Vancomycin sensitivity of Staphylococcus aureus isolates from hospital patients in Karachi, Pakistan

Methicillin-resistant Staphylococcus aureus (S. aureus) (MRSA), resistant to all antibiotics including Vancomycin, has been reported in Japan, USA, Canada and Brazil. Hence, the main objective of this study was to evaluate the possible presence of Vancomycin resistant or intermediate S.aureus in Karachi. A total of 850 clinical isolates were collected from two civil hospitals in the city between February 2006 and January 2007. They were identified using standard bacteriological methods.Sensitivity to recommended antibiotics was determined by disc diffusion, agar dilution, and E-test quantitative minimum inhibitory concentration (MIC). Susceptibility to natural or semi-natural products was determined by the agar dilution method. Out of 850 isolates, 250 were MRSA, of which 22% were resistant to 4 µg/ml Vancomycin, 24% to 8 µg/ml, 15.2% to 16 µg/ml, 10% to 20 µg/ml, and 13.2% to 30 µg/ml; the remaining 15.6% were sensitive to all used concentrations. Although we did not detect any Vancomycin-resistant S. aureus (VRSA), we found that 13% of the strains were intermediates (VISA), i.e. resistant to 30 µg/ml of Vancomycin. Because of the continuously increasing prevalence of VISA, it is imperative to minimize the use of Vancomycin. Indeed, the drug should only be prescribed for the treatment of documented, culture-proven infections with MRSA that are not susceptible to routine or alternative agents. This should help avoid the consequences of the development of Vancomycin resistant S. aureus (VRSA) in our environment

Modelling timing and tempo of adrenarche in a prospective cohort study

To better understand how health risk processes are linked to adrenarche, measures of adrenarcheal timing and tempo are needed. Our objective was to describe and classify adrenal trajectories, in terms of timing and tempo, in a population of children transitioning to adolescence with repeated measurements of salivary dehydroepiandrosterone (DHEA), DHEAsulphate, and testosterone. We analysed data from the Childhood to Adolescence Transition Study (CATS), a longitudinal study of 1239 participants, recruited at 8-9 years old and followed up annually. Saliva samples were assayed for adrenal hormones. Linear mixedeffect models with subject-specific random intercepts and slopes were used to model longitudinal hormone trajectories by sex and derive measures of adrenarcheal timing and tempo. The median values for all hormones were higher at each consecutive study wave for both sexes, and higher for females than males. For all hormones, between-individual variation in hormone levels at age 9 (timing) was moderately large and similar for females and males. Between-individual variation in hormone progression over time (tempo) was of moderate magnitude compared with the population average age-slope, which itself was small compared with overall hormone level at each age. This suggests that between-individual variation in tempo was less important for modelling hormone trajectories. Between-individual variation in timing was more important for determining relative adrenal hormonal level in childhood than tempo. This finding suggests that adrenal hormonal levels at age 8-9 years can be used to predict relative levels in early adolescence (up to 13 years)

Evaluating the Quality of Research into a Single Prognostic Biomarker: A Systematic Review and Meta-analysis of 83 Studies of C-Reactive Protein in Stable Coronary Artery Disease

Background Systematic evaluations of the quality of research on a single prognostic biomarker are rare. We sought to evaluate the quality of prognostic research evidence for the association of C-reactive protein (CRP) with fatal and nonfatal events among patients with stable coronary disease. Methods and Findings We searched MEDLINE (1966 to 2009) and EMBASE (1980 to 2009) and selected prospective studies of patients with stable coronary disease, reporting a relative risk for the association of CRP with death and nonfatal cardiovascular events. We included 83 studies, reporting 61,684 patients and 6,485 outcome events. No study reported a prespecified statistical analysis protocol; only two studies reported the time elapsed (in months or years) between initial presentation of symptomatic coronary disease and inclusion in the study. Studies reported a median of seven items (of 17) from the REMARK reporting guidelines, with no evidence of change over time. The pooled relative risk for the top versus bottom third of CRP distribution was 1.97 (95% confidence interval [CI] 1.78–2.17), with substantial heterogeneity (I2 = 79.5). Only 13 studies adjusted for conventional risk factors (age, sex, smoking, obesity, diabetes, and low-density lipoprotein [LDL] cholesterol) and these had a relative risk of 1.65 (95% CI 1.39–1.96), I2 = 33.7. Studies reported ten different ways of comparing CRP values, with weaker relative risks for those based on continuous measures. Adjusting for publication bias (for which there was strong evidence, Egger's p<0.001) using a validated method reduced the relative risk to 1.19 (95% CI 1.13–1.25). Only two studies reported a measure of discrimination (c-statistic). In 20 studies the detection rate for subsequent events could be calculated and was 31% for a 10% false positive rate, and the calculated pooled c-statistic was 0.61 (0.57–0.66). Conclusion Multiple types of reporting bias, and publication bias, make the magnitude of any independent association between CRP and prognosis among patients with stable coronary disease sufficiently uncertain that no clinical practice recommendations can be made. Publication of prespecified statistical analytic protocols and prospective registration of studies, among other measures, might help improve the quality of prognostic biomarker research

Association between proton pump inhibitor therapy and clostridium difficile infection: a contemporary systematic review and meta-analysis.

Abstract Introduction Emerging epidemiological evidence suggests that proton pump inhibitor (PPI) acid-suppression therapy is associated with an increased risk of Clostridium difficile infection (CDI). Methods Ovid MEDLINE, EMBASE, ISI Web of Science, and Scopus were searched from 1990 to January 2012 for analytical studies that reported an adjusted effect estimate of the association between PPI use and CDI. We performed random-effect meta-analyses. We used the GRADE framework to interpret the findings. Results We identified 47 eligible citations (37 case-control and 14 cohort studies) with corresponding 51 effect estimates. The pooled OR was 1.65, 95% CI (1.47, 1.85), I2 = 89.9%, with evidence of publication bias suggested by a contour funnel plot. A novel regression based method was used to adjust for publication bias and resulted in an adjusted pooled OR of 1.51 (95% CI, 1.26–1.83). In a speculative analysis that assumes that this association is based on causality, and based on published baseline CDI incidence, the risk of CDI would be very low in the general population taking PPIs with an estimated NNH of 3925 at 1 year. Conclusions In this rigorously conducted systemic review and meta-analysis, we found very low quality evidence (GRADE class) for an association between PPI use and CDI that does not support a cause-effect relationship

Validation of the SCID-hu Thy/Liv mouse model with four classes of licensed antiretrovirals.

BackgroundThe SCID-hu Thy/Liv mouse model of HIV-1 infection is a useful platform for the preclinical evaluation of antiviral efficacy in vivo. We performed this study to validate the model with representatives of all four classes of licensed antiretrovirals.Methodology/principal findingsEndpoint analyses for quantification of Thy/Liv implant viral load included ELISA for cell-associated p24, branched DNA assay for HIV-1 RNA, and detection of infected thymocytes by intracellular staining for Gag-p24. Antiviral protection from HIV-1-mediated thymocyte depletion was assessed by multicolor flow cytometric analysis of thymocyte subpopulations based on surface expression of CD3, CD4, and CD8. These mice can be productively infected with molecular clones of HIV-1 (e.g., the X4 clone NL4-3) as well as with primary R5 and R5X4 isolates. To determine whether results in this model are concordant with those found in humans, we performed direct comparisons of two drugs in the same class, each of which has known potency and dosing levels in humans. Here we show that second-generation antiretrovirals were, as expected, more potent than their first-generation predecessors: emtricitabine was more potent than lamivudine, efavirenz was more potent than nevirapine, and atazanavir was more potent than indinavir. After interspecies pharmacodynamic scaling, the dose ranges found to inhibit viral replication in the SCID-hu Thy/Liv mouse were similar to those used in humans. Moreover, HIV-1 replication in these mice was genetically stable; treatment of the mice with lamivudine did not result in the M184V substitution in reverse transcriptase, and the multidrug-resistant NY index case HIV-1 retained its drug-resistance substitutions.ConclusionGiven the fidelity of such comparisons, we conclude that this highly reproducible mouse model is likely to predict clinical antiviral efficacy in humans

Quaternary structure of a G-protein coupled receptor heterotetramer in complex with Gi and Gs

Background: G-protein-coupled receptors (GPCRs), in the form of monomers or homodimers that bind heterotrimeric G proteins, are fundamental in the transfer of extracellular stimuli to intracellular signaling pathways. Different GPCRs may also interact to form heteromers that are novel signaling units. Despite the exponential growth in the number of solved GPCR crystal structures, the structural properties of heteromers remain unknown. Results: We used single-particle tracking experiments in cells expressing functional adenosine A1-A2A receptors fused to fluorescent proteins to show the loss of Brownian movement of the A1 receptor in the presence of the A2A receptor, and a preponderance of cell surface 2:2 receptor heteromers (dimer of dimers). Using computer modeling, aided by bioluminescence resonance energy transfer assays to monitor receptor homomerization and heteromerization and G-protein coupling, we predict the interacting interfaces and propose a quaternary structure of the GPCR tetramer in complex with two G proteins. Conclusions: The combination of results points to a molecular architecture formed by a rhombus-shaped heterotetramer, which is bound to two different interacting heterotrimeric G proteins (Gi and Gs). These novel results constitute an important advance in understanding the molecular intricacies involved in GPCR function

Atomically dispersed Pt-N-4 sites as efficient and selective electrocatalysts for the chlorine evolution reaction

Chlorine evolution reaction (CER) is a critical anode reaction in chlor-alkali electrolysis. Although precious metal-based mixed metal oxides (MMOs) have been widely used as CER catalysts, they suffer from the concomitant generation of oxygen during the CER. Herein, we demonstrate that atomically dispersed Pt-N-4 sites doped on a carbon nanotube (Pt-1/CNT) can catalyse the CER with excellent activity and selectivity. The Pt-1/CNT catalyst shows superior CER activity to a Pt nanoparticle-based catalyst and a commercial Ru/Ir-based MMO catalyst. Notably, Pt-1/CNT exhibits near 100% CER selectivity even in acidic media, with low Cl- concentrations (0.1M), as well as in neutral media, whereas the MMO catalyst shows substantially lower CER selectivity. In situ electrochemical X-ray absorption spectroscopy reveals the direct adsorption of Cl- on Pt-N-4 sites during the CER. Density functional theory calculations suggest the PtN4C12 site as the most plausible active site structure for the CER

Quantifying Risk Factors for Human Brucellosis in Rural Northern Tanzania

Brucellosis is a zoonosis of veterinary, public health and economic significance in most developing countries. Human brucellosis is a severely debilitating disease that requires prolonged treatment with a combination of antibiotics. The disease can result in permanent and disabling sequel, and results in considerable medical expenses in addition to loss of income due to loss of working hours. A study was conducted in Northern Tanzania to determine the risk factors for transmission of brucellosis to humans in Tanzania. This was a matched case-control study. Any patient with a positive result by a competitive ELISA (c-ELISA) test for brucellosis, and presenting to selected hospitals with at least two clinical features suggestive of brucellosis such as headache, recurrent or continuous fever, sweating, joint pain, joint swelling, general body malaise or backache, was defined as a case. For every case in a district, a corresponding control was traced and matched by sex using multistage cluster sampling. Other criteria for inclusion as a control included a negative c-ELISA test result and that the matched individual would present to hospital if falls sick. Multivariable analysis showed that brucellosis was associated with assisted parturition during abortion in cattle, sheep or goat. It was shown that individuals living in close proximity to other households had a higher risk of brucellosis. People who were of Christian religion were found to have a higher risk of brucellosis compared to other religions. The study concludes that assisting an aborting animal, proximity to neighborhoods, and Christianity were associated with brucellosis infection. There was no association between human brucellosis and Human Immunodeficiency Virus (HIV) serostatus. Protecting humans against contact with fluids and tissues during assisted parturition of livestock may be an important means of reducing the risk of transferring brucellosis from livestock to humans. These can be achieved through health education to the communities where brucellosis is common

Impact of Reporting Bias in Network Meta-Analysis of Antidepressant Placebo-Controlled Trials

BACKGROUND: Indirect comparisons of competing treatments by network meta-analysis (NMA) are increasingly in use. Reporting bias has received little attention in this context. We aimed to assess the impact of such bias in NMAs. METHODS: We used data from 74 FDA-registered placebo-controlled trials of 12 antidepressants and their 51 matching publications. For each dataset, NMA was used to estimate the effect sizes for 66 possible pair-wise comparisons of these drugs, the probabilities of being the best drug and ranking the drugs. To assess the impact of reporting bias, we compared the NMA results for the 51 published trials and those for the 74 FDA-registered trials. To assess how reporting bias affecting only one drug may affect the ranking of all drugs, we performed 12 different NMAs for hypothetical analysis. For each of these NMAs, we used published data for one drug and FDA data for the 11 other drugs. FINDINGS: Pair-wise effect sizes for drugs derived from the NMA of published data and those from the NMA of FDA data differed in absolute value by at least 100% in 30 of 66 pair-wise comparisons (45%). Depending on the dataset used, the top 3 agents differed, in composition and order. When reporting bias hypothetically affected only one drug, the affected drug ranked first in 5 of the 12 NMAs but second (n = 2), fourth (n = 1) or eighth (n = 2) in the NMA of the complete FDA network. CONCLUSIONS: In this particular network, reporting bias biased NMA-based estimates of treatments efficacy and modified ranking. The reporting bias effect in NMAs may differ from that in classical meta-analyses in that reporting bias affecting only one drug may affect the ranking of all drugs