Activity-Based Nitric Oxide-Responsive Porphyrin for Site-Selective and Nascent Cancer Ablation.

Nitric oxide (NO) generated within the tumor microenvironment is an established driver of cancer progression and metastasis. Recent efforts have focused on leveraging this feature to target cancer through the development of diagnostic imaging agents and activatable chemotherapeutics. In this context, porphyrins represent an extraordinarily promising class of molecules, owing to their demonstrated use within both modalities. However, the remodeling of a standard porphyrin to afford a responsive chemical that can distinguish elevated NO from physiological levels has remained a significant research challenge. In this study, we employed a photoinduced electron transfer strategy to develop a panel of NO-activatable porphyrin photosensitizers (NOxPorfins) augmented with real-time fluorescence monitoring capabilities. The lead compound, NOxPorfin-1, features an o-phenylenediamine trigger that can effectively capture NO (via N2O3) to yield a triazole product that exhibits a 7.5-fold enhancement and a 70-fold turn-on response in the singlet oxygen quantum yield and fluorescence signal, respectively. Beyond demonstrating excellent in vitro responsiveness and selectivity toward NO, we showcase the potent photodynamic therapy (PDT) effect of NOxPorfin-1 in murine breast cancer and human non-small cellular lung cancer cells. Further, to highlight the in vivo efficacy, two key studies were executed. First, we utilized NOxPorfin-1 to ablate murine breast tumors in a site-selective manner without causing substantial collateral damage to healthy tissue. Second, we established a nascent human lung cancer model to demonstrate the unprecedented ability of NOxPorfin-1 to halt tumor growth and progression completely. The results of the latter study have tremendous implications for applying PDT to target metastatic lesions.

Unraveling the interplay of circadian rhythm and sleep deprivation on mood: A Real-World Study on first-year physicians.

The interplay between circadian rhythms, time awake, and mood remains poorly understood in the real-world. Individuals in high-stress occupations with irregular schedules or nighttime shifts are particularly vulnerable to depression and other mood disorders. Advances in wearable technology have provided the opportunity to study these interactions outside of a controlled laboratory environment. Here, we examine the effects of circadian rhythms and time awake on mood in first-year physicians using wearables. Continuous heart rate, step count, sleep data, and daily mood scores were collected from 2,602 medical interns across 168,311 days of Fitbit data. Circadian time and time awake were extracted from minute-by-minute wearable heart rate and motion measurements. Linear mixed modeling determined the relationship between mood, circadian rhythm, and time awake. In this cohort, mood was modulated by circadian timekeeping (p<0.001). Furthermore, we show that increasing time awake both deteriorates mood (p<0.001) and amplifies mood's circadian rhythm nonlinearly. These findings demonstrate the contributions of both circadian rhythms and sleep deprivation to underlying mood and show how these factors can be studied in real-world settings using Fitbits. They underscore the promising opportunity to harness wearables in deploying chronotherapies for psychiatric illness.

The Drosophila blood-brain barrier regulates sleep via Moody G protein-coupled receptor signaling.

Sleep is vital for most animals, yet its mechanism and function remain unclear. We found that permeability of the BBB (blood-brain barrier)-the organ required for the maintenance of homeostatic levels of nutrients, ions, and other molecules in the brain-is modulated by sleep deprivation (SD) and can cell-autonomously effect sleep changes. We observed increased BBB permeability in known sleep mutants as well as in acutely sleep-deprived animals. In addition to molecular tracers, SD-induced BBB changes also increased the penetration of drugs used in the treatment of brain pathologies. After chronic/genetic or acute SD, rebound sleep or administration of the sleeping aid gaboxadol normalized BBB permeability, showing that SD effects on the BBB are reversible. Along with BBB permeability, RNA levels of the BBB master regulator moody are modulated by sleep. Conversely, altering BBB permeability alone through glia-specific modulation of moody, gαo, loco, lachesin, or neuroglian-each a well-studied regulator of BBB function-was sufficient to induce robust sleep phenotypes. These studies demonstrate a tight link between BBB permeability and sleep and indicate a unique role for the BBB in the regulation of sleep.

The Impact of religiosity/spirituality on slowing the progression of substance use: Based on the National Epidemiological Survey of Alcohol and Related Conditions (NESARC-III).

BACKGROUND: Religiosity has been suggested to be protective against substance use disorder (SUD) initiation but its impact of the progression of development is not known. AIMS: This study investigated the impact of religiosity/spirituality on the development of heavy use and SUD following substance use initiation (alcohol, cannabis, and tobacco) utilizing data from the 2012 to 2013 National Epidemiologic Survey on Alcohol and Related Conditions-III. METHOD: Individuals with a known age at onset of substance initiation were included (n = 30,590, n = 11,126, and n = 14,083; for alcohol, cannabis, or tobacco users, respectively). Religiosity was measured by importance of religious/spiritual beliefs and frequency of religious service attendance. The percentage of individuals who progressed to an SUD after substance initiation in each substance was estimated. Discrete-time analysis and survival analysis were used to measure the impact of religiosity on the progression from substance initiation to heavy use and from heavy use to SUD. RESULTS: After controlling for various variables, religious services attendance frequency was statistically associated with a slower progression from substance initiation to heavy use for all three substances: tobacco by 8% to 15%, cannabis by 5% to 26%, and alcohol 9% (p ⩽ .01). Religious importance was associated with slower progression to heavy use in cannabis users by 16% to 21% (p ⩽ .02). Religiosity (believes and attendance) was associated with slowed progression from heavy use to SUD development in alcohol users only. CONCLUSIONS: The findings illustrate strongest association between attending religious services and lower probabilities of progressing to heavy/daily use after substance use initiation for alcohol, tobacco, and cannabis users. This indicates the potential use of religious services as social support for individuals with risky substance use.

Dietary restriction of cysteine and methionine sensitizes gliomas to ferroptosis and induces alterations in energetic metabolism.

Ferroptosis is mediated by lipid peroxidation of phospholipids containing polyunsaturated fatty acyl moieties. Glutathione, the key cellular antioxidant capable of inhibiting lipid peroxidation via the activity of the enzyme glutathione peroxidase 4 (GPX-4), is generated directly from the sulfur-containing amino acid cysteine, and indirectly from methionine via the transsulfuration pathway. Herein we show that cysteine and methionine deprivation (CMD) can synergize with the GPX4 inhibitor RSL3 to increase ferroptotic cell death and lipid peroxidation in both murine and human glioma cell lines and in ex vivo organotypic slice cultures. We also show that a cysteine-depleted, methionine-restricted diet can improve therapeutic response to RSL3 and prolong survival in a syngeneic orthotopic murine glioma model. Finally, this CMD diet leads to profound in vivo metabolomic, proteomic and lipidomic alterations, highlighting the potential for improving the efficacy of ferroptotic therapies in glioma treatment with a non-invasive dietary modification.

Reducing chronic disease may just be a walk in the park.

Wearable technology allows the collection of real-world granular data at scales that would be impossible using traditional collection methods. Master et al. demonstrate the power of this technology to estimate the risk of disease based on daily step counts.1.

Limited Mechanistic Link Between the Monod Equation and Methanogen Growth: a Perspective from Metabolic Modeling.

The Monod equation has been widely applied as the general rate law of microbial growth, but its applications are not always successful. By drawing on the frameworks of kinetic and stoichiometric metabolic models and metabolic control analysis, the modeling reported here simulated the growth kinetics of a methanogenic microorganism and illustrated that different enzymes and metabolites control growth rate to various extents and that their controls peak at either very low, intermediate, or very high substrate concentrations. In comparison, with a single term and two parameters, the Monod equation only approximately accounts for the controls of rate-determining enzymes and metabolites at very high and very low substrate concentrations, but neglects the enzymes and metabolites whose controls are most notable at intermediate concentrations. These findings support a limited link between the Monod equation and methanogen growth, and unify the competing views regarding enzyme roles in shaping growth kinetics. The results also preclude a mechanistic derivation of the Monod equation from methanogen metabolic networks and highlight a fundamental challenge in microbiology: single-term expressions may not be sufficient for accurate prediction of microbial growth. IMPORTANCE The Monod equation has been widely applied to predict the rate of microbial growth, but its application is not always successful. Using a novel metabolic modeling approach, we simulated the growth of a methanogen and uncovered a limited mechanistic link between the Monod equation and the methanogen's metabolic network. Specifically, the equation provides an approximation to the controls by rate-determining metabolites and enzymes at very low and very high substrate concentrations, but it is missing the remaining enzymes and metabolites whose controls are most notable at intermediate concentrations. These results support the Monod equation as a useful approximation of growth rates and highlight a fundamental challenge in microbial kinetics: single-term rate expressions may not be sufficient for accurate prediction of microbial growth.

Landmark-modulated directional coding in postrhinal cortex.

Visual landmarks can anchor an animal's internal sense of orientation to the external world. The rodent postrhinal cortex (POR) may facilitate this processing. Here, we demonstrate that, in contrast to classic head direction (HD) cells, which have a single preferred orientation, POR HD cells develop a second preferred orientation when an established landmark cue is duplicated along another environmental wall. We therefore refer to these cells as landmark-modulated-HD (LM-HD) cells. LM-HD cells discriminate between landmarks in familiar and novel locations, discriminate between visually disparate landmarks, and continue to respond to the previous location of a familiar landmark following its removal. Rats initially exposed to different stable landmark configurations show LM-HD tuning that may reflect the integration of visual landmark information into an allocentric HD signal. These results provide insight into how visual landmarks are integrated into a framework that supports the neural encoding of landmark-based orientation.

Analysis of Patients' Online Reviews of Orthopaedic Surgeons.

INTRODUCTION: Physician rating websites (PRWs) are an increasingly popular interface between patient and surgeon. Despite the growing popularity of PRWs, little guidance exists for orthopaedic surgeons regarding online reviews. We analyzed online ratings and comments to provide a better understanding of patients' values and expectations so that surgeons can tailor their practice accordingly to enhance their clinical care and online reputation. METHODS: Three common PRWs (Vitals, HealthGrades, and RateMDs) were queried from January 1, 2006, to May 18, 2020. Publicly available ratings, both quantitative (1 to 5 stars) and qualitative (free text comments), were collected. Comments were qualitatively tabulated as having positive or negative assessments for categories including outcome, personality, staff, surgical skill, visit time, bedside manner, wait time, diagnosis, knowledge, treatment, and advanced practice providers and analyzed using chi square goodness of fit. Quantitative comparisons of star ratings were made across surgeon years in practice, sex, practice setting, and PRW and compared using chi square independence testing. RESULTS: In total, 81% of patient comments were found to have a positive assessment. Comments regarding outcome (P < 0.001), staff (P = 0.001), surgical skill (P < 0.001), or knowledge (P = 0.001) were more likely to be positive. Reviews regarding bedside manner (P < 0.001), wait time (P < 0.001), diagnosis (P < 0.001), treatment (P < 0.001), or advanced practice providers (P < 0.001) were more likely to be negative. Surgeon sex was not associated with a difference in quantitative ratings (P = 0.131), unlike practice setting (P < 0.001) and PRW (P < 0.001). DISCUSSION: PRWs are a growing interface between surgeon and patient with a considerable effect on surgeon marketability. This study reveals a statistical association between certain patient-centered medical practices and positive patient reviews. This emphasizes the importance of ensuring that high standards are maintained throughout a physician's practice of maintaining a constant awareness of the fundamentals for effective patient care and of taking care to curate a physician's online presence.

Is Opioid-Limiting Legislation Effective for Hand Surgery Patients?

BACKGROUND: The Rhode Island State Legislature passed the Uniform Controlled Substances Act in 2016 to limit opioid prescriptions. We aimed to objectively evaluate its effect on opioid prescribing for hand surgery patients and also identify risk factors for prolonged opioid use. METHODS: A 6-month period (January-June 2016) prior to passage of the law was compared with a period following its implementation (July-December 2017). Thumb carpometacarpal arthroplasty and distal radius fracture fixation were classified as "major surgery" and carpal tunnel and trigger finger release as "minor surgery." Prescription Drug Monitoring Database was used to review controlled substances filled during the study periods. RESULTS: A total of 1380 patients met our inclusion criteria, with 644 prelaw and 736 postlaw patients. Patients undergoing "major surgery" saw a significant decrease in the number of pills issued in the first postoperative prescription (41.1 vs 21.0) and a corresponding decrease in morphine milligram equivalents (MMEs) (318.6 vs 159.2 MMEs) after implementation. A 30% decrease in MMEs was also seen in those undergoing "major surgery" in the first 30 days postoperatively (544.7 vs 381.7 MMEs). Risk factors for prolonged opioid use included male sex and preoperative opioid use. CONCLUSIONS: In Rhode Island, opioid-limiting legislation resulted in a significant decrease in the number of pills and MMEs of the initial prescription and a 30% decrease in total MMEs in the 30-day postoperative period after "major hand surgery." Additional research is needed to explore the association between legislation and clinical outcomes.

Bayesian Multi-View Clustering given complex inter-view structure.

Multi-view datasets are becoming increasingly prevalent. These datasets consist of different modalities that provide complementary characterizations of the same underlying system. They can include heterogeneous types of information with complex relationships, varying degrees of missingness, and assorted sample sizes, as is often the case in multi-omic biological studies. Clustering multi-view data allows us to leverage different modalities to infer underlying systematic structure, but most existing approaches are limited to contexts in which entities are the same across views or have clear one-to-one relationships across data types with a common sample size. Many methods also make strong assumptions about the similarities of clusterings across views. We propose a Bayesian multi-view clustering approach (BMVC) which can handle the realities of multi-view datasets that often have complex relationships and diverse structure. BMVC incorporates known and complex many-to-many relationships between entities via a probabilistic graphical model that enables the joint inference of clusterings specific to each view, but where each view informs the others. Additionally, BMVC estimates the strength of the relationships between each pair of views, thus moderating the degree to which it imposes dependence constraints. We benchmarked BMVC on simulated data to show that it accurately estimates varying degrees of inter-view dependence when inter-view relationships are not limited to one-to-one correspondence. Next, we demonstrated its ability to capture visually interpretable inter-view structure in a public health survey of individuals and households in Puerto Rico following Hurricane Maria. Finally, we showed that BMVC clusters integrate the complex relationships between multi-omic profiles of breast cancer patient data, improving the biological homogeneity of clusters and elucidating hypotheses for functional biological mechanisms. We found that BMVC leverages complex inter-view structure to produce higher quality clusters than those generated by standard approaches. We also showed that BMVC is a valuable tool for real-world discovery and hypothesis generation.

DNA methylation signatures reveal that distinct combinations of transcription factors specify human immune cell epigenetic identity.

Epigenetic reprogramming underlies specification of immune cell lineages, but patterns that uniquely define immune cell types and the mechanisms by which they are established remain unclear. Here, we identified lineage-specific DNA methylation signatures of six immune cell types from human peripheral blood and determined their relationship to other epigenetic and transcriptomic patterns. Sites of lineage-specific hypomethylation were associated with distinct combinations of transcription factors in each cell type. By contrast, sites of lineage-specific hypermethylation were restricted mostly to adaptive immune cells. PU.1 binding sites were associated with lineage-specific hypo- and hypermethylation in different cell types, suggesting that it regulates DNA methylation in a context-dependent manner. These observations indicate that innate and adaptive immune lineages are specified by distinct epigenetic mechanisms via combinatorial and context-dependent use of key transcription factors. The cell-specific epigenomics and transcriptional patterns identified serve as a foundation for future studies on immune dysregulation in diseases and aging.

The Environmental and Social Determinants of Health Matter in a Pandemic: Predictors of COVID-19 Case and Death Rates in New York City.

Our research objective was to determine which environmental and social factors were predictive of coronavirus disease 2019 (COVID-19) case and death rates in New York City (NYC), the original epicenter of the pandemic in the US, and any differential impacts among the boroughs. Data from various sources on the demographic, health, and environmental characteristics for NYC zip codes, neighborhoods, and boroughs were analyzed along with NYC government's reported case and death rates by zip code. At the time of analysis, the Bronx had the highest COVID-19 case and death rates, while Manhattan had the lowest rates. Significant predictors of a higher COVID-19 case rate were determined to be proportion of residents aged 65 years plus; proportion of residents under 65 years with a disability; proportion of White residents; proportion of residents without health insurance; number of grocery stores; and a higher ozone level. For COVID-19 death rates, predictors include proportion of residents aged 65 years plus; proportion of residents who are not US citizens; proportion on food stamps; proportion of White residents; proportion of residents under 65 years without health insurance; and a higher level of ozone. Results across boroughs were mixed, which highlights the unique demographic, socioeconomic, and community characteristics of each borough. To reduce COVID-19 inequities, it is vital that the NYC government center the environmental and social determinants of health in policies and community-engaged interventions adapted to each borough.

Larger Initial Opioid Prescriptions Following Total Joint Arthroplasty Are Associated with Greater Risk of Prolonged Use.

BACKGROUND: The ongoing U.S. opioid epidemic threatens quality of life and poses substantial economic and safety burdens to opioid abusers and their communities, physicians, and health-care systems. Public health experts have argued that prescription opioids are implicated in this epidemic; however, opioid dosing following surgical procedures remains controversial. The purpose of this study was to evaluate the relationship between initial opioid prescribing following total hip arthroplasty (THA) and total knee arthroplasty (TKA) and the risk and quantity of long-term opioid use. METHODS: Patients undergoing THA or TKA from January 1, 2016, to June 30, 2016, were identified. Preoperative 30-day opioid and benzodiazepine exposures were evaluated using the Rhode Island Prescription Drug Monitoring Program. Cumulative morphine milligram equivalents (MMEs) in the postoperative inpatient stay, initial outpatient opioid prescription, and prescriptions filled from 31 to 90 days (prolonged use) and 91 to 150 days (chronic use) following the surgical procedure were calculated. Regression analyses evaluated the association between the initial postoperative opioid dosing and prolonged or chronic use, controlling for demographic characteristics, procedure, preoperative opioid and benzodiazepine exposures, anesthesia type, and use of a peripheral nerve block. RESULTS: A total of 507 patients (198 who underwent a THA and 309 who underwent a TKA) were identified. Increased inpatient opioid dosing (odds ratio [OR], 1.49 per 1 standard deviation increase in inpatient opioid MMEs; p = 0.001) and increased dosing in the first outpatient prescription (OR, 1.26 per 1 standard deviation increase in initial outpatient prescription MMEs; p = 0.049) were each independently associated with an increased risk of prolonged opioid use. Additionally, increased inpatient dosing postoperatively was strongly associated with a greater risk of chronic use (OR, 1.77 per 1 standard deviation increase in inpatient MMEs; p < 0.001). Among the 30% (151 of 507) of patients requiring prolonged postoperative opioids, each 1-MME increase in the initial outpatient prescription dose was associated with a 0.997-MME increase in quantity filled during the prolonged period (p < 0.001). Among the 14% (73 of 507) of patients requiring chronic opioids, every 1-MME increase in the initial outpatient dose was associated with a 1.678-MME increase in chronic opioid dosing (p = 0.008). CONCLUSIONS: Increased opioid dosing in the early postoperative period following total joint arthroplasty (TJA) is associated with an increased risk of extended opioid use. A dose-dependent relationship between initial outpatient dosing and greater future quantities consumed by those with prolonged usage and those with chronic usage was noted. This study suggests that providers should attempt to minimize inpatient and early outpatient opioid utilization following TJA. Multimodal pain management strategies may be employed to assist in achieving adequate pain control while minimizing opioid utilization. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Mathematical modeling and experimental validation for expression microdissection.

Using laser excitation, expression microdissection (xMD) can selectively heat cancer cells targeted via immunohistochemical staining to enable their selective retrieval from tumor tissue samples, thus reducing misdiagnoses caused by contamination of noncancerous cells. Several theoretical models have been validated for the photothermal effect in highly light absorbing and scattering media. However, these models are not generally applicable to the physics behind the process of xMD. In this study, we propose a thermal model that can analyze the transient temperature distribution and heat melt zone in an xMD sample medium composed of a thermoplastic film and a tumor tissue sample sandwiched between two glass slides. Furthermore, we experimentally examined the model using an ink layer with controllable optical properties to serve as a microscale-thin, tissue-mimicking phantom and found the experimentally measured film temperature is in good agreement with the model predictions. The validated model can help researchers to optimize cell retrieval by xMD for improved diagnostics of cancer and other diseases.

Has a Prescription-limiting Law in Rhode Island Helped to Reduce Opioid Use After Total Joint Arthroplasty?

BACKGROUND: In the United States, since 2016, at least 28 of 50 state legislatures have passed laws regarding mandatory prescribing limits for opioid medications. One of the earliest state laws (which was passed in Rhode Island in 2016) restricted the maximum morphine milligram equivalents provided in the first postoperative prescription for patients defined as opioid-naïve to 30 morphine milligram equivalents per day, 150 total morphine milligram equivalents, or 20 total doses. While such regulations are increasingly common in the United States, their effects on opioid use after total joint arthroplasty are unclear. QUESTIONS/PURPOSES: (1) Are legislative limitations to opioid prescriptions in Rhode Island associated with decreased opioid use in the immediate (first outpatient prescription postoperatively), 30-day, and 90-day periods after THA and TKA? (2) Is this law associated with similar changes in postoperative opioid use among patients who are opioid-naïve and those who are opioid-tolerant preoperatively? METHODS: Patients undergoing primary THA or TKA between January 1, 2016 and June 28, 2016 (before the law was passed on June 28, 2016) were retrospectively compared with patients undergoing surgery between June 1, 2017 and December 31, 2017 (after the law's implementation on April 17, 2017). The lapse between the pre-law and post-law periods was designed to avoid confounding from potential voluntary practice changes by physicians after the law was passed but before its mandatory implementation. Demographic and surgical details were extracted from a large multi-specialty orthopaedic group's surgical billing database using Current Procedural Terminology codes 27130 and 27447. Any patients undergoing revision procedures, same-day bilateral arthroplasties, or a second primary THA or TKA in the 3-month followup period were excluded. Secondary data were confirmed by reviewing individual electronic medical records in the associated hospital system which included three major hospital sites. We evaluated 1125 patients. In accordance with the state's department of health guidelines, patients were defined as opioid-tolerant if they had filled any prescription for an opioid medication in the 30-day preoperative period. Data on age, gender, and the proportion of patients who were defined as opioid tolerant preoperatively were collected and found to be no different between the pre-law and post-law groups. The state's prescription drug monitoring program database was used to collect data on prescriptions for all controlled substances filled between 30 days preoperatively and 90 days postoperatively. The primary outcomes were the mean morphine milligram equivalents of the initial outpatient postoperative opioid prescription after discharge and the mean cumulative morphine milligram equivalents at the 30- and 90-day postoperative intervals. Secondary analyses included subgroup analyses by procedure and by preoperative opioid tolerance. RESULTS: After the law was implemented, the first opioid prescriptions were smaller for patients who were opioid-naïve (mean 156 ± 106 morphine milligram equivalents after the law's passage versus 451 ± 296 before, mean difference 294 morphine milligram equivalents; p < 0.001) and those who were opioid-tolerant (263 ± 265 morphine milligram equivalents after the law's passage versus 534 ± 427 before, mean difference 271 morphine milligram equivalents; p < 0.001); however, for cumulative prescriptions in the first 30 days postoperatively, this was only true among patients who were previously opioid-naïve (501 ± 416 morphine milligram equivalents after the law's passage versus 796 ± 597 before, mean difference 295 morphine milligram equivalents; p < 0.001). Those who were opioid-tolerant did not have a decrease in the cumulative number of 30-day morphine milligram equivalents (1288 ± 1632 morphine milligram equivalents after the law's passage versus 1398 ± 1274 before, mean difference 110 morphine milligram equivalents; p = 0.066). CONCLUSIONS: The prescription-limiting law was associated with a decline in cumulative opioid prescriptions at 30 days postoperatively filled by patients who were opioid-naïve before total joint arthroplasty. This may substantially impact public health, and these policies should be considered an important tool for healthcare providers, communities, and policymakers who wish to combat the current opioid epidemic. However, given the lack of a discernible effect on cumulative opioids filled from 30 to 90 days postoperatively, further investigations are needed to evaluate more effective policies to prevent prolonged opioid use after total joint arthroplasty, particularly in patients who are opioid-tolerant preoperatively. LEVEL OF EVIDENCE: Level III, therapeutic study.

Opioid-limiting legislation associated with decreased 30-day opioid utilization following anterior cervical decompression and fusion.

BACKGROUND CONTEXT: Since 2016, 35 of 50 US states have passed opioid-limiting laws. The impact on postoperative opioid prescribing and secondary outcomes following anterior cervical discectomy and fusion (ACDF) remains unknown. PURPOSE: To evaluate the effect of opioid-limiting regulations on postoperative opioid prescriptions, emergency department (ED) visits, unplanned readmissions, and reoperations following elective ACDF. STUDY DESIGN/SETTING: Retrospective review of prospectively-collected data. PATIENT SAMPLE: Two hundred and eleven patients (101 pre-law, 110 post-law) undergoing primary elective 1-3 level ACDF during specified pre-law (December 1st, 2015-June 30th, 2016) and post-law (June 1st, 2017-December 31st, 2017) study periods were evaluated. METHODS: Demographic, medical, surgical, clinical, and pharmacological data was collected from all patients. Total morphine milligram equivalents (MMEs) filled was compared at 30-day postoperative intervals, before and after stratification by preoperative opioid-tolerance. Thirty- and 90-day ED visit, readmission, and reoperation rates were calculated. Independent predictors of increased 30-day and chronic (>90 day) opioid utilization were evaluated. RESULTS: Demographic, medical, and surgical factors were similar pre-law versus post-law (all p>.05). Post-law, ACDF patients received fewer opioids in their first postoperative prescription (26.65 vs. 62.08 pills, p<.001; 202.23 vs. 549.18 MMEs, p<.001) and in their first 30 postoperative days (cumulative 30-day MMEs 444.14 vs. 877.87, p<.001). Furthermore, post-law reductions in cumulative 30-day MMEs were seen among both opioid-naïve (363.54 vs. 632.20 MMEs, p<.001) and opioid-tolerant (730.08 vs. 1,122.90 MMEs, p=.022) patient populations. Increased 30-day opioid utilization was associated with surgery in the pre-law period, preoperative opioid exposure, preoperative benzodiazepine exposure, and number of levels fused (all p<.05). Chronic (>90 day) opioid requirements were associated with preoperative opioid exposure (odds ratio 4.42, p<.001) but not with pre/post-law status (p>.05). Pre- and post-law patients were similar in terms of 30- or 90-day ED visits, unplanned readmissions, and reoperations (all p>.05). CONCLUSIONS: Implementation of mandatory opioid prescribing limits effectively decreased 30-day postoperative opioid utilization following ACDF without a rebound increase in prescription refills, ED visits, unplanned hospital readmissions, or reoperations for pain.

Opioid-Limiting Legislation Associated With Reduced Postoperative Prescribing After Surgery for Traumatic Orthopaedic Injuries.

OBJECTIVES: To evaluate opioid-prescribing patterns after surgery for orthopaedic trauma before and after implementation of opioid-limiting mandates in one state. DESIGN: Retrospective review. SETTING: Level-1 trauma center. PATIENTS/PARTICIPANTS: Seven hundred fifty-three patients (297 pre-law and 456 post-law) undergoing isolated fixation for 6 common fracture patterns during specified pre-law (January 1, 2016-June 28, 2016) and post-law (June 01, 2017-December 31, 2017) study periods. Polytrauma patients were excluded. INTERVENTION: Implementation of statewide legislation establishing strict limits on initial opioid prescriptions [150 total morphine milligram equivalents (MMEs), 30 MMEs per day, or 20 total doses]. MAIN OUTCOME MEASUREMENTS: Initial opioid prescription dose, cumulative MMEs filled by 30 and 90 days postoperatively. RESULTS: Pre-law and post-law patient groups did not differ in terms of age, sex, opioid tolerance, recent benzodiazepine use, or open versus closed fracture pattern (P > 0.05). The post-law cohort received significantly less opioids (363.4 vs. 173.6 MMEs, P < 0.001) in the first postoperative prescription. Furthermore, the post-law group received significantly less cumulative MMEs in the first 30 postoperative days (677.4 vs. 481.7 MMEs, P < 0.001); This included both opioid-naïve (633.7 vs. 478.1 MMEs, P < 0.001) and opioid-tolerant patients (1659.2 vs. 880.0 MMEs, P = 0.048). No significant difference in opioid utilization between pre- and post-law groups was noted after postoperative day 30. Independent risk factors for prolonged (>30 days) postoperative opioid use included male gender (odds ratio 2.0, 95% confidence interval 1.4-2.9, P < 0.001) and preoperative opioid use (odds ratio 5.1, 95% confidence interval 2.4-10.5, P < 0.001). CONCLUSIONS: Opioid-limiting legislation is associated with a statistically and clinically significant reduction in initial and 30-day opioid prescriptions after surgery for orthopaedic trauma. Preoperative opioid use and male gender are independently associated with prolonged postoperative opioid use in this population. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Opioid-Limiting Regulation: Effect on Patients Undergoing Knee and Shoulder Arthroscopy.

PURPOSE: To determine the effect prescription-limiting legislation passed in Rhode Island has had on opioids prescribed following arthroscopic knee and shoulder surgery at various time points, up to 90 days postoperatively. METHODS: All patients undergoing the 3 most common arthroscopic procedures at our institution (anterior cruciate ligament reconstruction, partial meniscectomy, and rotator cuff repair) were included. Patients were selected from 2 6-month study periods (prepassage and postimplementation of the law). The state's Prescription Drug Monitoring Program database was queried for controlled substances filled in the perioperative period (from 30 days preoperatively to 90 days postoperatively). Multiple logistic regressions were used to identify predictors of chronic (>30 days) opioid use. RESULTS: The morphine milligram equivalents (MMEs) prescribed in the initial postoperative script decreased from 319.04 (∼43 5-mg oxycodone tablets) in the prepassage to 152.45 MMEs (∼20 5-mg oxycodone tablets) in the postimplementation group (P < .001). The total MMEs filled in the first 30 days decreased from 520.93 to 299.94 MMEs (∼70 to ∼40 5-mg oxycodone tablets) (P < .001). MMEs filled between 30 and 90 days fell by 22.5% for all patients in this study; however, this change was not statistically significant (P = .263). Preoperative opioid use (odds ratio, 10.85; P < .001) and preoperative benzodiazepine use (odds ratio, 2.13; P = .005) predicted chronic opioid use postoperatively. CONCLUSIONS: State opioid-limiting legislation reduced cumulative MMEs following arthroscopic knee and shoulder surgery in the first 30 days. Further research assessing the impact of this legislation on postoperative pain control, patient satisfaction, and functional outcomes following surgery is warranted. LEVEL OF EVIDENCE: Level III, case-control study.