models. Results Analysis revealed two main clusters of patients in the trial, with differentiation mainly based on the clinical and anthropomorphic measurements of birth gestational age, birth weight, and head circumference. The anthropometric measurements of daily weight, birth weight, head circumference, and birth gestational age were highly correlated with respiratory dysfunction and co-morbidities We note that deviation from this predicted growth curve in PROP patients was associated with culture-proven sepsis, and may represent a more sensitive anthropomorphic biomarker than the weight percentile systems routinely used globally such as Fenton curves. We found that early deviation from our projected growth model was highly associated with patient fatality. However, over long-term predictions, models trained on PROP clinical trial patients showed significantly more error in the Uruguayan patients. Conclusions Although these prediction models built upon PROP data were not generalizable to Uruguayan patients, our data suggest that prediction models using simple anthropomorphic measurements, if trained on local patients, may be able to provide value as a low-cost in silico biomarker. We concluded that local investment in clinical informatics infrastructure is needed to train models based on locally extracted clinical data.

Germline mutations in ATM, CHEK2, and other known/potential breast cancer susceptibility genes among BRCA-negative Uruguayan patients with breast cancer.

10596 Background: Breast cancer (BC) is the most frequent and the leading cause of death from cancer in Uruguayan women. In a previous study, we found BRCA1/2 germline mutations in less than 25% of the Uruguayan breast/ovarian cancer families studied. Due the impact and relevance of genetic testing in BC prevention and with the commitment to assure a wide accessibility, we developed genetic testing facilities at the University Hospital with the aim of analyzing and characterizing germline mutations in non BRCA known susceptibility and likely susceptibility genes. Methods: We studied 104 families who met the National Comprehensive Cancer Network (NCCN) criteria of hereditary BC. Analysis by next generation sequencing of BRCA1/2 genes revealed that 23 out of 104 cases studied (22%) carried pathogenic variants. Germline DNA from 42 cases BRCA negative was sequenced and analyzed for nine additional susceptibility genes (ATM, BARD1, CDH1, CHEK2, NBN, PALB2, PTEN, STK11 y TP53) included in a genetic panel. Also, in 24 cases negative for this panel we analyzed large deletions in BRCA1/2 by multiplex ligation-dependent probe amplification (MLPA) testing. In addition, to identify novel non-canonical causative genes, we extended our analysis to a complete exome sequencing of cases tested negative in genetic panels and MLPA analysis. Results: Among the 42 cases BRCA negative the sequencing of the extended genetic panel revealed 12 (28.8%) variants, 8 of uncertain significance (VUS) and 4 pathogenic, 2 novel (one in the ATM gene: NM_000051: c.614T > G and other in p53: NM_000546: c.245insT) and 2 previously reported (one in PALB2: NM_024675: c.2186insA and one in PALB2/1: NM_024675c.G7T genes). Regarding the VUS, it is worth highlighting the one found in exon 12 of CHEK2 (NM_007194: c.1333T > C) which was unusually frequent (16.7%) in our cohort when compared with public databases. Analysis of large deletions in BRCA1/2 in 24 cases without mutations in the genetic panel were negative for MLPA testing. Otherwise, complete exome sequencing of germline DNA from 22 cases negative for BRCA1/2 and for the genetic panel, revealed 18 variants, 16 that generate stop codons and 2 that generate loss of the termination codon (stoploss), suggesting a high potential for pathogenicity. Some striking examples are represented by the PSG2, CEP 135 y CEP 162, ZNF17 and ZNF260 genes. Conclusions: Of the 42 BRCA-negative cases, 4 (9.5%) carried a PV in a cancer susceptibility gene. The negative results obtained with MLPA in cases negative for BRCA and the extended genetic panel suggest that large deletions of BRCA are not a relevant cause of cancer susceptibility in this cohort. Otherwise, whole exome sequencing of 22 cases negatives for the previous genetic test showed pathogenic or probably PV in genes with no current evidence of association with breast and ovarian cancer.

Outcomes in rectal cancer care in Uruguay: A study on quality indicators.

234 Background: For years, rectal cancer has been considered a model oncologic entity and significant therapeutic improvements have been made in the last two decades. However, evidence suggests there are important differences in quality of care between countries, institutions and teams. Therefore, population-based audits are of great importance to ensure quality cancer care. Quality indicators (QIs) provide information on safety and quality of cancer screening, diagnosis and treatment. Aim: To describe and analyze quality indicators for diagnosis and treatment of rectal carcinoma at a high-volume cancer center in Uruguay. Methods: A retrospective descriptive study was performed as a sub-analysis of a cohort of 971 patients. A total of 497 rectal or rectosigmoid-junction carcinoma patients treated between 2008 and 2020 at the Uruguayan National Cancer Institute were included. Previously validated target values formed the basis of the QIs used in this study. Each QI was reported as the proportion (% 95% CI) of patients fulfilling the criteria out of eligible patients. Kaplan–Meier method was used to calculate overall survival rates. Results: Mean age was 62 years, 59.5% were male, and 78% showed no evidence of disseminated disease at diagnosis. Diagnosis and staging: combined contrast-enhanced CT TAP scan was performed in 66% of the sample, 51% of cases had a total colonoscopy before elective curative intent surgery. Locoregional c-TN staging was assessed by high resolution MRI in 64% of cases. Only 30% and 63% of patients in the preoperatively irradiated and the nonirradiated groups had a minimum of 12 lymph nodes examined. Multimodal treatment: preoperative chemo-radiation was delivered for stages II and III middle/low-third rectal cancers in 81% of the cases. Adjuvant therapy was prescribed in 75% and 47% of stages III and II receiving surgery as upfront treatment, respectively. 78% of cStage IV patients received palliative chemotherapy. Surrogate indicators of outcome: 82% had distal tumor-free margins, although only 72% had a pathological circumferential radial margin ((y)pCRM) mentioned in the pathology report. Non-curative (R1,2) resections in M0 rectal carcinoma in our cohort was below the target value of <20%. 15% of our cases had a positive (y)pCRM. Treatment-outcomes: Our cumulative overall local recurrence was 12.6% and the 3-year overall survival rate was 84.8%. Conclusions: Continuous analysis of QIs in rectal cancer is necessary for internal quality management and for external quality assessment, to improve and compare treatment outcomes. Our results highlight the positive aspects of rectal cancer care at our center and reveal the weak points in diagnosis and treatment that need special attention. They will serve as a guide in the implementation of new strategies and programs that will aim to improve safety and quality of rectal cancer care for Uruguayan patients, regardless of where they live or are treated.

P-75 UPDATE OF CLINICO-EPIDEMIOLOGICAL CHARACTERISTICS OF PRIMARY BILIAR CHOLANGITIS IN URUGUAY

Primary biliary cholangitis (PBC) is an autoimmune cholestatic liver disease of increasing prevalence, female-predominant, and usually diagnosed in the fifth decade of life. To update the description of clinico-epidemiological characteristics of a series of Uruguayan patients diagnosed with PBC. Descriptive, multi-centric study including Uruguayan patients diagnosed with PBC (at least two of the following criteria: biochemical cholestasis, autoantibodies —AMA, antinuclear with anticentromere, sp100, or gp210 patterns— and compatible liver biopsy). Age, sex, symptoms, associated diseases, laboratory, imaging, histological and elastography parameters were recorded in the diagnosis. One hundred twenty-nine patients (81 belonging to the first report), 93% female, with an average age of 57 years old (23 - 81) were included. Sixty-nine percent had at least one symptom and 59% had pruritus. Eighty-three percent were AMA-positive and in 41% of patients one or more associated diseases were confirmed. (Table). Histological studies were available in 40 patients (31%), 26 (65%) of which had advanced liver fibrosis or cirrhosis. Elastography was available in 6 patients, 2 of which (33%) were diagnosed with cirrhosis. Six patients (5%) were diagnosed with cirrhosis due to presence of ascites. The global survival rate was 84%. Survival depending on the presence or absence of symptoms was 251 months (95% CI, 229 - 274) and 241 months (95% CI, 238 - 275) respectively (p>0.05). Median survival for cirrhotic patients was 201 months (CI 95%, 160 – 242) versus 191 (CI 95%, 172 – 210) for non-cirrhotics (p>0.05). As previously reported, female prevalence and frequent association with other diseases –mainly autoimmune– remain. The presence of symptoms or cirrhosis showed no association with survival.

Development of a Population Pharmacokinetic Model for Cyclosporine from Therapeutic Drug Monitoring Data.

Aim To develop a population pharmacokinetic model for Uruguayan patients under treatment with cyclosporine (CsA) that can be applied to TDM. Patients and Methods. A total of 53 patients under treatment with CsA were included. 37 patients with at least one pharmacokinetic profile described with four samples were considered for model building, while the remaining 16 were considered for the assessments of predictive performances. Pharmacokinetic parameter estimation was performed using a nonlinear mixed effect modelling implemented in the Monolix® software (version 2019R1, Lixoft, France); meanwhile, simulations were performed in R v.3.6.0 with the mlxR package. Results A two-compartment model with a first-order disposition model including lag time was used as a structural model. The final model was internally validated using prediction corrected visual predictive check (pcVPC) and other graphical diagnostics. A total of 621 CsA steady-state concentrations were analyzed for model development. Population estimates for the absorption constant (ka) and lag time were 0.523 h−1 and 0.512 h, respectively; apparent clearance (CL/F) was 30.3 L/h (relative standard error [RSE] ± 8.25%) with an interindividual variability of 39.8% and interoccasion variability of 38.0%; meanwhile, apparent clearance of distribution (Q/F) was 17.0 L/h (RSE ± 12.1%) with and interindividual variability of 53.2%. The covariate analysis identified creatinine clearance (ClCrea) as an individual factor influencing the Cl of CsA. The predictive capacity of the population model was demonstrated to be effective since predictions made for new patients were accurate for C1 and C2 (MPPEs below 50%). Bayesian forecasting improved significantly in the second and third occasions. Conclusion A population pharmacokinetic model was developed to reasonably estimate the individual cyclosporine clearance for patients. Hence, it can be utilized to individualize CsA doses for prompt and adequate achievement of target blood concentrations of CsA.

Alpha thalassemia and alpha-MRE haplotypes in Uruguayan patients with microcytosis and hypochromia without anemia.

Alpha thalassemia is the most common genetic disorder across the world, being the α-3.7 deletion the most frequent mutation. In order to analyze the spectrum and origin of alpha thalassemia mutations in Uruguay, we obtained a sample of 168 unrelated outpatients with normal hemoglobin levels with microcytosis and hypochromia from two cities: Montevideo and Salto. The presence of α-thalassemia mutations was investigated by gap-PCR, restriction endonucleases analysis and HBA2 and HBA1 genes sequencing, whereas the alpha-MRE haplotypes were investigated by sequencing. We found 55 individuals (32.7%) with α-thalassemia mutations, 51(30.4%) carrying the -α3.7 deletion, one with the -α4.2 deletion and three having the rare punctual mutation HBA2:c.-59C>T. Regarding alpha-MRE analysis, we observed a significant higher frequency of haplotype D, characteristic of African populations, in the sample with the -α3.7 deletion. These results show that α-thalassemia mutations are an important determinant of microcytosis and hypochromia in Uruguayan patients with microcytosis and hypochromia without anemia, mainly due to the -α3.7 deletion. The alpha-MRE haplotypes and the α-thalassemia mutations spectrum suggest a predominant, but not exclusive, African origin of these mutations in Uruguay.

Ancestry and TPMT-VNTR Polymorphism: Relationship with Hematological Toxicity in Uruguayan Patients with Acute Lymphoblastic Leukemia.

6-Mercaptopurine (6-MP) is a thiopurine drug widely used in childhood acute lymphoblastic leukemia (ALL) therapy. Genes such as TPMT and NUDT15 have an outstanding role in 6-MP metabolism. Mutations in both genes explain a significant portion of hematological toxicities suffered by ALL Uruguayan pediatric patients. A variable number tandem repeat in the TPMT promoter (TPMT-VNTR) has been associated with TPMT expression. This VNTR has a conservative architecture (AnBmC). To explore new causes of hematological toxicities related to ALL therapy, we genotyped the TPMT-VNTR of 130 Uruguayan pediatric patients. Additionally, individual genetic ancestry was estimated by 45 ancestry-informative markers (AIMs). Hematological toxicity was measured as the number of leukopenia events and 6-MP dose along the maintenance phase. As previously reported, we found TPMT*2 and TPMT*3C alleles were associated to TPMT-VNTR A2BC and AB2C, respectively. However, contrasting with other reports, TPMT*3A allele was found in a heterogeneous genetic background in linkage equilibrium. Patients carrying more than 5 A repeats present a significant higher number of leukopenia events among patients without TPMT and/or NUDT15 variants. Native American ancestry and the number of A repeats were significantly correlated with the number of leukopenia events. However, the correlation between Native American ancestry and the number of leukopenia events was lost when the number of A repeats was considered as covariate. This suggests that TPMT-VNTR alleles are more relevant than Native American ancestry in the hematological toxicity. Our results emphasize that TPMT-VNTR may be used as a pharmacogenetic biomarker to predict 6-MP-related hematological toxicity in ALL childhood therapy.

Análisis bacteriano comparativo de cuadros de Periodontitis Crónica y Agresiva en una población muestra de Uruguay

OBJECTIVES: Compare the prevalence of certain periodontal pathogens in cases of aggressive and chronic periodontitis according to the valid classification at the time of the studies, in 101 Uruguayan patients. METHODS: This analysis is based on the works of detection of periodontal pathogens in patients with chronic and aggressive periodontitis in Uruguay using conventional and molecular methods (1,2). Both works analysed the same microorganisms and used the same techniques of recovery and analysis. Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Tannerella forsythia, Prevotella intermedia and Fusobacterium nucleatum were studied. RESULTS: A higher prevalence of F. nucleatum, T. forsythia and P. gingivalis was noticed in chronic cases whereas higher detections of F. nucleatum and P. intermedia were observed in aggressive ones. Within the last one, a higher proportion of P. gingivalis and T. forsythia was detected in the generalized and A. actinomycetemcomitans in the localized ones. CONCLUSIONS: It was found that the patterns documented in the bibliography remained in our country (3,4).

Description of Molecular Prognostic Markers in AML Uruguayan Patients

Acute myeloblastic leukemias (AML) are the most frequent acute leukemias in adults. Recent genomic and candidate gene studies identified novel recurrent somatic mutations in patients with AML with biological, clinical and therapeutic significance. In Uruguay, the characterization of AML is dependent on the integration of cytomorphology, immunophenotype, cytogenetics and molecular biology (mutations in FLT3, NPM1, CEBPA and cKIT). This allows stratification in prognostic risk groups and rationalization of therapeutic resources. However, with this molecular markers, complete stratification is not always succesful in patients with normal karyotype ( NK) .In order to expand the AML genetic markers analysis in Uruguayan patients ( 3.000.0000 persons country ) ; DNA samples from 49 adult patients at the onset of the disease and 3 healthy controls were analyzed by next generation sequencing (NGS, Illumina) using a customized panel of 30 cancer associated genes. After excluding synonymous variants and those with a population frequency >1%, we ended with 493 variants in promoters and intron ends, and 173 in the 28 genes coding regions. Notably, all patients had at least one variant.While none of the non-coding region variants were reported as pathogenic in COSMIC and/or ClinVar databases, 45 of those falling in coding regions were reported as pathogenic. The pathogenic variants were detected in 36/49 patients and 1 healthy control distributed in 16 genes. The most affected genes were TET2, NRAS, DNMT3, FLT3 and cKIT with 7, 6, 5, 4, 4 variants respectively.This preliminar findings in this study, highlight the relevance of detecting gene variability underlying prognostic risk subgroups to deliver patient tailored clinical decision support. The correlation between the genetic abnormalities, associated with the clinicopahtological features and the epigenetic studies have prognostic significance, and are continued to be analyzed. DisclosuresNo relevant conflicts of interest to declare.

Pretreatment Hepatitis C Virus NS5A/NS5B Resistance-Associated Substitutions in Genotype 1 Uruguayan Infected Patients.

Hepatitis C Virus (HCV) infection treatment has dramatically changed with the advent of direct-acting antiviral agents (DAAs). However, the efficacy of DAAs can be attenuated by the presence of resistance-associated substitutions (RASs) before and after treatment. Indeed, RASs detected in DAA treatment-naïve HCV-infected patients could be useful for clinical management and outcome prediction. Although the frequency of naturally occurring HCV NS5A and NS5B RASs has been addressed in many countries, there are only a few reports on their prevalence in the South American region. The aim of this study was to investigate the presence of RASs to NS5A and NS5B inhibitors in a DAA treatment naïve cohort of Uruguayan patients infected with chronic hepatitis C and compare them with reports from other South American countries. Here, we found that naturally occurring substitutions conferring resistance to NS5A and NS5B inhibitors were present in 8% and 19.2%, respectively, of treatment-naïve HCV genotype 1 infected patients. Importantly, the baseline substitutions in NS5A and NS5B herein identified differ from the studies previously reported in Brazil. Furthermore, Uruguayan strains subtype 1a clustered within all major world clades, showing that HCV variants currently circulating in this country are characterized by a remarkable genetic diversity.

IL28B gene polymorphism rs12979860, but not rs8099917, contributes to the occurrence of chronic HCV infection in Uruguayan patients

BackgroundHost single-nucleotide polymorphisms (SNPs) near the interleukin 28B (IL28B) locus are associated with sustained virological response to antiviral therapy and with spontaneous Hepatitis C Virus (HCV) clearance. Prevalence of these SNPs varies depending on ethnicity. The impact of IL28B SNPs in HCV-infected patients is currently unknown in Uruguay. Therefore, the aim of this study was to evaluate and compare the distribution of polymorphisms in the IL28B gene (rs12979860 and rs8099917) among HCV-infected patients and healthy individuals in Uruguay and thus assess their possible association with the establishment of HCV infection.MethodsDNA was recovered from 92 non-infected individuals and 78 HCV-infected patients and SNPs were determined by RFLP and allelic discrimination by real-time PCR.ResultsThe distribution of rs12979860 genotypes for the infected population was 29.5%-CC, 47.4%-CT and 23.1%-TT and for the control group 45.7%, 42.4% and 11.9%, respectively. Prevalence in both infected and uninfected individuals is similar to that reported in other countries with admixed populations. The distribution of rs8099917 genotypes for the infected population was 57.7%-TT, 27.2%-TG and 14.1%-GG and for the control group 60.9%, 33.7% and 5.4%, respectively. The comparison of rs12979860 genotype distribution between the two populations evidenced a higher prevalence of the favourable genotype (CC) in the uninfected control group (p < 0.05). Additionally, results generated using logistic regression analysis show that individuals carrying rs12979860-TT or CT genotypes have a higher likelihood of developing chronic hepatitis upon infection with HCV, when compared to CC carriers, considering rs8099917 genotype as constant.ConclusionPatients with HCV infection have a statistically significant lower prevalence of the favourable rs12979860 genotype when compared to uninfected individuals; therefore we can establish that only IL28B rs12979860-CT and TT genotypes seem to contribute to the occurrence of chronic HCV infection in the cohort of Uruguayan population studied. Considering that a trend towards a higher frequency of “good” response genotypes was observed in responder patients, we believe that IL28B rs12979860 genotyping could be a useful tool for predicting different therapies outcome, including in the DAA era.

Characterization of Leptospira isolates from humans and the environment in Uruguay.

ABSTRACTLaboratory diagnosis of human leptospirosis usually relies on indirect methods exploring specific immune response. Isolation and identification of the involved strains are cumbersome, but can provide biological resources for pathogenic studies and relevant information for guiding prevention and control measures. The aim of the research we are hereby reporting was the characterization of Leptospira isolates obtained from humans and the environment in Uruguay. Blood cultures were performed from early samples of 302 Uruguayan patients, mainly rural workers, and from 36 water samples taken from their living or working environments. Eight human isolates and seven environmental isolates were obtained and analyzed by end point Polymerase Chain Reaction (PCR), Multilocus Variable Number of Tandem Repeat Analysis (MLVA) and other molecular methods. Human isolates corresponded to several serogroups and serovars of Leptospira interrogans and Leptospira kirschneri species, probably reflecting the infection with similar involved Leptospira species and serovars of an extended animal reservoir in rural settings of the country, mostly dedicated to meat and dairy production. Culture-positive patients were older than usually affected workers, and presented signs and symptoms of severe illness. A high organic and circulating bacterial burden may explain an easier positive result from these workers’ samples. Environmental isolates were mainly identified as Leptospira biflexa strains, with a single L. meyeri isolate of uncertain significance.

Methotrexate pharmacogenetics in Uruguayan adults with hematological malignant diseases

BackgroundIndividual variability is among the causes of toxicity and interruption of treatment in acute lymphoblastic leukemia (ALL) and severe non-Hodgkin lymphoma (NHL) patients under protocols including Methotrexate (MTX): 2,4-diamino-N10-methyl propyl-glutamic acid. Methods41 Uruguayan patients were recruited. Gene polymorphisms involved in MTX pathway were analyzed and their association with treatment toxicities and outcome was evaluated. ResultsGenotype distribution and allele frequency were determined for SLC19A1 G80A, MTHFR C677T and A1298C, TYMS 28bp copy number variation, SLCO1B1 T521C, DHFR C−1610G/T, DHFR C-680A, DHFR A-317G and DHFR 19bp indel. Multivariate analysis showed that DHFR-1610G/T (OR=0.107, p=0.018) and MTHFR677T alleles (OR=0.12, p=0.026) had a strong protective effect against hematologic toxicity, while DHFR-1610CC genotype increased this toxicity (OR=9, p=0.045). No more associations were found. ConclusionsThe associations found between gene polymorphisms and toxicities in this small cohort are encouraging for a more extensive research to gain a better dose individualization in adult ALL and NHL patients. Besides, genotype distribution showed to be different from other populations, reinforcing the idea that genotype data from other populations should not be extrapolated to ours.

Prevalence of EGFR Mutations in Lung Cancer in Uruguayan Population.

Background Incorporation of molecular analysis of the epidermal growth factor receptor (EGFR) gene into routine clinical practice represents a milestone for personalized therapy of the non-small-cell lung cancer (NSCLC). However, the genetic testing of EGFR mutations has not yet become a routine clinical practice in developing countries. In view of different prevalence of such mutations among different ethnicities and geographic regions, as well as the limited existing data from Latin America, our aim was to study the frequency of major types of activating mutations of the EGFR gene in NSCLC patients from Uruguay. Methods We examined EGFR mutations in exons 18 through 21 in 289 NSCLC Uruguayan patients by PCR-direct sequencing. Results EGFR mutations were detected in 53 of the 289 (18.3%) patients, more frequently in women (23.4%) than in men (14.5%). The distribution by exon was similar to that generally reported in the literature. Conclusions This first epidemiological study of EGFR mutations in Uruguay reveals a wide spectrum of mutations and an overall prevalence of 18.3%. The background ethnic structure of the Uruguayan population could play an important role in explaining our findings.

Naturally occurring NS3 resistance-associated variants in hepatitis C virus genotype 1: Their relevance for developing countries

Hepatitis C virus (HCV) is a major cause of global morbidity and mortality, with an estimated 130–150 million infected individuals worldwide. HCV is a leading cause of chronic liver diseases including cirrhosis and hepatocellular carcinoma. Current treatment options in developing countries involve pegylated interferon-α and ribavirin as dual therapy or in combination with one or more direct-acting antiviral agents (DAA). The emergence of resistance-associated variants (RAVs) after treatment reveals the great variability of this virus leading to a great difficulty in developing effective antiviral strategies. Baseline RAVs detected in DAA treatment-naïve HCV-infected patients could be of great importance for clinical management and outcome prediction. Although the frequency of naturally occurring HCV NS3 protease inhibitor mutations has been addressed in many countries, there are only a few reports on their prevalence in South America. In this study, we investigated the presence of RAVs in the HCV NS3 serine protease region by analysing a cohort of Uruguayan patients with chronic hepatitis C who had not been treated with any DAAs and compare them with the results found for other South American countries. The results of these studies revealed that naturally occurring mutations conferring resistance to NS3 inhibitors exist in a substantial proportion of Uruguayan treatment-naïve patients infected with HCV genotype 1 enrolled in these studies. The identification of these baseline RAVs could be of great importance for patients’ management and outcome prediction in developing countries.