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- Andronis, Christos, et al.
(författare)
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Molecular basis of mood and cognitive adverse events elucidated via a combination of pharmacovigilance data mining and functional enrichment analysis
- 2020
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Ingår i: Archives of Toxicology. - : Springer Nature. - 0340-5761 .- 1432-0738. ; 94:8, s. 2829-2845
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Tidskriftsartikel (refereegranskat)abstract
- Drug-induced Mood- and Cognition-related adverse events (MCAEs) are often only detected during the clinical trial phases of drug development, or even after marketing, thus posing a major safety concern and a challenge for both pharmaceutical companies and clinicians. To fill some gaps in the understanding and elucidate potential biological mechanisms of action frequently associated with MCAEs, we present a unique workflow linking observational population data with the available knowledge at molecular, cellular, and psychopharmacology levels. It is based on statistical analysis of pharmacovigilance reports and subsequent signaling pathway analyses, followed by evidence-based expert manual curation of the outcomes. Our analysis: (a) ranked pharmaceuticals with high occurrence of such adverse events (AEs), based on disproportionality analysis of the FDA Adverse Event Reporting System (FAERS) database, and (b) identified 120 associated genes and common pathway nodes possibly underlying MCAEs. Nearly two-thirds of the identified genes were related to immune modulation, which supports the critical involvement of immune cells and their responses in the regulation of the central nervous system function. This finding also means that pharmaceuticals with a negligible central nervous system exposure may induce MCAEs through dysregulation of the peripheral immune system. Knowledge gained through this workflow unravels putative hallmark biological targets and mediators of drug-induced mood and cognitive disorders that need to be further assessed and validated in experimental models. Thereafter, they can be used to substantially improve in silico/in vitro/in vivo tools for predicting these adversities at a preclinical stage.
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- Grinberg, Marianna, et al.
(författare)
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Toxicogenomics directory of chemically exposed human hepatocytes
- 2014
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Ingår i: Archives of Toxicology. - : Springer Science and Business Media LLC. - 1432-0738 .- 0340-5761. ; 88:12, s. 2261-2287
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Tidskriftsartikel (refereegranskat)abstract
- A long-term goal of numerous research projects is to identify biomarkers for in vitro systems predicting toxicity in vivo. Often, transcriptomics data are used to identify candidates for further evaluation. However, a systematic directory summarizing key features of chemically influenced genes in human hepatocytes is not yet available. To bridge this gap, we used the Open TG-GATES database with Affymetrix files of cultivated human hepatocytes incubated with chemicals, further sets of gene array data with hepatocytes from human donors generated in this study, and publicly available genome-wide datasets of human liver tissue from patients with non-alcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular cancer (HCC). After a curation procedure, expression data of 143 chemicals were included into a comprehensive biostatistical analysis. The results are summarized in the publicly available toxicotranscriptomics directory (http://wiki.toxbank.net/toxicogenomics-map/) which provides information for all genes whether they are up- or downregulated by chemicals and, if yes, by which compounds. The directory also informs about the following key features of chemically influenced genes: (1) Stereotypical stress response. When chemicals induce strong expression alterations, this usually includes a complex but highly reproducible pattern named 'stereotypical response.' On the other hand, more specific expression responses exist that are induced only by individual compounds or small numbers of compounds. The directory differentiates if the gene is part of the stereotypical stress response or if it represents a more specific reaction. (2) Liver disease-associated genes. Approximately 20 % of the genes influenced by chemicals are up- or downregulated, also in liver disease. Liver disease genes deregulated in cirrhosis, HCC, and NASH that overlap with genes of the aforementioned stereotypical chemical stress response include CYP3A7, normally expressed in fetal liver; the phase II metabolizing enzyme SULT1C2; ALDH8A1, known to generate the ligand of RXR, one of the master regulators of gene expression in the liver; and several genes involved in normal liver functions: CPS1, PCK1, SLC2A2, CYP8B1, CYP4A11, ABCA8, and ADH4. (3) Unstable baseline genes. The process of isolating and the cultivation of hepatocytes was sufficient to induce some stress leading to alterations in the expression of genes, the so-called unstable baseline genes. (4) Biological function. Although more than 2,000 genes are transcriptionally influenced by chemicals, they can be assigned to a relatively small group of biological functions, including energy and lipid metabolism, inflammation and immune response, protein modification, endogenous and xenobiotic metabolism, cytoskeletal organization, stress response, and DNA repair. In conclusion, the introduced toxicotranscriptomics directory offers a basis for a rationale choice of candidate genes for biomarker evaluation studies and represents an easy to use source of background information on chemically influenced genes.
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- Jacome, Cristina, et al.
(författare)
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Monitoring Adherence to Asthma Inhalers Using the InspirerMundi App : Analysis of Real-World, Medium-Term Feasibility Studies
- 2021
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Ingår i: Frontiers in Medical Technology. - : Frontiers Media S.A.. - 2673-3129. ; 3
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Tidskriftsartikel (refereegranskat)abstract
- Background: Poor medication adherence is a major challenge in asthma and objective assessment of inhaler adherence is needed. InspirerMundi app aims to monitor inhaler adherence while turning it into a positive experience through gamification and social support.Objective: We assessed the medium-term feasibility of the InspirerMundi app to monitor inhaler adherence in real-world patients with persistent asthma (treated with daily inhaled medication). In addition, we attempted to identify the characteristics of the patients related to higher app use.Methods: Two real-world multicenter observational studies, with one initial face-to-face visit and a 4-month telephone interview, were conducted in 29 secondary care centers from Portugal. During an initial face-to-face visit, patients were invited to use the app daily to register their asthma medication intakes. A scheduled intake was considered taken when patients took a photo of the medication (inhaler, blister, or others) using the image-based medication detection tool. Medication adherence was calculated as the number of doses taken as a percentage of the number scheduled. Interacting with the app =30 days was used as the cut-off for higher app use.Results: A total of 114 patients {median 20 [percentile 25 to percentile 75 (P25-P75) 16-36] years, 62% adults} were invited, 107 (94%) installed the app and 83 (73%) completed the 4-month interview. Patients interacted with the app for a median of 18 [3-45] days, translated on a median use rate of 15 [3-38]%. Median inhaler adherence assessed through the app was 34 [4-73]% when considering all scheduled inhalations for the study period. Inhaler adherence assessed was not significantly correlated with self-reported estimates. Median adherence for oral and other medication was 41 [6-83]% and 43 [3-73]%, respectively. Patients with higher app use were slightly older (p = 0.012), more frequently taking medication for other health conditions (p = 0.040), and more frequently prescribed long-acting muscarinic antagonists (LAMA, p = 0.024). After 4 months, Control of Allergic Rhinitis and Asthma Test (CARAT) scores improved (p < 0.001), but no differences between patients interacting with the app for 30 days or less were seen.Conclusions: The InspirerMundi app was feasible to monitor inhaler adherence in patients with persistent asthma. The persistent use of this mHealth technology varies widely. A better understanding of characteristics related to higher app use is still needed before effectiveness studies are undertaken.
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- Vale, Maria do Carmo, et al.
(författare)
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Classifying Functioning of Children and Adolescents with Intellectual Disability : The Utility of the International Classification of Functioning, Disability and Health for Children and Youth
- 2017
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Ingår i: Journal of Policy and Practice in Intellectual Disabilities. - : John Wiley & Sons. - 1741-1122 .- 1741-1130. ; 14:4, s. 285-292
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Tidskriftsartikel (refereegranskat)abstract
- Observational cross-sectional study carried out in a pediatric neurodevelopment unit of a tertiary-care hospital. A sample of 355 children with median ((min.–max.) 1.0–17.3) years with intellectual disability (30.4% borderline, 43.1% mild, 19.7% moderate, 5.1% severe, and 1.7% profound disability) was seen over a period of 3 years. Based on clinical observation and psychological evaluation, a neurodevelopmental pediatrician selected ICF-CY body functions codes, and respective qualifiers, to effectively describe functioning of children. Based on evaluation reports, a psychologist and a special educator assigned the previously chosen ICF-CY body functions codes to 139 and 67 children, respectively. Inter-rater agreement was estimated using simple and weighted Cohen's kappa coefficients and Gwet's AC1 statistic and Gwet's weighted kappa coefficient statistic. A set of eight ICF-CY codes was identified as efficiently describing impairments of body functions of children with intellectual disability: global mental functions b117 and b122; specific mental functions b147, b163, b164, and b167; and voice and speech functions b320 and b330. Results indicate a correspondence between the level of severity of qualifiers assigned to ICF-CY codes and the level of intellectual disability. Inter-rater agreement was variable among raters, with the best agreements found for qualifying intellectual functions (b117) and psychomotor functions (b122). A profile of eight ICF-CY codes effectively describes functioning of children with intellectual disability, providing an alternative to medically based classification, based on diagnoses with functionally based classification of children's characteristics. The findings contribute to define a comprehensive set of codes to reliably record individual differences of functioning in this population.
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