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Research Interests: Environmental Engineering, Environmental Science, Chemistry, Atmospheric Aerosols, Forest fire, and 14 morePortugal, Atmospheric sciences, Potassium, Wildfire, Forest Fires, Biomass burning, Organic carbon, Chemical Composition, Atmospheric Composition, Diacids, Levoglucosan, Organic Compound, Polyols, and Atmospheric Environment
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BackgroundTimely stratification of Crohn's disease (CD) is essential for patients' management. The use of noninvasive accurate biomarkers is key to monitor treatment and to pursue mucosal healing, the ultimate treatment endpoint... more
BackgroundTimely stratification of Crohn's disease (CD) is essential for patients' management. The use of noninvasive accurate biomarkers is key to monitor treatment and to pursue mucosal healing, the ultimate treatment endpoint in CD.ObjectiveWe aimed to evaluate the performance of readily available biomarkers and develop risk matrices to predict CD progression.MethodsData from 289 CD patients receiving infliximab (IFX) maintenance therapy for 2 years was collected; those patients were included in DIRECT, a prospective multicenter observational study. Disease progression was evaluated using two composite outcomes incorporating clinical and drug‐related factors, the first including IFX dose and/or frequency adjustments. Univariate and multivariable logistic regressions were used to calculate the odds ratios (OR) and to develop risk matrices.ResultsThe isolated presence of anemia at least once during follow‐up was a significant predictor of disease progression (OR 2.436 and 3...
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Aims: Inflammation-driven endothelitis seems to be a hallmark of acute heart failure (AHF) and cardiogenic shock (CS). Endocan, a soluble proteoglycan secreted by the activated endothelium, contributes to inflammation and endothelial... more
Aims: Inflammation-driven endothelitis seems to be a hallmark of acute heart failure (AHF) and cardiogenic shock (CS). Endocan, a soluble proteoglycan secreted by the activated endothelium, contributes to inflammation and endothelial dysfunction, but has been scarcely explored in human AHF. We aimed to evaluate serum (S-Endocan) and urinary endocan (U-Endocan) profiles in AHF and CS patients and to correlate them with biomarkers/parameters of inflammation, endothelial activation, cardiovascular dysfunction and prognosis.Methods: Blood and spot urine were collected from patients with AHF (n = 23) or CS (n = 25) at days 1–2 (admission), 3-4 and 5-8 and from controls (blood donors, n = 22) at a single time point. S-Endocan, U-Endocan, serum IL-1β, IL-6, tumour necrosis factor-α (S-TNF-α), intercellular adhesion molecule-1 (S-ICAM-1), vascular cell adhesion molecule-1 (S-VCAM-1) and E-selectin were determined by ELISA or multiplex immunoassays. Serum C-reactive protein (S-CRP), plasma B...
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Background Patients suffering from inflammatory bowel disease can be treated with the biologics adalimumab (ADL) or infliximab (IFX). Previous studies demonstrated the usefulness of therapeutic drug monitoring (TDM) to adjust the... more
Background Patients suffering from inflammatory bowel disease can be treated with the biologics adalimumab (ADL) or infliximab (IFX). Previous studies demonstrated the usefulness of therapeutic drug monitoring (TDM) to adjust the patient’s biologic concentration individually. Commercially available rapid assays support laboratories in the fast and easy detection of ADL and IFX concentrations but the assays’ dependency on serum as analyte matrix is a general hindrance for TDM, as serum preparation from whole blood is time-consuming and requires laboratory equipment. Patients and clinicians would thus benefit from rapid point-of-care (POC) and easy to use assays that are independent of laboratory equipment. The objective of this project was to expand existing serum lateral flow assays for the analysis of ADL or IFX in capillary blood and investigate potential interactions resulting from the blood matrix. Methods ADL and IFX lateral flow serum kits were optimized in such a way that bot...
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INTRODUCTION: Dipeptidyl peptidase-4 (DPP-4) is a membrane-bound glycoprotein that acts as a receptor but also exists in a soluble form. It has been recognized as a mediator of inflammation and considered a biomarker in inflammatory bowel... more
INTRODUCTION: Dipeptidyl peptidase-4 (DPP-4) is a membrane-bound glycoprotein that acts as a receptor but also exists in a soluble form. It has been recognized as a mediator of inflammation and considered a biomarker in inflammatory bowel disease (IBD). METHODS: We evaluated a prospectively recruited cohort, consisting of 101 patients with IBD, using validated clinical indexes; 22 patients with ulcerative colitis (UC) underwent endoscopic evaluation. Fecal DPP-4 (fDPP-4) levels were analyzed and correlated with clinical scores, Mayo endoscopic score (in UC patients), serum DPP-4, C-reactive protein, and fecal calprotectin. Immunohistochemical staining for DPP-4 in intestinal biopsies was also performed. RESULTS: When compared with remitters, median fDPP-4 levels were higher in patients with ileal Crohn's disease (CD) (7,584 [1,464–7,816] vs 2,104 [630–2,676] ng/mL, P = 0.015) and lower in patients with UC exhibiting clinical activity (1,213 [559–1,682] vs 7,814 [2,555–7,985] ng/mL, P < 0.001). Patients with UC presenting endoscopic activity also had lower levels than remitters (939 [559–1,420] vs 7,544 [4,531–7,940] ng/mL, P = 0.006). Fecal DPP-4 discriminated clinical activity from remission with areas under the curve of 0.76 (95% confidence interval [CI] 0.58–0.94, P = 0.015) and 0.80 (95% CI 0.68–0.93, P < 0.001) in CD and UC, respectively; it allowed to differentiate endoscopic activity in patients with UC, with areas under the curve of 0.84 (95% CI 0.63–1.00, P = 0.009). Immunohistochemical analysis revealed higher DPP-4 apical expression in UC remitters, but no statistically significant differences were revealed between patients with ileal CD. DISCUSSION: Our results suggest that fDPP-4 can be used as a biomarker of IBD activity, particularly in UC. The expression profiles in intestinal tissue might represent a functional compartmentalization of DPP-4 expression.
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MicroRNAs (miRNAs) are regulators of gene expression and play a key role in the pathophysiology of various disease processes, namely cardiovascular disease. This study aimed at the identification of the miRNA expression pattern of... more
MicroRNAs (miRNAs) are regulators of gene expression and play a key role in the pathophysiology of various disease processes, namely cardiovascular disease. This study aimed at the identification of the miRNA expression pattern of peripheral blood mononuclear cells derived from hypertensive subjects (HT) and non-hypertensive subjects with cardiac disease (CD) using a genome-wide approach. Furthermore, we explored the potential of orthogonal partial least squares-discrimination analysis (OPLS-DA) to analyze miRNA expression data. The homogeneity of the population was assessed with Principal Component Analysis (PCA) and verified by the clear separation of the three groups on the basis of the miRNA expression levels. Moreover, local PCA of HT group indicates the splitting of this group in two distinct subgroups. This distinction correlates with two subject’s characteristics (smoking habits and history of myocardial infarction) that are closest to the CD group. OPLS-DA analysis confirms...
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Subclinical intestinal inflammation is common in Crohn's disease (CD). We aimed to explore its impact in the disease progression of infliximab-treated patients and the usefulness of fecal calprotectin (FC) and C-reactive protein (CRP)... more
Subclinical intestinal inflammation is common in Crohn's disease (CD). We aimed to explore its impact in the disease progression of infliximab-treated patients and the usefulness of fecal calprotectin (FC) and C-reactive protein (CRP) as surrogate minimally invasive biomarkers. The registry-based, prospective, observational, multicenter study DIRECT followed infliximab-treated CD patients for two years in a tertiary care setting. Persistent inflammation definition was based on FC (>150, >250 or >350 μg/g) and/or serum CRP (>3 μg/ml) concentrations over two consecutive or at least three visits. Patients were categorized according to a composite outcome reflecting disease progression that incorporated surgery, hospitalizations, new fistulae, abscess or stricture and treatment escalation. Out of 322 DIRECT patients, 180 asymptomatic, infliximab-treated on maintenance regimen were included in the analysis. Patients developing the composite endpoint (n=96) presented higher median (inter-quartile range) levels of FC (205 [98-515], P=.045), but not CRP (2.50 [.80-6.00], P=.895). Biomarker-defined persistent subclinical inflammation prevalence ranged from 24% to 81%. Considering FC>250 in two consecutive visits, prevalence was 50%, odds of achieving the endpoint were increased 3-fold (OR=2.996 [1.557-5.776]) and time-to-outcome occurrence was significantly lower among subjects with persistent inflammation (median time: 11 months). Both clinical-related and treatment-related components were significantly associated with persistent inflammation. Definitions based on CRP>3, FC>150, FC>350, double biomarkers (FC>250 &/or CRP>3) or more visits did not improve predictive ability. Persistent inflammation, defined simply and readily by FC>250 over two consecutive visits, was associated with a significantly higher risk and shorter time-to-occurrence of a composite outcome reflecting disease progression in asymptomatic infliximab-treated CD patients.
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AIMS: The authors report a case of catatonia secondary to exposure to mephedrone, a semisynthetic derivative of the alkaloid cathinone, and review the literature on this substance that has been increasingly used as a recreational drug.... more
AIMS: The authors report a case of catatonia secondary to exposure to mephedrone, a semisynthetic derivative of the alkaloid cathinone, and review the literature on this substance that has been increasingly used as a recreational drug. CASE DESCRIPTION: A 14 year old boy was taken to the emergency room presenting severe psychomotor agitation with self and heteroaggressiveness followed by stupor, mutism and akinesia. On the admission examination the patient was unresponsive to stimuli. Complementary examination showed no significant changes. During hospitalization he had two episodes of severe psychomotor agitation and in the rest of the time he kept a pseudo-comatose state. After knowledge on the consumption of mephedrone prior to the onset of symptoms and facing the diagnostic hypothesis of catatonia, lorazepam was started, after which the patient showed rapid and complete recovery. CONCLUSIONS: According to the reviewed literature, this is the first published report of catatonia a...
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Background Serum dipeptidyl peptidase 4 (DPP-4) has drawn particular interest as a biomarker in inflammatory bowel disease (IBD), as this protease inactivates several peptides that participate in the inflammatory cascade. Methods Two... more
Background Serum dipeptidyl peptidase 4 (DPP-4) has drawn particular interest as a biomarker in inflammatory bowel disease (IBD), as this protease inactivates several peptides that participate in the inflammatory cascade. Methods Two prospectively recruited cohorts consisting of 195 patients (101 had Crohn’s disease [CD] and 94 had ulcerative colitis [UC]) were evaluated using clinical indexes and followed up to assess for treatment escalation. Sixty-eight patients underwent endoscopic evaluation at baseline. In the second cohort of 46 biologically treated patients, treatment response was assessed. Serum DPP-4, C-reactive protein (CRP), and fecal calprotectin levels were quantified at baseline and during follow-up. Results Median DPP-4 levels were significantly lower in active IBD patients when compared with remitters (CD: 1043 [831–1412] vs 1589 [1255–1956] ng/mL; P < 0.001; UC: 1317 [1058–1718] vs 1798 [1329–2305] ng/mL; P = 0.001) and healthy controls (2175 [1875–3371] ng/mL)....
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Background: The advent of Remicade® biosimilars, Remsima®, Inflectra® and, more recently, Flixabi®, has brought along the potential to decrease the costs associated with this therapy, therefore increasing its access to a larger group of... more
Background: The advent of Remicade® biosimilars, Remsima®, Inflectra® and, more recently, Flixabi®, has brought along the potential to decrease the costs associated with this therapy, therefore increasing its access to a larger group of patients. However, and in order to assure a soft transition, one must make sure the assays and algorithms previously developed and optimized for Remicade perform equally well with its biosimilars. This study aimed to: (a) validate the utilization of Remicade-optimized therapeutic drug monitoring assays for the quantification of Flixabi; and (b) determine the existence of Remicade, Remsima and Flixabi cross-immunogenicity. Methods: Healthy donors’ sera spiked with Remicade, Remsima and Flixabi were quantified using three different Remicade-quantification assays, and the reactivity of anti-Remicade and anti-Remsima sera to Remicade and to its biosimilars was assessed. Results: The results show that all tested Remicade-infliximab-optimized assays measur...
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Background and Aims The histological status of ulcerative colitis [UC] patients in clinical and endoscopic remission has gained space as an important prognostic marker and a key component of disease monitoring. Our main aims were to... more
Background and Aims The histological status of ulcerative colitis [UC] patients in clinical and endoscopic remission has gained space as an important prognostic marker and a key component of disease monitoring. Our main aims were to compare two histological indexes—the continuous Geboes score [GS] and the Robarts Histopathology index [RHI]—regarding their definitions of histological remission and response, and the ability of faecal calprotectin [FC] levels to discriminate between these statuses. Methods This was an analysis of three prospective cohorts including 422 patients previously enrolled in other studies. Results The two continuous scores [GS and RHI] were shown to be significantly correlated [correlation coefficient of 0.806, p < 0.001] and particularly close regarding their definition of histological response: 95% and 88% of all patients classified as having/not having [respectively] histological response according to RHI also did so according to GS. Moreover, median FC ...
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BERC-Luso is a project for building Ethics and Regulatory Capacity, to be developed in four sub-Saharan African countries: Angola, Guinea-Bissau, Mozambique and Cape Verde, and to be implemented in 2018–2021. National Ethics Committees... more
BERC-Luso is a project for building Ethics and Regulatory Capacity, to be developed in four sub-Saharan African countries: Angola, Guinea-Bissau, Mozambique and Cape Verde, and to be implemented in 2018–2021. National Ethics Committees (NECs) and National Regulatory Authorities (NRAs) have been engaged (6 institutions) with the partnership of 4 Portuguese institutions (experts in ethical review and regulatory supervision).Considering that: 1) clinical trials are fundamental to improve healthcare and develop biomedical research; but 2) can only take place within regulatory systems and under ethical review protocols; and 3) some African countries still lack an adequate legislative framework and the expertise to assure good ethical review and regulatory supervision, it is urgent to change the current situation.The BERC-Luso project will unfold at four different levels, each aiming at a specific goal in converging dynamics.Legislative level: Presentation of a comparative study ofthe Po...
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Background:The loss of response to adalimumab (ADL) has been related to low serum concentrations at trough. Currently, most methods commercially available for the quantification of ADL are enzyme-linked immunosorbent assay (ELISA) based,... more
Background:The loss of response to adalimumab (ADL) has been related to low serum concentrations at trough. Currently, most methods commercially available for the quantification of ADL are enzyme-linked immunosorbent assay (ELISA) based, with a turnaround time of approximately 8 h, delaying the target dosage adjustment to the subsequent infusion. In this study, we aimed to evaluate the performance of the newly available rapid-test ADL quantification assay by comparing it with three established ELISA methods, using spiked samples and a set of clinical samples.Methods:Spiked samples from control donors and 120 serum samples from inflammatory bowel disease (IBD) patients undergoing ADL therapy were quantified using lateral flow Quantum Blue®Adalimumab and, the ELISA formats from Immundiagnostik, R-Biopharm and an in-house assay.Results:The rapid-test assay had intraclass correlation coefficients of 0.590, 0.864 and 0.761 when comparing with the Immundiagnostik, R-Biopharm and in-house ...
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Research Interests: Endocrinology, Chemistry, Medicine, Biological Sciences, Internal Medicine, and 15 moreHypertension, Blood Pressure, Nitric oxide, Animals, Male, Dietary Supplements, Proline, Bioavailability, CHEMICAL SCIENCES, Rats, Urinary System, Saline, Angiotensin II, Biological Availability, and Medical and Health Sciences
Histological remission is being increasingly acknowledged as a therapeutic endpoint in patients with UC. The work hereafter described aimed to evaluate the concordance between three histological classification systems-Geboes Score (GS),... more
Histological remission is being increasingly acknowledged as a therapeutic endpoint in patients with UC. The work hereafter described aimed to evaluate the concordance between three histological classification systems-Geboes Score (GS), Nancy Index (NI) and RobartsHistopathologyIndex (RHI), as well as to evaluate their association with the endoscopic outcomes and the faecal calprotectin (FC) levels. Biopsy samples from 377 patients with UC were blindly evaluated using GS, NI and RHI. The results were compared with the patients' Mayo Endoscopic Score and FC levels. GS, NI and RHI have a good concordance concerning the distinction between patients in histological remission or activity. RHI was particularly close to NI, with 100% of all patients classified as being in remission with NI being identified as such with RHI and 100% of all patients classified as having activity with RHI being identified as such with NI. These scores could also predict the Mayo Endoscopic Score and the F...
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To evaluate the incidence of anastomotic strictures after intestinal resection in Crohn's disease (CD), demonstrate long-term efficacy and safety of endoscopic balloon dilation (EBD) in CD strictures and its impact on the diagnosis of... more
To evaluate the incidence of anastomotic strictures after intestinal resection in Crohn's disease (CD), demonstrate long-term efficacy and safety of endoscopic balloon dilation (EBD) in CD strictures and its impact on the diagnosis of subclinical postoperative endoscopic recurrence. Retrospective single tertiary center study based on prospectively collected data between 2010 and 2015 including anastomotic and non-anastomotic strictures. 29% of 162 CD patients included developed an anastomotic stricture. 43 patients with anastomotic strictures and 37 with non-anastomotic strictures underwent EBD; technical success was 97.7% and 100%, respectively, however, 63% and 41% needed repeat dilation during the 4.4-year follow-up. Longer periods between surgery and index colonoscopy and higher lactoferrin levels were associated with the presence of stricture after surgery. Calprotectin levels > 83.35 μg/g and current or past history of smoking were associated with a shorter time until n...
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Background: Therapeutic drug monitoring (TDM)-based algorithms can be used to guide infliximab (IFX) adjustments in inflammatory bowel disease (IBD) patients. This study aimed to explore a rapid IFX-quantification test from a clinical... more
Background: Therapeutic drug monitoring (TDM)-based algorithms can be used to guide infliximab (IFX) adjustments in inflammatory bowel disease (IBD) patients. This study aimed to explore a rapid IFX-quantification test from a clinical perspective. Methods: This manuscript describes a prospective cohort study involving 110 ulcerative colitis (UC) patients on the maintenance phase of IFX. IFX trough levels were quantified using a rapid quantification assay and a commonly-used reference kit. Results: Irrespective of the assay used to measure IFX, its through levels were statistically different between patients with and without endoscopic remission (Mayo endoscopic score = 0), as well as between patients stratified by their faecal calprotectin (FC) levels. Despite the fact that the two methods correlated well with each other [Spearman’s rank correlation coefficient = 0.843, p < 0.001; intraclass correlation coefficients = 0.857, 95% confidence interval (CI): 0.791–0.903], there was a...
Research Interests: Gastroenterology, Medicine, Optimization, Antibodies, Therapeutic drug monitoring, and 13 moreInflammatory Bowel Disease, Internal Medicine, Ulcerative colitis, Therapy, Cohort, Association, Intraclass Correlation Coefficient, Crohns Disease, Confidence Interval, ELISA kits, Calprotectin, Infliximab, and Faecal calprotectin
Background: The commercialization of CT-P13, an infliximab (IFX) biosimilar, has the potential to decrease health-related costs and enhance access to biological therapies. This study aimed to address the accuracy and inter-assay agreement... more
Background: The commercialization of CT-P13, an infliximab (IFX) biosimilar, has the potential to decrease health-related costs and enhance access to biological therapies. This study aimed to address the accuracy and inter-assay agreement of the CT-P13 quantification using four different assays initially developed to assess IFX. Methods: The four different methods, one in-house method and three commercially available kits, were used to quantify exogenously-spiked samples and the sera from 185 inflammatory bowel disease (IBD) patients on CT-P13 therapy. Results: The quantification of the spiked samples unveiled a consistent and accurate behaviour of three of the tested methods, with average percentage recoveries of 90%, 102% and 109%. Results from the clinical samples demonstrated that these three assays were also highly correlated, both concerning Spearman’s rank coefficients (range 0.890–0.947) and intraclass correlation coefficients (range 0.907–0.935). There were a few systematic...
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Although infliximab (IFX) is an efficient therapy for ulcerative colitis (UC) patients, a considerably high rate of therapeutic failures still occurs. This study aimed at a better understanding of IFX pharmacokinetics and pharmacodynamics... more
Although infliximab (IFX) is an efficient therapy for ulcerative colitis (UC) patients, a considerably high rate of therapeutic failures still occurs. This study aimed at a better understanding of IFX pharmacokinetics and pharmacodynamics among clinically-asymptomatic UC patients. This was a multicentric and prospective study involving 65 UC patients in the maintenance phase of IFX therapy. There were no significant differences between patients with positive and negative clinical, endoscopic and histological outcomes concerning their IFX trough levels (TLs), area under the IFX concentration vs. time curve (AUC), clearance and antibodies to infliximab (ATI) levels. However, the need to undergo therapeutic escalation later in disease development was significantly associated with higher ATI levels (2.62μg/mL vs. 1.15μg/mL, p=0.028). Moreover, and after adjusting for disease severity, the HR (hazard ratio) for therapeutic escalation was significantly decreased for patients with an ATI c...