Translating the Genome into Drugs.

The Human Genome Project ultimately aimed to translate DNA sequence into drugs. With the draft in hand, the Molecular Libraries Program set out to prosecute all genome-encoded proteins for drug discovery with automated high-throughput screening (HTS). This ambitious vision remains unfulfilled, even while innovations in sequencing technology have fully democratized access to genome-scale sequencing. Why? While the central dogma of biology allows us to chart the entirety of cellular metabolism through sequencing, there is no direct coding for chemistry. The rules of base pairing that relate DNA gene to RNA transcript and amino acid sequence do not exist for relating small-molecule structure with macromolecular binding partners and subsequently cellular function. Obtaining such relationships genome-wide is unapproachable via state-of-the-art HTS, akin to attempting genome-wide association studies using turn-of-the-millennium Sanger DNA sequencing.Our laboratory has been engaged in a multipronged technology development campaign to revolutionize molecular screening through miniaturization in pursuit of genome-scale drug discovery capabilities. The compound library was ripe for miniaturization: it clearly needed to become a consumable. We employed DNA-encoded library (DEL) synthesis principles in the development of solid-phase DELs prepared on microscopic beads, each harboring 100 fmol of a single library member and a DNA tag whose sequence describes the structure of the library member. Loading these DEL beads into 100 pL microfluidic droplets followed by online photocleavage, incubation, fluorescence-activated droplet sorting, and DNA sequencing of the sorted DEL beads reveals the chemical structures of bioactive compounds. This scalable library synthesis and screening platform has proven useful in several proof-of-concept projects involving current clinical targets.Moving forward, we face the problem of druggability and proteome-scale assay development. Developing biochemical or cellular assays for all genome-encoded targets is not scalable and likely impossible as most proteins have ill-defined or unknown activity and may not function outside of their native contexts. These are the dark undruggable expanses, and charting them will require advanced synthesis and analytical technologies that can generalize probe discovery, irrespective of mature protein function, to fulfill the Genome Project's vision of proteome-wide control of cellular pharmacology.

Association of Patient Race and Hospital with Utilization of Regional Anesthesia for Treatment of Postoperative Pain in Total Knee Arthroplasty: A Retrospective Analysis Using Medicare Claims.

BACKGROUND: Regional anesthesia for total knee arthroplasty has been deemed high priority by national and international societies, and its use can serve as a measure of healthcare equity. The association between utilization of regional anesthesia for postoperative pain and (1) race and (2) hospital in patients undergoing total knee arthroplasty was estimated. The hypothesis was that Black patients would be less likely than White patients to receive regional anesthesia, and that variability in regional anesthesia would more likely be attributable to the hospital where surgery occurred than race. METHODS: This study used Medicare fee-for-service claims for patients aged 65 yr or older who underwent primary total knee arthroplasty between January 1, 2011, and December 31, 2016. The primary outcome was administration of regional anesthesia for postoperative pain, defined as any peripheral (femoral, lumbar plexus, or other) or neuraxial (spinal or epidural) block. The primary exposure was self-reported race (Black, White, or Other). Clinical significance was defined as a relative difference of 10% in regional anesthesia administration. RESULTS: Data from 733,406 cases across 2,507 hospitals were analyzed: 90.7% of patients were identified as White, 4.7% as Black, and 4.6% as Other. Median hospital-level prevalence of use of regional anesthesia was 51% (interquartile range, 18 to 79%). Black patients did not have a statistically different probability of receiving a regional anesthetic compared to White patients (adjusted estimates: Black, 53.3% [95% CI, 52.5 to 54.1%]; White, 52.7% [95% CI, 52.4 to 54.1%]; P = 0.132). Findings were robust to alternate specifications of the exposure and outcome. Analysis of variance revealed that 42.0% of the variation in block administration was attributable to hospital, compared to less than 0.01% to race, after adjusting for other patient-level confounders. CONCLUSIONS: Race was not associated with administration of regional anesthesia in Medicare patients undergoing primary total knee arthroplasty. Variation in the use of regional anesthesia was primarily associated with the hospital where surgery occurred.

Building Block-Centric Approach to DNA-Encoded Library Design.

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.

Association between "Balance Billing" Legislation and Anesthesia Payments in California: A Retrospective Analysis.

BACKGROUND: Insured patients who receive out-of-network care may receive a "balance bill" for the difference between the practitioner's charge and their insurer's contracted rate. In 2017, California banned balance billing for anesthesia care. This study examined the association between California's law and subsequent payments for anesthesia care. The authors hypothesized that, after the law's implementation, there would be no change in in-network payment amounts, and that out-of-network payment amounts and the portion of claims occurring out-of-network would decline. METHODS: The study used average, quarterly, California county-level payment data (2013 to 2020) derived from a claims database of commercially insured patients. Using a difference-in-differences approach, the change was estimated in payment amounts for intraoperative or intrapartum anesthesia care, along with the portion of claims occurring out-of-network, after the law's implementation. The comparison group was office visit payments, expected to be unaffected by the law. The authors prespecified that they would refer to differences of 10% or greater as policy significant. RESULTS: The sample consisted of 43,728 procedure code-county-quarter-network combinations aggregated from 4,599,936 claims. The law's implementation was associated with a significant 13.6% decline in payments for out-of-network anesthesia care (95% CI, -16.5 to -10.6%; P < 0.001), translating to an average $108 decrease across all procedures (95% CI, -$149 to -$64). There was a statistically significant 3.0% increase in payments for in-network anesthesia care (95% CI, 0.9 to 5.1%; P = 0.007), translating to an average $87 increase (95% CI, $64 to $110), which may be notable in some circumstances but did not meet the study threshold for identifying a change as policy significant. There was a nonstatistically significant increase in the portion of claims occurring out-of-network (10.0%, 95% CI, -4.1 to 24.2%; P = 0.155). CONCLUSIONS: California's balance billing law was associated with significant declines in out-of-network anesthesia payments in the first 3 yr after implementation. There were mixed statistical and policy significant results for in-network payments and the proportion of out-of-network claims.

Building Block-Based Binding Predictions for DNA-Encoded Libraries.

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.

Reducing Opioid Use in Endocrine Surgery Through Patient Education and Provider Prescribing Patterns.

BACKGROUND: Postoperative 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. METHODS: We 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. RESULTS: Sixty 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. CONCLUSIONS: Clear 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.

Preoperative GLP-1 Receptor Agonist Use and Risk of Postoperative Respiratory Complications.

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.

Ocular protein optineurin shows reversibility from unfolded states and exhibits chaperone-like activity.

Optineurin (OPTN) is a multifunctional, ubiquitously expressed cytoplasmic protein, mutants of which are associated with primary open-angle glaucoma (POAG) and amyotrophic lateral sclerosis (ALS). The most abundant heat shock protein crystallin, known for its remarkable thermodynamic stability and chaperoning activity, allows ocular tissues to withstand stress. The presence of OPTN in ocular tissues is intriguing. Interestingly, OPTN also harbors heat shock elements in its promoter region. Sequence analysis of OPTN exhibits intrinsically disordered regions and nucleic acid binding domains. These properties hinted that OPTN might be endowed with sufficient thermodynamic stability and chaperoning activity. However, these attributes of OPTN have not yet been explored. Here, we studied these properties through thermal and chemical denaturation experiments and monitored the processes using CD, fluorimetry, differential scanning calorimetry, and dynamic light scattering. We found that upon heating, OPTN reversibly forms higher-order multimers. OPTN also displayed a chaperone-like function by reducing the thermal aggregation of bovine carbonic anhydrase. It regains its native secondary structure, RNA-binding property, and melting temperature (T m) after refolding from a thermally as well as chemically denatured state. From our data, we conclude that OPTN, with its unique ability to revert from the stress-mediated unfolded state and its unique chaperoning function, is a valuable protein of the ocular tissues.

Limited use of nonopioid analgesics after pediatric ambulatory surgery.

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.

Who gives a criterion shift? A uniquely individualistic cognitive trait.

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. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Language-Related Disparities in Pain Management in the Post-Anesthesia Care Unit for Children Undergoing Laparoscopic Appendectomy.

Race and ethnicity are associated with disparities in pain management in children. While low English language proficiency is correlated with minority race/ethnicity in the United States, it is less frequently explored in the study of health disparities. We therefore investigated whether English language proficiency influenced pain management in the post-anesthesia care unit (PACU) in a cohort of children who underwent laparoscopic appendectomy at our pediatric hospital in San Francisco. Our primary exposure was English language proficiency, and our primary outcome was administration of any opioid medication in the PACU. Secondary outcomes included the amount of opioid administered in the PACU and whether any pain score was recorded during the patient's recovery period. Statistical analysis included adjusting for demographic covariates including race in estimating the effect of language proficiency on these outcomes. In our cohort of 257 pediatric patients, 57 (22.2%) had low English proficiency (LEP). While LEP and English proficient (EP) patients received the same amount of opioid medication intraoperatively, in multivariable analysis, LEP patients had more than double the odds of receiving any opioid in the PACU (OR 2.45, 95% CI 1.22-4.92). LEP patients received more oral morphine equivalents (OME) than EP patients (1.64 OME/kg, CI 0.67-3.84), and they also had almost double the odds of having no pain score recorded during their PACU recovery period (OR 1.93, CI 0.79-4.73), although the precision of these estimates was limited by small sample size. Subgroup analysis showed that children over the age of 5 years, who were presumably more verbal and would therefore undergo verbal pain assessments, had over triple the odds of having no recorded pain score (OR 3.23, CI 1.48-7.06). In summary, English language proficiency may affect the management of children's pain in the perioperative setting. The etiology of this language-related disparity is likely multifactorial and should be investigated further.

Assessment of Unused Opioids Following Ambulatory Surgery.

BACKGROUND: Surgery is a risk factor for opioid initiation and subsequent abuse. Discharge opioid prescription patterns after surgery are often varied and not evidence based, which may lead to unnecessary prescription of opioids. We aimed to assess opioid prescribing and unused opioid prescriptions in ambulatory surgery patients at our academic hospital. METHODS: We conducted a retrospective observational study based on phone survey and electronic medical records. Adult patients who underwent ambulatory surgery at our large, multisite, tertiary-care hospital system were asked whether they were using the opioids that were prescribed at discharge. Our main outcomes were opioid prescription (defined as being prescribed an opioid on discharge) and unused opioid prescription (defined as being prescribed an opioid but not taking any opioids on postoperative day 1). We evaluated predictors of opioid prescription and unused opioid prescription through univariable and multivariable analyses. We also stratified outcomes by surgical service. RESULTS: Of 4248 adult patients who underwent ambulatory surgical procedures, 3279 (77.2%) responded to the survey. Of all responders, 2146 (65.4%) were prescribed postoperative opioids, and 1240 (57.8%) reported not taking them on postoperative day 1. The highest rates of unused opioid prescriptions were for patients whose primary service were orthopedic surgery (65%) and plastic surgery (62%). DISCUSSION: Opioid prescribing and unused opioid prescriptions are prevalent in our hospital's ambulatory surgical population. Patients undergoing selected ambulatory surgical procedures may not require as much opioid as is currently being prescribed.

Medicare savings from conservative management of low back pain.

OBJECTIVES: Low back pain (LBP) is a common and expensive clinical problem, resulting in tens of billions of dollars of direct medical expenditures in the United States each year. Although expensive imaging tests are commonly used, they do not improve outcomes when used in the initial management of idiopathic LBP. We estimated 1-year medical costs associated with early imaging of Medicare beneficiaries with idiopathic LBP. STUDY DESIGN: We used a 5% random sample of Medicare fee-for-service enrollees between 2006 and 2010 to determine 12-month costs following a diagnosis of idiopathic LBP. We analyzed costs of care and patient outcomes according to whether or not the patients had been referred for early imaging following their initial diagnosis. METHODS: We employed an instrumental variables analysis using risk-adjusted physician-level propensity to order imaging for patients without LBP as an instrument for imaging use among patients with LBP. We selected this approach to adjust for confounding by indication when estimating the relative costs of early imaging of LBP compared with conservative management. RESULTS: Early imaging is strongly associated with increased costs of care in the first year following LBP diagnosis. Patients receiving an early magnetic resonance imaging scan accrued $2500 more in Medicare expenditures than conservatively managed patients, and patients who received computed tomography accrued $19,900 more. CONCLUSIONS: Medicare beneficiaries with low-risk LBP frequently receive early imaging studies. Early imaging was associated with greater long-term costs than a conservative diagnostic strategy; Medicare expenditures could be reduced by $362 million annually by managing newly diagnosed LBP in accordance with clinical guidelines.

Association between concurrent use of prescription opioids and benzodiazepines and overdose: retrospective analysis.

Objectives To identify trends in concurrent use of a benzodiazepine and an opioid and to identify the impact of these trends on admissions to hospital and emergency room visits for opioid overdose.Design Retrospective analysis of claims data, 2001-13.Setting Administrative health claims database.Participants 315 428 privately insured people aged 18-64 who were continuously enrolled in a health plan with medical and pharmacy benefits during the study period and who also filled at least one prescription for an opioid.Interventions Concurrent benzodiazepine/opioid use, defined as an overlap of at least one day in the time periods covered by prescriptions for each drug. Main outcome measures Annual percentage of opioid users with concurrent benzodiazepine use; annual incidence of visits to emergency room and inpatient admissions for opioid overdose.Results 9% of opioid users also used a benzodiazepine in 2001, increasing to 17% in 2013 (80% relative increase). This increase was driven mainly by increases among intermittent, as opposed to chronic, opioid users. Compared with opioid users who did not use benzodiazepines, concurrent use of both drugs was associated with an increased risk of an emergency room visit or inpatient admission for opioid overdose (adjusted odds ratio 2.14, 95% confidence interval 2.05 to 2.24; P<0.001) among all opioid users. The adjusted odds ratio for an emergency room visit or inpatient admission for opioid overdose was 1.42 (1.33 to 1.51; P<0.001) for intermittent opioid users and 1.81 (1.67 to 1.96; P<0.001) chronic opioid users. If this association is causal, elimination of concurrent benzodiazepine/opioid use could reduce the risk of emergency room visits related to opioid use and inpatient admissions for opioid overdose by an estimated 15% (95% confidence interval 14 to 16).Conclusions From 2001 to 2013, concurrent benzodiazepine/opioid use sharply increased in a large sample of privately insured patients in the US and significantly contributed to the overall population risk of opioid overdose.

Incorporation of whole, ancient grains into a modern Asian Indian diet to reduce the burden of chronic disease.

Refined carbohydrates, such as white rice and white flour, are the mainstay of the modern Asian Indian diet, and may contribute to the rising incidence of type 2 diabetes and cardiovascular disease in this population. Prior to the 1950s, whole grains such as amaranth, barley, brown rice, millet, and sorghum were more commonly used in Asian Indian cooking. These grains and other non-Indian grains such as couscous, quinoa, and spelt are nutritionally advantageous and may be culturally acceptable carbohydrate substitutes for Asian Indians. This review focuses on practical recommendations for culturally sensitive carbohydrate modification in a modern Asian Indian diet to reduce type 2 diabetes and cardiovascular disease in this population.

Type 2 diabetes: identifying high risk Asian American subgroups in a clinical population.

AIMS: We compared the prevalence and treatment of type 2 diabetes across Asian American subgroups (Asian Indian, Chinese, Filipino, Japanese, Korean, Vietnamese) and Non-Hispanic Whites (NHWs) in a Northern California healthcare system. METHODS: A three-year, cross-sectional sample of patient electronic health records was accessed to compare diabetes prevalence in 21,816 Asian and 73,728 NHWs aged 35+ years. Diabetes was classified through ICD-9 codes, abnormal laboratory values, or use of oral anti-diabetic medication. Multivariate adjusted prevalence rates for each Asian subgroup, and adjusted odds ratios (OR) relative to NHWs, were compared. RESULTS: Age-adjusted prevalence ranged from 5.8% to 18.2% (women) and 8.1 to 25.3% (men). Age-adjusted ORs of Asian subgroups ranged 1.11-3.94 (women) and 1.14-4.56 (men). The odds of diabetes were significantly higher in Asian Indians (women OR 3.44, men OR 3.54) and Filipinos (women OR 3.94, men OR 4.56), compared to NHWs. Results for Asian Indians and Filipinos were similar with age-and-BMI adjustment. Treatment rates across subgroups were 59.7-82.0% (women) and 62.9-79.4% (men). CONCLUSIONS: Heterogeneity exists in the prevalence of diabetes across Asian subgroups, independent of obesity prevalence. Asian Indian and Filipino subgroups had particularly high prevalence of diabetes when compared to NHWs. Future studies should explore these clinically important differences among Asian subgroups.

Mechanical ventilation uncouples synthesis and assembly of elastin and increases apoptosis in lungs of newborn mice. Prelude to defective alveolar septation during lung development?

Prolonged mechanical ventilation (MV) with O2-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% O2 or air might lead to dysregulated elastin production and impaired lung septation. MV of newborn mice for 8 h with either 40% O2 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% O2, but not with air. We then extended MV with 40% O2 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.