The Right Way to Direct a Play

A director needs more than inspiration to guide their work. During grad school, I learned, abandoned, modified and re-embraced many tools for directing in order to develop my own process. In this paper, I examine the revelations and challenges that arose from my coursework and the plays I directed at The Theatre School: Circle Mirror Transformation by Annie Baker, The Lady From the Sea by Henrik Ibsen, The Merchant of Venice by William Shakespeare, Tender by Nikki Bloom, We Are Proud to Present a Presentation About the Herero of Namibia, Formerly Known as South West Africa, from the German Sudwestafrika, Between the Years 1884-1915 by Jackie Sibblies Drury, and The Fairytale Lives of Russian Girls by Meg Miroshnik. I came to grad school to learn THE RIGHT WAY TO DIRECT PLAYS.This thesis documents my discovery that there is no such thing

Examining the Perceived Impacts of Recreational Swimming Lessons for Children with Autism Spectrum Disorder

The purpose of this study was to examine the perceived impacts of recreational swimming lesson participation for children with Autism Spectrum Disorder (ASD). Although swimming lessons are a suitable form of physical activity for children with ASD, minimal research has examined the impacts of these lessons. The author conducted semi-structured interviews with an Applied Behaviour Analysis (ABA) certified therapist and a swim instructor, each with experience working with children with ASD in swimming lessons. The participants suggested that swimming lessons encouraged children with ASD to socialise. Both participants agreed that distractions in swimming lessons and barriers in communication created challenges for developing swimming skills. Finally, the participants described techniques they found appropriate for teaching children with ASD. These results aim to provide insights into the perceived impacts of recreational swimming lessons and appropriate techniques for lessons. Hopefully these insights may inspire parents/guardians of children with ASD to include swimming lessons into the routines of their children while also considering the safety risks of aquatic environments

Creating a simulation model of INTEGRIS Women's and Children's Services and evaluating needed capacity

The 4th floor of The INTEGRIS Baptist Medical Center in OKC houses Women's and Children's Services, a unit which cares for expecting mothers and women going through labor. This unit operates 24 hours per day and 7 days per week and is operated using three sub-units: Triage, Labor Delivery & Recovery (LDR), and Postpartum. The Senior Design Team (SDT) worked in collaboration with the INTEGRIS Continuous Improvement Team (CIT) to create a simulation model to verify whether the recent recommendations in the capacity allocation of the sub-units, made in response to capacity shortages, adequately service the demand.The SDT began their investigation with a debriefing of previous analysis completed by the CIT. Their study characterized the arrival times, length of stay, and current capacity in each sub-unit. It was found that there was great consistency in admissions, transfers, and discharges both daily and seasonally. The capacity issues experienced by the Women's and Children's Services did not appear to be a result of swings in demand in any one sub-unit. Instead, the sub-units experienced insufficient capacity to meet patient demand. Bottlenecks on the 4th floor caused the typical flow of patients to be altered and compounded capacity issues exhibited in the three sub-units. These observations indicated that there was a need to do a detailed capacity analysis of the 4th floor and to this end we developed a discrete event simulation model.The SDT began the creation of a simulation model by fitting distributions to the data using MATLAB. These distributions were later used to create the simulation model submitted by the SDT. Then, Simio was used to construct a representation of 4th floor operations. The model was verified by peer review and test runs. There were no logical errors in the model and patient flow correctly depicted actual operations. The model was validated by comparing actual demand and length of stay from 2019 data to the results generated by the model. This comparison confirmed that the model accurately represented current operations in Women's and Children's Services.After the simulation model baseline was completed, various alternatives to increase capacity were tested with experiments in Simio. The following alternatives were considered to resolve the capacity issues experienced by the Women's & Children's Services:Triage sub-unito 4-bed option: increased capacity by 1 bedo 5-bed option: increased capacity by 2 bedso 6-bed option: increased capacity by 3 bedsLDR/Postpartum sub-unito Add rooms: added rooms to the LDR/Postpartum sub-unitso LDRP: combined the LDR/Postpartum sub-units by converting all beds in both sub-units to include equipment necessary to care for both LDR and Postpartum patientsAnalysis of the Triage sub-unit showed that the 5-bed option was the most effective method to increase capacity. This alternative decreased wait times by 93%. The 5-bed option incurred a greater cost than the 4-bed option due to physical renovation and equipment acquisition costs. However, unlike the other alternatives, the 5-bed option did not require physical separation of the sub-unit and a subsequent decrease in sub-unit visibility. Reduction in sub-unit visibility had a significantly negative impact on the 4th floor.Analysis of the LDR and Postpartum sub-units showed that a combination of adding rooms and the LDRP alternative was the most effective way to mitigate capacity issues. Significant improvements were realized by implementing this change and adding five additional rooms to the unit. This alternative decreased the number of patients who experience wait times by 92% and decreased patient wait times by 72%. Unfortunately, the Women's & Children's Services did not have the ability to increase capacity in either of these sub-units at all. This restriction made the LDRP alternative the only one available for them to resolve capacity issues. Implementation of this plan will decrease the number of patients who experience wait times by 57% and decrease patient wait times by 49%. Conversion to LDRP rooms was less costly than increasing the overall capacity of the two sub-units separately. Additionally, less time was required to clean and maintain the rooms because patients will not require room transfer during their stay. This additional benefit serves to streamline processes on the 4th floor and will help the unit the meet patient demand

Designing for a Driverless Future in Downtown San Luis Obispo

The graduate class CRP 512 Introduction to Visual Communication and GIS, focuses on skill development in visual communications and GIS through a planning exercise. In the Winter quarter of 2018, the class was assigned the re-design of two blocks in downtown San Luis Obispo. The students focused on developing visions and design ideas for a future with autonomous vehicles

Phenothiazine-mediated rescue of cognition in tau transgenic mice requires neuroprotection and reduced soluble tau burden

Abstract Background It has traditionally been thought that the pathological accumulation of tau in Alzheimer's disease and other tauopathies facilitates neurodegeneration, which in turn leads to cognitive impairment. However, recent evidence suggests that tau tangles are not the entity responsible for memory loss, rather it is an intermediate tau species that disrupts neuronal function. Thus, efforts to discover therapeutics for tauopathies emphasize soluble tau reductions as well as neuroprotection. Results Here, we found that neuroprotection alone caused by methylene blue (MB), the parent compound of the anti-tau phenothiaziazine drug, Rember™, was insufficient to rescue cognition in a mouse model of the human tauopathy, progressive supranuclear palsy (PSP) and fronto-temporal dementia with parkinsonism linked to chromosome 17 (FTDP17): Only when levels of soluble tau protein were concomitantly reduced by a very high concentration of MB, was cognitive improvement observed. Thus, neurodegeneration can be decoupled from tau accumulation, but phenotypic improvement is only possible when soluble tau levels are also reduced. Conclusions Neuroprotection alone is not sufficient to rescue tau-induced memory loss in a transgenic mouse model. Development of neuroprotective agents is an area of intense investigation in the tauopathy drug discovery field. This may ultimately be an unsuccessful approach if soluble toxic tau intermediates are not also reduced. Thus, MB and related compounds, despite their pleiotropic nature, may be the proverbial "magic bullet" because they not only are neuroprotective, but are also able to facilitate soluble tau clearance. Moreover, this shows that neuroprotection is possible without reducing tau levels. This indicates that there is a definitive molecular link between tau and cell death cascades that can be disrupted.http://deepblue.lib.umich.edu/bitstream/2027.42/78314/1/1750-1326-5-45.xmlhttp://deepblue.lib.umich.edu/bitstream/2027.42/78314/2/1750-1326-5-45.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/78314/3/1750-1326-5-45-S1.PDFPeer Reviewe

Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche.

Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 × 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition

Genetically predicted cortisol levels and risk of venous thromboembolism

Introduction - In observational studies, venous thromboembolism (VTE) has been associated with Cushing’s syndrome and with persistent mental stress, two conditions associated with higher cortisol levels. However, it remains unknown whether high cortisol levels within the usual range are causally associated with VTE risk. We aimed to assess the association between plasma cortisol levels and VTE risk using Mendelian randomization. Methods - Three genetic variants in the SERPINA1/SERPINA6 locus (rs12589136, rs11621961 and rs2749527) were used to proxy plasma cortisol. The associations of the cortisol-associated genetic variants with VTE were acquired from the INVENT (28 907 cases and 157 243 non-cases) and FinnGen (6913 cases and 169 986 non-cases) consortia. Corresponding data for VTE subtypes were available from the FinnGen consortium and UK Biobank. Two-sample Mendelian randomization analyses (inverse-variance weighted method) were performed. Results - Genetic predisposition to higher plasma cortisol levels was associated with a reduced risk of VTE (odds ratio [OR] per one standard deviation increment 0.73, 95% confidence interval [CI] 0.62–0.87, p Conclusions - This study provides evidence that genetically predicted plasma cortisol levels in the high end of the normal range are associated with a decreased risk of VTE and that this association may be mediated by blood pressure. This study has implications for the planning of observational studies of cortisol and VTE, suggesting that blood pressure traits should be measured and accounted for

Phenotype harmonization and cross-study collaboration in GWAS consortia: the GENEVA experience

Genome-wide association study (GWAS) consortia and collaborations formed to detect genetic loci for common phenotypes or investigate gene-environment (G*E) interactions are increasingly common. While these consortia effectively increase sample size, phenotype heterogeneity across studies represents a major obstacle that limits successful identification of these associations. Investigators are faced with the challenge of how to harmonize previously collected phenotype data obtained using different data collection instruments which cover topics in varying degrees of detail and over diverse time frames. This process has not been described in detail. We describe here some of the strategies and pitfalls associated with combining phenotype data from varying studies. Using the Gene Environment Association Studies (GENEVA) multi-site GWAS consortium as an example, this paper provides an illustration to guide GWAS consortia through the process of phenotype harmonization and describes key issues that arise when sharing data across disparate studies. GENEVA is unusual in the diversity of disease endpoints and so the issues it faces as its participating studies share data will be informative for many collaborations. Phenotype harmonization requires identifying common phenotypes, determining the feasibility of cross-study analysis for each, preparing common definitions, and applying appropriate algorithms. Other issues to be considered include genotyping timeframes, coordination of parallel efforts by other collaborative groups, analytic approaches, and imputation of genotype data. GENEVA's harmonization efforts and policy of promoting data sharing and collaboration, not only within GENEVA but also with outside collaborations, can provide important guidance to ongoing and new consortia

Genome-Wide Gene-Environment Study Identifies Glutamate Receptor Gene GRIN2A as a Parkinson's Disease Modifier Gene via Interaction with Coffee

Our aim was to identify genes that influence the inverse association of coffee with the risk of developing Parkinson's disease (PD). We used genome-wide genotype data and lifetime caffeinated-coffee-consumption data on 1,458 persons with PD and 931 without PD from the NeuroGenetics Research Consortium (NGRC), and we performed a genome-wide association and interaction study (GWAIS), testing each SNP's main-effect plus its interaction with coffee, adjusting for sex, age, and two principal components. We then stratified subjects as heavy or light coffee-drinkers and performed genome-wide association study (GWAS) in each group. We replicated the most significant SNP. Finally, we imputed the NGRC dataset, increasing genomic coverage to examine the region of interest in detail. The primary analyses (GWAIS, GWAS, Replication) were performed using genotyped data. In GWAIS, the most significant signal came from rs4998386 and the neighboring SNPs in GRIN2A. GRIN2A encodes an NMDA-glutamate-receptor subunit and regulates excitatory neurotransmission in the brain. Achieving P2df = 10−6, GRIN2A surpassed all known PD susceptibility genes in significance in the GWAIS. In stratified GWAS, the GRIN2A signal was present in heavy coffee-drinkers (OR = 0.43; P = 6×10−7) but not in light coffee-drinkers. The a priori Replication hypothesis that “Among heavy coffee-drinkers, rs4998386_T carriers have lower PD risk than rs4998386_CC carriers” was confirmed: ORReplication = 0.59, PReplication = 10−3; ORPooled = 0.51, PPooled = 7×10−8. Compared to light coffee-drinkers with rs4998386_CC genotype, heavy coffee-drinkers with rs4998386_CC genotype had 18% lower risk (P = 3×10−3), whereas heavy coffee-drinkers with rs4998386_TC genotype had 59% lower risk (P = 6×10−13). Imputation revealed a block of SNPs that achieved P2df<5×10−8 in GWAIS, and OR = 0.41, P = 3×10−8 in heavy coffee-drinkers. This study is proof of concept that inclusion of environmental factors can help identify genes that are missed in GWAS. Both adenosine antagonists (caffeine-like) and glutamate antagonists (GRIN2A-related) are being tested in clinical trials for treatment of PD. GRIN2A may be a useful pharmacogenetic marker for subdividing individuals in clinical trials to determine which medications might work best for which patients

Genome-wide association study in 79,366 European-ancestry individuals informs the genetic architecture of 25-hydroxyvitamin D levels

Vitamin D is a steroid hormone precursor that is associated with a range of human traits and diseases. Previous GWAS of serum 25-hydroxyvitamin D concentrations have identified four genome-wide significant loci (GC, NADSYN1/DHCR7, CYP2R1, CYP24A1). In this study, we expand the previous SUNLIGHT Consortium GWAS discovery sample size from 16,125 to 79,366 (all European descent). This larger GWAS yields two additional loci harboring genome-wide significant variants (P = 4.7x10(-9) at rs8018720 in SEC23A, and P = 1.9x10(-14) at rs10745742 in AMDHD1). The overall estimate of heritability of 25-hydroxyvitamin D serum concentrations attributable to GWAS common SNPs is 7.5%, with statistically significant loci explaining 38% of this total. Further investigation identifies signal enrichment in immune and hematopoietic tissues, and clustering with autoimmune diseases in cell-type-specific analysis. Larger studies are required to identify additional common SNPs, and to explore the role of rare or structural variants and gene-gene interactions in the heritability of circulating 25-hydroxyvitamin D levels.Peer reviewe