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Greyson Junggren had an entrepreneurial spirit and started Elevate Hammock Company while he was still in college. His mission was to produce high-quality, durable hammocks that were made for the outdoors. Not knowing a lot about how to set the price for his hammocks when he first started his business, Greyson used a cost-plus/competitive approach. But after some time, he noticed that much of the market he had hoped to capture was staying with his higher priced competitors. While still generating and growing sales figures, Elevate Hammock Company was not capturing as much business from rival hammock companies in retail stores that Greyson expected and wanted. Greyson started to understand there was probably a real problem with his price when a very successful retailer in Taos, New Mexico ignored Greyson’s suggested retail price of US$55.00 and instead raised the price to US$65.00; and this resulted in an increase in the demand for Greyson’s hammocks. After 2 years in business, Greyson wondered if he should change his pricing strategy or his distribution model. What pricing strategy should he change to? And what other business strategies should he change or continue with if he did change his pricing strategy?

Decreasing student numbers and resources present major challenges facing foreign language programmes in English-speaking universities. These are compounded by the needs of a diverse student population, many of whom enter university with little or no experience of the target language (TL). Language programmes with limited resources are increasingly being asked to cater to beginners and elementary-level language students who require flexible timetabling, access to high-quality online independent study materials and communicatively focused, interactive classes. Blended Learning, which combines face-to-face classroom meetings with computer-mediated learning, provides an obvious and elegant solution. The success of Blended Learning hinges on the design-quality and integration of every aspect of the learning package. Online materials must provide enriched input; class lesson plans should emphasise student interaction and production; appropriate assessment practices are key to keeping students engaged. This chapter presents the experiences of creating and teaching Blended Learning courses for students learning foreign languages in New Zealand working at A1 (beginners) level of the Common European Framework of Reference: Spanish at Victoria University of Wellington, and French and Italian at the University of Auckland. In all three cases, we briefly outline the courses we designed. We then report on their ‘success’, as measured by student feedback (course questionnaires for French and Italian courses), level of online engagement (viewing and/or activity statistics) and comparative final grades statistics.

Femoral nerve blocks (FNBs) and periarticular injections (PAIs) are often used for analgesia following bone and joint surgery. The purpose of this retrospective analysis was to investigate the association of analgesic technique with outcomes. All patients receiving total knee arthroplasty (TKA) at a regional medical center in 2014 were analyzed. Patients were grouped by whether they received an FNB or PAI of bupivacaine liposome injectable suspension (Exparel) for postoperative analgesia. Outcome variables of pain perception, morphine equivalents administered, length of stay, and total cost of care were compared using 2-tailed t tests. Readmission rate was examined using a 2-sample z test for proportions. One hundred forty-four patients were included in the study. This analysis demonstrated an association between receiving an FNB and less pain perception (P = .0497). Results also demonstrated a possible relationship between less opioid consumption in patients receiving a PAI of liposomal bupivacaine (P = .037). No statistical differences were found for the other variables. Receiving a FNB was preferable regarding patients' pain perception. Patients received less opioid analgesic when they received a PAI, possibly relating to the particular surgeon performing the primary TKA. Patients were 5 times likelier to require hospital readmission in the PAI group.

In the current mining industry climate, early and detailed planning for mine closure is becoming increasingly important. Geotechnical inputs relating to stability of open pit excavations were often limited or cursory in past mine closures. Although broad guidelines based on general observations do exist in some countries, detailed deterministic approaches and design criteria specifically applicable to open pit excavations during mine closure have not been well established. Large open pits may be most sensitive to the economic impacts of geotechnical requirements/constraints for closure, particularly if unduly conservative approaches are employed. It is therefore necessary for these requirements and constraints to be carefully assessed for each pit, and for the most cost-effective measures to be identified. It is important that slope instabilities are well-documented during operations, and that good communication between various technical departments is maintained for closure planning and coordination. This paper presents examples of several scenarios in which pit slope stability assessment may be required at mine closure. These are focused specifically on the long-term stability of the open pit excavations, not the stability of any adjacent structures. The paper does not attempt to propose a set of guidelines but discusses techniques that may be used for assessment under various scenarios. Topics include estimation of rock mass degradation over time, assessment of long-term instability around pits, evaluation of slope buttressing options, and determination of exclusion zones around pit crests (and in-pit floors that must remain open to access).

This report documents the first example of a specific inhibitor of protein kinases with preferential binding to the activated kinase conformation: 5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one 11r (MK-8033), a dual c-Met/Ron inhibitor under investigation as a treatment for cancer. The design of 11r was based on the desire to reduce time-dependent inhibition of CYP3A4 (TDI) by members of this structural class. A novel two-step protocol for the synthesis of benzylic sulfonamides was developed to access 11r and analogues. We provide a rationale for the observed selectivity based on X-ray crystallographic evidence and discuss selectivity trends with additional examples. Importantly, 11r provides full inhibition of tumor growth in a c-Met amplified (GTL-16) subcutaneous tumor xenograft model and may have an advantage over inactive form kinase inhibitors due to equal potency against a panel of oncogenic activating mutations of c-Met in contrast to c-Met inhibitors without preferential binding to the active kinase...

PMI is the world's leading not-for-profit professional membership association for the project, program, and portfolio management profession. Now in its 46th year, the association provides global advocacy, collaboration, education, and research to more than 2.9 million professionals working in nearly every country in the world. To better support project practitioners in their role as “change agents,” PMI utilizes popular social media platforms, as well as a robust virtual community. Through social media, PMI creates an environment in which project practitioners create, curate, and share strong value-added content, take part in well-informed discussions, and collaborate to seek effective solutions.

A review of Gary Wilder, Freedom Time: Negritude, Decolonization and the Future of The World (Duke University Press, 2015).

Inhibition of microtubule affinity regulating kinase (MARK) represents a potentially attractive means of arresting neurofibrillary tangle pathology in Alzheimer’s disease. This manuscript outlines efforts to optimize a pyrazolopyrimidine series of MARK inhibitors by focusing on improvements in potency, physical properties and attributes amenable to CNS penetration. A unique cylcyclohexyldiamine scaffold was identified that led to remarkable improvements in potency, opening up opportunities to reduce MW, Pgp efflux and improve pharmacokinetic properties while also conferring improved solubility.

We describe multidrug-resistant (MDR) Salmonella Heidelberg infections associated with mechanically separated chicken (MSC) served at a county correctional facility. Twenty-three inmates met the case definition. All reported diarrhea, 19 (83%) reported fever, 16 (70%) reported vomiting, 4 (17%) had fever ≥103°F, and 3 (13%) were hospitalized. A case-control study found no single food item significantly associated with illness. Salmonella Heidelberg with an indistinguishable pulsed-field gel electrophoresis pattern was isolated from nine stool specimens; two isolates displayed resistance to a total of five drug classes, including the third-generation cephalosporin, ceftriaxone. MDR Salmonella Heidelberg might have contributed to the severity of illness. Salmonella Heidelberg indistinguishable from the outbreak subtype was isolated from unopened MSC. The environmental health assessment identified cross-contamination through poor food-handling practices as a possible contributing factor. Proper hand-washing techniques and safe food-handling practices were reviewed with the kitchen supervisor.

Synthesis, SAR, and evaluation of aryl triazoles as novel gamma secretase modulators (GSMs) are presented in this communication. Starting from the literature and in-house leads, we evaluated a range of five-membered heterocycles as replacements for olefins commonly found in non-acid GSMs. 1,2,3-C-aryl-triazoles were identified as suitable replacements which exhibited good modulation of γ-secretase activity, excellent pharmacokinetics and good central lowering of Aβ42 in Sprague-Dawley rats.

c-Met is a transmembrane tyrosine kinase that mediates activation of several signaling pathways implicated in aggressive cancer phenotypes. In recent years, research into this area has highlighted c-Met as an attractive cancer drug target, triggering a number of approaches to disrupt aberrant c-Met signaling. Screening efforts identified a unique class of 5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one kinase inhibitors, exemplified by 1. Subsequent SAR studies led to the development of 81 (MK-2461), a potent inhibitor of c-Met that was efficacious in preclinical animal models of tumor suppression. In addition, biochemical studies and X-ray analysis have revealed that this unique class of kinase inhibitors binds preferentially to the activated (phosphorylated) form of the kinase. This report details the development of 81 and provides a description of its unique biochemical properties.

While there is a considerable evidence base showing links between drug use and offending and clear evidence of the impact of treatment engagement on drug-related offending, there is a much smaller UK evidence base on ‘what works’ in treatment and criminal justice partnerships, particularly in the UK. The current study used police arrest data to measure changes in offending behaviour in 116 drug-using offenders who had tested positive for opiates or cocaine in custody suites on at least three occasions in the previous year. Participants were assigned to either an intensive form of ‘quasi-coercive’ treatment (the High Crime Causing Users, HCCU) or to treatment as usual from the community Drug Interventions Programme team. The study compares changes in offending in a high-rate offending group with a standard treatment intervention. The assessment of the effectiveness of the intervention was based on arrest rates in the 12 months before and after engagement with the programme, supplemented by data collected f...

Polycythemia vera (PV) is a myeloproliferative disorder characterized by increased red cell mass and splenomegaly in the absence of secondary causes [Tefferi A., Spivak J.L., Polycythemia vera: scientific advances and current practice. Semin Hematol 2005;42(4):206-20.]. Recently, several laboratories have discovered that the vast majority of patients with PV carry a single, activating mutation (V617F) in the pseudokinase domain of Janus kinase 2 (Jak2) [Zhao R, Xing S, Li Z, Fu X, Li Q, Krantz SB, et al., Identification of an acquired JAK2 mutation in polycythemia vera. J Biol Chem 2005;280(24):22788-92; James C, Ugo V, Le Couedic JP, Staerk J, Delhommeau F, Lacout C, et al., A unique clonal JAK2 mutation leading to constitutive signalling causes polycythemia vera. Nature 2005;434(7037):1144-8; Kralovics R, Passamonti F, Buser AS, Teo SS, Tiedt R, Passweg JR, et al., A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med 2005;352(17):1779-90; Levine RL, Wadleigh M, Cools J, Ebert BL, Wernig G, Huntly BJ, et al., Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell 2005;7(4):387-97.]. This discovery has spurred interest in developing therapies for PV via inhibition of Jak2. We induced polycythemia in mice by administering high dose recombinant erythropoietin (Epo) and determined that administration recapitulates almost all of the major and minor diagnostic features of human PV. We then tested a selective, small molecule inhibitor of Jak2 (Jak2i) and showed that this treatment prevents polycythemia. This prevention of polycythemia was accompanied by lower hematocrits, reduced spleen sizes and reductions in Stat5 phosphorylation (pStat5). Surprisingly, Epo rapidly (

Synthesis and SAR studies of novel triazolobenzazepinones as gamma secretase modulators (GSMs) are presented in this communication. Starting from our azepinone leads, optimization studies toward improving central lowering of Aβ42 led to the discovery of novel benzo-fused azepinones. Several benzazepinones were profiled in vivo and found to lower brain Aβ42 levels in Sprague Dawley rats and transgenic APP-YAC mice in a dose-dependent manner after a single oral dose. Compound 34 was further progressed into a pilot study in our cisterna-magna-ported rhesus monkey model, where we observed robust lowering of CSF Aβ42 levels.

Feminist literature sometimes posits that competition and cooperation are opposites. This dichotomy is important in that it is often invoked in order to explain why mainstream economics has focused on market activity to the exclusion of non-market activity, and why this fascination or focus is sexist. The purpose of this paper is to demonstrate that the competition/cooperation dichotomy is false. Once the dichotomy is dissolved, those activities which are seen as competitive (masculine) and those which are seen as cooperative (feminine) are no longer mutually exclusive but are, in fact, dependent upon one another. It is shown that the outcome of competition (more and better knowledge) enhances, and in some cases makes possible, cooperation. “The function of battle is destruction; of competition, construction.” Ludwig von Mises

Arrest referral has been identified as a key point of intervention for offenders who have a drug problem and who have been arrested. Previous research has however raised concerns from both service users and professionals surrounding the need for independence of arrest referral schemes from the police. Given that arrest referral workers in Birmingham are police-employed and that the arrest referral process has its own dedicated NHS-based treatment team, the current article looks at the potential of this new approach in contacting, referring and treating problematic drug users. A retrospective analysis of referrals made to treatment by arrest referral workers and treatment engagement was conducted. Within a six-month period 394 referrals were made to treatment, with 33.2% of those referred making a treatment demand. Offending and drug expenditure among the group was high. As with other schemes, ethnic minorities and women were under-represented in the numbers of both those referred and those engaging in treatment. The current article argues that, given the need for arrest referral schemes to work closely with the police in order to access and refer service users, arrest referral schemes are more reliant on good worker-client relationships and con-fidentiality than independence.

Bacterial transglycosylases are enzymes that couple the disaccharide subunits of peptidoglycan to form long carbohydrate chains. These enzymes are the target of the pentasaccharide antibiotic moenomycin as well as the proposed target of certain glycopeptides that overcome vancomycin resistance. Because bacterial transglycosylases are difficult enzymes to study, it has not previously been possible to evaluate how moenomycin inhibits them or to determine whether glycopeptide analogues directly target them. We have identified transglycosylase assay conditions that enable kinetic analysis of inhibitors and have examined the inhibition of Escherichia coli penicillin-binding protein 1b (PBP1b) by moenomycin as well as by various glycopeptides. We report that chlorobiphenyl vancomycin analogues that are incapable of binding substrates nevertheless inhibit E. coli PBP1b, which shows that these compounds interact directly with the enzyme. These findings support the hypothesis that chlorobiphenyl vancomycin derivatives overcome vanA resistance by targeting bacterial transglycosylases. We have also found that moenomycin is not competitive with respect to the lipid II substrate of PBP1b, as has long been believed. With the development of suitable methods to evaluate bacterial transglycosylases, it is now possible to probe the mechanism of action of some potentially very important antibiotics.

MurG is an essential glycosyltransferase that forms the glycosidic linkage between N- acetyl muramyl pentapeptide and N- acetyl glucosamine in the biosynthesis of the bacterial cell wall. This enzyme is a member of a major superfamily of NDP-glycosyltransferases for which no x-ray structures containing intact substrates have been reported. Here we present the 2.5-Å crystal structure of Escherichia coli MurG in complex with its donor substrate, UDP-GlcNAc. Combined with genomic analysis of other superfamily members and site-specific mutagenesis of E. coli MurG, this structure sheds light on the molecular basis for both donor and acceptor selectivity for the superfamily. This structural analysis suggests that it will be possible to evolve new glycosyltransferases from prototypical superfamily members by varying two key loops while maintaining the overall architecture of the family and preserving key residues.