A nurse manager succession planning model with associated empirical outcomes.

OBJECTIVE: Perceptions of leadership and management competency after a formal nurse manager succession planning program were evaluated. BACKGROUND: A lack of strategic workforce planning and development of a leadership pipeline contributes to a predicted nurse manager shortage. To meet the anticipated needs for future leadership, evidence-based action is critical. METHODS: A quasi-experimental mixed-methods, 1-group pretest/posttest research design was used. Nurses working in an acute care hospital were recruited for the study and selected using an objective evaluative process. RESULTS: Participant perceptions regarding their leadership and management competencies significantly increased after the leadership program. Program evaluations confirmed that participants found the program beneficial. One year after program completion, 100% of the program participants have been retained at the organization and 73% had transitioned to leadership roles. CONCLUSION: Succession planning and leadership development serve as beneficial and strategic mechanisms for identifying and developing high-potential individuals for leadership positions, contributing toward the future nursing leadership pipeline.

Leadership facilitation strategies to establish evidence-based practice in an acute care hospital.

AIM: To assess the impact of leadership facilitation strategies on nurses' beliefs of the importance and frequency of using evidence in daily nursing practice and the perception of organizational readiness in an acute care hospital. BACKGROUND: Integrating evidence in practice is a prominent issue for hospital nursing as knowledge and skills, beliefs, organizational infrastructure and nursing leadership must all be addressed. DESIGN: Prospective, descriptive comparative. METHOD: Three surveys were used in this prospective descriptive comparative study. Evidence-Based Practice Beliefs Scale, the Implementation Scale and Organizational Culture & Readiness for System-Wide Integration Survey measured change before and after facilitating strategies for evidence-based practice enculturation. Data were collected in December 2008 (N = 427) and in December 2010 (N = 469). RESULTS: Leadership facilitated infrastructure development in three major areas: incorporating evidence-based practice outcomes in the strategic plan; supporting mentors; and advocating for resources for education and outcome dissemination. With the interventions in place, the total group scores for beliefs and organizational readiness improved significantly. Analyses by job role showed that direct care nurses scores improved more than other role types. No differences were found in the implementation scores. CONCLUSION: Successful key strategies were evidence-based practice education and establishing internal opportunities to disseminate findings. Transformational nursing leadership drives organizational change and provides vision, human and financial resources and time that empowers nurses to include evidence in practice.

Pyrrolamide DNA gyrase inhibitors: fragment-based nuclear magnetic resonance screening to identify antibacterial agents.

DNA gyrase is an essential enzyme in bacteria, and its inhibition results in the disruption of DNA synthesis and, subsequently, cell death. The pyrrolamides are a novel class of antibacterial agents targeting DNA gyrase. These compounds were identified by a fragment-based lead generation (FBLG) approach using nuclear magnetic resonance (NMR) screening to identify low-molecular-weight compounds that bind to the ATP pocket of DNA gyrase. A pyrrole hit with a binding constant of 1 mM formed the basis of the design and synthesis of a focused library of compounds that resulted in the rapid identification of a lead compound that inhibited DNA gyrase with a 50% inhibitory concentration (IC(50)) of 3 µM. The potency of the lead compound was further optimized by utilizing iterative X-ray crystallography to yield DNA gyrase inhibitors that also displayed antibacterial activity. Spontaneous mutants were isolated in Staphylococcus aureus by plating on agar plates containing pyrrolamide 4 at the MIC. The resistant variants displayed 4- to 8-fold-increased MIC values relative to the parent strain. DNA sequencing revealed two independent point mutations in the pyrrolamide binding region of the gyrB genes from these variants, supporting the hypothesis that the mode of action of these compounds was inhibition of DNA gyrase. Efficacy of a representative pyrrolamide was demonstrated against Streptococcus pneumoniae in a mouse lung infection model. These data demonstrate that the pyrrolamides are a novel class of DNA gyrase inhibitors with the potential to deliver future antibacterial agents targeting multiple clinical indications.

Pyrrolamide DNA gyrase inhibitors: optimization of antibacterial activity and efficacy.

The pyrrolamides are a new class of antibacterial agents targeting DNA gyrase, an essential enzyme across bacterial species and inhibition results in the disruption of DNA synthesis and subsequently, cell death. The optimization of biochemical activity and other drug-like properties through substitutions to the pyrrole, piperidine, and heterocycle portions of the molecule resulted in pyrrolamides with improved cellular activity and in vivo efficacy.

Implementing relationship-based care.

OBJECTIVE: The authors describe verbal and nonverbal caring behaviors of nurses before and after implementation of a model of Relationship-Based Care (RBC). Nurse turnover and patient satisfaction were evaluated to support the organizational commitment to RBC. BACKGROUND: To become foundational for all interactions, caring behaviors must be enculturated among nurses, colleagues (professionals and nonprofessionals), and organizational leaders. METHODS: An observational design describing verbal and nonverbal caring behaviors prior to implementation of RBC and at 3 and 12 months after implementation. RESULTS: Findings suggest that verbal and nonverbal caring behaviors increased. Behaviors were sustained at 1 year. Nurse turnover rates decreased from 9.4% to 1.9%. CONCLUSION: Observable caring behaviors and nurse turnover rates improved with the implementation of RBC.

Showcasing differences between quality improvement, evidence-based practice, and research.

The literature confirms that much confusion exists regarding the terms quality improvement (QI), evidence-based practice (EBP), and research. A multifaceted approach was used to provide clarity regarding these three equally important concepts. First, the authors present a synthesis of the literature that discusses differences between QI, EBP, and research. Second, the authors introduce a newly created comparative table that synthesizes current literature and showcases differences between QI, EBP, and research. Finally, the authors highlight uses of the comparative table within multiple settings.

Antibacterial Spiropyrimidinetriones with N-Linked Azole Substituents on a Benzisoxazole Scaffold Targeting DNA Gyrase.

Herein, we report spiropyrimidinetriones (SPTs) incorporating N-linked azole substituents on a benzisoxazole scaffold with improved Gram-positive antibacterial activity relative to previously described analogues. SPTs have an unusual spirocyclic architecture and represent a new antibacterial class of bacterial DNA gyrase and topoisomerase IV inhibitors. They are not cross-resistant to fluoroquinolones and other DNA gyrase/topoisomerase IV inhibitors used clinically. The activity of the SPTs was assessed for DNA gyrase inhibition, and the antibacterial activity across Gram-positive and Gram-negative pathogens with N-linked 1,2,4-triazoles substituted on the 5-position provides the most worthwhile profile. Directed nucleophilic and electrophilic chemistry was developed to vary this 5-position with carbon, nitrogen, or oxygen substituents and explore structure-activity relationships including those around a target binding model. Compounds with favorable pharmacokinetic parameters were identified, and two compounds demonstrated cidality in a mouse model of Staphylococcus aureus infection.

Use of a High-Throughput Phenotypic Screening Strategy to Identify Amplifiers, a Novel Pharmacological Class of Small Molecules That Exhibit Functional Synergy with Potentiators and Correctors.

Cystic fibrosis (CF) is a lethal genetic disorder caused by mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Despite recent groundbreaking approval of genotype-specific small-molecule drugs, a significant portion of CF patients still lack effective therapeutic options that address the underlying cause of the disease. Through a phenotypic high-throughput screen of approximately 54,000 small molecules, we identified a novel class of CFTR modulators called amplifiers. The identified compound, the characteristics of which are represented here by PTI-CH, selectively increases the expression of immature CFTR protein across different CFTR mutations, including F508del-CFTR, by targeting the inefficiencies of early CFTR biosynthesis. PTI-CH also augments the activity of other CFTR modulators and was found to possess novel characteristics that distinguish it from CFTR potentiator and corrector moieties. The PTI-CH-mediated increase in F508del-CFTR did not elicit cytosolic or endoplasmic reticulum-associated cellular stress responses. Based on these data, amplifiers represent a promising new class of CFTR modulators for the treatment of CF that can be used synergistically with other CFTR modulators.

Room-Temperature Palladium-Catalyzed Amination of Aryl Bromides and Chlorides and Extended Scope of Aromatic C-N Bond Formation with a Commercial Ligand.

The reactions of aryl bromides with amines occurs at room temperature when using Pd(0) and P(t-Bu)(3) in a 1:1 ratio, and the reactions of aryl chlorides occur at room temperature or 70 degrees C. The arylation of indoles and the new arylation of carbamates also occur when using P(t-Bu)(3) as ligand.

Synthesis of a tetrahydronaphthyridine spiropyrimidinetrione DNA gyrase inhibiting antibacterial agent--differential substitution at all five carbon atoms of pyridine.

The synthesis of (-)-1, a potent antibacterial agent, was achieved stereoselectively in nine steps from readily available starting materials. Directed metalations were developed to assemble a pentasubstituted pyridine with appropriately positioned aldehyde and dimethylmorpholine substituents for a key tertiary amino effect reaction (T-reaction) that led to the spirocylic architecture. Ultimately, (-)-1 was isolated as the thermodynamically most favored stereoisomer.

Optimization of pyrrolamide topoisomerase II inhibitors toward identification of an antibacterial clinical candidate (AZD5099).

AZD5099 (compound 63) is an antibacterial agent that entered phase 1 clinical trials targeting infections caused by Gram-positive and fastidious Gram-negative bacteria. It was derived from previously reported pyrrolamide antibacterials and a fragment-based approach targeting the ATP binding site of bacterial type II topoisomerases. The program described herein varied a 3-piperidine substituent and incorporated 4-thiazole substituents that form a seven-membered ring intramolecular hydrogen bond with a 5-position carboxylic acid. Improved antibacterial activity and lower in vivo clearances were achieved. The lower clearances were attributed, in part, to reduced recognition by the multidrug resistant transporter Mrp2. Compound 63 showed notable efficacy in a mouse neutropenic Staphylococcus aureus infection model. Resistance frequency versus the drug was low, and reports of clinical resistance due to alteration of the target are few. Hence, 63 could offer a novel treatment for serious issues of resistance to currently used antibacterials.

Responses to work complexity: the novice to expert effect.

The purpose of this study was to explore the differences in how advanced beginners, competent, and expert nurses prioritize and reprioritize patient care. This qualitative study had a purposive sample of 23 nurses on cardiac/ telemetry units at five hospitals. Four themes emerged from the data: cognitive strategies, communication, integration of roles, and response to the work environment. As the nurses progressed in expertise, they were better able to organize, more effectively deal with interruptions, anticipate patient needs, integrate varied nursing roles into their work, and communicate effectively. The significance of this study is the identification of factors that affect the nurse's ability to work productively in today's care environment. It increases understanding of the graduate nurses' perception and response to the complexity and work of nursing. An understanding of these factors provides the basis for further research to understand and promote transition of nurses from advanced beginner to expert.

New carbon-linked azole oxazolidinones with improved potency and pharmacokinetics.

Substitution of phenyl oxazolidinones with carbon-linked azoles resulted in the discovery of a new class of potent oxazolidinones that have excellent Gram-positive activity. In addition, replacement of the C-5 acetamide side chains with a 4-methyl triazole diminished monoamine oxidase activity. The synthesis and biological evaluation of these compounds are reported.

Synthetic Studies in Phytochrome Chemistry.

An account is given of the author's several approaches to the synthesis of the parent chromophore of phytochrome (1), a protein-bound linear tetrapyrrole derivative that controls photomorphogenesis in higher plants. These studies culminated in enantioselective syntheses of both 2R- and 2S-phytochromobilin (4), as well as several (13)C-labeled derivatives designed to probe the site of Z,E-isomerization during photoexcitation. When reacted in vitro, synthetic 2R-4 and recombinant-derived phytochrome apoprotein N-C produced a protein-bound chromophore with identical difference spectra to naturally occurring 1.

Femtosecond excitation energy transport in triarylamine dendrimers.

The search for a model that can be used to describe the optical excitation migration in dendrimers has attracted great attention. In most cases in a dendrimer the conjugation is disrupted at the branching point; however, the excitation is delocalized. The strength of interactions among neighboring chromophores plays a key role in determining the energy migration mechanism. Conversely, having many identical chromophores held tightly together in an ordered macromolecular architecture will allow for many dipoles to be accessible for optical excitation. Therefore, the relative orientation of dipoles will be important in determining the mechanism of energy migration. Here we report the synthesis and photo-physical investigation of triarylamine-based dendrimers. Two important synthetic steps were utilized in the synthesis. First, we employed diphenylmethyl protective groups on the amines to assist in deprotective hydrogenolysis of the larger structures. Second, highly active catalysts for formation of both di- and triarylamines that are based on a 1:1 ratio of P(t-Bu)3 and Pd(dba)2 improved reaction yields of the C-N bond formation and decreased reaction times The energy migration processes in the dendrimers were investigated utilizing ultrafast time-resolved fluorescence anisotropy measurements. The fluorescence anisotropy of all three dendrimers decayed to a residual value within approximately 100 fs. This fluorescence anisotropy decay showed a general trend in decreasing with increasing dendrimer generation. The residual anisotropy value also showed a gradual decrease with an increase in the dendrimer generation. This fast energy depolarization is discussed through a coherent excitonic mechanism among dipoles oriented in different directions. We believe that the formation of coherent domains leads to fast energy migration extending over a large part of the dendrimer.