809 research outputs found
The "silent" global burden of congenital cytomegalovirus.
No full textSUMMARY
Human cytomegalovirus (CMV) is a leading cause of congenital
infections worldwide. In the developed world, following
the virtual elimination of circulating rubella, it is the commonest
nongenetic cause of childhood hearing loss and an important
cause of neurodevelopmental delay. The seroprevalence of
CMV in adults and the incidence of congenital CMV infection
are highest in developing countries (1 to 5% of births) and are
most likely driven by nonprimary maternal infections. However,
reliable estimates of prevalence and outcome from developing
countries are not available. This is largely due to the
dogma that maternal preexisting seroimmunity virtually eliminates
the risk for sequelae. However, recent data demonstrating
similar rates of sequelae, especially hearing loss, following
primary and nonprimary maternal infection have underscored
the importance of congenital CMV infection in resource-poor
settings. Although a significant proportion of congenital CMV
infections are attributable to maternal primary infection in
well-resourced settings, the absence of specific interventions
for seronegative mothers and uncertainty about fetal prognosis
have discouraged routine maternal antibody screening. Despite
these challenges, encouraging results from prototype vaccines
have been reported, and the first randomized phase III
trials of prenatal interventions and prolonged postnatal antiviral
therapy are under way. Successful implementation of strategies
to prevent or reduce the burden of congenital CMV infection
will require heightened global awareness among
clinicians and the general population. In this review, we highlight
the global epidemiology of congenital CMV and the implications
of growing knowledge in areas of prevention, diagnosis,
prognosis, and management for both low (50 to 70%)-
and high (70%)-seroprevalence settings
A randomized, controlled trial comparing ganciclovir to ganciclovir plus foscarnet (each at half dose) for preemptive therapy of cytomegalovirus infection in transplant recipients
No full textForty-eight patients who provided 2 consecutive blood samples that tested positive for cytomegalovirus DNA by polymerase chain reaction (PCR) were randomized to receive either full-dose ganciclovir ( 5 mg/kg intravenously [iv] twice daily) or half-dose ganciclovir (5 mg/kg iv once daily) plus half-dose foscarnet (90 mg/kg iv once daily) for 14 days. In the ganciclovir arm, 17 (71%) of 24 patients reached the primary end point of being CMV negative by PCR within 14 days of initiation of therapy, compared with 12 (50%) of 24 patients in the ganciclovir-plus-foscarnet arm (P = .12). Toxicity was greater in the combination-therapy arm. In patients who failed to reach the primary end point, baseline virus load was 0.77 log(10) higher, the replication rate before therapy was faster (1.5 vs. 2.7 days), and the viral decay rate was slower (2.9 vs. 1.1 days) after therapy. Bivariable logistic regression models identified baseline virus load, bone-marrow transplantation, and doubling time and half-life of decay as the major factors affecting response to therapy within 14 days. This study did not support a synergistic effect of ganciclovir plus foscarnet in vivo
Human cytomegalovirus (HCMV) replication dynamics in HCMV-naive and -experienced immunocompromised hosts
No full textHuman cytomegalovirus (HCMV) can infect both HCMV-naive and -experienced transplant patients. In this study, the growth rate of HCMV in HCMV-naive hosts (1.82 units/day; 95% confidence interval [CI], 1.44-2.56 units/day) was shown to be significantly faster than the growth rate of virus in HCMV-experienced hosts undergoing recurrent infection (0.61 units/ day; 95% CI, 0.55-0.7 units/day; P93% (95% CI, 89%-98%) is required to eliminate viral growth during infection of HCMV-naive liver transplant recipients, whereas lower efficacy levels are sufficient to reduce the R-0 value to <1 in hosts with prior HCMV immunity
Prospective study of human herpesvirus 6, human herpesvirus 7, and cytomegalovirus infections in human immunodeficiency virus-positive patients
No full textBlood samples from human immunodeficiency virus (HIV)-positive patients were monitored for cytomegalovirus (CMV), human herpesvirus 6 (HHV-6), and HHV-7 by PCR. We detected CMV in 17% of the patients, HHV-6 in 6%, and HHV-7 in 3%. The viral loads of CMV were significantly higher than those of HHV-6 (P = 0.007) or HHV-7 (P = 0.01). Detection of CMV and HHV-6 was associated with low and high CD4 counts, respectively
Shear transfer mechanism in reinforced engineered cementitious composite (ECC) beams: Quantification of Vs and Vc
No full textTo enhance the structural and seismic resistance, as well as durability of concrete structures, an ultra ductile fiber reinforced cementitious composites called Engineered Cementitious Composite (ECC), also known as Strain Hardening Cementitious Composite (SHCC), was developed. ECC has a similar compressive and tensile strength to conventional concrete, but it exhibits a pseudo-strain-hardening behaviour under uniaxial tension with excellent crack control ability. The ultimate tensile strain of ECC can reach 3–12%, which is 300–1200 times higher than that of concrete. It is reported that ECC can also exhibit at least twice as high shear carrying capacity compared to traditional concrete, signifying a potential to use ECC material in shear-resistance elements. However, the shear resisting mechanism of reinforced ECC (R/ECC) members is still not clear. In most existing codes and models, the shear strength of reinforced structural members (Vu) is divided into two parts, i.e., shear resistance coming from the matrix (Vc) and from the transverse reinforcement (Vs). To quantify accurately Vc and Vs and also their development throughout the loading, a well-designed testing method consisting of continuous strain quantification along the stirrups, was used in this research. Six steel reinforced beams incorporating different matrix (ECC, concrete and mortar) were tested under four-point bending. The test results indicated that Vc changed continuously with the propagation of shear crack, whereas the stirrups that crossed the critical shear crack, did not always yield at the ultimate shear resistance.Green Open Access added to TU Delft Institutional Repository ‘You share, we take care!’ – Taverne project https://www.openaccess.nl/en/you-share-we-take-care Otherwise as indicated in the copyright section: the publisher is the copyright holder of this work and the author uses the Dutch legislation to make this work public.Concrete Structure
Market Potential and Operational Scenarios for Virtual Coupling
No full textThis document evaluates the attractiveness of Virtual Coupling (VC) for different market segments (high-speed, main line, regional, urban/suburban, freight) and defines operational scenarios for each of them. A SWOT analysis identifies main strengths and weaknesses of the Virtual Coupling concept and corresponding opportunities and threats to each specific railway market segment. The research relies on a Delphi method with an extensive survey of expert opinions and stated travel preferences assuming VC has been implemented. The survey involved subject matter experts of the wide European railway industry including infrastructure managers, railway undertakings, system suppliers, transport authorities, railway institutions, private consultants and academics. In addition, travel preferences have been collected by interviewing European representatives belonging to other socio professional categories. Results show that the implementation of Virtual Coupling can be attractive to customers of high-speed, main line, regional and especially freight segments. Virtual Coupling has the potential of completely changing the way in which such segments operate and attract a modal shift from other transport modes to railways. Customers are even willing to pay higher fares for more frequent and flexible train services, especially on the regional and freight segments which are currently perceived as not satisfactory. Several operational scenarios have been defined based on the outcomes of the survey, setting market-attractive VC service headways for each market segment as well as specifying characteristics of rolling stock, power supply, traffic, and platform crowd management. Principles to couple/decouple convoys of virtually coupled trains are also provided based on the specific network characteristics of the different market segments.A SWOT analysis is presented which builds on the outcomes of the survey, the operational scenarios and brainstorming sessions with experts of the European railway industry. The main strengths identified for VC are a substantial increase in capacity and reduced operational costs with respect to Moving Block while mitigating delay propagation and improving reliability of ground/train communication. On the other hand, weaknesses of this concept refer to the fact that capacity gains at diverging junctions equipped with current switch technologies might be marginal, since here trains still need to be separated by a full braking distance. Also, the implementation of VC operations would require an investment to upgrade the overhead line system, platform lengths (to allow platoons of trains to stop) and possibly the switch technology. An upgrade of the switch technology towards faster and more reliable ones (e.g. Railtaxi and REPOINT) will unleash the full potential of VC operations. Significant opportunities will be brought about Virtual Coupling such as potential increase in the profit of infrastructure managers and operators as well as a deregulation of the current railway market which could be opened also to smaller transport operators due to the increase of available train paths and the decrease of operational costs by full train automation. In addition, the train-to-train communication could lead to the institution of cooperative consortia of railway operators which can be more economically beneficial than the current competitive market model. This would also provide the chance to migrate obsolescent command and control systems towards future-proof digital railway architectures. Possible threats to the introduction of this concept mainly relate to potential increase of train control complexity increasing risks of approval from the railway industry. The need for an initial investment might be not well received by infrastructure managers and local governments. As well as the necessity of partially changing policies, operational procedures and engineering rules currently in place. When overcoming such challenges, Virtual Coupling has potentials to fully revolutionise and improve current train operations so to induce a sustainable shift to railways.Transport and Plannin
Identification vs. Self-Verification in Virtual Communities (VC)
No full textIdentity-related processes have been identified as important in explaining virtual community (VC) member behavior as well as informing system design of VCs. In particular, the two distinct identity processes of self-verification and identification have been identified and investigated separately, portrayed as two distinctive or contradictory identity processes with different practical implications. This chapter compares and reconciles these two theoretical perspectives in explaining VC participation. Based on a critical and comprehensive review of prior literature, the author identifies three major theoretical gaps that suggest how VC research and management can be advanced through an identity perspective. Finally, the chapter is concluded by discussing key implications of applying identity perspectives in VC research and future research agenda.</jats:p
VC valuation and multiples: an exploration of comparable analysis of software start-ups
No full textThis master thesis seeks to better understand the investment valuation procedure followed by software venture capitalists (VC) in the European context. I explain how VCs perform fair value estimations of software start-ups with the emerging comparable analysis technique. Furthermore, this study examines the relative importance of start-up characteristics in determining the multiple and how these factors influence the VC’s valuation behaviour. Additionally, I explore whether this behaviour and the multiples paid can be explained by differences in VC firm experience at a time of historically low interest rates and record-breaking fund inflows. Based on 36 interviews with European VCs, primarily from the Benelux region, I find that all start-up characteristics matter in the determination of the multiple, but the management team a little more. As a result, software VCs are willing to pay higher multiples for stellar management teams than for exceptional business characteristics. In contrast with the other characteristics, poor traction does not necessarily kill the deal, but VCs might rather use it to enforce a lower valuation. Overall, VC firm experience is not a strong predictor of the valuation behaviour and ARR multiples paid for deals. However, I do find that more experienced VCs are willing to pay higher premiums for benchmark-exceeding traction than their less experienced counterparts.Management of Technology (MoT
The role of lamin A and emerin in mediating genome organisation
Get PDFThis thesis was submitted for the degree of Doctor of Philosophy and awarded by Brunel University.The nuclear matrix (NM) is proposed to be a permanent network of core filaments underlying thicker fibres, present regardless of transcriptional activity. It is found to be both RNA and protein rich; indeed, numerous important nuclear proteins are components of the structure. In addition to mediating the organisation of entire chromosomes, the NM has also been demonstrated to tether telomeres via their TTAGGG repeats. In order to examine telomeric interactions with the NM, a technique known as the DNA halo preparation has been employed. Regions of DNA that are tightly attached to the structure are found within a so-called residual nucleus, while those sequences forming lesser associations produce a halo of DNA. Coupled with various FISH methodologies, this technique allowed the anchorage of genomic regions by the NM, to be analysed. In normal fibroblasts, the majority of chromosomes and telomeres were extensively anchored to the NM. Such interactions did not vary significantly in proliferating and senescent nuclei. However, a decrease in NM-associated telomeres was detected in quiescence. Since lamin A is an integral component of the NM, it seemed pertinent to examine chromosome and telomere NM-anchorage in Hutchinson-Gilford Progeria Syndrome (HGPS) fibroblasts, which contain mutant forms of lamin A. Indeed, genome tethering by the NM was perturbed in HGPS. In immortalised HGPS fibroblasts, this disrupted anchorage appeared to be rescued; the implications of this finding will be discussed. This study also suggested that telomere-NM interactions are aberrant in X-linked Emery-Dreifuss Muscular Dystrophy (X-EDMD), which is caused by mutant forms of emerin, another NM-associated protein. The positioning of selected genes in control and X-EDMD cell lines was examined in un-extracted nuclei using 2D and 3D FISH. Subtle shifts in the organisation of these genes were detected in diseased cells; however, their expression levels remained unaltered. Furthermore, in order to examine the architectural integrity of the nuclear lamina in lamin A and emerin mutant cell lines, scanning electron microscopy (SEM) was employed. This work revealed that such structures were indeed compromised in disease. The findings presented in this thesis highlight the importance of lamin A and emerin in mediating the organisation of the genome and taken together, promote the hypothesis that dysfunctional NM dynamics may well contribute to disease pathology.EU FP6 Programme (Eurolaminopathies), Brunel University and the Progeria Research Fund
Almost Linear VC Dimension Bounds for Piecewise Polynomial Networks
No full textWe compute upper and lower bounds on the VC dimension and pseudo dimension of feedforward neural networks composed of piecewise polynomial activation functions. We show that if the number of layers is fixed, then the VC dimension and pseudo-dimension grow as W log W , where W is the number of parameters in the network. This result stands in opposition to the case where the the number of layers is unbounded, in which case the VC dimension and pseudo-dimension grow as W 2 . We combine our results with recently established approximation error rates, and determine error bounds for the problem of regression estimation by piecewise polynomial networks with unbounded weights. 1 Motivation It is a well known result of much recent work, that in order to derive useful performance bounds for classification, regression, and time series prediction, use must be made of both approximation as well as estimation error bounds. Approximation errors result Part of this work was done while the author..
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