Cause or consequence? Understanding the role of cortisol in the increased inflammation observed in depression

Glucocorticoids such as cortisol are a class of steroid hormones that play an important role in co-ordinating the body’s response to stress. Elevated cortisol levels and increased inflammation have frequently been reported in patients with depression. The currently accepted “glucocorticoid resistance” model posits this increased inflammation as a consequence of reduced sensitivity to cortisol’s putative anti-inflammatory action. However, opposing evidence has accumulated that supports a more recent model, which instead proposes that cortisol possesses immune potentiating properties and may thus directly cause the increased inflammation seen in depression. Despite all of this, a clear explanation of the neuroendocrine mechanism that contributes to the development of depression is still lacking and thus requires further investigation in improved future studies

Pharmacogenetic influences on the response to pharmacological treatment in autism spectrum disorders

Aim: About a third of patients with autism spectrum disorder (ASD) receive pharmacological treatment for comorbid symptoms. However, 30%-50% do not respond adequately and/or present severe and long-lasting side effects. Previous studies have reported the influence of variants in genes coding for drug targets on the efficacy and safety of pharmacological treatments, including genetic polymorphisms in dopaminergic and serotonergic systems. However, most studies have focused on the adult population, with relatively few studies in children and adolescents, and no clear biomarkers of response have been reported in these populations. The aim of our study was to identify genetic predictors of drug response in patients with ASD. This information may be used to personalise pharmacological treatment and improve the efficacy and safety of psychotropic drugs in patients with ASD. Methods: Genetic variants in dopaminergic and serotonergic drug targets (SLC6A3, DRD2, DRDRD3, DRD4, HTR2A, and HTR2C) and in other genes previously associated with treatment efficacy and/or induced side effects (ANKK1, BDNF, COMT, and HTR1A) were investigated in 176 children and adolescents diagnosed with ASD and undergoing pharmacological treatment. Results: A SLC6A3 genetic variant was associated with response to methylphenidate in our ASD cohort, whereas HTR2A and HTR2C allele and haplotype distributions were associated with adverse reactions such as somnolence, mood alterations, and BMI. ANKK1, COMT, and BDNF genetic variants were mainly associated with treatment side effects.Conclusion: If confirmed, these genetic variants may be used as predictors of clinical outcome and help to personalise pharmacological treatments in patients with ASD

Electronic health records (EHRs) in clinical research and platform trials:Application of the innovative EHR-based methods developed by EU-PEARL

Objective: Electronic Health Record (EHR) systems are digital platforms in clinical practice used to collect patients’ clinical information related to their health status and represents a useful storage of real-world data. EHRs have a potential role in research studies, in particular, in platform trials. Platform trials are innovative trial designs including multiple trial arms (conducted simultaneously and/or sequentially) on different treatments under a single master protocol. However, the use of EHRs in research comes with important challenges such as incompleteness of records and the need to translate trial eligibility criteria into interoperable queries. In this paper, we aim to review and to describe our proposed innovative methods to tackle some of the most important challenges identified. This work is part of the Innovative Medicines Initiative (IMI) EU Patient-cEntric clinicAl tRial pLatforms (EU-PEARL) project's work package 3 (WP3), whose objective is to deliver tools and guidance for EHR-based protocol feasibility assessment, clinical site selection, and patient pre-screening in platform trials, investing in the building of a data-driven clinical network framework that can execute these complex innovative designs for which feasibility assessments are critically important. Methods: ISO standards and relevant references informed a readiness survey, producing 354 criteria with corresponding questions selected and harmonised through a 7-round scoring process (0–1) in stakeholder meetings, with 85% of consensus being the threshold of acceptance for a criterium/question. ATLAS cohort definition and Cohort Diagnostics were mainly used to create the trial feasibility eligibility (I/E) criteria as executable interoperable queries. Results: The WP3/EU-PEARL group developed a readiness survey (eSurvey) for an efficient selection of clinical sites with suitable EHRs, consisting of yes-or-no questions, and a set-up of interoperable proxy queries using physicians’ defined trial criteria. Both actions facilitate recruiting trial participants and alignment between study costs/timelines and data-driven recruitment potential.Conclusion: The eSurvey will help create an archive of clinical sites with mature EHR systems suitable to participate in clinical trials/platform trials, and the interoperable proxy queries of trial eligibility criteria will help identify the number of potential participants. Ultimately, these tools will contribute to the production of EHR-based protocol design.</p

Current state-of-the-art and gaps in platform trials: 10 things you should know, insights from EU-PEARL

Summary: Platform trials bring the promise of making clinical research more efficient and more patient centric. While their use has become more widespread, including their prominent role during the COVID-19 pandemic response, broader adoption of platform trials has been limited by the lack of experience and tools to navigate the critical upfront planning required to launch such collaborative studies. The European Union-Patient-cEntric clinicAl tRial pLatform (EU-PEARL) initiative has produced new methodologies to expand the use of platform trials with an overarching infrastructure and services embedded into Integrated Research Platforms (IRPs), in collaboration with patient representatives and through consultation with U.S. Food and Drug Administration and European Medicines Agency stakeholders. In this narrative review, we discuss the outlook for platform trials in Europe, including challenges related to infrastructure, design, adaptations, data sharing and regulation. Documents derived from the EU-PEARL project, alongside a literature search including PubMed and relevant grey literature (e.g., guidance from regulatory agencies and health technology agencies) were used as sources for a multi-stage collaborative process through which the 10 more important points based on lessons drawn from the EU-PEARL project were developed and summarised as guidance for the setup of platform trials. We conclude that early involvement of critical stakeholder such as regulatory agencies or patients are critical steps in the implementation and later acceptance of platform trials. Addressing these gaps will be critical for attaining the full potential of platform trials for patients. Funding: Innovative Medicines Initiative 2 Joint Undertaking with support from the European Union’s Horizon 2020 research and innovation programme and EFPIA