688 research outputs found
Development and validation of a risk score for chronic kidney disease in HIV infection using prospective cohort data from the D:A:D study.
Chronic kidney disease (CKD) is a major health issue for HIV-positive individuals, associated with increased morbidity and mortality. Development and implementation of a risk score model for CKD would allow comparison of the risks and benefits of adding potentially nephrotoxic antiretrovirals to a treatment regimen and would identify those at greatest risk of CKD. The aims of this study were to develop a simple, externally validated, and widely applicable long-term risk score model for CKD in HIV-positive individuals that can guide decision making in clinical practice
Interleukin 6 Is a Stronger Predictor of Clinical Events Than High-Sensitivity C-Reactive Protein or D-Dimer During HIV Infection
BACKGROUND:āInterleukin 6 (IL-6), high-sensitivity C-reactive protein (hsCRP), and D-dimer levels are linked to adverse outcomes in human immunodeficiency virus (HIV) infection, but the strength of their associations with different clinical end points warrants investigation.
METHODS:āParticipants receiving standard of care in 2 HIV trials with measured biomarker levels were followed to ascertain all-cause death, nonāAIDS-related death, AIDS, cardiovascular disease (CVD), and nonāAIDS-defining malignancies. Hazard ratios (HRs) and 95% confidence intervals (CIs) of each end point for quartiles and log2-transformed IL-6, hsCRP, and D-dimer levels were calculated using Cox models. Marginal models modelling multiple events tested for equal effects of biomarker levels on different end points.
RESULTS:āAmong 4304 participants, there were 157 all-cause deaths, 117 nonāAIDS-related deaths, 101 AIDS cases, 121 CVD cases, and 99 nonāAIDS-defining malignancies. IL-6 was more strongly associated with most end points, compared with hsCRP. IL-6 appeared to be a stronger predictor than D-dimer for CVD and nonāAIDS-defining malignancies, but 95% CIs overlapped. Independent associations of IL-6 were stronger for nonāAIDS-related death (HR, 1.71; 95% CI, 1.43ā2.04) and all-cause death (HR, 1.56; 95% CI, 1.33ā1.84) and similar for CVD (HR, 1.35; 95% CI, 1.12ā1.62) and nonāAIDS-defining malignancies (HR, 1.30; 95% CI, 1.06ā1.61). There was heterogeneity of IL-6 (P < .001) but not hsCRP (P = .15) or D-dimer (P = .20) as a predictor for different end points.
CONCLUSIONS:āIL-6 is a stronger predictor of fatal events than of CVD and nonāAIDS-defining malignancies. Adjuvant antiinflammatory and antithrombotic therapies should be tested in HIV-infected individuals
Cryo-electron microscopy reveals two distinct typeĀ IV pili assembled by the same bacterium
This is the final version. Available on open access from Nature Research via the DOI in this recordData availability:
EM maps have been deposited in the Electron Microscopy Data Bank (EMDB, https://www.ebi.ac.uk/pdbe/emdb/) with accession codes EMD-10647 (wide pilus, PilA4) and EMD-10648 (narrow pilus, PilA5). Models have been deposited in the Protein Data Bank (PDB, https://www.rcsb.org/) with accession codes 6XXD (PilA4) and 6XXE (PilA5). The MS proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE75 partner repository (https://www.ebi.ac.uk/pride/) with dataset identifier PXD017353. The source data underlying Figs. 5cāe and 6, Supplementary Figs. 2, 3b, c, 4aāc, 5e and 6e, f, and Supplementary Table 4 are provided in the Source Data file. Uncropped versions of gels and blots (for Fig. 5c, d, and Supplementary Figs. 2b and 4aāc) and twitching images (for Fig. 6a) are also shown in Supplementary Fig. 10.Type IV pili are flexible filaments on the surface of bacteria, consisting of a helical assembly of pilin proteins. They are involved in bacterial motility (twitching), surface adhesion, biofilm formation and DNA uptake (natural transformation). Here, we use cryo-electron microscopy and mass spectrometry to show that the bacterium Thermus thermophilus produces two forms of type IV pilus (āwideā and ānarrowā), differing in structure and protein composition. Wide pili are composed of the major pilin PilA4, while narrow pili are composed of a so-far uncharacterized pilin which we name PilA5. Functional experiments indicate that PilA4 is required for natural transformation, while PilA5 is important for twitching motility.Biotechnology & Biological Sciences Research Council (BBSRC)Max-Planck-SocietyUniversity of ExeterDeutsche Forschungsgemeinschaf
Association of Suboptimal Antiretroviral Therapy Adherence With Inflammation in Virologically Suppressed Individuals Enrolled in the SMART Study
Suboptimal (ie, <100%) antiretroviral therapy (ART) adherence has been associated with heightened inflammation in cohort studies, even among people with virologic suppression. We aimed to evaluate this association among participants in the Strategies for Management of Antiretroviral Therapy (SMART) study who had virologic suppression (HIV-1 VL < 200 copies/mL) at enrollment. Based on self-reported adherence (7-day recall), plasma concentrations of interleukin 6 and D-dimer were 9% (95% confidence interval [CI], 1%-18%; P = .02) and 11% (95% CI, 1%-22%; P = .03) higher in participants who reported suboptimal vs 100% adherence, respectively. These findings confirm previous observations and support the hypothesis that suboptimal ART adherence, even in the context of virologic suppression, may have significant biological consequences. ClinicalTrials.gov number NCT00027352
Incomplete ART adherence is associated with higher inflammation in individuals who achieved virologic suppression in the START study
INTRODUCTION: Suboptimal ART adherence, despite HIV viral suppression, has been associated with chronic residual inflammation. Whether this association extends to individuals who initiate ART during early HIV infection remains unknown, which was the objective of this study. METHODS: Plasma levels of interleukinā6 (ILā6), highāsensitivity Cāreactive protein, serum amyloid A protein (SAA), ILā27, soluble intercellular adhesion moleculeā1, soluble vascular adhesion moleculeā1, Dādimer and the CD4+/CD8+ Tācell ratio, were analysed at baseline and eight months after ART initiation in treatmentānaĆÆve participants with HIV and CD4+ Tācells >500 cells/mm^{3} enrolled in the immediate arm of START. Adherence was assessed by sevenāday selfāreport. Multivariable linear regression was utilized to analyse the association between ART adherence and each biomarker at the eightāmonth visit in participants who achieved virologic suppression (<50 copies/mL). RESULTS: We evaluated 1627 participants (422 female) who achieved virologic suppression at the eightāmonth visit in the period between 2009 and 2013. Median (IQR) CD4+ Tācell count before ART was 651 (585, 769) cells/mm^{3}. Incomplete adherence was reported in 109 (7%) participants at the eight month visit. After adjusting for covariates, plasma ILā6 was 1.12 (95% CI, 1.00 to 1.26; p = 0.047) fold higher in participants reporting incomplete versus 100% adherence. A similar association for SAA was observed in an exploratory analysis (1.29 (95% CI 1.04 to 1.60); p = 0.02). No significant differences in other biomarkers were observed. CONCLUSIONS: Incomplete ART adherence was associated with higher ILā6 levels in individuals who achieved virologic suppression early after ART initiation in START. A potential similar association for SAA requires confirmation. These findings suggest a role for identifying strategies to maximize ART adherence even during virologic suppression. ClinicalTrials.gov number: NCT00867048
A recursive field-normalized bibliometric performance indicator: An application to the field of library and information science
Two commonly used ideas in the development of citation-based research
performance indicators are the idea of normalizing citation counts based on a
field classification scheme and the idea of recursive citation weighing (like
in PageRank-inspired indicators). We combine these two ideas in a single
indicator, referred to as the recursive mean normalized citation score
indicator, and we study the validity of this indicator. Our empirical analysis
shows that the proposed indicator is highly sensitive to the field
classification scheme that is used. The indicator also has a strong tendency to
reinforce biases caused by the classification scheme. Based on these
observations, we advise against the use of indicators in which the idea of
normalization based on a field classification scheme and the idea of recursive
citation weighing are combined
Identification of New Agonists and Antagonists of the Insect Odorant Receptor Co-Receptor Subunit
BACKGROUND: Insects detect attractive and aversive chemicals using several families of chemosensory receptors, including the OR family of olfactory receptors, making these receptors appealing targets for the control of insects. Insect ORs are odorant-gated ion channels, comprised of at least one common subunit (the odorant receptor co-receptor subunit, Orco) and at least one variable odorant specificity subunit. Each of the many ORs of an insect species is activated or inhibited by an unique set of odorants that interact with the variable odorant specificity subunits, making the development of OR directed insect control agents complex and laborious. However, several N-,2-substituted triazolothioacetamide compounds (VUAA1, VU0450667 and VU0183254) were recently shown to act directly on the highly conserved Orco subunit, suggesting that broadly active compounds can be developed. We have explored the chemical space around the VUAA1 structure in order to identify new Orco ligands. PRINCIPAL FINDINGS: We screened ORs from several insect species, using heterologous expression in Xenopus oocytes and an electrophysiological assay, with a panel of 22 compounds structurally related to VUAA1. By varying the nitrogen position in the pyridine ring and altering the moieties decorating the phenyl ring, we identified two new agonists and a series of competitive antagonists. Screening smaller compounds, similar to portions of the VUAA1 structure, also yielded competitive antagonists. Importantly, we show that Orco antagonists inhibit odorant activation of ORs from several insect species. Detailed examination of one antagonist demonstrated inhibition to be through a non-competitive mechanism. CONCLUSIONS: A similar pattern of agonist and antagonist sensitivity displayed by Orco subunits from different species suggests a highly conserved binding site structure. The susceptibility to inhibition of odorant activation by Orco antagonism is conserved across disparate insect species, suggesing the ligand binding site on Orco as a promising target for the development of novel, broadly active insect repellants
Induction of Blood Brain Barrier Tight Junction Protein Alterations by CD8 T Cells
Disruption of the blood brain barrier (BBB) is a hallmark feature of immune-mediated neurological disorders as diverse as viral hemorrhagic fevers, cerebral malaria and acute hemorrhagic leukoencephalitis. Although current models hypothesize that immune cells promote vascular permeability in human disease, the role CD8 T cells play in BBB breakdown remains poorly defined. Our laboratory has developed a novel murine model of CD8 T cell mediated central nervous system (CNS) vascular permeability using a variation of the Theiler's virus model of multiple sclerosis. In previous studies, we observed that MHC class IIā/ā (CD4 T cell deficient), IFN-Ī³Rā/ā, TNF-Ī±ā/ā, TNFR1ā/ā, TNFR2ā/ā, and TNFR1/TNFR2 double knockout mice as well as those with inhibition of IL-1 and LTĪ² activity were susceptible to CNS vascular permeability. Therefore, the objective of this study was to determine the extent immune effector proteins utilized by CD8 T cells, perforin and FasL, contributed to CNS vascular permeability. Using techniques such as fluorescent activated cell sorting (FACS), T1 gadolinium-enhanced magnetic resonance imaging (MRI), FITC-albumin leakage assays, microvessel isolation, western blotting and immunofluorescent microscopy, we show that in vivo stimulation of CNS infiltrating antigen-specific CD8 T cells initiates astrocyte activation, alteration of BBB tight junction proteins and increased CNS vascular permeability in a non-apoptotic manner. Using the aforementioned techniques, we found that despite having similar expansion of CD8 T cells in the brain as wildtype and Fas Ligand deficient animals, perforin deficient mice were resistant to tight junction alterations and CNS vascular permeability. To our knowledge, this study is the first to demonstrate that CNS infiltrating antigen-specific CD8 T cells have the capacity to initiate BBB tight junction disruption through a non-apoptotic perforin dependent mechanism and our model is one of few that are useful for studies in this field. These novel findings are highly relevant to the development of therapies designed to control immune mediated CNS vascular permeability
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