A COMPARISON OF CAUSALITY ASSESSMENT TOOLS FOR SUSPECTED ADVERSE DRUG REACTIONS IN HOSPITALIZED PATIENTS AT A TERTIARY CARE HOSPITAL

Objective: The objective of the study was to compare six causality assessment (CA) tools for suspected adverse drug reactions (ADRs) reported in hospitalized patients at a tertiary care hospital in India. Methods: Intensive ADR monitoring was performed in indoor patients of two randomly selected medicine units. A detailed case report of each suspected ADR (n=120) was provided to six independent experts for CA using either visual analog scale (VAS) or WHO-UMC scale. Investigator assessed causality using Naranjo’s scale, Koh et al. scale, the French method, and Karch and Lasagna scale. Similar causality categories from these scales were coded for correlation. Agreement among experts and that between various CA tools were analyzed using Cohen’s kappa and Fleiss kappa. Reasons for disagreements among different scales were evaluated. Results: A variation was observed in the total number of drugs suspected to cause ADR by experts and investigator. “Likely” and “Plausible” causality were suggested frequently by experts using VAS whereas “Possible” causal association was frequent according to experts using the WHO-UMC scale and also by the investigator using algorithms except Koh et al. scale. None to the slight agreement was observed among experts who used VAS (k=0.117), whereas a substantial agreement was observed among experts using the WHO-UMC scale (k=0.707). A substantial agreement was observed between Karch and Lasagna scale and the French method (k=0.740). Both scales demonstrated moderate agreement with Naranjo’s scale. Disagreement among the WHO-UMC scale, the French method, and Karch and Lasagna scale were associated with polypharmacy, serious ADRs, non-availability of laboratory data, and skin and subcutaneous tissue ADRs. Conclusion: A higher inter-rater agreement with the WHO-UMC scale suggests its utility for CA of suspected ADRs in indoor patients. The French method and Karch and Lasagna scale can be used for CA in hospitalized patients as an adjunct to Naranjo’s scale. Factors associated with disagreement should be considered at the time of reporting ADRs and evaluating causality

The Stokes Phenomenon and Quantum Tunneling for de Sitter Radiation in Nonstationary Coordinates

We study quantum tunneling for the de Sitter radiation in the planar coordinates and global coordinates, which are nonstationary coordinates and describe the expanding geometry. Using the phase-integral approximation for the Hamilton-Jacobi action in the complex plane of time, we obtain the particle-production rate in both coordinates and derive the additional sinusoidal factor depending on the dimensionality of spacetime and the quantum number for spherical harmonics in the global coordinates. This approach resolves the factor of two problem in the tunneling method.Comment: LaTex 10 pages, no figur

Back reaction, emission spectrum and entropy spectroscopy

Recently, an interesting work, which reformulates the tunneling framework to directly produce the Hawking emission spectrum and entropy spectroscopy in the tunneling picture, has been received a broad attention. However, during the emission process, most related observations have not incorporated the effects of back reaction on the background spacetime, whose derivations are therefore not the desiring results for the real physical process. With this point as a central motivation, in this paper we suitably adapt the \emph{reformulated} tunneling framework so that it can well accommodate the effects of back reaction to produce the Hawking emission spectrum and entropy spectroscopy. Consequently, we interestingly find that, when back reaction is considered, the Parikh-Wilczek's outstanding observations that, an isolated radiating black hole has an unitary-evolving emission spectrum that is \emph{not} precisely thermal, but is related to the change of the Bekenstein-Hawking entropy, can also be reproduced in the reformulated tunneling framework, meanwhile the entropy spectrum has the same form as that without inclusion of back reaction, which demonstrates the entropy quantum is \emph{independent} of the effects of back reaction. As our final analysis, we concentrate on the issues of the black hole information, but \emph{unfortunately} find that, even including the effects of back reaction and higher-order quantum corrections, such tunneling formalism can still not provide a mechanism for preserving the black hole information.Comment: 16 pages, no figure, use JHEP3.cls. to be published in JHE

Quantum corrections and black hole spectroscopy

In the work \cite{BRM,RBE}, black hole spectroscopy has been successfully reproduced in the tunneling picture. As a result, the derived entropy spectrum of black hole in different gravity (including Einstein's gravity, Einstein-Gauss-Bonnet gravity and Ho\v{r}ava-Lifshitz gravity) are all evenly spaced, sharing the same forms as $S_n=n$, where physical process is only confined in the semiclassical framework. However, the real physical picture should go beyond the semiclassical approximation. In this case, the physical quantities would undergo higher-order quantum corrections, whose effect on different gravity shares in different forms. Motivated by these facts, in this paper we aim to observe how quantum corrections affect black hole spectroscopy in different gravity. The result shows that, in the presence of higher-order quantum corrections, black hole spectroscopy in different gravity still shares the same form as $S_n=n$, further confirming the entropy quantum is universal in the sense that it is not only independent of black hole parameters, but also independent of higher-order quantum corrections. This is a desiring result for the forthcoming quantum gravity theory.Comment: 14 pages, no figure, use JHEP3.cls. to be published in JHE

Utilization of a deoxynucleoside diphosphate substrate by HIV reverse transcriptase

Background: Deoxynucleoside triphosphates (dNTPs) are the normal substrates for DNA sysnthesis is catalyzed by polymerases such as HIV-1 reverse transcriptase (RT). However, substantial amounts of deoxynucleoside diphosphates (dNDPs) are also present in the cell. Use of dNDPs in HIV-1 DNA sysnthesis could have significant implications for the efficacy of nucleoside RT inhibitors such as AZT which are first line therapeutics fro treatment of HIV infection. Our earlier work on HIV-1 reverse transcriptase (RT) suggested that the interaction between the γ phosphate of the incoming dNTP and RT residue K65 in the active site is not essential for dNTP insertion, implying that this polymerase may be able to insert dNPs in addition to dNTPs. Methodology/Principal Findings: We examined the ability of recombinant wild type (wt) and mutant RTs with substitutions at residue K65 to utilize a dNDP substrate in primer extension reactions. We found that wild type HIV-1 RT indeed catalyzes incorporation of dNDP substrates whereas RT with mutations of residue K645 were unable to catalyze this reaction. Wild type HIV-1 RT also catalyzed the reverse reaction, inorganic phosphate-dependent phosphorolysis. Nucleotide-mediated phosphorolytic removal of chain-terminating 3′-terminal nucleoside inhibitors such as AZT forms the basis of HIV-1 resistance to such drugs, and this removal is enhanced by thymidine analog mutations (TAMs). We found that both wt and TAM-containing RTs were able to catalyze Pi-mediated phosphorolysis of 3′-terminal AZT at physiological levels of Pi with an efficacy similar to that for ATP-dependent AZT-excision. Conclusion: We have identified two new catalytic function of HIV-1 RT, the use of dNDPs as substrates for DNA synthesis, and the use of Pi as substrate for phosphorolytic removal of primer 3′-terminal nucleotides. The ability to insert dNDPs has been documented for only one other DNA polymerase The RB69 DNA polymerase and the reverse reaction employing inorganic phosphate has not been documented for any DNA polymerase. Importantly, our results show that Pi-mediated phosphorolysis can contribute to AZT resistance and indicates that factors that influence HIV resistance to AZT are more complex than previously appreciated. © 2008 Garforth et al

High-Resolution Imaging of the Retinal Nerve Fiber Layer in Normal Eyes Using Adaptive Optics Scanning Laser Ophthalmoscopy

To conduct high-resolution imaging of the retinal nerve fiber layer (RNFL) in normal eyes using adaptive optics scanning laser ophthalmoscopy (AO-SLO).AO-SLO images were obtained in 20 normal eyes at multiple locations in the posterior polar area and a circular path with a 3-4-mm diameter around the optic disc. For each eye, images focused on the RNFL were recorded and a montage of AO-SLO images was created.AO-SLO images for all eyes showed many hyperreflective bundles in the RNFL. Hyperreflective bundles above or below the fovea were seen in an arch from the temporal periphery on either side of a horizontal dividing line to the optic disc. The dark lines among the hyperreflective bundles were narrower around the optic disc compared with those in the temporal raphe. The hyperreflective bundles corresponded with the direction of the striations on SLO red-free images. The resolution and contrast of the bundles were much higher in AO-SLO images than in red-free fundus photography or SLO red-free images. The mean hyperreflective bundle width around the optic disc had a double-humped shape; the bundles at the temporal and nasal sides of the optic disc were narrower than those above and below the optic disc (P<0.001). RNFL thickness obtained by optical coherence tomography correlated with the hyperreflective bundle widths on AO-SLO (P<0.001)AO-SLO revealed hyperreflective bundles and dark lines in the RNFL, believed to be retinal nerve fiber bundles and Müller cell septa. The widths of the nerve fiber bundles appear to be proportional to the RNFL thickness at equivalent distances from the optic disc

Erythropoietin in the intensive care unit: beyond treatment of anemia

Erythropoietin (EPO) is the major hormone stimulating the production and differentiation of red blood cells. EPO is used widely for treating anemia of critical illness or anemia induced by chemotherapy. EPO at pharmacological doses is used in this setting to raise hemoglobin levels (by preventing the apoptosis of erythroid progenitor cells) and is designed to reduce patient exposure to allogenic blood through transfusions. Stroke, heart failure, and acute kidney injury are a frequently encountered clinical problem. Unfortunately, in the intensive care unit advances in supportive interventions have done little to reduce the high mortality associated with these conditions. Tissue protection with EPO at high, nonpharmacological doses after injury has been found in the brain, heart, and kidney of several animal models. It is now well known that EPO has anti-apoptotic effects in cells other than erythroid progenitor cells, which is considered to be independent of EPOs erythropoietic activities. This review article summarizes what is known in preclinical models of critical illness and discusses why this does not correlate with randomized, controlled clinical trials