Punishments and the dominance identity in networks.

In this study, we examine the effects of the structure of a network, the dominance identity of the actors, and the actors' ability to reward or punish on the use of punishment and the development of social bonds in a network. As expected, we find that peripheral rather than central actors in a network use punishment more, as do those with a high dominance identity. We also find that persons use punishment to increase or decrease their perceived level of dominance when their dominance identity is not verified. However, the patterns of interaction that develop in the network are an interactive function of network position, actor's dominance identity, and punishment use. We discuss how the social psychological drive to control one's identity interacts with social structural factors in the network to create different cultures of dyadic interaction.

Status and competitive choice.

In this paper, we extend the logic of existing sociological theory on status to explain how status processes can inform selection in competitive choice situations. We argue that in the absence of knowledge about the specific abilities of others and assuming a desire to win, when given the opportunity to "pick their battles," people will draw on overt status differences as a basis for selecting a competitor from a pool of possible competitors. Results from three studies indicate that, as predicted, status differences affect competitor selection, with individuals choosing to compete against those who are relatively lower status based on diffuse characteristics. Moreover, consistent with expectation state theories, results from two studies show that the expectations that people form for their potential competitors based on status differences mediate this relationship. We conclude by discussing the implications of this research.

Utilizing Native Directing Groups: Synthesis of a Selective IKur Inhibitor, BMS-919373, via a Regioselective C-H Arylation.

BMS-919373 is a highly functionalized quinazoline under investigation as a selective, potent IKur current blocker. By utilizing the aminomethylpyridine side chain at C-4, a selective C-H functionalization at C-5 was invented, enabling the efficient synthesis of this molecule. The strategy of leveraging this inherent directing group allowed the synthesis of this complex heterocycle in only six steps from commodity chemicals. The scope of the C-H activation was further investigated, and the generality of the transformation across a series of bicyclic aromatic heterocycles was explored.

Utilizing Native Directing Groups: Mechanistic Understanding of a Direct Arylation Leads to Formation of Tetracyclic Heterocycles via Tandem Intermolecular, Intramolecular C-H Activation.

A mechanistic study on a direct arylation using a native picolylamine directing group is reported. Kinetic studies determined the concentration dependence of substrates and catalysts, as well as catalyst degradation, which led to the development of a new set of reaction conditions capable of affording a robust kinetic profile. During reaction optimization, a small impurity was observed, which was determined to be a dual C-H activation product. A second set of conditions were found to flip the selectivity of the C-H activation to form this tetracycle in high yield. A catalytic cycle is proposed for the intermolecular/intramolecular C-H activation pathway.

The fairness identity and the emergence of inequality.

Social exchange theories explain how differences in structural power can generate inequalities in exchange networks. We argue here that even in the absence of structural power differences, inequality can emerge out of the identity process. We posit that when structurally equivalent actors are uncertain about the resource levels available for distribution, different levels of the fairness identity and responses to identity non-verification will influence how they negotiate for resources. Results from an experiment that varies the fairness identity level and the identity verification of actors in two different equal power exchange networks confirm this. Absent structural power differences, the level of the fairness identity, identity non-verification, and structure of the network mutually influence the distribution of resources such that some dyads earn as much as two and a half times more than others. We discuss our findings as they pertain to unearthing the processes by which group inequalities arise and persist.

Synthesis of Selective Estrogen Receptor Degrader GDC-0810 via Stereocontrolled Assembly of a Tetrasubstituted All-Carbon Olefin.

We report an efficient synthesis of GDC-0810 on the basis of a sequence involving a highly stereoselective lithium tert-butoxide-mediated enolization-tosylation (≥95:5 E: Z) and a Pd-catalyzed Suzuki-Miyaura cross-coupling as key steps. Global deprotection, pyrrolidine salt formation, and final active pharmaceutical ingredient (API) form control/isolation produced GDC-0810 free acid in a 40% overall yield with >99.0% purity as ascertained by HPLC analysis.

Highly Stereoselective Synthesis of Tetrasubstituted Acyclic All-Carbon Olefins via Enol Tosylation and Suzuki-Miyaura Coupling.

A highly stereocontrolled synthesis of tetrasubstituted acyclic all-carbon olefins has been developed via a stereoselective enolization and tosylate formation, followed by a palladium-catalyzed Suzuki-Miyaura cross-coupling of the tosylates and pinacol boronic esters in the presence of a Pd(OAc)2/RuPhos catalytic system. Both the enol tosylation and Suzuki-Miyaura coupling reactions tolerate an array of electronically and sterically diverse substituents and generate high yield and stereoselectivity of the olefin products. Judicious choice of substrate and coupling partner provides access to either the E- or Z-olefin with excellent yield and stereochemical fidelity. Olefin isomerization was observed during the Suzuki-Miyaura coupling. However, under the optimized cross-coupling reaction conditions, the isomerization was suppressed to <5% in most cases. Mechanistic probes indicate that the olefin isomerization occurs via an intermediate, possibly a zwitterionic palladium carbenoid species.

Revisiting a Classic Transformation: A Lossen Rearrangement Initiated by Nitriles and "Pseudo-Catalytic" in Isocyanate.

The direct conversion of a hydroxamic acid to an amine has been accomplished in a single step in the synthesis of HIV drug candidate BMS-955176. This process utilizes catalytic base and proceeds under mild conditions (CH3CN, cat. DBU, 60 °C), without the need for strong electrophiles required for typical Lossen rearrangements, and can be applied to aliphatic and aromatic hydroxamic acids. Through investigation of the kinetics of this transformation, a mechanism was revealed involving a novel initiation pathway and a self-propagation cycle. The initiation pathway involves activation of hydroxamic acid by nitriles and subsequent Lossen rearrangement to generate the corresponding isocyanate. The isocyanate functions as a "pseudo-catalyst" for this system, leading to generation of product through a second Lossen rearrangement and regeneration of a new isocyanate molecule. Thorough mechanistic understanding allowed for this highly efficient process to be implemented on a 55 kg scale in 95.5% isolated yield.

Synthesis of HIV-Maturation Inhibitor BMS-955176 from Betulin by an Enabling Oxidation Strategy.

A concise and scalable second generation synthesis of HIV maturation inhibitor BMS-955176 is described. The synthesis is framed by an oxidation strategy highlighted by a CuI mediated aerobic oxidation of betulin, a highly selective PIFA mediated dehydrogenation of an oxime, and a subsequent Lossen rearrangement which occurs through a unique reaction mechanism for the installation of the C17 amino functionality. The synthetic route proceeds in 7 steps with 47% overall yield and begins from the abundant and inexpensive natural product betulin.

Impact of Inpatient Automatic Therapeutic Substitutions on Postdischarge Medication Prescribing.

Background: Automatic therapeutic substitution (ATS) is the act of therapeutic interchange, in which patients are transitioned from a nonformulary preadmission medication to an equivalent formulary medication upon admission. ATS protocols are able to provide several benefits; however, if medications are unreconciled at the time of discharge, then use may lead to duplication or omission resulting in adverse outcomes. The objective was to assess the impact of preidentified ATS protocol use during admission on duplication and omission postdischarge. Methods: This study included adults who received a preidentified ATS upon admission. The primary outcome was the incidence of duplication or omission at the time of discharge. The secondary outcome was the incidence of duplication or omission at the time of discharge in moderate-to-high readmission risk patients with completed transitions of care (TOC) services compared with incomplete TOC services. Results: A total of 689 encounters were assessed for appropriate reconciliation, duplication, or omission at time of discharge. The incidence of duplication or omission at the time of discharge was 9% (n = 62). Of the 689 encounters, 287 were assessed for the secondary outcome. The rate of duplication or omission at the time of discharge was 10% (n = 19) in the complete TOC services group and 8% (n = 8) in the incomplete TOC services group (P = .6763). Conclusion: This study identified a high rate of appropriate reconciliation of ATS protocols at the time of discharge, which illustrates ATS protocols are a safe medication use management strategy if implemented as intended.

Assessment of final product dosing accuracy when using volumetric technique in the preparation of chemotherapy.

BACKGROUND: Studies have compared gravimetric and volumetric dosing accuracies in chemotherapy agents, finding high accuracy in gravimetric measurements with a mean deviation of ± 0.06%, while volumetric measurements had a mean deviation of ± 3.02%. METHODS: Chemotherapy doses prepared under a biological safety cabinet containing two weights from the precision scale between 15 December 2010 and 30 March 2011 were eligible for inclusion. Empty syringes attached to a closed-system transfer device were weighed prior to product manipulation. The product was then prepared using the syringe pull-back method (volumetric technique) and the same syringe containing drug was weighed (gravimetric method). RESULTS: A total of 1156 compounded sterile products were eligible for the study. The mean percent volume difference of preparations included was -0.53% with a range of -64.9% to 94.22% for individual doses. Of the prepared doses, 71.7% were within ± 5% and 87.4% were within ± 10% of the ordered dose. Secondary outcomes found to be associated with an increased percent volume difference were the pediatric population, smaller volumes prepared, drugs requiring reconstitution compared to already in solution, and final product dispensed to the patient in syringes. CONCLUSION: While the mean value of volumetric measurements is within the generally understood acceptable range for dispensing chemotherapy, the range of measurements is highly variable. Future studies are warranted to better understand the reasons behind the variation and to evaluate the impact of workflow changes on improving final product accuracy.

Pharmacy-Initiated Transitions of Care Services: An Opportunity to Impact Patient Satisfaction.

PURPOSE: A transitions of care program at an academic teaching hospital was designed to reengineer the fragmented discharge process. The team included a pharmacy technician, called a transition specialist, who coordinated the medication needs of discharging patients. This study intends to assess the impact of the transitions of care program on patient satisfaction scores. METHODS: Two datasets of Press Ganey and Hospital Consumer Assessment of Healthcare Providers (HCAHPS) were analyzed. Patients eligible for inclusion were age 18 years or older and successfully discharged from the study facility. All participants received usual care by a servicebased pharmacist, medication counseling by a nurse prior to discharge, and other standard of care services by the inpatient medical team. The intervention group received the previously stated usual care plus services by the transitions of care program. RESULTS: The results from HCAHPS scores proved inconclusive. The results from the Press Ganey dataset found that the surgery transplant service demonstrated statistically significant improvement for satisfaction scores, and they warrant further review. CONCLUSIONS: Results demonstrate that HCAHPS metrics do not correlate with the successes or lack thereof of the transitions of care program. Press Ganey might be a potential surrogate marker for assessing the impact of this program. This study is the first to qualitatively evaluate pharmacy transitions of care service using patient satisfaction scores.

The role of mannitol as a nephroprotectant in patients receiving cisplatin therapy.

OBJECTIVE: To review the efficacy and safety of concomitant mannitol administration with cisplatin therapy to reduce the incidence of nephrotoxicity. DATA SOURCES: A literature search was performed via MEDLINE, PubMed, and the Cochrane Library (1945-August 2011) using the terms mannitol, cisplatin, nephrotoxicity, and forced diuresis. Reference citations from the publications identified were also reviewed. STUDY SELECTION AND DATA EXTRACTION: The search was limited to studies conducted in humans. All studies in which mannitol was used for forced diuresis with cisplatin therapy were evaluated. DATA SYNTHESIS: Cisplatin therapy can lead to transient and permanent renal impairment. Molecular and histologic changes occur in the renal tubules, which contribute to nephrotoxicity. The adverse effect profile of cisplatin is well documented, but the prevention strategies to alleviate renal impairment due to treatment are less understood. Mannitol plus hydration has been used for several years to alleviate toxicity associated with cisplatin therapy. However, the data for mannitol administration have not been convincing. When the use of mannitol and hydration is compared directly to hydration alone, mannitol shows no benefit. In some patients, not only was mannitol not protective, its administration was associated with worsening renal function. CONCLUSIONS: Although mannitol plus hydration is used to decrease cisplatin-induced nephrotoxicity, there are no compelling data that the addition of mannitol is more nephroprotective than the use of hydration alone. Appropriate hydration remains the most reasonable strategy to reduce the incidence of cisplatin-induced nephrotoxicity.

Development of an innovative partnership between a health-system department of pharmacy and external community pharmacies.

PURPOSE: Our organization implemented a health-system pharmacy/community pharmacy transitions of care (TOC) program, developing a scalable model to improve care transitions from the health system to the community setting for shared patients. SUMMARY: In this report, we describe our organization's experiences in taking a purposeful approach to building and pilot testing a partnership between our department of pharmacy and 14 community pharmacies within a larger statewide network to improve TOC across care settings. We have been successful in partnering with our electronic health record (EHR) vendor to enhance access capabilities to allow for documentation by community pharmacists (external to the organization) to be included in the patient record as a note. The goal of the partnership with community pharmacies is to elevate TOC for patients, identify and resolve medication therapy problems that may occur post discharge and lead to poor outcomes, and improve continuity of care across practice settings. CONCLUSION: Our department of pharmacy has led a successful initiative to promote collaboration with local external community pharmacies. This program has led to innovative advancements in EHR capabilities, promoting transparency in the documentation of pharmacy services and making this documentation visible to all care team members.

Kinetic and mechanistic insight into the thermodynamic degradation of saxagliptin.

The dipeptidyl peptidase-IV inhibitor saxagliptin (Onglyza) can undergo a thermodynamically favored cyclization to form the corresponding cyclic amidine. The kinetics and mechanism of this conversion were examined to develop a commercial synthesis that afforded saxagliptin with only trace levels of this key byproduct. Important findings of this work are the identification of a profound solvent effect and the determination of an autocatalytic pathway. Both of these phenomena result from transition structures involving proton transfer.

Vemurafenib (PLX4032): an orally available inhibitor of mutated BRAF for the treatment of metastatic melanoma.

OBJECTIVE: To summarize the preclinical and clinical data on vemurafenib, approved by the Food and Drug Administration (FDA) on August 17, 2011, and discuss the drug's clinical advantages and limitations. DATA SOURCES: An English-language literature search of MEDLINE/PubMed (1966-August 2011), using the terms PLX4032, RG7204, RO5185426, vemurafenib, and metastatic melanoma, was conducted. In addition, information and data were obtained from meeting abstracts, clinical trial registries, and news releases from the FDA. STUDY SELECTION AND DATA EXTRACTION: All relevant published articles and abstracts on vemurafenib were included. Clinical trial registries and meeting abstracts were used to obtain information regarding ongoing trials. All peer-reviewed articles containing information regarding the clinical safety and efficacy of vemurafenib were evaluated for inclusion. DATA SYNTHESIS: Before the recent approval (March 2011) of ipilimumab, there was no first-line standard-of-care therapy, with proven overall survival benefit, for the treatment of malignant metastatic melanoma. Unlike ipilimumab, which acts through immune-modulation, vemurafenib is a novel, molecularly targeted therapeutic with preferential efficacy toward a specific mutated oncogenic BRAF-signaling mediator. In recently published results of a Phase 3 clinical trial comparing dacarbazine with vemurafenib, vemurafenib prolonged progression-free and overall survival, with confirmed objective response rate of 48% (95% CI 42 to 55) versus 5% (95% CI 3 to 9) for patients who received dacarbazine (p < 0.001). CONCLUSIONS: Vemurafenib offers a novel, first-line, personalized therapy for patients who have mutated BRAF. Clinical trials of vemurafenib in combination with ipilimumab or other targeted or cytotoxic chemotherapeutic agents may provide more effective regimens with long-term clinical benefit.

Effectiveness and impact of a structured research approach for health-system pharmacy administration and leadership residents.

PURPOSE: Required competency areas, goals, and objectives for both postgraduate year 1 (PGY1) pharmacy residencies and postgraduate year 2 (PGY2) health-system pharmacy administration and leadership (HSPAL) residencies indicate the importance of research in the residency program by specifying it as a required part of the training process. Research is critical in the field of health-system pharmacy administration, which is built upon the principles of evaluation and assessment, ensuring that all activities implemented in an organization are evaluated through data collection and assessment to determine their impact. Additionally, the research structure provides residents the opportunity to share research broadly, and it also provides the platform for other institutions to implement successful ideas of interest to them. SUMMARY: This article describes the impact of having a structured, publication-focused research program in an HSPAL residency. The research process has provided follow-up projects (n = 7) and grant participation (n = 6). Additionally, the process has yielded a 66% publication rate, with 21 of 32 thesis substitutes published in various journals. The department of pharmacy at the residency site has noticed that the continued refinement, scoping, and robust methodologies of projects have been essential to their impact in the literature and in dissemination of the accumulated body of knowledge. CONCLUSION: A structured residency research program has provided direction to HSPAL residents and ensured successful scoping and completion of their research. Intentionality in this aspect has provided HSPAL residents with opportunities for publications, grants, and strong research experiences. Overall, the department of pharmacy has been positively impacted through implementation of services that were evaluated through a structured HSPAL pharmacy residency research program.

New medical therapy: hyperbarics.

This article reviews the essentials hyperbaric medicine. Specifically, we review the basic mechanism of action, the six most common indications for treatment, methods of accessing care, typical treatment concerns, and effectiveness of hyperbaric medicine.

Implementation of the flipped residency research model to enhance residency research training.

PURPOSE: The attainment of fundamental research skills to create and disseminate new knowledge is imperative for the advancement of pharmacy practice. Research training is an important component of postgraduate residency training; however, the traditional model of performing residency research has several limitations that have hindered the ability of residents to complete high-quality research projects. Therefore, our institution developed and implemented the flipped residency research model with the 2013-2014 pharmacy practice residency class. SUMMARY: The flipped residency research model modifies the research timeline to better align research activities with residents' abilities at specific time points during the year. In the 4 years following implementation of the flipped residency research model, our institution found improvements in a number of areas pertaining to the research process compared with an evaluation of the 7 years prior to implementation. A decrease in the number of reviews required from institutional review boards was observed, resulting in improved institutional review board efficiency. The flipped residency research model also addressed limitations surrounding manuscript development and submission, as demonstrated by an improved publication rate. Additionally, residents who participated in the flipped residency research model self-reported increased comfort with research-related abilities associated with study design, implementation, manuscript development and submission, and biostatistics. CONCLUSION: The modified research timeline of the flipped residency research model better aligns research activities with resident experiences and abilities. This realignment has translated to demonstrable impact in the success of residency projects and dissemination of results. Research is needed to investigate the impact of the flipped residency research model on longer term scholarly success.

Impact of an innovative partnership in patient care between an academic medical center department of pharmacy and a school of pharmacy.

PURPOSE: Pharmacy departments and schools of pharmacy have long held professional affiliations. However, the success of each entity is often not interdependent and aligned. In 2010, our institutions found ourselves in a position where the complementary motivations of each aligned to support a more meaningful and committed engagement, leading to the development of the Partnership in Patient Care. The impact of the partnership was evaluated 7 years postimplementation, and both the successes realized and the lessons learned are described. SUMMARY: The partnership provided many advantages to our pharmacy department and the school of pharmacy. This initial iteration of the partnership was a strong proof of concept that an intentional approach to the relationship between a school of pharmacy and a pharmacy department can lead to substantive improvements in a wide array of meaningful outcomes. We experienced an increase in the number of student rotation months completed, growth in the American Society of Health-System Pharmacists-accredited residency programs, and enhanced clinical services. However, the partnership was not without challenges. For instance, lack of a formalized tracking method made certain outcomes difficult to track. CONCLUSION: The purposeful establishment of the Partnership in Patient Care, built on the needs of a school of pharmacy and an academic medical center pharmacy department, allowed our institutions to develop an intertwined mission and vision. Over the initial years of the partnership, many successes were realized and lessons were learned. Both the successes and the challenges are serving as the foundation for future iterations of the partnership.