Manchester University

Background Canagliflozin is a sodium-glucose cotransporter 2 inhibitor that reduces glycemia as well as blood pressure, body weight, and albuminuria in people with diabetes. We report the effects of treatment with canagliflozin on cardiovascular, renal, and safety outcomes. Methods The CANVAS Program integrated data from two trials involving a total of 10,142 participants with type 2 diabetes and high cardiovascular risk. Participants in each trial were randomly assigned to receive canagliflozin or placebo and were followed for a mean of 188.2 weeks. The primary outcome was a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. Results The mean age of the participants was 63.3 years, 35.8% were women, the mean duration of diabetes was 13.5 years, and 65.6% had a history of cardiovascular disease. The rate of the primary outcome was lower with canagliflozin than with placebo (occurring in 26.9 vs. 31.5 participants per 1000 patient-years; hazard ratio, 0.86; 95% confidence interval [CI], 0.75 to 0.97; P<0.001 for noninferiority; P=0.02 for superiority). Although on the basis of the prespecified hypothesis testing sequence the renal outcomes are not viewed as statistically significant, the results showed a possible benefit of canagliflozin with respect to the progression of albuminuria (hazard ratio, 0.73; 95% CI, 0.67 to 0.79) and the composite outcome of a sustained 40% reduction in the estimated glomerular filtration rate, the need for renal-replacement therapy, or death from renal causes (hazard ratio, 0.60; 95% CI, 0.47 to 0.77). Adverse reactions were consistent with the previously reported risks associated with canagliflozin except for an increased risk of amputation (6.3 vs. 3.4 participants per 1000 patient-years; hazard ratio, 1.97; 95% CI, 1.41 to 2.75); amputations were primarily at the level of the toe or metatarsal. Conclusions In two trials involving patients with type 2 diabetes and an elevated risk of cardiovascular disease, patients treated with canagliflozin had a lower risk of cardiovascular events than those who received placebo but a greater risk of amputation, primarily at the level of the toe or metatarsal. (Funded by Janssen Research and Development; CANVAS and CANVAS-R ClinicalTrials.gov numbers, NCT01032629 and NCT01989754 , respectively.).

The optimum routing of a fleet of trucks of varying capacities from a central depot to a number of delivery points may require a selection from a very large number of possible routes, if the number of delivery points is also large. This paper, after considering certain theoretical aspects of the problem, develops an iterative procedure that enables the rapid selection of an optimum or near-optimum route. It has been programmed for a digital computer but is also suitable for hand computation.

Wiebe E Bijker, Thomas P Hughes and Trevor Pinch (eds) 1987 London: MIT x + 405 pp price £29.95 ISBN 0 262 02262 1

Importance: The clinical management of BRCA1 and BRCA2 mutation carriers requires accurate, prospective cancer risk estimates. Objectives: To estimate age-specific risks of breast, ovarian, and contralateral breast cancer for mutation carriers and to evaluate risk modification by family cancer history and mutation location. Design, Setting, and Participants: Prospective cohort study of 6036 BRCA1 and 3820 BRCA2 female carriers (5046 unaffected and 4810 with breast or ovarian cancer or both at baseline) recruited in 1997-2011 through the International BRCA1/2 Carrier Cohort Study, the Breast Cancer Family Registry and the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer, with ascertainment through family clinics (94%) and population-based studies (6%). The majority were from large national studies in the United Kingdom (EMBRACE), the Netherlands (HEBON), and France (GENEPSO). Follow-up ended December 2013; median follow-up was 5 years. Exposures: BRCA1/2 mutations, family cancer history, and mutation location. Main Outcomes and Measures: Annual incidences, standardized incidence ratios, and cumulative risks of breast, ovarian, and contralateral breast cancer. Results: Among 3886 women (median age, 38 years; interquartile range [IQR], 30-46 years) eligible for the breast cancer analysis, 5066 women (median age, 38 years; IQR, 31-47 years) eligible for the ovarian cancer analysis, and 2213 women (median age, 47 years; IQR, 40-55 years) eligible for the contralateral breast cancer analysis, 426 were diagnosed with breast cancer, 109 with ovarian cancer, and 245 with contralateral breast cancer during follow-up. The cumulative breast cancer risk to age 80 years was 72% (95% CI, 65%-79%) for BRCA1 and 69% (95% CI, 61%-77%) for BRCA2 carriers. Breast cancer incidences increased rapidly in early adulthood until ages 30 to 40 years for BRCA1 and until ages 40 to 50 years for BRCA2 carriers, then remained at a similar, constant incidence (20-30 per 1000 person-years) until age 80 years. The cumulative ovarian cancer risk to age 80 years was 44% (95% CI, 36%-53%) for BRCA1 and 17% (95% CI, 11%-25%) for BRCA2 carriers. For contralateral breast cancer, the cumulative risk 20 years after breast cancer diagnosis was 40% (95% CI, 35%-45%) for BRCA1 and 26% (95% CI, 20%-33%) for BRCA2 carriers (hazard ratio [HR] for comparing BRCA2 vs BRCA1, 0.62; 95% CI, 0.47-0.82; P=.001 for difference). Breast cancer risk increased with increasing number of first- and second-degree relatives diagnosed as having breast cancer for both BRCA1 (HR for ≥2 vs 0 affected relatives, 1.99; 95% CI, 1.41-2.82; P<.001 for trend) and BRCA2 carriers (HR, 1.91; 95% CI, 1.08-3.37; P=.02 for trend). Breast cancer risk was higher if mutations were located outside vs within the regions bounded by positions c.2282-c.4071 in BRCA1 (HR, 1.46; 95% CI, 1.11-1.93; P=.007) and c.2831-c.6401 in BRCA2 (HR, 1.93; 95% CI, 1.36-2.74; P<.001). Conclusions and Relevance: These findings provide estimates of cancer risk based on BRCA1 and BRCA2 mutation carrier status using prospective data collection and demonstrate the potential importance of family history and mutation location in risk assessment.

In this paper, we use data from the Carnegie Mellon Survey on industrial R&amp;D to evaluate for the U.S. manufacturing sector the influence of “public”(i.e., university and government R&amp;D lab) research on industrial R&amp;D, the role that public research plays in industrial R&amp;D, and the pathways through which that effect is exercised. We find that public research is critical to industrial R&amp;D in a small number of industries and importantly affects industrial R&amp;D across much of the manufacturing sector. Contrary to the notion that university research largely generates new ideas for industrial R&amp;D projects, the survey responses demonstrate that public research both suggests new R&amp;D projects and contributes to the completion of existing projects in roughly equal measure overall. The results also indicate that the key channels through which university research impacts industrial R&amp;D include published papers and reports, public conferences and meetings, informal information exchange, and consulting. We also finnd that, after controlling for industry, the influence of public research on industrial R&amp;D is disproportionately greater for larger firms as well as start-ups.

This article examines associations between gluten, polymorphisms of the major histocompatibility complex, and mucosal pathology representative of the spectrum of gluten sensitivity. Sequences of wheat, rye, and barley prolamins contain recurring tetrapeptide motifs that are predicted to have beta-reverse-turn secondary structure and that, with in vitro assays, appear active. Structural polymorphisms of major histocompatibility complex subloci identify codon switches within the second exon that control the third hypervariable region in the outer domain of the beta chain. Observations of the intestinal response to gluten reveal five interrelated lesions (preinfiltrative, infiltrative, hyperplastic, destructive, and hypoplastic) that are interpretable as cell-mediated immunologic responses. These responses originate in the lamina propria, where a series of antigen-specific inflammatory processes has now been identified. There is no evidence that celiac sprue is a disease of jejunal enterocytes. Furthermore, the role of intraepithelial space lymphocytes in pathogenesis, if relevant, needs further experimental dissection. Also awaiting further definition are polymorphisms of the celiac lymphocyte antigen receptor and their relationship to gliadin oligopeptide(s) and predisposing genes. The nature and basis of nonresponsive celiac sprue require more thoughtful initiatives to elucidate the immunologic mechanism(s) of unresponsiveness and evaluate possible means of reversal. Finally, a more sensible definition of gluten sensitivity (unhampered by qualitative morphological imagery) is ultimately called for in order to accommodate the biomolecular advances addressed in this review.

Journal Article International Production and the Multinational Enterprise Get access International Production and the Multinational Enterprise. By John H. DUNNING. London: George Allen and Unwin, 1981. Pp. vii+ 439. £20.00 hard­back, £8.95 paperback.) Fred Burton Fred Burton University of Manchester Institute of Science and Technology Search for other works by this author on: Oxford Academic Google Scholar The Economic Journal, Volume 92, Issue 366, 1 June 1982, Pages 434–435, https://doi.org/10.2307/2232466 Published: 01 June 1982

We describe a general, simple and inexpensive method for the isolation of DNA from filamentous fungi. Starting from freeze-dried mycelium 01–015% by weight can be isolated as high molecular weight DNA suitable for restriction and ligation in 2 h. The preparation can be done in Eppendorf tubes and allows the processing of many samples in parallel. We have used the method with the basidiomycetes Phanerochaete chrysosporium, Coprinus cinereus and the ascomycete Aspergillus nidulans and others have used it with Trichoderma reesei, Aspergillus niger and for the isolation of DNA from tomato plants.

Exosomes are small intracellular membrane-based vesicles with different compositions that are involved in several biological and pathological processes. The exploitation of exosomes as drug delivery vehicles offers important advantages compared to other nanoparticulate drug delivery systems such as liposomes and polymeric nanoparticles; exosomes are non-immunogenic in nature due to similar composition as body׳s own cells. In this article, the origin and structure of exosomes as well as their biological functions are outlined. We will then focus on specific applications of exosomes as drug delivery systems in pharmaceutical drug development. An overview of the advantages and challenges faced when using exosomes as a pharmaceutical drug delivery vehicles will also be discussed.

A great deal of research has been conducted over recent years in the field of occupational stress and its relationship to physical and mental illness. This paper attempts to provide a framework for examining this work, with the dual objectives of broadening the existing psychological literature with the extensive medical data available and also highlighting the research gaps in this area. By emphasizing the medical evidence it is hoped that we may encourage greater interdisciplinary work in the growing field of stress at work.

In this new textbook Ian Parker provides a systematic introduction to discourse research and the essential theoretical debates of the area. It defends a realist position, discusses accounts of postmodernity and sets out criteria for the identification of discourses. Discourse Dynamics is addressed to both undergraduate students in psychology, and postgraduates and researchers new to discourse theory. It should offer useful reading for anyone interested in project research and those seeking an understanding of the issues involved in discourse analysis. It addresses the concerns of all those looking at qualitative textual research in the human sciences.

The Square Kilometre Array (SKA) will be an ultrasensitive radio telescope, built to further the understanding of the most important phenomena in the Universe, including some pertaining to the birth and eventual death of the Universe itself. Over the next few years, the SKA will make the transition from an early formative to a well-defined design. This paper outlines how the scientific challenges are translated into technical challenges, how the application of recent technology offers the potential of affordably meeting these challenges, and how the choices of technology will ultimately be made. The SKA will be an array of coherently connected antennas spread over an area about 3000 km in extent, with an aggregate antenna collecting area of up to 106 m <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">2</sup> at centimeter and meter wavelengths. A key scientific requirement is the ability to carry out sensitive observations of the sky over large areas (surveys). The ldquosurvey speedrdquo of the SKA will be enabled by the application of the most up-to-date signal-processing technology available. The SKA science impact will be widely felt in astroparticle physics and cosmology, fundamental physics, galactic and extragalactic astronomy, solar system science, and astrobiology.

Synopsis A method of analysis is described for determining the factor of safety of an embankment against failure on a cylindrical slip surface. The analysis is in terms of effectivce stress and leads to two equa-tions of equilibrium, the first in respect of forces and the second in respect of moments. Using this method of analysis, the factors affecting the accuracy of Bishop's simplified method have been investigated. Charts have been obtained for three different values of the pore pressure coefficient (r u ) which identify the position of the critical slip circle. A set of stability charts is also given. On décrit une méthode d'analyse pour déterminer le facteur de sécurité d'un remblai contre la rupture sur une surface de glissement cylindrique. L'analyse est faite d'après la contrainte effective ett amène à deux équations d'équilibre, la première se rapportant aux forces et la deuxième aux moments. En utilisant cette méthod d'analyse, on a étudié les facteurs qui affectent la précision de la méthode simplifiée de Bishop. On est arrivé à des diagram-mes pour les trois valeurs différentes de coefficient de pression interstitielle (r u ) quiidentifient la position du cercle de glissement critique. On donne aussi un groupe de diagrammes de stabilité.

Abstract When two metals are allowed together in various proportions, a series of solid phases is formed. A characteristic phase diagram of a binary alloy system has regions of single phase, throughout which the alloy is homogeneous, alternating with regions in which two neighbouring phases coexist. The composition of a single phase can be varied continuously over a certain range. This feature of an alloy is in contrast to tire constant atomic ratio of a chemical compound, and is explained by the nature of the binding forces in an alloy which are predominantly those between the metal atoms of both kinds on the one hand and the common electronic system on the other hand, as opposed to the binding forces between atom and atom which predominate in other chemical compounds. Not only may the atomic ratio in a given phase be varied, but also an orderly space distribution of one kind of atom relative to the other, as found in topical chemical compounds, does not necessarily exist in an alloy. Although each phase is distinguished by possessing a characteristic crystalline structure which differs from that of other phases in the same alloy system, yet this structure may be merely an orderly arrangement of sites occupied by atoms. The manner in which the atoms are distributed amongst the sites of a given phase is often variable, and is, for instance, affected by the thermal treatment which the alloy has undergone.

The characteristic lengths of the oscillating wakes of bluff bodies is discussed; in particular, those used in the universal non-dimensional frequencies proposed by Roshko (1954 b ) and Goldburg, Washburn &amp; Florsheim (1965). It is concluded that these are equivalent at high Reynolds number. A closer examination leads to the conclusion that there are two simultaneous characteristic lengths; the scale of the formation region, and the width to which the free shear layers diffuse. Discussion of the mechanics of the formation region results in a physical basis for the determination of the frequency by these two characteristic lengths. The ideas developed are applied to the effects of splitter plates in the wake. The possibility of a high-Reynolds-number symmetrical formation region is suggested as an explanation of the very small lift values observed in the absence of free-stream disturbances.

Abstract If two materials are brought into contact and then separated they are found to be charged; this is the phenomenon of ‘contact electrification’. The subject falls naturally into three divisions—electrification of metals by metals; of insulators by metals; and of insulators by insulators. The first of these is well understood; charge transfer between metals is such as to bring the two Fermi levels into coincidence. The second division, electrification of insulators by metals, has been much studied recently and takes up the main part of our review; our understanding remains imperfect, chiefly because of lack of knowledge about the relevant electron states in insulators. Electrification of insulators by insulators has not been studied so extensively, but there is evidence that an understanding of the metal/insulator case will lead to an understanding of the insulator/insulator case as well.

OBJECTIVE: To assess, in the general diabetic population, 1) the prevalence of painful neuropathic symptoms; 2) the relationship between symptoms and clinical severity of neuropathy; and 3) the role of diabetes type, sex, and ethnicity in painful neuropathy. RESEARCH DESIGN AND METHODS: Observational study of a large cohort of diabetic patients receiving community-based health care in northwest England (n = 15,692). Painful diabetic neuropathy (PDN) was assessed using neuropathy symptom score (NSS) and neuropathy disability score (NDS). RESULTS: Prevalence of painful symptoms (NSS ≥5) and PDN (NSS ≥5 and NDS ≥3) was 34 and 21%, respectively. Painful symptoms occurred in 26% of patients without neuropathy (NDS ≤2) and 60% of patients with severe neuropathy (NDS >8). Adjusted risk of painful neuropathic symptoms in type 2 diabetes was double that of type 1 diabetes (odds ratio [OR] = 2.1 [95% CI 1.7-2.4], P < 0.001) and not affected by severity of neuropathy, insulin use, foot deformities, smoking, or alcohol. Women had 50% increased adjusted risk of painful symptoms compared with men (OR = 1.5 [1.4-1.6], P < 0.0001). Despite less neuropathy in South Asians (14%) than Europeans (22%) and African Caribbeans (21%) (P < 0.0001), painful symptoms were greater in South Asians (38 vs. 34 vs. 32%, P < 0.0001). South Asians without neuropathy maintained a 50% increased risk of painful neuropathy symptoms compared with other ethnic groups (P < 0.0001). CONCLUSIONS: One-third of all community-based diabetic patients have painful neuropathy symptoms, regardless of their neuropathic deficit. PDN was more prevalent in patients with type 2 diabetes, women, and people of South Asian origin. This highlights a significant morbidity due to painful neuropathy and identifies key groups who warrant screening for PDN.

Didier Fassin, translated by Rachel Gomme, Berkeley, University of California Press, 2011, 336 pp., £18.95, ISBN 9780520271173 Humanitarianism occupies an uncertain place between ethics, politics a...

Corporate reputation has attracted interest from a wide range of academic disciplines. It is also a growing focus for business and media attention. This paper examines the construct of corporate reputation, first by untangling the terminological problems that have been caused by the interdisciplinary nature of much of the earlier work in the area. The construct of reputation and the allied constructs of image and identity are each reviewed. A structure is proposed in which the three constructs can be seen as labelling different but allied concepts. I then move on to consider how reputation has been measured. The paper uncovers considerable confusion in the use of what might appear to be basic terms and links this to a subsequent lack of grounded measurement tools in the sector, until relatively recently. With a clearer understanding of the construct of corporate reputation and the allied constructs of image and identity, researchers are now well placed to test the relationships widely claimed by practitioners between corporate reputation and other variables such as commercial performance and employee and customer satisfaction. The review ends by illustrating some of the issues that can be assessed from the basis of a clearer conceptualization of reputation and its measurement.

There is current evidence to demonstrate a close association between fungal sensitisation and asthma severity. Whether such an association is causal remains to be confirmed, but this is explored by means of a detailed literature review. There is evidence from two randomised controlled trials that, in the example of allergic bronchopulmonary aspergillosis (ABPA), treatment with systemic antifungal therapy can offer a therapeutic benefit to approximately 60% of patients. ABPA is only diagnosed if a combination of clinical and immunological criteria is achieved. It is not known whether such cases are a discrete clinical entity or part of a spectrum of the pulmonary allergic response to fungi or fungal products. This paper describes the epidemiological evidence that associates severity of asthma with fungi and discusses possible pathogenetic mechanisms. Many airborne fungi are involved, including species of Alternaria, Aspergillus, Cladosporium and Penicillium, and exposure may be indoors, outdoors or both. The potential for a therapeutic role of antifungal agents for patients with severe asthma and fungal sensitisation is also explored. Not only are many patients with severe asthma desperately disabled by their disease, but, in the UK alone, asthma accounts for 1,500 deaths per yr. The healthcare costs of these patients are enormous and any treatment option merits close scrutiny. Within this report, the case for the consideration of a new term related to this association is put forward. The current authors propose the term "severe asthma with fungal sensitisation". However, it is recognised that enhanced and precise definition of fungal sensitisation will require improvements in diagnostic testing.