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Background: Dopamine transporter (DAT) PET provides higher resolution than DAT SPECT and opportunity for integrated imaging with MRI. The radioligand [18F]FE-PE2I is highly selective for the DAT, and PET measurements with this radioligand have good reliability and repeatability in patients with non-advanced Parkinson’s disease. Objectives: To validate [18F]FE-PE2I PET as measurement tool of longitudinal DAT changes in patients with Parkinson’s disease. Methods: Thirty-seven subjects with Parkinson’s disease (Hoehn and Yahr stage

Purpose: Regulatory authorities including the Food and Drug Administration and the European Medicines Agency are encouraging to conduct clinical trials using routinely collected data. The aim of the TransFAIR experimental comparison was to evaluate, within real-life conditions, the ability of the Electronic Health Records to Electronic Data Capture (EHR2EDC) module to accurately transfer from EHRs to EDC systems patients' data of clinical studies in various therapeutic areas., Methods: A prospective study including six clinical trials from three different sponsors running in three hospitals across Europe has been conducted. The same data from the six studies were collected using both traditional manual data entry and the EHR2EDC module. The outcome variable was the percentage of data accurately transferred using the EHR2EDC technology. This percentage was calculated considering all collected data and the data in four domains: demographics (DM), vital signs (VS), laboratories (LB) and concomitant medications (CM)., Results: Overall, 6143 data points (39.6% of the data in the scope of the TransFAIR study and 16.9% when considering all data) were accurately transferred using the platform. LB data represented 65.4% of the data transferred; VS data, 30.8%; DM data, 0.7% and CM data, 3.1%., Conclusions: The objective of accurately transferring at least 15% of the manually entered trial datapoints using the EHR2EDC module was achieved. Collaboration and codesign by hospitals, industry, technology company, supported by the Institute of Innovation through Health Data was a success factor in accomplishing these results. Further work should focus on the harmonisation of data standards and improved interoperability to extend the scope of transferable EHR data., Competing Interests: Competing interests: The EIThealth funds the EHR2EDC project in which the experimentation described in the article took place. EIT reimburse hospitals for the expenses related to the project.And Sanofi, Janssen and ICON provided partial financial support to hospital consortium partners to attend workshops, covering travel and meal related-costs., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Background: Correlations between dopamine transporter (DAT) availability and Parkinson's disease (PD) motor symptoms vary depending on the imaging modality, choice of regions of interest and clinical measures. We aimed to validate the PET radioligand [ 18 F]FE-PE2I as a clinical biomarker in PD, hypothesizing negative correlations between DAT availability in specified nigrostriatal regions with symptom duration, disease stage and motor symptom scores., Methods: We included 41 PD patients (age 45-79 years; H&Y stage < 3) and 37 healthy control subjects in a cross-sectional study with dynamic [ 18 F]FE-PE2I PET. Binding potential (BP ND ) was estimated in the caudate nucleus, putamen, ventral striatum, sensorimotor striatum, and substantia nigra using the cerebellum as reference region., Results: We found negative correlations (p < 0.02) between symptom duration and BP ND in the putamen and sensorimotor striatum (r s  = - .42; r s  = - .51), and between H&Y stage and BP ND in caudate nucleus, putamen, sensorimotor striatum, and substantia nigra (r s between - .40 and - .54). The first correlations were better described with exponential fitting. MDS-UPDRS-III in 'OFF' state correlated negatively (p < 0.04) with BP ND in the sensorimotor striatum (r s  = - .47), and excluding tremor score also in the putamen (r s  = - .45)., Conclusion: Results are in agreement with earlier findings in in vivo and post-mortem studies and validate [ 18 F]FE-PE2I as a functional PD biomarker for PD severity., Trial Registration: EudraCT 2011-0020050, Registered April 26 2011; EudraCT 2017-003327-29, Registered October 08 2017; EudraCT 2017-001585-19, Registered August 2 2017. https://eudract.ema.europa.eu/ ., (© 2023. The Author(s).)

Background: Dopamine transporter (DAT) PET provides higher resolution than DAT SPECT and opportunity for integrated imaging with MRI. The radioligand [ 18 F]FE-PE2I is highly selective for the DAT, and PET measurements with this radioligand have good reliability and repeatability in patients with non-advanced Parkinson's disease., Objectives: To validate [ 18 F]FE-PE2I PET as measurement tool of longitudinal DAT changes in patients with Parkinson's disease., Methods: Thirty-seven subjects with Parkinson's disease (Hoehn and Yahr stage < 3) were included in a longitudinal PET study with [ 18 F]FE-PE2I. DAT availability (BP ND ) in the caudate nucleus, putamen, sensorimotor striatum, and substantia nigra, was estimated with parametric imaging using Logan graphical analysis and cerebellum as reference region. For comparison with DAT-SPECT literature, sample size calculations for disease intervention studies were made., Results: Baseline and follow-up PET data (interval: 2.3 ± 0.5 years) were available for 25 patients (9 females, 16 males). Median age was 64.7 years (range 46-76); symptom duration: 3 years (0.25-14); Hoehn and Yahr stage (H&Y): 1 (1-2). Annualized DAT decline and effect size were: -8.5 ± 6.6 % and 1.08 for caudate nucleus; -7.1 ± 6.1 % and 1.02 for putamen; -8.3 ± 8.5 % and 0.99 for sensorimotor striatum; -0.11 ± 9.3 % and 0.11 for substantia nigra. The estimated minimum sample size needed for a treatment trial using [ 18 F]FE-PE2I PET as imaging marker is 2-3 times lower than is reported in literature on [ 123 I]FP-CIT SPECT., Conclusions: Longitudinal [ 18 F]FE-PE2I PET measurements in non-advanced PD demonstrate a striatal DAT decline consistent with previous SPECT and PET studies. No obvious changes of DAT availability were observed in the substantia nigra, indicating perhaps slower progression or compensatory changes. The effect sizes were numerically larger than reported in the literature for other DAT radioligands, suggesting that [ 18 F]FE-PE2I might detect smaller DAT changes, and can be well used as progression marker in clinical trials., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)

Big data is central to new developments in global clinical science aiming to improve the lives of patients. Technological advances have led to the routine use of structured electronic healthcare records with the potential to address key gaps in clinical evidence. The covid-19 pandemic has demonstrated the potential of big data and related analytics, but also important pitfalls. Verification, validation, and data privacy, as well as the social mandate to undertake research are key challenges. The European Society of Cardiology and the BigData@Heart consortium have brought together a range of international stakeholders, including patient representatives, clinicians, scientists, regulators, journal editors and industry. We propose the CODE-EHR Minimum Standards Framework as a means to improve the design of studies, enhance transparency and develop a roadmap towards more robust and effective utilisation of healthcare data for research purposes., (This article has been co-published with permission in The BMJ, the Lancet Digital Health, and the European Heart Journal © the Authors 2022.)

Big data is important to new developments in global clinical science that aim to improve the lives of patients. Technological advances have led to the regular use of structured electronic health-care records with the potential to address key deficits in clinical evidence that could improve patient care. The COVID-19 pandemic has shown this potential in big data and related analytics but has also revealed important limitations. Data verification, data validation, data privacy, and a mandate from the public to conduct research are important challenges to effective use of routine health-care data. The European Society of Cardiology and the BigData@Heart consortium have brought together a range of international stakeholders, including representation from patients, clinicians, scientists, regulators, journal editors, and industry members. In this Review, we propose the CODE-EHR minimum standards framework to be used by researchers and clinicians to improve the design of studies and enhance transparency of study methods. The CODE-EHR framework aims to develop robust and effective utilisation of health-care data for research purposes., Competing Interests: Declaration of interests The BigData@Heart project has received funding from the Innovative Medicines Initiative (IMI) 2 Joint Undertaking (grant 116074) which receives support from the Horizon 2020 research and innovation programme of the European Union and the European Federation of Pharmaceutical Industries and Associations. The funders had no role in considering the study design; in the collection, analysis, or interpretation of data; in the writing of the report; or in the decision to submit the Review for publication. DK reports grants from the European Union and the European Federation of Pharmaceutical Industries and Associations Innovative Medicines Initiative (116074), the National Institute for Health Research (NIHR CDF-2015-08-074 RATE-AF; NIHR130280 DaRe2THINK; and NIHR132974 D2T-NeuroVascular), the British Heart Foundation (PG/17/55/33087, AA/18/2/34218 and FS/CDRF/21/21032), and the ESC. DK is supported by educational grants from Boehringer Ingelheim, Bristol Myers Squibb (BMS)-Pfizer Alliance, Bayer, Daiichi Sankyo, Boston Scientific, the NIHR and University of Oxford Biomedical Research Centre, the British Heart Foundation and University of Birmingham Accelerator Award (STEEER-AF NCT04396418), Amomed Pharma, Istituto Di Ricovero e Cura a Carattere Scientifico San Raffaele, and Menarini (NCT0083244). DK receives advisory board personal fees from Bayer, Amomed, Protherics Medicines Development, and Myokardia. FWA reports grants from IMI BigData@Heart. SDA reports grants and personal fees from Vifor Pharma, Abbott, and Abbott Vascular; and personal fees from Bayer, Boehringer Ingelheim, Servier, Cardiac Dimensions, Actimed, AstraZeneca, Amgen, Bioventrix, Janssen, Respicardia, V-Wave, Brahms, Cordio, and Occlutech. CB reports grants from Medical Research Council, Boehringer Ingelheim, and NIHR. AB reports grants from AstraZeneca. BB reports grants from the European Commission. GB reports grants from the European Commission (IMI project support) and Bayer. BC reports non-financial support from Roche Diagnostics and iRhythm. CC reports grants from the European Commission. MRC reports personal fees from AstraZeneca. FC reports personal fees from Amgen, AstraZeneca, Servier, and BMS; and advisory board fees from GlyCardial Diagnostics. MC reports personal fees from Vifor Pharma. AD reports salary from Bayer. MF reports salary from AstraZeneca. CPG reports personal fees from AstraZeneca, Amgen, Bayer, Boehringer Ingelheim, Daiichi Sankyo, Vifor Pharma, Menarini, Wondr Medical, Raisio Group, and Oxford University Press; and grants from BMS, Abbott, British Heart Foundation, NIHR, and ESC. MI reports grants from World Economic Forum, Swedish Innovation Agency, and the European Commission; and collaboration with Frisq. SL reports grants from the European Commission. TFL reports grants from Abbott, Amgen, Novartis, Boehringer Ingelheim, Servier, Vifor Pharma, Sanofi, and AstraZeneca; and personal fees from Daichi Sankyo, Pfizer, and Menarini. LR reports salary from Bayer. CS reports personal fees from Bayer. BT reports personal fees from Servier. GvT reports grants from IMI. KvB reports grants from IMI BigData@Heart. PEV reports personal fees from Hygeia Hospitals Group, Hellenic Healthcare Group, ESC, and Servier. TV is working as an editor at The BMJ and Acta Médica Portuguesa and is Vice President of the European Union of General Practitioners. MV reports grants from the European Commission. SW reports grants from Abbott, Amgen, AstraZeneca, BMS, Bayer, Biotronik, Boston Scientific, Cardinal Health, CardioValve, CSL Behring, Daiichi Sankyo, Edwards Lifesciences, Guerbet, InfraRedx, Johnson & Johnson, Medicure, Medtronic, Novartis, Polares, OrPha Suisse, Pfizer, Regeneron, Sanofi-Aventis, Sinomed, Terumo, and V-Wave. SW serves as an unpaid advisory board member or unpaid member of the steering or executive group of trials funded by Abbott, Abiomed, Amgen, AstraZeneca, BMS, Boston Scientific, Biotronik, Cardiovalve, Edwards Lifesciences, MedAlliance, Medtronic, Novartis, Polares, Sinomed, V-Wave, and Xeltis. He has not received personal payments by pharmaceutical companies or device manufacturers. SW is a member of the steering or executive committee group of several investigator-initiated trials that receive funding by industry without effect on his personal remuneration. SW is an unpaid member of the Pfizer Research Award selection committee in Switzerland and of the Women as One Awards Committee. SW is a member of the Clinical Study Group of the Deutsches Zentrum für Herz Kreislauf-Forschung and of the Advisory Board of the Australian Victorian Heart Institute. He is Chairperson of the ESC Congress Program Committee, former Chairperson of the ESC Clinical Practice Guidelines Committee, and Deputy Editor of the Journal of the American College of Cardiology Cardiovascular Interventions. All other authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

The notion that a neuron transmits the same set of neurotransmitters at all of its post-synaptic connections, typically known as Dale's law, is well supported throughout the majority of the brain and is assumed in almost all theoretical studies investigating the mechanisms for computation in neuronal networks. Dale's law has numerous functional implications in fundamental sensory processing and decision-making tasks, and it plays a key role in the current understanding of the structure-function relationship in the brain. However, since exceptions to Dale's law have been discovered for certain neurons and because other biological systems with complex network structure incorporate individual units that send both positive and negative feedback signals, we investigate the functional implications of network model dynamics that violate Dale's law by allowing each neuron to send out both excitatory and inhibitory signals to its neighbors. We show how balanced network dynamics, in which large excitatory and inhibitory inputs are dynamically adjusted such that input fluctuations produce irregular firing events, are theoretically preserved for a single population of neurons violating Dale's law. We further leverage this single-population network model in the context of two competing pools of neurons to demonstrate that effective decision-making dynamics are also produced, agreeing with experimental observations from honeybee dynamics in selecting a food source and artificial neural networks trained in optimal selection. Through direct comparison with the classical two-population balanced neuronal network, we argue that the one-population network demonstrates more robust balanced activity for systems with less computational units, such as honeybee colonies, whereas the two-population network exhibits a more rapid response to temporal variations in network inputs, as required by the brain. We expect this study will shed light on the role of neurons violating Dale's law found in experiment as well as shared design principles across biological systems that perform complex computations., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Barranca, Bhuiyan, Sundgren and Xing.)

Management of Parkinson's disease traditionally relies solely on clinical assessment. The PKG objectively measures affected persons' movements in daily life. The present study evaluated how often PKG data changed treatment decisions in routine clinical care and to what extent the clinical assessment and the PKG interpretation differed. PKG recordings were performed before routine visits. The neurologist first made a clinical assessment without reviewing the PKG. Signs and symptoms were recorded, and a treatment plan was documented. Afterward, the PKG was evaluated. Then, the neurologist decided whether to change the initial treatment plan or not. PKG review resulted in a change in the initial treatment plan in 21 of 66 participants (31.8%). The clinical assessment and the PKG review differed frequently, mainly regarding individual overall presence of motor problems (67%), profile of bradykinesia/wearing off (79%), dyskinesia (35%) and sleep (55%). PKG improved the dialogue with the participant in 88% of cases. PKG and clinical variables were stable when they were repeated after 3-6 months. In conclusion, PKG information changes treatment decisions in nearly a third of people with Parkinson's disease in routine care. Standard clinical assessment and PKG evaluation are often non-identical. Objective measurements in people living with Parkinson's disease can add therapeutically relevant information.

Objectives: Type 1 diabetes mellitus (T1DM) may be associated with cognitive impairment and notably a decline in psychomotor speed, information processing speed and attention. The mechanism for this decline is uncertain. Previous studies by our group and others have demonstrated a decline in EEG-power and event-related potential amplitude in T1DM. The objectives of the present study were to explore whether 1) the association between event-related potential (N100) amplitude and psychomotor speed is different between T1DM and healthy subjects, and 2) the decline in N100 amplitude depends on duration of diabetes., Methods: Patients with T1DM (N = 204) and healthy control subjects (N = 358) were included in a cross-sectional study. Event-related brain potentials were recorded with auditory reaction tasks. Psychomotor speed was evaluated with the Grooved Pegboard test in a subset of the patients (N = 70) and the healthy control subjects (N = 89)., Results: Patients with T1DM had a decrease in the N100 amplitude that correlated with a decline in psychomotor speed, longer duration of diabetes and increasing age. In healthy controls, the N100 amplitude did not decrease with age and the association between psychomotor speed and N100 amplitude was absent., Conclusion: The association between psychomotor speed and N100 amplitude is likely to be a specific trait for T1DM since it was not found in healthy controls and was dependent on diabetes duration. Our findings indicate that the pathogenesis of cognitive decline in T1DM may involve a disease-related factor with a long-term influence on the N100 amplitude., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Quantification of dopamine transporter (DAT) availability with [ 18 F]FE-PE2I PET enables the detection of presynaptic dopamine deficiency and provides a potential progression marker for Parkinson`s disease (PD). Simplified quantification is feasible, but the time window of short acquisition protocols may have a substantial impact on the reliability of striatal binding estimates. Dynamic [ 18 F]FE-PE2I PET data of cross-sectional (33 PD patients, 24 controls), test-retest (9 patients), and longitudinal (12 patients) cohorts were used to assess the variability and reliability of specific binding ratios (SBR) measured during early peak and late pseudo-equilibrium. Receiver operating characteristics area under the curve (PD vs. controls) was high for early (0.996) and late (0.991) SBR. Early SBR provided more favourable effect size, absolute variability, and standard error of measurement than late SBR (caudate: 1.29 vs. 1.23; 6.9% vs. 9.8%; 0.09 vs. 0.20; putamen: 1.75 vs. 1.67; 7.7% vs. 14.0%; 0.08 vs. 0.17). The annual percentage change was comparable for both time windows (-7.2%-8.5%), but decline was significant only for early SBR. Whereas early and late [ 18 F]FE-PE2I PET acquisitions have similar discriminative power to separate PD patients and controls, the early peak equilibrium acquisition can be recommended if [ 18 F]FE-PE2I is used to measure longitudinal changes of DAT availability.

Background: Reliable quantification of dopamine transporter (DAT), a biomarker for Parkinson's disease (PD), is essential for diagnostic purposes as well as for evaluation of potential disease-modifying treatment. Due to degeneration of dopaminergic neurons and thus lower expected radioligand binding to DAT, higher measurement variability in PD patients might be expected than earlier reproducibility results in healthy controls. Therefore, we aimed to examine the test-retest properties of [ 18 F]FE-PE2I-PET in PD patients., Methods: Nine patients with PD (Hoehn and Yahr stage < 3) were included (men/women 6/3; mean age 65.2 ± 6.8 years). Each patient underwent two [ 18 F]FE-PE2I-PET measurements within 7-28 days. The outcome measure was non-displaceable binding potential generated using wavelet-aided parametric imaging with cerebellum as reference region. We assessed test-retest performance using estimates of reliability and repeatability. Regions for primary analysis were caudate, putamen, ventral striatum, and substantia nigra. Exploratory analysis was performed for functional subdivisions of the striatum. We also compared the more vs. less affected side., Results: [ 18 F]FE-PE2I showed absolute variability estimates of 5.3-7.6% in striatal regions and 11% in substantia nigra and ICCs of 0.74-0.97 (median 0.91). The absolute variability for functional striatal subdivisions was 6.0-9.6% and ICCs of 0.76-0.91 (median 0.91). The less affected substantia nigra exhibited greater consistency than the more affected side. According to power calculations based on the current sample size, DAT changes of 5-11% in the striatum and 28% in the substantia nigra can be detected with a power of 0.8 (p < 0.0125)., Conclusion: DAT-PET measurements with [ 18 F]FE-PE2I in PD patients showed good repeatability and reliability. The slightly lower reliability in the substantia nigra in patients may be explained by lower DAT density and smaller anatomical size. Power calculations suggest that [ 18 F]FE-PE2I PET is a suitable marker for longitudinal DAT decline in PD., Trial Registration: EudraCT 2017-003327-29.

Clinical trial data collection still relies on a manual entry from information available in the medical record. This process introduces delay and error risk. Automating data transfer from Electronic Health Record (EHR) to Electronic Data Capture (EDC) system, under investigators' supervision, would gracefully solve these issues. The present paper describes the design of the evaluation of a technology allowing EHR to act as eSource for clinical trials. As part of the EHR2EDC project, for 6 ongoing clinical trials, running at 3 hospitals, a parallel semi-automated data collection using such technology will be conducted focusing on a limited scope of data (demographic data, local laboratory results, concomitant medication and vital signs). The evaluation protocol consists in an individual participant data prospective meta-analysis comparing regular clinical trial data collection to the semi-automated one. The main outcome is the proportion of data correctly entered. Data quality and associated workload for hospital staff will be compared as secondary outcomes. Results should be available in 2020.

Objective: To investigate if changes in brain network function and connectivity contribute to the abnormalities in visual event related potentials (ERP) in relapsing-remitting multiple sclerosis (RRMS), and explore their relation to a decrease in cognitive performance., Methods: We evaluated 72 patients with RRMS and 89 healthy control subjects in a cross-sectional study. Visual ERP were generated using illusory and non-illusory stimuli and recorded using 21 EEG scalp electrodes. The measured activity was modelled using Dynamic Causal Modelling. The model network consisted of 4 symmetric nodes including the primary visual cortex (V1/V2) and the Lateral Occipital Complex. Patients and controls were tested with a neuropsychological test battery consisting of 18 cognitive tests covering six cognitive domains., Results: We found reduced cortical connectivity in bottom-up and interhemispheric connections to the right lateral occipital complex in patients (p < 0.001). Furthermore, interhemispherical connections were related to cognitive dysfunction in several domains (attention, executive function, visual perception and organization, processing speed and global cognition) for patients (p < 0.05). No relation was seen between cortical network connectivity and cognitive function in the healthy control subjects., Conclusion: Changes in the functional connectivity to higher cortical regions provide a neurobiological explanation for the changes of the visual ERP in RRMS., Significance: This study suggests that changes in connectivity to higher cortical regions partly explain visual network dysfunction in RRMS where a lower interhemispheric connectivity may contribute to impaired cognitive function., (Copyright © 2019. Published by Elsevier B.V.)

Objective: To determine if inclusion/exclusion (I/E) criteria of clinical trial protocols can be represented as structured queries and executed using a secure federated research platform (InSite) on hospital electronic health records (EHR) systems, to estimate the number of potentially eligible patients., Methods: Twenty-three clinical trial protocols completed during 2011-2017 across diverse disease areas were analyzed to construct queries that were executed with InSite using EHR records from 24 European hospitals containing records of >14 million patients. The number of patients matching I/E criteria of each protocol was estimated., Results: All protocols could be formalized to some extent into a medical coding system (e.g. ICD-10CM, ATC, LOINC, SNOMED) and mapped to local hospital coding systems. The median number of I/E criteria of protocols tested was 29 (range: 14-47). A median of 55% (range 38-89%) of I/E criteria in each protocol could be transformed into a computable format. The median number of eligible patients identified was 26 per hospital site (range: 1-134)., Conclusion: Clinical trial I/E eligibility criteria can be structured computationally and executed as queries on EHR systems to estimate the patient recruitment pool at each site. The results further suggest that an increase in structured coded information in EHRs would increase the number of I/E criteria that could be evaluated. Additional work is needed on broader deployment of federated platforms such as InSite., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Introduction: The Electronic Health Records for Clinical Research (EHR4CR) technological platform has been developed to enable the trustworthy reuse of hospital electronic health records data for clinical research. The EHR4CR platform can enhance and speed up clinical research scenarios: protocol feasibility assessment, patient identification for recruitment in clinical trials, and clinical data exchange, including for reporting serious adverse events. Our objective was to seed a multi-stakeholder ecosystem to enable the scalable exploitation of the EHR4CR platform in Europe, and to assess its economic sustainability., Materials and Methods: Market analyses were conducted by a multidisciplinary task force to define an EHR4CR emerging ecosystem and multi-stakeholder value chain. This involved mapping stakeholder groups and defining their unmet needs, incentives, potential barriers for adopting innovative solutions, roles and interdependencies. A comprehensive business model, value propositions, and sustainability strategies were developed accordingly. Using simulation modelling (including Monte Carlo simulations) and a 5-year horizon, the potential financial outcomes of the business model were forecasted from the perspective of an EHR4CR service provider., Results: A business ecosystem was defined to leverage the EHR4CR multi-stakeholder value chain. Value propositions were developed describing the expected benefits of EHR4CR solutions for all stakeholders. From an EHR4CR service provider's viewpoint, the business model simulation estimated that a profitability ratio of up to 1.8 could be achieved at year 1, with potential for growth in subsequent years depending on projected market uptake., Conclusions: By enhancing and speeding up existing processes, EHR4CR solutions promise to transform the clinical research landscape. The ecosystem defined provides the organisational framework for optimising the value and benefits for all stakeholders involved, in a sustainable manner. Our study suggests that the exploitation of EHR4CR solutions appears profitable and sustainable in Europe, with a growth potential depending on the rates of market and hospital adoption., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background: In the development of new drugs for severe asthma, it is a challenge from an ethical point of view to randomize severe asthma patients to placebo, and to obtain long-term safety data due to discontinuations. The aim of this study was to evaluate the feasibility of using electronic health record (EHR) data to create a real-world reference population of uncontrolled asthmatic patients to supplement the concurrent control/placebo group in long-term studies of asthma., Methods: EHR data from 36 primary care centres and a University hospital in Sweden were linked to Swedish mandatory health registers (2005-2013), creating a population covering 33 890 asthma patients, including data on co-morbidities, risk factors and laboratory/respiratory measurements. A severe asthma EHR reference cohort was established. We used logistic regression to estimate the propensity score (probability) of each RCT or EHR patient existing in the EHR cohort given their covariates., Results: We created an EHR-derived reference cohort of 240 patients, matching the placebo group (N = 151) in an RCT of severe asthma. The exacerbation rate during follow-up in the EHR study population was 1.24 (weighted) compared to 0.9 in the RCT placebo group. Patients in the EHR cohort were of similar age as in the RCT placebo group, 50.6 years versus 50.1 years; had slightly higher body mass index 27.0 kg/m 2 versus 27.3 kg/m 2 ; and consisted of 40% versus 34% males., Conclusions: The results indicate that EHRs provide an opportunity to supplement the control group in RCTs of severe diseases.

Background: Cognitive impairment in multiple sclerosis (MS) is common and has severe implications. Natalizumab (NZ) has documented effects on relapse rate and radiological disease activity in relapsing-remitting MS (RRMS) but studies regarding its specific effects on cognitive functioning are few. Previous studies have reported improvement, however, often lacking relevant control groups. The objective of the present study was to evaluate the cognitive effects of NZ treatment, compared to patients on stable first-line treatment and healthy control subjects., Methods: MS patients starting NZ (MS-NZ), MS controls with stable interferon beta therapy (MS-C) and healthy control subjects (HC) were evaluated twice with one year interval, using a cognitive test battery covering six cognitive domains. The effects of NZ on levels of self-reported depression, fatigue, daytime sleepiness and perceived health were also examined., Results: MS patients (MS-NZ and MS-C) had significantly lower baseline cognitive performance compared to HC (global score, p=0.002), but there were no significant differences between MS-NZ and MS-C. At follow-up, both MS-NZ and MS-C had improved significantly in four and five cognitive domains, respectively, and in global score (p=0.013 and p<0.001, respectively). HC improved significantly in three cognitive domains but not in global score. A regression analysis including baseline cognitive z-score and z-score change showed that participants with lower baseline scores had a significantly greater improvement, compared to those with better initial performance (p=0.021). There were no significant changes in depression, fatigue, daytime sleepiness or perceived health in MS-NZ or MS-C., Conclusions: Initiation of NZ therapy did not result in true cognitive improvement over one year. Presumably, the increased test performance in both MS groups was artificial and due to retest effects that were stronger in patients with lower baseline performance. Adequate control groups are essential when evaluating cognitive functioning in intervention trials among RRMS patients., (Copyright © 2016 Elsevier B.V. All rights reserved.)

The European Institute for Innovation through Health Data ( i ~HD, www.i-hd.eu) has been formed as one of the key sustainable entities arising from the Electronic Health Records for Clinical Research (IMI-JU-115189) and SemanticHealthNet (FP7-288408) projects, in collaboration with several other European projects and initiatives supported by the European Commission. i ~HD is a European not-for-profit body, registered in Belgium through Royal Assent. i ~HD has been established to tackle areas of challenge in the successful scaling up of innovations that critically rely on high-quality and interoperable health data. It will specifically address obstacles and opportunities to using health data by collating, developing, and promoting best practices in information governance and in semantic interoperability. It will help to sustain and propagate the results of health information and communication technology (ICT) research that enables better use of health data, assessing and optimizing their novel value wherever possible. i ~HD has been formed after wide consultation and engagement of many stakeholders to develop methods, solutions, and services that can help to maximize the value obtained by all stakeholders from health data. It will support innovations in health maintenance, health care delivery, and knowledge discovery while ensuring compliance with all legal prerequisites, especially regarding the insurance of patient's privacy protection. It is bringing multiple stakeholder groups together so as to ensure that future solutions serve their collective needs and can be readily adopted affordably and at scale.

Introduction: The widespread adoption of electronic health records (EHR) provides a new opportunity to improve the efficiency of clinical research. The European EHR4CR (Electronic Health Records for Clinical Research) 4-year project has developed an innovative technological platform to enable the re-use of EHR data for clinical research. The objective of this cost-benefit assessment (CBA) is to assess the value of EHR4CR solutions compared to current practices, from the perspective of sponsors of clinical trials., Materials and Methods: A CBA model was developed using an advanced modeling approach. The costs of performing three clinical research scenarios (S) applied to a hypothetical Phase II or III oncology clinical trial workflow (reference case) were estimated under current and EHR4CR conditions, namely protocol feasibility assessment (S1), patient identification for recruitment (S2), and clinical study execution (S3). The potential benefits were calculated considering that the estimated reduction in actual person-time and costs for performing EHR4CR S1, S2, and S3 would accelerate time to market (TTM). Probabilistic sensitivity analyses using Monte Carlo simulations were conducted to manage uncertainty., Results: Should the estimated efficiency gains achieved with the EHR4CR platform translate into faster TTM, the expected benefits for the global pharmaceutical oncology sector were estimated at €161.5m (S1), €45.7m (S2), €204.5m (S1+S2), €1906m (S3), and up to €2121.8m (S1+S2+S3) when the scenarios were used sequentially., Conclusions: The results suggest that optimizing clinical trial design and execution with the EHR4CR platform would generate substantial added value for pharmaceutical industry, as main sponsors of clinical trials in Europe, and beyond., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Cognitive dysfunction is common in multiple sclerosis (MS). Different factors may moderate the degree of cognitive deficit. The aim of the present study was to distinguish different mechanisms for cognitive reserve in relapsing-remitting MS (RRMS). The effects of clinical variables (physical disability, depression), premorbid intelligence (years of education, vocabulary knowledge), visual event-related potential measures (P300) and response time (RT) were studied in RRMS patients (n=71) and healthy subjects (n=89). Patients with high P300 amplitude and short RT had better cognitive performance. This effect was significantly weaker in controls. High P300 and short RT may be physiological markers of a cognitive reserve in RRMS. In contrast, the association between cognitive scores and premorbid intelligence was similar in patients and in control subjects. The effects of physiological reserve and clinical variables were studied in a hierarchical linear regression model of cognitive performance in RRMS. P300 amplitude and RT explained a considerable amount of variance in global cognitive performance (34%, p<0.001). The effects of P300 and RT were not moderated by premorbid intelligence. Physical disability and depression added significantly to explained variance, and the final model accounted for 44% (p<0.001) of the variation. We conclude that physiological reserve is the strongest moderator of cognitive impairment in RRMS., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Objective: To explore if cognitive impairment in relapsing-remitting multiple sclerosis (RRMS) is associated with abnormal neural function and if there is evidence of neural compensatory mechanisms., Methods: Seventy-two RRMS patients and 89 healthy control subjects were included in a cross-sectional study. Event-related brain potential (P300) and response time (RT) were recorded with visual and auditory choice reaction tasks. Cognitive function was evaluated with an 18 item test battery., Results: Patients had a decrease in cognitive function (p<0.001 for global score) and increased visual P300 amplitude frontally. P300 amplitude was normal in other brain areas and RT was normal. P300 latency was normal except for an increase in auditory latency occipitally. Cognitive performance correlated positively with parietal P300 amplitude in patients but not in controls. Cognition had stronger correlation (negative) with RT in patients than in controls., Conclusions: Patients with low P300 amplitude and long RT were more often cognitively impaired. This indicates that general factors such as signal amplitude and speed are limiting for cognitive function in RRMS patients. The increase in frontal P300 amplitude may be a compensatory effect., Significance: Our findings suggest that high amplitude and fast speed may be protective against cognitive impairment., (Copyright © 2014 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

Objectives: To describe the IMI EHR4CR project which is designing and developing, and aims to demonstrate, a scalable, widely acceptable and efficient approach to interoperability between EHR systems and clinical research systems., Methods: The IMI EHR4CR project is combining and extending several previously isolated state-of-the-art technical components through a new approach to develop a platform for reusing EHR data to support medical research. This will be achieved through multiple but unified initiatives across different major disease areas (e.g. cardiovascular, cancer) and clinical research use cases (protocol feasibility, patient identification and recruitment, clinical trial execution and serious adverse event reporting), with various local and national stakeholders across several countries and therefore under various legal frameworks., Results: An initial instance of the platform has been built, providing communication, security and terminology services to the eleven participating hospitals and ten pharmaceutical companies located in seven European countries. Proof-of-concept demonstrators have been built and evaluated for the protocol feasibility and patient recruitment scenarios. The specifications of the clinical trial execution and the adverse event reporting scenarios have been documented and reviewed., Conclusions: Through a combination of a consortium that brings collectively many years of experience from previous relevant EU projects and of the global conduct of clinical trials, of an approach to ethics that engages many important stakeholders across Europe to ensure acceptability, of a robust iterative design methodology for the platform services that is anchored on requirements of an underlying Service Oriented Architecture that has been designed to be scalable and adaptable, EHR4CR could be well placed to deliver a sound, useful and well accepted pan-European solution for the reuse of hospital EHR data to support clinical research studies., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Although much information is already available publically from information-sharing initiatives such as ClinicalTrials.gov, information about clinical programs is unstructured, inconsistent, and incomplete. Clinical research within bioscience companies, health care, academia, and governmental agencies could benefit from easier access to best practices, historical information, and improved information sharing. Facilitating information sharing requires a standardized information model. Information standards today focus on individual clinical trials and the representation of clinical trial data. Although work is ongoing to expand standards to cover the protocol, these are insufficient to capture the objectives, rationale, and design thinking behind clinical programs. An information model is proposed to cover the rationalization and decision-making aspects of designing a clinical program and its associated trials. This paper is the output of a newly formed multicompany working group that examines the merits of a clinical program-level information standard. An example information model is presented to explain the concept.

Clinical research is on the threshold of a new era in which electronic health records (EHRs) are gaining an important novel supporting role. Whilst EHRs used for routine clinical care have some limitations at present, as discussed in this review, new improved systems and emerging research infrastructures are being developed to ensure that EHRs can be used for secondary purposes such as clinical research, including the design and execution of clinical trials for new medicines. EHR systems should be able to exchange information through the use of recently published international standards for their interoperability and clinically validated information structures (such as archetypes and international health terminologies), to ensure consistent and more complete recording and sharing of data for various patient groups. Such systems will counteract the obstacles of differing clinical languages and styles of documentation as well as the recognized incompleteness of routine records. Here, we discuss some of the legal and ethical concerns of clinical research data reuse and technical security measures that can enable such research while protecting privacy. In the emerging research landscape, cooperation infrastructures are being built where research projects can utilize the availability of patient data from federated EHR systems from many different sites, as well as in international multilingual settings. Amongst several initiatives described, the EHR4CR project offers a promising method for clinical research. One of the first achievements of this project was the development of a protocol feasibility prototype which is used for finding patients eligible for clinical trials from multiple sources., (© 2013 The Association for the Publication of the Journal of Internal Medicine.)

It is unclear how cognitive impairment in multiple sclerosis (MS) is influenced by physical disability, fatigue, and depression. Our aim was to identify the strongest clinical predictors for cognitive impairment in relapsing-remitting MS (RRMS) patients. The clinical risk factors included in the analysis were physical disability (EDSS), fatigue (FSS), the somatic and nonsomatic components of depression (BDI), disease progression rate [Multiple Sclerosis Severity Score (MSSS)], and psychotropic medication. Cognitive impairment had a prevalence of 30.5% in patients affecting preferentially attention, executive functions, processing speed and visual perception/organization. MSSS was not associated with cognitive impairment, depression, or fatigue. In regression models, cognitive performance was best predicted by the nonsomatic symptoms of depression alone or in combination with physical disability. Exclusion of patients with any psychotropic medication did not influence the results. Our results underscore the importance of evaluating depressive symptoms when suspecting cognitive impairment in patients with RRMS.

Exposure measurements should be performed as close as possible to the nose and mouth for a more correct assessment of exposure. User-friendly sampling equipment, with a minimum of handling before, during and after measurement, should not affect ordinary work. In diffusive (passive) sampling, no extra equipment as sampling pumps is needed, making the measurements more acceptable to the user. The diffusive samplers are normally attached on a shoulder, on a breast-pocket or on the lapel. There are, however, difficulties if true breathing-zone sampling is to be performed, since available diffusive samplers normally cannot be arranged close to the nose/mouth. The purpose of this work was to study the performance of a miniaturized tube type diffusive sampler attached to a headset for true breathing-zone sampling. The basis for this miniaturization was the Perkin Elmer ATD tube. Both the size of the tube and the amount of adsorbent was decreased for the miniaturized sampler. A special tube holder to be used with a headset was designed for the mini tube. The mini tube is thermally desorbed inside a standard PE tube. The new sampler was evaluated for the determination of styrene, both in laboratory experiments and in field measurements. As reference method, diffusive sampling with standard Perkin Elmer tubes, thermal desorption and gas chromatographic (GC) analysis was used. The sampling rate was determined to 0.356 mL min(-1) (CV 9.6%) and was not significantly affected by concentration, sampling time or relative humidity.

The aim of this study was to investigate the relation between two toxic volatile organic compounds, 1,3-butadiene and benzene, and a commonly used indicator of vehicle exhaust fumes, NO(2). This was to see if NO(2) can be used to indicate personal exposure to carcinogenic substances or at least estimate ambient levels measured at a stationary point. During the winter of 2001, 40 randomly selected persons living in the City of Umea (in the north of Sweden) were recruited to the study. Personal measurements of 1,3-butadiene, benzene and NO(2) were performed for one week, and were repeated for 20 of the 40 participants. Additional information was gathered using a diary kept by each participant. During the same time period weekly stationary measurements were performed at one urban background station and one street station in the city centre. The results from the personal measurements showed a negligible association of NO(2) with 1,3-butadiene (r= 0.06) as well as with benzene (r= 0.10), while the correlation coefficient between 1,3-butadiene and benzene was high and significant (r= 0.67). In contrast to the personal measurements, the stationary measurements showed strong relations between 1,3-butadiene, benzene and NO(2) both within and in-between the street and urban background station. This study supports NO(2) as a potential indicator for 1,3-butadiene and benzene levels in streets or urban background air, while the weak relations found for the personal measurements do not support the use of NO(2) as an indicator for personal 1,3-butadiene and benzene exposure.

Diffusive samplers for monitoring of air quality are user-friendly devices that can normally be operated by the user himself. Hence these samplers are suitable for self-assessment. Practical and work organisational aspects of self-assessment of chemical exposure were studied in different occupational settings. It was found that the diffusive sampler used in these studies, the Perkin-Elmer tube in combination with thermal desorption, worked well for the purpose and could be correctly handled by the individuals using it. The results from self-assessments agreed well with expert measurements carried out by an occupational hygienist. However, in order to obtain a sustainable system of self-assessment strong organizational support is needed.

A system for fiber-optic probing in dissolution testing of solid pharmaceutical formulations has been constructed. The system is based on an imaging spectrometer and a charged coupled device (CCD) detector and includes 12 fiber-optic probes with a novel dual-path design. UV light was produced by a small arc deuterium lamp illuminating an optical fiber bundle. Twelve fiber-optic dipping probes were constructed with a reflection geometry. A 5 mm diameter lens was used to achieve a parallel light beam. The light passed back and forth through the flow-through cuvette defined by a sapphire window and a coated aluminium mirror. The mirror was cut in half and each segment was tilted and set at different distances from the window to obtain two separate paths with different lengths. Two receiver fibers were used for each probe to collect the transmitted light. The 24 receiver fibers from the 12 probes were bunched to a linear bundle and fed to an imaging spectrometer and the corresponding spectra were detected with a 512 x 512 pixel cooled CCD detector. The sampling interval was typically a few seconds for all probes. A software package was developed for data recording and on-line analysis. The program includes tools for multi-component analysis. The system was tested for different tablet formulations. Prednisone 50 mg tablets, normally used for control tests of dissolution baths, were followed for 3 h. Secondly, an extended release low dosage tablet was followed for 7 h resulting in a linear dissolution profile. Finally, a combination tablet containing two active drugs was tested for 60 min profiles. In the latter case, separate dissolution curves for the two active components were obtained. Future work will mainly focus on further development of the multi-component capability of the system.

In this study three different types of samplers for the determination of 1,6-hexamethylene diisocyanate in air were compared. The experimental set up was a simulation of real life conditions with spray painting operations performed inside a commercial, full sized, spray box. The sampling methods were 1-(2-methoxyphenyl)-piperazine impregnated on glass fibre filter, and the same reagent in impinger, and also dibutylamine in impinger. All analyses were performed by LC-MS-MS. The determined concentrations varied between 20 and 90 microg m(-3) with relative standard deviations from 7 to 17% for each method. No significant difference was found between the three methods using ANOVA with a significance level of alpha = 0.05.

Tube type samplers with two different adsorbents, Chromosorb 106 and Tenax TA, were evaluated by laboratory experiments and field tests for simultaneous diffusive sampling of alpha-pinene, beta-pinene and delta 3-carene and subsequent thermal desorption-gas chromatographic analysis. No statistically significant effects of exposure time, concentrations of monoterpenes or relative humidity were found for samplers with Chromosorb 106 when running a factorial design, with the exception of the adsorption of delta 3-carene, for which some weak effects were noted. Samplers with Tenax TA were affected by the sampling time as well as the concentration for all terpenes, with a strong interaction effect between these two factors. The terpenes showed good storage stability on both adsorbents. No effect of back-diffusion was noted when using Chromosorb 106, while Tenax TA showed some back-diffusion effects. The uptake rates, in ml min-1, for the terpenes on Chromosorb 106 were 0.36 for alpha-pinene, 0.36 for beta-pinene and 0.40 for delta 3-carene. The corresponding average values on Tenax TA were 0.30 for alpha-pinene, 0.32 for beta-pinene and 0.38 for delta 3-carene. The field validation proved that diffusive sampling on Chromosorb 106 agreed well with pumped sampling on charcoal for stationary samples, while the personal samples indicated a discrepancy of 25% between Chromosorb 106 and charcoal samples. Tenax TA generally gave lower results than Chromosorb 106 in all field samples. Samplers packed with Chromosorb 106 could be used to monitor terpene levels in workplaces such as sawmills. The major advantages with this method are the sampling procedure, which is simple to perform compared to other techniques, the easily automated analysis procedure and the possibility to reuse the samplers.

The formation of morphine from codeine and ethylmorphine is mainly mediated by the polymorphic enzyme CYP2D6. The objective of this study was to investigate whether CYP2D6 poor metabolizers (PM) and CYP2D6 extensive metabolizers (EM) would respond differently during testing for opiate drugs of abuse in urine after intake of these drugs. Five PM and five EM of dextromethorphan were administered single oral doses of codeine (25 mg) and ethylmorphine (25 mg), and the urinary excretion of parent compounds and selected metabolites was observed for 72 hours. Analysis was performed with GC-MS after hydrolysis of the glucuronide conjugates. Selected urine samples were screened for the presence of opiates by the Abbott ADx immunoassay method. The results from one PM and one EM were excluded because of technical analytical problems. EM excreted significantly more morphine than PM after intake of both codeine (6.5% vs. 1.1% of the dose; p < 0.05) and ethylmorphine (11.0% vs. 3.0% of the dose; p < 0.05). Screening results were positive significantly longer for EM than for PM after codeine intake (mean, 33 hours vs. 17 hours; p < 0.05), and the same trend, albeit nonsignificantly, was noted for ethylmorphine (mean, 33 hours vs. 24 hours). Regardless of CYP2D6 phenotype, significantly more morphine was formed after intake of ethylmorphine than after intake of codeine (7.0% vs. 3.8% of the dose; p < 0.05). There were high correlations between dextromethorphan metabolic ratios and the ratios of codeine to morphine, ethylmorphine to morphine, norcodeine to normorphine, and norethylmorphine to normorphine (r = 0.80 to 0.92; p = 0.030 to 0.001). Although this study should be interpreted with caution because of the few subjects included and the single-dose design, it demonstrates that the CYP2D6 phenotype clearly affects the results when testing for opiates in urine after intake of codeine and ethylmorphine.

The gastrointestinal transit and tablet erosion of felodipine extended release (ER) tablets 10 mg were studied by gamma scintigraphy in eight healthy young males after administration under fasting and nonfasting conditions. Plasma concentrations of felodipine were also measured. Gastric emptying after administration together with food (mean, 3.2 hr) was slower in all subjects compared to emptying under fasting conditions (mean, 0.6 hr). The mean small intestinal transit times for the two study conditions did not differ significantly (5.1 and 4.7 hr, respectively). Tablets did not leave the colon in any subject within 14 hr after administration. Felodipine was shown to be absorbed in the colon, although the major part of the dose was absorbed in the small intestine. The absorption rate of felodipine was related to erosion of the hydrophilic matrix tablet. Tablet erosion and hence drug absorption were slower in the more distal parts of the gastrointestinal tract. Administration together with food did not significantly affect tablet erosion.

A flow injection analysis (FIA) extraction method has been developed for the analysis of felodipine tablets in connection with dissolution rate testing. The water-soluble oxidation product of felodipine, a pyridine derivative, was extracted into chloroform and measured at 275 nm spectrophotometrically. The FIA-extraction method has been compared with the present liquid chromatographic (LC) method. The sampling rate for the FIA-extraction (60 samples h-1) is 5 times higher than for the LC method. The FIA-extraction method has a standard deviation of 1% for both standards and samples which is the same as for the LC method.