Neural network emulation of the human ventricular cardiomyocyte action potential for more efficient computations in pharmacological studies

Computer models of the human ventricular cardiomyocyte action potential (AP) have reached a level of detail and maturity that has led to an increasing number of applications in the pharmaceutical sector. However, interfacing the models with experimental data can become a significant computational burden. To mitigate the computational burden, the present study introduces a neural network (NN) that emulates the AP for given maximum conductances of selected ion channels, pumps, and exchangers. Its applicability in pharmacological studies was tested on synthetic and experimental data. The NN emulator potentially enables massive speed-ups compared to regular simulations and the forward problem (find drugged AP for pharmacological parameters defined as scaling factors of control maximum conductances) on synthetic data could be solved with average root-mean-square errors (RMSE) of 0.47 mV in normal APs and of 14.5 mV in abnormal APs exhibiting early afterdepolarizations (72.5% of the emulated APs were alining with the abnormality, and the substantial majority of the remaining APs demonstrated pronounced proximity). This demonstrates not only very fast and mostly very accurate AP emulations but also the capability of accounting for discontinuities, a major advantage over existing emulation strategies. Furthermore, the inverse problem (find pharmacological parameters for control and drugged APs through optimization) on synthetic data could be solved with high accuracy shown by a maximum RMSE of 0.22 in the estimated pharmacological parameters. However, notable mismatches were observed between pharmacological parameters estimated from experimental data and distributions obtained from the Comprehensive in vitro Proarrhythmia Assay initiative. This reveals larger inaccuracies which can be attributed particularly to the fact that small tissue preparations were studied while the emulator was trained on single cardiomyocyte data. Overall, our study highlights the potential of NN emulators as powerful tool for an increased efficiency in future quantitative systems pharmacology studies

Structure of Dark Triad Dirty Dozen Across Eight World Regions

The Dark Triad (i.e., narcissism, psychopathy, Machiavellianism) has garnered intense attention over the past 15 years. We examined the structure of these traits’ measure—the Dark Triad Dirty Dozen (DTDD)—in a sample of 11,488 participants from three W.E.I.R.D. (i.e., North America, Oceania, Western Europe) and five non-W.E.I.R.D. (i.e., Asia, Middle East, non-Western Europe, South America, sub-Saharan Africa) world regions. The results confirmed the measurement invariance of the DTDD across participants’ sex in all world regions, with men scoring higher than women on all traits (except for psychopathy in Asia, where the difference was not significant). We found evidence for metric (and partial scalar) measurement invariance within and between W.E.I.R.D. and non-W.E.I.R.D. world regions. The results generally support the structure of the DTDD

First Sagittarius A* Event Horizon Telescope results. II. EHT and multiwavelength observations, data processing, and calibration

We present Event Horizon Telescope (EHT) 1.3 mm measurements of the radio source located at the position of the supermassive black hole Sagittarius A* (Sgr A*), collected during the 2017 April 5–11 campaign. The observations were carried out with eight facilities at six locations across the globe. Novel calibration methods are employed to account for Sgr A*'s flux variability. The majority of the 1.3 mm emission arises from horizon scales, where intrinsic structural source variability is detected on timescales of minutes to hours. The effects of interstellar scattering on the image and its variability are found to be subdominant to intrinsic source structure. The calibrated visibility amplitudes, particularly the locations of the visibility minima, are broadly consistent with a blurred ring with a diameter of ∼50 μas, as determined in later works in this series. Contemporaneous multiwavelength monitoring of Sgr A* was performed at 22, 43, and 86 GHz and at near-infrared and X-ray wavelengths. Several X-ray flares from Sgr A* are detected by Chandra, one at low significance jointly with Swift on 2017 April 7 and the other at higher significance jointly with NuSTAR on 2017 April 11. The brighter April 11 flare is not observed simultaneously by the EHT but is followed by a significant increase in millimeter flux variability immediately after the X-ray outburst, indicating a likely connection in the emission physics near the event horizon. We compare Sgr A*'s broadband flux during the EHT campaign to its historical spectral energy distribution and find that both the quiescent emission and flare emission are consistent with its long-term behavior.http://iopscience.iop.org/2041-8205Physic

First Sagittarius A* Event Horizon Telescope Results. II. EHT and Multiwavelength Observations, Data Processing, and Calibration

We present Event Horizon Telescope (EHT) 1.3 mm measurements of the radio source located at the position of the supermassive black hole Sagittarius A* (Sgr A*), collected during the 2017 April 5–11 campaign. The observations were carried out with eight facilities at six locations across the globe. Novel calibration methods are employed to account for Sgr A*'s flux variability. The majority of the 1.3 mm emission arises from horizon scales, where intrinsic structural source variability is detected on timescales of minutes to hours. The effects of interstellar scattering on the image and its variability are found to be subdominant to intrinsic source structure. The calibrated visibility amplitudes, particularly the locations of the visibility minima, are broadly consistent with a blurred ring with a diameter of ∼50 μas, as determined in later works in this series. Contemporaneous multiwavelength monitoring of Sgr A* was performed at 22, 43, and 86 GHz and at near-infrared and X-ray wavelengths. Several X-ray flares from Sgr A* are detected by Chandra, one at low significance jointly with Swift on 2017 April 7 and the other at higher significance jointly with NuSTAR on 2017 April 11. The brighter April 11 flare is not observed simultaneously by the EHT but is followed by a significant increase in millimeter flux variability immediately after the X-ray outburst, indicating a likely connection in the emission physics near the event horizon. We compare Sgr A*’s broadband flux during the EHT campaign to its historical spectral energy distribution and find that both the quiescent emission and flare emission are consistent with its long-term behavior

Impact of Different Approaches to Preparing Notes for Analysis With Natural Language Processing on the Performance of Prediction Models in Intensive Care.

To evaluate whether different approaches in note text preparation (known as preprocessing) can impact machine learning model performance in the case of mortality prediction ICU.DesignClinical note text was used to build machine learning models for adults admitted to the ICU. Preprocessing strategies studied were none (raw text), cleaning text, stemming, term frequency-inverse document frequency vectorization, and creation of n-grams. Model performance was assessed by the area under the receiver operating characteristic curve. Models were trained and internally validated on University of California San Francisco data using 10-fold cross validation. These models were then externally validated on Beth Israel Deaconess Medical Center data.SettingICUs at University of California San Francisco and Beth Israel Deaconess Medical Center.SubjectsTen thousand patients in the University of California San Francisco training and internal testing dataset and 27,058 patients in the external validation dataset, Beth Israel Deaconess Medical Center.InterventionsNone.Measurements and main resultsMortality rate at Beth Israel Deaconess Medical Center and University of California San Francisco was 10.9% and 7.4%, respectively. Data are presented as area under the receiver operating characteristic curve (95% CI) for models validated at University of California San Francisco and area under the receiver operating characteristic curve for models validated at Beth Israel Deaconess Medical Center. Models built and trained on University of California San Francisco data for the prediction of inhospital mortality improved from the raw note text model (AUROC, 0.84; CI, 0.80-0.89) to the term frequency-inverse document frequency model (AUROC, 0.89; CI, 0.85-0.94). When applying the models developed at University of California San Francisco to Beth Israel Deaconess Medical Center data, there was a similar increase in model performance from raw note text (area under the receiver operating characteristic curve at Beth Israel Deaconess Medical Center: 0.72) to the term frequency-inverse document frequency model (area under the receiver operating characteristic curve at Beth Israel Deaconess Medical Center: 0.83).ConclusionsDifferences in preprocessing strategies for note text impacted model discrimination. Completing a preprocessing pathway including cleaning, stemming, and term frequency-inverse document frequency vectorization resulted in the preprocessing strategy with the greatest improvement in model performance. Further study is needed, with particular emphasis on how to manage author implicit bias present in note text, before natural language processing algorithms are implemented in the clinical setting

Impact of Different Approaches to Preparing Notes for Analysis With Natural Language Processing on the Performance of Prediction Models in Intensive Care.

To evaluate whether different approaches in note text preparation (known as preprocessing) can impact machine learning model performance in the case of mortality prediction ICU.DesignClinical note text was used to build machine learning models for adults admitted to the ICU. Preprocessing strategies studied were none (raw text), cleaning text, stemming, term frequency-inverse document frequency vectorization, and creation of n-grams. Model performance was assessed by the area under the receiver operating characteristic curve. Models were trained and internally validated on University of California San Francisco data using 10-fold cross validation. These models were then externally validated on Beth Israel Deaconess Medical Center data.SettingICUs at University of California San Francisco and Beth Israel Deaconess Medical Center.SubjectsTen thousand patients in the University of California San Francisco training and internal testing dataset and 27,058 patients in the external validation dataset, Beth Israel Deaconess Medical Center.InterventionsNone.Measurements and main resultsMortality rate at Beth Israel Deaconess Medical Center and University of California San Francisco was 10.9% and 7.4%, respectively. Data are presented as area under the receiver operating characteristic curve (95% CI) for models validated at University of California San Francisco and area under the receiver operating characteristic curve for models validated at Beth Israel Deaconess Medical Center. Models built and trained on University of California San Francisco data for the prediction of inhospital mortality improved from the raw note text model (AUROC, 0.84; CI, 0.80-0.89) to the term frequency-inverse document frequency model (AUROC, 0.89; CI, 0.85-0.94). When applying the models developed at University of California San Francisco to Beth Israel Deaconess Medical Center data, there was a similar increase in model performance from raw note text (area under the receiver operating characteristic curve at Beth Israel Deaconess Medical Center: 0.72) to the term frequency-inverse document frequency model (area under the receiver operating characteristic curve at Beth Israel Deaconess Medical Center: 0.83).ConclusionsDifferences in preprocessing strategies for note text impacted model discrimination. Completing a preprocessing pathway including cleaning, stemming, and term frequency-inverse document frequency vectorization resulted in the preprocessing strategy with the greatest improvement in model performance. Further study is needed, with particular emphasis on how to manage author implicit bias present in note text, before natural language processing algorithms are implemented in the clinical setting