What Have I Learned?

Peter Caswell had always viewed the families bottling business as his birthright. He was stunned when his father sold the business while he was still in college. After becoming a successful personal injury lawyer with a bright future, he learns of the Brustlin Bottling Company that was for sale. In the case Peter reviews with Alan Dawes, his long time friend, information he has developed on five successful companies in the boutique soft drink bottling business. He is trying to decide his next steps a strategy to employ in the business

Transfer Pricing In Transnational Operations: A Case- And Literature-Based Analysis

This paper represents a combined case- and literature-based analysis of transnational pricing and highlights the difference in the issues and perspectives of the business and academic environments.  Following an introduction to the issue (noting the growing importance of the transfer of goods from one organizational entity to another within a multinational firm), a short case - The Henderson Company - illustrates how a relatively simple announcement can lead to a lengthy and heated discussion that points out the differences in opinion both between the headquarters and the subsidiaries and between the various regional entities themselves.  The analysis of the case reflecting the concerns and perspectives of the members of the international management team (in terms of involvement and partnership, legal and operational concerns, competitive marketing strategy, and evaluation, compensation, and motivational issues) is followed by a literature-based analysis that looks at the complexities of the situation in terms of management, economics, taxation, and finance research.  The paper concludes with the recognition that the issue of transnational pricing is a complex one that needs to be addressed from both an organizational perspective and from an international viewpoint emphasizing the development of ways of more accurately reflecting cost allocations

The Diabetes Remission Clinical Trial (DiRECT): protocol for a cluster randomised trial

Background: Despite improving evidence-based practice following clinical guidelines to optimise drug therapy, Type 2 diabetes (T2DM) still exerts a devastating toll from vascular complications and premature death. Biochemical remission of T2DM has been demonstrated with weight loss around 15kg following bariatric surgery and in several small studies of non-surgical energy-restriction treatments. The non-surgical Counterweight-Plus programme, running in Primary Care where obesity and T2DM are routinely managed, produces >15 kg weight loss in 33 % of all enrolled patients. The Diabetes UK-funded Counterpoint study suggested that this should be sufficient to reverse T2DM by removing ectopic fat in liver and pancreas, restoring first-phase insulin secretion. The Diabetes Remission Clinical Trial (DiRECT) was designed to determine whether a structured, intensive, weight management programme, delivered in a routine Primary Care setting, is a viable treatment for achieving durable normoglycaemia. Other aims are to understand the mechanistic basis of remission and to identify psychological predictors of response. Methods/Design: Cluster-randomised design with GP practice as the unit of randomisation: 280 participants from around 30 practices in Scotland and England will be allocated either to continue usual guideline-based care or to add the Counterweight-Plus weight management programme, which includes primary care nurse or dietitian delivery of 12-20weeks low calorie diet replacement, food reintroduction, and long-term weight loss maintenance. Main inclusion criteria: men and women aged 20-65years, all ethnicities, T2DM 0-6years duration, BMI 27-45 kg/m2. Tyneside participants will undergo Magnetic Resonance (MR) studies of pancreatic and hepatic fat, and metabolic studies to determine mechanisms underlying T2DM remission. Co-primary endpoints: weight reduction ≥ 15 kg and HbA1c <48 mmol/mol at one year. Further follow-up at 2 years. Discussion: This study will establish whether a structured weight management programme, delivered in Primary Care by practice nurses or dietitians, is a viable treatment to achieve T2DM remission. Results, available from 2018 onwards, will inform future service strategy

Within-trial cost and 1-year cost-effectiveness of the DiRECT/Counterweight-Plus weight-management programme to achieve remission of type 2 diabetes

No abstract available

Measurement and interpretation of skin prick test results

Background: There are several methods to read skin prick test results in type-I allergy testing. A commonly used method is to characterize the wheal size by its 'average diameter'. A more accurate method is to scan the area of the wheal to calculate the actual size. In both methods, skin prick test (SPT) results can be corrected for histamine-sensitivity of the skin by dividing the results of the allergic reaction by the histamine control. The objectives of this study are to compare different techniques of quantifying SPT results, to determine a cut-off value for a positive SPT for histamine equivalent prick -index (HEP) area, and to study the accuracy of predicting cashew nut reactions in double-blind placebo-controlled food challenge (DBPCFC) tests with the different SPT methods. Methods: Data of 172 children with cashew nut sensitisation were used for the analysis. All patients underwent a DBPCFC with cashew nut. Per patient, the average diameter and scanned area of the wheal size were recorded. In addition, the same data for the histamine-induced wheal were collected for each patient. The accuracy in predicting the outcome of the DBPCFC using four different SPT readings (i.e. average diameter, area, HEP-index diameter, HEP-index area) were compared in a Receiver-Operating Characteristic (ROC) plot. Results: Characterizing the wheal size by the average diameter method is inaccurate compared to scanning method. A wheal average diameter of 3 mm is generally considered as a positive SPT cut-off value and an equivalent HEP-index area cut-off value of 0.4 was calculated. The four SPT methods yielded a comparable area under the curve (AUC) of 0.84, 0.85, 0.83 and 0.83, respectively. The four methods showed comparable accuracy in predicting cashew nut reactions in a DBPCFC. Conclusions: The 'scanned area method' is theoretically more accurate in determining the wheal area than the 'average diameter method' and is recommended in academic research. A HEP-index area of 0.4 is determined as cut-off value for a positive SPT. However, in clinical practice, the 'average diameter method' is also useful, because this method provides similar accuracy in predicting cashew nut allergic reactions in the DBPCFC

Time course of normalization of functional β-cell capacity in the Diabetes Remission Clinical Trial after weight loss in type 2 diabetes

Objective: To assess functional β-cell capacity in type 2 diabetes during 2 years of remission induced by dietary weight loss. Research Design and Methods: A Stepped Insulin Secretion Test with Arginine was used to quantify functional β-cell capacity by hyperglycemia and arginine stimulation. Thirty-nine of 57 participants initially achieved remission (HbA1c <6.5% [<48 mmol/mol] and fasting plasma glucose <7 mmol/L on no antidiabetic drug therapy) with a 16.4 ± 7.7 kg weight loss and were followed up with supportive advice on avoidance of weight regain. At 2 years, 20 participants remained in remission in the study. A nondiabetic control (NDC) group, matched for age, sex, and weight after weight loss with the intervention group, was studied once. Results: During remission, median (interquartile range) maximal rate of insulin secretion increased from 581 (480–811) pmol/min/m2 at baseline to 736 (542–998) pmol/min/m2 at 5 months, 942 (565–1,240) pmol/min/m2 at 12 months (P = 0.028 from baseline), and 936 (635–1,435) pmol/min/m2 at 24 months (P = 0.023 from baseline; n = 20 of 39 of those initially in remission). This was comparable to the NDC group (1,016 [857–1,507] pmol/min/m2) by 12 (P = 0.064) and 24 (P = 0.244) months. Median first-phase insulin response increased from baseline to 5 months (42 [4–67] to 107 [59–163] pmol/min/m2; P < 0.0001) and then remained stable at 12 and 24 months (110 [59–201] and 125 [65–166] pmol/min/m2, respectively; P < 0.0001 vs. baseline) but lower than that of the NDC group (250 [226–429] pmol/min/m2; P < 0.0001). Conclusions: A gradual increase in assessed functional β-cell capacity occurred after weight loss, becoming similar to NDC participants by 12 months. This was unchanged at 2 years with continuing remission of type 2 diabetes

Remission of human type 2 diabetes requires decrease in liver and pancreas fat content but is dependent upon capacity for beta cell recovery

The Diabetes Remission Clinical Trial reported return and persistence of non-diabetic blood glucose control in 46% of people with type 2 diabetes of up to 6 years duration. Detailed metabolic studies were performed on a subgroup (intervention, n = 64; control, n = 26). In the intervention group, liver fat content decreased (16.0% ± 1.3% to 3.1% ± 0.5%, p < 0.0001) immediately after weight loss. Similarly, plasma triglyceride and pancreas fat content decreased whether or not glucose control normalized. Recovery of first-phase insulin response (0.04[−0.05–0.32] to 0.11[0.0005–0.51] nmol/min/m2, p < 0.0001) defined those who returned to non-diabetic glucose control and this was durable at 12 months (0.11[0.005–0.81] nmol/min/m2, p = 0.0001). Responders were similar to non-responders at baseline but had shorter diabetes duration (2.7 ± 0.3 versus 3.8 ± 0.4 years; p = 0.02). This study demonstrates that β cell ability to recover long-term function persists after diagnosis, changing the previous paradigm of irreversible loss of β cell function in type 2 diabetes

Esterase Cleavable 2D Assemblies of Magnetic Iron Oxide Nanocubes: Exploiting Enzymatic Polymer Disassembling to Improve Magnetic Hyperthermia Heat Losses

Here, we report a nanoplatform based on iron oxide nanocubes (IONCs) coated with a bioresorbable polymer that, upon exposure to lytic enzymes can be disassembled increasing the heat performances in comparison with the initial clusters. We have developed bi-dimensional (2D) clusters by exploiting benchmark iron oxide nanocubes as heat mediators for magnetic hyperthermia and a polyhydroxyalkanoate (PHA) copolymer, a biodegradable polymer produced by bacteria that can be digested by intracellular esterase enzymes. The comparison of magnetic heat performance of the 2D assemblies with 3D centro-symmetrical assemblies or single iron oxide nanocubes emphasize the benefit of the 2D assembly. On one hand, the heat losses of 2D assemblies dispersed in water are better than the 3D assemblies, but worse than for single nanocubes. On the other hand, when the bi-dimensional magnetic beads (2D-MNBs) are incubated with the esterase enzyme at a physiological temperature, their magnetic heat performances began to progressively increase. After 2 hours of incubation, specific absorption rate values of the 2D assembly double the ones of individually coated nanocubes. Such an increase can be mainly correlated to the splitting of the 2D-MNBs into smaller size clusters with a chain- like configuration containing few nanocubes. Moreover, 2D-MNBs exhibited non-variable-heat performances even after intentionally inducing their aggregation. Magnetophoresis measurements indicate a comparable response of 3D and 2D clusters to external magnets (0.3T) that is by far faster than that of single nanocubes. This feature is crucial for a physical accumulation of magnetic materials in the presence of magnetic field gradients. This system is the first example of a nanoplatform that, upon exposure to lytic enzymes, such as those present in a tumor environment, can be disassembled from the initial 2D-MNB organization to chain-like assemblies with clear improvement of the heat magnetic losses resulting in better heat dissipation performances. The potential application of 2D nano-assemblies based on the cleavable PHAs for preserving their magnetic losses inside cells will benefit hyperthermia therapies mediated by magnetic nanoparticles under alternating magnetic fields

Neutrino properties and the decay of the lightest supersymmetric particle

Supersymmetry with broken R-parity can explain the neutrino mass squared differences and mixing angles observed in neutrino oscillation experiments. In the minimal model, where R-parity is broken only by bilinear terms, certain decay properties of the lightest supersymmetric particle (LSP) are correlated with neutrino mixing angles. Here we consider charginos, squarks, gluinos and sneutrinos being the LSP and calculate their decay properties in bilinear R-parity breaking supersymmetry. Together with the decays of charged scalars and neutralinos calculated previously this completes the proof that bilinear R-parity breaking as the source of neutrino masses will be testable at future colliders. Moreover, we argue that in case of GMSB, the decays of the NLSP can be used to test the model.Comment: 15 pages, 8 figure

Aberrant behaviours of reaction diffusion self-organisation models on growing domains in the presence of gene expression time delays

Turing’s pattern formation mechanism exhibits sensitivity to the details of the initial conditions suggesting that, in isolation, it cannot robustly generate pattern within noisy biological environments. Nonetheless, secondary aspects of developmental self-organisation, such as a growing domain, have been shown to ameliorate this aberrant model behaviour. Furthermore, while in-situ hybridisation reveals the presence of gene expression in developmental processes, the influence of such dynamics on Turing’s model has received limited attention. Here, we novelly focus on the Gierer–Meinhardt reaction diffusion system considering delays due the time taken for gene expression, while incorporating a number of different domain growth profiles to further explore the influence and interplay of domain growth and gene expression on Turing’s mechanism. We find extensive pathological model behaviour, exhibiting one or more of the following: temporal oscillations with no spatial structure, a failure of the Turing instability and an extreme sensitivity to the initial conditions, the growth profile and the duration of gene expression. This deviant behaviour is even more severe than observed in previous studies of Schnakenberg kinetics on exponentially growing domains in the presence of gene expression (Gaffney and Monk in Bull. Math. Biol. 68:99–130, 2006). Our results emphasise that gene expression dynamics induce unrealistic behaviour in Turing’s model for multiple choices of kinetics and thus such aberrant modelling predictions are likely to be generic. They also highlight that domain growth can no longer ameliorate the excessive sensitivity of Turing’s mechanism in the presence of gene expression time delays. The above, extensive, pathologies suggest that, in the presence of gene expression, Turing’s mechanism would generally require a novel and extensive secondary mechanism to control reaction diffusion patterning