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DNA-encoded library technology grants access to nearly infinite opportunities to explore the chemical structure space for drug discovery. Successful navigation depends on the design and synthesis of libraries with appropriate physicochemical properties (PCPs) and structural diversity while aligning with practical considerations. To this end, we analyze combinatorial library design constraints including the number of chemistry cycles, bond construction strategies, and building block (BB) class selection in pursuit of ideal library designs. We compare two-cycle library designs (amino acid + carboxylic acid, primary amine + carboxylic acid) in the context of PCPs and chemical space coverage, given different BB selection strategies and constraints. We find that broad availability of amines and acids is essential for enabling the widest exploration of chemical space. Surprisingly, cost is not a driving factor, and virtually, the same chemical space can be explored with budget BBs.

DNA-encoded libraries (DELs) provide the means to make and screen millions of diverse compounds against a target of interest in a single experiment. However, despite producing large volumes of binding data at a relatively low cost, the DEL selection process is susceptible to noise, necessitating computational follow-up to increase signal-to-noise ratios. In this work, we present a set of informatics tools to employ data from prior DEL screen(s) to gain information about which building blocks are most likely to be productive when designing new DELs for the same target. We demonstrate that similar building blocks have similar probabilities of forming compounds that bind. We then build a model from the inference that the combined behavior of individual building blocks is predictive of whether an overall compound binds. We illustrate our approach on a set of three-cycle OpenDEL libraries screened against soluble epoxide hydrolase (sEH) and report performance of more than an order of magnitude greater than random guessing on a holdout set, demonstrating that our model can serve as a baseline for comparison against other machine learning models on DEL data. Lastly, we provide a discussion on how we believe this informatics workflow could be applied to benefit researchers in their specific DEL campaigns.

BackgroundPostoperative opioid use can lead to dependence, contributing to the opioid epidemic in the United States. New persistent opioid use after minor surgeries occurs in 5.9% of patients. With increased documentation of persistent opioid use postoperatively, surgeons must pursue interventions to reduce opioid use perioperatively.MethodsWe performed a prospective cohort study to assess the feasibility of a preoperative intervention via patient education or counseling and changes in provider prescribing patterns to reduce postoperative opioid use. We included adult patients undergoing thyroidectomy and parathyroidectomy from January 22, 2019 to February 28, 2019 at a tertiary referral, academic endocrine surgery practice. Surveys were administered to assess pain and patient satisfaction postoperatively. Prescription, demographic, and comorbidity data were collected from the electronic health record.ResultsSixty six patients (74.2% women, mean age 58.6 [SD 14.9] y) underwent thyroidectomy (n = 35), parathyroidectomy (n = 24), and other cervical endocrine operations (n = 7). All patients received a preoperative educational intervention in the form of a paper handout. 90.9% of patients were discharged with prescriptions for nonopioid pain medications, and 7.6% were given an opioid prescription on discharge. Among those who received an opioid prescription, the median quantity of opioids prescribed was 135 (IQR 120-150) oral morphine equivalents. On survey, four patients (6.1%) reported any postoperative opioid use, and 94.6% of patients expressed satisfaction with their preoperative education and postoperative pain management.ConclusionsClear and standardized education regarding postoperative pain management is feasible and associated with high patient satisfaction. Initiation of such education may support efforts to minimize unnecessary opioid prescriptions in the population undergoing endocrine surgery.

Individuals should "strategically" shift decision criteria when there are disproportionate likelihoods or consequences for falsely identifying versus missing target items. Despite being explicitly aware of the advantages for criterion shifting, people on "average" do not shift extremely, leading many theories to conclude that people are generally suboptimal at placing decision criteria. However, assessments of individual differences reveal that some people actually do criterion shift quite well while others fail to shift entirely. These individual differences may carry meaningful information about the nature and consistency of a person's decision-making strategies, but no studies have systematically assessed the stability of strategic criterion shifting within individuals over time. We assessed criterion shifting stability by administering test-retest recognition memory and visual detection tests where we induced decision biases through instruction, payoff, and base rate manipulations. Criterion shifting tendencies proved to be stable within and across decision domains regardless of the inducement. Individual differences in criterion shifting could not be explained by personality characteristics, metacognitive sensitivity, motivation, or performance on other cognitive tasks. Reports of confidence ratings, which are used to assess various criterion placements, showed no relationship to the extent of criterion shifting unless participants received instructions to make certain response types with high confidence only. Participants who inadequately shifted criteria still tended to set extreme criteria for reporting high confidence, suggesting that these individuals are "capable" of shifting to greater extents, but appear "unwilling" to do so. These findings demonstrate that strategic criterion shifting tendencies are a stable and uniquely individualistic cognitive trait.

This research report explores the potential racial disparity in the use of regional nerve blocks for total knee arthroplasty (TKA) in hospitals. The study found that hospitals with a higher proportion of Black patients undergoing TKA were less likely to administer nerve blocks. This difference persisted even after accounting for patient characteristics. The findings suggest that there may be a racial disparity in access to nerve blockade for pain management during TKA. However, it is important to note that the study has limitations and may not apply to the entire US population. [Extracted from the article]

Aim: To compare the outcome of I-GEL AND LTS-D in adult patients undergoing elective non laproscopic surgery. Material and Methods: The present study was conducted on 60 ASA grade I and II patients of either sex between 18 to 60 years of age. The sample size calculated was 30 in each group. Patients were randomly divided using close envelope technique into following two groups of 30 patients in each group i.e. Group A (n=30) = I-GEL and Group B (n=30) =LTSD. We assessed the ease of insertion, attempts and time for insertion, hemodynamic changes and complications. Results: When compared to LTSD the attempts required to insertion was less for I - GEL, but it was not statistically significant. When compared to LTSD the time required to insertion of I - GEL was less in duration and compared to LTSD, the ease of insertion for I - GEL was easier. Traumatic injury to the airway was less in I - GEL than LTSD. In postoperative adverse events sore throat and hoarseness of voice seen in LTSD was more than I-GEL. Conclusion: I -GEL was better in view of ease of insertion, placement was rapid, less changes in hemodynamic parameters and also less traumatic to airways than LTSD. [ABSTRACT FROM AUTHOR]

A recent analysis published in the Journal of the American Medical Association found no association between the use of GLP-1 receptor agonists (GLP-1 RAs) before surgery and postoperative respiratory complications in patients who underwent emergency surgery. The study focused on emergency surgery patients because they were likely unable to withhold their GLP-1 RA medications before the procedure and were expected to have a higher risk of pulmonary aspiration. The study concluded that the routine full-stomach precautions taken by anesthesiologists during emergency surgeries were safe and effective for patients taking GLP-1 RAs, suggesting that these precautions would also be safe for patients undergoing elective surgery. The study also addressed concerns about the sensitivity of claims-based codes to detect postoperative respiratory complications and clarified the difference between "guidelines" and "guidance" in relation to GLP-1 RA medication withholding times. [Extracted from the article]

This cohort study evaluates the risk of postoperative respiratory complications among patients with diabetes undergoing surgery who had vs those who had not a prescription fill for glucagon-like peptide 1 receptor agonists. [ABSTRACT FROM AUTHOR]

Prolonged mechanical ventilation (MV) with [O.sub.2]-rich gas inhibits lung growth and causes excess, disordered accumulation of lung elastin in preterm infants, often resulting in chronic lung disease (CLD). Using newborn mice, in which alveolarization occurs postnatally, we designed studies to determine how MV with either 40% [O.sub.2] or air might lead to dysregulated elastin production and impaired lung septation. MV of newborn mice for 8 h with either 40% 02 or air increased lung mRNA for tropoelastin and lysyl oxidase, relative to unventilated controls, without increasing lung expression of genes that regulate elastic fiber assembly (lysyl oxidase-like-1, fibrillin-1, fibrillin-2, fibulin-5, emilin-1). Serine elastase activity in lung increased fourfold after MV with 40% [O.sub.2], but not with air. We then extended MV with 40% [O.sub.2] to 24 h and found that lung content of tropoelastin protein doubled, whereas lung content of elastin assembly proteins did not change (lysyl oxidases, fibrillins) or decreased (fibulin-5, emilin-1). Quantitative image analysis of lung sections showed that elastic fiber density increased by 50% after MV for 24 h, with elastin distributed throughout the walls of air spaces, rather than at septal tips, as in control lungs. Dysregulation of elastin was associated with a threefold increase in lung cell apoptosis (TUNEL and caspase-3 assays), which might account for the increased air space size previously reported in this model. Our findings of increased elastin synthesis, coupled with increased elastase activity and reduced lung abundance of proteins that regulate elastic fiber assembly, could explain altered lung elastin deposition, increased apoptosis, and defective septation, as observed in CLD. lung growth and development; bronchopulmonary dysplasia; neonatal chronic lung disease; tropoelastin; lysyl oxidases; fibrillins; fibulin-5; emilin-1; serine elastase activity; lung cell apoptosis; alveolar septation

Objective: This study sought to determine the rate at which nonopioid analgesics were utilized in postoperative pain management plans after pediatric ambulatory surgery in patients who were also prescribed postoperative opioids., Design: Retrospective cohort analysis., Participants: Patients ≤ 21 years old who were prescribed opioid medications after undergoing ambulatory surgery at a tertiary-care medical center., Methods: Postoperative day 1 (POD1) opioid prescription and use survey data along with electronic medical record data were extracted and analyzed for patients meeting inclusion criteria between April 2017 and December 2017., Main Outcome Measure: Recommendation to take nonopioid analgesics after discharge., Results: A total of 849 (63.2 percent) patients responded to the survey and 275 (32.4 percent) of these cases were prescribed postoperative opioids. Of the 273 cases included in this study, 137 (50.2 percent) received recommendations to take at least one nonopioid analgesic as well, and 164 (60.1 percent) reported using their prescribed opioids on POD1. Opioid use did not vary significantly with nonopioid analgesic recommendations. There was significant variability in opioid and nonopioid analgesic prescribing and recommendation patterns across surgical subspecialties., Conclusions: There was limited use of nonopioid analgesics in postoperative pain management plans after pediatric ambulatory surgery. This leaves many patients with only opioid-based agents as the first-line medication for postoperative pain management. These findings highlight an opportunity to educate prescribers and patients on the importance of step-wise multimodal analgesic plans.