THE ASSOCIATION OF CYP2D6 AND mu-OPIOID RECEPTOR GENOTYPESAND POSTOPERATIVE NAUSEA AND VOMITING IN ADULT ORTHOPEDIC PATIENTS WITH SINGLE EXTREMITY FRACTURES

Often considered the big little problem, postoperative nausea and vomiting (PONV) is a common surgical complication. Treatment of pain with opioids is the primary cause of PONV although other risk factors include female gender, non smoking status and history of PONV or motion sickness. Research has focused on medications to prevent or treat PONV, and risk factors that contribute to PONV. Genetics may also play a role. The purpose of this study was to explore the association of CYP2D6 and mu-opioid receptor genotypes with PONV in patients with single extremity fractures. Subjects (n=143), aged 18-70 were recruited for this exploratory, descriptive study. Informed consent was obtained. PONV was collected by self-report and chart audit. Saliva samples were collected for DNA extraction. Results of Taqman® allele discrimination were used to assign a CYP2D6 classification of poor metabolizer (PM), intermediate metabolizer (IM) extensive metabolizer (EM) and ultrarapid metabolizer (UM). Two SNPS of the mu-opioid receptor gene were analyzed, A118G and C17T by Polymerace Chain Reaction (PCR). Due to genetic differences within ethnic groups, only Caucasians (n=112) were included in the CYP2D6 analysis. The incidence of PONV in the PACU was 38%, increasing to 50% when assessed for 48 hours. CYP2D6 classification results were: 7 (6%) PM group; 34 (30%) IM group; 71 (63%), EM group; and no ultrarapid metabolizers. Gender and history of PONV were significant risk factors in this study (p<.05). There was a trend for age (p=.071), but smoking was not significant (p=.505). The CYP2D6 EM group served as the reference for binary logistic regression analysis which revealed a significant difference with the CYP2D6 PM group for presence of PONV (p =.003). The sample size for the mu-opioid receptor genotype analysis was 82, the genotype distribution was 58 (70%) AA or CC (wild type) and 24 (30%) polymorphism (AG, GG, CT, or TT were combined). No statistical differences were found in the mu-opioid receptor genotype groups for PONV. Ultimately personalized medicine will allow health care providers to treat all patients individually, so it is important for clinical genetic research to identify those risks that may lead to a negative outcome

Partial Computation in Real-Time Database Systems

A critical component of real-time systems in the database, which is used to store external input such as environmental readings from sensors, as well as system information. Typically these databases are large, due to vast quantities of historical data, and are distributed, due to the distributed topology of the devices controlling the application. Hence, sophisticated database management systems are needed. However, most of the time database systems are hand-coded. Off-the-shelf database management systems are not used due in part to a lack of predictability of response [1, 2]. We motivate the use of partial computation of database queries as a method of improving the fault-tolerance and predictability of response in real-time database systems

Population Dynamics Based on Resource Availability & Founding Effects: Live & Computational Models

With the looming global population crisis, it is more important now than ever that students understand what factors influence population dynamics. We present three learning modules with authentic, student-centered investigations that explore rates of population growth and the importance of resources. These interdisciplinary modules integrate biology, mathematics, and computer-literacy concepts aligned with the Next Generation Science Standards. The activities are appropriate for middle and high school science classes and for introductory college-level biology courses. The modules incorporate experimentation, data collection and analysis, drawing conclusions, and application of studied principles to explore factors affecting population dynamics in fruit flies. The variables explored include initial population structure, food availability, and space of the enclosed population. In addition, we present a computational simulation in which students can alter the same variables explored in the live experimental modules to test predictions on the consequences of altering the variables. Free web-based graphing (Joinpoint) and simulation software (NetLogo) allows students to work at home or at school

Temporary Bridging Agents for use in Drilling and Completion of Enhanced Geothermal Systems

CSI Technologies, in conjunction with Alta Rock Energy and the University of Utah have undergone a study investigating materials and mechanisms with potential for use in Enhanced Geothermal Systems wells as temporary diverters or lost circulation materials. Studies were also conducted with regards to particle size distribution and sealing effectiveness using a lab-scale slot testing apparatus to simulate fractures. From the slot testing a numerical correlation was developed to determine the optimal PSD for a given fracture size. Field trials conducted using materials from this study were also successful

An Anti-American Ban On Critique: A Critical Policy Commentary

We are a group of educational leaders who are doctoral candidates and faculty members in the Educational Leadership for Social Justice EdD program at California State University, East Bay. Our work centers around 1) creating shared knowledge about inequities and how they are reproduced by institutional systems, such as education, and 2) finding ways to address these systemic issues to create a more equal, healthy society. This work is informed by multiple critical perspectives, such as critical pedagogy (Freire, 1970; hooks, 1994), critical race theory (Ladson-Billings &amp; Tate, 1995), and Black feminisms (Collins, 2002; Crenshaw, 1989). These perspectives, while varying somewhat, offer a common thread guided by the understanding that the world operates via power relations that privilege some groups while subordinating others; but these relationships, and the oppressions that result, are masked by the dominant culture’s insistence on painting reality with a brush of neutrality and a failure to engage with our history in a way that helps us understand and act on its repercussions on humanity

Explosive volcanism in complex impact craters on Mercury and the Moon: influence of tectonic regime on depth of magmatic intrusion

Vents and deposits attributed to explosive volcanism occur within numerous impact craters on both the Moon and Mercury. Given the similarities between the two bodies it is probable that similar processes control this spatial association on both. However, the precise morphology and localization of the activity differs on the two bodies, indicating that the nature of structures beneath impact craters and/or volcanic activity may also be different. To explore this, we analyze sites of explosive volcanism within complex impact craters on the Moon and Mercury, comparing the scale and localization of volcanic activity and evidence for post-formation modification of the host crater. We show that the scale of vents and deposits is consistently greater on Mercury than on the Moon, indicating greater eruption energy, powered by a higher concentration of volatiles. Additionally, while the floors of lunar craters hosting explosive volcanism are commonly fractured, those on Mercury are not. The most probable explanation for these differences is that the state of regional compression acting on Mercury's crust through most of the planet's history results in deeper magma storage beneath craters on Mercury than on the Moon. The probable role of the regional stress regime in dictating the depth of intrusion on Mercury suggests that it may also play a role in the depth of sub-crater intrusion on the Moon and on other planetary bodies. Examples on the Moon (and also on Mars) commonly occur at locations where flexural extension may facilitate shallower intrusion than would be driven by the buoyancy of the magma alone

Human and mouse essentiality screens as a resource for disease gene discovery

The identification of causal variants in sequencing studies remains a considerable challenge that can be partially addressed by new gene-specific knowledge. Here, we integrate measures of how essential a gene is to supporting life, as inferred from viability and phenotyping screens performed on knockout mice by the International Mouse Phenotyping Consortium and essentiality screens carried out on human cell lines. We propose a cross-species gene classification across the Full Spectrum of Intolerance to Loss-of-function (FUSIL) and demonstrate that genes in five mutually exclusive FUSIL categories have differing biological properties. Most notably, Mendelian disease genes, particularly those associated with developmental disorders, are highly overrepresented among genes non-essential for cell survival but required for organism development. After screening developmental disorder cases from three independent disease sequencing consortia, we identify potentially pathogenic variants in genes not previously associated with rare diseases. We therefore propose FUSIL as an efficient approach for disease gene discovery. Discovery of causal variants for monogenic disorders has been facilitated by whole exome and genome sequencing, but does not provide a diagnosis for all patients. Here, the authors propose a Full Spectrum of Intolerance to Loss-of-Function (FUSIL) categorization that integrates gene essentiality information to aid disease gene discovery

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

Common, low-frequency, rare, and ultra-rare coding variants contribute to COVID-19 severity

The combined impact of common and rare exonic variants in COVID-19 host genetics is currently insufficiently understood. Here, common and rare variants from whole-exome sequencing data of about 4000 SARS-CoV-2-positive individuals were used to define an interpretable machine-learning model for predicting COVID-19 severity. First, variants were converted into separate sets of Boolean features, depending on the absence or the presence of variants in each gene. An ensemble of LASSO logistic regression models was used to identify the most informative Boolean features with respect to the genetic bases of severity. The Boolean features selected by these logistic models were combined into an Integrated PolyGenic Score that offers a synthetic and interpretable index for describing the contribution of host genetics in COVID-19 severity, as demonstrated through testing in several independent cohorts. Selected features belong to ultra-rare, rare, low-frequency, and common variants, including those in linkage disequilibrium with known GWAS loci. Noteworthily, around one quarter of the selected genes are sex-specific. Pathway analysis of the selected genes associated with COVID-19 severity reflected the multi-organ nature of the disease. The proposed model might provide useful information for developing diagnostics and therapeutics, while also being able to guide bedside disease management. © 2021, The Author(s)