The VERA software: Implementation of the acute fish toxicity endpoint and its application to pharmaceutical compounds.

The Virtual Extensive Read-Across software (VERA) is a new tool for read-across using a global similarity score, molecular groups, and structural alerts to find clusters of similar substances; these clusters are then used to identify suitable similar substances and make an assessment for the target substance. A beta version of VERA GUI is free and available at vegahub.eu; the source code of the VERA algorithm is available on GitHub. In the past we described its use to assess carcinogenicity, a classification endpoint. The aim here is to extend the automated read-across approach to assess continuous endpoints as well. We addressed acute fish toxicity. VERA evaluation on the acute fish toxicity endpoint was done on a dataset containing general substances (pesticides, industrial products, biocides, etc.), obtaining an overall R2 of 0.68. We employed the VERA algorithm also on active pharmaceutical ingredients (APIs). We included a portion of the APIs in the training dataset to predict APIs, successfully achieving an overall R2 of 0.63. VERA evaluates the assessment's reliability, and we reached an R2 of 0.78 and Root Mean Square Error (RMSE) of 0.44 for predictions with high reliability.

Systematic evaluation of high-throughput PBK modelling strategies for the prediction of intravenous and oral pharmacokinetics in humans.

Physiologically based kinetic (PBK) modelling offers a mechanistic basis for predicting the pharmaco-/toxicokinetics of compounds and thereby provides critical information for integrating toxicity and exposure data to replace animal testing with in vitro or in silico methods. However, traditional PBK modelling depends on animal and human data, which limits its usefulness for non-animal methods. To address this limitation, high-throughput PBK modelling aims to rely exclusively on in vitro and in silico data for model generation. Here, we evaluate a variety of in silico tools and different strategies to parameterise PBK models with input values from various sources in a high-throughput manner. We gather 2000 + publicly available human in vivo concentration-time profiles of 200 + compounds (IV and oral administration), as well as in silico, in vitro and in vivo determined compound-specific parameters required for the PBK modelling of these compounds. Then, we systematically evaluate all possible PBK model parametrisation strategies in PK-Sim and quantify their prediction accuracy against the collected in vivo concentration-time profiles. Our results show that even simple, generic high-throughput PBK modelling can provide accurate predictions of the pharmacokinetics of most compounds (87% of Cmax and 84% of AUC within tenfold). Nevertheless, we also observe major differences in prediction accuracies between the different parameterisation strategies, as well as between different compounds. Finally, we outline a strategy for high-throughput PBK modelling that relies exclusively on freely available tools. Our findings contribute to a more robust understanding of the reliability of high-throughput PBK modelling, which is essential to establish the confidence necessary for its utilisation in Next-Generation Risk Assessment.

The VEGA Tool to Check the Applicability Domain Gives Greater Confidence in the Prediction of In Silico Models.

A sound assessment of in silico models and their applicability domain can support the use of new approach methodologies (NAMs) in chemical risk assessment and requires increasing the users' confidence in this approach. Several approaches have been proposed to evaluate the applicability domain of such models, but their prediction power still needs a thorough assessment. In this context, the VEGA tool capable of assessing the applicability domain of in silico models is examined for a range of toxicological endpoints. The VEGA tool evaluates chemical structures and other features related to the predicted endpoints and is efficient in measuring applicability domain, enabling the user to identify less accurate predictions. This is demonstrated with many models addressing different endpoints, towards toxicity of relevance to human health, ecotoxicological endpoints, environmental fate, physicochemical and toxicokinetic properties, for both regression models and classifiers.

Intelligent consensus predictions of bioconcentration factor of pharmaceuticals using 2D and fragment-based descriptors.

Bioconcentration factors (BCFs) are markers of chemical substance accumulation in organisms, and they play a significant role in determining the environmental risk of various chemicals. Experiments to obtain BCFs are expensive and time-consuming; therefore, it is better to estimate BCF early in the chemical development process. The current research aims to evaluate the ecotoxicity potential of 122 pharmaceuticals and identify possible important structural attributes using BCF as the determining feature against a group of fish species. We have calculated the theoretical 2D descriptors from the OCHEM platform and SiRMS descriptor calculating software. The regression-based quantitative structure-property relationship (QSPR) modeling was used to identify the chemical features responsible for acute fish bioconcentration. Multiple models with the "intelligent consensus" algorithm were employed for the regression-based approach improving the predictive ability of the models. To ensure the robustness and interpretability of the developed models, rigorous validation was performed employing various statistical internal and external validation metrics. From the developed models, it can be specified that the presence of large lipophilic and electronegative moieties greatly enhances the bioaccumulative potential of pharmaceuticals, whereas the hydrophilic characteristics have shown a negative impact on BCF. Furthermore, the developed models were employed to screen the DrugBank database (https://go.drugbank.com/) for assessing the BCF properties of the entire database. The evidence acquired from the modeled descriptors might be used for aquatic risk assessment in the future, with the added benefit of providing an early caution of their probable negative impact on aquatic ecosystems for regulatory purposes.

Virtual Extensive Read-Across: A New Open-Access Software for Chemical Read-Across and Its Application to the Carcinogenicity Assessment of Botanicals.

Read-across applies the principle of similarity to identify the most similar substances to represent a given target substance in data-poor situations. However, differences between the target and the source substances exist. The present study aims to screen and assess the effect of the key components in a molecule which may escape the evaluation for read-across based only on the most similar substance(s) using a new open-access software: Virtual Extensive Read-Across (VERA). VERA provides a means to assess similarity between chemicals using structural alerts specific to the property, pre-defined molecular groups and structural similarity. The software finds the most similar compounds with a certain feature, e.g., structural alerts and molecular groups, and provides clusters of similar substances while comparing these similar substances within different clusters. Carcinogenicity is a complex endpoint with several mechanisms, requiring resource intensive experimental bioassays and a large number of animals; as such, the use of read-across as part of new approach methodologies would support carcinogenicity assessment. To test the VERA software, carcinogenicity was selected as the endpoint of interest for a range of botanicals. VERA correctly labelled 70% of the botanicals, indicating the most similar substances and the main features associated with carcinogenicity.

International eDelphi Study to Reach Consensus on the Methotrexate Dosing Regimen in Patients With Psoriasis.

Importance: A clear dosing regimen for methotrexate in psoriasis is lacking, and this might lead to a suboptimal treatment. Because methotrexate is affordable and globally available, a uniform dosing regimen could potentially optimize the treatment of patients with psoriasis worldwide. Objective: To reach international consensus among psoriasis experts on a uniform dosing regimen for treatment with methotrexate in adult and pediatric patients with psoriasis and identify potential future research topics. Design, Setting, and Participants: Between September 2020 and March 2021, a survey study with a modified eDelphi procedure that was developed and distributed by the Amsterdam University Medical Center and completed by 180 participants worldwide (55 [30.6%] resided in non-Western countries) was conducted in 3 rounds. The proposals on which no consensus was reached were discussed in a conference meeting (June 2021). Participants voted on 21 proposals with a 9-point scale (1-3 disagree, 4-6 neither agree nor disagree, 7-9 agree) and were recruited through the Skin Inflammation and Psoriasis International Network and European Academy of Dermatology and Venereology in June 2020. Apart from being a dermatologist/dermatology resident, there were no specific criteria for participation in the survey. The participants worked mainly at a university hospital (97 [53.9%]) and were experienced in treating patients with psoriasis with methotrexate (163 [91.6%] had more than 10 years of experience). Main Outcomes and Measures: In a survey with eDelphi procedure, we tried to reach consensus on 21 proposals. Consensus was defined as less than 15% voting disagree (1-3). For the consensus meeting, consensus was defined as less than 30% voting disagree. Results: Of 251 participants, 180 (71.7%) completed all 3 survey rounds, and 58 participants (23.1%) joined the conference meeting. Consensus was achieved on 11 proposals in round 1, 3 proposals in round 2, and 2 proposals in round 3. In the consensus meeting, consensus was achieved on 4 proposals. More research is needed, especially for the proposals on folic acid and the dosing of methotrexate for treating subpopulations such as children and vulnerable patients. Conclusions and Relevance: In this eDelphi consensus study, consensus was reached on 20 of 21 proposals involving methotrexate dosing in patients with psoriasis. This consensus may potentially be used to harmonize the treatment with methotrexate in patients with psoriasis.

NMR spectroscopy and chemometric models to detect a specific non-porcine ruminant contaminant in pharmaceutical heparin.

Heparin has been used successfully as a clinical antithrombotic for almost one century. Its isolation from animal sources (mostly porcine intestinal mucosa) involves multistep purification processes starting from the slaughterhouse (as mucosa) to the pharmaceutical plant (as the API). This complex supply chain increases the risk of contamination and adulteration, mainly with non-porcine ruminant material. The structural similarity of heparins from different origins, the natural variability of the heparin within samples from each source as well as the structural changes induced by manufacturing processes, require increasingly sophisticated methods capable of detecting low levels of contamination. The application of suitable multivariate classification approaches on API 1H NMRspectra serve as rapid and reliable tools for product authentication and the detection of contaminants. Soft Independent Modeling of Class Analogies (SIMCA), Discriminant Analysis (DA), Partial Least Square Discriminant Analysis (PLS-DA) and local classification methods (kNN, BNN and N3) were tested on about one hundred certified heparin samples produced by 14 different manufacturers revealing that Partial Least Squares Discriminant Analysis (PLS-DA) provided the best discrimination of contaminated batches, with a balanced accuracy of 97%.

Using VEGAHUB Within a Weight-of-Evidence Strategy.

Industrial needs and regulatory requirements have played a significant role in accelerating the use of nontesting methods including in silico tools as alternatives to animal testing. The main interest is not solely on the use of in silico tools, or in read-across, but on better toxicological safety assessment of substances, and for this purpose more advanced, integrated strategies have to be implemented. VEGAHUB wants to promote this broader view, not necessarily focused on a specific approach. Applying multiple tools and complementary approaches instead of one technique may provide more elements for a more robust evaluation, but at the same time it is important to have a conceptual scheme to integrate multiple, heterogeneous lines of evidence. We will show how the user can benefit from the diversity of tools available within the platform VEGAHUB for assessing the biological properties of chemical substances on an example of (non)mutagenicity.

Fenomenologia da vida em pesquisas clínicas / Phenomenology of Life in clinical researches / Fenomenología de la vida en investigaciones clínicas

Apresentaremos uma possível operacionalidade da Fenomenologia da Vida de Michel Henry e seu método em situações clínicas. Neste método investigamos o conceito desenvolvido por Michel Henry nesta fenomenologia denominado corpopropriação e a intuição reflexiva na compreensão e intervenção clínica. É a relação terapêutica em instituições de saúde que é colocada em primeiro plano, tanto nos cuidados a um paciente adulto com transtorno psiquiátrico quanto em grupo com crianças acolhidas. Verifica-se como os terapeutas se corpo-apropriam de seus pacientes e como estes se corpo-apropriam de seus sofrimentos nos cuidados clínicos, bem como o uso das reflexões intuitivas no diálogo. Os resultados nos mostram que um corpo doente pode ser humanizado na relação terapêutica e tem possibilidades de encarnar vivências, ampliando assim a mobilidade afetiva, do sofrer ao fruir de si. No entanto, se a relação não tiver sustentação e continuidade, dificilmente se consegue a estabilidade dessa transformação, mas deixa marcas enraizadas em cada encontro inter-humano.

We will present a possible operationalization of Michel Henry's Phenomenology of Life and his method in clinical situations. This method investigates the concept developed by Michel Henry in this phenomenology called corpspropriation and the reflexive intuition in the comprehension and clinical intervention. It is a therapeutic relationship in health institutions that is placed In the foreground, both in the care of an adult patient with psychiatric disorder and in a group with sheltered children. It is verified how therapists body-apropriation of their patients and how they body-appropriate their sufferings in clinical care, as well as the use of intuitive reflections in dialogue. The results show that a sick body can be humanized in the therapeutic relationship and has possibilities of embodying experiences, thus increasing the affective mobility, of suffering when enjoying oneself. However, if the relationship does not have support and continuity, it is difficult to achieve the stability of this transformation, but leaves marks rooted in each inter-human encounter.

Presentaremos una posible operatividad de la Fenomenología de la Vida de Michel Henry y su método en situaciones clínicas. En este método investigamos el concepto desarrollado por Michel Henry en esta fenomenología denominado cuerpopropriación y la intuición reflexiva en la comprensión e intervención clínica. Es la relación terapéutica en instituciones de salud que es colocada en primer plan, tanto en el cuidado a un paciente adulto con trastorno psiquiátrico como en grupo con niños huérfanos. Se verifica cómo los terapeutas se apropian de sus pacientes y cómo éstos se apropian de sus sufrimientos en los cuidados clínicos, así como el uso de las reflexiones intuitivas en el diálogo. Los resultados nos muestran que un cuerpo enfermo puede ser humanizado en la relación terapéutica y tiene posibilidades de encarnar vivencias, ampliando así la movilidad afectiva, del sufrir al goce de sí. Sin embargo, si la relación no tiene sustentación y continuidad, difícilmente se consigue la estabilidad de esa transformación, pero deja marcas enraizadas en cada encuentro interhumano.

La histopatología como herramienta diagnóstica en la uña psoriática / Histopathology as a diagnostic tool in the psoriatic nail

La diferenciación clínica entre la distrofia ungueal causada por infección fúngica de aquella producida por la psoriasis representa un reto para el clínico. El examen directo con KOH, cultivo micológico y ocasionalmente, el estudio histológico de la lámina y el lecho ungueales es necesario para diferenciarlos. a) Estudiar la lámina y el lecho ungueal de las manos y los pies de pacientes con psoriasis mediante estudio histológico y coloraciones especiales, para establecer el diagnóstico de psoriasis ungueal. Esto permitiría el diagnóstico adecuado de psoriasis vs. micosis ungueal. b) Utilizar una técnica atraumática sin riesgo de distrofia permanente de la uña. Se incluyen 21 pacientes, de uno u otro sexo, adultos, con diagnóstico de psoriasis de la lámina y lecho ungueal por la técnica de la avulsión del 1/3 distal lateral y se estudiaron desde el punto de vista del examen directo micológico, cultivo micológico e histopatológico con coloraciones de Hematoxilina & Eosina y PAS. El estudio histopatológico con la coloración de PAS y el examen directo micológico tanto para las uñas de las manos y de los pies, demostraron ser equivalentes para detectar hifas/esporas en las uñas de los pacientes psoriáticos. El cultivo micológico es altamente específico pero menos sensible en el diagnóstico de micosis ungueal de los pies en los pacientes con psoriasis. Sin embargo, en las uñas de las manos el examen directo micológico y el cultivo micológico fueron concordantes ya que todos los casos eran negativos. Chi cuadrado (Mc Nemar). La técnica de la avulsión lateral de la uña nos proporciona el contenido de tejido suficiente para estudio sin causar distrofia ungueal. El estudio histopatológico demostró ser útil para diagnóstico de psoriasis y/o micosis ungueal en las uñas de las manos de los pacientes psoriáticos