Entropy and bispectral index for assessment of sedation, analgesia and the effects of unpleasant stimuli in critically ill patients: an observational study

INTRODUCTION: Sedative and analgesic drugs are frequently used in critically ill patients. Their overuse may prolong mechanical ventilation and length of stay in the intensive care unit. Guidelines recommend use of sedation protocols that include sedation scores and trials of sedation cessation to minimize drug use. We evaluated processed electroencephalography (response and state entropy and bispectral index) as an adjunct to monitoring effects of commonly used sedative and analgesic drugs and intratracheal suctioning. METHODS: Electrodes for monitoring bispectral index and entropy were placed on the foreheads of 44 critically ill patients requiring mechanical ventilation and who previously had no brain dysfunction. Sedation was targeted individually using the Ramsay Sedation Scale, recorded every 2 hours or more frequently. Use of and indications for sedative and analgesic drugs and intratracheal suctioning were recorded manually and using a camera. At the end of the study, processed electroencephalographical and haemodynamic variables collected before and after each drug application and tracheal suctioning were analyzed. Ramsay score was used for comparison with processed electroencephalography when assessed within 15 minutes of an intervention. RESULTS: The indications for boli of sedative drugs exhibited statistically significant, albeit clinically irrelevant, differences in terms of their association with processed electroencephalographical parameters. Electroencephalographical variables decreased significantly after bolus, but a specific pattern in electroencephalographical variables before drug administration was not identified. The same was true for opiate administration. At both 30 minutes and 2 minutes before intratracheal suctioning, there was no difference in electroencephalographical or clinical signs in patients who had or had not received drugs 10 minutes before suctioning. Among patients who received drugs, electroencephalographical parameters returned to baseline more rapidly. In those cases in which Ramsay score was assessed before the event, processed electroencephalography exhibited high variation. CONCLUSIONS: Unpleasant or painful stimuli and sedative and analgesic drugs are associated with significant changes in processed electroencephalographical parameters. However, clinical indications for drug administration were not reflected by these electroencephalographical parameters, and barely by sedation level before drug administration or tracheal suction. This precludes incorporation of entropy and bispectral index as target variables for sedation and analgesia protocols in critically ill patients.

IDENTIFICATION OF GENES CONTROLLING BIOLOGICAL PROCESSES AND PATHWAYS THROUGH STATISTICAL ANALYSIS AND NETWORK RECONSTRUCTION

The developmental processes and functions of an organism are controlled by the genes and the proteins that are derived from these genes. The identification of key genes and the reconstruction of gene networks can provide a model to help us understand the regulatory mechanisms for the initiation and progression of biological processes or functional abnormalities (e.g. diseases) in living organisms. In this dissertation, I have developed statistical methods to identify the genes and transcription factors (TFs) involved in biological processes, constructed their regulatory networks, and also evaluated some existing association methods to find robust methods for coexpression analyses. Two kinds of data sets were used for this work: genotype data and gene expression microarray data. On the basis of these data sets, this dissertation has two major parts, together forming six chapters. The first part deals with developing association methods for rare variants using genotype data (chapter 4 and 5). The second part deals with developing and/or evaluating statistical methods to identify genes and TFs involved in biological processes, and construction of their regulatory networks using gene expression data (chapter 2, 3, and 6). For the first part, I have developed two methods to find the groupwise association of rare variants with given diseases or traits. The first method is based on kernel machine learning and can be applied to both quantitative as well as qualitative traits. Simulation results showed that the proposed method has improved power over the existing weighted sum method (WS) in most settings. The second method uses multiple phenotypes to select a few top significant genes. It then finds the association of each gene with each phenotype while controlling the population stratification by adjusting the data for ancestry using principal components. This method was applied to GAW 17 data and was able to find several disease risk genes. For the second part, I have worked on three problems. First problem involved evaluation of eight gene association methods. A very comprehensive comparison of these methods with further analysis clearly demonstrates the distinct and common performance of these eight gene association methods. For the second problem, an algorithm named the bottom-up graphical Gaussian model was developed to identify the TFs that regulate pathway genes and reconstruct their hierarchical regulatory networks. This algorithm has produced very significant results and it is the first report to produce such hierarchical networks for these pathways. The third problem dealt with developing another algorithm called the top-down graphical Gaussian model that identifies the network governed by a specific TF. The network produced by the algorithm is proven to be of very high accuracy.

UNDERSTANDING FARMERS’ PERCEPTIONS AND THE EFFECTS OF SHEA TREE Vitellaria paradoxa DISTRIBUTION IN AGROFORESTRY PARKLANDS OF THE UPPER WEST REGION, GHANA

Agroforestry parklands represent a vast majority of the agricultural landscape under subsistent-oriented farming in semi-arid West Africa. Parklands are characterized by the growth of well- maintained trees (e.g., shea) on cultivated fields as a result of both environmental and human influences. Shea (Vitellaria paradoxa) provides a cultural and economic benefit to the local people of Ghana, especially women. Periods between traditional fallow rotation systems have reduced recently due to agricultural development and a demand for higher production. As a result, shea trees, which regenerate during fallow periods, has decreased over the landscape. The aim of this study was to determine beneficial spatial distributions of V. paradoxa to maintain high yields of staple crops, and how management of V. paradoxa will differ between male and female farmers as a result of farmer based needs and use of shea. Vegetation growth and grain yield of maize (Zea mays) associated with individual trees, clumped trees, and open fields were measured. Soil moisture and light availability were also measured to determine how V. paradoxa affected resource availability of maize in either clumped or scattered distributions of V. paradoxa. As expected, light availability increased as measurement locations moved farther away from all trees. However, soil moisture was actually greater under trees in clumps than under individual trees. Maize stalk height and cob length showed no difference between clumped and single trees at each measurement location. Grain yield per plot and per cob increased as measurement locations moved farther from single trees, but was actually greater near clumped trees that in the open field subplots. Cob length and maize stalk height increased with greater light availability, but grain yield per cob or per plot showed no relationship with light, but were not affected by soil moisture. Conversely, grain yield increased with increasing soil moisture, but had no relationship with light availability. Initial farming capital is the largest constraint to female farmers; therefore the collection of shea can help provide women with added income that could meet their specific farming needs. Our data indicate that overall effects of maintaining clumped distributions of V. paradoxa provided beneficial microclimates for staple crops when compared to single trees. It is recommended that male and female farmers allow shea to grow in clumped spatial distributions rather than maintaining scattered, individual trees.

Creating Lakes from Open Pit Mines: Processes and Considerations, Emphasis on Northern Environments

Creating Lakes from Open Pit Mines: Processes and Considerations, Emphasis on Northern Environments. This document summarizes the literature of mining pit lakes (through 2007), with a particular focus on issues that are likely to be of special relevance to the creation and management of pit lakes in northern climates. Pit lakes are simply waterbodies formed by filling the open pit left upon the completion of mining operations with water. Like natural lakes, mining pit lakes display a huge diversity in each of these subject areas. However, pit lakes are young and therefore are typically in a non-equilibrium state with respect to their rate of filling, water quality, and biology. Separate sections deal with different aspects of pit lakes, including their morphometry, geology, hydrogeology, geochemistry, and biology. Depending on the type and location of the mine, there may be opportunities to enhance the recreational or ecological benefits of a given pit lake, for example, by re-landscaping and re-vegetating the shoreline, by adding engineered habitat for aquatic life, and maintaining water quality. The creation of a pit lake may be a regulatory requirement to mitigate environmental impacts from mining operations, and/or be included as part of a closure and reclamation plan. Based on published case studies of pit lakes, large-scale bio-engineering projects have had mixed success. A common consensus is that manipulation of pit lake chemistry is difficult, expensive, and takes many years to achieve remediation goals. For this reason, it is prudent to take steps throughout mine operation to reduce the likelihood of future water quality problems upon closure. Also, it makes sense to engineer the lake in such a way that it will achieve its maximal end-use potential, whether it be permanent and safe storage of mine waste, habitat for aquatic life, recreation, or water supply.

Antiaggregatory and proangiogenic effects of a novel recombinant human dual specificity anti-integrin antibody

BACKGROUND: beta(3)-Integrins are involved in platelet aggregation via alpha(IIb)beta(3) [glycoprotein (GP)IIb-GPIIIa], and in angiogenesis via endothelial alpha(V)beta(3). Cross-reactive ligands with antiaggregatory and proangiogenic effects, both desirable in peripheral vasculopathies, have not yet been described. OBJECTIVES: In vitro and in vivo characterization of antiaggregatory and proangiogenic effects of two recombinant human Fab fragments, with emphasis on beta(3)-integrins. METHODS: Recombinant Fab fragments were obtained by phage display technology. Specificity, affinity and IC(50) were determined by immunodot assays, enzyme-linked immunosorbent assay (ELISA), and Scatchard plot analysis, and by means of human umbilical vein endothelial cells (HUVECs). Functional analyses included ELISA for interaction with fibrinogen binding to GPIIb-GPIIIa, flow cytometry for measurement of activation parameters and competitive inhibition experiments, human platelet aggregometry, and proliferation, tube formation and the chorioallantoic membrane (CAM) assay for measurement of angiogenic effects. RESULTS: We observed specific and high-affinity binding to an intact GPIIb-GPIIIa receptor complex of two human Fab autoantibody fragments, with no platelet activation. Dose-dependent fibrinogen binding to GPIIb-GPIIIa and platelet aggregation were completely inhibited. One Fab fragment was competitively inhibited by abciximab and its murine analog monoclonal antibody (mAb) 7E3, whereas the other Fab fragment bound to cultured HUVECs, suggesting cross-reactivity with alpha(V)beta(3), and also demonstrated proangiogenic effects in tube formation and CAM assays. CONCLUSIONS: These Fab fragments are the first entirely human anti-GPIIb-GPIIIa Fab fragments with full antiaggregatory properties; furthermore, they do not activate platelets. The unique dual-specificity anti-beta(3)-integrin Fab fragment may represent a new tool for the study and management of peripheral arterial vasculopathies.