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- Systematic review with network meta-analysis on the treatments for latent tuberculosis infection in children and adolescentsPublication . Santos, Josiane M.; Fachi, Mariana M.; Beraldi-Magalhães, Francisco; Böger, Beatriz; Junker, Allan M.; Domingos, Eric L.; Imazu, Priscila; Fernandez-Llimos, Fernando; Tonin, Fernanda; Pontarolo, RobertoBackground: We aimed to synthesize the evidence on the efficacy and safety of different treatment regimens for latent tuberculosis infection (LTBI) in children and adolescents. Methods: A systematic review with network meta-analysis was performed (CRD142933). Searches were conducted in Pubmed and Scopus (Nov-2021). Randomized controlled trials comparing treatments for LTBI (patients up to 15 years), and reporting data on the incidence of the disease, death, or adverse events were included. Networks using the Bayesian framework were built for each outcome of interest. Results were reported as odds ratio (OR) with 95% credibility intervals (CrI). Rank probabilities were calculated via the surface under the cumulative ranking analysis (SUCRA) (Addis-v.1.16.8). GRADE approach was used to rate evidence's certainty. Results: Seven trials (n = 8696 patients) were included. Placebo was significantly associated with a higher incidence of tuberculosis compared to all active therapies. Combinations of isoniazid (15–25 mg/kg/week) plus rifapentine (300–900 mg/week), followed by isoniazid plus rifampicin (10 mg/kg/day) were ranked as best approaches with lower probabilities of disease incidence (10% and 19.5%, respectively in SUCRA) and death (20%). Higher doses of isoniazid monotherapy were significantly associated with more deaths (OR 18.28, 95% ICr [1.02, 48.60] of 4–6 mg/kg/day vs. 10 mg/kg/3x per week). Conclusions: Combined therapies of isoniazid plus rifapentine or rifampicin for short-term periods should be used as the first-line approach for treating LTBI in children and adolescents. The use of long-term isoniazid as monotherapy and at higher doses should be avoided for this population.
- Optimizing the use of systemic corticosteroids in severe asthma (ROSA II project): a national Delphi consensus studyPublication . Marques, J.; Duarte-Ramos, F.; Ferreira, M. B.; Lima, R.; Lopes, C.; Sokolova, A.; Tonin, Fernanda; Loureiro, C. C.Although the prevalence of severe asthma is not high (5–10% of patients), it is responsible for a large part of the overall disease burden and costs (50–60% of total costs), especially if the condition remains uncontrolled (which occurs in around 40% of cases). Currently, for patients without disease control or presenting frequent exacerbations despite optimal therapy, add-on treatments, traditionally long-acting anticholinergics, oral corticosteroids (OCS), or biologic agents (monoclonal antibodies) are recommended. Nonetheless, the long-term use of oral/systemic corticosteroids (CS) is significantly associated with adverse effects, acute and chronic complications that may decrease health-related quality of life and worsen prognosis, thus requiring additional monitoring and management. Conversely, target therapies (i.e., omalizumab, mepolizumab, reslizumab, benralizumab, and more recently, dupilumab) have been developed grounded on the different phenotypes and endotypes of severe asthma, and are gradually reducing the reliance on OCS (i.e., greater specificity for achieving disease control by reducing the risk of exacerbations and requirements for rescue medication and OCS, with limited adverse events).
- Use of biochemical tests and machine learning in the search for potential diagnostic biomarkers of COVID-19, HIV/AIDS, and pulmonary tuberculosisPublication . Cobre, Alexandre; Morais, Amiel; Selege, Fosfato; Stremel, Dile; Wiens, Astrid; Ferreira, Luana; Tonin, Fernanda; Pontarolo, RobertoThis study aims to develop, validate, and evaluate machine learning algorithms for predicting the diagnosis of coronavirus disease (COVID-19), human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS), pulmonary tuberculosis (TB), and HIV/TB co-infection. We also investigated potential biomarkers associated with the diagnosis. Data from biochemical and hematological tests of infected and controls were collected in a single general hospital, totalizing 6,418 patients. The discriminant analysis by partial least squares (PLS-DA) model had the highest performance in predicting the diagnosis of COVID-19, HIV/AIDS, TB, and HIV/TB co-infection with an accuracy of 94, 97, 95, and 96%, respectively. The biomarkers calcium, lactate dehydrogenase, red blood cells (RBC), white blood cells, neutrophils, basophils, eosinophils, hemoglobin, and hematocrit were associated with COVID-19. HIV infection was associated with mean corpuscular volume, platelets, neutrophils, and mean platelet volume. Red blood cell distribution width and urea were associated with infection by Mycobacterium tuberculosis. The following biomarkers were associated with HIV/TB co-infection: lymphocytes, RBC, hematocrit, hemoglobin, aspartate transaminase, alanine transaminase, and glycemia. The PLS-DA model can optimize COVID-19, HIV/AIDS, TB, and HIV/TB co-infection diagnostics. Some biomarkers were potential diagnostic indicators and could be evaluated during the screening of these diseases.
- Naringenin-4'-glucuronide as a new drug candidate against the COVID-19 Omicron variant: a study based on molecular docking, molecular dynamics, MM/PBSA and MM/GBSAPublication . Cobre, Alexandre de Fátima; Neto, Moisés Maia; Melo, Eduardo Borges de; Fachi, Mariana Millan; Ferreira, Luana Mota; Tonin, Fernanda; Pontarolo, RobertoThis study aimed to identify natural bioactive compounds (NBCs) as potential inhibitors of the spike (S1) receptor binding domain (RBD) of the COVID-19 Omicron variant using computer simulations (in silico). NBCs with previously proven biological in vitro activity were obtained from the ZINC database and analyzed through virtual screening, molecular docking, molecular dynamics (MD), molecular mechanics/Poisson-Boltzmann surface area (MM/PBSA), and molecular mechanics/generalized Born surface area (MM/GBSA). Remdesivir was used as a reference drug in docking and MD calculations. A total of 170,906 compounds were analyzed. Molecular docking screening revealed the top four NBCs with a high affinity with the spike (affinity energy <-7 kcal/mol) to be ZINC000045789238, ZINC000004098448, ZINC000008662732, and ZINC000003995616. In the MD analysis, the four ligands formed a complex with the highest dynamic equilibrium S1 (mean RMSD <0.3 nm), lowest fluctuation of the complex amino acid residues (RMSF <1.3), and solvent accessibility stability. However, the ZINC000045789238-spike complex (naringenin-4'-O glucuronide) was the only one that simultaneously had minus signal (-) MM/PBSA and MM/GBSA binding free energy values (-3.74 kcal/mol and -15.65 kcal/mol, respectively), indicating favorable binding. This ligand (naringenin-4'-O glucuronide) was also the one that produced the highest number of hydrogen bonds in the entire dynamic period (average = 4601 bonds per nanosecond). Six mutant amino acid residues formed these hydrogen bonds from the RBD region of S1 in the Omicron variant: Asn417, Ser494, Ser496, Arg403, Arg408, and His505. Naringenin-4'-O-glucuronide showed promising results as a potential drug candidate against COVID-19. In vitro, and preclinical studies are needed to confirm these findings.
- The International Collaboration of Pharmacy Journal Editors (ICPJE) formally constituted to foster quality around clinical and social pharmacy practice research publicationsPublication . Alves da Costa, F.; Fernandez-Llimos, F.; Desselle, S.; Arnet, I.; Babar, Z.; Bond, C.; Cordina, M.; Garcia Cardenas, V.; El Hajj, M. S.; Jacobsen, R.; Law, A. V.; Nørgaard, L.S.; Polidori, C.; Shcherbakova, N.; Stewart, D.; Tonin, Fernanda; Weidmann, A. E.The Granada statements were a result of the need to strengthen clinical, social, and administrative pharmacy practice as an area of knowledge that translates into practice, research, and policy. As a response, a group of clinical and social pharmacy practice journal editors launched an initiative in Granada in 2022 to discuss ways to improve the quality of publications in this area, which culminated in the Granada statements. Eighteen statements were developed, clustered into six main domains:1) the appropriate use of terminology; 2) developing impactful abstracts; 3) having the required peer reviews; 4) preventing journal scattering; 5) more effective and wiser use of journal and article performance metrics; and 6)authors’ selection of the most appropriate pharmacy practice journal to submit their work. The full Granada statements have been published in 14 journals. These pioneering statements are rooted in similar endeavors undertaken by scholars in other health professions groups, fostering the concept of interdisciplinary consensus and advancing scientific paradigms.
- The role of benralizumab in eosinophilic immune dysfunctions: a case report-based literature reviewPublication . Gomes, Margarida; Mendes, Ana; Ferreira, Filipa; Branco, Joana; Tonin, Fernanda; Pedro, M. ElisaIn the past years, the knowledge of eosinophils playing a primary pathophysiologic role in several associated conditions has led to the development of biologics targeting therapies aiming at normalizing the immune response, reducing chronic inflammation, and preventing tissue damage. To better illustrate the potential relationship between different eosinophilic immune dysfunctions and the effects of biological therapies in this scenario, here, we present a case of a 63-year-old male first referred to our department in 2018 with a diagnosis of asthma, polyposis, and rhinosinusitis and presenting a suspicion of nonsteroidal anti-inflammatory drugs' allergy. He also had a past medical history of eosinophilic gastroenteritis/duodenitis (eosinophilia counts >50 cells/high-power field HPF). The use of multiple courses of corticosteroid therapy failed to completely control these conditions. In October 2019, after starting benralizumab (an antibody directed against the alpha chain of the IL-5 cytokine receptor) as an add-on treatment for severe eosinophilic asthma, important clinical improvements were reported both in the respiratory (no asthma exacerbations) and gastrointestinal systems (eosinophilia count 0 cells/HPF). The patient's quality of life also increased. Since June 2020, systemic corticosteroid therapy was reduced without worsening gastrointestinal symptoms or eosinophilic inflammation. This case warns of the importance of early recognition and appropriate individualized treatment of eosinophilic immune dysfunctions and suggests the conduction of further larger studies on the use of benralizumab in gastrointestinal syndromes aiming at better understanding its relying mechanisms of action in the intestinal mucosa.
- Improving the quality of publications in and advancing the entire paradigms of clinical and social pharmacy practice research: the Granada statementsPublication . Fernandez-Llimos, Fernando; Desselle, Shane; Stewart, Derek; Garcia-Cardenas, Victoria; Babar, Zaheer-Ud-Din; Bond, Christine; Dago, Ana; Jacobsen, Ramune; Nørgaard, Lotte Stig; Polidori, Carlo; Sanchez-Polo, Manuel; Santos-Ramos, Bernardo; Shcherbakova, Natalia; Tonin, FernandaPharmacy and pharmaceutical sciences embrace a series of different disciplines. Pharmacy practice has been defined as “the scientific discipline that studies the different aspects of the practice of pharmacy and its impact on health care systems, medicine use, and patient care”. Thus, pharmacy practice studies embrace both clinical pharmacy and social pharmacy elements. Like any other scientific discipline, clinical and social pharmacy practice disseminates research findings using scientific journals. Clinical pharmacy and social pharmacy journal editors have a role in promoting the discipline by enhancing the quality of the articles published. As has occurred in other health care areas (i.e., medicine and nursing), a group of clinical and social pharmacy practice journal editors gathered in Granada, Spain to discuss how journals could contribute to strengthening pharmacy practice as a discipline. The result of that meeting was compiled in these Granada Statements, which comprise 18 recommendations gathered into six topics: the appropriate use of terminology, impactful abstracts, the required peer reviews, journal scattering, more effective and wiser use of journal and article performance metrics, and authors’ selection of the most appropriate pharmacy practice journal to submit their work.
- Bioactive compounds as potential angiotensin-converting enzyme II inhibitors against COVID-19: a scoping reviewPublication . Matos, Pedro Henrique de; Silva, Thalita Prates da; Mansano, Amanda Benites; Gancedo, Naiara Cássia; Tonin, Fernanda; Pelloso, Fernando Castilho; Petruco, Marcus Vinicius; Melo, Eduardo Borges de; Fernandez-Llimos, Fernando; Sanches, Andreia Cristina Conegero; Mello, João Carlos Palazzo de; Chierrito, Danielly; Araújo, Daniela Cristina de MedeirosObjective and design: The current study aimed to summarize the evidence of compounds contained in plant species with the ability to block the angiotensin-converting enzyme 2 (ACE-II), through a scoping review. Methods: PubMed and Scopus electronic databases were used for the systematic search and a manual search was performed RESULTS: Studies included were characterized as in silico. Among the 200 studies retrieved, 139 studies were listed after the exclusion of duplicates, and 74 were included for the full read. Among them, 32 studies were considered eligible for the qualitative synthesis. The most evaluated class of secondary metabolites was flavonoids with quercetin and curcumin as most actives substances and terpenes (isothymol, limonin, curcumenol, anabsinthin, and artemisinin). Other classes also evaluated were alkaloid, saponin, quinone, substances found in essential oils, and primary metabolites such as the aminoacid L-tyrosine and the lipidic compound 2-monolinolenin. Conclusion: This review suggests the most active substance from each class of metabolites, which presented the strongest affinity to the ACE-II receptor, which contributes as a basis for choosing compounds and directing further experimental and clinical investigation on the applications these compounds in biotechnological and health processes as in COVID-19 pandemic.
- Pharmacoeconomic analysis methodsPublication . Tonin, Fernanda; Leonart, Leticia P.; Casas, CesarIn the last years, the growing interest of healthcare professionals, policy-makers, and other stakeholders in enlarging the role of economic evaluations was driven by several factors such as evidence-based healthcare culture, patient-centered actions, and quality-linked incentives, associated with an essential increase in financial constraints and pressures on healthcare budgets. Pharmacoeconomics, as a branch of health economics, focuses on balancing the costs and benefits (i.e., consequences) of intervention towards using limited resources, aiming at maximizing value to patients, healthcare payers, and society. These concepts are part of the Health Technology Assessment process that informs clinical and governmental players about medical, social, and economic implications of the development, diffusion, and health technologies. This chapter aims to provide an overview of the essential concepts in pharmacoeconomic analysis methods, including studies classification (e.g., budget-impact analysis, cost-minimization analysis, cost-effectiveness analysis, cost-utility analysis), types of costs and outcomes, modeling approaches (e.g., decision trees or state transition models), and new trending analysis (e.g., the value of information and value-based healthcare analyses), and additionally discuss some recommendations for future studies towards evidence synthesis and practical application.
- Novel COVID-19 biomarkers identified through multi-omics data analysis: N-acetyl-4-O-acetylneuraminic acid, N-acetyl-L-alanine, N-acetyltriptophan, palmitoylcarnitine, and glycerol 1-myristatePublication . Cobre, Alexandre de Fátima; Alves, Alexessander Couto; Gotine, Ana Raquel; Domingues, Karime Zeraik; Lazo, Raul Edison; Ferreira, Luana Mota; Tonin, Fernanda; Pontarolo, RobertoThis study aims to apply machine learning models to identify new biomarkers associated with the early diagnosis and prognosis of SARS-CoV-2 infection. Plasma and serum samples from COVID-19 patients (mild, moderate, and severe), patients with other pneumonia (but with negative COVID-19 RT-PCR), and healthy volunteers (control) from hospitals in four different countries (China, Spain, France, and Italy) were analyzed by GC-MS, LC-MS, and NMR. Machine learning models (PCA and PLS-DA) were developed to predict the diagnosis and prognosis of COVID-19 and identify biomarkers associated with these outcomes. A total of 1410 patient samples were analyzed. The PLS-DA model presented a diagnostic and prognostic accuracy of around 95% of all analyzed data. A total of 23 biomarkers (e.g., spermidine, taurine, L-aspartic, L-glutamic, L-phenylalanine and xanthine, ornithine, and ribothimidine) have been identified as being associated with the diagnosis and prognosis of COVID-19. Additionally, we also identified for the first time five new biomarkers (N-Acetyl-4-O-acetylneuraminic acid, N-Acetyl-L-Alanine, N-Acetyltriptophan, palmitoylcarnitine, and glycerol 1-myristate) that are also associated with the severity and diagnosis of COVID-19. These five new biomarkers were elevated in severe COVID-19 patients compared to patients with mild disease or healthy volunteers. The PLS-DA model was able to predict the diagnosis and prognosis of COVID-19 around 95%. Additionally, our investigation pinpointed five novel potential biomarkers linked to the diagnosis and prognosis of COVID-19: N-Acetyl-4-O-acetylneuraminic acid, N-Acetyl-L-Alanine, N-Acetyltriptophan, palmitoylcarnitine, and glycerol 1-myristate. These biomarkers exhibited heightened levels in severe COVID-19 patients compared to those with mild COVID-19 or healthy volunteers.