RGS4 controls airway hyperresponsiveness through GAP-independent mechanisms.

Regulators of G protein signaling (RGS) proteins constrain G protein-coupled receptor (GPCR)-mediated and other responses throughout the body primarily, but not exclusively, through their GTPase-activating protein activity. Asthma is a highly prevalent condition characterized by airway hyper-responsiveness (AHR) to environmental stimuli resulting in part from amplified GPCR-mediated airway smooth muscle contraction. Rgs2 or Rgs5 gene deletion in mice enhances AHR and airway smooth muscle contraction, whereas RGS4 KO mice unexpectedly have decreased AHR because of increased production of the bronchodilator prostaglandin E2 (PGE2) by lung epithelial cells. Here, we found that knockin mice harboring Rgs4 alleles encoding a point mutation (N128A) that sharply curtails RGS4 GTPase-activating protein activity had increased AHR, reduced airway PGE2 levels, and augmented GPCR-induced bronchoconstriction compared with either RGS4 KO mice or WT controls. RGS4 interacted with the p85α subunit of PI3K and inhibited PI3K-dependent PGE2 secretion elicited by transforming growth factor beta in airway epithelial cells. Together, these findings suggest that RGS4 affects asthma severity in part by regulating the airway inflammatory milieu in a G protein-independent manner.

Intrinsic endothelial hyperresponsiveness to inflammatory mediators drives acute episodes in models of Clarkson disease.

Clarkson disease, or monoclonal gammopathy-associated idiopathic systemic capillary leak syndrome (ISCLS), is a rare, relapsing-remitting disorder featuring the abrupt extravasation of fluids and proteins into peripheral tissues, which in turn leads to hypotensive shock, severe hemoconcentration, and hypoalbuminemia. The specific leakage factor(s) and pathways in ISCLS are unknown, and there is no effective treatment for acute flares. Here, we characterize an autonomous vascular endothelial defect in ISCLS that was recapitulated in patient-derived endothelial cells (ECs) in culture and in a mouse model of disease. ISCLS-derived ECs were functionally hyperresponsive to permeability-inducing factors like VEGF and histamine, in part due to increased endothelial nitric oxide synthase (eNOS) activity. eNOS blockade by administration of N(γ)-nitro-l-arginine methyl ester (l-NAME) ameliorated vascular leakage in an SJL/J mouse model of ISCLS induced by histamine or VEGF challenge. eNOS mislocalization and decreased protein phosphatase 2A (PP2A) expression may contribute to eNOS hyperactivation in ISCLS-derived ECs. Our findings provide mechanistic insights into microvascular barrier dysfunction in ISCLS and highlight a potential therapeutic approach.

Fluorescent ratiometric supramolecular tandem assays for phosphatase and phytase enzymes.

Ratiometric fluorescent assays have a built-in correction factor which enhances assay accuracy and reliability. We have developed fluorescent ratiometric supramolecular tandem assays for phosphatase and phytase enzymes using a mixture of three molecular components. One of the molecules is a tetra-cationic fluorescence quencher called CalixPyr which can bind and quench the polyanionic pyrene fluorophore, CMP, that emits at 430 nm. Polyphosphates can disrupt the CMP/CalixPyr complex and alter the fluorescence intensity (responsive signal). CalixPyr has no effect on the fluorescence emission of cationic pentamethine cyanine fluorophore, cCy5, which emits at 665 nm and acts as a non-responsive reference signal. The continuous ratiometric fluorescent assay for alkaline phosphatase monitored hydrolytic consumption of adenosine triphosphate (ATP). The continuous ratiometric fluorescent assay for phytase activity monitored hydrolytic consumption of phytate. With further development this latter assay may be useful for high throughput assessment of phytase activity in individual batches of fortified animal feed. It is likely that the three-molecule mixture (CMP, CalixPyr, cCy5) can become a general assay platform for other enzymes that catalyse addition/removal of phosphate groups from appropriate molecular substrates.

Detection and Mitigation of Neurovascular Uncoupling in Brain Gliomas.

Functional magnetic resonance imaging (fMRI) with blood oxygen level-dependent (BOLD) technique is useful for preoperative mapping of brain functional networks in tumor patients, providing reliable in vivo detection of eloquent cortex to help reduce the risk of postsurgical morbidity. BOLD task-based fMRI (tb-fMRI) is the most often used noninvasive method that can reliably map cortical networks, including those associated with sensorimotor, language, and visual functions. BOLD resting-state fMRI (rs-fMRI) is emerging as a promising ancillary tool for visualization of diverse functional networks. Although fMRI is a powerful tool that can be used as an adjunct for brain tumor surgery planning, it has some constraints that should be taken into consideration for proper clinical interpretation. BOLD fMRI interpretation may be limited by neurovascular uncoupling (NVU) induced by brain tumors. Cerebrovascular reactivity (CVR) mapping obtained using breath-hold methods is an effective method for evaluating NVU potential.

Perioperative Management of Comorbidities in Spine Surgery.

The number of spinal operations performed in the United States has significantly increased in recent years. Along with these rising numbers, there has been a corresponding increase in the number of patient comorbidities. The focus of this article is to review comorbidities in Spine surgery patients and outline strategies to optimize patients and avoid complications.

Relative rates of cancers and deaths in Australian communities with PFAS environmental contamination associated with firefighting foams: A cohort study using linked data.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) are environmental contaminants that are potentially harmful to health. We examined if rates of selected cancers and causes of deaths were elevated in three Australian communities with local environmental contamination caused by firefighting foams containing PFAS. The affected Australian communities were Katherine in Northern Territory, Oakey in Queensland and Williamtown in New South Wales. METHODS: All residents identified in the Medicare Enrolment File (1983-2019)-a consumer directory for Australia's universal healthcare-who ever lived in an exposure area (Katherine, Oakey and Williamtown), and a sample of those who ever lived in selected comparison areas, were linked to the Australian Cancer Database (1982-2017) and National Death Index (1980-2019). We estimated standardised incidence ratios (SIRs) for 23 cancer outcomes, four causes of death and three control outcomes, adjusting for sex, age and calendar time of diagnosis. FINDINGS: We observed higher rates of prostate cancer (SIR=1·76, 95 % confidence interval (CI) 1·36-2·24) in Katherine; laryngeal cancer (SIR=2·71, 95 % CI 1·30-4·98), kidney cancer (SIR=1·82, 95 % CI 1·04-2·96) and coronary heart disease (CHD) mortality (SIR=1·81, 95 % CI 1·46-2·33) in Oakey; and lung cancer (SIR=1·83, 95 % CI 1·39-2·38) and CHD mortality (SIR=1·22, 95 % CI 1·01-1·47) in Williamtown. We also saw elevated SIRs for control outcomes. SIRs for all other outcomes and overall cancer were similar across exposure and comparison areas. INTERPRETATION: There was limited evidence to support an association between living in a PFAS exposure area and risks of cancers or cause-specific deaths.

Hepatic mTORC2 Signaling Facilitates Acute Glucagon Receptor Enhancement of Insulin-Stimulated Glucose Homeostasis in Mice.

Long-term glucagon receptor (GCGR) agonism is associated with hyperglycemia and glucose intolerance, while acute GCGR agonism enhances whole-body insulin sensitivity and hepatic AKTSer473 phosphorylation. These divergent effects establish a critical gap in knowledge surrounding GCGR action. mTOR complex 2 (mTORC2) is composed of seven proteins, including RICTOR, which dictates substrate binding and allows for targeting of AKTSer473. We used a liver-specific Rictor knockout mouse (RictorΔLiver) to investigate whether mTORC2 is necessary for insulin receptor (INSR) and GCGR cross talk. RictorΔLiver mice were characterized by impaired AKT signaling and glucose intolerance. Intriguingly, RictorΔLiver mice were also resistant to GCGR-stimulated hyperglycemia. Consistent with our prior report, GCGR agonism increased glucose infusion rate and suppressed hepatic glucose production during hyperinsulinemic-euglycemic clamp of control animals. However, these benefits to insulin sensitivity were ablated in RictorΔLiver mice. We observed diminished AKTSer473 and GSK3α/ßSer21/9 phosphorylation in RictorΔLiver mice, whereas phosphorylation of AKTThr308 was unaltered in livers from clamped mice. These signaling effects were replicated in primary hepatocytes isolated from RictorΔLiver and littermate control mice, confirming cell-autonomous cross talk between GCGR and INSR pathways. In summary, our study reveals the necessity of RICTOR, and thus mTORC2, in GCGR-mediated enhancement of liver and whole-body insulin action.

Ethnography and user-centered design to inform context-driven implementation.

Despite pervasive findings pointing to its inextricable role in intervention implementation, context remains poorly understood in implementation science. Existing approaches for describing context (e.g., surveys, interviews) may be narrow in scope or superficial in their elicitation of contextual data. Thus, in-depth and multilevel approaches are needed to meaningfully describe the contexts into which interventions will be implemented. Moreover, many studies assess context without subsequently using contextual information to enhance implementation. To be useful for improving implementation, though, methods are needed to apply contextual information during implementation. In the case example presented in this paper, we embedded an ethnographic assessment of context within a user-centered design approach to describe implementation context and apply that information to promote implementation. We developed a patient-reported outcome measure-based clinical intervention to assess and address the pervasive unmet needs of young adults with cancer: the Needs Assessment & Service Bridge (NA-SB). In this paper, we describe the user-centered design process that we used to anticipate context modifications needed to deliver NA-SB and implementation strategies needed to facilitate its implementation. Our ethnographic contextual inquiry yielded a rich understanding of local implementation context and contextual variation across potential scale-up contexts. Other methods from user-centered design (i.e., translation tables and a design team prototyping workshop) allowed us to translate that information into specifications for NA-SB delivery and a plan for implementation. Embedding ethnographic methods within a user-centered design approach can help us to tailor interventions and implementation strategies to their contexts of use to promote implementation.

The field of implementation science studies how to better integrate research evidence into practice. To accomplish this integration, it is important to understand the contexts into which interventions are being implemented. For example, implementation may be influenced by contextual factors such as patient/provider beliefs about an intervention, budget constraints, leadership buy-in, an organization's readiness to change, and many others. Understanding these factors upfront can allow us to adapt interventions to better suit context (e.g., tailoring intervention content to patients' needs), change context to make it more ready for implementation (e.g., changing provider workflow to accommodate an intervention), and anticipate strategies that may be needed to implement an intervention (e.g., delivering training on the intervention to providers). To do this, the field of implementation science is in need of methods for assessing context and using that information to improve implementation. In this paper, we present several methods, including ethnography and methods from user-centered design, for using context to inform implementation efforts.

Glucagon receptor signaling regulates weight loss via central KLB receptor complexes.

Glucagon regulates glucose and lipid metabolism and promotes weight loss. Thus, therapeutics stimulating glucagon receptor (GCGR) signaling are promising for obesity treatment; however, the underlying mechanism(s) have yet to be fully elucidated. We previously identified that hepatic GCGR signaling increases circulating fibroblast growth factor 21 (FGF21), a potent regulator of energy balance. We reported that mice deficient for liver Fgf21 are partially resistant to GCGR-mediated weight loss, implicating FGF21 as a regulator of glucagon's weight loss effects. FGF21 signaling requires an obligate coreceptor (ß-Klotho, KLB), with expression limited to adipose tissue, liver, pancreas, and brain. We hypothesized that the GCGR-FGF21 system mediates weight loss through a central mechanism. Mice deficient for neuronal Klb exhibited a partial reduction in body weight with chronic GCGR agonism (via IUB288) compared with controls, supporting a role for central FGF21 signaling in GCGR-mediated weight loss. Substantiating these results, mice with central KLB inhibition via a pharmacological KLB antagonist, 1153, also displayed partial weight loss. Central KLB, however, is dispensable for GCGR-mediated improvements in plasma cholesterol and liver triglycerides. Together, these data suggest GCGR agonism mediates part of its weight loss properties through central KLB and has implications for future treatments of obesity and metabolic syndrome.

Clinical 7-T MRI for neuroradiology: strengths, weaknesses, and ongoing challenges.

Since the relatively recent regulatory approval for clinical use in both Europe and North America, 7-Tesla (T) MRI has been adopted for clinical practice at our institution. Based on this experience, this article reviews the unique features of 7-T MRI neuroimaging and addresses the challenges of establishing a 7-T MRI clinical practice. The underlying fundamental physics principals of high-field strength MRI are briefly reviewed. Scanner installation, safety considerations, and artifact mitigation techniques are discussed. Seven-tesla MRI case examples of neurologic diseases including epilepsy, vascular abnormalities, and tumor imaging are presented to illustrate specific applications of 7-T MRI. The advantages of 7-T MRI in conjunction with advanced neuroimaging techniques such as functional MRI are presented. Seven-tesla MRI produces more detailed information and, in some cases, results in specific diagnoses where previous 3-T studies were insufficient. Still, persistent technical issues for 7-T scanning present ongoing challenges for radiologists.

Higher temporal resolution multiband fMRI provides improved presurgical language maps.

PURPOSE: We investigated the hypothesis that increasing fMRI temporal resolution using a multiband (MB) gradient echo-echo planar imaging (GRE-EPI) pulse sequence provides fMRI language maps of higher statistical quality than those acquired with a traditional GRE-EPI sequence. METHODS: This prospective study enrolled 29 consecutive patients receiving language fMRI prior to a potential brain resection for tumor, AVM, or epilepsy. A 4-min rhyming task was performed at 3.0 Tesla with a traditional GRE-EPI pulse sequence (TR = 2000, TE = 30, matrix = 64/100%, slice = 4/0, FOV = 24, slices = 30, time points = 120) and an additional MB GRE-EPI pulse sequence with an acceleration factor of 6 (TR = 333, TE = 30, matrix 64/100%, slice = 4/0, FOV = 24, time points = 720). Spatially filtered t statistical maps were generated. Volumes of interest (VOIs) were drawn around activations at Broca's, dorsolateral prefrontal cortex, Wernicke's, and the visual word form areas. The t value maxima were measured for the overall brain and each of the VOIs. A paired t test was performed for the corresponding traditional and MB GRE-EPI measurements. RESULTS: The mean age of subjects was 42.6 years old (18-75). Sixty-two percent were male. The average overall brain t statistic maxima for the MB pulse sequence (t = 15.4) was higher than for the traditional pulse sequence (t = 9.3, p = < .0001). This also held true for Broca's area (p < 0.0001), Wernicke's area (p < .0001), dorsolateral prefrontal cortex (p < .0001), and the visual word form area (p < .0001). CONCLUSION: A MB GRE-EPI fMRI pulse sequence employing high temporal resolution provides clinical fMRI language maps of greater statistical significance than those obtained with a traditional GRE-EPI sequence.

Isolated Diffuse Choroidal Hemangioma: A Variant of Sturge-Weber Syndrome?

The authors report a case of a diffuse choroidal hemangioma in the left eye of a 17-year-old girl. No evidence of leptomeningeal angiomatosis was found on magnetic resonance imaging and neither the medical history nor the clinical examination revealed a port wine birthmark on the left side of the face. Fine telangiectatic vessels were found on the bulbar conjunctiva of the ipsilateral eye. Because of the shared destination of the vessel-trigeminal-ectoderm complex that migrates toward the optic placode, forming choriocapillaris, upper facial skin (upper eyelid), and conjunctival vessels, an embryological basis can be offered for ophthalmic angiomatosis of Sturge-Weber syndrome. The authors propose that vascular angiomatosis of upper eyelid skin and conjunctiva are phenotypically equivalent and may be present or absent, independent of each other. Their proposed expansion of Sturge-Weber syndrome diagnostic criteria needs to be validated by a comprehensive review of ophthalmic features of Sturge-Weber syndrome. [J Pediatr Ophthalmol Strabismus. 2020;57:e43-e47.].

Impact of successful pediatric ureteropelvic junction obstruction surgery on urinary HIP/PAP and BD-1 levels.

INTRODUCTION: In the pediatric patient whose ureteropelvic junction obstruction (UPJO) is not always symptomatic, imaging is the most common means of detecting surgical success. There is interest, however, in other means of post-operative monitoring. A panel of antimicrobial peptides (AMPs) has been previously found to be elevated in UPJO, but the impact of surgical correction on these AMPs is unknown. OBJECTIVE: To determine if elevated levels of candidate urinary AMP biomarkers of urinary tract obstruction decrease following UPJO repair. STUDY DESIGN: Pediatric patients undergoing surgical correction of an UPJO were recruited for participation. Bladder urine from uninfected consenting/assenting patients was collected immediately prior to surgery and then at least 6 months afterward. Based on prior studies demonstrating significant elevation of beta defensin 1 (BD-1), hepatocarcinoma-intestine-pancreas/pancreatitis-associated protein (HIP/PAP), cathelicidin (LL-37), and neutrophil gelatinase-associated lipocalin (NGAL) in patients with UPJO versus control patients, we performed enzyme-linked immunosorbent assays on these four AMPs to compare their expression before and after surgical intervention. If found to significantly decrease, AMP levels were compared to healthy controls. AMP levels were normalized to urine creatinine. Results were analyzed with paired t test or Wilcoxon test using Graphpad software. Correlation was calculated using Pearson or Spearman correlation. A p-value of <0.05 was considered significant. RESULTS: 13 UPJO patients were included in this study; 9 were male (69%). Age at surgery was a median of 4.3 years (average 6.1, range 0.4-18.4 years). Follow-up urine samples were collected a median of 27.4 months after surgery (average 27.4; range 7.8-45.3 months). All 13 patients had clinical improvement and/or signs of improved hydronephrosis on post-operative imaging. HIP/PAP and BD-1 significantly decreased in post-surgical samples compared to pre-surgical samples (p = 0.02 and 0.01, respectively); NGAL and LL-37 did not significantly change. Overall, HIP/PAP decreased in 12 patients (92%) and BD-1 decreased in 11 patients (85%). BD-1 levels after successful repair were not different from healthy controls (p = 0.06). DISCUSSION: Urinary biomarkers of obstruction should detect significant obstructive pathology as well as reflect its resolution. This would enable their use in post-operative monitoring and augment current methods of determining successful surgical outcome through imaging. CONCLUSIONS: The AMPs HIP/PAP and BD-1 are significantly elevated in UPJO but then significantly decrease after pyeloplasty, with BD-1 returning to healthy control levels. As a result, these AMPs could serve as markers of successful surgical intervention.

Glucagon-Receptor Signaling Reverses Hepatic Steatosis Independent of Leptin Receptor Expression.

Glucagon (GCG) is an essential regulator of glucose and lipid metabolism that also promotes weight loss. We have shown that glucagon-receptor (GCGR) signaling increases fatty acid oxidation (FAOx) in primary hepatocytes and reduces liver triglycerides in diet-induced obese (DIO) mice; however, the mechanisms underlying this aspect of GCG biology remains unclear. Investigation of hepatic GCGR targets elucidated a potent and previously unknown induction of leptin receptor (Lepr) expression. Liver leptin signaling is known to increase FAOx and decrease liver triglycerides, similar to glucagon action. Therefore, we hypothesized that glucagon increases hepatic LEPR, which is necessary for glucagon-mediated reversal of hepatic steatosis. Eight-week-old control and liver-specific LEPR-deficient mice (LeprΔliver) were placed on a high-fat diet for 12 weeks and then treated with a selective GCGR agonist (IUB288) for 14 days. Liver triglycerides and gene expression were assessed in liver tissue homogenates. Administration of IUB288 in both lean and DIO mice increased hepatic Lepr isoforms a-e in acute (4 hours) and chronic (72 hours,16 days) (P < 0.05) settings. LeprΔliver mice displayed increased hepatic triglycerides on a chow diet alone (P < 0.05), which persisted in a DIO state (P < 0.001), with no differences in body weight or composition. Surprisingly, chronic administration of IUB288 in DIO control and LeprΔliver mice reduced liver triglycerides regardless of genotype (P < 0.05). Together, these data suggest that GCGR activation induces hepatic Lepr expression and, although hepatic glucagon and leptin signaling have similar liver lipid targets, these appear to be 2 distinct pathways.

Krt5+ urothelial cells are developmental and tissue repair progenitors in the kidney.

Congenital urinary tract obstruction (UTO) is the leading cause of chronic kidney disease in children; however, current management strategies do not safeguard against progression to end-stage renal disease, highlighting the need for interventions to limit or reverse obstructive nephropathy. Experimental UTO triggers renal urothelial remodeling that culminates in the redistribution of basal keratin 5-positive (Krt5+) renal urothelial cells (RUCs) and the generation of uroplakin-positive (Upk)+ RUCs that synthesize a protective apical urothelial plaque. The cellular source of Upk+ RUCs is currently unknown, limiting the development of strategies to promote renal urothelial remodeling as a therapeutic approach. In the present study, we traced the origins of adult Upk+ RUCs during normal development and in response to UTO. Fate mapping analysis demonstrated that adult Upk+ RUCs derive from embryonic and neonatal Krt5+ RUCs, whereas Krt5+ RUCs lose this progenitor capacity and become lineage restricted by postnatal day 14. However, in response to UTO, postnatal day 14-labeled adult Krt5+ RUCs break their lineage restriction and robustly differentiate into Upk+ RUCs. Thus, Krt5+ RUCs drive renal urothelial formation during normal ontogeny and after UTO by differentiating into Upk+ RUCs in a temporally restricted manner.

Pilot Test of an Adapted Intervention to Improve Timeliness of Referrals to Hospice and Palliative Care for Eligible Home Health Patients.

Background: Casarett et al. tested an intervention to improve timeliness of referrals to hospice. Although efficacious in the nursing home setting, it was not tested in other settings of care for seriously ill patients. We, therefore, adapted Casarett's intervention for use in home health (HH). Objective: To assess feasibility, acceptability, and patient outcomes of the adapted intervention. Design: We conducted a nine-week observational pilot test. Setting/Subjects: We conducted our pilot study with two HH agencies. Eligible patients included those who were high risk or frail (identified by the agencies' analytic software as being moderate to high risk for hospitalization or a candidate for hospice referral). Clinical managers identified eligible patients and registered nurses then delivered the intervention, screening patients for hospice appropriateness by asking about care goals, needs, and preferences and initiating appropriate follow-up for patients who screened positive. Measurements: We collected quantitative data on patient enrollment rates and outcomes (election of hospice and/or palliative care). We collected qualitative data on pilot staff experience with the intervention and suggestions for improvement. Results: Pilot HH agencies were able to implement the intervention with high fidelity with minimal restructuring of workflows; 14% of patients who screened positive for hospice appropriateness elected hospice or palliative care. Conclusions: Our findings suggest the adapted intervention was feasible and acceptable to enhance timeliness of hospice and palliative care referral in the HH setting. Additional adaptations suggested by pilot participants could improve impact of the intervention.

The islet-expressed Lhx1 transcription factor interacts with Islet-1 and contributes to glucose homeostasis.

The LIM-homeodomain (LIM-HD) transcription factor Islet-1 (Isl1) interacts with the LIM domain-binding protein 1 (Ldb1) coregulator to control expression of key pancreatic ß-cell genes. However, Ldb1 also has Isl1-independent effects, supporting that another LIM-HD factor interacts with Ldb1 to impact ß-cell development and/or function. LIM homeobox 1 (Lhx1) is an Isl1-related LIM-HD transcription factor that appears to be expressed in the developing mouse pancreas and in adult islets. However, roles for this factor in the pancreas are unknown. This study aimed to determine Lhx1 interactions and elucidate gene regulatory and physiological roles in the pancreas. Co-immunoprecipitation using ß-cell extracts demonstrated an interaction between Lhx1 and Isl1, and thus we hypothesized that Lhx1 and Isl1 regulate similar target genes. To test this, we employed siRNA-mediated Lhx1 knockdown in ß-cell lines and discovered reduced Glp1R mRNA. Chromatin immunoprecipitation revealed Lhx1 occupancy at a domain also known to be occupied by Isl1 and Ldb1. Through development of a pancreas-wide knockout mouse model ( Lhx1∆Panc), we demonstrate that aged Lhx1∆Panc mice have elevated fasting blood glucose levels, altered intraperitoneal and oral glucose tolerance, and significantly upregulated glucagon, somatostatin, pancreatic polypeptide, MafB, and Arx islet mRNAs. Additionally, Lhx1∆Panc mice exhibit significantly reduced Glp1R, an mRNA encoding the insulinotropic receptor for glucagon-like peptide 1 along with a concomitant dampened Glp1 response and mild glucose intolerance in mice challenged with oral glucose. These data are the first to reveal that the Lhx1 transcription factor contributes to normal glucose homeostasis and Glp1 responses.

Preoperative Narcotic Use and Inferior Outcomes After Anatomic Total Shoulder Arthroplasty: A Clinical and Radiographic Analysis.

INTRODUCTION: Our purpose was to determine whether the chronic use of preoperative narcotics adversely affected clinical and/or radiographic outcomes. METHODS: Seventy-three patients (79 shoulders) with primary total shoulder arthroplasty for osteoarthritis were evaluated clinically and radiographically at preoperative visits and postoperatively at a minimum follow-up of 2 years: 26 patients (28 shoulders) taking chronic narcotic pain medication for at least 3 months before surgery and 47 patients (51 shoulders) who were not taking narcotics preoperatively. RESULTS: Postoperatively, significant differences were noted between the narcotic and nonnarcotic groups regarding American Shoulder and Elbow Surgeons scores and visual analog scale scores, as well as forward elevation, external rotation, and all strength measurements (P < 0.01). The nonnarcotic group had markedly higher American Shoulder and Elbow Surgeons scores, better overall range of motion and strength, and markedly lower visual analog scale scores than the narcotic group. CONCLUSION: Chronic preoperative narcotic use seems to be a notable indicator of poor outcomes of anatomic total shoulder arthroplasty for glenohumeral osteoarthritis.