Dissecting Policy Designs: An Application of the Institutional Grammar Tool

An enduring challenge for the policy and political sciences is valid and reliable depiction of policy designs. One emerging approach for dissecting policy designs is the application of Sue Crawford and Elinor Ostrom's institutional grammar tool. The grammar tool offers a method to identify, systematically, the core elements that comprise policies, including target audiences, expected patterns of behavior, and formal modes of sanctioning for noncompliance. This article provides three contributions to the study of policy designs by developing and applying the institutional grammar tool. First, we provide revised guidelines for applying the institutional grammar tool to the study of policy design. Second, an additional component to the grammar, called the oBject, is introduced. Third, we apply the modified grammar tool to four policies that shape Colorado State Aquaculture to demonstrate its effectiveness and utility in illuminating institutional linkages across levels of analysis. The conclusion summarizes the contributions of the article as well as points to future research and applications of the institutional grammar tool. © 2011 Policy Studies Organization.

The incidence of unacceptable movement with motor evoked potentials during craniotomy for aneurysm clipping.

OBJECTIVE: To review the experience at a single institution with motor evoked potential (MEP) monitoring during intracranial aneurysm surgery to determine the incidence of unacceptable movement. METHODS: Neurophysiology event logs and anesthetic records from 220 craniotomies for aneurysm clipping were reviewed for unacceptable patient movement or reason for cessation of MEPs. Muscle relaxants were not given after intubation. Transcranial MEPs were recorded from bilateral abductor hallucis and abductor pollicis muscles. MEP stimulus intensity was increased up to 500 V until evoked potential responses were detectable. RESULTS: Out of 220 patients, 7 (3.2%) exhibited unacceptable movement with MEP stimulation-2 had nociception-induced movement and 5 had excessive field movement. In all but one case, MEP monitoring could be resumed, yielding a 99.5% monitoring rate. CONCLUSIONS: With the anesthetic and monitoring regimen, the authors were able to record MEPs of the upper and lower extremities in all patients and found only 3.2% demonstrated unacceptable movement. With a suitable anesthetic technique, MEP monitoring in the upper and lower extremities appears to be feasible in most patients and should not be withheld because of concern for movement during neurovascular surgery.

Adenosine-induced flow arrest to facilitate intracranial aneurysm clip ligation: dose-response data and safety profile.

BACKGROUND: Adenosine-induced transient flow arrest has been used to facilitate clip ligation of intracranial aneurysms. However, the starting dose that is most likely to produce an adequate duration of profound hypotension remains unclear. We reviewed our experience to determine the dose-response relationship and apparent perioperative safety profile of adenosine in intracranial aneurysm patients. METHODS: This case series describes 24 aneurysm clip ligation procedures performed under an anesthetic consisting of remifentanil, low-dose volatile anesthetic, and propofol in which adenosine was used. The report focuses on the doses administered; duration of systolic blood pressure <60 mm Hg (SBP(<60 mm Hg)); and any cardiovascular, neurologic, or pulmonary complications observed in the perioperative period. RESULTS: A median dose of 0.34 mg/kg ideal body weight (range: 0.29-0.44 mg/kg) resulted in a SBP(<60 mm Hg) for a median of 57 seconds (range: 26-105 seconds). There was a linear relationship between the log-transformed dose of adenosine and the duration of a SBP(<60 mm Hg) (R(2) = 0.38). Two patients developed transient, hemodynamically stable atrial fibrillation, 2 had postoperative troponin levels >0.03 ng/mL without any evidence of cardiac dysfunction, and 3 had postoperative neurologic changes. CONCLUSIONS: For intracranial aneurysms in which temporary occlusion is impractical or difficult, adenosine is capable of providing brief periods of profound systemic hypotension with low perioperative morbidity. On the basis of these data, a dose of 0.3 to 0.4 mg/kg ideal body weight may be the recommended starting dose to achieve approximately 45 seconds of profound systemic hypotension during a remifentanil/low-dose volatile anesthetic with propofol induced burst suppression.

Dissecting the Functional Impacts of Non-Coding Genetic Variation

A large proportion of the variation in traits between individuals can be attributed to variation in the nucleotide sequence of the genome. The most commonly studied traits in human genetics are related to disease and disease susceptibility. Although scientists have identified genetic causes for over 4,000 monogenic diseases, the underlying mechanisms of many highly prevalent multifactorial inheritance disorders such as diabetes, obesity, and cardiovascular disease remain largely unknown. Identifying genetic mechanisms for complex traits has been challenging because most of the variants are located outside of protein-coding regions, and determining the effects of such non-coding variants remains difficult. In this dissertation, I evaluate the hypothesis that such non-coding variants contribute to human traits and diseases by altering the regulation of genes rather than the sequence of those genes. I will specifically focus on studies to determine the functional impacts of genetic variation associated with two related complex traits: gestational hyperglycemia and fetal adiposity. At the genomic locus associated with maternal hyperglycemia, we found that genetic variation in regulatory elements altered the expression of the HKDC1 gene. Furthermore, we demonstrated that HKDC1 phosphorylates glucose in vitro and in vivo, thus demonstrating that HKDC1 is a fifth human hexokinase gene. At the fetal-adiposity associated locus, we identified variants that likely alter VEPH1 expression in preadipocytes during differentiation. To make such studies of regulatory variation high-throughput and routine, we developed POP-STARR, a novel high throughput reporter assay that can empirically measure the effects of regulatory variants directly from patient DNA. By combining targeted genome capture technologies with STARR-seq, we assayed thousands of haplotypes from 760 individuals in a single experiment. We subsequently used POP-STARR to identify three key features of regulatory variants: that regulatory variants typically have weak effects on gene expression; that the effects of regulatory variants are often coordinated with respect to disease-risk, suggesting a general mechanism by which the weak effects can together have phenotypic impact; and that nucleotide transversions have larger impacts on enhancer activity than transitions. Together, the findings presented here demonstrate successful strategies for determining the regulatory mechanisms underlying genetic associations with human traits and diseases, and value of doing so for driving novel biological discovery.

Influence of Outlet Boundary Conditions on Cerebrovascular Aneurysm Hemodynamics

Computational fluid dynamic (CFD) studies of blood flow in cerebrovascular aneurysms have potential to improve patient treatment planning by enabling clinicians and engineers to model patient-specific geometries and compute predictors and risks prior to neurovascular intervention. However, the use of patient-specific computational models in clinical settings is unfeasible due to their complexity, computationally intensive and time-consuming nature. An important factor contributing to this challenge is the choice of outlet boundary conditions, which often involves a trade-off between physiological accuracy, patient-specificity, simplicity and speed. In this study, we analyze how resistance and impedance outlet boundary conditions affect blood flow velocities, wall shear stresses and pressure distributions in a patient-specific model of a cerebrovascular aneurysm. We also use geometrical manipulation techniques to obtain a model of the patient’s vasculature prior to aneurysm development, and study how forces and stresses may have been involved in the initiation of aneurysm growth. Our CFD results show that the nature of the prescribed outlet boundary conditions is not as important as the relative distributions of blood flow through each outlet branch. As long as the appropriate parameters are chosen to keep these flow distributions consistent with physiology, resistance boundary conditions, which are simpler, easier to use and more practical than their impedance counterparts, are sufficient to study aneurysm pathophysiology, since they predict very similar wall shear stresses, time-averaged wall shear stresses, time-averaged pressures, and blood flow patterns and velocities. The only situations where the use of impedance boundary conditions should be prioritized is if pressure waveforms are being analyzed, or if local pressure distributions are being evaluated at specific time points, especially at peak systole, where the use of resistance boundary conditions leads to unnaturally large pressure pulses. In addition, we show that in this specific patient, the region of the blood vessel where the neck of the aneurysm developed was subject to abnormally high wall shear stresses, and that regions surrounding blebs on the aneurysmal surface were subject to low, oscillatory wall shear stresses. Computational models using resistance outlet boundary conditions may be suitable to study patient-specific aneurysm progression in a clinical setting, although several other challenges must be addressed before these tools can be applied clinically.

Mechanosensitive neurons on the internal reproductive tract contribute to egg-laying-induced acetic acid attraction in Drosophila.

Selecting a suitable site to deposit their eggs is an important reproductive need of Drosophila females. Although their choosiness toward egg-laying sites is well documented, the specific neural mechanism that activates females' search for attractive egg-laying sites is not known. Here, we show that distention and contraction of females' internal reproductive tract triggered by egg delivery through the tract plays a critical role in activating such search. We found that females start to exhibit acetic acid (AA) attraction prior to depositing each egg but no attraction when they are not laying eggs. Artificially distending the reproductive tract triggers AA attraction in non-egg-laying females, whereas silencing the mechanosensitive neurons we identified that can sense the contractile status of the tract eliminates such attraction. Our work uncovers the circuit basis of an important reproductive need of Drosophila females and provides a simple model for dissecting the neural mechanism that underlies a reproductive need-induced behavioral modification.

Targeted Gene Repression Technologies for Regenerative Medicine, Genomics, and Gene Therapy

Gene regulation is a complex and tightly controlled process that defines cell function in physiological and abnormal states. Programmable gene repression technologies enable loss-of-function studies for dissecting gene regulation mechanisms and represent an exciting avenue for gene therapy. Established and recently developed methods now exist to modulate gene sequence, epigenetic marks, transcriptional activity, and post-transcriptional processes, providing unprecedented genetic control over cell phenotype. Our objective was to apply and develop targeted repression technologies for regenerative medicine, genomics, and gene therapy applications. We used RNA interference to control cell cycle regulation in myogenic differentiation and enhance the proliferative capacity of tissue engineered cartilage constructs. These studies demonstrate how modulation of a single gene can be used to guide cell differentiation for regenerative medicine strategies. RNA-guided gene regulation with the CRISPR/Cas9 system has rapidly expanded the targeted repression repertoire from silencing single protein-coding genes to modulation of genes, promoters, and other distal regulatory elements. In order to facilitate its adaptation for basic research and translational applications, we demonstrated the high degree of specificity for gene targeting, gene silencing, and chromatin modification possible with Cas9 repressors. The specificity and effectiveness of RNA-guided transcriptional repressors for silencing endogenous genes are promising characteristics for mechanistic studies of gene regulation and cell phenotype. Furthermore, our results support the use of Cas9-based repressors as a platform for novel gene therapy strategies. We developed an in vivo AAV-based gene repression system for silencing endogenous genes in a mouse model. Together, these studies demonstrate the utility of gene repression tools for guiding cell phenotype and the potential of the RNA-guided CRISPR/Cas9 platform for applications such as causal studies of gene regulatory mechanisms and gene therapy.

Dosimetric Evaluation of Metal Artefact Reduction using Metal Artefact Reduction (MAR) Algorithm and Dual-energy Computed Tomography (CT) Method

Purpose: Computed Tomography (CT) is one of the standard diagnostic imaging modalities for the evaluation of a patient’s medical condition. In comparison to other imaging modalities such as Magnetic Resonance Imaging (MRI), CT is a fast acquisition imaging device with higher spatial resolution and higher contrast-to-noise ratio (CNR) for bony structures. CT images are presented through a gray scale of independent values in Hounsfield units (HU). High HU-valued materials represent higher density. High density materials, such as metal, tend to erroneously increase the HU values around it due to reconstruction software limitations. This problem of increased HU values due to metal presence is referred to as metal artefacts. Hip prostheses, dental fillings, aneurysm clips, and spinal clips are a few examples of metal objects that are of clinical relevance. These implants create artefacts such as beam hardening and photon starvation that distort CT images and degrade image quality. This is of great significance because the distortions may cause improper evaluation of images and inaccurate dose calculation in the treatment planning system. Different algorithms are being developed to reduce these artefacts for better image quality for both diagnostic and therapeutic purposes. However, very limited information is available about the effect of artefact correction on dose calculation accuracy. This research study evaluates the dosimetric effect of metal artefact reduction algorithms on severe artefacts on CT images. This study uses Gemstone Spectral Imaging (GSI)-based MAR algorithm, projection-based Metal Artefact Reduction (MAR) algorithm, and the Dual-Energy method.

Materials and Methods: The Gemstone Spectral Imaging (GSI)-based and SMART Metal Artefact Reduction (MAR) algorithms are metal artefact reduction protocols embedded in two different CT scanner models by General Electric (GE), and the Dual-Energy Imaging Method was developed at Duke University. All three approaches were applied in this research for dosimetric evaluation on CT images with severe metal artefacts. The first part of the research used a water phantom with four iodine syringes. Two sets of plans, multi-arc plans and single-arc plans, using the Volumetric Modulated Arc therapy (VMAT) technique were designed to avoid or minimize influences from high-density objects. The second part of the research used projection-based MAR Algorithm and the Dual-Energy Method. Calculated Doses (Mean, Minimum, and Maximum Doses) to the planning treatment volume (PTV) were compared and homogeneity index (HI) calculated.

Results: (1) Without the GSI-based MAR application, a percent error between mean dose and the absolute dose ranging from 3.4-5.7% per fraction was observed. In contrast, the error was decreased to a range of 0.09-2.3% per fraction with the GSI-based MAR algorithm. There was a percent difference ranging from 1.7-4.2% per fraction between with and without using the GSI-based MAR algorithm. (2) A range of 0.1-3.2% difference was observed for the maximum dose values, 1.5-10.4% for minimum dose difference, and 1.4-1.7% difference on the mean doses. Homogeneity indexes (HI) ranging from 0.068-0.065 for dual-energy method and 0.063-0.141 with projection-based MAR algorithm were also calculated.

Conclusion: (1) Percent error without using the GSI-based MAR algorithm may deviate as high as 5.7%. This error invalidates the goal of Radiation Therapy to provide a more precise treatment. Thus, GSI-based MAR algorithm was desirable due to its better dose calculation accuracy. (2) Based on direct numerical observation, there was no apparent deviation between the mean doses of different techniques but deviation was evident on the maximum and minimum doses. The HI for the dual-energy method almost achieved the desirable null values. In conclusion, the Dual-Energy method gave better dose calculation accuracy to the planning treatment volume (PTV) for images with metal artefacts than with or without GE MAR Algorithm.