Traffic pollution and the incidence of cardiorespiratory outcomes in an adult cohort in London.

OBJECTIVES: The epidemiological evidence for adverse health effects of long-term exposure to air and noise pollution from traffic is not coherent. Further, the relative roles of background versus near traffic pollution concentrations in this process are unclear. We investigated relationships between modelled concentrations of air and noise pollution from traffic and incident cardiorespiratory disease in London. METHODS: Among 211 016 adults aged 40-79 years registered in 75 Greater London practices between 2005 and 2011, the first diagnosis for a range of cardiovascular and respiratory outcomes were identified from primary care and hospital records. Annual baseline concentrations for nitrogen oxide (NOx), particulate matter with a median aerodynamic diameter <2.5 μm (PM2.5) attributable to exhaust and non-exhaust sources, traffic intensity and noise were estimated at 20 m(2) resolution from dispersion models, linked to clinical data via residential postcode. HRs were adjusted for confounders including smoking and area deprivation. RESULTS: The largest observed associations were between traffic-related air pollution and heart failure (HR=1.10 for 20 μg/m(3) change in NOx, 95% CI 1.01 to 1.21). However, no other outcomes were consistently associated with any of the pollution indicators, including noise. The greater variations in modelled air pollution from traffic between practices, versus within, hampered meaningful fine spatial scale analyses. CONCLUSIONS: The associations observed with heart failure may suggest exacerbatory effects rather than underlying chronic disease. However, the overall failure to observe wider associations with traffic pollution may reflect that exposure estimates based on residence inadequately represent the relevant pattern of personal exposure, and future studies must address this issue

On the exponential transform of lemniscates

It is known that the exponential transform of a quadrature domain is a rational function for which the denominator has a certain separable form. In the present paper we show that the exponential transform of lemniscate domains in general are not rational functions, of any form. Several examples are given to illustrate the general picture. The main tool used is that of polynomial and meromorphic resultants.Comment: 19 pages, to appear in the Julius Borcea Memorial Volume, (eds. Petter Branden, Mikael Passare and Mihai Putinar), Trends in Mathematics, Birkhauser Verla

Taylor approximations of operator functions

This survey on approximations of perturbed operator functions addresses recent advances and some of the successful methods.Comment: 12 page

Neurocognitive function in HIV infected patients on antiretroviral therapy

OBJECTIVE To describe factors associated with neurocognitive (NC) function in HIV-positive patients on stable combination antiretroviral therapy. DESIGN We undertook a cross-sectional analysis assessing NC data obtained at baseline in patients entering the Protease-Inhibitor-Monotherapy-Versus-Ongoing-Triple therapy (PIVOT) trial. MAIN OUTCOME MEASURE NC testing comprised of 5 domains. Raw results were z-transformed using standard and demographically adjusted normative datasets (ND). Global z-scores (NPZ-5) were derived from averaging the 5 domains and percentage of subjects with test scores >1 standard deviation (SD) below population means in at least two domains (abnormal Frascati score) calculated. Patient characteristics associated with NC results were assessed using multivariable linear regression. RESULTS Of the 587 patients in PIVOT, 557 had full NC results and were included. 77% were male, 68% Caucasian and 28% of Black ethnicity. Mean (SD) baseline and nadir CD4+ lymphocyte counts were 553(217) and 177(117) cells/µL, respectively, and HIV RNA was <50 copies/mL in all. Median (IQR) NPZ-5 score was -0.5 (-1.2/-0) overall, and -0.3 (-0.7/0.1) and -1.4 (-2/-0.8) in subjects of Caucasian and Black ethnicity, respectively. Abnormal Frascati scores using the standard-ND were observed in 51%, 38%, and 81%, respectively, of subjects overall, Caucasian and Black ethnicity (p<0.001), but in 62% and 69% of Caucasian and Black subjects using demographically adjusted-ND (p = 0.20). In the multivariate analysis, only Black ethnicity was associated with poorer NPZ-5 scores (P<0.001). CONCLUSIONS In this large group of HIV-infected subjects with viral load suppression, ethnicity but not HIV-disease factors is closely associated with NC results. The prevalence of abnormal results is highly dependent on control datasets utilised. TRIAL REGISTRY ClinicalTrials.gov, NCT01230580

Tumor innate immunity primed by specific interferon-stimulated endogenous retroviruses.

Mesenchymal tumor subpopulations secrete pro-tumorigenic cytokines and promote treatment resistance1-4. This phenomenon has been implicated in chemorefractory small cell lung cancer and resistance to targeted therapies5-8, but remains incompletely defined. Here, we identify a subclass of endogenous retroviruses (ERVs) that engages innate immune signaling in these cells. Stimulated 3 prime antisense retroviral coding sequences (SPARCS) are oriented inversely in 3' untranslated regions of specific genes enriched for regulation by STAT1 and EZH2. Derepression of these loci results in double-stranded RNA generation following IFN-γ exposure due to bi-directional transcription from the STAT1-activated gene promoter and the 5' long terminal repeat of the antisense ERV. Engagement of MAVS and STING activates downstream TBK1, IRF3, and STAT1 signaling, sustaining a positive feedback loop. SPARCS induction in human tumors is tightly associated with major histocompatibility complex class 1 expression, mesenchymal markers, and downregulation of chromatin modifying enzymes, including EZH2. Analysis of cell lines with high inducible SPARCS expression reveals strong association with an AXL/MET-positive mesenchymal cell state. While SPARCS-high tumors are immune infiltrated, they also exhibit multiple features of an immune-suppressed microenviroment. Together, these data unveil a subclass of ERVs whose derepression triggers pathologic innate immune signaling in cancer, with important implications for cancer immunotherapy

Establishment of one-step SYBR green-based real time-PCR assay for rapid detection and quantification of chikungunya virus infection

Chikungunya virus (CHIKV) is a mosquito-borne alphavirus and one of the prevalent re-emerging arbovirus in tropical and subtropical regions of Asia, Africa, and Central and South America. It produces a spectrum of illness ranging from inapparent infection to moderate febrile illness as well as severe arthralgia or arthritis affecting multiple joints. In this study, a quantitative, one-step real-time SYBR Green-based RT-PCR system for the non-structural protein 2 (nsP2) of CHIKV that can quantify a wide range of viral RNA concentrations was developed. Comparisons between the conventional semi-quantitative RT-PCR assay, immunofluorescence detection method and the one-step SYBR Green-based RT-PCR assay in the detection of CHIKV infection revealed much rapid and increase sensitivity of the latter method. Furthermore, this newly developed assay was validated by in vitro experiments in which ribavirin, a well-known RNA virus inhibitor, showed a dose-dependent inhibition of virus replication on cells that was assessed by viral infectivity and viral RNA production. Our results demonstrate the potential of this newly developed one-step SYBR Green I-based RT-PCR assay may be a useful tool in rapid detection of CHIKV and monitoring the extent of viral replication possibly in patients' samples

No neurocognitive advantage for immediate antiretroviral treatment in adults with greater than 500 CD4+ T-cell counts

OBJECTIVE: To compare the effect of immediate versus deferred antiretroviral treatment (ART) on neuropsychological test performance in treatment-naive HIV-positive adults with >500 CD4+ cells/μL. DESIGN: Randomized trial. METHODS: The START parent study randomized participants to commence immediate versus deferred ART until CD4+ <350 cells/μL. The START Neurology substudy used 8 neuropsychological tests, at baseline, months 4, 8, 12 and annually, to compare groups for changes in test performance. Test results were internally standardized to z-scores. The primary outcome was the average of the eight test z-scores (QNPZ-8). Mean changes in QNPZ-8 from baseline were compared by intent-to-treat using longitudinal mixed models. Changes from baseline to specific time points were compared using ANCOVA models. RESULTS: 592 participants had a median age of 34 years; median baseline CD4+ count of 629 cells/μL; the mean follow-up was 3.4 years. ART was used for 94% and 32% of accrued person-years in the immediate and deferred groups, respectively. There was no difference between the immediate and deferred ART groups in QNPZ-8 change through follow-up [-0.018 (95% CI: -0.062 to 0.027, p = 0.44)], or at any visit. However, QNPZ-8 scores increased in both arms during the first year, by 0.22 and 0.24, respectively (p < 0.001 for increase from baseline). CONCLUSIONS: We observed substantial improvement in neurocognitive test performance during the first year in both study arms, underlining the importance of using a control group in studies assessing neurocognitive performance over time. Immediate ART neither benefitted nor harmed neurocognitive performance in individuals with CD4+ cell counts above 500 cells/μL

Gait disorders are associated with non-cardiovascular falls in elderly people: a preliminary study

BACKGROUND: The association between unexplained falls and cardiovascular causes is increasingly recognized. Neurally mediated cardiovascular disorders and hypotensive syndromes are found in almost 20 percent of the patients with unexplained falls. However, the approach to these patients remains unclear. Gait assessment might be an interesting approach to these patients as clinical observations suggests that those with cardiovascular or hypotensive causes may not manifest obvious gait alterations. Our primary objective is to analyze the association between gait disorders and a non-cardiovascular cause of falls in patients with unexplained falls. A second objective is to test the sensitivity and specificity of a gait assessment approach for detecting non-cardiovascular causes when compared with intrinsic-extrinsic classification. METHODS: Cross-sectional study performed in a falls clinic at a university hospital in 41 ambulatory elderly participants with unexplained falls. Neurally mediated cardiovascular conditions, neurological diseases, gait and balance problems were assessed. Gait disorder was defined as a gait velocity < 0.8 m/s or Tinetti Gait Score <9. An attributable etiology of the fall was determined in each participant. Comparisons between the gait assessment approach and the attributable etiology regarding a neurally mediated cardiovascular cause were performed. Fisher exact test was used to test the association hypothesis. Sensitivity and specificity of gait assessment approach and intrinsic-extrinsic classification to detect a non-cardiovascular mediated fall was calculated with 95% confidence intervals (CI95%). RESULTS: A cardiovascular etiology (orthostatic and postprandial hypotension, vasovagal syndrome and carotid sinus hypersensitivity) was identified in 14% of participants (6/41). Of 35 patients with a gait disorder, 34 had a non-cardiovascular etiology of fall; whereas in 5 out of 6 patients without a gait disorder, a cardiovascular diagnosis was identified (p < 0.001). Sensitivity and specificity of the presence of gait disorder for identifying a non-cardiovascular mediated cause was 97.1% (CI95% = 85–99) and 83% (CI95% = 36–99), respectively. CONCLUSION: In community dwelling older persons with unexplained falls, gait disorders were associated with non-cardiovascular diagnosis of falls. Gait assessment was a useful approach for the detection of a non-cardiovascular mediated cause of falls, providing additional value to this assessment

Chronic non-specific low back pain - sub-groups or a single mechanism?

Copyright 2008 Wand and O'Connell; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Background: Low back pain is a substantial health problem and has subsequently attracted a considerable amount of research. Clinical trials evaluating the efficacy of a variety of interventions for chronic non-specific low back pain indicate limited effectiveness for most commonly applied interventions and approaches. Discussion: Many clinicians challenge the results of clinical trials as they feel that this lack of effectiveness is at odds with their clinical experience of managing patients with back pain. A common explanation for this discrepancy is the perceived heterogeneity of patients with chronic non-specific low back pain. It is felt that the effects of treatment may be diluted by the application of a single intervention to a complex, heterogeneous group with diverse treatment needs. This argument presupposes that current treatment is effective when applied to the correct patient. An alternative perspective is that the clinical trials are correct and current treatments have limited efficacy. Preoccupation with sub-grouping may stifle engagement with this view and it is important that the sub-grouping paradigm is closely examined. This paper argues that there are numerous problems with the sub-grouping approach and that it may not be an important reason for the disappointing results of clinical trials. We propose instead that current treatment may be ineffective because it has been misdirected. Recent evidence that demonstrates changes within the brain in chronic low back pain sufferers raises the possibility that persistent back pain may be a problem of cortical reorganisation and degeneration. This perspective offers interesting insights into the chronic low back pain experience and suggests alternative models of intervention. Summary: The disappointing results of clinical research are commonly explained by the failure of researchers to adequately attend to sub-grouping of the chronic non-specific low back pain population. Alternatively, current approaches may be ineffective and clinicians and researchers may need to radically rethink the nature of the problem and how it should best be managed