Showing papers by "University of Manchester published in 2002"

Voriconazole versus Amphotericin B for Primary Therapy of Invasive Aspergillosis

Abstract: Background Voriconazole is a broad-spectrum triazole that is active against aspergillus species. We conducted a randomized trial to compare voriconazole with amphotericin B for primary therapy of invasive aspergillosis. Methods In this randomized, unblinded trial, patients received either intravenous voriconazole (two doses of 6 mg per kilogram of body weight on day 1, then 4 mg per kilogram twice daily for at least seven days) followed by 200 mg orally twice daily or intravenous amphotericin B deoxycholate (1 to 1.5 mg per kilogram per day). Other licensed antifungal treatments were allowed if the initial therapy failed or if the patient had an intolerance to the first drug used. A complete or partial response was considered to be a successful outcome. Results A total of 144 patients in the voriconazole group and 133 patients in the amphotericin B group with definite or probable aspergillosis received at least one dose of treatment. In most of the patients, the underlying condition was allogeneic hematop...

Comparative assessment of large-scale data sets of protein-protein interactions.

Abstract: Comprehensive protein protein interaction maps promise to reveal many aspects of the complex regulatory network underlying cellular function. Recently, large-scale approaches have predicted many new protein interactions in yeast. To measure their accuracy and potential as well as to identify biases, strengths and weaknesses, we compare the methods with each other and with a reference set of previously reported protein interactions.

Prevalence, expenditures, and complications of multiple chronic conditions in the elderly

Abstract: Methods: A cross-sectional analysis was conducted on a nationally random sample of 1217103 Medicare feefor-service beneficiaries aged 65 and older living in the United States and enrolled in both Medicare Part A and Medicare Part B during 1999. Multiple logistic regression was used to analyze the influence of age, sex, and number of types of chronic conditions on the risk of incurring inpatient hospitalizations for ambulatory care sensitive conditions and hospitalizations with preventable complications among aged Medicare beneficiaries. Results: In 1999, 82% of aged Medicare beneficiaries had 1 or more chronic conditions, and 65% had multiple chronic conditions. Inpatient admissions for ambulatory care sensitive conditions and hospitalizations with preventable complications increased with the number of chronic conditions. For example, Medicare beneficiaries with 4 or more chronic conditions were 99 times more likely than a beneficiary without any chronic conditions to have an admission for an ambulatory care sensitive condition (95% confidence interval, 86-113). Per capita Medicare expenditures increased with the number of types of chronic conditions from $211 among beneficiaries without a chronic condition to $13973 among beneficiaries with 4 or more types of chronic conditions. Conclusions: The risk of an avoidable inpatient admission or a preventable complication in an inpatient setting increases dramatically with the number of chronic conditions. Better primary care, especially coordination of care, could reduce avoidable hospitalization rates, especially for individuals with multiple chronic conditions.

Links and Impacts: The Influence of Public Research on Industrial R&D

Abstract: In this paper, we use data from the Carnegie Mellon Survey on industrial R&D to evaluate for the U.S. manufacturing sector the influence of ?public?(i.e., university and government R&D lab) research on industrial R&D, the role that public research plays in industrial R&D, and the pathways through which that effect is exercised. We find that public research is critical to industrial R&D in a small number of industries and importantly affects industrial R&D across much of the manufacturing sector. Contrary to the notion that university research largely generates new ideas for industrial R&D projects, the survey responses demonstrate that public research both suggests new R&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&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&D is disproportionately greater for larger firms as well as start-ups.

Global production networks and the analysis of economic development

Abstract: This article outlines a framework for the analysis of economic integration and its relation to the asymmetries of economic and social development. Consciously breaking with state-centric forms of social science, it argues for a research agenda that is more adequate to the exigencies and consequences of globalization than has traditionally been the case in 'development studies'. Drawing on earlier attempts to analyse the cross-border activities of firms, their spatial configurations and developmental consequences, the article moves beyond these by proposing the framework of the 'global production network' (GPN). It explores the conceptual elements involved in this framework in some detail and then turns to sketch a stylized example of a GPN. The article concludes with a brief indication of the benefits that could be delivered by research informed by GPN analysis.

Low-penetrance susceptibility to breast cancer due to CHEK2(*)1100delC in noncarriers of BRCA1 or BRCA2 mutations

Abstract: Mutations in BRCA1 and BRCA2 confer a high risk of breast and ovarian cancer, but account for only a small fraction of breast cancer susceptibility. To find additional genes conferring susceptibility to breast cancer, we analyzed CHEK2 (also known as CHK2), which encodes a cell-cycle checkpoint kinase that is implicated in DNA repair processes involving BRCA1 and p53 (refs 3,4,5). We show that CHEK2(*)1100delC, a truncating variant that abrogates the kinase activity, has a frequency of 1.1% in healthy individuals. However, this variant is present in 5.1% of individuals with breast cancer from 718 families that do not carry mutations in BRCA1 or BRCA2 (P = 0.00000003), including 13.5% of individuals from families with male breast cancer (P = 0.00015). We estimate that the CHEK2(*)1100delC variant results in an approximately twofold increase of breast cancer risk in women and a tenfold increase of risk in men. By contrast, the variant confers no increased cancer risk in carriers of BRCA1 or BRCA2 mutations. This suggests that the biological mechanisms underlying the elevated risk of breast cancer in CHEK2 mutation carriers are already subverted in carriers of BRCA1 or BRCA2 mutations, which is consistent with participation of the encoded proteins in the same pathway.

Placental-specific IGF-II is a major modulator of placental and fetal growth

Abstract: Imprinted genes in mammals are expressed from only one of the parental chromosomes, and are crucial for placental development and fetal growth1,2,3,4. The insulin-like growth factor II gene (Igf2) is paternally expressed in the fetus and placenta5. Here we show that deletion from the Igf2 gene of a transcript (P0)6,7 specifically expressed in the labyrinthine trophoblast of the placenta leads to reduced growth of the placenta, followed several days later by fetal growth restriction. The fetal to placental weight ratio is thus increased in the absence of the P0 transcript. We show that passive permeability for nutrients of the mutant placenta is decreased, but that secondary active placental amino acid transport is initially upregulated, compensating for the decrease in passive permeability. Later the compensation fails and fetal growth restriction ensues. Our study provides experimental evidence for imprinted gene action in the placenta that directly controls the supply of maternal nutrients to the fetus, and supports the genetic conflict theory of imprinting8. We propose that the Igf2 gene, and perhaps other imprinted genes, control both the placental supply of, and the genetic demand for, maternal nutrients to the mammalian fetus.

The North-West Diabetes Foot Care Study: incidence of, and risk factors for, new diabetic foot ulceration in a community-based patient cohort.

Abstract: Aims To determine the incidence of, and clinically relevant risk factors for, new foot ulceration in a large cohort of diabetic patients in the community healthcare setting. Methods Diabetic patients (n = 9710) underwent foot screening in six districts of North-west England in various healthcare settings. All were assessed at baseline for demographic information, medical and social history, neuropathy symptom score, neuropathy disability score, cutaneous pressure perception (insensitivity to the 10 g monofilament), foot deformities, and peripheral pulses. Two years later, patients were followed up via postal questionnaire to determine the incidence of new foot ulcers. Cox’s proportional hazards regression analysis was used to determine the independent, relative risk of baseline variables for new foot ulceration. Results New foot ulcers occurred in 291/6613 patients who completed and returned their 2-year follow-up questionnaire (2.2% average annual incidence). The following factors were independently related to new foot ulcer risk: ulcer present at baseline (relative risk (95% confidence interval)) 5.32 (3.71–7.64), past history of ulcer 3.05 (2.16–4.31), abnormal neuropathy disability score (≥ 6/10) 2.32 (1.61–3.35), any previous podiatry attendance 2.19 (1.50–3.20), insensitivity to the 10 g monofilament 1.80 (1.36–2.39), reduced pulses 1.80 (1.40–2.32), foot deformities 1.57 (1.22–2.02), abnormal ankle reflexes 1.55 (1.01–2.36) and age 0.99 (0.98–1.00). Conclusions More than 2% of community-based diabetic patients develop new foot ulcers each year. The neuropathy disability score, 10 g monofilament and palpation of foot pulses are recommended as screening tools in general practice.

Toward automatic simulation of aging effects on face images

Abstract: The process of aging causes significant alterations in the facial appearance of individuals When compared with other sources of variation in face images, appearance variation due to aging displays some unique characteristics Changes in facial appearance due to aging can even affect discriminatory facial features, resulting in deterioration of the ability of humans and machines to identify aged individuals We describe how the effects of aging on facial appearance can be explained using learned age transformations and present experimental results to show that reasonably accurate estimates of age can be made for unseen images We also show that we can improve our results by taking into account the fact that different individuals age in different ways and by considering the effect of lifestyle Our proposed framework can be used for simulating aging effects on new face images in order to predict how an individual might look like in the future or how he/she used to look in the past The methodology presented has also been used for designing a face recognition system, robust to aging variation In this context, the perceived age of the subjects in the training and test images is normalized before the training and classification procedure so that aging variation is eliminated Experimental results demonstrate that, when age normalization is used, the performance of our face recognition system can be improved

Epidemiology and genetics of rheumatoid arthritis.

Abstract: The prevalence of rheumatoid arthritis (RA) is relatively constant in many populations, at 0.5–1.0%. However, a high prevalence of RA has been reported in the Pima Indians (5.3%) and in the Chippewa Indians (6.8%). In contrast, low occurrences have been reported in populations from China and Japan. These data support a genetic role in disease risk. Studies have so far shown that the familial recurrence risk in RA is small compared with other autoimmune diseases. The main genetic risk factor of RA is the HLA DRB1 alleles, and this has consistently been shown in many populations throughout the world. The strongest susceptibility factor so far has been the HLA DRB1*0404 allele. Tumour necrosis factor alleles have also been linked with RA. However, it is estimated that these genes can explain only 50% of the genetic effect. A number of other non-MHC genes have thus been investigated and linked with RA (e.g. corticotrophin releasing hormone, oestrogen synthase, IFN-γ and other cytokines). Environmental factors have also been studied in relation to RA. Female sex hormones may play a protective role in RA; for example, the use of the oral contraceptive pill and pregnancy are both associated with a decreased risk. However, the postpartum period has been highlighted as a risk period for the development of RA. Furthermore, breastfeeding after a first pregnancy poses the greatest risk. Exposure to infection may act as a trigger for RA, and a number of agents have been implicated (e.g. Epstein–Barr virus, parvovirus and some bacteria such as Proteus and Mycoplasma). However, the epidemiological data so far are inconclusive. There has recently been renewed interest in the link between cigarette smoking and RA, and the data presented so far are consistent with and suggestive of an increased risk.

On the evidential reasoning algorithm for multiple attribute decision analysis under uncertainty

Abstract: In multiple attribute decision analysis (MADA), one often needs to deal with both numerical data and qualitative information with uncertainty. It is essential to properly represent and use uncertain information to conduct rational decision analysis. Based on a multilevel evaluation framework, an evidential reasoning (ER) approach has been developed for supporting such decision analysis, the kernel of which is an ER algorithm developed on the basis of the framework and the evidence combination rule of the Dempster-Shafer (D-S) theory. The approach has been applied to engineering design selection, organizational self-assessment, safety and risk assessment, and supplier assessment. In this paper, the fundamental features of the ER approach are investigated. New schemes for weight normalization and basic probability assignments are proposed. The original ER approach is further developed to enhance the process of aggregating attributes with uncertainty. Utility intervals are proposed to describe the impact of ignorance on decision analysis. Several properties of the new ER approach are explored, which lay the theoretical foundation of the ER approach. A numerical example of a motorcycle evaluation problem is examined using the ER approach. Computation steps and analysis results are provided in order to demonstrate its implementation process.

Tacit Knowledge, Innovation and Economic Geography

Abstract: The aim of this paper is to outline the importance of tacit knowledge in the innovation process and to highlight the way that geographical location not only influences the relationship between knowledge and innovative activity, but also affects the way that such interaction influences the geography of innovation and economic activity. After a discussion about the nature of knowledge, the paper explores the relationship that exists between knowledge and geography. The paper then reviews, using as an analytical lens, the growing body of literature on knowledge spillovers which affirm the importance of geography. However, the discussion then seeks to outline some crucial gaps that remain in our conceptualisation of the knowledge spillover and transfer process. The paper then highlights the neglected role of knowledge demand and consumption in a spatial context, before concluding with a review of areas for future research.

Mutations in IRF6 cause Van der Woude and popliteal pterygium syndromes.

Abstract: Interferon regulatory factor 6 (IRF6) belongs to a family of nine transcription factors that share a highly conserved helix–turn–helix DNA-binding domain and a less conserved protein-binding domain. Most IRFs regulate the expression of interferon-α and -β after viral infection1, but the function of IRF6 is unknown. The gene encoding IRF6 is located in the critical region for the Van der Woude syndrome (VWS; OMIM 119300) locus at chromosome 1q32–q41 (refs 2,3). The disorder is an autosomal dominant form of cleft lip and palate with lip pits4, and is the most common syndromic form of cleft lip or palate. Popliteal pterygium syndrome (PPS; OMIM 119500) is a disorder with a similar orofacial phenotype that also includes skin and genital anomalies5. Phenotypic overlap6 and linkage data7 suggest that these two disorders are allelic. We found a nonsense mutation in IRF6 in the affected twin of a pair of monozygotic twins who were discordant for VWS. Subsequently, we identified mutations in IRF6 in 45 additional unrelated families affected with VWS and distinct mutations in 13 families affected with PPS. Expression analyses showed high levels of Irf6 mRNA along the medial edge of the fusing palate, tooth buds, hair follicles, genitalia and skin. Our observations demonstrate that haploinsufficiency of IRF6 disrupts orofacial development and are consistent with dominant-negative mutations disturbing development of the skin and genitalia.

Efficacy and Safety of Voriconazole in the Treatment of Acute Invasive Aspergillosis

Abstract: To evaluate the efficacy and safety of voriconazole in acute invasive aspergillosis (IA), an open, noncomparative multicenter study was conducted. Immunocompromised patients with IA were treated with intravenously administered voriconazole 6 mg/kg twice a day (b.i.d.) twice and then 3 mg/kg b.i.d. for 6-27 days, followed by 200 mg b.i.d. administered orally for up to 24 weeks. Response was assessed by clinical and radiographic change. A total of 116 patients were assessable. IA was proven in 48 (41%) and probable in 68 patients. Voriconazole was given as primary therapy in 60 (52%). Good responses were seen in 56 (48%); 16 (14%) showed complete response and 40 (34%) partial response. A stable response was seen in 24 patients (21%), and 36 (31%) of the infections failed to respond to therapy. Good responses were seen in 60% of those with pulmonary or tracheobronchial IA (n=84), 16% with cerebral IA (n=19), 58% with hematologic disorders (n=67), and 26% of allogeneic stem cell transplant recipients (n=23). Voriconazole is efficacious in treating acute IA.

The BABAR detector

Abstract: BABAR, the detector for the SLAC PEP-II asymmetric e+e- B Factory operating at the upsilon 4S resonance, was designed to allow comprehensive studies of CP-violation in B-meson decays. Charged particle tracks are measured in a multi-layer silicon vertex tracker surrounded by a cylindrical wire drift chamber. Electromagentic showers from electrons and photons are detected in an array of CsI crystals located just inside the solenoidal coil of a superconducting magnet. Muons and neutral hadrons are identified by arrays of resistive plate chambers inserted into gaps in the steel flux return of the magnet. Charged hadrons are identified by dE/dx measurements in the tracking detectors and in a ring-imaging Cherenkov detector surrounding the drift chamber. The trigger, data acquisition and data-monitoring systems, VME- and network-based, are controlled by custom-designed online software. Details of the layout and performance of the detector components and their associated electronics and software are presented.

Research methods used in developing and applying quality indicators in primary care

Abstract: Quality indicators have been developed throughout Europe primarily for use in hospitals, but also increasingly for primary care. Both development and application are important but there has been less research on the application of indicators. Three issues are important when developing or applying indicators: (1) which stakeholder perspective(s) are the indicators intended to reflect; (2) what aspects of health care are being measured; and (3) what evidence is available? The information required to develop quality indicators can be derived using systematic or non-systematic methods. Non-systematic methods such as case studies play an important role but they do not tap in to available evidence. Systematic methods can be based directly on scientific evidence by combining available evidence with expert opinion, or they can be based on clinical guidelines. While it may never be possible to produce an error free measure of quality, measures should adhere, as far as possible, to some fundamental a priori characteristics (acceptability, feasibility, reliability, sensitivity to change, and validity). Adherence to these characteristics will help maximise the effectiveness of quality indicators in quality improvement strategies. It is also necessary to consider what the results of applying indicators tell us about quality of care.

The prevalence of rheumatoid arthritis in the United Kingdom: new estimates for a new century

Abstract: Background. It is 40 yr since the last age- and sex-specific estimates of the prevalence of rheumatoid arthritis (RA) for the UK were published. Since then the classification criteria for RA have been revised and there has been evidence of a fall in the incidence of RA, especially in women. Objectives. To estimate the age- and sex-specific point prevalence of RA (defined as fulfilment of a modification of the 1987 ACR classification criteria for RA on the day of assessment). The estimate was made in the primary care setting in Norfolk, UK. Methods. A stratified random sample was drawn from seven age and gender bands. The 7050 individuals selected were mailed a screening questionnaire. Positive responders were invited to attend for a clinical examination. The sample was matched against the names in the Norfolk Arthritis Register (NOAR), a register of incident cases of inflammatory polyarthritis which has been in existence since 1990. Results. The overall response rate was 82%. Sixty-six cases of RA were identified. Extrapolated to the population of the UK, the overall minimum prevalence of RA is 1.16% in women and 0.44% in men. A number of incident cases of RA previously notified to NOAR were not identified as cases in the survey because they had entered into treatment-induced remission. In addition, some cases who failed to attend for examination had significant disability. These prevalence figures are therefore an underestimate. Conclusions. The prevalence of RA in women, but not in men, in the UK may have fallen since the 1950s.

Ferrite devices and materials

Abstract: The development and current status of microwave ferrite technology is reviewed in this paper. An introduction to the physics and fundamentals of key ferrite devices is provided, followed by a historical account of the development of ferrimagnetic spinel and garnet (YIG) materials. Key ferrite components, i.e., circulators and isolators, phase shifters, tunable filters, and nonlinear devices are also discussed separately.

A minimum description length approach to statistical shape modeling

Abstract: We describe a method for automatically building statistical shape models from a training set of example boundaries/surfaces. These models show considerable promise as a basis for segmenting and interpreting images. One of the drawbacks of the approach is, however, the need to establish a set of dense correspondences between all members of a set of training shapes. Often this is achieved by locating a set of "landmarks" manually on each training image, which is time consuming and subjective in two dimensions and almost impossible in three dimensions. We describe how shape models can be built automatically by posing the correspondence problem as one of finding the parameterization for each shape in the training set. We select the set of parameterizations that build the "best" model. We define "best" as that which minimizes the description length of the training set, arguing that this leads to models with good compactness, specificity and generalization ability. We show how a set of shape parameterizations can be represented and manipulated in order to build a minimum description length model. Results are given for several different training sets of two-dimensional boundaries, showing that the proposed method constructs better models than other approaches including manual landmarking-the current gold standard. We also show that the method can be extended straightforwardly to three dimensions.

Reliable estimation of generalized linear mixed models using adaptive quadrature.

Abstract: Generalized linear mixed models or multilevel regression models have become increasingly popular. Several methods have been proposed for estimating such models. However, to date there is no single method that can be assumed to work well in all circumstances in terms of both parameter recovery and com- putational efficiency. Stata's xt commands for two-level generalized linear mixed models (e.g., xtlogit) employ Gauss-Hermite quadrature to evaluate and maxi- mize the marginal log likelihood. The method generally works very well, and often better than common contenders such as MQL and PQL, but there are cases where quadrature performs poorly. Adaptive quadrature has been suggested to overcome these problems in the two-level case. We have recently implemented a multilevel version of this method ingllamm, a program that fits a large class of multilevel latent variable models including multilevel generalized linear mixed models. As far as we know, this is the first time that adaptive quadrature has been proposed for multilevel models. We show that adaptive quadrature works well in problems where ordinary quadrature fails. Furthermore, even when ordinary quadrature works, adaptive quadrature is often computationally more efficient since it requires fewer quadrature points to achieve the same precision.

Depression in rheumatoid arthritis: a systematic review of the literature with meta-analysis.

Abstract: OBJECTIVE: This systematic review and meta-analysis examined the strength of association between rheumatoid arthritis and depression. In addition, we investigated the extent to which sociodemographic characteristics, level of pain, and method of assessing depression might affect the degree of depression. METHODS: CD-ROM databases and bibliographies were searched to identify all studies comparing depression in patients with rheumatoid arthritis and control subjects using standardized assessments. Effect sizes (Pearson's r) and probabilities were combined across studies. We examined the extent to which the association between rheumatoid arthritis and depression could be attributed to level of pain (using contrasts), sociodemographic differences between groups (combining methodologically restricted studies), and methods of assessing depression (examining heterogeneity across studies). RESULTS: Twelve independent studies comparing depression in patients with rheumatoid arthritis with depression in healthy control subjects were found. Effect sizes for depression were small to moderate (r =.21, p <.0001; heterogeneous). This effect was not reduced in studies controlling for sociodemographic characteristics (r =.27, p <.0001). The effect sizes did vary in a linear manner in proportion to the effect size for pain (z = 2.67, p =.0064). The effect sizes produced by different measures of depression were heterogeneous (chi(2) for Fisher's Z = 24.6, p =.0002), with the Hospital Anxiety and Depression Scale giving effect sizes most dissimilar to those of other measures. CONCLUSIONS: Depression is more common in patients with rheumatoid arthritis than in healthy individuals. This difference is not due to sociodemographic differences between groups, but it may be attributable, in part, to the levels of pain experienced. Variation in the methods of assessing depression partly accounts for the differences among studies examining the levels of depression in patients with rheumatoid arthritis.

The intestinal epithelial stem cell

Abstract: This article considers the role of the adult epithelial stem cell, with particular reference to the intestinal epithelial stem cell. Although the potential of adult stem cells has been revealed in a number of recent publications, the organization and control of the stem cell hierarchy in epithelial tissues is still not fully understood. The intestinal epithelium is an excellent model in which to study such hierarchies, having a distinctive polarity and high rate of cell proliferation and migration. Studies on the small intestinal crypt provide insight into the characteristics of the stem cells in normal and regenerating circumstances and demonstrate why a thorough understanding of these cells is an essential pre-requisite for stem cell based therapeutic approaches.

Evaluating Tax Policy for Location Decisions

Abstract: We consider the impact of taxation when investors face a discrete choice between two or more mutually exclusive projects; in particular we consider the location choice of multinationals. Such choices depend on an effective average tax rate. We propose a precise measure of this rate, which is shown to be equal to a weighted average of an effective marginal tax rate and an adjusted statutory tax rate, where the weights depend on the profitability of the investment. Estimates of the distribution of this measure are presented and compared for domestic and international investment in the USA, France, Germany, and the UK. We analyse the impact of harmonising corporate tax rates in Europe on incentives to locate in France, Germany and the UK.