Progression from ocular hypertension to visual field loss in the English hospital eye service

Background There are more than one million National Health Service visits in England and Wales each year for patients with glaucoma or ocular hypertension (OHT). With the ageing population and an increase in optometric testing, the economic burden of glaucoma-related visits is predicted to increase. We examined the conversion rates of OHT to primary open-angle glaucoma (POAG) in England and assessed factors associated with risk of conversion. Methods Electronic medical records of 45 309 patients from five regionally different glaucoma clinics in England were retrospectively examined. Conversion to POAG from OHT was defined by deterioration in visual field (two consecutive tests classified as stage 1 or worse as per the glaucoma staging system 2). Cox proportional hazards models were used to examine factors (age, sex, treatment status and baseline intraocular pressure (IOP)) associated with conversion. Results The cumulative risk of conversion to POAG was 17.5% (95% CI 15.4% to 19.6%) at 5 years. Older age (HR 1.35 per decade, 95% CI 1.22 to 1.50, p<0.001) was associated with a higher risk of conversion. IOP-lowering therapy (HR 0.45, 95% CI 0.35 to 0.57, p<0.001) was associated with a lower risk of conversion. Predicted 5-year conversion rates for treated and untreated groups were 14.0% and 26.9%, respectively. Conclusion Less than one-fifth of OHT patients managed in glaucoma clinics in the UK converted to POAG over a 5-year period, suggesting many patients may require less intensive follow-up. Our study provides real-world evidence for the efficacy of current management (including IOP-lowering treatment) at reducing risk of conversion

Direct transition to high-dimensional chaos through a global bifurcation

In the present work we report on a genuine route by which a high-dimensional (with d>4) chaotic attractor is created directly, i.e., without a low-dimensional chaotic attractor as an intermediate step. The high-dimensional chaotic set is created in a heteroclinic global bifurcation that yields an infinite number of unstable tori.The mechanism is illustrated using a system constructed by coupling three Lorenz oscillators. So, the route presented here can be considered a prototype for high-dimensional chaotic behavior just as the Lorenz model is for low-dimensional chaos.Comment: 7 page

Scaling and synchronization in a ring of diffusively coupled nonlinear oscillators

Chaos synchronization in a ring of diffusively coupled nonlinear oscillators driven by an external identical oscillator is studied. Based on numerical simulations we show that by introducing additional couplings at $(mN_c+1)$-th oscillators in the ring, where $m$ is an integer and $N_c$ is the maximum number of synchronized oscillators in the ring with a single coupling, the maximum number of oscillators that can be synchronized can be increased considerably beyond the limit restricted by size instability. We also demonstrate that there exists an exponential relation between the number of oscillators that can support stable synchronization in the ring with the external drive and the critical coupling strength $\epsilon_c$ with a scaling exponent $\gamma$. The critical coupling strength is calculated by numerically estimating the synchronization error and is also confirmed from the conditional Lyapunov exponents (CLEs) of the coupled systems. We find that the same scaling relation exists for $m$ couplings between the drive and the ring. Further, we have examined the robustness of the synchronous states against Gaussian white noise and found that the synchronization error exhibits a power-law decay as a function of the noise intensity indicating the existence of both noise-enhanced and noise-induced synchronizations depending on the value of the coupling strength $\epsilon$. In addition, we have found that $\epsilon_c$ shows an exponential decay as a function of the number of additional couplings. These results are demonstrated using the paradigmatic models of R\"ossler and Lorenz oscillators.Comment: Accepted for Publication in Physical Review

Bacillus Calmette-Guérin Induces PD-L1 Expression on Antigen-Presenting Cells via Autocrine and Paracrine Interleukin-STAT3 Circuits

Bacillus Calmette-Guérin (BCG) is the only licensed vaccine for tuberculosis (TB), and is also used as an immunotherapy for bladder cancer and other malignancies due to its immunostimulatory properties. Mycobacteria spp., however, are well known for their numerous immune evasion mechanisms that limit the true potential of their therapeutic use. One such major mechanism is the induction of programmed death ligand-1 (PD-L1), which mitigates adaptive immune responses. Here, we sought to unravel the molecular pathways behind PD-L1 up-regulation on antigen-presenting cells (APCs) by BCG. We found that infection of APCs with BCG induced PD-L1 up-regulation, but that this did not depend on direct infection, suggesting a soluble mediator for this effect. BCG induced potent quantities of IL-6 and IL-10, and the downstream transcription factor STAT3 was hyper-phosphorylated. Intracellular analyses revealed that levels of PD-L1 molecules were associated with the STAT3 phosphorylation state, suggesting a causal link. Neutralisation of the IL-6 or IL-10 cytokine receptors dampened STAT3 phosphorylation and BCG-mediated up-regulation of PD-L1 on APCs. Pharmacological inhibition of STAT3 achieved the same effect, confirming an autocrine-paracrine cytokine loop as a mechanism for BCG-mediated up-regulation of PD-L1. Finally, an in vivo immunisation model showed that BCG vaccination under PD-L1 blockade could enhance antigen-specific memory CD4 T-cell responses. These novel findings could lead to refinement of BCG as both a vaccine for infectious disease and as a cancer immunotherapy

In situ measurement of the acoustic performance of a full scale tramway low height noise barrier prototype

International audienceThe performance of a full scale low height barrier prototype meant to attenuate tramway noise is measured in situ. The prototype is made of a simple L-shape assembly of pressed wood boards covered on the source side with fibrous absorbing material, and has been set up temporarily in a residential area in the town of Saint-Martin-d'H` eres, near Grenoble, through which a tramway line passes. A series of pass-by measurements were made at a close receiver location corresponding to the typical height of human ears, with and without the device. The tram speed has been measured as well using an auxiliary microphone located very close to the track. A significant variability in pass-by levels has been found between the different trams, even when applying an approximate correction for speed. However it is shown that the barrier provides on average an attenuation of more than 10 dB(A), during the whole pass-by. Spectral analysis of the recorded signals is carried out as well to estimate the barrier insertion loss more accurately. Furthermore, comparisons between measurements and simplistic BEM calculations show that numerical predictions can yield rather good estimates of the actual in situ performance, within a few dB(A)

Human resource management and innovation: looking across levels

Studies are starting to explore the role of HRM in fostering organizational innovation but empirical evidence remains contradictory and theory fragmented. This is partly because extant literature by and large adopts a unitary level of analysis, rather than reflecting on the multi-level demands that innovation presents. Building on an emergent literature focused on HRM’s role in shaping innovation, we shed light on the question of whether, and how, HRM might influence employees’ innovative behaviours in the direction of strategically important goals. Drawing upon institutional theory, our contributions are three-fold: to bring out the effect of two discrete HRM configurations- one underpinned by a control and the other by an entrepreneurial ethos, on attitudes and behaviours at the individual level; to reflect the way in which employee innovative behaviours arising from these HRM configurations coalesce to shape higher-level phenomena, such as organizational-level innovation; and to bring out two distinct patterns of bottom-up emergence, one driven primarily by composition and the other by both composition and compilation

Analysis of the shearing instability in nonlinear convection and magnetoconvection

Numerical experiments on two-dimensional convection with or without a vertical magnetic field reveal a bewildering variety of periodic and aperiodic oscillations. Steady rolls can develop a shearing instability, in which rolls turning over in one direction grow at the expense of rolls turning over in the other, resulting in a net shear across the layer. As the temperature difference across the fluid is increased, two-dimensional pulsating waves occur, in which the direction of shear alternates. We analyse the nonlinear dynamics of this behaviour by first constructing appropriate low-order sets of ordinary differential equations, which show the same behaviour, and then analysing the global bifurcations that lead to these oscillations by constructing one-dimensional return maps. We compare the behaviour of the partial differential equations, the models and the maps in systematic two-parameter studies of both the magnetic and the non-magnetic cases, emphasising how the symmetries of periodic solutions change as a result of global bifurcations. Much of the interesting behaviour is associated with a discontinuous change in the leading direction of a fixed point at a global bifurcation; this change occurs when the magnetic field is introduced

Repetitive element hypomethylation in blood leukocyte DNA and cancer incidence, prevalence, and mortality in elderly individuals : the Normative Aging Study

BACKGROUND: Global genomic hypomethylation is a common epigenetic event in cancer that mostly results from hypomethylation of repetitive DNA elements. Case-control studies have associated blood leukocyte DNA hypomethylation with several cancers. Because samples in case-control studies are collected after disease development, whether DNA hypomethylation is causal or just associated with cancer development is still unclear. METHODS: In 722 elderly subjects from the Normative Aging Study cohort, we examined whether DNA methylation in repetitive elements (Alu, LINE-1) was associated with cancer incidence (30 new cases, median follow-up: 89 months), prevalence (205 baseline cases), and mortality (28 deaths, median follow-up: 85 months). DNA methylation was measured by bisulfite pyrosequencing. RESULTS: Individuals with low LINE-1 methylation (<median) had a 3.0-fold (95%CI 1.3-6.9) increased incidence of all cancers combined. LINE-1 and Alu methylation were not significantly associated with cancer prevalence at baseline (all cancers combined). However, individuals with low LINE-1 methylation (<median) had a 3.2-fold (95% CI 1.4-7.5) higher prevalence of lung cancer. Individuals with low LINE-1 or Alu methylation (<median) had increased cancer mortality (HR = 3.2, 95%CI 1.3-7.9 for LINE-1; HR = 2.5, 95%CI 1.1-5.8 for Alu). CONCLUSION: These findings suggest that individuals with lower repetitive element methylation are at high risk of developing and dying from cancer

Allergen sensitization is associated with increased dna methylation in older men

Background: Variation in epigenetic modifications, arising from either environmental exposures or internal physiological changes, can influence gene expression and may ultimately contribute to complex diseases such as asthma and allergies. We examined the association of asthma and allergic phenotypes with DNA methylation levels of retrotransposon-derived elements. Methods: We used data from 704 men (mean age 73 years) in the longitudinal Normative Aging Study to assess the relationship between asthma, allergic phenotypes and DNA methylation levels of the retrotransposon-derived elements Alu and long interspersed nuclear element (LINE)-1. Retrotransposons represent a large fraction of the genome (>30%) and are heavily methylated to prevent expression. Percent methylation of Alu and LINE-1 elements in peripheral white blood cells was quantified using PCR pyrosequencing. Data on sensitization to common allergens from skin prick testing, asthma and methacholine responsiveness were gathered approximately 8 years prior to DNA methylation analysis. Results: Prior allergen sensitization was associated with increased methylation of Alu (\u3b2 = 0.32 for sensitized vs. nonsensitized patients; p = 0.003) in models adjusted for pack-years of smoking, body mass index, current smoking, air pollutants, percentage of eosinophils, white blood cell count and age. Of the men interviewed, 5% of subjects reported a diagnosis of asthma. Neither Alu nor LINE-1 methylation was associated with asthma. Conclusions: These data suggest that increased DNA methylation of repetitive elements may be associated with allergen sensitization but does not appear to be associated with asthma. Future work is needed to identify potential underlying mechanisms for these relationships