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Global product platforms can reduce production costs through economies of scale and learning but may decrease revenues by restricting the ability to customize for each market. We model the global platforming problem as a Nash equilibrium among oligopolistic competing firms, each maximizing its profit across markets with respect to its pricing, design, and platforming decisions. We develop and compare two methods to identify Nash equilibria: (1) a sequential iterative optimization (SIO) algorithm, in which each firm solves a mixed-integer nonlinear programming problem globally, with firms iterating until convergence; and (2) a mathematical program with equilibrium constraints (MPEC) that solves the Karush Kuhn Tucker conditions for all firms simultaneously. The algorithms’ performance and results are compared in a case study of plug-in hybrid electric vehicles where firms choose optimal battery capacity and whether to platform or differentiate battery capacity across the US and Chinese markets. We examine a variety of scenarios for (1) learning rate and (2) consumer willingness to pay (WTP) for range in each market. For the case of two firms, both approaches find the Nash equilibrium in all scenarios. On average, the SIO approach solves 200 times faster than the MPEC approach, and the MPEC approach is more sensitive to the starting point. Results show that the optimum for each firm is to platform when learning rates are high or the difference between consumer willingness to pay for range in each market is relatively small. Otherwise, the PHEVs are differentiated with low-range for China and high-range for the US.

Peer reviewed: True, Funder: Trinity College Dublin; FundRef: http://dx.doi.org/10.13039/501100001637, Macrophages are a highly adaptive population of innate immune cells. Polarization with IFNγ and LPS into the 'classically activated' M1 macrophage enhances pro-inflammatory and microbicidal responses, important for eradicating bacteria such as Mycobacterium tuberculosis. By contrast, 'alternatively activated' M2 macrophages, polarized with IL-4, oppose bactericidal mechanisms and allow mycobacterial growth. These activation states are accompanied by distinct metabolic profiles, where M1 macrophages favor near exclusive use of glycolysis, whereas M2 macrophages up-regulate oxidative phosphorylation (OXPHOS). Here, we demonstrate that activation with IL-4 and IL-13 counterintuitively induces protective innate memory against mycobacterial challenge. In human and murine models, prior activation with IL-4/13 enhances pro-inflammatory cytokine secretion in response to a secondary stimulation with mycobacterial ligands. In our murine model, enhanced killing capacity is also demonstrated. Despite this switch in phenotype, IL-4/13 trained murine macrophages do not demonstrate M1-typical metabolism, instead retaining heightened use of OXPHOS. Moreover, inhibition of OXPHOS with oligomycin, 2-deoxy glucose or BPTES all impeded heightened pro-inflammatory cytokine responses from IL-4/13 trained macrophages. Lastly, this work identifies that IL-10 attenuates protective IL-4/13 training, impeding pro-inflammatory and bactericidal mechanisms. In summary, this work provides new and unexpected insight into alternative macrophage activation states in the context of mycobacterial infection.

Our body clock drives rhythms in the expression of genes that have a 24-h periodicity. The transcription factor BMAL1 is a crucial component of the molecular clock. A number of physiological processes, including immune function, are modulated by the circadian clock. Asthma, a disease with very strong clinical evidence demonstrating regulation by circadian variation, is of particular relevance to circadian control of immunity. Airway hypersensitivity and asthma attacks are more common at night in humans. The molecular basis for this is unknown, and there is no model of asthma in animals with genetic distortion of the molecular clock. We used mice lacking BMAL1 in myeloid cells (BMAL1-LysM−/−) to determine the role of BMAL1 in allergic asthma. Using the ovalbumin model of allergic asthma, we demonstrated markedly increased asthma features, such as increased lung inflammation, demonstrated by drastically higher numbers of eosinophils and increased IL-5 levels in the lung and serum, in BMAL1-LysM−/− mice. In vitro studies demonstrated increased proinflammatory chemokine and mannose receptor expression in IL-4- as well as LPS-treated macrophages from BMAL1-LysM−/− mice compared with wild-type controls. This suggests that Bmal1 is a potent negative regulator in myeloid cells in the context of allergic asthma. Our findings might explain the increase in asthma incidents during the night, when BMAL1 expression is low.

Objective: To explore perceptions of pharmacy graduates and preceptors regarding a new undergraduate pharmacy degree. Method: Data from focus groups and interviews with pharmacy graduates and preceptors were qualitatively analysed by thematic coding. Results: Participants identified strengths such as clinical knowledge and research skills; areas needing improvement were communications and calculations. Other areas identified by both graduates and preceptors included organization and management skills, longer externship experiential learning and extemporaneous compounding. It was suggested that extending the duration of the externship experience would facilitate the shift into the workplace and consolidate undergraduate learning. The internship programme was considered essential for personal development and for putting theory into practice. Conclusion: Both preceptors and graduates were satisfied with the undergraduate program. The knowledge, skills and attitudes displayed by graduates were considered to be adequate, providing a firm foundation for future practice.

A 65 year old man presented to the emergency department with a 10 day history of dark urine, general malaise, and progressive shortness of breath. He had a history of rheumatic heart disease and had been on warfarin since he had a metallic mitral valve replacement in 1984. He was a retired teacher, drank a minimal amount of alcohol, and was a non-smoker. He had no family history of cancer. On examination he was jaundiced with a sinus tachycardia (120 beats/min) and a pansystolic murmur. His other vital signs were normal. On examination, his other systems were normal except for mild suprapubic tenderness, as were the results of a digital rectal examination. His urine was rust coloured (fig 1⇓) with no blood clots. Urine dipstick was positive for blood (3+), protein (3+), and leucocytes (3+), but negative for nitrites. No red blood cells or casts were noted during microscopy. Fig 1 Patient’s urine on admission The table⇓ shows the results of his initial laboratory investigations. A peripheral blood film showed red cell fragments, polychromasia, and normal platelets (a representative smear is shown in fig 2⇓). The results of chest radiography, computed tomography of the kidneys, and ultrasound of the urinary tract were also unremarkable. Serial sepsis screens and three sets of blood cultures for endocarditis were all negative. View this table: Laboratory test results on admission Fig 2 A representative blood film showing red cell fragments (arrows) ### 1. What are the causes of dark urine? #### Answer Haematuria, menstrual contamination, haemoglobinuria, and myoglobinuria will cause dark urine that is positive for blood on urine dipstick testing. Red cells …

We present sensitivities for the MiniBooNE experiment to a rare exotic pion decay producing a massive particle, Q^0. This type of decay represents one possible explanation for the timing anomaly reported by the KARMEN collaboration. MiniBooNE will be able to explore an area of the KARMEN signal that has not yet been investigated.