Publications by authors named "Ricardo Ferreira"

306 Publications

The Interaction between and Mycotoxigenic in Maize Flour.

Insects 2021 Aug 14;12(8). Epub 2021 Aug 14.

Instituto Superior de Agronomia, Universidade de Lisboa, Tapada da Ajuda, 1349-017 Lisboa, Portugal.

is one of the most common insect pests of stored products. Its presence makes cereals more susceptible to the spread of the fungi , which may produce mycotoxins. The aim of this work was to evaluate the influence of adults on the development of a mycotoxigenic strain in maize flour as well as the influence of this fungus on the insects. Maize flour was exposed to , spores of or to both. The results revealed an interaction between and as the flour exposed to both organisms was totally colonized by the fungus whereas almost all the insects were killed. Aflatoxin B1 (AFB1) revealed a significantly higher concentration in the flour inoculated with both organisms (18.8 µg/kg), being lower when exposed only to , suggesting that the presence of insects may trigger fungal development and enhance mycotoxin production. The ability of these organisms to thrive under the same conditions and the chemical compounds they release makes the interaction between them a subject of great importance to maintain the safety of stored maize. This is the first work evaluating the interaction between and mycotoxin production.
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http://dx.doi.org/10.3390/insects12080730DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8396807PMC
August 2021

Technological Potential of a Lupin Protein Concentrate as a Nutraceutical Delivery System in Baked Cookies.

Foods 2021 Aug 19;10(8). Epub 2021 Aug 19.

LEAF, Instituto Superior de Agronomia, Universidade de Lisboa, 1349-017 Lisbon, Portugal.

Previous reports have shown that lupin protein extracts (LE) contain a polypeptide named deflamin with a potent matrix metalloproteinase (MMP)-9 inhibitory activity. The aim of our study was to develop an efficient delivery method for incorporating deflamin into cookies using different alternative flours. A lupin protein concentrate (10 g protein/100 g cookie dough) was added to gluten and gluten-free flours to produce savoury cookies, and its impacts on the physical properties of doughs and cookies, as well on the maintenance of deflamin's anti-MMP-9 activity, were analysed. The results showed that the biochemical compositions of all cookies with LE presented higher protein and ash contents when compared to the control cookies. Rice, buckwheat and oat doughs were firmer than the others, whereas the addition of LE to kamut and buckwheat flours made cookies significantly firmer than the controls. Additionally, strong interactions between LE and several flours were observed, yielding different impacts on the MMP-9 bioactivity. Overall, the only flour that did not interfere with the desired nutraceutical activities was buckwheat, with 60% MMP-9 inhibitory activity and a concomitant reduction of colon cancer migration; hence, buckwheat flour was revealed to be a good vehicle to deliver bioactive deflamin, showing strong potential as a functional food to be used in preventive or curative approaches to gastrointestinal diseases.
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http://dx.doi.org/10.3390/foods10081929DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8393273PMC
August 2021

Occurrence of Leishmania infection in the immediate geographic region of Ji-Paraná, Rondônia State, Brazil.

Rev Soc Bras Med Trop 2021 20;54:e02122021. Epub 2021 Aug 20.

Fundação Oswaldo Cruz, Fiocruz Rondônia, Porto Velho, RO, Brasil.

Introduction: This study evaluated the epidemiology of American cutaneous leishmaniasis in the immediate region of Ji-Paraná, Rondônia State.

Methods: Samples and epidemiological data were collected from 105 patients.

Results: Leishmania infection was observed in 58 (55.2%) patients, and Leishmania braziliensis was present in 82.9% of the 41 sequenced samples. Infected patients were predominantly male (93.1%). Leishmania infection was twice as prevalent among rural inhabitants versus urban inhabitants. Lesions were more frequent in the upper limbs (arms/hands, 41.82%).

Conclusions: The present data corroborate the zoonotic profile of cutaneous leishmaniasis; this information could help to improve surveillance and control strategies.
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http://dx.doi.org/10.1590/0037-8682-0212-2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8405217PMC
August 2021

Non-volatile artificial synapse based on a vortex nano-oscillator.

Sci Rep 2021 Aug 9;11(1):16094. Epub 2021 Aug 9.

INL, Avenida Mestre José Veiga, s/n, 4715-330, Braga, Portugal.

In this work, a new mechanism to combine a non-volatile behaviour with the spin diode detection of a vortex-based spin torque nano-oscillator (STVO) is presented. Experimentally, it is observed that the spin diode response of the oscillator depends on the vortex chirality. Consequently, fixing the frequency of the incoming signal and switching the vortex chirality results in a different rectified voltage. In this way, the chirality can be deterministically controlled via the application of electrical signals injected locally in the device, resulting in a non-volatile control of the output voltage for a given input frequency. Micromagnetic simulations corroborate the experimental results and show the main contribution of the Oersted field created by the input RF current density in defining two distinct spin diode detections for different chiralities. By using two non-identical STVOs, we show how these devices can be used as programmable non-volatile synapses in artificial neural networks.
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http://dx.doi.org/10.1038/s41598-021-95569-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8352962PMC
August 2021

An Up-Scalable and Cost-Effective Methodology for Isolating a Polypeptide Matrix Metalloproteinase-9 Inhibitor from Seeds.

Foods 2021 Jul 19;10(7). Epub 2021 Jul 19.

LEAF, Instituto Superior de Agronomia, Universidade de Lisboa, 1349-017 Lisbon, Portugal.

One of the most challenging problems with food-borne bioactive compounds is that there are commonly no cost-effective, generally recognized as safe (GRAS) methods for obtaining gram quantities of their purified forms. Here we aimed at developing a method to isolate deflamin, an oligomeric protein from lupin seeds with anti-inflammatory and anticancer activity through matrix metalloprotease (MMP)-9 inhibition. Our goal was to develop a GRAS method that could be easily up-scalable whilst maintaining deflamin's activity. A sequential precipitation methodology was developed, using an aqueous extraction, followed by heat denaturation, acid precipitation and solubilization in ethanol. A final precipitation with 90% ethanol yielded a purified protein which was sequenced through mass spectrometry and tested for its MMP inhibitory activity using the Dye-quenched (DQ) gelatin assay and the standard wound healing assay in HT29 cells. The developed method yielded a purified oligomer, which represented 0.1% (/) of total dry seed weight and was positively confirmed to be deflamin. It further showed to effectively reduce MMP-9 gelatinolytic activity as well as colon cancer cell migration, hence corroborating the effectiveness of our method. Overall, this is the first reported method for isolating an MMP-9 inhibitor from legume seeds, which is up-scalable to an industrial level, in a cost-effective manner.
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http://dx.doi.org/10.3390/foods10071663DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8306530PMC
July 2021

Suitability for e-health of non-pharmacological interventions in connective tissue diseases: scoping review with a descriptive analysis.

RMD Open 2021 Jul;7(2)

Section for Outcomes Research, Medical University of Vienna, Vienna, Austria

Objective: Non-pharmacological interventions support patients with connective tissue diseases to better cope with and self-manage their diseases. This study aimed to map existing evidence on non-pharmacological interventions in patients with systemic lupus erythematosus (SLE), systemic sclerosis (SSc) and mixed connective tissue diseases regarding content, feasibility and potential suitability in an e-health setting.

Methods: A literature search was performed in eight different databases in July 2020. The intervention's content was extracted using the 'Better reporting of interventions: template for intervention description and replication (TIDieR) checklist and guide'. A Sankey diagram and descriptive statistics were used to analyse the data and illustrate the relationships between the interventions.

Results: Of 8198 identified records, 119 papers were eligible. One hundred and four of them (87.4%) were conducted between 2000 and 2020, mainly in the USA (SLE n=24 (21.2%), SSc n=16 (14.2%)), Brazil (SLE n=8 (7.1%), SSc n=5 (4.4%)) and Italy (SLE n=0 (0%), SSc n=12 (10.6%)). Fifty-two studies (SLE n=24 (21.2%), SSc n=28 (24.8%)) used multicomponent interventions. The single interventions were physical exercises (SLE n=16 (14.2%), SSc n=17 (15.0%)), coaching/counselling (SLE n=11 (18.0%), SSc n=0 (0%)) and education (SLE n=2 (1.8%), SSc n=3 (2.7%)). Primary outcomes focused on physical function (SLE n=1 (0.9%), SSc n=15 (13.3%)), mouth opening in SSc (n=4 (5.9%)) and physical capacity (SLE n=2 (1.8%), SSc n=1 (0.9%)). No interventions for mixed connective tissue disease were found.

Conclusion: There was a great variety in the intervention's content due to differences in body structure, activity limitations and participation restrictions in SLE and SSc. These results highlight the need for personalised, multicomponent, non-pharmacological interventions, which could be delivered as e-health interventions.
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http://dx.doi.org/10.1136/rmdopen-2021-001710DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8323400PMC
July 2021

Health Care Workers not in the frontline are more frequently carriers of Coronavirus Disease 2019: The Experience of a Tertiary Portuguese Hospital.

Infect Prev Pract 2020 Dec 1;2(4):100099. Epub 2020 Nov 1.

Nursing Research Centre, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.

Background: Health care workers (HCWs) have a high risk of infection with coronavirus disease 2019 (COVID-19), especially those treating patients with confirmed or suspected diagnosis (front-line).

Aim: To evaluate the incidence and prevalence of the COVID-19 infection among HCWs and to analyse the risk factors and the clinical characteristics among infected ones.

Methods: Observational, retrospective, single-center study (Centro Hospitalar e Universitário de Coimbra, Portugal). Data were collected from March 1 to June 30, 2020.

Findings: Overall, 211 (2.63%) out of 8037 HCWs were diagnosed with COVID-19. Most of the infections occurred during the early stage of disease outbreak. Among the infected HCWs, only 20.9% (n=44) were from the front-line. Both front-line and non-front-line HCWs were exposed primarily to patients (48.6% in both groups), but the non-front-line were (presumably) more infected by colleagues (10.8% vs 24.8%, =0.04). Front-line HCWs performed more family isolation than non-front-line (88.9% vs 82.5%, >0.05) and presumably less family members were infected in the former group (19.4% vs 26.3%, >0.05). The proportion of HCWs with asymptomatic infection was statistically significantly lower in the front-line group (2.4% vs 19.9%, =0.05).

Conclusion: The prevention and control actions implemented were effective in mitigating the COVID-19 outbreak; HCW infections occurred mainly in the early stages. Non-front -line HCWs were at a higher risk, warranting specific attention and interventions targeting this group.
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http://dx.doi.org/10.1016/j.infpip.2020.100099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7603952PMC
December 2020

In Silico Prediction of Permeability Coefficients.

Methods Mol Biol 2021 ;2315:243-261

Red Glead Discovery AB, Lund, Sweden.

In silico simulations of biological systems are of the significant importance to obtain insights on specific processes that experimental protocols have difficulty to elucidate. More particularly, and to ensure that a given molecule is able to reach its cellular target, the development of computational methods able to quickly estimate the cellular permeabilities for small molecules can become an important tool in the early stages of drug development. Herein, a computational protocol for predicting permeability coefficients, concerning both membranes and proteins, is presented and discussed.
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http://dx.doi.org/10.1007/978-1-0716-1468-6_14DOI Listing
August 2021

Semi-industrial development of nutritious and healthy seafood dishes from sustainable species.

Food Chem Toxicol 2021 Sep 19;155:112431. Epub 2021 Jul 19.

CIIMAR, Interdisciplinary Centre of Marine and Environmental Research, University of Porto, Terminal de Cruzeiros do Porto de Leixões, Av. General Norton de Matos S/N, 4450-208, Matosinhos, Portugal. Electronic address:

This study aimed to devise innovative, tailor-made, appealing, tasty and semi-industrialized dishes, using sustainable and under-utilized seafood species (bib, common dab, common carp, blue mussel and blue whiting), that can meet the specific nutritional and functional needs of children (8-10-years), pregnant women (20-40-years) and seniors (≥60-years). Hence, contests were organised among cooking schools from 6 European countries and the best recipes/dishes were reformulated, semi-industrially produced and chemically and microbiologically evaluated. The dishes intended for: (i) children and pregnant women had EPA + DHA and I levels that reached the target quantities, supporting the claim as "high in I"; and (ii) seniors were "high in protein" (24.8%-Soup_S and 34.0%-Balls_S of the energy was provided by proteins), "high in vitamin B12", and had Na contents (≤0.4%) below the defined limit. All dishes reached the vitamin D target value. Sausages_C, Roulade_P, Fillet_P and Balls_S had a well-balanced protein/fat ratio. Roulade_P presented the highest n-3 PUFA/n-6 PUFA ratio (3.3), while Sausages_C the lowest SFA/UNS ratio (0.2). Dishes were considered safe based on different parameters (e.g. Hg-T, PBDEs, Escherichia coli). All represent dietary sources contributing to meet the reference intakes of target nutrients (33->100%), providing valuable options to overcome nutritional and functional imbalances of the three groups.
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http://dx.doi.org/10.1016/j.fct.2021.112431DOI Listing
September 2021

Microbial Blends: Terminology Overview and Introduction of the Neologism "Skopobiota".

Front Microbiol 2021 2;12:659592. Epub 2021 Jul 2.

LEAF-Linking Landscape, Environment, Agriculture and Food-Research Center, Instituto Superior de Agronomia, Universidade de Lisboa, Lisbon, Portugal.

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http://dx.doi.org/10.3389/fmicb.2021.659592DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8283781PMC
July 2021

Considerations and priorities for incorporating the patient perspective on remission in rheumatoid arthritis: An OMERACT 2020 special interest group report.

Semin Arthritis Rheum 2021 Oct 11;51(5):1108-1112. Epub 2021 Jul 11.

Department of Epidemiology & Data Science; and Amsterdam Rheumatology and Immunology Center, Amsterdam University Medical Centers, Vrije Universiteit, Amsterdam, the Netherlands.

Objective: To determine how best to incorporate the patient perspective into rheumatoid arthritis remission criteria.

Methods: At OMERACT 2020, several studies, including a longitudinal multi-centre study testing the validity of adding patient-valued domains to the ACR/EULAR criteria, were presented and discussed by the virtual Special Interest Group.

Results: Overall consensus was that there is insufficient evidence to change the remission criteria at this point. Future work should focus on measurement of the new domain of independence, clarifying the value of the patient global assessment, and optimizing the input of domains that patients value in the criteria.

Conclusion: Incorporating the patient perspective into remission criteria should be further explored.
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http://dx.doi.org/10.1016/j.semarthrit.2021.07.010DOI Listing
October 2021

Pediatric population with cystic fibrosis in the centre of Portugal: Candidates for new therapies.

J Pediatr (Rio J) 2021 Jul 9. Epub 2021 Jul 9.

Faculdade de Medicina da Universidade de Coimbra, Clínica Universitária de Pediatria, Coimbra, Portugal; Centro Hospitalar e Universitário de Coimbra, Centro de Desenvolvimento da Criança e Centro de Investigação e Formação Clínica, Hospital Pediátrico, Coimbra, Portugal.

Objectives: Cystic fibrosis (CF) is a severe autosomal recessive disease that results from mutations in a gene encoding the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein, a chloride channel. This study aims to characterize the clinical and genetic features of a cohort of pediatric people with CF (PwCF) in the center of Portugal and to determine which ones are candidates for the new drugs modulating the CFTR channel.

Methods: A review of the demographic, genetic and clinical characteristics of PwCF undergoing follow-up at a CF reference center was carried out.

Results: Twenty-three PwCF (12 male), with a median age of 12 years, were followed up. All patients carry the F508del mutation in at least one allele. Fifteen PwCF were F508del-homozygous, median BMI z-score was -0.13, all are pancreatic insufficient and median FEV1 value was 78.1%. These PwCF are eligible for dual therapy (lumacaftor/tezacaftor+ivacaftor) and for triple therapy (tezacaftor+ivacaftor+elexacaftor). PwCF with 711 +1G->T (n = 2), 2184insA (n = 1) mutations and a novel mutation c.3321dup (n = 1) have minimal function mutation and patients with a residual function mutation: R334W (n = 3) and P5L (n = 1) have a less severe phenotype. All these patients, because they also carry F508del mutation, are elegible to triple therapy.

Conclusions: Genetic and molecular characterization of PwCF poses an important step not just for CF diagnosis and prognosis which is tightly correlated with the clinical phenotype, but also for the eligibility of CFTR modulator drugs.
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http://dx.doi.org/10.1016/j.jped.2021.05.010DOI Listing
July 2021

Patient-Physician discordance in assessment of disease activity in Rheumatoid Arthritis patients.

Acta Reumatol Port 2021 Apr-Jun;46(2):103-109

Serviço de Reumatologia, Centro Hospitalar e Universitário de Coimbra.

Background: In rheumatoid arthritis (RA), global disease activity is commonly evaluated, from the patient's and the physician's perspective, through a 100mm visual analogue scale (VAS) and plays an important role in the assessment of diseases activity and treatment decisions. Our aim was to determine patient-physician discordance in the assessment of disease activity and to explore its determinants.

Methods: Cross sectional study including RA patients (ACR/EULAR 2010 classification criteria). The discrepancy between patients-physicians (∆PPhGA) was defined as PGA minus PhGA, and a difference > |20mm| was considered as "discordant". Correlation between ∆PPhGA and other variables was assessed through Pearson's correlation and comparison between groups through t-test. Variables with p < 0.05 or considered clinically relevant were included in multivariable linear regression analysis to identify determinants for ∆PPhGA. A p < 0.05 was considered statistically significant.

Results: In total, 467 patients with RA were included (81.2% female; mean age 63.9% ± 12.2 years). PGA and PhGA were discordant in 61.7% of the cases. The proportion of concordance increased (p < 0.01) when considering only patients in remission (DAS 28 3V < 2.6). In multivariable analysis (R2adjusted=0.27), VAS-pain-patient (β 0.74, 95% CI 0.62-0.88, p=0.00) and TJC (β 0.16, 95% CI 0.45-0.48, p=0.02) remained associated with a higher ∆PPhGA.

Conclusion: Our study confirmed that a significant discrepancy between patients and physicians in the assessment of global disease activity is frequent in clinical practice, and is probably due to valorization of different parameters by the two groups.
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July 2021

High patient global assessment scores in patients with rheumatoid arthritis otherwise in remission do not reflect subclinical inflammation.

Joint Bone Spine 2021 Jun 21;88(6):105242. Epub 2021 Jun 21.

Rheumatology Department, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal; Faculty of Medicine, Coimbra Institute for Clinical and Biomedical Research (i.CIBR), University of Coimbra, Coimbra, Portugal. Electronic address:

Objectives: To assess whether high patient global assessment (PGA) scores by patients with rheumatoid arthritis (RA) otherwise in remission reflect subclinical inflammation.

Methods: Cross-sectional, single-center study, including consecutive RA patients. Remission states were defined based on the ACR/EULAR Boolean definition: 4V-remission (tender and swollen 28-joint counts (TJC28/SJC28), C-reactive protein (CRP), and PGA all≤1), PGA-near-remission (the same, except PGA>1), and non-remission (any of TJC28, SJC28, CRP>1). A blinded expert musculoskeletal ultrasonographer scanned 44 joints, 38 tendon sheaths, 4 bursae on the same day of the clinical evaluation. Each structure was assessed for the presence of Grey Scale synovial hypertrophy (GS) and Power Doppler (PD), both scored using a semi-quantitative scale (0-3 points). The Global OMERACT-EULAR Synovitis Score (GLOESS, 0-132, primary outcome), and a global tenosynovitis/bursitis score (GTBS) were compared between remission states, using non-parametric tests. Different sensitivity analyses comparing GS and PD subscores were performed.

Results: In total, 130 patients (mean age 63 years, 86% female, average disease duration 14 years) were included 40 being in 4V-remission, 40 in PGA-near-remission, 50 in non-remission. 4v-remission and PGA-near-remission presented similar median (IQR) GLOESS, [6 (5-11) and 4 (1-7), P>0.05, respectively] and GTBS [0 (0-1) and 0 (0-2), P>0.05, respectively]. The same was observed in GS, PD scores, and in global synovitis score considering only the 16 joints not included in 28-joint counts. These observations were confirmed in patients with≤5 years disease duration.

Conclusions: Subclinical inflammation is not present among persons with elevated PGA who are otherwise in remission. PGA-near-remission patients would be exposed to the risk of overtreatment if current treatment recommendations were strictly followed. This study supports the need to reconsider the role of PGA in definitions used to target immunosuppressive therapy and to provide a separate and enhanced focus to the patient's experience of the disease.
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http://dx.doi.org/10.1016/j.jbspin.2021.105242DOI Listing
June 2021

Interferon-Gamma-Producing CD8 Tissue Resident Memory T Cells Are a Targetable Hallmark of Immune Checkpoint Inhibitor-Colitis.

Gastroenterology 2021 Oct 17;161(4):1229-1244.e9. Epub 2021 Jun 17.

Translational Gastroenterology Unit, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom; National Institute for Health Research Oxford Biomedical Research Centre, Oxford University Hospitals National Health Service Foundation Trust, John Radcliffe Hospital, Oxford, United Kingdom. Electronic address:

Background & Aims: The pathogenesis of immune checkpoint inhibitor (ICI)-colitis remains incompletely understood. We sought to identify key cellular drivers of ICI-colitis and their similarities to idiopathic ulcerative colitis, and to determine potential novel therapeutic targets.

Methods: We used a cross-sectional approach to study patients with ICI-colitis, those receiving ICI without the development of colitis, idiopathic ulcerative colitis, and healthy controls. A subset of patients with ICI-colitis were studied longitudinally. We applied a range of methods, including multiparameter and spectral flow cytometry, spectral immunofluorescence microscopy, targeted gene panels, and bulk and single-cell RNA sequencing.

Results: We demonstrate CD8 tissue resident memory T (T) cells are the dominant activated T cell subset in ICI-colitis. The pattern of gastrointestinal immunopathology is distinct from ulcerative colitis at both the immune and epithelial-signaling levels. CD8 T cell activation correlates with clinical and endoscopic ICI-colitis severity. Single-cell RNA sequencing analysis confirms activated CD8 T cells express high levels of transcripts for checkpoint inhibitors and interferon-gamma in ICI-colitis. We demonstrate similar findings in both anti-CTLA-4/PD-1 combination therapy and in anti-PD-1 inhibitor-associated colitis. On the basis of our data, we successfully targeted this pathway in a patient with refractory ICI-colitis, using the JAK inhibitor tofacitinib.

Conclusions: Interferon gamma-producing CD8 T cells are a pathological hallmark of ICI-colitis and a novel target for therapy.
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http://dx.doi.org/10.1053/j.gastro.2021.06.025DOI Listing
October 2021

Definition of Treatment Targets in Rheumatoid Arthritis: Is It Time for Reappraisal?

J Rheumatol 2021 Jun 1. Epub 2021 Jun 1.

R.J. Ferreira, RN, PhD, Nursing Specialist in Chronic Diseases, Invited Professor, Rheumatology Department, Centro Hospitalar e Universitário de Coimbra, and Health Sciences Research Unit: Nursing (UICiSA:E), Nursing School of Coimbra (ESEnfC), Coimbra, Portugal; R.B. Landewé, MD, PhD, Rheumatologist, Full Professor of Rheumatology, Rheumatology, Zuyderland Medical Center, Heerlen, and Amsterdam Rheumatology Center, AMC, Amsterdam, the Netherlands; J.A. da Silva, MD, PhD, Rheumatologist, Full Professor of Rheumatology, Head of Department, Rheumatology Department, Centro Hospitalar e Universitário de Coimbra, and Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, Portugal. The authors have no conflicts of interest. Photo for RJF courtesy of the European Alliance of Associations for Rheumatology (EULAR). Address correspondence to Dr. R.J. Ferreira, Serviço de Reumatologia, Consulta Externa, Piso 7, Centro Hospitalar e Universitário de Coimbra, EPE. Avenida Dr. Bissaya Barreto, 3000-075 Coimbra. Portugal. Email:

In the current issue of , Kremer and colleagues compare the Clinical Disease Activity Index (CDAI) with a slightly modified Corrona Routine Assessment of Patient Index Data 3 (cRAPID3) in terms of correlation and disease activity categorization, using 2 large US registries of patients with rheumatoid arthritis (RA). Overall, a low concordance between these 2 composite indices (κ = 0.29) was found in terms of disease activity categories, despite a moderate correlation between their numerical global scores (r = 0.58 and 0.72, for the BRASS and CORRONA registries, respectively).
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http://dx.doi.org/10.3899/jrheum.210050DOI Listing
June 2021

2021 EULAR recommendations for the implementation of self-management strategies in patients with inflammatory arthritis.

Ann Rheum Dis 2021 Oct 7;80(10):1278-1285. Epub 2021 May 7.

National Rheumatoid Arthritis Society, Littlewick Green, UK.

Background: An important but often insufficient aspect of care in people with inflammatory arthritis (IA) is empowering patients to acquire a good understanding of their disease and building their ability to deal effectively with the practical, physical and psychological impacts of it. Self-management skills can be helpful in this regard.

Objectives: To develop recommendations for the implementation of self-management strategies in IA.

Methods: A multidisciplinary taskforce of 18 members from 11 European countries was convened. A systematic review and other supportive information (survey of healthcare professionals (HCPs) and patient organisations) were used to formulate the recommendations.

Results: Three overarching principles and nine recommendations were formulated. These focused on empowering patients to become active partners of the team and to take a more proactive role. The importance of patient education and key self-management interventions such as problem solving, goal setting and cognitive behavioural therapy were highlighted. Role of patient organisations and HCPs in promoting and signposting patients to available resources has been highlighted through the promotion of physical activity, lifestyle advice, support with mental health aspects and ability to remain at work. Digital healthcare is essential in supporting and optimising self-management and the HCPs need to be aware of available resources to signpost patients.

Conclusion: These recommendations support the inclusion of self-management advice and resources in the routine management of people with IA and aim to empower and support patients and encourage a more holistic, patient-centred approach to care which could result in improved patient experience of care and outcomes.
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http://dx.doi.org/10.1136/annrheumdis-2021-220249DOI Listing
October 2021

Molecular Dynamics Studies of Therapeutic Liquid Mixtures and Their Binding to Mycobacteria.

Front Pharmacol 2021 20;12:626735. Epub 2021 Apr 20.

Red Glead Discovery AB, Lund, Sweden.

Tuberculosis is an highly contagious disease still considered by the WHO as one of most infectious diseases worldwide. The therapeutic approach, used to prevent and treat tuberculosis targets the complex, comprises a combination of drugs administrated for long periods of time, which, in many cases, could cause several adverse effects and, consequently, low compliance of the patient to the treatment and drug-resistance. Therefore, therapeutic liquid mixtures formulated with anti-tuberculosis drugs and/or adjuvants in tuberculosis therapy are an interesting approach to prevent toxic effects and resistance to anti-tuberculosis drugs. The herein formulated therapeutic liquid mixtures, including ethambutol, arginine, citric acid and water under different molar ratios, were studied through a molecular dynamics approach to understand how ethambutol and arginine could be stabilized by the presence of citric acid and/or water in the mixture. To gain insights on how the uptake of these mixtures into the mycobacteria cell may occur and how a mycobacterial ABC transporter could contribute to this transport, multiple simultaneous ligand docking was performed. Interactions between citric acid and ethambutol involving the carboxyl and hydroxyl groups of citric acid with the amines of ethambutol were identified as the most critical ones. Water molecules present in the mixture provides the necessary network of hydrogen bonds that stabilize the mixture. Molecular docking additionally provided an interesting hypothesis on how the different mixture components may favor binding of ethambutol to an ABC importer. The data presented in this work helps to better understand these mixtures as well as to provide cues on the mechanisms that allow them to cross the mycobacterial cell membrane.
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http://dx.doi.org/10.3389/fphar.2021.626735DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8096353PMC
April 2021

Access to Metal Centers and Fluxional Hydride Coordination Integral for CO Insertion into [Fe(μ-H)] Clusters.

Inorg Chem 2021 May 26;60(10):7228-7239. Epub 2021 Apr 26.

Center for Catalysis and Florida Center for Heterocyclic Chemistry, Department of Chemistry, University of Florida, Gainesville, Florida 32611, United States.

CO insertion into tri(μ-hydrido)triiron(II) clusters ligated by a tris(β-diketiminate) cyclophane is demonstrated to be balanced by sterics for CO approach and hydride accessibility. Time-resolved NMR and UV-vis spectra for this reaction for a complex in which methoxy groups border the pocket of the hydride donor (FeH, ) result in a decreased activation barrier and increased kinetic isotope effect consistent with the reduced sterics. For the ethyl congener FeH (), no correlation is found between rate and reaction solvent or added Lewis acids, implying CO coordination to an Fe center in the mechanism. The estimated hydricity (50 kcal/mol) based on observed H/D exchange with BD requires Fe-O bond formation in the product to offset an endergonic CO insertion. μ-hydride coordination is noted to lower the activation barrier for the first CO insertion event in DFT calculations.
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http://dx.doi.org/10.1021/acs.inorgchem.1c00244DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8247455PMC
May 2021

Primary cardiac hydatic cyst with multiple locations: an unusual case of chest pain.

Gen Thorac Cardiovasc Surg 2021 Jul 12;69(7):1147-1150. Epub 2021 Apr 12.

Cardiothoracic Surgery Department, Hospital de Santa Maria-CHLN, Av. Prof. Egas Moniz, 1649-035, Lisboa, Portugal.

Cardiac echinococcosis is a rare manifestation of Echinococcus infection, affecting 0.5-2% of the patients. Since it may be a life-threatening condition, surgical treatment should be always considered. Herein, here we present a case of a 66-year-old male with chest pain. Subsequent exams confirmed the diagnosis of multiple cardiac hydatic cysts. The patient initiated treatment with albendazole and was submitted to a surgical resection with cardiopulmonary bypass. A complete surgical resection was achieved, and patient remains asymptomatic without disease signs of recurrence on imaging exams. We highlight the necessity of cardiac screening in echinococcosis cases and the surgical management in this case.
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http://dx.doi.org/10.1007/s11748-021-01631-3DOI Listing
July 2021

Portuguese multidisciplinary recommendations for non-pharmacological and non-surgical interventions in patients with rheumatoid arthritis.

Acta Reumatol Port 2021 Jan-Mar;46(1):40-54

Background: Patients with rheumatoid arthritis (RA) report significant levels of disease impact, which are improved, but not fully abrogated by immunosuppressive therapy, even when remission is achieved. This imposes the need for adjuvant interventions targeting the uncontrolled domains of disease impact. Non-pharmacological interventions are widely used for this purpose, but they have not been the object of professional recommendations or guidelines.

Objective: To propose multidisciplinary recommendations to inform clinical care providers regarding the employment of non-pharmacological and non-surgical interventions in the management of patients with RA.

Methods: The EULAR standardized operating procedures for the development of recommendations were followed. First, a systematic literature review was performed. Then, a multidisciplinary Technical Expert Panel (TEP) met to develop and discuss the recommendations and research agenda. For each developed recommendation i) the level of evidence and grade of recommendation were determined, and ii) the level of agreement among TEP members was set. A recommendation was adopted if approved by ≥75% of the TEP members, and the level of agreement was considered high when ≥8. All relevant national societies were included in this construction process to attain their endorsement.

Results: Based on evidence and expert opinion, the TEP developed and agreed on five overarching principles and 12 recommendations for non-pharmacological and non-surgical interventions in patients with RA. The mean level of agreement between the TEP members ranged between 8.5 and 9.9. The recommendations include a broad spectrum of intervention areas, such as exercise, hydrokinesiotherapy, psychological interventions, orthoses, education, general management of comorbidities, among others; and they set the requirements for their application.

Conclusions: These recommendations are based on the consensus judgment of clinical experts from a wide range of disciplines and patients' representatives from Portugal. Given the evidence for effectiveness, feasibility and safety, non-pharmacological and non-surgical interventions should be an integral part of standard care for people with RA. It is hoped that these recommendations should be widely implemented in clinical practice. The target audience for these recommendations includes all health professionals involved in the care of patients with RA. The target patient population includes adult Portuguese people with RA.
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April 2021

Standardization of an experimental model of intradural injection after spinal cord injury in rats.

Clinics (Sao Paulo) 2021 26;76:e2740. Epub 2021 Mar 26.

Departamento de Ortopedia e Traumatologia, Instituto de Ortopedia e Traumatologia, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, BR.

Objectives: The intrathecal route has not yet been thoroughly standardized and evaluated in an experimental model of spinal cord injury (SCI) in Wistar rats. The objective of this study was to standardize and evaluate the effect of intradural injection in this animal model.

Method: The animals were divided into 6 groups: 1) laminectomy and intradural catheter; 2) laminectomy, intradural catheter and infusion; 3) only SCI; 4) SCI and intradural catheter; 5) SCI, intradural catheter and infusion; and 6) control (laminectomy only). Motor evaluations were performed using the Basso, Beattie and Bresnahan (BBB) scale and the horizontal ladder test; motor evoked potentials were measured for functional evaluation, and histological evaluation was performed as well. All experimental data underwent statistical analysis.

Results: Regarding motor evoked potentials, the groups with experimental SCI had worse results than those without, but neither dural puncture nor the injection of intrathecal solution aggravated the effects of isolated SCI. Regarding histology, adverse tissue effects were observed in animals with SCI. On average, the BBB scores had the same statistical behaviour as the horizontal ladder results, and at every evaluated timepoint, the groups without SCI presented scored significantly better than those with SCI (p<0.05). The difference in performance on motor tests between rats with and without experimental SCI persisted from the first to the last test.

Conclusions: The present work standardizes the model of intradural injection in experimental SCI in rats. Intrathecal puncture and injection did not independently cause significant functional or histological changes.
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http://dx.doi.org/10.6061/clinics/2021/e2740DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7978664PMC
April 2021

The methodological quality is insufficient in clinical practice guidelines in the context of COVID-19: systematic review.

J Clin Epidemiol 2021 07 7;135:125-135. Epub 2021 Mar 7.

Cochrane Austria, Department for Evidence-based Medicine and Evaluation, Danube University Krems, Krems an der Donau, Austria; RTI International, Research Triangle Park, NC, USA.

Objectives: The number of published clinical practice guidelines related to COVID-19 has rapidly increased. This study explored if basic methodological standards of guideline development have been met in the published clinical practice guidelines related to COVID-19.

Study Design And Setting: Rapid systematic review from February 1 until April 27, 2020 using MEDLINE [PubMed], CINAHL [Ebsco], Trip and manual search, including all types of healthcare workers providing any kind of healthcare to any patient population in any setting.

Results: There were 1342 titles screened and 188 guidelines included. The highest average AGREE II domain score was 89% for scope and purpose, the lowest for rigor of development (25%). Only eight guidelines (4%) were based on a systematic literature search and a structured consensus process by representative experts (classified as the highest methodological quality). The majority (156; 83%) was solely built on an informal expert consensus. A process for regular updates was described in 27 guidelines (14%). Patients were included in the development of only one guideline.

Conclusion: Despite clear scope, most publications fell short of basic methodological standards of guideline development. Clinicians should use guidelines that include up-to-date information, were informed by stakeholder involvement, and employed rigorous methodologies.
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http://dx.doi.org/10.1016/j.jclinepi.2021.03.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7937325PMC
July 2021

Validity and reliability of the EULAR instrument RAID.7 as a tool to assess individual domains of impact of disease in rheumatoid arthritis: a cross-sectional study of 671 patients.

RMD Open 2021 02;7(1)

INSERM, Institut Pierre Louis d'Epidémiologie et de Santé Publique, INSERM, Sorbonne Université, Paris, France.

Objective: The rheumatoid arthritis impact of disease (RAID) questionnaire comprises seven patient-important domains of disease impact (pain, function, fatigue, sleep disturbance, emotional well-being, physical well-being, coping). RAID was validated as a pooled-weighted score. Its seven individual items separately could provide a valuable tool in clinical practice to guide interventions targeting the patient's experience of the disease. The aim was to separately assess the psychometric properties of each of the seven numeric rating scale (NRS) of the RAID (RAID.7).

Material And Methods: Post hoc analyses of data from the cross-sectional RAID study and from the Rainbow study, an open-label 12-week trial of etanercept in patients with RA. Construct validity of each NRS was assessed cross-sectionally in the RAID data set by Spearman's correlation with the respective external instrument of reference. Using the rainbow data set, we assessed reliability through intraclass correlation coefficient between the screening and the baseline visits and responsiveness (sensitivity to change) by standardised response mean between baseline and 12 weeks.

Results: A total of 671 patients with RA with features of established disease were analysed, 563 and 108 from RAID and Rainbow, respectively. The NRS correlated moderately to strongly with the respective external instrument of reference (r=0.62-0.81). Reliability ranged from 0.64 (0.51-0.74) (pain) to 0.83 (0.76-0.88) (sleep disturbance) and responsiveness from 0.93 (0.73-1.13) (sleep disturbance) to 1.34 (1.01-1.64) (pain).

Conclusion: The separate use of the individual NRS of RAID (RAID.7) is valid, feasible, reliable and sensitive to change, representing an opportunity to improve the assessment and treatment of disease impact with minimal questionnaire burden.

Trial Registration Number: NCT00768053.
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http://dx.doi.org/10.1136/rmdopen-2020-001539DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7871340PMC
February 2021

Functionalization of Betulinic Acid with Polyphenolic Fragments for the Development of New Amphiphilic Antioxidants.

Antioxidants (Basel) 2021 Jan 20;10(2). Epub 2021 Jan 20.

LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal.

The present work aimed at the valorization of biomass derived compounds by their transformation into new added-value compounds with enhanced antioxidant properties. In this context, betulinic acid (BA) was decorated with polyphenolic fragments, and polyhydroxylated ()-2-benzylidene-19,28-epoxyoleanane-3,28-diones - were obtained. For that, the synthetic strategy relied on base-promoted aldol condensation reactions of methyl betulonate, which was previously prepared from natural BA, with appropriate benzaldehydes, followed by cleavage of the methyl protecting groups with BBr. It is noteworthy that the HBr release during the work-up of the cleavage reactions led to the rearrangement of the lupane-type skeleton of the expected betulonic acid derivatives into oleanane-type compounds -. The synthesized compounds - were designed to have specific substitution patterns at C-2 of the triterpene scaffold, allowing the establishment of a structure-activity relationship. The radical scavenging ability of - was evaluated using the 2,2-diphenyl-1-picrylhydrazyl radical (DPPH) and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid radical cation (ABTS) scavenging assays. In particular, derivative , bearing a catechol unit, revealed to be the most efficient scavenger against both free radicals DPPH and ABTS. Subsequently, we designed two analogues of the hit derivative in order to achieve more potent antioxidant agents: (i) the first analogue carries an additional unsaturation in its lateral chain at C-2 (analogue ) and (ii) in the second analogue, E-ring was kept in its open form (analogue ). It was observed that the presence of an extended π-conjugated system at C-2 contributed to an increased scavenging effect, since analogue was more active than , α-tocopherol, and in the ABTS assay.
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http://dx.doi.org/10.3390/antiox10020148DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7909560PMC
January 2021

EULAR recommendations for the reporting of ultrasound studies in rheumatic and musculoskeletal diseases (RMDs).

Ann Rheum Dis 2021 07 22;80(7):840-847. Epub 2021 Jan 22.

UVSQ, Inserm U1173, Infection et inflammation, Laboratory of Excellence INFLAMEX, Université Paris-Saclay, Montigny-le-Bretonneux, France

Objective: To produce European League Against Rheumatism (EULAR) recommendations for the reporting of ultrasound studies in rheumatic and musculoskeletal diseases (RMDs).

Methods: Based on the literature reviews and expert opinion (through Delphi surveys), a taskforce of 23 members (12 experts in ultrasound in RMDs, 9 in methodology and biostatistics together with a patient research partner and a health professional in rheumatology) developed a checklist of items to be reported in every RMD study using ultrasound. This checklist was further refined by involving a panel of 79 external experts (musculoskeletal imaging experts, methodologists, journal editors), who evaluated its comprehensibility, feasibility and comprehensiveness. Agreement on each proposed item was assessed with an 11-point Likert scale, grading from 0 (total disagreement) to 10 (full agreement).

Results: Two face-to-face meetings, as well as two Delphi rounds of voting, resulted in a final checklist of 23 items, including a glossary of terminology. Twenty-one of these were considered 'mandatory' items to be reported in every study (such as blinding, development of scoring systems, definition of target pathologies) and 2 'optional' to be reported only if applicable, such as possible confounding factors (ie, ambient conditions) or experience of the sonographers.

Conclusion: An EULAR taskforce developed a checklist to ensure transparent and comprehensive reporting of aspects concerning research and procedures that need to be presented in studies using ultrasound in RMDs. This checklist, if widely adopted by authors and editors, will greatly improve the interpretability of study development and results, including the assessment of validity, generalisability and applicability.
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http://dx.doi.org/10.1136/annrheumdis-2020-219816DOI Listing
July 2021

Mapping the risk for transmission of urban schistosomiasis in the Brazilian Northeast.

Geospat Health 2020 12 29;15(2). Epub 2020 Dec 29.

Aggeu Magalhães Institute, Oswaldo Cruz Foundation, Recife, Pernambuco.

This is an analysis of the risk of schistosomiasis transmission in the city of Recife in the Northeast of Brazil based on the number of schistosomiasis cases (Schistosoma mansoni) registered for the period 2007-2017 together with data resulting from active search of breeding sites of the Biomphalaria snail intermediate host. The analyses were performed using Kernel Density Estimation (KDE), SaTScan and Map Algebra methodology using human socio-demographic data and biotic and abiotic data from the snail breeding sites. Investigating 44 breeding sites resulted in a total of 3.800 snails, 31.8% of which were positive for S. mansoni DNA. These data were considered in relation to total of 652 schistosomiasis cases. The KDE showed two high-risk and two medium-risk clusters, while three significant clusters were identified by SaTScan. Combining these data with the Map Algebra methodology showed that all high-risk neighbourhoods had breeding sites with snails positive for S. mansoni. It was concluded that schistosomiasis transmission cannot be controlled without basic sanitation and sewage management in the presence of Biomphalaria snails. The technique of Map Algebra was found to be fundamental for the analysis and demonstration of areas with a high probability of schistosomiasis transmission.
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http://dx.doi.org/10.4081/gh.2020.861DOI Listing
December 2020

Cleavage of cluster iron-sulfide bonds in cyclophane-coordinated FeS complexes.

Dalton Trans 2021 Jan 4;50(3):816-821. Epub 2021 Jan 4.

Department of Chemistry, Center for Catalysis, University of Florida, Gainesville, FL 32611-7200, USA.

Reaction of the tri(μ-sulfido)triiron(iii) tris(β-diketiminate) cyclophane complex, FeSL (1), or of the di(μ-sulfido)diiron(iii) complex FeSHL (5), with the related tri(bromide)triiron(ii) complex FeBrL (2) results in electron and ligand redistribution to yield the mixed-ligand multiiron complexes, including FeBrSL (3) and FeBrSHL (4). The cleavage and redistribution observed in these complexes is reminiscent of necessary Fe-S bond cleavage for substrate activation in nitrogenase enzymes, and provides a new perspective on the lability of Fe-S bonds in FeS clusters.
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http://dx.doi.org/10.1039/d0dt03805aDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880558PMC
January 2021

Pedrolane, a Polycyclic Diterpene Scaffold Containing a Bicyclo[2.2.1]heptane System, from .

Org Lett 2021 01 29;23(2):274-278. Epub 2020 Dec 29.

Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal.

Pedrolide (), a diterpenoid with an unprecedented carbon skeleton, pedrolane, containing a bicycle[2.2.1]heptane system, is reported. This structural feature is hypothesized to involve an intramolecular cyclization, via Michael addition, and a ring contraction, via 1,2-alkyl shift or a Pinacol rearrangement of rings A and B, from a tigliane-type 5/7/6/3-tetracyclic ring precursor. The structure of was established using spectroscopic techniques, single-crystal X-ray diffraction, and calculations. Pedrolide reversed multidrug resistance mediated by P-glycoprotein.
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http://dx.doi.org/10.1021/acs.orglett.0c03647DOI Listing
January 2021
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