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The application of natural language processing for the extraction of mechanistic information in toxicology

To study the ways in which compounds can induce adverse effects, toxicologists have been constructing Adverse Outcome Pathways (AOPs). An AOP can be considered as a pragmatic tool to capture and visualize mechanisms underlying different types of toxicity inflicted by any kind of stressor, and describes the interactions between key entities that lead to the adverse outcome on multiple biological levels of organization. The construction or optimization of an AOP is a labor intensive process, which currently depends on the manual search, collection, reviewing and synthesis of available scientific literature. This process could however be largely facilitated using Natural Language Processing (NLP) to extract information contained in scientific literature in a systematic, objective, and rapid manner that would lead to greater accuracy and reproducibility. This would support researchers to invest their expertise in the substantive assessment of the AOPs by replacing the time spent on evidence gathering by a critical review of the data extracted by NLP. As case examples, we selected two frequent adversities observed in the liver: namely, cholestasis and steatosis denoting accumulation of bile and lipid, respectively. We used deep learning language models to recognize entities of interest in text and establish causal relationships between them. We demonstrate how an NLP pipeline combining Named Entity Recognition and a simple rules-based relationship extraction model helps screen compounds related to liver adversities in the literature, but also extract mechanistic information for how such adversities develop, from the molecular to the organismal level. Finally, we provide some perspectives opened by the recent progress in Large Language Models and how these could be used in the future. We propose this work brings two main contributions: 1) a proof-of-concept that NLP can support the extraction of information from text for modern toxicology and 2) a template open-source model for recognition of toxicological entities and extraction of their relationships. All resources are openly accessible via GitHub (https://github.com/ontox-project/en-tox).

Efficacy of Physical Exercise to Offset Anthracycline‐Induced Cardiotoxicity: A Systematic Review and Meta‐Analysis of Clinical and Preclinical Studies

BackgroundPhysical exercise is an intervention that might protect against doxorubicin‐induced cardiotoxicity. In this meta‐analysis and systematic review, we aimed to estimate the effect of exercise on doxorubicin‐induced cardiotoxicity and to evaluate mechanisms underlying exercise‐mediated cardioprotection using (pre)clinical evidence.Methods and ResultsWe conducted a systematic search in PubMed, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) databases. Cochrane's and Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE) risk‐of‐bias tools were used to assess the validity of human and animal studies, respectively. Cardiotoxicity outcomes reported by ≥3 studies were pooled and structured around the type of exercise intervention. Forty articles were included, of which 3 were clinical studies. Overall, in humans (sample sizes ranging from 24 to 61), results were indicative of exercise‐mediated cardioprotection, yet they were not sufficient to establish whether physical exercise protects against doxorubicin‐induced cardiotoxicity. In animal studies (n=37), a pooled analysis demonstrated that forced exercise interventions significantly mitigated in vivo and ex vivo doxorubicin‐induced cardiotoxicity compared with nonexercised controls. Similar yet slightly smaller effects were found for voluntary exercise interventions. We identified oxidative stress and related pathways, and less doxorubicin accumulation as mechanisms underlying exercise‐induced cardioprotection, of which the latter could act as an overarching mechanism.ConclusionsAnimal studies indicate that various exercise interventions can protect against doxorubicin‐induced cardiotoxicity in rodents. Less doxorubicin accumulation in cardiac tissue could be a key underlying mechanism. Given the preclinical evidence and limited availability of clinical data, larger and methodologically rigorous clinical studies are needed to clarify the role of physical exercise in preventing cardiotoxicity in patients with cancer.RegistrationURL: https://www.crd.york.ac.uk/prospero; Unique identifier: CRD42019118218.

Harmonizing and improving European education in prescribing

Aim: Improvement and harmonization of European clinical pharmacology and therapeutics (CPT) education is urgently required. Because digital educational resources can be easily shared, adapted to local situations and re-used widely across a variety of educational systems, they may be ideally suited for this purpose. Methods: With a cross-sectional survey among principal CPT teachers in 279 out of 304 European medical schools, an overview and classification of digital resources was compiled. Results: Teachers from 95 (34%) medical schools in 26 of 28 EU countries responded, 66 (70%) of whom used digital educational resources in their CPT curriculum. A total of 89 of such resources were described in detail, including e-learning (24%), simulators to teach pharmacokinetics and/or pharmacodynamics (10%), virtual patients (8%), and serious games (5%). Together, these resources covered 235 knowledge-based learning objectives, 88 skills, and 13 attitudes. Only one third (27) of the resources were in-part or totally free and only two were licensed open educational resources (free to use, distribute and adapt). A narrative overview of the largest, free and most novel resources is given. Conclusion: Digital educational resources, ranging from e-learning to virtual patients and games, are widely used for CPT education in EU medical schools. Learning objectives are based largely on knowledge rather than skills or attitudes. This may be improved by including more real-life clinical case scenarios. Moreover, the majority of resources are neither free nor open. Therefore, with a view to harmonizing international CPT education, more needs to be learned about why CPT teachers are not currently sharing their educational materials.

Feasibility of a Dutch post-discharge parenting intervention (TOP program) for moderate preterm born infants

Background and aim: Moderate preterm (MP) birth is associated with an increased risk of developmental problems. However, post-discharge support for this group is scarce. The aim of this study was to evaluate the feasibility of a post-discharge parenting program (TOP program) for MP infants. Three feasibility dimensions were evaluated (1) recruitment capability and compliance, (2) intervention acceptability, and (3) limited efficacy testing. Methods: A group of MP infants with a gestational age (GA) between 320/7‐346/7 weeks and their parents received six home visits by a TOP interventionist until 6 months corrected age (CA). A pre-posttest intervention design with quantitative and qualitative measures was used. Recruitment capability and compliance, acceptability, and satisfaction with the intervention were evaluated using a questionnaire, checklists, interviews, and a focus group. Infant socio-emotional development, parental distress, self-efficacy, and reflective functioning were measured with questionnaires. Observation measurements were used for infant motor development and parental sensitivity. Results: Thirty-two families completed the six home visits. The satisfaction rate (scale 0–10) was remarkably high (Mean 9.4, range: 8–10). Parents reported that the program was suitable, enhanced their understanding of their infants' developmental needs, and increased their self-efficacy. The infants showed age-appropriate motor and socio-emotional development post-intervention. Parental self-efficacy, reflective functioning, and sensitivity improved from pre to post intervention, with small to large effect sizes. Conclusion: The study demonstrated high compliance, acceptability, and satisfaction with the TOP program for MP infants with promising infant and parent outcomes. This study contributes to the preparatory work prior to a larger scale evaluation and dissemination.

Combination of heliox and CPAP without a ventilator

Lower or Higher Oxygenation Targets for Acute Hypoxemic Respiratory Failure

Abstract Background Patients with acute hypoxemic respiratory failure in the intensive care unit (ICU) are treated with supplemental oxygen, but the benefits and harms of different oxygenation targ...