Unplanned Emergency and Urgent Care Visits After Outpatient Orthopaedic Surgery.

INTRODUCTION: This study sought to determine (1) incident risk, (2) chief report, (3) risk factors, and (4) total cost of unplanned healthcare visits to an emergency and/or urgent care (ED/UC) facility within 30 days of an outpatient orthopaedic procedure. METHODS: This was a retrospective database review of 5,550 outpatient surgical encounters from a large metropolitan healthcare system between 2012 and 2016. Statistical analysis consisted of measuring the ED/UC incident risk, respective to the procedures and anatomical region. Patient-specific risk factors were evaluated through multigroup comparative statistics. RESULTS: Of the 5,550 study patients, 297 (5.4%) presented to an ED/UC within 30 days of their index procedure, with 23 (0.4%) needing to be readmitted. Native English speakers, patients older than 45 years, and nonsmokers had significant reduced relative risk of unplanned ED or UC visit within 30 days of index procedure (P < 0.01). In addition, hand tendon repair/graft had the greatest risk incidence for ED/UC visit (11.0%). Unplanned ED/UC reimbursements totaled $146,357.34, averaging $575.65 per visit. DISCUSSION: This study provides an evaluation of outpatient orthopaedic procedures and their relationship to ED/UC visits. Specifically, this study identifies patient-related and procedural-related attributes that associate with an increased risk for unplanned healthcare utilization.

Cannabidiol reduces withdrawal symptoms in nicotine-dependent rats.

RATIONALE: Cannabidiol (CBD) reduces craving in animal models of alcohol and cocaine use and is known to modulate nicotinic receptor function, suggesting that it may alleviate symptoms of nicotine withdrawal. However, preclinical evaluation of its efficacy is still lacking. OBJECTIVES: The goal of this study was to test the preclinical efficacy of a chronic CBD treatment in reducing nicotine dependence using measures of withdrawal symptoms including somatic signs, hyperalgesia, and weight gain during acute and protracted abstinence. METHODS: Male and female Wistar rats were made dependent on nicotine using osmotic minipumps (3.15 mg/kg/day) for 2 weeks, after which minipumps were removed to induce spontaneous withdrawal. Three groups received CBD injections at doses of 7.5, 15, and 30 mg/kg/day for 2 weeks, starting 1 week into chronic nicotine infusion. The control groups included rats with nicotine minipumps that received vehicle injections of sesame oil instead of CBD; rats implanted with saline minipumps received sesame oil injections (double vehicle) or the highest dose of CBD 30 mg/kg/day. Throughout the experiment, serum was collected for determination of CBD and nicotine concentrations, mechanical sensitivity threshold and withdrawal scores were measured, and body weight was recorded. RESULTS: CBD prevented rats from exhibiting somatic signs of withdrawal and hyperalgesia during acute and protracted abstinence. There was no dose-response observed for CBD, suggesting a ceiling effect at the doses used and the potential for lower effective doses of CBD. The saline minipump group did not show either somatic signs of withdrawal or hyperalgesia during acute and protracted abstinence, and the highest dose of CBD used (30 mg/kg/day) did not alter these results. CONCLUSIONS: This preclinical study suggests that using CBD as a strategy to alleviate the withdrawal symptoms upon nicotine cessation may be beneficial.

Cigarette Smoking Trajectories in Adult Former Smokers Using the JUUL System.

Objective: In this study, we assessed cigarette smoking over 12 months among adult former smokers who newly purchased a JUUL Starter Kit (JSK). Methods: Prevalence of past 30-day smoking and factors associated with smoking were assessed among adult (age ≥ 21) former established smokers, stratified as recent (quitting ≤ 12 months) and long-term quitters (> 12 months), who purchased a JSK and completed ≥ 1 of 6 follow-up assessments (N = 4786). Results: Recent quitters had higher rates (16.6%-19.9%) of past 30-day smoking than long-term quitters (6.4%-9.2%) across the 12-month period; smoking prevalence did not significantly increase over time in either subgroup. Few participants (6.5% of recent quitters, 2.8% of long-term quitters) reported smoking at both 9 and 12 months, a pattern that might indicate persistent smoking. Past 30-day JUUL use remained high (≥ 87%) across the 12 months. Participants who used JUUL more frequently were less likely to smoke. Conclusions: Among former smokers who purchased JUUL, prevalence rates of smoking were low and stable across the 12-month period, suggesting there was not a growing cohort of former smokers resuming smoking. Smoking was more common in recent quitters than long-term quitters. Greater use of JUUL was associated with reduced odds of smoking resumption.

Clinical Heinz Body Anemia in a Cat After Repeat Propofol Administration Case Report.

Heinz body formation has been reported in cats repeatedly administered propofol for anesthesia induction, although the resultant changes were deemed of little clinical significance (1, 2). This report suggests repeated propofol administration to some individual cats might induce anemia with clinical signs and cessation of propofol administration may result in rapid resolution. A 9-years-old American Domestic Shorthair cat receiving a 20-fraction radiation protocol for lateral thoracic fibrosarcoma showed lethargy, decreased appetite and activity, and Heinz body (3+ on blood smear examination) anemia (packed cell volume 22%; reference interval 24-45%) after 12 repeated propofol anesthesia inductions. The anesthesia induction protocol was adjusted to exclude propofol. Over the following week, the anemia resolved (packed cell volume, 30%), and the cat's activity level, appetite and attitude improved. The total dose of propofol received over the 12 treatments was 62.4 mg/kg.

Advances in smoking cessation pharmacotherapy: Non-nicotinic approaches in animal models.

The landscape of worldwide tobacco use is changing, with a decrease in traditional smoking and an exponential rise in electronic cigarette use. No new nicotine cessation pharmacotherapies have come to market in the last 10 years. The current therapies that have been approved by the United States Food and Drug Administration for nicotine cessation include nicotine replacement therapy, varenicline, a nicotinic acetylcholine receptor partial agonist, and the atypical antidepressant bupropion. Nicotine replacement therapy and varenicline both act on nicotinic acetylcholine receptors. Bupropion inhibits the dopamine transporter, the norepinephrine transporter, and the nicotinic acetylcholine receptors to inhibit smoking behavior. Notwithstanding these treatments, rates of successful nicotine cessation in clinical trials remain low. Recent pharmacological approaches to improve nicotine cessation rates in animal models have turned their focus away from activating nicotinic acetylcholine receptors. The present review focuses on such pharmacological approaches, including nicotine vaccines, anti-nicotine antibodies, nicotine-degrading enzymes, cannabinoids, and metformin. Both immunopharmacological and enzymatic approaches rely on restricting and degrading nicotine within the periphery, thus preventing psychoactive effects of nicotine on the central nervous system. In contrast, pharmacologic inhibition of the enzymes which degrade nicotine could affect smoking behavior. Cannabinoid receptor agonists and antagonists interact with the dopamine reward pathway and show efficacy in reducing nicotine addiction-like behaviors in preclinical studies. Metformin is currently approved by the Food and Drug Administration for the treatment of diabetes. It activates specific intracellular kinases that may protect against the lower metabolism, higher oxidation, and inflammation that are associated with nicotine withdrawal. Further studies are needed to investigate non-nicotinic targets to improve the treatment of tobacco use disorder. This article is part of the special issue on 'Contemporary Advances in Nicotine Neuropharmacology'.

Validation of a nicotine vapor self-administration model in rats with relevance to electronic cigarette use.

The debate about electronic cigarettes is dividing healthcare professionals, policymakers, manufacturers, and communities. A key limitation in our understanding of the cause and consequences of vaping is the lack of animal models of nicotine vapor self-administration. Here, we developed a novel model of voluntary electronic cigarette use in rats using operant behavior. We found that rats voluntarily exposed themselves to nicotine vapor to the point of reaching blood nicotine levels that are similar to humans. The level of responding on the active (nicotine) lever was similar to the inactive (air) lever and lower than the active lever that was associated with vehicle (polypropylene glycol/glycerol) vapor, suggesting low positive reinforcing effects and low nicotine vapor discrimination. Lever pressing behavior with nicotine vapor was pharmacologically prevented by the α4ß2 nicotinic acetylcholine receptor partial agonist and α7 receptor full agonist varenicline in rats that self-administered nicotine but not vehicle vapor. Moreover, 3 weeks of daily (1 h) nicotine vapor self-administration produced addiction-like behaviors, including somatic signs of withdrawal, allodynia, anxiety-like behavior, and relapse-like behavior after 3 weeks of abstinence. Finally, 3 weeks of daily (1 h) nicotine vapor self-administration produced cardiopulmonary abnormalities and changes in α4, α3, and ß2 nicotinic acetylcholine receptor subunit mRNA levels in the nucleus accumbens and medial prefrontal cortex. These findings validate a novel animal model of nicotine vapor self-administration in rodents with relevance to electronic cigarette use in humans and highlight the potential addictive properties and harmful effects of chronic nicotine vapor self-administration.

Grey eosinophils in a Miniature Schnauzer with a poorly differentiated mast cell tumor.

A 10-year-old female spayed Miniature Schnauzer was presented for investigation of an intra-nasal mass. The mass was diagnosed by histopathologic examination as an undifferentiated round cell neoplasm with an infiltrate of segmented leukocytes, interpreted as neutrophilic inflammation. The mass was treated with palliative radiation and systemic chemotherapy due to the presence of regional lymph node metastasis. During subsequent monitoring over several months, the peripheral leukocyte concentration was repeatedly within reference intervals to slightly increased with low numbers of toxic neutrophils. Four months after the initial diagnosis, there was a significant leukocytosis of 66 100 cells/µL, and 39 700 cells/µL of the leukocytes had variably mature, lobulated, and hypolobulated nuclei, and grey cytoplasm with clear vacuoles, resembling grey eosinophils. To further characterize these cells, peripheral blood smears from the patient and a canine control with eosinophilia were stained for alkaline phosphatase (AP), peroxidase, and esterase activities, and with Luxol fast blue (LFB). Histopathologic sections of the nasal mass were stained with LFB and immunohistochemically for tryptase. On blood smears, the cytoplasm of the suspected grey eosinophils stained for AP and granules stained with LFB confirmed that there was an eosinophilic lineage. Peroxidase staining was weak, and esterase staining was absent. On histopathologic sections from the nasal mass, the segmented leukocytes contained LFB-staining granules, indicating an eosinophilic infiltrate was present. Neoplastic cells expressed tryptase, which confirms a mast cell lineage. Our findings suggest that grey eosinophils might be under-recognized and interpreted incorrectly as toxic neutrophils. This report expands the canine breeds in which these eosinophils have been identified.

Increased Health Care Utilization and Costs during Allogeneic Hematopoietic Cell Transplantation for Acute Leukemia and Myelodysplastic Syndromes in Adolescents and Young Adults Compared with Children: A Multicenter Study.

Allogeneic hematopoietic cell transplantation (HCT) is a curative option for patients with acute leukemia and myelodysplastic syndromes (MDS) but is associated with significant cost. Compared with children (age <15 years), adolescents and young adults (AYA; age 15 to 39 years) undergoing HCT have an increased risk for transplantation-related complications. However, whether such complications translate into increased resource utilization and costs during HCT remains unknown. Therefore, we conducted a multicenter database study using the Pediatric Health Information System database, an administrative database containing resource utilization data from 49 US tertiary children's hospitals to compare inpatient costs and resource utilization in children and AYA undergoing HCT for acute leukemia and MDS. The International Classification of Diseases, Ninth Revision, Clinical Modification codes were used to identify HCT recipients and transplantation-related complications occurring up to 1 year post-HCT. We identified 1693 HCT recipients at pediatric centers between January 2010 and September 2014. Eighty percent of the total costs (from admission for HCT up to 1 year post-HCT) occurred during the initial transplantation admission. During initial admission, although AYA and children had a similar median length of stay (LOS) of 43 days, AYA incurred significantly greater adjusted costs ($338,458 versus $275,723; P < .001) and costs per hospital day ($7122 versus $5838; P < .001). Median total costs and costs per day during subsequent time periods post-HCT were also significantly greater in the AYA group. In multivariable analysis, increasing age at HCT, LOS, use of cord blood or an unrelated donor, occurrence of any graft-versus-host disease, infection, and use of dialysis or mechanical ventilation were significant drivers of increased cost at initial admission. In conclusion, allogeneic HCT for acute leukemia and MDS is associated with higher costs in AYA recipients than in children. Therefore, directing efforts and resources aimed at reducing HCT-related costs may be advantageous in this high-risk group.

Randomised clinical trial of community-based peer-led and psychologist-led group treatment for hoarding disorder.

BACKGROUND: Treatment for hoarding disorder is typically performed by mental health professionals, potentially limiting access to care in underserved areas. AIMS: We aimed to conduct a non-inferiority trial of group peer-facilitated therapy (G-PFT) and group psychologist-led cognitive-behavioural therapy (G-CBT). METHOD: We randomised 323 adults with hording disorder 15 weeks of G-PFT or 16 weeks of G-CBT and assessed at baseline, post-treatment and longitudinally (≥3 months post-treatment: mean 14.4 months, range 3-25). Predictors of treatment response were examined. RESULTS: G-PFT (effect size 1.20) was as effective as G-CBT (effect size 1.21; between-group difference 1.82 points, t = -1.71, d.f. = 245, P = 0.04). More homework completion and ongoing help from family and friends resulted in lower severity scores at longitudinal follow-up (t = 2.79, d.f. = 175, P = 0.006; t = 2.89, d.f. = 175, P = 0.004). CONCLUSIONS: Peer-led groups were as effective as psychologist-led groups, providing a novel treatment avenue for individuals without access to mental health professionals. DECLARATION OF INTEREST: C.A.M. has received grant funding from the National Institutes of Health (NIH) and travel reimbursement and speakers' honoraria from the Tourette Association of America (TAA), as well as honoraria and travel reimbursement from the NIH for serving as an NIH Study Section reviewer. K.D. receives research support from the NIH and honoraria and travel reimbursement from the NIH for serving as an NIH Study Section reviewer. R.S.M. receives research support from the National Institute of Mental Health, National Institute of Aging, the Hillblom Foundation, Janssen Pharmaceuticals (research grant) and the Alzheimer's Association. R.S.M. has also received travel support from the National Institute of Mental Health for Workshop participation. J.Y.T. receives research support from the NIH, Patient-Centered Outcomes Research Institute and the California Tobacco Related Research Program, and honoraria and travel reimbursement from the NIH for serving as an NIH Study Section reviewer. All other authors report no conflicts of interest.

Crystallography Coupled with Kinetic Analysis Provides Mechanistic Underpinnings of a Nicotine-Degrading Enzyme.

Nicotine oxidoreductase (NicA2) is a bacterial flavoenzyme, which catalyzes the first step of nicotine catabolism by oxidizing S-nicotine into N-methyl-myosmine. It has been proposed as a biotherapeutic for nicotine addiction because of its nanomolar substrate binding affinity. The first crystal structure of NicA2 has been reported, establishing NicA2 as a member of the monoamine oxidase (MAO) family. However, substrate specificity and structural determinants of substrate binding and/or catalysis have not been explored. Herein, analysis of the pH-rate profile, single-turnover kinetics, and binding data establish that pH does not significantly affect the catalytic rate and product release is not rate-limiting. The X-ray crystal structure of NicA2 with S-nicotine refined to 2.65 Å resolution reveals a hydrophobic binding site with a solvent exclusive cavity. Hydrophobic interactions predominantly orient the substrate, promoting the binding of a deprotonated species and supporting a hydride-transfer mechanism. Notably, NicA2 showed no activity against neurotransmitters oxidized by the two isoforms of human MAO. To further probe the substrate range of NicA2, enzyme activity was evaluated using a series of substrate analogues, indicating that S-nicotine is the optimal substrate and substitutions within the pyridyl ring abolish NicA2 activity. Moreover, mutagenesis and kinetic analysis of active-site residues reveal that removal of a hydrogen bond between the pyridyl ring of S-nicotine and the hydroxyl group of T381 has a 10-fold effect on KM, supporting the role of this bond in positioning the catalytically competent form of the substrate. Together, crystallography combined with kinetic analysis provides a deeper understanding of this enzyme's remarkable specificity.

An enzymatic advance in nicotine cessation therapy.

A nicotine-degrading enzyme termed NicA2 was altered (NicA2-J1) through fusion of an albumin binding domain to increase its half-life. Examination of NicA2-J1 in vivo demonstrated a complete blockade of brain nicotine access, which in turn blunted nicotine's psychoactive effects. These data further support development of pharmacokinetic nicotine cessation therapeutics.

Cucurbit[7]uril-Tetramethylrhodamine Conjugate for Direct Sensing and Cellular Imaging.

This paper describes the design and synthesis of a conjugate (Q7R) comprising the synthetic host cucurbit[7]uril (Q7) linked to the fluorescent dye tetramethylrhodamine (TMR), and the characterization of its optical and guest-binding properties as well as its cellular uptake. Q7R was synthesized in two steps from monofunctionalized azidobutyl-Q7 and NHS-activated TMR. The fluorescence of Q7R is quenched upon guest binding, and this observable was used to determine equilibrium dissociation constant (Kd) values. Unexpectedly, the Kd values for guests binding to Q7R and to unmodified Q7 were essentially identical. Therefore, Q7R can directly report binding to Q7 without an energetic penalty due to the conjugated fluorophore. This result demonstrates a potentially general strategy for the design of single-component host-indicator conjugates that respond sensitively to analytes without perturbing the binding properties of the host. The unique properties of Q7R enabled measurement of Kd values across 3 orders of magnitude and at concentrations as low as 0.7 nM. This result is particularly relevant given the unmatched range of guests and binding affinities demonstrated for Q7. Confocal fluorescence microscopy of live and fixed HT22 neurons revealed the cellular uptake of Q7R and its punctate localization in the cytoplasm. Q7R did not alter cell growth at concentrations up to 2.2 µM over 4 days. These experiments demonstrate the feasibility of Q7R as a direct sensor for guest binding and as a cell-permeable compound for imaging applications.