Publications by authors named "Ipek Guler"

17 Publications

  • Page 1 of 1

Predictive power of early-warning scores used in hospital emergency departments: a systematic review and meta-analysis.

Emergencias 2021 Oct;33(5):374-381

Departamento de Enfermería, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, España. Universidad de Córdoba, Córdoba, España. Hospital Universitario Reina Sofía de Córdoba, Córdoba, España.

Objectives: To assess the predictive power of scores used in hospital emergency departments (EDs) to give early warning of risk for mortality and hospital ward or intensive care unit (ICU) admission.

Material And Methods: Systematic review and meta-analysis. We searched MEDLINE, Embase, the Web of Science, and the Cochrane Library. Observational studies and clinical trials published between January 1, 1950, and June 12, 2020 that used early-warning scores in hospital EDs were included. The main outcomes were mortality (at 24, 48, and more than 72 hours), hospital admission, and ICU admission.

Results: Nine studies entered into the systematic review; 4 of them, with 165 580 patients, were included in the meta-analysis. The studies were heterogeneous with respect to the scores used. The one used most often was the National Early Warning Score (NEWS). The meta-analysis of studies using the NEWS scale showed that it had good predictive power for mortality: the area under the curve (AUC) of the receiver operating characteristic was 0.88 (95%, CI, 0.87-0.89; P .001, I2 = 0%) at 24 hours and 0.86 (0.84-0.88; P .001; I2 = 49.3%) at 48 hours. The AUC for inhospital mortality was 0.77 (95% CI, 0.74-0.80; P .001; I2 = 96.2%). The NEWS score had adequate power for predicting risk of hospital ward and ICU admission.

Conclusion: Early warning scores used in hospital EDs are able to predict risk of early and in-hospital mortality.
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October 2021

Assessment of Subclinical Psychotic Symptoms in Patients with Rheumatoid Arthritis and Spondyloarthritis.

J Clin Med 2021 Aug 4;10(16). Epub 2021 Aug 4.

Maimonides Institute of Biomedical Research of Córdoba (IMIBIC), 14004 Cordoba, Spain.

Inflammatory and autoimmune processes have been associated with the onset of depressive and psychotic symptoms. Rheumatoid arthritis (RA) and spondyloarthritis (SpA) are rheumatic diseases with an inflammatory etiology. A high prevalence of depressive and anxiety-related comorbidity has been reported for both diseases, with no evidence of a greater prevalence of psychosis. The objective of the present study was to evaluate for the first time subclinical psychotic symptoms in patients with RA and SpA. This is a cross-sectional, single-center study including RA and SpA patients, as well as healthy controls. Abnormal psychotic experiences (positive, negative, and depressive symptoms) were evaluated using the Community Assessment of Psychic Experiences (CAPE-42). Functional capacity was evaluated using the Short-Form Health Survey SF-12. We compared the CAPE and SF-12 scores between the three groups. We recruited 385 individuals: 218 with RA, 100 with SpA, and 67 healthy controls. According to the CAPE scale, the frequency of subclinical psychotic symptoms was greater in patients than in healthy controls (RA, 1.90 vs. 1.63, < 0.001; SpA, 1.88 vs. 1.63, = 0.001). Distress was also greater in patients than in controls owing to the presence of symptoms. No differences were observed between the three groups for the mental dimension scores in the SF-12 Health Survey (43.75 in RA, 45.54 in SpA, and 43.19 in healthy controls). Our findings point to a greater prevalence of subclinical psychotic symptoms in patients with RA and patients with SpA than in the general population. The results suggest an association between inflammation and depression/subclinical psychotic symptoms.
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http://dx.doi.org/10.3390/jcm10163461DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8396915PMC
August 2021

Molecular diagnosis of polycystic ovary syndrome in obese and non-obese women by targeted plasma miRNA profiling.

Eur J Endocrinol 2021 Oct 8;185(5):637-652. Epub 2021 Oct 8.

Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Spain.

Objective: Polycystic ovary syndrome (PCOS) is diagnosed based on the clinical signs, but its presentation is heterogeneous and potentially confounded by concurrent conditions, such as obesity and insulin resistance. miRNA have recently emerged as putative pathophysiological and diagnostic factors in PCOS. However, no reliable miRNA-based method for molecular diagnosis of PCOS has been reported. The aim of this study was to develop a tool for accurate diagnosis of PCOS by targeted miRNA profiling of plasma samples, defined on the basis of unbiased biomarker-finding analyses and biostatistical tools.

Methods: A case-control PCOS cohort was cross-sectionally studied, including 170 women classified into four groups: non-PCOS/lean, non-PCOS/obese, PCOS/lean, and PCOS/obese women. High-throughput miRNA analyses were performed in plasma, using NanoString technology and a 800 human miRNA panel, followed by targeted quantitative real-timePCR validation. Statistics were applied to define optimal normalization methods, identify deregulated biomarker miRNAs, and build classification algorithms, considering PCOS and obesity as major categories.

Results: The geometric mean of circulating hsa-miR-103a-3p, hsa-miR-125a-5p, and hsa-miR-1976, selected among 125 unchanged miRNAs, was defined as optimal reference for internal normalization (named mR3-method). Ten miRNAs were identified and validated after mR3-normalization as differentially expressed across the groups. Multinomial least absolute shrinkage and selection operator regression and decision-tree models were built to reliably discriminate PCOS vs non-PCOS, either in obese or non-obese women, using subsets of these miRNAs as performers.

Conclusions: We define herein a robust method for molecular classification of PCOS based on unbiased identification of miRNA biomarkers and decision-tree protocols. This method allows not only reliable diagnosis of non-obese women with PCOS but also discrimination between PCOS and obesity.

Capsule: We define a novel protocol, based on plasma miRNA profiling, for molecular diagnosis of PCOS. This tool not only allows proper discrimination of the condition in non-obese women but also permits distinction between PCOS and obesity, which often display overlapping clinical presentations.
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http://dx.doi.org/10.1530/EJE-21-0552DOI Listing
October 2021

In1-ghrelin splicing variant as a key element in the pathophysiological association between obesity and prostate cancer.

J Clin Endocrinol Metab 2021 Jul 13. Epub 2021 Jul 13.

Maimonides Institute of Biomedical Research of Cordoba (IMIBIC), 14004 Cordoba, Spain.

Context: Recent studies emphasize the importance of considering the metabolic status to develop personalized medicine approaches. This is especially relevant in prostate cancer (PCa), wherein the diagnostic capability of PSA dramatically drops when considering patients with PSA levels ranging 3-10 ng/mL, the so-called "grey-zone". Hence, additional non-invasive diagnostic and/or prognostic PCa biomarkers are urgently needed, especially in the metabolic-status context.

Objective: To assess the potential relation of urine In1-ghrelin (a ghrelin splicing variant) levels with metabolic-related/pathological conditions (e.g. obesity/diabetes/BMI/insulin-glucose levels), and to define its potential clinical value in PCa (diagnostic/prognostic capacity) and relationship with PCa-risk in patients with PSA in the grey-zone.

Methods: Urine In1-ghrelin levels were measured by radioimmunoassay in a clinically/metabolically/pathologically well-characterized cohort of patients without (n=397) or with (n=213) PCa with PSA in the grey-zone.

Results: Key obesity-related factors associated with PCa-risk (BMI/diabetes/glucose/insulin) were strongly correlated to In1-ghrelin levels. Importantly, In1-ghrelin levels were higher in PCa patients compared to control patients (with suspect of PCa but negative-biopsy). Moreover, high In1-ghrelin levels were associated with increased PCa-risk and linked to PCa-aggressiveness (e.g. tumour-stage/lymphovascular-invasion). In1-ghrelin levels added significant diagnostic value to a clinical model consisting of age, suspicious-DRE, previous-biopsy, and PSA levels. Furthermore, a multivariate model consisting of clinical and metabolic variables, including In1-ghrelin levels, showed high specificity and sensitivity to diagnose PCa (AUC=0.740).

Conclusions: Urine In1-ghrelin levels are associated with obesity-related factors and PCa risk/aggressiveness, and could represent a novel and valuable non-invasive PCa biomarker, as well as a potential link in the pathophysiological relationship between obesity and PCa.
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http://dx.doi.org/10.1210/clinem/dgab516DOI Listing
July 2021

Venous Thromboembolism in Patients Discharged after COVID-19 Hospitalization.

Semin Thromb Hemost 2021 Jun 23;47(4):362-371. Epub 2021 Apr 23.

Department of Cardiovascular Diseases, University Hospitals Leuven, Leuven, Belgium.

Background:  Venous thromboembolism (VTE) is a frequent complication of COVID-19, so that the importance of adequate in-hospital thromboprophylaxis in patients hospitalized with COVID-19 is well established. However, the incidence of VTE after discharge and whether postdischarge thromboprophylaxis is beneficial and safe are unclear. In this prospective observational single-center study, we report the incidence of VTE 6 weeks after hospitalization and the use of postdischarge thromboprophylaxis.

Methods:  Patients hospitalized with confirmed COVID-19 were invited to a multidisciplinary follow-up clinic 6 weeks after discharge. D-dimer and C-reactive protein were measured, and all patients were screened for deep vein thrombosis with venous duplex-ultrasound. Additionally, selected high-risk patients received computed tomography pulmonary angiogram or ventilation-perfusion (V/Q) scan to screen for incidental pulmonary embolism.

Results:  Of 485 consecutive patients hospitalized from March through June 2020, 146 patients were analyzed, of which 39% had been admitted to the intensive care unit (ICU). Postdischarge thromboprophylaxis was prescribed in 28% of patients, but was used more frequently after ICU stay (61%) and in patients with higher maximal D-dimer and C-reactive protein levels during hospitalization. Six weeks after discharge, elevated D-dimer values were present in 32% of ward and 42% of ICU patients. Only one asymptomatic deep vein thrombosis (0.7%) and one symptomatic pulmonary embolism (0.7%) were diagnosed with systematic screening. No bleedings were reported.

Conclusion:  In patients who had been hospitalized with COVID-19, systematic screening for VTE 6 weeks after discharge revealed a low incidence of VTE. A strategy of selectively providing postdischarge thromboprophylaxis in high-risk patients seems safe and potentially effective.
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http://dx.doi.org/10.1055/s-0041-1727284DOI Listing
June 2021

A Diet-Dependent Microbiota Profile Associated with Incident Type 2 Diabetes: From the CORDIOPREV Study.

Mol Nutr Food Res 2020 Oct 16:e2000730. Epub 2020 Oct 16.

Lipids and Atherosclerosis Research Unit, Internal Medicine Unit, Reina Sofia University Hospital, Cordoba, 14004, Spain.

Scope: The differences between the baseline gut microbiota of patients who developed type 2 diabetes (T2D) consuming a low-fat (LF) or a Mediterranean (Med) diet are explored and risk scores are developed to predict the individual risk of developing T2D associated with the consumption of LF or Med diet.

Methods And Results: All the patients from the CORDIOPREV study without T2D at baseline (n = 462) whose fecal sample are available, are included. Gut microbiota is analyzed by 16S sequencing and the risk of T2D after a median follow-up of 60 months assessed by Cox analysis. Linear discriminant analysis effect size (LEfSe) analysis shows a different baseline gut microbiota in patients who developed T2D consuming LF and Med diets. A higher abundance of Paraprevotella, and lower Gammaproteobacteria and B. uniformis are associated with T2D risk when an LF diet is consumed. In contrast, higher abundances of Saccharibacteria, Betaproteobacteria, and Prevotella are associated with T2D risk when a Med diet is consumed.

Conclusion: The results suggest that different interactions between the microbiome and dietary patterns may partially determine the risk of T2D development, which may be used for selecting personalized dietary models to prevent T2D.
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http://dx.doi.org/10.1002/mnfr.202000730DOI Listing
October 2020

Fibula free flap in maxillomandibular reconstruction. Factors related to osteosynthesis plates' complications.

J Craniomaxillofac Surg 2020 Oct 19;48(10):994-1003. Epub 2020 Aug 19.

Oral and Maxillofacial Surgery Service, Reina Sofía University Hospital, Córdoba, Spain.

The aim of this paper is to identify risk factors associated with the development of osteosynthesis plates' related complications in fibula free flap reconstructions. This is a case series study of consecutive fibula free flaps. Clinical and radiological variables were recorded. Patient outcomes were evaluated with special attention to osteosynthesis plates' related complications; these included plate exposure, plate fracture, loosening of screws, non-union, bone resorption, oro-cutaneous fistulas, and bone exposure. We have done a descriptive analysis, univariate analysis, and multivariate logistic regression model to explore possible risk factors for osteosynthesis plates' related complications. Data analysis was performed using R software (version 3.5.0). 111 fibula free flaps were studied. 29 patients (26.1%) developed osteosynthesis plates' related complications. The mean time to osteosynthesis plates' related complications was 22 months; range (1-120); the median and mode were 12 months. Patients with preoperative radiotherapy (34% vs 14%, p = 0.021), and secondary reconstruction (31% vs 15%, p = 0.053) had a higher incidence of osteosynthesis plates' related complications. In the univariate analysis, "preoperative radiotherapy" (OR 3.07, 95%CI = 1.139-8.242, p = 0.025) and "extraoral soft-tissue defect" (OR 2.907, 95%CI = 1.032-8.088, p = 0.042) were risk factors for osteosynthesis plates' related complications. We have observed an interaction effect: patients with mandibular Brown's classes III + IV and "secondary reconstruction" have a higher risk for osteosynthesis plates' related complications; more than 47.30 times compared to Brown's class I and "primary reconstruction" (p = 0.026). Different factors may contribute to the development of osteosynthesis plates' related complications. Our study adds important information about these. Patients with higher risk of developing complications should be informed that a second intervention to remove the plates might be necessary.
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http://dx.doi.org/10.1016/j.jcms.2020.08.003DOI Listing
October 2020

Association of Tumor Budding With Immune Evasion Pathways in Primary Colorectal Cancer and Patient-Derived Xenografts.

Front Med (Lausanne) 2020 3;7:264. Epub 2020 Jul 3.

Instituto Maimónides de Investigación Biomédica de Córdoba, Córdoba, Spain.

Tumor budding has been found to be of prognostic significance for several cancers, including colorectal cancer (CRC). Additionally, the molecular classification of CRC has led to the identification of different immune microenvironments linked to distinct prognosis and therapeutic response. However, the association between tumor budding and the different molecular subtypes of CRC and distinct immune profiles have not been fully elucidated. This study focused, firstly, on the validation of derived xenograft models (PDXs) for the evaluation of tumor budding and their human counterparts and, secondly, on the association between tumor budding and the immune tumor microenvironment by the analysis of gene expression signatures of immune checkpoints, Toll-like receptors (TLRs), and chemokine families. Clinical CRC samples with different grades of tumor budding and their corresponding PDXs were included in this study. Tumor budding grade was reliably reproduced in early passages of PDXs, and high-grade tumor budding was intimately related with a poor-prognosis CMS4 mesenchymal subtype. In addition, an upregulation of negative regulatory immune checkpoints (PDL1, TIM-3, NOX2, and IDO1), TLRs (TLR1, TLR3, TLR4, and TLR6), and chemokine receptors and ligands (CXCR2, CXCR4, CXCL1, CXCL2, CXCL6, and CXCL9) was detected in high-grade tumor budding in both human samples and their corresponding xenografts. Our data support a close link between high-grade tumor budding in CRC and a distinctive immune-suppressive microenvironment promoting tumor invasion, which may have a determinant role in the poor prognosis of the CMS4 mesenchymal subtype. In addition, our study demonstrates that PDX models may constitute a robust preclinical platform for the development of novel therapies directed against tumor budding in CRC.
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http://dx.doi.org/10.3389/fmed.2020.00264DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7347987PMC
July 2020

Reduction in Circulating Advanced Glycation End Products by Mediterranean Diet Is Associated with Increased Likelihood of Type 2 Diabetes Remission in Patients with Coronary Heart Disease: From the Cordioprev Study.

Mol Nutr Food Res 2021 01 23;65(1):e1901290. Epub 2020 Jun 23.

Maimonines Institute for Biomedical Research of Córdoba (IMIBIC), Córdoba, 14004, Spain.

Scope: It is hypothesized that decreased advanced glycation end products (AGEs) levels could affect type 2 diabetes mellitus (T2DM) remission in newly diagnosed patients through the consumption of two healthy diets.

Methods And Results: Patients from CORDIOPREV study, all with previous cardiovascular events, with T2DM at the beginning of the study are included. Patients are randomized to a Mediterranean or a low-fat diet for five years. No different diabetes remission rates are found among diets. Serum methylglioxal (MG) and carboximethyllysine (CML), levels dietary AGE, as well as gene expression of AGER1 and RAGE are measured. Serum MG decreases only after the consumption of the Mediterranean diet. Moreover, a COX regression analysis shows that each SD decrease in the MG, occurring after the Mediterranean diet, increases the probability of T2DM remission with HR:2.56(1.02-6.25) and p = 0.046 and each SD increase in disposition index at baseline increases the probability of remission with HR:1.94(1.32-2.87) and p = 0.001.

Conclusions: It is demonstrated that the reduction of serum AGEs levels and the modulation of its metabolism, occurring after the consumption of a Mediterranean diet, might be involved in the molecular mechanism underlying the T2DM remission of newly diagnosed patients with coronary heart disease.
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http://dx.doi.org/10.1002/mnfr.201901290DOI Listing
January 2021

Telomere-based risk models for the early diagnosis of clinically significant prostate cancer.

Prostate Cancer Prostatic Dis 2021 03 4;24(1):88-95. Epub 2020 May 4.

Life Length SL, Madrid, Spain.

Background: The objective of this study was to explore telomere-associated variables (TAV) as complementary biomarkers in the early diagnosis of prostate cancer (PCa), analyzing their application in risk models for significant PCa (Gleason score > 6).

Methods: As part of a larger prospective longitudinal study of patients with suspicion of PCa undergoing prostate biopsy according to clinical practice, a subgroup of patients (n = 401) with PSA 3-10 ng/ml and no prior biopsies was used to evaluate the contribution of TAV to discern non-significant PCa from significant PCa. The cohort was randomly split for training (2/3) and validation (1/3) of the models. High-throughput quantitative fluorescence in-situ hybridization was used to evaluate TAV in peripheral blood mononucleated cells. Models were generated following principal component analysis and random forest and their utility as risk predictors was evaluated by analyzing their predictive capacity and accuracy, summarized by ROC curves, and their clinical benefit with decision curves analysis.

Results: The median age of the patients was 63 years, with a median PSA of 5 ng/ml and a percentage of PCa diagnosis of 40.6% and significant PCa of 19.2%. Two TAV-based risk models were selected (TAV models 1 and 2) with an AUC ≥ 0.83 in the full study cohort, and AUC > 0.76 in the internal validation cohort. Both models showed an improvement in decision capacity when compared to the application of the PCPT-RC in the low-risk probabilities range. In the validation cohort, with TAV models 1 and 2, 33% /48% of biopsies would have been avoided losing 0/10.3% of significant PCa, respectively. The models were also tested and validated on an independent, retrospective, non contemporary cohort.

Conclusions: Telomere analysis through TAV should be considered as a new risk-score biomarker with potential to increase the prediction capacity of significant PCa in patients with PSA between 3-10 ng/ml.
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http://dx.doi.org/10.1038/s41391-020-0232-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8012205PMC
March 2021

Clinical Utility of Ghrelin-O-Acyltransferase (GOAT) Enzyme as a Diagnostic Tool and Potential Therapeutic Target in Prostate Cancer.

J Clin Med 2019 Nov 22;8(12). Epub 2019 Nov 22.

Maimonides Institute for Biomedical Research of Córdoba (IMIBIC), 14004 Córdoba, Spain.

Recent data suggested that plasma Ghrelin O-Acyl Transferase enzyme (GOAT) levels could represent a new diagnostic biomarker for prostate cancer (PCa). In this study, we aimed to explore the diagnostic and prognostic/aggressiveness capacity of GOAT in urine, as well as to interrogate its putative pathophysiological role in PCa. We analysed urine/plasma levels of GOAT in a cohort of 993 patients. In vitro (i.e., cell-proliferation) and in vivo (tumor-growth in a xenograft-model) approaches were performed in response to the modulation of GOAT expression/activity in PCa cells. Our results demonstrate that plasma and urine GOAT levels were significantly elevated in PCa patients compared to controls. Remarkably, GOAT significantly outperformed PSA in the diagnosis of PCa and significant PCa in patients with PSA levels ranging from 3 to 10 ng/mL (the so-called PSA grey-zone). Additionally, urine GOAT levels were associated to clinical (e.g., Gleason-score, PSA levels) and molecular (e.g., // expression) aggressiveness parameters. Indeed, overexpression increased, while its silencing/blockade decreased cell-proliferation in PCa cells. Moreover, xenograft tumors derived from GOAT-overexpressing PCa (DU145) cells were significantly higher than those derived from the mock-overexpressing cells. Altogether, our results demonstrate that GOAT could be used as a diagnostic and aggressiveness marker in urine and a therapeutic target in PCa.
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http://dx.doi.org/10.3390/jcm8122056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6947219PMC
November 2019

Characterization of the C1q-Binding Ability and the IgG1-4 Subclass Profile of Preformed Anti-HLA Antibodies by Solid-Phase Assays.

Front Immunol 2019 2;10:1712. Epub 2019 Aug 2.

Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Reina Sofia University Hospital, University of Cordoba, Cordoba, Spain.

Humoral alloimmunity, particularly that triggered by preformed antibodies against human leukocyte antigens (HLA), is associated with an increased prevalence of rejection and reduced transplant survival. The high sensitivity of solid phase assays, based on microbeads coated with single antigens (SAB), consolidated them as the gold-standard method to characterize anti-HLA antibodies, ensuring a successful allograft allocation. Mean fluorescence intensity (MFI) provided by SAB is regularly used to stratify the immunological risk, assuming it as a reliable estimation of the antibody-level, but it is often limited by artifacts. Beyond MFI, other properties, such as the complement-binding ability or the IgG1-4 subclass profile have been examined to more accurately define the clinical relevance of antibodies and clarify their functional properties. However, there are still unresolved issues. Neat serum-samples from 20 highly-sensitized patients were analyzed by SAB-panIgG, SAB-IgG1-4 subclass and SAB-C1q assays. All 1:16 diluted serum-samples were additionally analyzed by SAB-panIgG and SAB-IgG1-4 subclass assays. A total of 1,285 anti-HLA antibodies were identified as positive, 473 (36.8%) of which were C1q-binding. As expected, serum-dilution enhanced the correlation between the C1q-binding ability and the antibody-strength, measured as the MFI (r = 0.248 vs. r = 0.817). SAB-subclass assay revealed at least one IgG1-4 subclass in 1,012 (78.8%) positive antibody-specificities. Among them, strong complement-binding subclasses, mainly IgG1, were particularly frequent (98.9%) and no differences were found between C1q- and non-C1q-binding antibodies regarding their presence (99.4 vs. 98.5%; = 0.193). In contrast, weak or non-C1q-binding subclasses (IgG2/IgG4) were more commonly detected in C1q-binding antibodies (78.9 vs. 38.6%; < 0.001). Interestingly, a strong association was found between the C1q-binding ability and the IgG1 strength (r = 0.796). Though lower, the correlation between the IgG2 strength and the C1q-binding ability was also strong (r = 0.758), being both subclasses closely related (r = 0.817). We did not find any correlation with the C1q-binding ability considering the remaining subclasses. In conclusion, we demonstrate that a particular profile of IgG subclasses (IgG1/IgG3) itself does not determine at all the ability to bind complement of anti-HLA antibodies assessed by SAB-C1q assay. It is the IgG subclass strength, mainly of IgG1, which usually appears in combination with IgG2, that best correlates with it.
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http://dx.doi.org/10.3389/fimmu.2019.01712DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6687874PMC
October 2020

"Readiness to Change" Predicts Efficacy of Reduction among Smokers with Severe Mental Illness.

Eur Addict Res 2019 4;25(5):256-262. Epub 2019 Jun 4.

Centro de Investigación Biomédica en Red de Salud Mental, Oviedo, Spain.

Aims: Smoking cessation in subjects with a severe mental illness (SMI) is a challenging but attainable goal. Furthermore, the identification of variables involved in the quitting process is a highly relevant factor in clinical practice. This study aimed to analyze the influence of smokers' motivation in smoking reduction and cessation and select the most suitable way of measuring motivation.

Methods: This is a secondary analysis of a 9-month, multicenter trial examining a Multicomponent Smoking Cessation Program in 82 adult outpatients with SMI. At the end of the preparation stage, the smokers' motivational level was evaluated with the University of Rhode Island Change Assessment Scale. This allowed us to rate subjects using a continuous measure ("Readiness to Change," RTC) and group them in "Stages of Change" (SOC). Regression analyses were carried out to identify predictors of the efficacy outcomes: a reduction in at least 50% of the cigarettes smoked per day (CPD), a reduction in the expired carbon monoxide (CO), and complete abstinence from smoking.

Results: We studied differences in measurements of motivational levels independently (RTC and SOC) for patients who had a reduction in at least 50% of the CPD and for patients who achieved complete abstinence from smoking. However, these differences did not reach statistical significance during the follow-up study with a logistic mixed-effects model. In a linear mixed-effects model, the reduction of expired CO was significantly associated with RTC, at the end of the active treatment phase and during follow-up (β: -1.51; SD 0.82; p < 0.01).

Conclusion: The motivation level achieved in the preparation phase predicted the reduction of expired CO over a given period when calculated by a continuous measure (RTC).
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http://dx.doi.org/10.1159/000500450DOI Listing
January 2020

Liraglutide in a real-world setting: Joint modeling of metabolic response, prediction of efficacy, and cardiovascular risk.

Endocrinol Diabetes Nutr (Engl Ed) 2019 Jun - Jul;66(6):376-384. Epub 2018 Dec 6.

Servicio Endocrinología, Complejo Hospitalario Universitario de Vigo, Spain.

Introduction And Objectives: The worldwide prevalence of type 2 diabetes mellitus increases in parallel to that of obesity. Liraglutide (LRG), a glucagon-like peptide-1 receptor agonist, can reduce body weight. This study assessed the metabolic efficacy of LRG in real-world clinical practice.

Methods: An observational, retrospective cohort study including patients treated with LRG for at least one year (187 patients). Anthropometric and metabolic variables, a composite endpoint, factors predicting response to LRG, and cardiovascular risk over time were assessed. A linear mixed-effects model with a bivariate structure was constructed to investigate the time-dependent relationship between weight and HbA1c values.

Results: HbA1c levels and weight significantly decreased in the first 12 weeks, and the decrease persisted at 12 and 24 months in all subgroups studied. Mean weight and HbA1c decreases after 24 months were 8.5kg and 1.7% respectively. HbA1c values <7% were achieved by 42% of patients at 12 months and by 40% at 24 months. Treatment with LRG allowed for reduction in insulin dose. No serious adverse events were noted. Cardiovascular risk decreased from high to moderate-low.

Conclusions: Under standard clinical practice conditions, LRG achieved a better metabolic response than seen in clinical trials. Efficacy at 12 weeks of treatment is a good predictor of response. LRG allows for delaying or reducing insulin dose by improving both weight and glucose control. Cardiovascular risk improved.
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http://dx.doi.org/10.1016/j.endinu.2018.09.005DOI Listing
January 2020

Post-operative stress hyperglycemia is a predictor of mortality in liver transplantation.

Diabetol Metab Syndr 2018 19;10:35. Epub 2018 Apr 19.

4Clinical Epidemiology Unit, Hospital Clínico Universitario de Santiago, Santiago, Spain.

Background: A significant association is known between increased glycaemic variability and mortality in critical patients. To ascertain whether glycaemic profiles during the first week after liver transplantation might be associated with long-term mortality in these patients, by analysing whether diabetic status modified this relationship.

Method: Observational long-term survival study includes 642 subjects undergoing liver transplantation from July 1994 to July 2011. Glucose profiles, units of insulin and all variables with influence on mortality are analysed using joint modelling techniques.

Results: Patients registered a survival rate of 85% at 1 year and 65% at 10 years, without differences in mortality between patients with and without diabetes. In glucose profiles, however, differences were observed between patients with and without diabetes: patients with diabetes registered lower baseline glucose values, which gradually rose until reaching a peak on days 2-3 and then subsequently declined, diabetic subjects started from higher values which gradually decreased across the first week. Patients with diabetes showed an association between mortality and age, Model for End-Stage Liver Disease score (MELD) score and hepatitis C virus; among non-diabetic patients, mortality was associated with age, body mass index, malignant aetiology, red blood cell requirements and parenteral nutrition. Glucose profiles were observed to be statistically associated with mortality among patients without diabetes (= 0.022) but not among patients who presented with diabetes prior to transplantation (= 0.689).

Conclusions: Glucose profiles during the first week after liver transplantation are different in patients with and without diabetes. While glucose profiles are associated with long-term mortality in patients without diabetes, after adjusting for potential confounding variables such as age, cause of transplantation, MELD, nutrition, immunosuppressive drugs, and units of insulin administered, this does not occur among patients with diabetes.
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http://dx.doi.org/10.1186/s13098-018-0334-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5909230PMC
April 2018

Two-stage model for multivariate longitudinal and survival data with application to nephrology research.

Biom J 2017 Nov;59(6):1204-1220

Instituto de Ciencias Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal.

In many follow-up studies different types of outcomes are collected including longitudinal measurements and time-to-event outcomes. Commonly, it is of interest to study the association between them. Joint modeling approaches of a single longitudinal outcome and survival process have recently gained increasing attention from both frequentist and Bayesian perspective. However, in many studies several longitudinal biomarkers are of interest and instead of selecting one single biomarker, the relationships between all these outcomes and their association with survival needs to be investigated. Our motivating study comes from Peritoneal Dialysis Programme in Nephrology research from Nephrology Unit, CHP (Hospital de Santo António), Porto, Portugal in which the interest relies on the possible association between various biomarkers (calcium, phosphate, parathormone, and creatinine) and the patients' survival. To this aim, we propose a two-stage model-based approach for multivariate longitudinal and survival data that allowed us to study such complex association structure. The multivariate model suggested in this paper provided new insights in the area of nephrology research showing valid results in comparison with those models studying each longitudinal biomarker with survival separately.
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http://dx.doi.org/10.1002/bimj.201600244DOI Listing
November 2017

New insights in growth of phenylketonuric patients.

Eur J Pediatr 2015 May 1;174(5):651-9. Epub 2014 Nov 1.

Unit of Diagnosis and Treatment of Congenital Metabolic Diseases, Department of Pediatrics, Hospital Clínico Universitario de Santiago de Compostela, A Choupana s/n,, 15706, Santiago de Compostela, A Coruña, Spain,

Unlabelled: Treatment of phenylketonuria involves a restriction in the intake of natural proteins. This can lead to growth impairment. Weight, height and body mass index of 109 hyperphenylalaninemic patients (mild hyperphenylalaninemia (HPA) and phenylketonuria (PKU)) were determined from birth until 18 years, every 6 months, and differences to the healthy population, depending on the age, sex and phenotype, were analyzed. Data collection was longitudinal retrospective during 31 years. Statistical analysis of z-score values was performed by advanced statistical tools. Long-term evolution of anthropometric z-scores showed no significant statistical differences between PKU and mild HPA individuals, according to the general population. For PKU individuals, height is slightly lower and weight slightly higher than in the healthy population, but differences are smaller than one standard deviation. Nevertheless, over-time evolutions of female height z-scores are different in each type of pathology, with a crossover between 8 and 12 years (p = 0.0186).

Conclusions: It is nowadays possible to achieve a long-term normal growth in PKU patients with appropriate dietary treatment. There is however an acceleration of growth up to 8 years old for PKU female patients that leads to a slightly lower final height. Detection of this behaviour was possible by using nonlinear mixed effects models.
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http://dx.doi.org/10.1007/s00431-014-2446-8DOI Listing
May 2015
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