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.

Clozapine re-trial in a patient with repeated life threatening pneumonias.

BACKGROUND AND AIM OF THE WORK: There has been an increasing amount of evidence to suggest a link between Clozapine and pneumonia. Whilst an exact mechanism for disease causation has not been identified excess salivation, impaired swallowing and abnormalities within the immune system have all been implicated. Within forensic services there is often a need to treat complex patients with Clozapine, even when a past history of pneumonia is present. METHODS: We present a case report on a forensic inpatient who has suffered repeated episodes of Clozapine associated pneumonia and highlight methods for good practice. RESULTS: Where appropriate, Clozapine can still be used in complex patients who have suffered previous pneumonias and have additional risk factors for chest infections, provided that robust risk reduction, infection surveillance and treatment interventions are employed. CONCLUSIONS: Practical measures can be employed to enable safe treatment of forensic patients with Clozapine, this includes risk factors for chest infections being carefully controlled such as asthma, Chronic Obstructive Airways Disease or diabetes. Patients should be carefully monitored for signs of infection by way of regular physical examinations and appropriate tests when required. Should signs of pneumonia arise the dose of Clozapine may need to be reduced and the infection aggressively treated with antibiotic medication.

The interaction between kynurenine pathway, suicidal ideation and augmentation therapy with minocycline in patients with treatment-resistant depression.

BACKGROUND AND AIMS: We investigated kynurenine pathway (KP) metabolites levels and their association with suicidal ideation in patients with treatment-resistant depression (TRD) and elevated peripheral inflammation. The effect of antidepressant augmentation with minocycline on KP metabolites was tested. METHODS: We analysed data from MINocycline in DEPression, a 4-week, randomized, placebo controlled (1:1) trial of minocycline added to antidepressant treatment in 39 TRD patients (n = 18 minocycline; n = 21 placebo) with C-reactive protein (CRP) ⩾1 mg/L. At baseline and at week 4, we collected data on suicidality (Beck Depression Inventory) and blood samples to measure inflammatory markers and KP metabolites. We tested (1) the association of KP metabolites ratios with inflammatory markers and suicidal ideation at baseline and (2) the role of suicidality and treatment (minocycline vs placebo) in affecting KP changes over time. RESULTS: At baseline, kynurenine/tryptophan (KYN/TRP) ratio positively correlated with high-sensitivity CRP (Spearman's ρ = 0.35, p = 0.02) and IL-10, (ρ = 0.41, p = 0.009); and tumour necrosis factor was positively correlated with quinolinic acid/3-hydroxykynurenine ratio (ρ = 0.55, p < 0.001). Moreover, participants with suicidal ideation showed higher levels of KYN/TRP (U = 143.000, p = 0.02) than those without suicidal ideation. There was no significant effect of minocycline on KP metabolites changes from baseline to week 4. However, in the minocycline group, the number of participants with suicidal thoughts decreased from 44.4% (8/18) to 22.2% (4/18). CONCLUSION: Increased KP neurotoxic metabolites are associated with elevated peripheral inflammation in depressed individuals, particularly in those with suicidal ideation. Targeting KP in this population could be a potential effective personalized approach. Whether this includes minocycline should be investigated in future larger trials.

Aluminum in tobacco and cannabis and smoking-related disease.

PURPOSE: The study aimed to confirm the very high content of aluminum in tobacco and cannabis and to provide for the first time evidence that such aluminum could be biologically available. METHODS: Complete digestion of tobacco and cannabis was achieved using a 50:50 mixture of 14 M HNO3 and 0.1 M NaF. Total Al in digests was measured by graphite furnace atomic absorption spectrometry. A bespoke cigarette smoking apparatus was used to determine if aluminum in active or passive tobacco/cannabis smoke would be trapped by a surrogate lung fluid. RESULTS: The aluminum content of tobacco and cannabis was confirmed to be high, as much as 0.37% and 0.4% by weight respectively. Aluminum in tobacco and cannabis smoke, whether actively (drawn) or passively inhaled, was shown to accumulate significantly in surrogate lung fluids, thus demonstrating its potential biological availability. CONCLUSIONS: Active and passive smoking of tobacco or cannabis will increase the body burden of aluminum and thereby contribute to respiratory, neurological and other smoking-related disease.