Text-mining in electronic healthcare records can be used as efficient tool for screening and data collection in cardiovascular trials: a multicenter validation study

Objective: This study aimed to validate trial patient eligibility screening and baseline data collection using text-mining in electronic healthcare records (EHRs), comparing the results to those of an international trial. Study Design and Setting: In three medical centers with different EHR vendors, EHR-based text-mining was used to automatically screen patients for trial eligibility and extract baseline data on nineteen characteristics. First, the yield of screening with automated EHR text-mining search was compared with manual screening by research personnel. Second, the accuracy of extracted baseline data by EHR text mining was compared to manual data entry by research personnel. Results: Of the 92,466 patients visiting the out-patient cardiology departments, 568 (0.6%) were enrolled in the trial during its recruitment period using manual screening methods. Automated EHR data screening of all patients showed that the number of patients needed to screen could be reduced by 73,863 (79.9%). The remaining 18,603 (20.1%) contained 458 of the actual participants (82.4% of participants). In trial participants, automated EHR text-mining missed a median of 2.8% (Interquartile range [IQR] across all variables 0.4e8.5%) of all data points compared to manually collected data. The overall accuracy of automatically extracted data was 88.0% (IQR 84.7e92.8%). Conclusion: Automatically extracting data from EHRs using text-mining can be used to identify trial participants and to collect baseline informatio

Altered spin state equilibrium in the T309V mutant of cytochrome P450 2D6: a spectroscopic and computational study

Cytochrome P450 2D6 (CYP2D6) is one of the most important cytochromes P450 in humans. Resonance Raman data from the T309V mutant of CYP2D6 show that the substitution of the conserved I-helix threonine situated in the enzyme’s active site perturbs the heme spin equilibrium in favor of the six-coordinated low-spin species. A mechanistic hypothesis is introduced to explain the experimental observations, and its compatibility with the available structural and spectroscopic data is tested using quantum-mechanical density functional theory calculations on active-site models for both the CYP2D6 wild type and the T309V mutant

Serial femtosecond crystallography reveals that photoactivation in a fluorescent protein proceeds via the hula twist mechanism

Chromophore cis/trans photoisomerization is a fundamental process in chemistry and in the activation of many photosensitive proteins. A major task is understanding the effect of the protein environment on the efficiency and direction of this reaction compared to what is observed in the gas and solution phases. In this study, we set out to visualize the hula twist (HT) mechanism in a fluorescent protein, which is hypothesized to be the preferred mechanism in a spatially constrained binding pocket. We use a chlorine substituent to break the twofold symmetry of the embedded phenolic group of the chromophore and unambiguously identify the HT primary photoproduct. Through serial femtosecond crystallography, we then track the photoreaction from femtoseconds to the microsecond regime. We observe signals for the photoisomerization of the chromophore as early as 300 fs, obtaining the first experimental structural evidence of the HT mechanism in a protein on its femtosecond-to-picosecond timescale. We are then able to follow how chromophore isomerization and twisting lead to secondary structure rearrangements of the protein β-barrel across the time window of our measurements

GROMEX: A scalable and versatile fast multipole method for biomolecular simulation

Atomistic simulations of large biomolecular systems with chemicalvariability such as constant pH dynamic protonation offer multiple challenges inhigh performance computing. One of them is the correct treatment of the involvedelectrostatics in an efficient and highly scalable way. Here we review and assess twoof the main building blocks that will permit such simulations: (1) An electrostaticslibrary based on the Fast Multipole Method (FMM) that treats local alternativecharge distributions with minimal overhead, and (2) Aλ-dynamics module workingin tandem with the FMM that enables various types of chemical transitions duringthe simulation. Ourλ-dynamics and FMM implementations do not rely on third-party libraries but are exclusively using C++ language features and they aretailored to the specific requirements of molecular dynamics simulation suites suchas GROMACS. The FMM library supports fractional tree depths and allows forrigorous error control and automatic performance optimization at runtime. Near-optimal performance is achieved on various SIMD architectures and on GPUsusing CUDA. For exascale systems, we expect our approach to outperform currentimplementations based on Particle MeshEwald (PME) electrostatics, becauseFMM avoids the communication bottlenecks caused by the parallel fast Fouriertransformations needed for PME