Thompson Sampling─An Efficient Method for Searching Ultralarge Synthesis on Demand Databases.

Over the last five years, virtual screening of ultralarge synthesis on-demand libraries has emerged as a powerful tool for hit identification in drug discovery programs. As these libraries have grown to tens of billions of molecules, we have reached a point where it is no longer cost-effective to screen every molecule virtually. To address these challenges, several groups have developed heuristic search methods to rapidly identify the best molecules on a virtual screen. This article describes the application of Thompson sampling (TS), an active learning approach that streamlines the virtual screening of large combinatorial libraries by performing a probabilistic search in the reagent space, thereby never requiring the full enumeration of the library. TS is a general technique that can be applied to various virtual screening modalities, including 2D and 3D similarity search, docking, and application of machine-learning models. In an illustrative example, we show that TS can identify more than half of the top 100 molecules from a docking-based virtual screen of 335 million molecules by evaluating 1% of the data set.

Smallest Maximum Intramolecular Distance: A Novel Method to Mitigate Pregnane Xenobiotic Receptor Activation.

Induction of cytochrome P450 isoform 3A4 via activation of the pregnane xenobiotic receptor (PXR) is a concern for pharmaceutical discovery and development, as it can lead to drug-drug interactions. We present a novel molecular descriptor, the smallest maximum intramolecular distance (SMID), which is correlated with PXR activation, and a method for using the SMID descriptor to guide discovery chemists in modifying lead compounds to decrease PXR activation.

Gray Box Optimization for Mk Landscapes (NK Landscapes and MAX-kSAT).

This article investigates Gray Box Optimization for pseudo-Boolean optimization problems composed of M subfunctions, where each subfunction accepts at most k variables. We will refer to these as Mk Landscapes. In Gray Box Optimization, the optimizer is given access to the set of M subfunctions. We prove Gray Box Optimization can efficiently compute hyperplane averages to solve non-deceptive problems in [Formula: see text] time. Bounded separable problems are also solved in [Formula: see text] time. As a result, Gray Box Optimization is able to solve many commonly used problems from the evolutional computation literature in [Formula: see text] evaluations. We also introduce a more general class of Mk Landscapes that can be solved using dynamic programming and discuss properties of these functions. For certain type of problems Gray Box Optimization makes it possible to enumerate all local optima faster than brute force methods. We also provide evidence that randomly generated test problems are far less structured than those found in real-world problems.

Extensive exploration of structure activity relationships for the SARS-CoV-2 macrodomain from shape-based fragment merging and active learning.

The macrodomain contained in the SARS-CoV-2 non-structural protein 3 (NSP3) is required for viral pathogenesis and lethality. Inhibitors that block the macrodomain could be a new therapeutic strategy for viral suppression. We previously performed a large-scale X-ray crystallography-based fragment screen and discovered a sub-micromolar inhibitor by fragment linking. However, this carboxylic acid-containing lead had poor membrane permeability and other liabilities that made optimization difficult. Here, we developed a shape-based virtual screening pipeline - FrankenROCS - to identify new macrodomain inhibitors using fragment X-ray crystal structures. We used FrankenROCS to exhaustively screen the Enamine high-throughput screening (HTS) collection of 2.1 million compounds and selected 39 compounds for testing, with the most potent compound having an IC50 value equal to 130 µM. We then paired FrankenROCS with an active learning algorithm (Thompson sampling) to efficiently search the Enamine REAL database of 22 billion molecules, testing 32 compounds with the most potent having an IC50 equal to 220 µM. Further optimization led to analogs with IC50 values better than 10 µM, with X-ray crystal structures revealing diverse binding modes despite conserved chemical features. These analogs represent a new lead series with improved membrane permeability that is poised for optimization. In addition, the collection of 137 X-ray crystal structures with associated binding data will serve as a resource for the development of structure-based drug discovery methods. FrankenROCS may be a scalable method for fragment linking to exploit ever-growing synthesis-on-demand libraries.

Defining Levels of Automated Chemical Design.

One application area of computational methods in drug discovery is the automated design of small molecules. Despite the large number of publications describing methods and their application in both retrospective and prospective studies, there is a lack of agreement on terminology and key attributes to distinguish these various systems. We introduce Automated Chemical Design (ACD) Levels to clearly define the level of autonomy along the axes of ideation and decision making. To fully illustrate this framework, we provide literature exemplars and place some notable methods and applications into the levels. The ACD framework provides a common language for describing automated small molecule design systems and enables medicinal chemists to better understand and evaluate such systems.

Superwoman's kryptonite: The superwoman schema and perceived barriers to weight management among U.S. Black women.

The role that the superwoman schema (SWS) plays in U.S. Black women's perceptions of barriers (biological, psychological, and sociological) to healthy weight management is unknown. This exploratory study examined whether 122 women classified as normal weight, overweight or obese differed in their perceptions of types of barriers and if the SWS predicted perceived barriers to weight management. Women classified as obese reported more barriers than those classified as normal weight. The SWS uniquely positively predicted perceived psychological and sociological barriers. Our findings suggest that the SWS may play a vital role in the self-management of weight in U.S. Black women.

Outcomes after Surgical Repair of Medial Meniscal Root Tears: A Review.

At the present time, there is a paucity of literature regarding medial meniscal posterior root repair and outcomes. This review seeks to examine the currently available data to further elucidate the clinical risks and benefits and any associated risks of medial meniscal posterior root repair. A systematic literature search was performed up to July 2018 in the databases of Medline via PubMed, EBSCOhost, and EMBASE. The results were reviewed independently by two authors and appropriate articles were reviewed and eligibility determined based on established criteria. The best-evidence synthesis was subsequently used. Thirteen studies (324 patients) were included in this review with a mean patient age of 54 years. There were no control studies with nonoperative treatment of medial meniscal posterior root tears. All studies included a minimum of 10 patients in a case series or case-control manner. Of patients treated with medial meniscal posterior root repair, 62.43% demonstrated complete healing on follow-up magnetic resonance imaging (MRI) or second-look arthroscopy. Among them, 32.60% demonstrated incomplete healing, loosening of the construct, or excessive scar tissues formation. Also, 4.97% demonstrated complete failure or retearing of the construction. At a mean follow-up period of 33 months, patients demonstrated a mean improvement in Lysholm's score of 30.5 (p < 0.00001), International Knee Documentation Committee (IKDC) score of 31.9 (p < 0.00001), and HSS Knee Score of 38.3 (p < .00001). Surgical repair of medial meniscus posterior root tears appears to result in highly satisfying subjective outcomes. Patients included in this review meet criteria for both statistically and clinically significant improvement, based on published guidelines for minimal clinically important difference. Despite this, however, postoperative MRI and second-look arthroscopy demonstrate a relatively high rate of incomplete healing (32.60%) or retearing and failure of the construct (4.97%). More highly powered studies are required to confirm these findings.

Ultrasound Examination Techniques for Elbow Injuries in Overhead Athletes.

Elbow pain is a frequent complaint among overhead athletes. Standard evaluation of the elbow uses history and physical examination, with radiographic imaging and MRI aiding in the confirmation of diagnosis. Musculoskeletal ultrasonography (US) provides dynamic, functional assessment of tendons and ligaments in the elbow, allowing the visualization of structures under stress and motion. Stress US offers the ability to detect injuries to the ulnar collateral ligament by measuring changes in joint space under stress. The freedom of dynamic imaging means results are dependent on the skill of the US operator to obtain the most accurate and complete evaluation. US is cost efficient and portable, allowing for quick examination at the point of care. This article provides a technique guide for sports medicine specialists performing US examination of the elbow.

Within-person relationships among daily self-esteem, need satisfaction, and authenticity.

This study examined the within-person relationships among daily self-esteem, felt authenticity (i.e., the operation of one's "true self"), and satisfaction of psychological needs for autonomy, competence, and relatedness. We also included measures of affect to control for the variance these constructs might share with affect. Over a 2-week period, 116 participants responded daily to measures of these variables. Multilevel random-coefficients modeling revealed that authenticity, autonomy, competence, and relatedness were all positively and significantly related to daily reports of self-esteem, even when we controlled for the contributions of pleasant and unpleasant affect. We discuss the roles of authenticity and psychological needs in daily feelings of self-worth.

Non-medical use of prescription opioids and public health in Canada: an urgent call for research and interventions development.

While the public health problem of psychoactive drug use is well recognized, the emerging phenomenon of non-medical use of prescription opioids has been largely ignored in Canada. Most evidence on this issue and related harms in North America to date come from the United States (US), where the prevalence of non-medical opioid use in key populations, as well as related morbidity and mortality, recently have risen substantially. Also, given the increases in the overall consumption of prescription opioids similar to those in the US, a substantial expansion of problems related to non-medical opioid use appears to be occurring in Canada. For example, recent major increases in the use of prescription opioids--rather than heroin--are documented for street drug users in Canadian cities. However, a comprehensive assessment of the problem of non-medical prescription opioid use is hindered by the spotty--or absent--nature of crucial indicators and data. We urge that the necessary efforts and resources for systematic assessment of the evolving phenomenon of non-medical opioid use and its key facets be established in Canada, and that policy-makers implement sensible intervention strategies targeting this problem within a public health framework, specifically avoiding unintended negative consequences (e.g., undermining access to pain treatment).

Mindfulness as a means of reducing aggressive behavior: dispositional and situational evidence.

Recent research and theory suggest that mindfulness, or enhanced attention and awareness in the present moment [Brown and Ryan, 2003], may be linked to lower levels of ego-involvement and, as a result, may have implications for lowering hostility and aggressive behavior. Accordingly, we conducted two studies to examine the potential aggression-mitigating role of mindfulness. In Study 1, we found that dispositional mindfulness correlated negatively with self-reported aggressiveness and hostile attribution bias. In Study 2, participants made mindful before receiving social rejection feedback displayed less-aggressive behavior than did rejected participants not made mindful. Discussion centers on potential mechanisms by which mindfulness operates to reduce aggressive behavior.

Early clinical cxperience with the SIGN hip construct: a retrospective case series.

BACKGROUND: As the population ages, the developing world industrializes, and more urban centers emerge, the burden of orthopedic trauma will steadily increase. SIGN Fracture Care International has developed a unique intramedullary device for fixation of hip fractures in low-resource settings lacking fluoroscopy. The purpose of this study is to report the safety profile and complication rate for a consecutive series of hip fracture patients managed using this implant. METHODS: We conducted a retrospective analysis of the first 170 patients treated with the SIGN Hip Construct (SHC) from 2009 to 2014 using the SIGN Online Surgical Database (SOSD). Patients with follow-up greater than 12 weeks and adequate radiographs were included. Data recorded include patient demographics, time-to-surgery, union rate, AO/OTA classification, complications, neck-shaft angle, and clinical outcomes including painless weight bearing and knee flexion greater than 90°. RESULTS: Of 170 patients, 71 met inclusion criteria with mean follow-up of 39 weeks. Mean age was 49.5 and by WHO, regions were Africa (27), Eastern Mediterranean (21), Western Pacific (17), Americas (3), and Southeast Asia (3). Fractures included intertrochanteric (55), subtrochanteric (7), femoral neck (4), and combined (5). Reduction quality was good in 35 (49%), acceptable in 19 (27%), and poor in 17 (24%). Major complications consisted of varus collapse (6), non- or delayed union (3), intra-articular screw (5), and infection (3). Average postoperative neck-shaft angle was 126° and 119.3° at final follow-up. CONCLUSIONS: This is the first comprehensive report of a novel implant for hip fractures specifically designed for low-resource settings. The early clinical data and outcomes suggest that the SHC can be safely inserted in the absence of fluoroscopy, and facilitates early mobilization while maintaining acceptable reduction until union.

Understanding covariate shift in model performance.

Three (3) different methods (logistic regression, covariate shift and k-NN) were applied to five (5) internal datasets and one (1) external, publically available dataset where covariate shift existed. In all cases, k-NN's performance was inferior to either logistic regression or covariate shift. Surprisingly, there was no obvious advantage for using covariate shift to reweight the training data in the examined datasets.

Perceived Physician-informed Weight Status Predicts Accurate Weight Self-Perception and Weight Self-Regulation in Low-income, African American Women.

BACKGROUND: Obese African American women under-appraise their body mass index (BMI) classification and report fewer weight loss attempts than women who accurately appraise their weight status. This cross-sectional study examined whether physician-informed weight status could predict weight self-perception and weight self-regulation strategies in obese women. METHODS: A convenience sample of 118 low-income women completed a survey assessing demographic characteristics, comorbidities, weight self-perception, and weight self-regulation strategies. BMI was calculated during nurse triage. Binary logistic regression models were performed to test hypotheses. RESULTS: The odds of obese accurate appraisers having been informed about their weight status were six times greater than those of under-appraisers. The odds of those using an "approach" self-regulation strategy having been physician-informed were four times greater compared with those using an "avoidance" strategy. DISCUSSION: Physicians are uniquely positioned to influence accurate weight self-perception and adaptive weight self-regulation strategies in underserved women, reducing their risk for obesity-related morbidity.

Non-medical prescription opioid use, prescription opioid-related harms and public health in Canada: an update 5 years later.

Five years ago, we highlighted Canada's emerging problem of prescription opioid (PO)-related harms and emphasized the need for targeted surveillance, research and interventions. Overall levels of PO use in the Canadian population have grown by 70% since then, while at the same time levels of non-medical PO use (NMPOU) in general and in key risk populations have continued to be high; furthermore, PO-related harms - specifically morbidity (e.g., treatment admissions) and mortality (e.g., overdose deaths) - have risen substantively. Unfortunately, major knowledge gaps related to systematic monitoring of PO-related harms continue to exist; for example, no national morbidity or mortality statistics are available. Investigator-driven research has generated important insights into the epidemiology and impacts of PO-related harms: high correlations between population-level PO dispensing and/or PO dosing and harms; high rates of co-occurrence of NMPOU and co-morbidities; and distinct NMPOU-related risk dynamics among street drug users. Select policy measures have been implemented only recently at the federal and provincial levels; these interventions remain to be systematically evaluated, especially given preliminary indications of reductions in PO-related harms (e.g., NMPOU) unfolding prior to the interventions. For these purposes, improvements in surveillance tools and research resources devoted to the extensive public health problem of PO-related harms in Canada continue to be urgently needed.

From cues to signals: evolution of interspecific communication via aposematism and mimicry in a predator-prey system.

Current theory suggests that many signaling systems evolved from preexisting cues. In aposematic systems, prey warning signals benefit both predator and prey. When the signal is highly beneficial, a third species often evolves to mimic the toxic species, exploiting the signaling system for its own protection. We investigated the evolutionary dynamics of predator cue utilization and prey signaling in a digital predator-prey system in which prey could evolve to alter their appearance to mimic poison-free or poisonous prey. In predators, we observed rapid evolution of cue recognition (i.e. active behavioral responses) when presented with sufficiently poisonous prey. In addition, active signaling (i.e. mimicry) evolved in prey under all conditions that led to cue utilization. Thus we show that despite imperfect and dishonest signaling, given a high cost of consuming poisonous prey, complex systems of interspecific communication can evolve via predator cue recognition and prey signal manipulation. This provides evidence supporting hypotheses that cues may serve as stepping-stones in the evolution of more advanced communication and signaling systems that incorporate information about the environment.

Iterative refinement of a binding pocket model: active computational steering of lead optimization.

Computational approaches for binding affinity prediction are most frequently demonstrated through cross-validation within a series of molecules or through performance shown on a blinded test set. Here, we show how such a system performs in an iterative, temporal lead optimization exercise. A series of gyrase inhibitors with known synthetic order formed the set of molecules that could be selected for "synthesis." Beginning with a small number of molecules, based only on structures and activities, a model was constructed. Compound selection was done computationally, each time making five selections based on confident predictions of high activity and five selections based on a quantitative measure of three-dimensional structural novelty. Compound selection was followed by model refinement using the new data. Iterative computational candidate selection produced rapid improvements in selected compound activity, and incorporation of explicitly novel compounds uncovered much more diverse active inhibitors than strategies lacking active novelty selection.