Risk factors for visual field deterioration in the United Kingdom Glaucoma Treatment Study

OBJECTIVE: The United Kingdom Glaucoma Treatment Study (UKGTS) investigated the visual field (VF) preserving effect of medical treatment in open-angle glaucoma (OAG). The objective of this analysis was to identify risk factors associated with VF deterioration. DESIGN: Randomized, double masked, placebo-controlled, multicentre trial. PARTICIPANTS: Five hundred sixteen participants with previously untreated OAG were prospectively recruited in 10 UK centres. METHODS: Eligibility criteria were modeled on those for the Early Manifest Glaucoma Trial. Study participants were randomized to either latanoprost 0.005% or placebo eye drops. The observation period was 2 years and involved, among other procedures, VF testing and intraocular pressure (IOP) measurement at 11 scheduled visits, with clustering of tests at baseline, 18 months, and 24 months. Guided Progression Analysis pattern deviation maps were used to determine VF deterioration. Cox regression was used to compute the hazard ratios (HRs) and respective 95% confidence intervals (CIs) whilst accounting for the correlation within sites. Model selection was guided by backwards stepwise selection conducted on the model containing all variables which were significant at the 0.2 level in the univariable analysis. Follow-up variables which showed collinearity with baseline values were not retained in the final model. MAIN OUTCOME MEASURES: Time-to-VF deterioration. RESULTS: Treatment with latanoprost reduced the HR for VF deterioration by 58% (HR 0.42; 95% CI 0.27-0.67, P=0.001). Factors associated with deterioration were bilateral disease (HR 1.59 for yes versus no; 95% CI 1.02-2.50, P=0.041), higher baseline IOP (HR 1.07 per mmHg; 95% CI 1.02-1.12, P=0.008) and disc haemorrhage at visit 1 (HR 2.08; 95% CI 1.07-4.04, P=0.030). Smoking (current or previous) was associated with a reduced HR for VF deterioration (HR 0.59; 95% CI 0.37-0.93, P=0.023). No other evaluated factors were found to be statistically significant in the multivariable analysis. CONCLUSIONS: In the UKGTS, treatment with latanoprost halved VF deterioration risk. Bilateral disease, higher IOP and disc haemorrhage were confirmed as risk factors for deterioration; smoking history appeared to be protective against VF deterioration

Imaging Outcomes in Clinical Trials of Treatments for Glaucoma

Currently, all therapies for glaucoma have been licensed based on their ability to lower intraocular pressure (IOP). However, the main outcome of interest to people with glaucoma is vision-related (VR) quality of life (QoL). Instruments measuring VR QoL are unlikely to be sensitive enough to function as the primary outcome for clinical trials, 1 but they remain important as secondary outcomes to capture side-effects of treatment. Although lowering IOP has been shown to slow visual field (VF) loss, 2 IOP is a far-removed surrogate for VR QoL in glaucoma. Furthermore, IOP obviously would be an inappropriate outcome for a trial of a neuroprotective treatment with no effect on IOP. In contrast, the association of VR QoL measures with VF loss and other measures of vision has been established. 3 Measurements of visual function are recognized by regulatory authorities as the appropriate primary outcome measure for clinical trials in glaucoma, 4 and the major clinical trials that have evaluated vision function as the primary outcome have used progressive VF loss as the main outcome measure

OCT Signal Enhancement with Deep Learning

PURPOSE: To establish whether deep learning methods are able to improve the signal-to-noise ratio of time-domain (TD) optical coherence tomography (OCT) images to approach that of spectral-domain (SD) OCT. DESIGN: Method agreement study and progression-detection in a randomized, double-masked, placebo-controlled, multi-centre trial for open-angle glaucoma (OAG) [UK Glaucoma Treatment Study (UKGTS)]. PARTICIPANTS: Cohort for training and validation: 77 stable OAG participants with TDOCT and SDOCT imaging at up to 11 visits within 3 months. Cohort for testing: 284 newly-diagnosed OAG patients with TDOCT from a cohort of 516 recruited at 10 UK centres between 2007 and 2010. METHODS: An ensemble of generative adversarial networks (GANs) was trained on TDOCT and SDOCT image pairs from the training dataset and applied to TDOCT images from the testing dataset. TDOCT were converted to synthesized SDOCT images and segmented via Bayesian fusion on the output of the GANs. MAIN OUTCOME MEASURES: 1) Bland-Altman analysis to assess agreement between TDOCT and synthesized SDOCT average retinal nerve fibre layer thickness (RNFLT) measurements and the SDOCT RNFLT. 2) Analysis of the distribution of the rates of RNFLT change in TDOCT and synthesized SDOCT in the two treatments arms of the UKGTS was compared. A Cox model for predictors of time-to-incident VF progression was computed with the TDOCT and the synthesized SDOCT. RESULTS: The 95% limits of agreement between TDOCT and SDOCT were [26.64, -22.95], between synthesized SDOCT and SDOCT were [8.11, -6.73], and between SDOCT and SDOCT were [4.16, -4.04]. The mean difference in the rate of RNFL change between UKGTS treatment and placebo arms with TDOCT was 0.24 (p=0.11) and with synthesized SDOCT was 0.43 (p=0.0017). The hazard ratio for RNFLT slope in Cox regression modeling for time to incident VF progression was 1.09 (95% CI 1.02 to 1.21) (p=0.035) for TDOCT and 1.24 (95% CI 1.08 to 1.39) (p=0.011) for synthesized SDOCT. CONCLUSIONS: Image enhancement significantly improved the agreement of TDOCT RNFLT measurements with SDOCT RNFLT measurements. The difference, and its significance, in rates of RNFLT change in the UKGTS treatment arms was enhanced and RNFLT change became a stronger predictor of VF progression

Liver Enzyme Abnormalities and Associated Risk Factors in HIV Patients on Efavirenz-Based HAART with or without Tuberculosis Co-Infection in Tanzania.

To investigate the timing, incidence, clinical presentation, pharmacokinetics and pharmacogenetic predictors for antiretroviral and anti-tuberculosis drug induced liver injury (DILI) in HIV patients with or without TB co-infection. A total of 473 treatment naïve HIV patients (253 HIV only and 220 with HIV-TB co-infection) were enrolled prospectively. Plasma efavirenz concentration and CYP2B6*6, CYP3A5*3, *6 and *7, ABCB1 3435C/T and SLCO1B1 genotypes were determined. Demographic, clinical and laboratory data were collected at baseline and up to 48 weeks of antiretroviral therapy. DILI case definition was according to Council for International Organizations of Medical Sciences (CIOMS). Incidence of DILI and identification of predictors was evaluated using Cox Proportional Hazards Model. The overall incidence of DILI was 7.8% (8.3 per 1000 person-week), being non-significantly higher among patients receiving concomitant anti-TB and HAART (10.0%, 10.7 per 1000 person-week) than those receiving HAART alone (5.9%, 6.3 per 1000 person-week). Frequency of CYP2B6*6 allele (p = 0.03) and CYP2B6*6/*6 genotype (p = 0.06) was significantly higher in patients with DILI than those without. Multivariate cox regression model indicated that CYP2B6*6/*6 genotype and anti-HCV IgG antibody positive as significant predictors of DILI. Median time to DILI was 2 weeks after HAART initiation and no DILI onset was observed after 12 weeks. No severe DILI was seen and the gain in CD4 was similar in patients with or without DILI. Antiretroviral and anti-tuberculosis DILI does occur in our setting, presenting early following HAART initiation. DILI seen is mild, transient and may not require treatment interruption. There is good tolerance to HAART and anti-TB with similar immunological outcomes. Genetic make-up mainly CYP2B6 genotype influences the development of efavirenz based HAART liver injury in Tanzanians

Roles for Treg expansion and HMGB1 signaling through the TLR1-2-6 axis in determining the magnitude of the antigen-specific immune response to MVA85A

© 2013 Matsumiya et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are creditedA better understanding of the relationships between vaccine, immunogenicity and protection from disease would greatly facilitate vaccine development. Modified vaccinia virus Ankara expressing antigen 85A (MVA85A) is a novel tuberculosis vaccine candidate designed to enhance responses induced by BCG. Antigen-specific interferon-γ (IFN-γ) production is greatly enhanced by MVA85A, however the variability between healthy individuals is extensive. In this study we have sought to characterize the early changes in gene expression in humans following vaccination with MVA85A and relate these to long-term immunogenicity. Two days post-vaccination, MVA85A induces a strong interferon and inflammatory response. Separating volunteers into high and low responders on the basis of T cell responses to 85A peptides measured during the trial, an expansion of circulating CD4+ CD25+ Foxp3+ cells is seen in low but not high responders. Additionally, high levels of Toll-like Receptor (TLR) 1 on day of vaccination are associated with an increased response to antigen 85A. In a classification model, combined expression levels of TLR1, TICAM2 and CD14 on day of vaccination and CTLA4 and IL2Rα two days post-vaccination can classify high and low responders with over 80% accuracy. Furthermore, administering MVA85A in mice with anti-TLR2 antibodies may abrogate high responses, and neutralising antibodies to TLRs 1, 2 or 6 or HMGB1 decrease CXCL2 production during in vitro stimulation with MVA85A. HMGB1 is released into the supernatant following atimulation with MVA85A and we propose this signal may be the trigger activating the TLR pathway. This study suggests an important role for an endogenous ligand in innate sensing of MVA and demonstrates the importance of pattern recognition receptors and regulatory T cell responses in determining the magnitude of the antigen specific immune response to vaccination with MVA85A in humans.This work was funded by the Wellcome Trust. MM has a Wellcome Trust PhD studentship and HM is a Wellcome Trust Senior Fello

An autosomal recessive leucoencephalopathy with ischemic stroke, dysmorphic syndrome and retinitis pigmentosa maps to chromosome 17q24.2-25.3

Background Single-gene disorders related to ischemic stroke seem to be an important cause of stroke in young patients without known risk factors. To identify new genes responsible of such diseases, we studied a consanguineous Moroccan family with three affected individuals displaying hereditary leucoencephalopathy with ischemic stroke, dysmorphic syndrome and retinitis pigmentosa that appears to segregate in autosomal recessive pattern. Methods All family members underwent neurological and radiological examinations. A genome wide search was conducted in this family using the ABI PRISM linkage mapping set version 2.5 from Applied Biosystems. Six candidate genes within the region linked to the disease were screened for mutations by direct sequencing. Results Evidence of linkage was obtained on chromosome 17q24.2-25.3. Analysis of recombination events and LOD score calculation suggests linkage of the responsible gene in a genetic interval of 11 Mb located between D17S789 and D17S1806 with a maximal multipoint LOD score of 2.90. Sequencing of seven candidate genes in this locus, ATP5H, FDXR, SLC25A19, MCT8, CYGB, KCNJ16 and GRIN2C, identified three missense mutations in the FDXR gene which were also found in a homozygous state in three healthy controls, suggesting that these variants are not disease-causing mutations in the family. Conclusion A novel locus for leucoencephalopathy with ischemic stroke, dysmorphic syndrome and retinitis pigmentosa has been mapped to chromosome 17q24.2-25.3 in a consanguineous Moroccan family

Behavioral responses to injury and death in wild Barbary macaques (Macaca sylvanus)

The wounding or death of a conspecific has been shown to elicit varied behavioral responses throughout thanatology. Recently, a number of reports have presented contentious evidence of epimeletic behavior towards the dying and dead among non-human animals, a behavioral trait previously considered uniquely human. Here, we report on the behavioral responses of Barbary macaques, a social, non-human primate, to the deaths of four group members (one high-ranking adult female, one high-ranking adult male, one juvenile male, and one female infant), all caused by road traffic accidents. Responses appeared to vary based on the nature of the death (protracted or instant) and the age class of the deceased. Responses included several behaviors with potential adaptive explanations or consequences. These included exploration, caretaking (guarding, carrying, and grooming), and proximity to wounded individuals or corpses, and immediate as well as longer-lasting distress behaviors from other group members following death, all of which have been reported in other non-human primate species. These observations add to a growing body of comparative evolutionary analysis of primate thanatology and help to highlight the multifaceted impacts of human-induced fatalities on an endangered and socially complex primate. © 2016, Japan Monkey Centre and Springer Japan

Analytical Investigations of Toxic p-Phenylenediamine (PPD) Levels in Clinical Urine Samples with Special Focus on MALDI-MS/MS

Para-phenylenediamine (PPD) is a common chromophoric ingredient in oxidative hair-dyes. In some African countries like Sudan, Egypt and Morocco but also in India this chemical is used alone or in combination with colouring extracts like Henna for dyeing of the hair or the skin. Excessive dermal exposure to PPD mainly leads to the N-mono- and N,N′-diacetylated products (MAPPD, DAPPD) by N-acetyltransferase 1 and 2 (NAT1 and 2) catalyzed reactions. Metabolites and PPD are mainly excreted via renal clearance. Despite a low risk of intoxication when used in due form, there are numerous cases of acute intoxication in those countries every year. At the ENT Hospital - Khartoum (Sudan) alone more than 300 cases are reported every year (∼10% fatal), mostly caused by either an accidental or intended (suicidal) high systemic exposure to pure PPD. Intoxication leads to a severe clinical syndrome including laryngeal edema, rhabdomyolysis and subsequent renal failure, neurotoxicity and acute toxic hepatitis. To date, there is no defined clinical treatment or antidote available and treatment is largely supportive. Herein, we show the development of a quick on-site identification assay to facilitate differential diagnosis in the clinic and, more importantly, the implementation of an advanced analytical platform for future in-depth investigations of PPD intoxication and metabolism is described. The current work shows a sensitive (∼25 µM) wet chemistry assay, a validated MALDI-MS/MS and HPLC-UV assay for the determination of PPD and its metabolites in human urine. We show the feasibility of the methods for measuring PPD over a range of 50–1000 µM. The validation criteria included linearity, lower limit of quantification (LLOQ), accuracy and precision, recovery and stability. Finally, PPD concentrations were determined in clinical urine samples of cases of acute intoxication and the applied technique was expanded to identify MAPPD and DAPPD in the identical samples

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente