Browsing by Author "Pontarolo, Roberto"
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- Accuracy of COVID-19 diagnostic tests via infrared spectroscopy: a systematic review and meta-analysisPublication . Cobre, Alexandre de Fátima; Fachi, Mariana Millan; Domingues, Karime Zeraik Abdalla; Lazo, Raul Edison Luna; Ferreira, Luana Mota; Tonin, Fernanda; Pontarolo, RobertoThis study aims to synthesize the evidence on the accuracy parameters of COVID-19 diagnosis methods using infrared spectroscopy (FTIR). A systematic review with searches in PubMed and Embase was performed (September 2023). Studies reporting data on test specificity, sensitivity, true positive, true negative, false positive, and false negative using different human samples were included. Meta-analysis of accuracy estimates with 95 % confidence intervals and area under the ROC Curve (AUC) were conducted (Meta-Disc 1.4.7). Seventeen studies were included - all of them highlighted regions 650-1800 cm-1 and 2300-3900 cm-1 as most important for diagnosing COVID-19. The FTIR technique presented high sensitivity [0.912 (95 %CI, 0.878-0.939), especially in vaccinated [0.959 (CI95 %, 0.908-0.987)] compared to unvaccinated [0.625 (CI95 %, 0.584-0.664)] individuals for COVID-19. Overall specificity was also high [0.886 (95 %CI, 0.855-0.912), with increased rates in vaccinated [0.884 (CI95 %, 0.819-0.932)] than in unvaccinated [0.667 (CI95 %, 0.629-0.704)] patients. These findings reveal that FTIR is an accurate technique for detecting SARS-CoV-2 infection in different biological matrices with advantages including low cost, rapid and environmentally friendly with minimal preparation analyses. This could lead to an easy implementation of this technique in practice as a screening tool for patients with suspected COVID-19, especially in low-income countries.
- Comparative efficacy and safety of systemic antifungal agents for candidemia: a systematic review with network meta-analysis and multicriteria acceptability analysesPublication . Domingos, Eric L.; Vilhena, Raquel O.; Santos, Josiane M.; Fachi, Mariana M.; Böger, Beatriz; Adam, Livia M.; Tonin, Fernanda; Pontarolo, RobertoAim: Invasive candidiasis is the main fungal infection in patients attending health services and is associated with high mortality rates and prolonged hospital stay. We aimed to comparatively evaluate the efficacy and safety of antifungal agents for treating candidemia. Methods: A systematic review with network meta-analysis (NMA), the surface under the cumulative ranking analysis (SUCRA), and stochastic multicriteria acceptability analyses (SMAA) were performed (PROSPERO-CRD42020149264). Searches were conducted in PubMed and Scopus (Nov-2021). Randomised controlled trials evaluating the effect of oral antifungals (any dose or regimen) on mycological cure, discontinuation rates, and adverse events were included. Results: Overall, 13 trials (n=3,632) were analysed. No significant differences among therapies were found for the efficacy outcomes; however, caspofungin (50-150 mg), rezafungin (200-400mg), and micafungin (100-150 mg) were considered the most promising therapies, leading to higher rates of both clinical and mycological responses (SUCRA overall response over 60%). Fluconazole (400 mg) was rated as the last option for overall response (17%). Rezafungin (200-400mg) and micafungin (100 mg) were associated with lower discontinuation rates (<40%); conventional amphotericin B (0.6-0.7mg/kg) was more likely to be discontinued (OR 0.08 [95% CrI 0.00-0.95] vs. caspofungin 150 mg) and may impair liver function (87%). Conclusion: Echinocandins should be listed as first-line treatments for invasive candidiasis following a priority order of caspofungin and micafungin. Rezafungin, an under-development echinocandin, represents a potential option that should be further investigated. Azoles and liposomal amphotericin B can be used as second-line treatments in cases of fungal resistance or hypersensitivity.
- Critical appraisal of dyslipidaemia clinical practice guidelines: a scoping reviewPublication . Deffert, Flávia; Tonin, Fernanda; Pontarolo, Roberto; Fernandez-Llimos, FernandoBackground information: Dyslipidaemia, the unbalanced level of lipoproteins and triglycerides, contributes to or aggravates cardiovascular diseases. In 2019, high LDL-c levels were responsible for 5 million deaths worldwide. Several clinical practice guidelines (CPG) about dyslipidaemia aiming at guiding healthcare professionals towards more assertive decisions exist. However, previous studies reported low quality of the clinical content and evidence supporting recommendations provided by CPGs in different areas, and a lack of involvement of multi-professional experts and stakeholders, such as pharmacists, in their development. This may lead to inconsistencies and risk of bias in decision-making and negatively impact patients’ outcomes. The quality of CPG can be assessed through Appraisal of Guidelines, Research and Evaluation (AGREE) tools as the AGREE II (methodological assessment) and AGREE REX (clinical recommendations). Purpose: We aim to evaluate the quality of available CPG on dyslipidaemia and assess the extent of involvement of stakeholders using AGREE II and AGREE REX appraisal tools.
- Definitions and indexing of 'simulated patient’ studies in health: a classification system proposalPublication . Tonin, Fernanda; Pina, Isabela; Pontarolo, Roberto; Fernandez-Llimos, FernandoBackground information: Several inconsistencies in the definition and indexing of the term ‘simulated patient’ have been reported in the health literature, including in pharmacy practice. Purpose: To propose a classification system for studies on ‘simulated patient’ and to assess the coverage of ‘simulated patient’ in the National Library of Medicine’s (NLM) Medical Subject Headings (MeSH) thesaurus.
- Diagnosis and prognosis of COVID-19 employing analysis of patients' plasma and serum via LC-MS and machine learningPublication . Cobre, Alexandre de Fátima; Surek, Monica; Stremel, Dile Pontarolo; Fachi, Mariana Millan; Borba, Helena Hiemisch; Tonin, Fernanda; Pontarolo, RobertoObjective: To implement and evaluate machine learning (ML) algorithms for the prediction of COVID-19 diagnosis, severity, and fatality and to assess biomarkers potentially associated with these outcomes. Material and methods: Serum (n = 96) and plasma (n = 96) samples from patients with COVID-19 (acute, severe, and fatal illness) from two independent hospitals in China were analyzed by LC-MS. Samples from healthy volunteers and from patients with pneumonia caused by other viruses (i.e. negative RT-PCR for COVID-19) were used as controls. Seven different ML-based models were built: PLS-DA, ANNDA, XGBoostDA, SIMCA, SVM, LREG, and KNN. Results: The PLS-DA model presented the best performance for both datasets, with accuracy rates to predict the diagnosis, severity, and fatality of COVID-19 of 93%, 94%, and 97%, respectively. Low levels of the metabolites ribothymidine, 4-hydroxyphenylacetoylcarnitine and uridine were associated with COVID-19 positivity, whereas high levels of N-acetyl-glucosamine-1-phosphate, cysteinylglycine, methyl isobutyrate, l-ornithine, and 5,6-dihydro-5-methyluracil were significantly related to greater severity and fatality from COVID-19. Conclusion: The PLS-DA model can help to predict SARS-CoV-2 diagnosis, severity, and fatality in daily practice. Some biomarkers typically increased in COVID-19 patients’ serum or plasma (i.e. ribothymidine, N-acetyl-glucosamine-1-phosphate, l-ornithine, 5,6-dihydro-5-methyluracil) should be further evaluated as prognostic indicators of the disease.
- The effects of nutritional supplementation for children and adolescents with sickle cell disease: a systematic review and meta-analysesPublication . Orsi, Bruna C.; Gorski, Daniela; Krul, Naila E.; Wiens, Astrid; Brito, Miguel; Tonin, Fernanda; Pontarolo, RobertoBackground & aims: Sickle cell disease (SCD), a neglected chronic genetic blood disorder that severely impacts the pediatric population, often leading to premature death, is associated with compromised nutritional status. This study aimed to evaluate the effect of nutritional supplementation on SCD-related complications. Methods: A systematic review with searches in PubMed, Scopus, and Web of Science was performed. Randomized controlled trials (RCT) assessing diet or supplements as a complementary therapy for children and adolescents with SCD were included (PROSPERO: CRD42024532369). The data for outcomes of interest (efficacy, safety) were pooled using pairwise and network meta-analyses with ranking (p-score) analysis. The results were presented as odds ratio or mean differences with 95 % confidence intervals (NMAstudio2.0). Results: Twenty RCTs were included (2002–2023) (n = 2058), analyzing 9 dietary supplements on different regimens. All patients use hydroxyurea as an active treatment. Supplementation with fatty acids (n = 3 studies) and l-arginine (n = 4) presented higher efficacy and safety, significantly improving pain intensity, vaso-occlusive crises (VOC), and inflammation when compared to usual care/placebo (p < 0.05). Vitamin D3 (n = 6) at different dosages may reduce respiratory complications and length of hospital stay, yet further studies are needed to confirm its significant effects. Evidence is limited and of poor quality regarding the effects of add-on vitamin A (n = 2), magnesium sulfate (n = 2), and zinc (n = 4) for this population. Conclusions: The complementary use of certain supplements (fatty acids, l-arginine, vitamin D3) can enhance the management of VOC and improve patients' physiological functions. These supplements are often affordable and can contribute towards the reduction of opioid use and shorten patients' hospital stays - especially in low/middle-income countries where resources are scarce. Although further studies are needed to refine these findings (e.g., appropriate doses/regimens), practical guidelines and decision-makers may benefit from updated evidence.
- Efficacy and safety of daily treatments for drug-susceptible pulmonary tuberculosis: a systematic review and network meta-analysisPublication . Imazu, Priscila; Santos, Josiane M.; Beraldi-Magalhães, Francisco; Fernandez-Llimos, Fernando; Tonin, Fernanda; Pontarolo, RobertoObjectives: To evaluate and update the evidence on the comparative efficacy and safety of antimicrobial drugs regimens for treating pulmonary drug-susceptible tuberculosis (DS-TB). Methods: A systematic review was performed with searches in PubMed and Scopus (PROSPERO-CRD42019141463). We included randomised controlled trials comparing the effect of any antimicrobial regimen lasting at least 2 weeks. The outcomes of interest were culture conversion and incidence of adverse events. Bayesian network meta-analyses and surface under the cumulative ranking curve (SUCRA) analyses were performed. Results were reported as odds ratio with 95% credibility intervals. Key findings: Fifteen studies were included in the meta-analysis (n = 7560 patients). No regimen was statistically more effective than the WHO standard approach (rifampicin, isoniazid, ethambutol, and pyrazinamide). The use of rifapentine 450 mg instead of rifampicin in the standard regimen demonstrated to be statistically safer than all other options for serious adverse events (e.g. hepatotoxicity, arthralgia) (OR ranging from 0.0 [Crl 0.00-0.04] to 0.0 [0.00-0.97]; SUCRA probabilities of 10%). Therapies containing rifapentine (Rp1500HEZ, Rp900HEZ) and moxifloxacin (RMEZ, RHMZ) are effective regarding culture conversion, but statistical uncertainty on their safety profile exists. Conclusion: The WHO standard regimen remains an overall effective and safe alternative for DS-TB. For intensive phase treatments, drugs combinations with rifapentine and moxifloxacin seem to reduce treatment duration while maintaining efficacy.
- Identifying 124 new anti-HIV drug candidates in a 37 billion-compound database: an integrated approach of machine learning (QSAR), molecular docking, and molecular dynamics simulationPublication . Cobre, Alexandre de Fátima; Ara, Anderson; Alves, Alexessander Couto; Neto, Moisés Maia; Fachi, Mariana Millan; Beca, Laize Botas; Tonin, Fernanda; Pontarolo, RobertoRecent data from the World Health Organization reveals that in 2023, 38.8 million people were living with HIV. Within this population, there were 1.5 million new cases and 650 thousand deaths attributed to the disease. This study employs an integrated approach involving QSAR-based machine learning models, molecular docking, and molecular dynamics simulations to identify potential compounds for inhibiting the bioactivity of the CC chemokine receptor type 5 (CCR5) protein, a key entry point for HIV. Using non-redundant experimental data from the CHEMBL database, 40 different machine learning algorithms were trained and the top four models (XGBoost, Histogram gradient Boosting, Light Gradient Boosted Machine, and Extra Trees Regression) were utilized to predict anti-HIV bioactivity for 37 billion compounds in the ZINC-22 database. The screening resulted in the identification of 124 new anti-HIV drug candidates, confirmed through molecular docking and dynamics simulations. The study underscores the therapeutic potential of these compounds, paving the way for further in vitro and in vivo investigations. The convergence of machine learning and experimental findings presents a promising avenue for significant advancements in pharmaceutical research, particularly in the treatment of viral diseases such as HIV. To guarantee the reproducibility of our study, we have made the Python code (Google Collab) and the associated database available on GitHub. You can access them through the following link: GitHub Link: https://github.com/AlexandreCOBRE/code
- Machine learning-based virtual screening, molecular docking, drug-likeness, pharmacokinetics and toxicity analyses to identify new natural inhibitors of the glycoprotein spike (S1) od SARS-CoV-2Publication . Cobre, Alexandre; Böger, Beatriz; Fachi, Mariana; Ehrenfried, Carlos; Stremel, Dile; De Melo, Eduardo; Tonin, Fernanda; Pontarolo, RobertoTo identify natural bioactive compounds (NBCs) as potential inhibitors of the spike (S1) by means of in silico assays. NBCs with previously proven biological in vitro activity were obtained from the ZINC database and analyzed through virtual screening and molecular docking to identify those with higher affinity to the spike protein. Eight machine learning models were used to validate the results: Principal Component Analysis (PCA), Artificial Neural Network (ANN), Support Vector Machine (SVM), k-Nearest Neighbors (KNN), Partial Least Squares-Discriminant Analysis (PLS-DA), Gradient Boosted Tree Discriminant Analysis (XGBoostDA), Soft Independent Modelling of Class Analogies (SIMCA) and Logistic Regression Discriminate Analysis (LREG). Selected NBCs were submitted to drug-likeness prediction using Lipinski’s and Veber’s rule of five. A prediction of pharmacokinetic parameters and toxicity was also performed (ADMET). Antivirals currently used for COVID-19 (remdesivir and molnupiravir) were used as a comparator. A total of 170,906 compounds were analyzed. Of these, 34 showed a greater affinity with the S1 (affinity energy < -7 kcal mol-1). Most of these compounds belonged to the class of coumarins (benzopyrones), presenting a benzene ring fused to a lactone (group of heterosides). The PLS-DA model was able to reproduce the results of the virtual screening and molecular docking (accuracy of 97.0%). Of the 34 compounds, only NBC5 (feselol), NBC14, NBC15, and NBC27 had better results in ADMET predictions. These had a similar binding affinity to S1 when compared to remdesivir and molnupirvir. Feselol and three other NBCs were the most promising candidates for treating COVID-19. In vitro and in vivo studies are needed to confirm these findings.
- Mapping the characteristics, methodological quality and standards of reporting of network meta-analyses on antithrombotic therapies: an overviewPublication . Sousa, Patricia Guerrero de; Mainka, Felipe Fernando; Tonin, Fernanda; Pontarolo, RobertoBackground: Although a large number of network meta-analyses (NMAs) in the field of cardiology are available, little is known about their methodological quality. We aimed to map the characteristics and critically appraised the standards of conduct and evidence reporting of NMAs assessing antithrombotic therapies for the treatment or prophylaxis of heart diseases and cardiac surgical procedures. Methods: We systematically searched PubMed and Scopus to identify NMAs comparing the clinical effects of antithrombotic therapies. Overall characteristics of the NMAs were extracted and their reporting quality and methodological quality were evaluated using the PRISMA-NMA checklist and AMSTAR-2, respectively. Results: We found 86 NMAs published between 2007 and 2022. Comparisons among direct-acting oral anticoagulants were available in 61 (71%) NMAs. Although around 75% of NMAs stated that they followed international guidelines for conduct and reporting, only one-third provided a protocol/register. Complete search strategies and publication bias assessment were lacking in around 53% and 59% of studies, respectively. Most NMAs (n = 77, 90%) provided supplemental material; however, only 5 (6%) made the complete raw data available. Network diagrams were depicted in most studies (n = 67, 78%), yet network geometry was described in only 11 (12.8%) of them. Mean adherence to the PRISMA-NMA checklist was 65.1 ± 16.5%. AMSTAR-2 assessment showed 88% of the NMAs had critically low methodological quality. Conclusion: Although there is a wide diffusion of NMA-type studies on antithrombotics for heart diseases, their methodological and reporting quality remains suboptimal. This may reflect fragile clinical practices due to misleading conclusions from critically low-quality NMAs.