An Elastin-like Polypeptide-fusion peptide targeting capsid-tegument interface as an antiviral against cytomegalovirus infection.

The tegument protein pp150 of Human Cytomegalovirus (HCMV) is known to be essential for the final stages of virus maturation and mediates its functions by interacting with capsid proteins. Our laboratory has previously identified the critical regions in pp150 important for pp150-capsid interactions and designed peptides similar in sequence to these regions, with a goal to competitively inhibit capsid maturation. Treatment with a specific peptide (PepCR2 or P10) targeted to pp150 conserved region 2 led to a significant reduction in murine CMV (MCMV) growth in cell culture, paving the way for in vivo testing in a mouse model of CMV infection. However, the general pharmacokinetic parameters of peptides, including rapid degradation and limited tissue and cell membrane permeability, pose a challenge to their successful use in vivo. Therefore, we designed a biopolymer-stabilized elastin-like polypeptide (ELP) fusion construct (ELP-P10) to enhance the bioavailability of P10. Antiviral efficacy and cytotoxic effects of ELP-P10 were studied in cell culture, and pharmacokinetics, biodistribution, and antiviral efficacy were studied in a mouse model of CMV infection. ELP-P10 maintained significant antiviral activity in cell culture, and this conjugation significantly enhanced P10 bioavailability in mouse tissues. The fluorescently labeled ELP-P10 accumulated to higher levels in mouse liver and kidneys as compared to the unconjugated P10. Moreover, viral titers from vital organs of MCMV-infected mice indicated a significant reduction of virus load upon ELP-P10 treatment. Therefore, ELP-P10 has the potential to be developed into an effective antiviral against CMV infection.

Pharmacological inhibition of receptor-interacting protein kinase 2 (RIPK2) elicits neuroprotective effects following experimental ischemic stroke.

Ischemic stroke induces a debilitating neurological insult, where inflammatory processes contribute greatly to the expansion and growth of the injury. Receptor-interacting protein kinase 2 (RIPK2) is most well-known for its role as the obligate kinase for NOD1/2 pattern recognition receptor signaling and is implicated in the pathology of various inflammatory conditions. Compared to a sham-operated control, ischemic stroke resulted in a dramatic increase in the active, phosphorylated form of RIPK2, indicating that RIPK2 may be implicated in the response to stroke injury. Here, we assessed the effects of pharmacological inhibition of RIPK2 to improve post-stroke outcomes in mice subjected to experimental ischemic stroke. We found that treatment at the onset of reperfusion with a RIPK2 inhibitor, which inhibits the phosphorylation and activation of RIPK2, resulted in marked improvements in post-stroke behavioral outcomes compared to the vehicle-administered group assessed 24 h after stroke. RIPK2 inhibitor-treated mice exhibited dramatic reductions in infarct volume, concurrent with reduced damage to the blood-brain barrier, as evidenced by reduced levels of active matrix metalloproteinase-9 (MMP-9) and leakage of blood-borne albumin in the ipsilateral cortex. To explore the protective mechanism of RIPK2 inhibition, we next pretreated mice with RIPK2 inhibitor or vehicle and examined transcriptomic alterations occurring in the ischemic brain 6 h after stroke. We observed a dramatic reduction in neuroinflammatory markers in the ipsilateral cortex of the inhibitor-treated group while also attaining a comprehensive view of the vast transcriptomic alterations occurring in the brain with inhibitor treatment through bulk RNA-sequencing of the injured cortex. Overall, we provide significant novel evidence that RIPK2 may represent a viable target for post-stroke pharmacotherapy and potentially other neuroinflammatory conditions.

Analysis of rising cases of adolescent opioid use presentations to the emergency department and their management.

OBJECTIVE: We sought to answer the question of how adolescents (ages 12-17 years old) with opioid-related presentations are currently managed in the ED. The two main outcomes were the proportion of visits where naloxone and buprenorphine were both used and prescribed, and the rate of revisits to the emergency department in the six months following ED presentation. METHODS: This was a multi-center retrospective cross-sectional study. We studied patients presenting to the ED who were 12-17 years old with an opioid-related presentation. RESULTS: Two-hundred and thirty-one patients were identified out of 571 encounters screened. Of these presentations, 77/231 (33%) were girls and 154/231 (67%) were boys. The majority of patients were Latino (64%; n=147); 26% were white (n=59), 6% were middle eastern or Arab (14), and 4% were black (10). Incidence of opioid use disorder per 100,000 presentations increased by 2800% from 2014 to 2022 (21/100,000 +/- 10 [2014] to 600/100,000 +/- 50 [2022]). A plurality of cases was related to opioid withdrawal (42%; 97). On discharge from the ED, 29% of patients received naloxone. For patients in withdrawal, 4% received a prescription for buprenorphine. Twenty-nine percent of patients had a return to the ED in the six months following initial visit. CONCLUSIONS: Adolescent opioid-related presentations to the ED are rapidly increasing. Increasing ED presentations, compounded by a high 6-month revisit rate, pose a management challenge amid limited outpatient resources for this population. Opioid agonist therapy and naloxone are not routinely provided. Increasing the use of both are two ways to improve the quality of care for this population.

Increasing number and shifting demographics of adolescent opioid use disorder presentations to the emergency department.

INTRODUCTION: Opioid use has been increasing in adolescents; however, lacking are data describing sex, ethnicity, and age groups most affected. We identified and characterized the trend in the adolescent population who presented to the emergency departments (ED) of a large hospital system. METHODS: We obtained data directly from the electronic medical record for patients aged 12-21 years from January 2014 to December 2022. We identified opioid-related visits by primary diagnosis. Trends were compared amongst age groups and by sex and reported ethnicity. RESULTS: Opioid-related presentations increased in all age groups and were significantly increased in adolescents aged 13-17 years compared to patients aged 18-21 years (1700% [range: 1000-3300%] v 400% [200-800%]; p = 0.02). Adolescents presenting to the ED with opioid-related primary diagnoses were more likely to be Hispanic and male in our region. DISCUSSION: Over the last two years (2021-22) there was a significant increase in opioid-related presentations to our hospital system amongst adolescents and an acceleration post-COVID. In 2022, emergency department presentations shifted to younger teenagers and from white young adults to Hispanic adolescents. The increased number of cases posed management problems in the ED given the lack of outpatient treatment options. CONCLUSION: Opioid-related ED presentations are increasing in adolescents with post-COVID increases in male, Hispanic, and younger patients in our region. Pathways for outpatient treatment need to be developed for adolescents with OUD.

Super Interferometric Range Resolution.

We probe the fundamental underpinnings of range resolution in coherent remote sensing. We use a novel class of self-referential interference functions to show that we can greatly improve upon currently accepted bounds for range resolution. We consider the range resolution problem from the perspective of single-parameter estimation of amplitude versus the traditional temporally resolved paradigm. We define two figures of merit: (i) the minimum resolvable distance between two depths and (ii) for temporally subresolved peaks, the depth resolution between the objects. We experimentally demonstrate that our system can resolve two depths greater than 100× the inverse bandwidth and measure the distance between two objects to approximately 20 µm (35 000 times smaller than the Rayleigh-resolved limit) for temporally subresolved objects using frequencies less than 120 MHz radio waves.

Elastin-like polypeptide delivery of anti-inflammatory peptides to the brain following ischemic stroke.

Inflammatory processes are activated following ischemic stroke that lead to increased tissue damage for weeks following the ischemic insult, but there are no approved therapies that target this inflammation-induced secondary injury. Here, we report that SynB1-ELP-p50i, a novel protein inhibitor of the nuclear factor kappa B (NF-κB) inflammatory cascade bound to the drug carrier elastin-like polypeptide (ELP), decreases NF-κB induced inflammatory cytokine production in cultured macrophages, crosses the plasma membrane and accumulates in the cytoplasm of both neurons and microglia in vitro, and accumulates at the infarct site where the blood-brain barrier (BBB) is compromised following middle cerebral artery occlusion (MCAO) in rats. Additionally, SynB1-ELP-p50i treatment reduces infarct volume by 11.86% compared to saline-treated controls 24 h following MCAO. Longitudinally, SynB1-ELP-p50i treatment improves survival for 14 days following stroke with no effects of toxicity or peripheral organ dysfunction. These results show high potential for ELP-delivered biologics for therapy of ischemic stroke and other central nervous system disorders and further support targeting inflammation in ischemic stroke.

Elastin-like polypeptide delivery of anti-inflammatory peptides to the brain following ischemic stroke.

Inflammatory processes are activated following ischemic strokes and lead to increased tissue damage for weeks following the ischemic insult, but there are no approved therapies that target this inflammation-induced secondary injury. Here, we report that SynB1-ELP-p50i, a novel protein inhibitor of the nuclear factor kappa B (NF-κB) inflammatory cascade bound to drug carrier elastin-like polypeptide (ELP), is able to enter both neurons and microglia, cross the blood-brain barrier, localize exclusively in the ischemic core and penumbra in Wistar-Kyoto and spontaneously hypertensive rats (SHRs), and reduce infarct volume in male SHRs. Additionally, in male SHRs, SynB1-ELP-p50i treatment improves survival for 14 days following stroke with no effects of toxicity or peripheral organ dysfunction. These results show high potential for ELP-delivered biologics for therapy of ischemic stroke and other central nervous system disorders and further support targeting inflammation in ischemic stroke.

Expediting Treatment of Trauma Patients in the Emergency Department: Rapid Trauma Evaluation (RTE).

BACKGROUND: Criteria for trauma determination evolves. We developed/evaluated a Rapid Trauma Evaluation (RTE) process for a trauma patient subset not meeting preestablished trauma criteria. METHODS: Retrospective study (July 2019 - May 2020) for patients either > 65 years with ground level fall within 24 hours or in a motorcycle collision (MCC) arriving by EMS not meeting ACS trauma-criteria. RTE process was immediate evaluation by nurse/EMT, room placement, physician notification, undressing/gowning, vital signs, head-to-toe assessment, upgrade trauma status. Number/type of admissions, discharges, trauma upgrades, LOS obtained via trauma-registry and chart-review. For comparison, historic controls (HC) were used [all patients meeting RTE criteria seen in the ED prior to RTE (Apr- June 2019)]. RESULTS: The RTE cohort (n=755) was 77% falls,23% MCCs, median age 82 [IQR 74-88] years; 42% male-Among falls, 3.2% required a modified-upgrade; 0.7% full-upgrade, 55% admitted [29.4% trauma). HC (n=575) was 92.3% falls, 7.7% MCCs, median age 81 (IQR: 67-88) years, 40.5% males-57.4% admitted (22% trauma). RTE MCC median age 42 (IQR:30-49) years, 84.4% male- 21.9% were upgraded [(6 modified-trauma; 1 full-trauma; 43.8% admitted (85.7% trauma)]. HC MCC median age 29 (IQR: 23-41) years, 95.5% male, 54.5% admitted (75% trauma]. No difference on demographics, admissions or discharges between groups (P>0.05) except HC MCC was younger (P<0.005). RTE median LOS was shorter than HC [203 (IQR: 147-278) minutes vs. 286 (IQR: 205-392) minutes, P<0.001]. CONCLUSIONS: Patients > 65 years with a ground level fall or in a MCC arriving via EMS not meeting ACS trauma criteria may benefit from RTE.

Effect of Nudges to Clinicians, Patients, or Both to Increase Statin Prescribing: A Cluster Randomized Clinical Trial.

Importance: Statins reduce the risk of major adverse cardiovascular events, but less than one-half of individuals in America who meet guideline criteria for a statin are actively prescribed this medication. Objective: To evaluate whether nudges to clinicians, patients, or both increase initiation of statin prescribing during primary care visits. Design, Setting, and Participants: This cluster randomized clinical trial evaluated statin prescribing of 158 clinicians from 28 primary care practices including 4131 patients. The design included a 12-month preintervention period and a 6-month intervention period between October 19, 2019, and April 18, 2021. Interventions: The usual care group received no interventions. The clinician nudge combined an active choice prompt in the electronic health record during the patient visit and monthly feedback on prescribing patterns compared with peers. The patient nudge was an interactive text message delivered 4 days before the visit. The combined nudge included the clinician and patient nudges. Main Outcomes and Measures: The primary outcome was initiation of a statin prescription during the visit. Results: The sample comprised 4131 patients with a mean (SD) age of 65.5 (10.5) years; 2120 (51.3%) were male; 1210 (29.3%) were Black, 106 (2.6%) were Hispanic, 2732 (66.1%) were White, and 83 (2.0%) were of other race or ethnicity, and 933 (22.6%) had atherosclerotic cardiovascular disease. In unadjusted analyses during the preintervention period, statins were prescribed to 5.6% of patients (105 of 1876) in the usual care group, 4.8% (97 of 2022) in the patient nudge group, 6.0% (104 of 1723) in the clinician nudge group, and 4.7% (82 of 1752) in the combined group. During the intervention, statins were prescribed to 7.3% of patients (75 of 1032) in the usual care group, 8.5% (100 of 1181) in the patient nudge group, 13.0% (128 of 981) in the clinician nudge arm, and 15.5% (145 of 937) in the combined group. In the main adjusted analyses relative to usual care, the clinician nudge significantly increased statin prescribing alone (5.5 percentage points; 95% CI, 3.4 to 7.8 percentage points; P = .01) and when combined with the patient nudge (7.2 percentage points; 95% CI, 5.1 to 9.1 percentage points; P = .001). The patient nudge alone did not change statin prescribing relative to usual care (0.9 percentage points; 95% CI, -0.8 to 2.5 percentage points; P = .32). Conclusions and Relevance: Nudges to clinicians with and without a patient nudge significantly increased initiation of a statin prescription during primary care visits. The patient nudge alone was not effective. Trial Registration: ClinicalTrials.gov Identifier: NCT04307472.

Nurse practitioner job preference: A discrete choice experiment.

BACKGROUND: Nurse practitioners play a critical role in improving the access to care and in meeting the needs for health care. However, prior to the COVID-19 pandemic, the average turnover rate of nurse practitioners was 10 % with associated total direct cost that ranged from $85,832 to $114,919 for each episode of turnover in the United States. Little is known about the job preference of nurse practitioners and the cost savings to an organization that provides jobs with characteristics attractive to nurse practitioners. OBJECTIVE: The aim of this study was to identify the preferred job characteristics that are associated with nurse practitioners' job choices; and to determine the extent to which nurse practitioners would need to be compensated for practicing without these characteristics. DESIGN: A two-stage design using a mixed method approach. SETTING(S): The state of Georgia in the United States. PARTICIPANTS: 2757 nurse practitioners who were actively licensed were invited to participate. Of the 412 participants, 372 actively employed in Georgia were included in the analysis. METHODS: A 2-stage discrete choice experiment was designed. Stage-1 was a qualitative design using a focus group to identify nurse practitioners' preferred job characteristics. Stage-2 was a quantitative design using survey distribution and analysis. A mixed logit model was used for ranking nurse practitioners' preferred job characteristics and the extent to which they would need to be compensated. RESULTS: On average nurse practitioners were 47.4 years of age; the majority were female (90 %), white (75.3 %), and educated at the master's level (88.7 %). Participants did not value teams that were not very cohesive (ß = -1.50); administration that was not very responsive and supportive (ß = -1.04); being supervised by a physician (ß = -0.58); not having their own panel of patients (ß = -0.42); and not billing under their own National Provider Identifier (ß = -0.18). Participants would need an increase in annual income of USD$21,780 for practicing in a not very cohesive team; USD$15,280 for practicing with a not very responsive administration; and USD$21,450 for being supervised by a physician. CONCLUSIONS: A cohesive, responsive, and supportive working environment and being able to practice independently are important characteristics for nurse practitioners when choosing a job. Healthcare managers should provide a workplace culture that reflects these preferred job characteristics to attract and retain nurse practitioners. Policymakers should consider reforming the scope of practice legislation to promote the independent practice of nurse practitioners.

Doppler Gyroscopes: Frequency vs Phase Estimation.

We consider the fundamental roles of frequency versus phase in parameter estimation, specifically in the Sagnac effect. We describe a novel, ultrasensitive gyroscope based on the extremely steep frequency-dependent gain of a liquid crystal light valve. We provide compelling experimental evidence that the Doppler shift is fundamental in the Sagnac effect giving clarity to a long-debated question. We experimentally show orders of magnitude improvement in sensitivity relative to the standard quantum limit of a gyroscope based on phase estimation.

Leveraging and Improving Refill Protocols at Your Health System.

OBJECTIVES: Medication refill processing is a repetitive and predictable time-intensive task for ambulatory primary and specialty care. Refill protocols are a clinical decision support (CDS) tool that allows clinicians to quickly and safely determine appropriateness of a refill request. Our health system opted to improve the quality and breadth of electronic health record vendor-supplied protocols to consistently leverage best practices and emerging evidence and to create novel protocols that further support clinicians. METHODS: We established a refill protocol governance group to guide new protocol build and to review existing protocols regularly to keep current with emerging guidelines. Data-driven prioritization was used to create new protocols for the most frequently refilled medications, as well as for less-prescribed but higher risk medications. Ad-hoc specialist inclusion as subject-matter experts provided greater detail, accuracy, and broader consensus in protocol criteria. RESULTS: Approximately 11 million refills are processed each year by our health system's providers. The proportion of refill requests supported by a protocol increased over a 2-year period from 49 to 82%, representing a net increase of 3.63 million refills in the second measurement year as compared to the start of the first measurement year. All published refill protocols were reviewed by the governance group over the measurement years for compliance with clinical guidelines. In addition to the structure of the refill protocols' CDS, the process was supported by filters that enable practices to quickly approve refills that pass protocol, providing more time for clinicians to review refills that fail a protocol or for which no protocol exists. CONCLUSION: A refill protocol is a valuable CDS tool that can improve efficiency, effectiveness, and user satisfaction when processing refill requests. A refill protocol governance structure is an effective way to review, edit, and build refill protocols within a health system.

Elastin-Like Polypeptide: VEGF-B Fusion Protein for Treatment of Preeclampsia.

[Figure: see text].

Targeting the NF-κB pathway for therapy of ischemic stroke.

Ischemic strokes occur when a major cerebral artery or its branches are occluded, resulting in activation of inflammatory processes that cause secondary tissue injury, breakdown of the blood-brain barrier, edema or hemorrhage. Treatments that inhibit inflammatory processes may thus be highly beneficial. A key regulator of the inflammatory process is the nuclear factor kappa B (NF-κB) pathway. In its active form, NF-κB regulates expression of proinflammatory and proapoptotic genes. The molecules that interact with NF-κB, and the subunits that compose NF-κB itself, represent therapeutic targets that can be modulated to decrease inflammation. This review focuses on our current understanding of the NF-κB pathway and the potential benefits of inhibiting NF-κB in ischemia-reperfusion injury of the brain.

Patient familiarity with, understanding of, and preferences for clinical trial endpoints and terminology.

BACKGROUND: Although there is increased attention to designing and explaining clinical trials in ways that are clinically meaningful for patients, there is limited information on patient preferences, understanding, and perceptions of this content. METHODS: Maximum difference scaling (MaxDiff) methodology was used to develop a survey for assessing patients' understanding of 19 clinical terms and perceived importance of 9 endpoint surrogate phrases used in clinical trials and consent forms. The survey was administered electronically to individuals with metastatic breast cancer affiliated with the Metastatic Breast Cancer Alliance. Analyses were performed using Bayesian P values with statistical software. RESULTS: Among 503 respondents, 77% had a college degree, 70% were diagnosed with metastatic disease ≥2 years before survey completion, and 77% had received ≥2 lines of systemic therapy. Less than 35% of respondents reported understanding "fairly well" the terms symptomatic progression, duration of disease control, time to treatment cessation, and endpoints. Income level and time since onset of metastatic disease correlated with comprehension. Patients who had received ≥6 lines of therapy perceived that time until serious side effects (P < .001) and time on therapy (P < .001) were more important compared with those who had received only 1 line of therapy. Positively phrased parameters were associated with increased perceived importance. CONCLUSIONS: Even among educated, heavily pretreated patients, many commonly used clinical research terms are poorly understood. Comprehension and the perceived importance of trial endpoints vary over the course of disease. These observations may inform the design, discussion, and reporting of clinical trials.

Patient Portal Usage and Outcomes Among Adult Patients with Uncontrolled Asthma.

BACKGROUND: Patient-clinician communication, essential for favorable asthma outcomes, increasingly relies on information technology including the electronic heath record-based patient portal. For patients with chronic disease living in low-income neighborhoods, the benefits of portal communication remain unclear. OBJECTIVE: To describe portal activities and association with 12-month outcomes among low-income patients with asthma formally trained in portal use. METHODS: In a longitudinal observational study within a randomized controlled trial, 301 adults with uncontrolled asthma were taught 7 portal tasks: reviewing upcoming appointments, scheduling appointments, reviewing medications, locating laboratory results, locating immunization records, requesting refills, and messaging. Half the patients were randomized to receive up to 4 home visits by community health workers. Patients' portal use by activities, rate of usage over time, frequency of appointments with asthma physicians, and asthma control and quality of life were assessed over time and estimated as of 12 months from randomization. RESULTS: Fewer than 60% of patients used the portal independently. Among users, more than half used less than 1 episode per calendar quarter. The most frequent activities were reading messages and viewing laboratory results and least sending messages and making appointments. Higher rates of portal use were not associated with keeping regular appointments during follow-up, better asthma control, or higher quality of life at 12-month postintervention. CONCLUSIONS: Patients with uncontrolled asthma used the portal irregularly if at all, despite in-person training. Usage was not associated with regular appointments or with clinical outcomes. Patient portals need modification to accommodate low-income patients with uncontrolled asthma.

Biopolymer-Delivered, Maternally Sequestered NF-κB (Nuclear Factor-κB) Inhibitory Peptide for Treatment of Preeclampsia.

Preeclampsia is a hypertensive disorder of pregnancy that causes significant acute and long-term risk to the mother and the baby. The multifaceted maternal syndrome is driven by overproduction of circulating anti-angiogenic factors, widespread inflammation, and endothelial dysfunction. Nuclear factor-κB (NF-κB) is a transcription factor that plays a central role in the inflammatory response. Its activity is increased in the preeclamptic placenta, and it promotes the systemic endothelial dysfunction present in preeclampsia. There is an acute need for new therapeutics targeted to the causative pathways of preeclampsia. Our group has developed a drug delivery system based on the bioengineered protein ELP (elastin-like polypeptide) that is capable of stabilizing therapeutics in the maternal circulation and preventing their placental transfer. Here we used the ELP carrier system to deliver a peptide known to inhibit the NF-κB pathway. This polypeptide, containing a cell-penetrating peptide and an NF-κB inhibitory peptide derived from the p50 nuclear localization sequence (abbreviated SynB1-ELP-p50i), blocked NF-κB activation and prevented TNF-α (tumor necrosis factor alpha)-induced endothelin production in vitro. Fusion of the p50i peptide to the SynB1-ELP carrier slowed its plasma clearance and prevented its placental transfer in pregnant rats, resulting in increased deposition in the maternal kidney, liver, and placenta relative to the free peptide. When administered in a rat model of placental ischemia, SynB1-ELP-p50i partially ameliorated placental ischemia-induced hypertension and reduced placental TNF-α levels with no signs of toxicity. These data support the continued development of ELP-delivered NF-κB inhibitors as maternally sequestered anti-inflammatory agents for preeclampsia therapy.

Implementation of a multi-modal pain regimen to decrease inpatient opioid exposure after injury.

INTRODUCTION: In 2013, we implemented a pill-based, multi-modal pain regimen (MMPR) in order to decrease in-hospital opioid exposure after injury at our trauma center. We hypothesized that the MMPR would decrease inpatient oral morphine milligram equivalents (MME), decrease opioid prescriptions at discharge, and result in similar Numerical Rating Scale (NRS) pain scores. METHODS: Adult patients admitted to a level-1 trauma center with ≥1 rib fracture from 2010 to 2017 were included - spanning 3 years before and 4 years after MMPR implementation. MME were summarized as medians and interquartile range (IQR) by year of admission. The effect of the MMPR on daily total MME was estimated using Bayesian generalized linear model. RESULTS: Over the 8 year study period, 6,933 patients who met study inclusion criteria were included. No significant differences between years were observed in Abbreviated Injury Scale (AIS) Chest or Injury Severity Scores (ISS). After introduction of the MMPR, there was a significant reduction in median total MME administered per patient day from 60 MME/patient day (IQR 36-91 MME/patient day) pre-MMPR implementation to 37 MME/patient day (IQR 18-61 MME/patient day) in 2017, p < 0.01. Total MME administered per patient day decreased by 31% in 2017 as compared to 2010 (rate ratio 0.69, 95% CI 0.64-0.75). Average NRS pain scores decreased by 0.8 points (95% CI -0.87, -0.81) from 2010 to 2017. CONCLUSION: The introduction of a multi-modal pain regimen resulted in significant reduction in in-patient opioid exposure after injury. The reduction in inpatient opioid use from 2010 to 2017 was equivalent to 11 mg less oxycodone or 17 mg less hydrocodone per patient per day. Additionally, use of the MMPR was associated with a reduction in NRS pain scores.