Recent reports indicate that statins are associated with an increased risk for new-onset diabetes mellitus (DM) compared with placebo and that this relation is dose dependent. The aim of this study ...was to perform a comprehensive network meta-analysis of randomized controlled trials (RCTs) investigating the impact of different types and doses of statins on new-onset DM. RCTs comparing different types and doses of statins with placebo were searched for using the MEDLINE, Embase, and Cochrane databases. A search of RCTs pertinent to this meta-analysis covering the period from November 1994 to October 2012 was conducted by 2 independent investigators using the MEDLINE, Cochrane, Google Scholar, and Embase databases as well as abstracts and presentations from major cardiovascular meetings. Seventeen RCTs reporting the incidence of new-onset DM during statin treatment and including a total of 113,394 patients were identified. The RCTs compared either a statin versus placebo or high-dose versus moderate-dose statin therapy. Among different statins, pravastatin 40 mg/day was associated with the lowest risk for new-onset DM compared with placebo (odds ratio 1.07, 95% credible interval 0.86 to 1.30). Conversely, rosuvastatin 20 mg/day was numerically associated with 25% increased risk for DM compared with placebo (odds ratio 1.25, 95% credible interval 0.82 to 1.90). The impact on DM appeared to be intermediate with atorvastatin 80 mg/day compared with placebo (odds ratio 1.15, 95% credible interval 0.90 to 1.50). These findings were replicated at moderate doses. In conclusion, different types and doses of statins show different potential to increase the incidence of DM.
The virally encoded integrase protein is an essential enzyme in the life cycle of the HIV-1 virus and represents an attractive and validated target in the development of therapeutics against HIV ...infection. Drugs that selectively inhibit this enzyme, when used in combination with inhibitors of reverse transcriptase and protease, are believed to be highly effective in suppressing the viral replication. Among the HIV-1 integrase inhibitors, the β-diketo acids (DKAs) represent a major lead for anti-HIV-1 drug development. In this study, novel bifunctional quinolonyl diketo acid derivatives were designed, synthesized, and tested for their inhibitory ability against HIV-1 integrase. The compounds are potent inhibitors of integrase activity. Particularly, derivative 8 is a potent IN inhibitor for both steps of the reaction (3‘-processing and strand transfer) and exhibits both high antiviral activity against HIV-1 infected cells and low cytotoxicity. Molecular modeling studies provide a plausible mechanism of action, which is consistent with ligand SARs and enzyme photo-cross-linking experiments.
Objectives
Simplified methods for virological monitoring in resource-limited settings are increasingly needed. We evaluated the performance of the VERSANT® HIV-1 RNA (kPCR) assay for the ...determination of HIV-1 viral load from dried blood spots (DBS). Assay sensitivity and correlation with plasma quantification values were assessed.
Methods
A total of 98 DBS were prepared from fresh blood samples of HIV-infected patients. DBS were kept at room temperature for 6 weeks or 7 months before processing while the corresponding plasma samples were stored at −80°C. DBS were first pre-treated in a special DBS buffer. The DBS extracts and the plasma samples were then purified and amplified using the VERSANT assay reagents.
Results
In the first series of tests, performed after 6 weeks of storage, there was good correlation between quantification of viral load in plasma and in DBS (r = 0.95, P < 0.001). The detection rate in DBS was 100% when plasma levels were >1000 copies/mL. The sensitivity and specificity of the DBS assay were 88.2% 95% confidence interval (CI) 79.4-93.6 and 69.2% (95% CI 42.0-87.4), respectively. Using the 5000 copies/mL threshold (defining virological failure in resource-limited settings), both positive and negative predictive values were high (95.2% and 87.5%, respectively). After 7 months of storage there was a modest decrease in the detection rate and less significant correlations for samples with HIV-RNA <5000 copies/mL.
Conclusions
Quantification of HIV-RNA from DBS by the VERSANT automated sample preparation and detection method can be used to diagnose virological failure in HIV-positive patients.
SUMMARY
A discordant response to highly active antiretroviral therapy (HAART) occurs when CD4 T cell counts are stable or increased over time despite persistently detectable HIV‐RNA levels. In order ...to identify immunological factors affecting discordant treatment responses, a total of 27 HIV‐infected patients were studied: (a) 10 naive patients (mean CD4+ = 101·5 cells/µl; mean HIV‐RNA = 4·8 log10 copies/ml); (b) seven responder patients (mean CD4+ = 908·9 cells/µl); and (c) 10 discordant patients (mean CD4+ = 396·1 cells/µl; mean HIV‐RNA = 5·4 log10 copies/ml). Five healthy blood donors were included as HIV‐seronegative controls. The following parameters were evaluated: interleukin (IL)‐15 production by monocyte‐derived dendritic cells (MDDC) after stimulation with lypopolysaccaride (LPS) and Candida albicans; recall and HIV‐1‐specific antigen lymphocyte proliferation (LP). Increased levels of IL‐15 production by MDDC after stimulation with LPS and C. albicans were found both in discordant patients and responder patients. Conversely, a strong reduction of IL‐15 levels was observed in naive patients. Discordant patients developed positive LP responses to C. albicans and HIV‐1 p24. LP in response to C. albicans and HIV‐1 p24 was also positive in responder patients. Decreased LP response was found in naive patients. In conclusion, HIV‐infected patients with discordant viro‐immunological responses to HAART present increased levels of IL‐15 production by MDDC and enhanced recall and HIV‐1‐specific antigen LP responses, suggesting an improvement in indices of immune function.
The existing muon detectors for high-energy physics experiments are mainly made of gas chambers such as Resistive Plate Chambers, Limited Streamer Tubes or Multi Wire Proportional Chambers. With the ...increasing luminosity of the new accelerators and the increment in dimensions of the experiments the development of a new detection technique, which is robust, cheap and capable to sustain high particle rate, is mandatory. We present the technology proposed for the Super B muon system. The detector is based on MINOS style extruded scintillators coupled to wavelength shifting fibers. The light readout is done by means of Silicon Photomultiplier devices. We report the R&D results on prototypes that can be operated either with binary readout, measuring only one coordinate, or with a TDC readout that can measure both the coordinate at the same time with adequate precision. Efficiency and time resolution will be discussed for different prototype geometry as well as the main operational issues related to the photodetectors, like stability, noise rate and neutron damage. A full-scale prototype with the same geometry designed for the SuperB experiment is under construction in our lab and it will be tested with a muon/pion beam at FNAL next fall. The structure optimization has been studied using a GEANT4 Monte Carlo simulation and the expected muon identification performances have been evaluated with a neural network algorithm, we present preliminary results of the optimization and its implication for the SuperB muon system.
A major challenge of AIDS research is the development of therapeutic vaccine strategies capable of inducing the humoral and cellular arms of the immune responses against HIV-1. In this work, we ...evaluated the capability of DCs pulsed with aldrithiol-2-inactivated HIV-1 in inducing a protective antiviral human immune response in SCID mice reconstituted with human PBL (hu-PBL-SCID mice). Immunization of hu-PBL-SCID mice with DCs generated after exposure of monocytes to GM-CSF/IFN-alpha (IFN-DCs) and pulsed with inactivated HIV-1 resulted in a marked induction of human anti-HIV-1 antibodies, which was associated with the detection of anti-HIV neutralizing activity in the serum. This vaccination schedule also promoted the generation of a human CD8+ T cell response against HIV-1, as measured by IFN-gamma Elispot analysis. Notably, when the hu-PBL-SCID mice immunized with antigen-pulsed IFN-DCs were infected with HIV-1, inhibition of virus infection was observed as compared with control animals. These results suggest that IFN-DCs pulsed with inactivated HIV-1 can represent a valuable approach of immune intervention in HIV-1-infected patients.
We report on the decay to two photons of the χc0(13P0) charmonium resonance formed in p̄p interactions at Fermilab experiment E835. We have measured the product of branching ratios ...BR(χc0→p̄p)×BR(χc0→γγ)=(6.52±1.18(stat)+0.48−0.72(sys))×10−8. Using values from the 2002 PDG, this measurement leads to the partial width Γ(χc0→γγ)=2.9±0.9 keV.
Background
AIDS defining events occur infrequently in the presence of CD4 counts above 200 cells/µL. It is, however, uncertain for most of the AIDS defining conditions whether this threshold can be ...considered equally safe in patients with a previously very low CD4 nadir.
Methods
We evaluated in detail all the AIDS defining events observed during a 48‐week clinical trial in 1251 nucleoside reverse transcriptase inhibitor‐experienced patients who started protease inhibitors (PIs) at CD4 counts below 50 cells/µL. The type of event, immunological status at the moment of event and time between start of PI treatment and event occurrence were analysed cumulatively and by event type; event rates were calculated.
Results
Concomitant data on CD4 counts were available for 338 AIDS defining events (81% of total events). Median time between start of treatment with PI and event was 94.5 days and median absolute CD4 value at the occurrence of event was 20 per µL. Only 14 events (in 12 patients) were observed above the threshold of 200 CD4 cells/µL. An analysis of the 67 deaths with concomitantly available CD4 counts (57%) showed a median CD4 count of 10 cells/µL, with only four deaths occurring in the presence of a CD4 count above 100 cells/µL.
Conclusions
Very few clinical AIDS defining conditions were observed in patients who start PIs at very low CD4 counts and with treatment restore absolute values in CD4 counts above 200 cells/µL. This threshold can therefore be considered a clinically effective goal of treatment with respect to occurrence of all AIDS defining conditions in patients starting PIs in very advanced HIV disease.
Background
Most of the studies evaluating rash in HIV‐positive patients have focused on nonnucleoside reverse transcriptase inhibitors (NNRTI), particularly nevirapine, and little is known about the ...occurrence of rash and the risk factors for its development in patients receiving regimens not based on NNRTI.
Methods We evaluated all cases of rash observed during a 48‐week randomized multicentre trial in 1251 nucleoside‐experienced patients who started treatment with protease inhibitors (ritonavir or indinavir) at CD4 counts below 50 cells/μL. Incidence rates for rash were calculated according to gender, clinical status, age, use of highly active antiretroviral therapy (HAART), Pneumocystis carinii pneumonia (PCP) prophylaxis and use of individual antiretroviral drugs at enrolment. Differences between groups defined according to the above characteristics were tested for statistical significance using the log‐rank test in a Kaplan‐Meier survival analysis. All factors that gave results in the univariate analyses below the significance level of 0.05 were included in a multivariate analysis using a Cox regression model.
Results During a follow‐up period of 9690 person‐months, 66 patients (5.3%) developed rash (0.68 events/100 person‐months). In the univariate analyses, risk of rash did not differ with trial treatment (indinavir or ritonavir), clinical status, PCP prophylaxis, or age. During follow‐up, rash was observed in 7.5% of enrolled women and in 4.5% of enrolled men (P=0.03). Serious rash occurred in 4.5% of enrolled women and in 1.6% of enrolled men (P=0.003). Use of HAART (P<0.001) and inclusion of zidovudine and of zalcitabine in the prescribed regimen (P=0.02) appeared to be associated with a lower risk of rash. In the multivariate analysis, the variables that remained significantly predictive of rash were gender (risk for women compared to men: 1.65, 95% confidence interval (CI): 1.00–2.72, P=0.048) and use of a non‐HAART regimen (risk for non‐HAART patients compared to HAART: 2.73, 95% CI: 1.49–5.02, P=0.001).
Conclusions In our study, about 5% of HIV‐positive patients who started treatment with protease inhibitors at very low CD4 counts developed rash, generally in the first few weeks after treatment. Risk was significantly higher in women and in patients who did not receive a HAART regimen. Our data indicate that women have a higher risk of rash than men, also with regimens that do not include NNRTI.
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