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    IL-10 and IL-6/IL-10 as predictive biomarkers for treatment response in non-infectious uveitis
    (Frontiers Media SA, 2025-05-13)
    Rodrigo A. Valenzuela
    ;
    Fabian Vega-Tapia
    ;
    Nathaly Elizalde
    ;
    Ivan Flores
    ;
    Felipe M. Rojas
    Uveitis, a group of heterogeneous diseases causing ocular inflammation, is a major contributor to vision loss globally. While systemic corticosteroids (CS) are the mainstay treatment, identifying CS-refractory patients remains a significant challenge. This study aimed to explore cytokine expression and Glucocorticoid Receptor (GR) levels as biomarkers for the early detection of CS-refractory cases in non-infectious uveitis. We assayed blood samples from 19 patients with non-infectious uveitis, for the expression of IL-6, IL-17A, TNF-α, IL-10 and GRα. The cohort included 11 refractory and 8 sensitive patients, categorized based on their clinical response to corticosteroids (prednisone 1 mg/kg/day). Blood draws were conducted at three time points (at baseline, day 7- and day 14 after CS initiation), and peripheral blood mononuclear cells (PBMCs) were isolated to measure cytokine and GRα transcript levels via real-time PCR. The expression levels of GRα and cytokines IL-6, IL-17A and TNF-α did not show significant changes between CS-sensitive and CS-refractory patients on the different days of treatment. However, IL-10 expression levels as the day14-to-day7 ratio were significantly higher in patients sensitive to CS therapy. A higher day14-to-day7 ratio was also found for the IL-6/IL-10, IL-17A/IL-10 and GRα/IL-10 ratios. ROC curve analysis demonstrated a robust predictive performance of IL-10 mRNA expression and the IL-6/IL-10 ratio for identifying CS-refractory patients. In conclusion, the expression of IL-10 and the IL-6/IL-10 ratio hold promise as early predictive biomarkers for CS treatment refractoriness in patients with non-infectious uveitis. These findings offer valuable insights into personalized treatment strategies, potentially leading to improved clinical outcomes.
    Scopus© Citations 6  1
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    Methylated Reprimo Cell-Free DNA as a Non-Invasive Biomarker for Gastric Cancer
    (MDPI AG, 2025-04-03)
    María José Maturana
    ;
    Oslando Padilla
    ;
    Pablo M. Santoro
    ;
    Maria Alejandra Alarcón
    ;
    Wilda Olivares
    Restrictions resulting from the COVID-19 pandemic abruptly reversed the slow decline of the diagnosis and mortality rates of gastric cancer (GC). This scenario highlights the importance of developing cost-effective methods for mass screening and evaluation of treatment response. In this study, we evaluated a non-invasive method based on the circulating methylated cell-free DNA (cfDNA) of Reprimo (RPRM), a tumor suppressor gene associated with the development of GC. Methylated RPRM cfDNA was analyzed in three de-identified cohorts: Cohort 1 comprised 81 participants with GC and 137 healthy donors (HDs); Cohort 2 comprised 27 participants with GC undergoing gastrectomy and/or chemotherapy analyzed at the beginning and after three months of treatment; and Cohort 3 comprised 1105 population-based participants in a secondary prevention program who underwent esophagogastroduodenal (EGD) endoscopy. This cohort includes 180 normal participants, 845 participants with premalignant conditions (692 with chronic atrophic gastritis [AG] and 153 with gastric intestinal metaplasia/low-grade dysplasia [GIM/LGD]), 21 with high-grade dysplasia/early GC [HGD/eGC], and 59 with advanced GC [aGC]). A nested case-control substudy was performed using a combination of methylated RPRM cfDNA and pepsinogens (PG)-I/II ratio. The dense CpG island of the promoter region of the RPRM gene was bisulfite sequenced and analyzed to develop a fluorescence-based real-time PCR assay (MethyLight). This assay allows the determination of the absolute number of copies of methylated RPRM cfDNA. A targeted sequence of PCR amplicon products confirmed the gastric origin of the plasma-isolated samples. In Cohort 1, the mean value of GCs (32,240.00 copies/mL) was higher than that of the HD controls (139.00 copies/mL) (p < 0.0001). After dividing this cohort into training–validation subcohorts, we identified an area under the curve of 0.764 (95% confidence interval (CI) = 0.683–0.845) in the training group. This resulted in a cut-off value of 87.37 copies/mL (sensitivity 70.0% and specificity 80.2%). The validation subcohort predicted a sensitivity of 66.67% and a specificity of 83.33%. In Cohort 2 (monitoring treatment response), RPRM levels significantly decreased in responders (p = 0.0042) compared to non-responders. In Cohort 3 (population-based participants), 18.9% %, 24.1%, 30.7%, 47.0%, and 71.2% of normal, AG, GIM/LGD, HGD/eGC, and aGC participants tested positive for methylated RPRM cfDNA, respectively. Overall sensitivity and specificity in distinguishing normal/premalignant conditions vs. GC were 65.0% (95% CI 53.52% to 75.33%) and 75.9% (95% CI 73.16% to 78.49%), respectively, with an accuracy of 75.11% (95% CI 72.45% to 77.64%). Logistic regression analyses revealed an OR of 1.85 (95% CI 1.11–3.07, p = 0.02) and an odds ratio (OR) of 3.9 (95% CI 1.53–9.93, p = 0.004) for the risk of developing GIM/LGD and HGD/eGC, respectively. The combined methylated RPRM cfDNA and PG-I/II ratio reached a sensitivity of 78.9% (95% CI 54.43% to 93.95%) and specificity of 63.04% (95% CI 52.34% to 72.88%) for detecting HGD/eGC vs. three to six age- and sex-matched participants with premalignant conditions. Our results demonstrate that methylated RPRM cfDNA should be considered a direct biomarker for the non-invasive detection of GC and a predictive biomarker for treatment response.
      1Scopus© Citations 4
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    Dilated optic nerve sheath by ultrasound predicts mortality among patients with acute intracerebral hemorrhage
    (2023)
    Francisco Antunes Dias
    ;
    Maria Clara Zanon Zotin
    ;
    Frederico Fernandes Alessio-Alves
    ;
    Rui Kleber do Vale Martins Filho
    ;
    Clara Monteiro Antunes Barreira
    <jats:title>Abstract</jats:title><jats:p> Background Intracerebral hemorrhage (ICH) is a deadly disease and increased intracranial pressure (ICP) is associated with worse outcomes in this context.</jats:p><jats:p> Objective We evaluated whether dilated optic nerve sheath diameter (ONSD) depicted by optic nerve ultrasound (ONUS) at hospital admission has prognostic value as a predictor of mortality at 90 days.</jats:p><jats:p> Methods Prospective multicenter study of acute supratentorial primary ICH patients consecutively recruited from two tertiary stroke centers. Optic nerve ultrasound and cranial computed tomography (CT) scans were performed at hospital admission and blindly reviewed. The primary outcome was mortality at 90-days. Multivariate logistic regression, ROC curve, and C-statistics were used to identify independent predictors of mortality.</jats:p><jats:p> Results Between July 2014 and July 2016, 57 patients were evaluated. Among those, 13 were excluded and 44 were recruited into the trial. Their mean age was 62.3 ± 13.1 years and 12 (27.3%) were female. On univariate analysis, ICH volume on cranial CT scan, ICH ipsilateral ONSD, Glasgow coma scale, National Institute of Health Stroke Scale (NIHSS) and glucose on admission, and also diabetes mellitus and current nonsmoking were predictors of mortality. After multivariate analysis, ipsilateral ONSD (odds ratio [OR]: 6.24; 95% confidence interval [CI]: 1.18–33.01; p = 0.03) was an independent predictor of mortality, even after adjustment for other relevant prognostic factors. The best ipsilateral ONSD cutoff was 5.6mm (sensitivity 72% and specificity 83%) with an AUC of 0.71 (p = 0.02) for predicting mortality at 90 days.</jats:p><jats:p> Conclusion Optic nerve ultrasound is a noninvasive, bedside, low-cost technique that can be used to identify increased ICP in acute supratentorial primary ICH patients. Among these patients, dilated ONSD is an independent predictor of mortality at 90 days.</jats:p>
      3
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    Development and internal validation of a multifactorial risk prediction model for gallbladder cancer in a high‐incidence country
    (2023)
    Felix Boekstegers
    ;
    Dominique Scherer
    ;
    Carol Barahona Ponce
    ;
    Katherine Marcelain
    ;
    Valentina Gárate‐Calderón
    <jats:title>Abstract</jats:title><jats:p>Since 2006, Chile has been implementing a gallbladder cancer (GBC) prevention program based on prophylactic cholecystectomy for gallstone patients aged 35 to 49 years. The effectiveness of this prevention program has not yet been comprehensively evaluated. We conducted a retrospective study of 473 Chilean GBC patients and 2137 population‐based controls to develop and internally validate three GBC risk prediction models. The Baseline Model accounted for gallstones while adjusting for sex and birth year. Enhanced Model I also included the non‐genetic risk factors: body mass index, educational level, Mapuche surnames, number of children and family history of GBC. Enhanced Model II further included Mapuche ancestry and the genotype for rs17209837. Multiple Cox regression was applied to assess the predictive performance, quantified by the area under the precision‐recall curve (AUC‐PRC) and the number of cholecystectomies needed (NCN) to prevent one case of GBC at age 70 years. The AUC‐PRC for the Baseline Model (0.44%, 95%CI 0.42‐0.46) increased by 0.22 (95%CI 0.15‐0.29) when non‐genetic factors were included, and by 0.25 (95%CI 0.20‐0.30) when incorporating non‐genetic and genetic factors. The overall NCN for Chileans with gallstones (115, 95%CI 104‐131) decreased to 92 (95%CI 60‐128) for Chileans with a higher risk than the median according to Enhanced Model I, and to 80 (95%CI 59‐110) according to Enhanced Model II. In conclusion, age, sex and gallstones are strong risk factors for GBC, but consideration of other non‐genetic factors and individual genotype data improves risk prediction and may optimize allocation of financial resources and surgical capacity.</jats:p>
      5Scopus© Citations 16
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      1  1Scopus© Citations 5
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    Recurrence of hepatocellular carcinoma after liver transplantation: Prognostic and predictive factors of survival in a Latin American cohort
    (2020)
    Claudia Maccali
    ;
    Aline L. Chagas
    ;
    Ilka Boin
    ;
    Emilio Quiñonez
    ;
    Sebastián Marciano
      13Scopus© Citations 18
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    Predictive Validity of Developmental Screening Questionnaires for Identifying Children With Later Cognitive or Educational Difficulties: A Systematic Review
    (2021) ; ;
    Olenkha Cepeda
    ;
    Pamela Serón
    <jats:p><jats:bold>Context:</jats:bold> Parent/caregiver completing developmental screening questionnaires (DSQs) for children before 5 years of age is currently recommended. The DSQs recommended by the American Academy of Pediatrics (AAP) are the Ages and Stages Questionnaires (ASQ), Parents' Evaluation of Developmental Status (PEDS), and the Survey of Well-being of Young Children (SWYC). Nevertheless, their predictive validity has not been well-established.</jats:p><jats:p><jats:bold>Objective:</jats:bold> To assess in the current literature, the value of AAP-recommended DSQs (ASQ, PEDS, SWYC) administered between 0 and 5 years of age, for predicting long-term cognitive achievement and/or school performance (CA/SP), after 1 year or more of evaluation and at/or after age 5 years, in the general population.</jats:p><jats:p><jats:bold>Data Sources:</jats:bold> Cochrane, MEDLINE PubMed, CINAHL, EMBASE, Web of Science, Scielo, and Scopus databases (until March 2021).</jats:p><jats:p><jats:bold>Study Selection:</jats:bold> Two authors selected the studies. Forward and backward citation follow-up was done; authors of DSQ were contacted to identify additional studies.</jats:p><jats:p><jats:bold>Data Extraction:</jats:bold> Cohorts were identified, and authors of selected studies were contacted to corroborate and complete extracted data.</jats:p><jats:p><jats:bold>Results:</jats:bold> Thirty-two publications, corresponding to 10 cohorts, were included. All cohorts used ASQ. Only cohort using PEDS was identified but did not meet the inclusion criteria. No cohorts conducted with SWYC were identified. Associations between ASQ and CA/SP were extracted for eight cohorts. The odds ratios were <jats:underline>&amp;gt;</jats:underline>3, and the area under the curve was 0.66–0.87. A trade-off between sensitivity and specificity was observed.</jats:p><jats:p><jats:bold>Limitations:</jats:bold> Heterogeneity in population characteristics and in DSQ adaptations.</jats:p><jats:p><jats:bold>Conclusions:</jats:bold> A positive association between ASQ and later CA/SP was found in different social, cultural, and economic settings. Additional studies are necessary to determine the impact factors in the predictive capacity of DSQs.</jats:p><jats:p><jats:bold>Systematic Review Registration:</jats:bold> PROSPERO, identifier: CRD42020183883.</jats:p>
    Scopus© Citations 8  1  1
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    The impacts of social determinants of health and cardiometabolic factors on cognitive and functional aging in Colombian underserved populations
    (2023)
    Hernando Santamaria-Garcia
    ;
    Sebastian Moguilner
    ;
    Odir Antonio Rodriguez-Villagra
    ;
    Felipe Botero-Rodriguez
    ;
    Stefanie Danielle Pina-Escudero
    <jats:title>Abstract</jats:title><jats:p>Global initiatives call for further understanding of the impact of inequity on aging across underserved populations. Previous research in low- and middle-income countries (LMICs) presents limitations in assessing combined sources of inequity and outcomes (i.e., cognition and functionality). In this study, we assessed how social determinants of health (SDH), cardiometabolic factors (CMFs), and other medical/social factors predict cognition and functionality in an aging Colombian population. We ran a cross-sectional study that combined theory- (structural equation models) and data-driven (machine learning) approaches in a population-based study (<jats:italic>N</jats:italic> = 23,694;<jats:italic>M</jats:italic> = 69.8 years) to assess the best predictors of cognition and functionality. We found that a combination of SDH and CMF accurately predicted cognition and functionality, although SDH was the stronger predictor. Cognition was predicted with the highest accuracy by SDH, followed by demographics, CMF, and other factors. A combination of SDH, age, CMF, and additional physical/psychological factors were the best predictors of functional status. Results highlight the role of inequity in predicting brain health and advancing solutions to reduce the cognitive and functional decline in LMICs.</jats:p>
    Scopus© Citations 10  1
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    Scopus© Citations 3  1  9
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    Validation of Picture Free and Cued Selective Reminding Test for Illiteracy in Lima, Peru
    (2022)
    Rosa Montesinos
    ;
    Jose F. Parodi
    ;
    Monica M. Diaz
    ;
    Eder Herrera-Perez
    ;
    Elizabeth Valeriano-Lorenzo
    <jats:p> Dementia in Latin America is a crucial public health problem. Identifying brief cognitive screening (BCS) tools for the primary care setting is crucial, particularly for illiterate individuals. We evaluated tool performance characteristics and validated the free and total recall sections of the Free and Cued Selective Reminding Test-Picture version (FCSRT-Picture) to discriminate between 63 patients with early Alzheimer’s disease dementia (ADD), 60 amnestic mild cognitive impairment (aMCI) and 64 cognitively healthy Peruvian individuals with illiteracy from an urban area. Clinical, functional, and cognitive assessments were performed. FCSRT-Picture performance was assessed using receiver operating characteristic curve analyses. The mean ± standard deviation scores were 7.7 ± 1.0 in ADD, 11.8 ± 1.6 in aMCI, and 29.5 ± 1.8 in controls. The FCSRT-Picture had better performance characteristics for distinguishing controls from aMCI compared with several other BCS tools, but similar characteristics between controls and early ADD. The FCSRT-Picture is a reliable BCS tool for illiteracy in Peru. </jats:p>
    Scopus© Citations 4  1