ANT2681: SAR Studies Leading to the Identification of a Metallo-ß-lactamase Inhibitor with Potential for Clinical Use in Combination with Meropenem for the Treatment of Infections Caused by NDM-Producing Enterobacteriaceae.

The clinical effectiveness of the important ß-lactam class of antibiotics is under threat by the emergence of resistance, mostly due to the production of acquired serine- (SBL) and metallo-ß-lactamase (MBL) enzymes. To address this resistance issue, multiple ß-lactam/ß-lactamase inhibitor combinations have been successfully introduced into the clinic over the past several decades. However, all of those combinations contain SBL inhibitors and, as yet, there are no MBL inhibitors in clinical use. Consequently, there exists an unaddressed yet growing healthcare problem due to the rise in recent years of highly resistant strains which produce New Delhi metallo (NDM)-type metallo-carbapenemases. Previously, we reported the characterization of an advanced MBL inhibitor lead compound, ANT431. Herein, we discuss the completion of a lead optimization campaign culminating in the discovery of the preclinical candidate ANT2681, a potent NDM inhibitor with strong potential for clinical development.

Smartphone-Based Blood Pressure Measurement Using Transdermal Optical Imaging Technology.

BACKGROUND: Cuff-based blood pressure measurement lacks comfort and convenience. Here, we examined whether blood pressure can be determined in a contactless manner using a novel smartphone-based technology called transdermal optical imaging. This technology processes imperceptible facial blood flow changes from videos captured with a smartphone camera and uses advanced machine learning to determine blood pressure from the captured signal. METHODS: We enrolled 1328 normotensive adults in our study. We used an advanced machine learning algorithm to create computational models that predict reference systolic, diastolic, and pulse pressure from facial blood flow data. We used 70% of our data set to train these models and 15% of our data set to test them. The remaining 15% of the sample was used to validate model performance. RESULTS: We found that our models predicted blood pressure with a measurement bias±SD of 0.39±7.30 mm Hg for systolic pressure, -0.20±6.00 mm Hg for diastolic pressure, and 0.52±6.42 mm Hg for pulse pressure, respectively. CONCLUSIONS: Our results in normotensive adults fall within 5±8 mm Hg of reference measurements. Future work will determine whether these models meet the clinically accepted accuracy threshold of 5±8 mm Hg when tested on a full range of blood pressures according to international accuracy standards.

Perception and Modeling of Affective Qualities of Musical Instrument Sounds across Pitch Registers.

Composers often pick specific instruments to convey a given emotional tone in their music, partly due to their expressive possibilities, but also due to their timbres in specific registers and at given dynamic markings. Of interest to both music psychology and music informatics from a computational point of view is the relation between the acoustic properties that give rise to the timbre at a given pitch and the perceived emotional quality of the tone. Musician and nonmusician listeners were presented with 137 tones produced at a fixed dynamic marking (forte) playing tones at pitch class D# across each instrument's entire pitch range and with different playing techniques for standard orchestral instruments drawn from the brass, woodwind, string, and pitched percussion families. They rated each tone on six analogical-categorical scales in terms of emotional valence (positive/negative and pleasant/unpleasant), energy arousal (awake/tired), tension arousal (excited/calm), preference (like/dislike), and familiarity. Linear mixed models revealed interactive effects of musical training, instrument family, and pitch register, with non-linear relations between pitch register and several dependent variables. Twenty-three audio descriptors from the Timbre Toolbox were computed for each sound and analyzed in two ways: linear partial least squares regression (PLSR) and nonlinear artificial neural net modeling. These two analyses converged in terms of the importance of various spectral, temporal, and spectrotemporal audio descriptors in explaining the emotion ratings, but some differences also emerged. Different combinations of audio descriptors make major contributions to the three emotion dimensions, suggesting that they are carried by distinct acoustic properties. Valence is more positive with lower spectral slopes, a greater emergence of strong partials, and an amplitude envelope with a sharper attack and earlier decay. Higher tension arousal is carried by brighter sounds, more spectral variation and more gentle attacks. Greater energy arousal is associated with brighter sounds, with higher spectral centroids and slower decrease of the spectral slope, as well as with greater spectral emergence. The divergences between linear and nonlinear approaches are discussed.

Modeling Music Emotion Judgments Using Machine Learning Methods.

Emotion judgments and five channels of physiological data were obtained from 60 participants listening to 60 music excerpts. Various machine learning (ML) methods were used to model the emotion judgments inclusive of neural networks, linear regression, and random forests. Input for models of perceived emotion consisted of audio features extracted from the music recordings. Input for models of felt emotion consisted of physiological features extracted from the physiological recordings. Models were trained and interpreted with consideration of the classic debate in music emotion between cognitivists and emotivists. Our models supported a hybrid position wherein emotion judgments were influenced by a combination of perceived and felt emotions. In comparing the different ML approaches that were used for modeling, we conclude that neural networks were optimal, yielding models that were flexible as well as interpretable. Inspection of a committee machine, encompassing an ensemble of networks, revealed that arousal judgments were predominantly influenced by felt emotion, whereas valence judgments were predominantly influenced by perceived emotion.

Predicting musically induced emotions from physiological inputs: linear and neural network models.

Listening to music often leads to physiological responses. Do these physiological responses contain sufficient information to infer emotion induced in the listener? The current study explores this question by attempting to predict judgments of "felt" emotion from physiological responses alone using linear and neural network models. We measured five channels of peripheral physiology from 20 participants-heart rate (HR), respiration, galvanic skin response, and activity in corrugator supercilii and zygomaticus major facial muscles. Using valence and arousal (VA) dimensions, participants rated their felt emotion after listening to each of 12 classical music excerpts. After extracting features from the five channels, we examined their correlation with VA ratings, and then performed multiple linear regression to see if a linear relationship between the physiological responses could account for the ratings. Although linear models predicted a significant amount of variance in arousal ratings, they were unable to do so with valence ratings. We then used a neural network to provide a non-linear account of the ratings. The network was trained on the mean ratings of eight of the 12 excerpts and tested on the remainder. Performance of the neural network confirms that physiological responses alone can be used to predict musically induced emotion. The non-linear model derived from the neural network was more accurate than linear models derived from multiple linear regression, particularly along the valence dimension. A secondary analysis allowed us to quantify the relative contributions of inputs to the non-linear model. The study represents a novel approach to understanding the complex relationship between physiological responses and musically induced emotion.