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The first drugs discovered using DNA-encoded chemical library (DEL) screens have entered late-stage clinical development. However, DEL technology as a whole still suffers from poor chemical purity resulting in suboptimal performance. In this work, we report a technique to overcome this issue through self-purifying release of the DEL after magnetic bead-based synthesis. Both the first and last building blocks of each assembled library member were linked to the beads by tethers that could be cleaved by mutually orthogonal chemistry. Sequential cleavage of the first and last tether, with washing in between, ensured that the final library comprises only the fully complete compounds. The outstanding purity attained by this approach enables a direct correlation of chemical display and encoding, allows for an increased chemical reaction scope, and facilitates the use of more diversity elements while achieving greatly improved signal-to-noise ratios in selections.

Introduction: Arterial spin labeling (ASL) is a functional neuroimaging technique that has been frequently used to investigate acute pain states. A major advantage of ASL as opposed to blood-oxygen-level-dependent functional neuroimaging is its applicability for low-frequency designs. As such, ASL represents an interesting option for studies in which repeating an experimental event would reduce its ecological validity. Whereas most ASL pain studies so far have used thermal stimuli, to our knowledge, no ASL study so far has investigated pain responses to sharp mechanical pain., Methods: As a proof of concept, we investigated whether ASL has the sensitivity to detect brain activation within core areas of the nociceptive network in healthy controls following a single stimulation block based on 96 s of mechanical painful stimulation using a blunt blade., Results: We found significant increases in perfusion across many regions of the nociceptive network such as primary and secondary somatosensory cortices, premotor cortex, posterior insula, inferior parietal cortex, parietal operculum, temporal gyrus, temporo-occipital lobe, putamen, and the cerebellum. Contrary to our hypothesis, we did not find any significant increase within ACC, thalamus, or PFC. Moreover, we were able to detect a significant positive correlation between pain intensity ratings and pain-induced perfusion increase in the posterior insula., Conclusion: We demonstrate that ASL is suited to investigate acute pain in a single event paradigm, although to detect activation within some regions of the nociceptive network, the sensitivity of our paradigm seemed to be limited. Regarding the posterior insula, our paradigm was sensitive enough to detect a correlation between pain intensity ratings and pain-induced perfusion increase. Previous experimental pain studies have proposed that intensity coding in this region may be restricted to thermal stimulation. Our result demonstrates that the posterior insula encodes intensity information for mechanical stimuli as well., (© 2021 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

We leveraged the largely untapped resource of electronic health record data to address critical clinical and epidemiological questions about Coronavirus Disease 2019 (COVID-19). To do this, we formed an international consortium (4CE) of 96 hospitals across five countries (www.covidclinical.net). Contributors utilized the Informatics for Integrating Biology and the Bedside (i2b2) or Observational Medical Outcomes Partnership (OMOP) platforms to map to a common data model. The group focused on temporal changes in key laboratory test values. Harmonized data were analyzed locally and converted to a shared aggregate form for rapid analysis and visualization of regional differences and global commonalities. Data covered 27,584 COVID-19 cases with 187,802 laboratory tests. Case counts and laboratory trajectories were concordant with existing literature. Laboratory tests at the time of diagnosis showed hospital-level differences equivalent to country-level variation across the consortium partners. Despite the limitations of decentralized data generation, we established a framework to capture the trajectory of COVID-19 disease in patients and their response to interventions., Competing Interests: Competing interestsR.B. and A.M. are shareholders of Biomeris s.r.l., (© The Author(s) 2020.)

Ventilation heterogeneity is frequent in bronchial asthma and can be assessed using multiple breath wash-out testing (MBW). Most data is available in paediatric patients and using nitrogen as a tracer gas. We aimed to evaluate sulphur hexafluoride (SF 6 ) MBW in adult asthmatics. Spirometry, whole-body plethysmography, impulse oscillometry and SF 6 -MBW were prospectively performed. MBW parameters reflecting global (lung clearance index, LCI), acinar (S acin ) and conductive (S cond ) ventilation heterogeneity were derived from three consecutive wash-outs. LCI was calculated for the traditional 2.5% and an earlier 5% stopping point that has the potential to reduce wash-out times. 91 asthmatics (66%) and 47 non-asthmatic controls (34%) were included in final analysis. LCI 2.5 and LCI 5 were higher in asthmatics (p < 0.001). Likewise, S acin and S cond were elevated (p < 0.001 and p < 0.01). Coefficient of variation was 3.4% for LCI 2.5 and 3.5% for LCI 5 in asthmatics. Forty-one asthmatic patients had normal spirometry. ROC analysis revealed an AUC of 0.906 for the differentiation from non-asthmatic controls exceeding diagnostic performance of individual and conventional parameters (AUC = 0.819, p < 0.05). SF 6 -MBW is feasible and reproducible in adult asthmatics. Ventilation heterogeneity is increased as compared to non-asthmatic controls persisting in asthmatic patients with normal spirometry. Diagnostic performance is not affected using an earlier LCI stopping point while reducing wash-out duration considerably.

This study aimed to investigate whether the differences in pain perception between patients with borderline personality disorder (BPD) and healthy subjects (HCs) can be explained by differences in the glutamate/GABA ratio in the posterior insula. In total, 29 BPD patients and 31 HCs were included in the statistical analysis. Mechanical pain sensitivity was experimentally assessed with pinprick stimuli between 32 and 512 mN on a numeric rating scale. The metabolites were measured in the right posterior insula using the MEshcher-GArwood Point-RESolved Spectroscopy sequence for single-voxel magnetic resonance spectroscopy (1H-MRS). The 256- and the 512-mN pinprick stimuli were perceived as significantly less painful by the BPD patient group compared with HCs. No differences were found between groups for the glutamate/GABA ratios. A positive correlation between the glutamate/GABA ratio and the pain intensity ratings to 256- and 512-mN pinpricks could be found in the combined and in the HC group. In the BPD patient group, the correlations between the glutamate/GABA ratio and the pain intensity ratings to 256- and 512-mN pinpricks did not reach significance. In conclusion, the study showed that individual differences in pain perception may in part be explained by the individual glutamate/GABA ratio in the posterior insula. However, this possible mechanism does not explain the differences in pain perception between BPD patients and HCs.

Introduction: Data quality (DQ) is an important prerequisite for secondary use of electronic health record (EHR) data in clinical research, particularly with regards to progressing towards a learning health system, one of the MIRACUM consortium's goals. Following the successful integration of the i2b2 research data repository in MIRACUM, we present a standardized and generic DQ framework., State of the Art: Already established DQ evaluation methods do not cover all of MIRACUM's requirements., Concept: A data quality analysis plan was developed to assess common data quality dimensions for demographic-, condition-, procedure- and department-related variables of MIRACUM's research data repository., Implementation: A data quality analysis (DQA) tool was developed using R scripts packaged in a Docker image with all the necessary dependencies and R libraries for easy distribution. It integrates with the i2b2 data repository at each MIRACUM site, executes an analysis on the data and generates a DQ report., Lessons Learned: Our DQA tool brings the analysis to the data and thus meets the MIRACUM data protection requirements. It evaluates established DQ dimensions of data repositories in a standardized and easily distributable way. This analysis allowed us to reveal and revise inconsistencies in earlier versions of the ETL jobs. The framework is portable, easy to deploy across different sites and even further adaptable to other database schemes., Conclusion: The presented framework provides the first step towards a unified, standardized and harmonized EHR DQ assessment in MIRACUM. DQ issues can now be systematically identified by individual hospitals to subsequently implement site- or consortium-wide feedback loops to increase data quality.

The Demonstrator study aims to analyse comorbidities and rare diseases among patients from German university hospitals within the German Medical Informatics Initiative. This work aimed to design and determine the feasibility of a model to assess the quality of the claims data used in the study. Several data quality issues were identified affecting small amounts of cases in one of the participating sites. As a next step an extension to all participating sites is planned.