Efficacy of a Lidocaine-Impregnated Elastrator Band for Castration and Tail Docking in Lambs.

The primary objective of this study was to demonstrate the non-inferiority between lidocaine-impregnated ligation bands (LLBs) and control bands (CBs) with respect to the efficacy of castration and tail docking. Secondary objectives were to compare castration and tail-docking success, evaluate local site reactions, and compare average daily gain (ADG) between the treatment groups. A total of 238 male lambs were enrolled and randomly assigned to receive LLBs or CBs on their tail and scrotum. Lambs were weighed, had a health assessment, and the band site was observed on -3, 7, 14, 21, 28, 35, and 42 days after the bands were applied. A linear regression model was built to assess average daily gain, whereas a repeated measures model was used to evaluate body weight differences at each of the measured timepoints. Furthermore, logistic regression models were used to evaluate associations with casting outcomes. Few differences were noted between treatment groups with respect to casting success for the scrotum and tail and ADG over the entire experimental period. Non-inferiority calculations demonstrated no differences in tail docking and scrotal casting success, with casting occurring for the majority of animals by d 21 and d 42 for castration and tail docking, respectively. However, lambs receiving LLBs gained more weight from d -3 to 7 (+0.03 kg/d; 95% CI: 0 to 0.07), which may be an indication of effective pain control during the first week following band application. Overall, the use of an LLB does not affect the time to successful casting of the tail and could improve short-term growth when compared to a control band. Further studies are needed to compare LLBs to multimodal methods of pain relief.

Efficacy and Safety of Lidocam Topical Gel (4% Lidocaine-0.3% Meloxicam) for Pain and Inflammation Management during Castration and Tail Docking in Piglets.

(1) Background: It has been well established that castration and tail docking are both painful during and following the procedure, yet there are limited convenient and effective products to address both short-term and long-term pain. Lidocam Topical Gel (LTG) (4% lidocaine and 0.3% meloxicam) was developed to address industry needs for an effective and safe product to address animal welfare concerns regarding castration and tail docking in piglets. (2) Methods: Study 1: Male piglets aged 4-8 days of age were treated with LTG (n = 30) or a control gel (n = 30). Approximately 30 min after application of the gel, the piglets were surgically castrated and tail docked. The efficacy of pain control during the surgical procedures and post-procedure (24 h) pain and inflammation control were evaluated using both behavioral and physiological measurements. Study 2: Meloxicam residue depletion following LTG treatment was followed for 28 days. Study 3: Clinical and pathological safety were evaluated in five groups of eight piglets receiving LTG with: (1) no treatment, (2) nominal topical dose, (3) two times the nominal topical dose, (4) three times the nominal topical dose, and 5) one times the nominal topical dose and 2 mL of LTG by oral gavage daily for 3 days. (3) Results: LTG-treated piglets had a significant reduction in electrocutaneous stimulation response before the procedures and 4 and 24 h post-procedures. Stress vocalization intensity and duration were less in piglets receiving LTG during the surgical procedures. Plasma cortisol and substance P were significantly lower in LTG-treated piglets 3 h after castration and tail docking. The weight and average daily gain were significantly increased in piglets receiving LTG. LTG did not interfere with wound healing or cause irritation at the application sites. There were no abnormal clinical or pathological findings associated with the use of LTG at three times the nominal dose given daily for three days. As meloxicam persisted in the application site tissue, a slaughter withdrawal time of 24 days was determined. (4) Conclusions: When applied to the skin 30 min before castration and tail docking, LTG is effective in surgical pain control and provides post-surgical pain control for up to 24 h. LTG is safe for use in piglets and provides an acceptable withdrawal time for commercial use. LTG is a potentially effective product for commercial use for piglet castration and tail docking.

National Quality Program Achieves Improvements in Safety Culture and Reduction in Preventable Harms in Community Hospitals.

BACKGROUND: Through an innovative affiliation, Duke University Health System (DUHS), a large and complex academic health system, and LifePoint Health® (LifePoint [LP]) collaborated to create a joint venture, DLP Healthcare (DLP) to measurably improve culture and quality and patient safety metrics in community hospitals across the United States. A structured approach to quality was developed in DLP hospitals and later refined and spread to all LP hospitals through the National Quality Program (NQP). METHODS: The NQP was designed to drive organizationwide performance improvement through use of a framework of leadership, performance improvement, and culture. A comprehensive quality assessment of each DLP and LP hospital led to the creation of a customized improvement plan that was specific to the performance level of individual hospitals and aligned with strategic organizational goals. The improvement process was data driven, managed with defined improvement methodologies and practices, and implemented in a culture that honors teamwork, mutual respect, accountability and provider well-being. RESULTS: Implementation of the NQP has led to significant improvements in patient safety metrics and in safety culture, which have now been sustained for more than seven years. Aggregate harm, as measured by administrative claims data-based harms per 1,000 inpatient-days, was reduced by 62.5% between January 2011 and December 2017, as compared to 2010 baseline data. CONCLUSION: The LP and Duke journey to achieve high reliability in community hospitals has yielded significant improvement in measures of patient safety and culture. The results are consistent with literature supporting the link between culture and overall performance.

A Multiplexed Fluorescent Calcium and NFAT Reporter Gene Assay to Identify GPCR Agonists.

Intracellular calcium response and resulting calcium signaling to an agonist-GPCR interaction are important for the measurement of compound activity in the GPCR drug development. The increase in cytosol calcium concentration can be measured by the fluorescent calcium indicator dye such as Fluo-4 in a quick assay (in 3-5 minutes) using the fluorescence imaging plate reader. The calcium signaling through the transcription factors such as NFAT that induces gene expression can be measured by the reporter gene assay that links to the expression of reporter enzyme such as the beta-lactamase that requires 5-hour incubation. We have evaluated a multiplexed assay that sequentially measures the calcium response to a GPCR agonist in a rapid fluorescent calcium dye assay, followed by a NFAT beta-lactamase assay, and compared them in the single assay format. We found that the agonist activity determined in the multiplexed assay were comparable with these determined in the single assay format and the Z' factors were all >0.5. Five active compounds were identified that were active in both calcium dye assay and beta-lactamase assay. Therefore, our results demonstrated the utility of this multiplexed calcium assay for screening of GPCR compounds that can cross validate the primary hits and help to eliminate the false positive compounds.

Strategies for safe care of critical care perinatal patients.

In most inpatient settings, the complexity of care required by individual patients coupled with the wide range of services provided within a single institution mean patients are routinely cared for in highly specialized units. Service lines, such as surgical services; intensive care; emergency services; and maternity, typically operate cooperatively, but independently, within larger facilities. Units are distinguished from one another, not only by their mission, geographic location, and work processes, but by the expertise and specialty knowledge of clinicians who practice there. From a patient safety perspective, specialty care is advantageous because it promotes clinical benchmarking, standardization of practice norms, acquisition and maintenance of specialty knowledge and skills, and interdisciplinary teamwork.

Discovery of N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]furo[2,3-c]pyridine-5-carboxamide as an agonist of the alpha7 nicotinic acetylcholine receptor: in vitro and in vivo activity.

A novel alpha7 nAChR agonist, N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]furo[2,3-c]pyridine-5-carboxamide (3a, PHA-709829), has been identified for the potential treatment of cognitive deficits in schizophrenia. The compound shows potent and selective alpha7 in vitro activity, excellent brain penetration, good rat oral bioavailability and robust in vivo efficacy in a rat auditory sensory gating model.

Design, synthesis, structure-activity relationship, and in vivo activity of azabicyclic aryl amides as alpha7 nicotinic acetylcholine receptor agonists.

A novel set of azabicyclic aryl amides have been identified as potent and selective agonists of the alpha7 nAChR. A two-pronged approach was taken to improve the potential hERG liability of previously disclosed alpha7 nAChR agonist, PNU-282,987, while maintaining the compound's other desirable pharmacological properties. The first approach involved further exploration of the aryl carboxylic acid fragment of PNU-282,987, while the second approach focused on modification of the azabicyclic amine portion of PNU-282,987. The best compounds from each series are characterized by rapid brain penetration, good oral bioavailability in rat, and demonstrate in vivo efficacy in a rat P50 auditory sensory gating assay. At least one analog from each series (1h, 1o, 2a, 9a, and 18a) shows an improved hERG safety profile over PNU-282,987.

Identification of novel inhibitors of the transforming growth factor beta1 (TGF-beta1) type 1 receptor (ALK5).

Screening of our internal compound collection for inhibitors of the transforming growth factor beta1 (TGF-beta1) type I receptor (ALK5) identified several hits. Optimization of the dihydropyrroloimidazole hit 2 by introduction of a 2-pyridine and 3,4-methylenedioxyphenyl group gave 7, a selective ALK5 inhibitor. With this information, optimization of the triarylimidazole hit 8 gave the selective inhibitor 14, which inhibits TGF-beta1-induced fibronectin mRNA formation while displaying no measurable cytotoxicity in the 48 h XTT assay.

Identification of a novel nuclear guanosine triphosphate-binding protein differentially expressed in renal disease.

A novel guanosine triphosphate-binding protein, chronic renal failure gene (CRFG), was discovered by differential display PCR to be regulated differentially in renal disease. Within the rat kidney, CRFG mRNA was localized to the outer medulla and was highly expressed in epithelial cells. The specific renal expression of CRFG mRNA in the outer medulla was reduced dramatically in several rat models of renal disease, including diabetic nephropathy, partial nephrectomy, ischemia, and anti-Thy1.1-induced nephritis. CRFG was localized selectively in the nucleus of human and rodent cells, as determined by immunocytochemistry and green fluorescence fusion protein. Cellular mRNA levels of CRFG were also increased after serum administration, when cells proliferate. These data suggest that CRFG may be involved in regulating guanosine triphosphate-dependent nuclear events that are associated with cell proliferation and that are important in normal renal function and essential for growth and development.