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1.
Molecular Cancer Therapeutics ; 20(12 SUPPL 1), 2021.
Article in English | EMBASE | ID: covidwho-1822118

ABSTRACT

Intro: Deregulated protein synthesis is a common trait across solid and hematologic malignancies and an attractive target for cancer therapy. Rocaglates compounds that inhibit eukaryotic initiation factor 4A1 (eIF4A1), the essential DEAD-box RNA helicase that resolves mRNA 5'UTR secondary structures during cap-dependent translation initiation. Rocaglates' unique mechanism of action causes sequence-selective mRNA binding by eIF4A1, clamping the inactive helicase onto the transcript. This suppresses translation globally and affects many oncogenic and pro-survival transcripts in particular. Zotatifin, the first-in class synthetic rocaglate, is currently in Phase I clinical trials for the treatment of solid tumors and as an antiviral against SARS-CoV2. Currently, eIF4A1 and DDX3 are the only reported targets of rocaglate-mediated RNA clamping. Employing unbiased proteomic approaches, we have discovered that rocaglates, thought to act as pure eIF4A/translation inhibitors, extensively remodel the translation machinery and translatome. Additionally, mass-spec interrogation for proteins interacting with specific RNA sequences reveals novel targets of rocaglate-mediated, sequence-specific RNA clamping. Methods: We conducted original mass-spectrometry analyses of translational reprogramming by rocaglates. TMT-pSILAC assessed acute changes in protein production, while MATRIX, which captures high-resolution profiles of the translation machinery, revealed translation factors that drive reprogramming in response to rocaglate exposure. We validated results biochemically, in cellulo, and in vivo using patient-derived xenograft (PDX) mouse models. To probe existing and novel rocaglate RNA-clamping targets, we developed unbiased “clampome” assays - in cellulo protein-RNA-pull downs followed by mass-spec analysis of proteins with increased binding to RNA in the presence of rocaglates. Results: We find rocaglates, including zotatifin, have effects far more complex than simple “translational inhibition” as currently defined. Indeed, translatome analysis by TMT-pSILAC revealed myriad up-regulated proteins that drive hitherto unrecognized cytotoxic mechanisms. The GEF-H1 guanine exchange factor, for example, drives anti-survival RHOA/JNK activation, suggesting novel candidate biomarkers of rocaglate clinical outcomes. Translation-machinery analysis by MATRIX identifed rocaglate-induced dependence on specific translation factors including eEF1ϵ1 that drive remodeling. Novel rocaglate RNA-binding targets revealed by clampome studies remain under detailed evaluation as mediators of drug activities. Discussion: Our original proteome-level interrogation revealed that the complete cellular response to these historical “translation inhibitors” is mediated by comprehensive translational landscape remodeling. Effects on a broader suite of RNA binding proteins than eIF4A1 alone we suggest mediate the potent antitumor activities of these unique compounds, elucidation of which permits development of novel precision approaches to targeted translational deregulation in cancer.

2.
FASEB Journal ; 35(SUPPL 1), 2021.
Article in English | EMBASE | ID: covidwho-1821975

ABSTRACT

Considerable attention has been paid to immunological approaches to dealing with the Covid-19 pandemic. In addition, existing pharmaceuticals, such as the modified mononucleotide Remdesvir, have been studied in the context of the viral infection. This study looks at different classes of compounds, natural products, some already ingested by millions of people every day, and asks if there is evidence that they might bind to Covid19 viral proteins and possibly interfere with viral replication. In this study, the Universal Natural Products Database was used to search for compounds that bind to the SARS-CoV-2 3CL Protease. The database was interrogated using the Smina docking program, a branch of Autodock Vina. Those compounds that were predicted by Smina to bind better than -9 kcal/mole were then successively interrogated with LeDock, a program that gives results that are considerably different from Smina. The compounds with predicted binding values of -11 kcal/mole or lower by both programs were then studied by observing their predicted binding using several programs that enable the examination of ligand-protein interactions. While this study identified many compounds of potential interest, this report concentrates on compounds that are commonly found in foodstuffs. Some but not all of these compounds are structurally close to those compounds that have been classified by others as Pan-Assay Interference Compounds, PAINS.

3.
FASEB Journal ; 35(SUPPL 1), 2021.
Article in English | EMBASE | ID: covidwho-1821974

ABSTRACT

Symbiotic interaction between the human body and its microbiota is an important issue of modern biomedicine and personalized medicine. However, little is known on molecular mechanisms of that relationship. Bearing in mind the ubiquitous participation of peptides in biomolecular interactions and regulatory processes we attempted direct search of blood peptides originated from microbial proteins. LC-MS/MS analysis was carried out of blood serum and plasma samples taken from 20 healthy donors on Q Exactive HF-X Hybrid Quadrupole-Orbitrap mass-spectrometer. Sample preparation was carried out based on our previously developed method of peptide desorption from the surface of major blood plasma proteins followed by standard chromatographic steps. Mascot and X! Tandem search engines were used for peptide identification. Human protein sequences were taken from UniProt Knowledgebase and sequences of human microbiota proteins-from NIH Human Microbiome Project (HMP). As a result, out of 13625 identified peptides 912 were unique fragments of microbial precursors, which is 6.69% of the total amount of detected bloodstream peptides. In 30 cases peptide identification was confirmed by mass-spectral study of individual synthetic samples. Absolute quantification by the mass-spectrometric method of multiple reaction monitoring (MRM) confirmed the presence of bacterial peptides in plasma and serum in the range of approximately 0.1 nMol/L to 1 mkMol/L, which is comparable to physiologically significant hormone concentrations in human blood in normal conditions. Analysis of the in silico obtained hydrolyzates of microbiotic proteins showed that significant number of the identified peptides are derived from the precursor proteins as a result of hydrolysis with trypsin, chymotrypsin and pepsin, the main proteases of the gastrointestinal system. 60% of the identified “microbial” peptides are derived from the intestine flora, about 20% - from oral microbiota and 20% fall on the remaining microbiotic communities. Most of the precursor proteins refer to intracellular, cytoplasmic proteins. The isolated fraction of peripheral blood mononuclear cells showed increase secretion of proinflammatory cytokines, colony stimulating factors and chemoattractants as the response to the addition of some of the identified microbiotic peptides. The data obtained serve as a basis for the ongoing study of the functional properties of microbiome derived peptides.

4.
FASEB Journal ; 35(SUPPL 1), 2021.
Article in English | EMBASE | ID: covidwho-1821961

ABSTRACT

Introduction Traditional medical education has recently seen major challenges due to the coronavirus (COVID-19) pandemic. New pedagogical methods, including augmented reality (AR) and virtual reality (VR), are on the rise as alternatives to traditional teaching methods. While AR enhances real world experiences by overlaying information, VR immerses users in a computerized world rather than enhancing reality. It is crucial to understand the limitations of these learning modalities and that at best these approaches should be used to supplement and not replace traditional medical education. Objectives This study is part of a larger project that investigates the advantages and disadvantages of AR/VR in medical education. This portion of the study focused on the limitations of AR/VR and the parameters that we explored are professional and interpersonal skill development, visual haptic training, problem solving skills, physician-patient relationship, technological limitations, and financial challenges. Methods This study is a part of a systematic review of the literature seeking to identify the strengths and weaknesses associated with application of AR/VR to medical education. In this portion of the larger study we outline the limitations of AR/VR in medical education. Results Our research indicates that AR/VR may not provide the same learning experience with regards to professional and interpersonal skill development. In person anatomy learning provides an immersive visuohaptic training experience, which has been shown to promote better recall results in comparison to visual or haptic training alone. Current VR headsets have struggles with regards to video quality and latency, which can cause a sensory mismatch called cybersickness. With the high cost of medical education, AR/VR may bring additional financial burdens for students. A study showed one simulation session totaled nearly $107,000. Conclusion Virtual and augmented reality are rapidly being adopted in many academic fields, and while it is certain that tools using these modalities will be used in medical programs, it is important to understand the limitations that these learning tools pose. VR and AR learning environments can be incredibly fruitful, but in their still-nascent state these technologies are best used as a supplementation to well-vetted existing educational approaches rather than a replacement.

5.
FASEB Journal ; 35(SUPPL 1), 2021.
Article in English | EMBASE | ID: covidwho-1821960

ABSTRACT

Introduction and Objectives Novel SARS-CoV-2 virus has been implicated in prompting a bold immune response that leads to severe Coronavirus disease 2019 (COVID-19). Recent studies have shown that SARSCoV-2-infected monocytes and macrophages are stimulated to produce an overabundance of pro-inflammatory cytokines and chemokines to generate a cytokine storm. Cytokines in excess can contribute to local tissue inflammation and the pathogenesis of COVID-19. However, the mechanism by which SARS-CoV-2 signal macrophage-derived inflammatory response remains unclear. In the present study, we used RAW 264.7 cells, a wellcharacterized macrophage model, to study the in vitro effects of SARS-CoV-2 on reactive oxygen species (ROS) production and its potential role in the signal transduction of cytokine production. Methods The effect of SARS-CoV-2 on ROS and cytokine generation in macrophages was assessed by treating RAW 264.7 cells with SARS-CoV-2 heat inactivated virus (0-20 million viral particles) or recombinant proteins for 24 hours. 2',7'-Dichlorodihydrofluorescein (2',7'-DCF) fluorescence analysis was utilized to quantify ROS generation within the RAW 264.7 macrophage cell line. Cell culture medium was sampled to quantify the levels of tumor necrosis factor (TNF) using enzyme-linked immunosorbent assay (ELISA). To assess the effects of SARS-CoV-2 on mitochondrial function, cells were treated with SARS-CoV-2 heat inactivated virus (0-20 million viral particles) for 24 hrs. Mitochondria-derived superoxide was measured using the MitoSOX™ red mitochondrial superoxide indicator. Results Treatment of RAW 264.7 cells with inactivated SARS-CoV-2 viral particles or recombinant proteins stimulated ROS production. Mitochondria-derived superoxide and hydrogen peroxide production were increased in response to inactivated SARS-CoV-2 viral particles and recombinant protein exposure. The increased ROS generation is linked to macrophage activation induced by SARS-CoV-2 exposures. Along with the ROS generation, increased TNF production was observed. Conclusions The results of this study suggest that both SARS-CoV-2 viral proteins and heat-inactivated viral particle exposures cause significant generation of ROS and cytokines by RAW 264.7 cells. ROS generation and the subsequent cytokine release apparently play a significant role in the pathogenesis associated with the SARS-CoV-2 viral infection. The imbalanced cellular defense system against oxidative stress commonly associated with aging could explain the increased occurrence of more severe SARS-CoV-2 illness in seniors and in patients with underlying health conditions. Based on the results from this study, we propose that antioxidants such as N-acetyl-L-cysteine, resveratrol, or Vitamin E in combination with antiinflammatory drug could be used to control excess ROS and cytokines in patients with severe COVID-19.

6.
FASEB Journal ; 35(SUPPL 1), 2021.
Article in English | EMBASE | ID: covidwho-1821935

ABSTRACT

SARS-COV-2, or COVID-19, is a respiratory virus infecting over 86 million people worldwide. In addition to respiratory infections, SARS-COV-2 has been shown to include cardiovascular (CV) complications, including myocarditis and acute coronary syndrome. Risk of severe complications from SARS-COV-2 in individuals with existing CV and metabolic disease has been shown to be increased. Evidence indicates SARS-COV-2 enters tissues via the angiotensin-converting enzyme 2 (ACE2) receptor and that the virus is primed and activated by transmembrane protease, serine 2 (TMPRSS2). The goal of this study was to determine ACE2 and TMPRSS2 mRNA levels in pre-clinical swine models of heart failure (HF). We hypothesized sex, pressure-overload, and comorbidities would increase ACE2 and TMPRSS2 mRNA levels. A retrospective analysis was conducted in previously completed studies in our lab including: 1) Female, intact Ossabaw swine that were either lean control or western diet-fed aortic-banded (N=4-5/group);2) Female Yucatan mini-swine subject to ovariectomy and/or aortic banding (N=5-8/group);and 3) Sedentary and exercise trained male, intact Yucatan mini-swine that were aortic banded. ACE2 and TMPRSS2 mRNA levels were evaluated in the left ventricle (LV), right ventricle (RV), and coronary vasculature using qRT-PCR. Linear regression analysis was used to determine differences between the following variables: pig species, sex hormones, aortic banding, comorbidities, exercise training, and tissue. Data was log-transformed to meet linear regression assumptions. ACE2 and TMPRSS2 mRNA levels were significantly influenced by sex, comorbidity, and tissue type. TMPRSS2 mRNA levels were also influenced by species and disease status. Specifically, ACE2 mRNA levels decreased 57.1% in the LV and increased 169.9% in the RV of males compared to coronary vessels in intact females. TMPRSS2 mRNA levels increased in the LV and RV of males (1,218.6% and 5,479.8%, respectively) compared to coronary vessels in intact females. ACE2 and TMPRSS2 mRNA levels increased 344% and 453.4%, respectively, in the LV of Ossabaw swine fed a Western Diet compared to coronary vessels from Yucatan and Ossabaw swine without comorbidities. Species differences indicated TMPRSS2 mRNA levels increased 449.2% in the RV and 498.6% in the LV in Yucatan mini-swine compared to coronary vessels in Ossabaw swine. A 107.3% increase in TMPRSS2 mRNA level was observed in male swine without HF compared to female intact swine with HF highlighting the importance of sex and disease state. Exercise training did not impact ACE2 or TMPRSS2 mRNA levels irrespective of tissue. In conclusion, these results suggest differences in RV, LV and coronary mRNA levels of ACE2 and TMPRSS2 are dependent upon sex and comorbidities. TMPRSS2 levels are additionally influenced by pig species and pressureoverload. These results provide insight into how ACE2 and TMPRSS2 mRNA levels may influence the cardiovascular involvement of SARS-COV-2 infection in an experimental setting of pre-clinical HF incorporating different swine species, sex, and comorbidities.

7.
FASEB Journal ; 35(SUPPL 1), 2021.
Article in English | EMBASE | ID: covidwho-1821901

ABSTRACT

The physiology of critical care patients is more complex than normally appreciated. Patients arrive at the intensive care unit (ICU) or the pediatric ICU (PICU) with a variety of infections, trauma, organ damage, and dysfunctional immune systems. This population is the prime target for testing and applying new precision medicine tools to decipher the unique biology occurring within each patient. This is particularly important as COVID-19 has made such an impact on the United States healthcare system. Thus, there is a need to develop strategies to find multiple levels of information while minimizing the number of tests performed, shifting the balance of testing to more proactive than reactive. With the collection of ∼2mL of blood (about half a teaspoon), our collaboration between Spectrum Health and Michigan State University has shown the ability to use PAXgene tubes and RNAseq to simultaneously map human gene/transcript signatures, score panels of corresponding risk genes, deconvolute immune cells, detect markers of organ/cell damage, detect RNA from bacteria/viruses/plants/fungi, profile the immune repertoire, address how patients are unique from other samples, and address common/rare genetic mutations. These tools have been applied to three cohorts of patients (and age matched controls) for critical care medicine physiology understanding for nearly all ages: 1) Infants with Respiratory syncytial virus (RSV);2) Kids with multiple organ dysfunction syndrome;and 3) Adults with hospitalized or lethal COVID-19. Our findings from these tools shows the complexity of immune system activation, secondary infections, and under appreciated interactions of the immune cell disorder overlapping COVID-19 pathology. The promise of blood-based transcriptomics to reveal cellular and cell free signatures opens a door for building more detailed physiological mechanisms from precision medicine.

8.
FASEB Journal ; 35(SUPPL 1), 2021.
Article in English | EMBASE | ID: covidwho-1821872

ABSTRACT

Objective Online/computer-assisted learning has been used extensively in medical education in standalone and hybrid formats. Because of time restraints, the online format may be ideal for providing foundational review material in clinical courses, but the effectiveness of the online format for review purposes in this setting has not been adequately investigated. This project compared student learning and satisfaction delivered by two different methods in a special populations course for third-year doctor of chiropractic students. The two methods of delivery were: 1) a face-to-face lecture (F2FL) on pediatric spinal anatomy, and 2) an online learning module (OLM) covering the same material. Methods This study was approved by the institutional IRB. A cohort comparison, mixed methods study design compared student learning and satisfaction of a pediatric spinal anatomy review delivered through a F2FL (n=22) and OLM (n=18) in two successive 2019 (pre-COVID) course offerings. Previously validated pre- and post-tests for the material were given to the students one week prior and one week following the intervention (either F2FL or week-long availability of the OLM). An instructor not affiliated with the course completed a “Similarity of Material Assessment” that evaluated the similarity of content in each method of delivery. Identical tests were given to each group. In addition, a survey assessing the method of delivery, comfort with technology, and preference of F2FL vs. OLM of review material, was completed by both groups immediately following administration of the post-test. Differences between pre-and post-test results were assessed using repeated measures ANOVA with F2FL and OLM as groups and pre-and post-test results as repeated measures. Results The content presented to the F2FL and OLM groups was judged to be the same by the independent instructor. Testing results showed an improvement with both groups from preto post-test [F2FL 54.6%, p<0.0001 vs. OLM 48.9%, p<0.0001 (OLM 52.35%, p<0.0001 with one dramatic outlier removed)], with no significant difference between test results between the F2FL and OLM groups [p=0.53 (p=0.82 with outlier removed)]. The survey showed: 83.3% of OLM students felt the online method was effective and 88.9% would prefer the material to be presented online;80% of the F2F group thought the lecture was engaging/effective and 60% would have preferred to have the material presented online. Conclusions The OLM was found to be as effective as the F2FL for the content assessed, and students were highly satisfied with the online method of instruction of the anatomy review material. This strategy could potentially be applied to provide additional review materials fundamental to other clinical courses. The OLM method allows for the material to be developed and given by content experts while also freeing valuable in-class time to be used for more experiential learning in clinical courses.

9.
FASEB Journal ; 35(SUPPL 1), 2021.
Article in English | EMBASE | ID: covidwho-1821868

ABSTRACT

Colleges and universities across the globe were challenged by the necessity of abruptly transitioning their courses to online or hybrid models to adhere to COVID-19 social distancing guidelines. Second year, Doctor of Physical Therapy (DPT) students were surveyed regarding their learning experiences during an online Foundational Sciences course that included a mix of anatomy, physiology, pathology and pharmacology instruction. The purpose was to gain perceptions into best strategies for online instruction for those content areas that promoted course objective competency with an emphasis on learner engagement. Fifty-four DPT students were surveyed following the completion of an 8-week summer semester Foundational Sciences course at the University of the Incarnate Word, School of Physical Therapy, DPT program. The 7-question anonymous survey addressed content delivered both synchronously (live) and asynchronously (prerecorded or self-regulated) with regard to time, synchronous class size and format (large group vs. breakout room), use of asynchronous voiceovers and video tutorials, and rating of specific activities promoting engagement. Open feedback questions addressed virtual course elements that students identified as most and least supportive of content mastery. Fifty responses were collected (93% response rate). Findings from the survey indicated a preference for synchronous sessions of 1.5 hr (94%) in length with the combination of both large and small group (breakout room) sessions (90%). Sixty percent of respondents preferred having a mix of synchronous classes with the entire cohort of 54 learners and smaller synchronous sessions with half the cohort. While 50% indicated a preference for more asynchronous PowerPoint voiceovers, 46% indicated that they preferred not having asynchronous voiceovers that aligned with every synchronous class. Activities promoting engagement received mixed ratings overall using a 5-point Likert scale ranging from poor to excellent. Activities that received majority satisfactory ratings included Poll Everywhere (44%), Zoom annotation tool (40%), Zoom breakout room activities (44%) and StudyMate flashcards (56%). Activities with roughly equivalent ratings for satisfactory, very good and excellent included asynchronous voiceovers (28-36%) and Kahoot quizzes (26-38%). The inclusion of guest speakers was least favorable (32% combined poor and fair responses) out of all the activities utilized to enhance engagement. Respondent open feedback indicated that accessibility to recorded synchronous sessions and asynchronous voiceovers were most valuable to their learning. Question interruptions during synchronous sessions and discussion-based breakout room sessions with less structure was least helpful to their learning. Respondents consistently identified optimal duration and format of online instructional delivery but varied in their responses related to activities promoting learner engagement. This finding could be attributed to variations in learning styles and merits further study. Knowledge derived from educators' experience during the rapidly evolving and adaptive teaching environment of 2020 can be utilized to transform educational approaches in a post COVID-19 era.

10.
FASEB Journal ; 35(SUPPL 1), 2021.
Article in English | EMBASE | ID: covidwho-1821854

ABSTRACT

In March 2020, TTUHSC opened a new 20,000sf Institute of Anatomical Sciences for human gross anatomy. When the COVID-19 pandemic struck and many schools shifted from in person to online teaching, we hypothesized that if safety measures were used, in person cadaveric anatomy could be safely taught without a decrease in student performance. To test this, we reduced onsite attendance to less than 25% of room capacity. Masks were required at all times and students were instructed to social distance. Six students were assigned per cadaver, but only two students dissected at a time. The other four students reviewed and completed dissections and/or reviewed in groups of two at other allotted times. Thus, students dissected only every third lab. Dissection and lab review attendance was mandatory and students were nearly 100% compliant. Teaching assistants recorded dissected prosections reviews, and these videos were uploaded to password protected course files for independent learning. Students were provided iPads in the laboratory and access to three software packages for use on and off site. All students had access to multiple formative quizzes and exams, and three new online practice practical exams were created. To help reduce testing anxiety, a pass/fail system replaced categorical grading. However, all written and practical exams were conducted on site and in person. At TTUHSC, we have developed an exam question database to track historical student performance including a 25-question optional pre-block practice exam used to assess incoming student anatomical aptitude. In 2020, 90% of incoming students (93% in 2019) took the pre-block exam and scored an average of 28% (24% in 2019). In 2020, despite vastly different content delivery approaches (>80% of lectures were on Zoom) and reduced in-person dissection requirements, students modestly outperformed their 2019 counterparts. Overall exam averages were 89% in 2020 compared to 87% in 2019. If a categorical system was in place, 66% of students would have earned Honors or High Pass in 2020 compared to 61% in 2019. Our formative assessments were highly predictive of summative exam performance, and students reported that they reduced exam stress. Furthermore, summative exam averages correlated strongly with NBME performance (p<0.0001, r =0.63). TTUHSC medical students estimated that a majority of their peers at other medical schools did not have any in person dissection in 2020. Our students ranked in person laboratory dissection as the most useful learning activity, 88% reported that our COVID-19 preparations were very good to outstanding, and 97% were satisfied with the quality of their anatomy education. We conclude that 1) When using appropriate precautions, in person cadaveric anatomy can be taught safely during a pandemic;2) cadaveric dissection is essential for mastery of anatomical concepts;and 3) coupling online learning modalities with rigorous formative assessments prevented a modest reduction in cadaveric dissection opportunities from negatively impacting student performance. 2.

11.
FASEB Journal ; 35(SUPPL 1), 2021.
Article in English | EMBASE | ID: covidwho-1821838

ABSTRACT

Due to the COVID-19 pandemic, there is increased interest to effectively deliver educational curricula remotely to diverse student populations. Case-based cadaveric MRI visualization and extended reality (XR) technology enhances learning experiences in medicine. The purpose of this study was to demonstrate that a virtual, multi-departmental workflow utilizing MRI, XR technology, and a “patient” group, represented by the John A. Burns School of Medicine (JABSOM) Willed Body Program, supplements case-based learning and promotes student exploration and engagement equally in cross-cultural cohorts represented by American and Turkish medical students. Virtual case-based learning activities were developed and presented to American medical students at JABSOM and Turkish medical students, selected based on education and English proficiency, via Zoom. Subject, medical history, and physical exam data were presented to students who were then divided into breakout rooms where hypotheses regarding cadaveric, neurological findings were generated. Students then reviewed radiology and pathology reports and accessed relevant 3D segmented, photogrammetric and illustrative models. An optional survey was completed to evaluate student opinion based on a 5-point Likert scale. Comparisons between groups were performed using a non-parametric Mann Whitney U test. Data was reported as mean, median (min-max), and percentile. Significant differences (two-tailed P) less than 0.05 were significant. Results revealed significant differences between American (n=40) and Turkish (n=16) student opinion. The Turkish scale was significantly higher when asked if MRI scans of cadavers were useful as online learning tools (p =0.002), if MRI scans of cadavers provided an understanding of relevant anatomy (p<0.001), if 3D models provided a better understanding of anatomical relationships (p<0.001), whether students would like more interactive sessions using MRI scans (p<0.001), and if students would use similar resources in the future (p<0.001). The American scale was higher when asked if students were able to communicate effectively with their breakout groups (p=0.037). The learning activity was positively received by both cohorts as shown by no average score less than a 4 out of 5 for each question. The American scales may have been lower due to having previous experience with similar activities, whereas the learning activity was novel and exciting to Turkish students. Differences in communicating effectively in breakout rooms can be explained by the fact that American students were broken into longitudinal dissection groups, whereas Turkish students were randomly assigned. Based on these results, case-based learning, utilizing MRI and XR technology, enhances the learning experience of medical students and can be expanded to cross-cultural student populations.

12.
FASEB Journal ; 35(SUPPL 1), 2021.
Article in English | EMBASE | ID: covidwho-1821823

ABSTRACT

The SARS-CoV-2 virus is responsible for the COVID-19 pandemic which continues to impact nearly every person on Earth, having caused over 1.8 million deaths. Two anti-SARS-CoV monoclonal antibodies (MAbs) 80R and 362 are known to bind to epitopes on the spike protein receptor-binding domain (RBD) and neutralize the virus. To investigate this further and hypothesize structures for potentially more effective antibodies, undergraduate students cooperated in teams as part of the CREST (Connecting Researchers, Educators, and STudents) Program with the Center for Biological Modeling. Working collaboratively, students from eight universities nationwide applied their knowledge to build 3-D printed models to explain a particular protein-based molecular story using crystal structures of proteins described in the literature. The Nova Southeastern University (NSU) CREST team modeled and compared the 80R antibody that binds to SARS-CoV-1 and the MAb362 antibody that can bind to both SARS-CoV-1 and SARS-CoV-2. Students developed skills with protein visualization software including Pymol and Jmol to design models which showed the 80R and 362 antibodies binding to the RBD of the corresponding proteins. By studying the point mutation differences between the two antibodies (80R and 362), a potentially more universal antibody (named NSU1 in this study) was modeled. This hypothesized antibody was expected to bind more effectively to future mutations in the SARS spike protein. At the binding interface between these antibodies and the SARS spike protein, MAb362 mutations trend smaller and less polar including: Arg149Ser, Asn151Ser, Asp170Gly, and Trp213Ser. Due to the trend of smaller amino acids appearing in the MAb362 binding interface, it was hypothesized that more space in this area could allow antibodies to be more resistant to future SARS-CoV spike protein structure variations. NSU1 was modeled based on MAb362 with the following four additional mutations: Asp103Gly, Trp104Leu, Gly170Ser, and Arg211Val. All of these except for Gly170 are mutations that decreased size and polarity of amino acid residues within the binding interface. Position 170 is Asp on the 80R structure and thus a mutation to Ser is still expected to maintain this trend of smaller residues in the antibody. Due to the additional space created due to these amino acid substitutions in the binding region between the antibody and RBD of the spike protein, NSU1 was predicted to be more resistant to spike protein mutations. These models allowed for deeper understanding of the impact that mutations in antibodies can have on binding interactions with viral proteins. Additionally, the modeling process also provided insight into the molecular structure of a potentially more universal antibody against variations in SARS-CoV.

13.
FASEB Journal ; 35(SUPPL 1), 2021.
Article in English | EMBASE | ID: covidwho-1821817

ABSTRACT

Background The novel SARS-CoV-2 virus inflicts far-reaching health decrements, both directly and through secondary inflammatory stimulation. To date, there is little information regarding the effects of COVID-19 on the heart after infection, especially among young healthy adults. Purpose We sought to determine whether contracting SARS-CoV-2 affects cardiac function in young, otherwise healthy adults and whether these alterations recede after testing positive for SARS-CoV-2. Methods Transthoracic echocardiography was performed on 7 subjects with SARS-CoV-2 (3F/4M, 21±1y, 24±2 kg m ) who tested positive 3-4 weeks prior to baseline testing followed by 1- month and 2-month follow-up testing. A parasternal long-axis view was utilized to measure septal and left ventricular posterior wall thickness, left ventricular volume, and left ventricular outflow tract dimensions. A four-chamber view was utilized to measure mitral and tricuspid valve, left ventricular, and pulmonary vein function. Data are mean±SD. Results Stroke volume (Baseline: 44±11ml, 1-month: 42±13ml, 2-month: 54±12ml) and stroke index (Baseline: 24±6ml/m

14.
Anesthesia and Analgesia ; 134(4 SUPPL):15, 2022.
Article in English | EMBASE | ID: covidwho-1820615

ABSTRACT

Introduction: Telehealth provides an opportunity to deliver health care by reducing physical barriers. Although the adoption of telehealth has increased, the COVID-19 pandemic expedited the expansion and support for telehealth due to a need for social distancing and changes to reimbursement. While telehealth can bridge gaps in care, the rapid adoption of telehealth technology may lead to an increased digital divide, whereby technology can exacerbate existing health disparities. Understanding the impact of telehealth on health disparities is an important component toward achieving health equity. The goal of our study was to describe telehealth utilization among a pediatric pain clinic population and understand if patient demographic factors were associated with differences in telehealth utilization. Methods: Following IRB approval, we conducted a retrospective study of all pediatric pain clinic patients seen by telehealth at the Children's Hospital Los Angeles from 4/2020 to 5/2021. Patient demographic details and telehealth utilization data were ed from electronic health records. The primary outcome was telehealth appointment no-show or cancellation within 24 hours. Statistical analysis was conducted using SAS. Results: Our study included 550 patients, with 241 (43.8%) patients seen as new patient visits and 309 (56.2%) having their follow-up visits during the study time period. The median age was 15-years old. The most frequent self-reported race was White (24.6%), followed by Black (6.4%), and Asian (2.8%), with reports of Other (51.8%) and Unknown (14.2%). Our cohort self-reported their ethnicity as Hispanic (38.3%), Non-Hispanic (29.3%), with a group of Unknown (32.4%). The most common self-reported language was English (85.8%), followed by Spanish (14.0%). Most patients had government insurance (61.6%) versus commercial (38.4%). For all appointments, 14.9% were cancelled <24 hours/no-show, whereas new appointments had 21.2% of patients cancelled/no-show and follow-up appointments were cancelled/no-show in 10.0% of appointments. Among new patient visits, ethnicity and government insurance status were statistically associated with being cancelled <24 hours from appointment, or no-shows (p<0.05). Among new patient visits, those who identified as “Other” were more than twice as likely to cancel/no-show than those who identify as White. Discussion: In our study of pediatric pain clinic patients, ethnicity and insurance status were significantly associated with patients who had cancellations and no-shows for telehealth appointments. These factors may represent barriers related to the utilization of telehealth and are opportunities to further study how to reduce the digital divide and work toward health equity. We also found there were a large number of patients who self-identified their race as “Other” or “Unknown.” Improving the accurate collection of demographic data remains an important foundation toward identifying and reducing disparities in health and health care.

15.
Anesthesia and Analgesia ; 134(4 SUPPL):12-14, 2022.
Article in English | EMBASE | ID: covidwho-1820600

ABSTRACT

Background/Introduction: Amidst the COVID-19 pandemic, the sudden demand for virtual medical visits drove the drastic expansion of telemedicine across all medical specialties. Current literature demonstrates limited knowledge on the impact of telehealth on appointment adherence particularly in preoperative anesthesia evaluations. We hypothesized that there would be increased completion of preoperative anesthesia appointments in patients who received telemedicine visits. Methods: We performed a retrospective cohort study of adult patients at UCLA who received preoperative anesthesia evaluations by telemedicine or in-person within the Department of Anesthesiology and Perioperative Medicine from January to September 2021 and assessed appointment adherence. The primary outcome was incidence of appointment completion. The secondary outcomes included appointment no show and cancellations. Patient demographic characteristics including sex, age, ASA physical status class, race, ethnicity, primary language, interpreter service requested, patient travel distance to clinic, and insurance payor were also evaluated. Demographic characteristics, notably race and ethnicity, are presented as captured in the electronic health record and we recognize its limitations and inaccuracies in illustrating how people identify. Patient reported reasons for cancellations were also reviewed and categorized into thematic groups by two physicians. Statistical comparison was performed using independent samples t test, Pearson's chi-square, and Fischer's exact test. Results: Of 1332 patients included in this study, 956 patients received telehealth visits while 376 patients received in-person preoperative anesthesia evaluations. Compared to the in-person group, the telemedicine group had more appointment completions (81.38% vs 76.60%, p = 0.0493). There were fewer cancellations (12.55% vs 19.41%, p = 0.0029) and no statistical difference in appointment no-shows (6.07% vs 3.99%, p = 0.1337) in the telemedicine group (Figure 1). Compared to the in-person group, patients who received telemedicine evaluations were younger (55.81 ± 18.38 vs 65.97 ± 15.19, p < 0.001), less likely American Indian and Alaska Native (0.31% vs 1.60%, p = 0.0102), more likely of Hispanic or Latino ethnicity (16.63% vs 12.23%, p = 0.0453), required less interpreter services (4.18% vs 9.31%, p = 0.0003), had more private insurance coverage (53.45% vs 37.50%, p < 0.0001) and less Medicare coverage (37.03% vs 50.53%, p < 0.0001). Main reasons for cancellation included patient request, surgery rescheduled/cancelled/already completed, and change in method of appointment. Conclusions: In 2021, preoperative anesthesia evaluation completion was greater in patients who received telemedicine appointments compared to those who received in-person evaluations at UCLA. We also demonstrate potential shortcomings of telemedicine in serving patients who are older, require interpreter services, or are non-privately insured. Knowledge of these factors can provide feedback to improve access and equity to telehealth for patients from all backgrounds, particularly during the COVID pandemic as virtual evaluations increase. (Table Presented).

16.
Anesthesia and Analgesia ; 134(4 SUPPL):25-26, 2022.
Article in English | EMBASE | ID: covidwho-1820598

ABSTRACT

Background High-risk surgeries account for 12% of the cases performed but represent 80% of the postoperative mortality [1]. The ASA (American Society of Anesthesiology) score, used since 1941, categorizes risk based on patient's comorbidities [2]. Such stratification is of utmost importance, enabling therapeutic decision making, distribution of resources, decision sharing with patients, and billing. By exploiting clinical databases, risk scores could become automatically extracted from medical records, personalized for different populations, and quickly provide insights on several outcomes. By clustering a population with unsupervised artificial intelligence (AI) algorithms, we can create subgroups without specifying how to subdivide them. By identifying discriminative features, the AI creates subgroups from which we extract the typical profile, or phenotype, before describing the associated outcomes [3]. This recent approach identified subgroups among covid-19 and septic patients [3, 4]. The objective of this project is to export this concept for the first time to a surgical population and, considering the democratization of “Enhanced Recovery after Surgery” protocol, to identify phenotypes and associated outcomes in a population undergoing colectomy [5]. Methods Using the patient data warehouse (PDW) from University of California in Los Angeles (UCLA), we retrospectively extracted all surgical cases containing “colectomy” in the procedure name, which occurred between 2013, inception of the database, and November 2021 [6]. Institutional Review Board of UCLA waived the need for patient's consent. We selected 56 relevant variables, including demographic data, comorbidities, and medication. Unsupervised K-means clustering was applied to the data, and the optimal number of phenotypes was determined based on discrimination of significant binary outcomes, including mortality, intensive care unit (ICU) length of stay (LOS) over 10 days, and hospital LOS over 20 days. Continuous data, including age and preoperative vitals were normalized with a min-max algorithm before clustering. A random forest plot algorithm was used to identify the 15 most relevant features linked to mortality and compare the clustering results in a restricted set. Results We identified three major phenotypes in the population (N=2273) based on the major characteristics described in Table 1, with an overall mortality of 0.08%. Despite being younger (average age: 52), phenotype 1 had the highest in-hospital mortality risk with 3.4% (15/437) and had longer ICU LOS (10.1% stayed > 10d), and hospital LOS (26.7% stayed >20d). This subgroup mostly contained patients undergoing urgent surgery (90%) with intestine obstruction (26%). While phenotypes 2 and 3 both were elective and included most cancer cases, mortality and LOS varied significantly between groups (mortality: 0.06% vs 2.1%;ICU>10d: 0.5% vs 7.2%;hospital LOS>20d: 2.4% vs 11.3% ). Phenotype 2 was generally younger (57 vs 62 years old) and presented less comorbidities (see Figure 1). Cases lengths were similar across all groups, and phenotype 3 received more intravenous fluids. In this cohort, phenotype 1 (19.5% of procedures) accounted for 83.3% of deaths, 74,5% of prolonged ICU LOS, and 68,4% of prolonged hospital LOS. Clustering on the restricted feature built after random forest plot algorithm provided similar results. Discussion and conclusion By identifying 3 phenotypes in the colectomy population, we could discriminate patients' outcome and trajectory of care. We confirmed that despite having few comorbidities, the highest risk of complication and prolonged ICU/hospital LOS correlates with urgent surgeries. In other words, urgency seems more correlated to adverse outcomes than comorbidities or ASA score. These results confirm the effectiveness of clustering the surgical population for risk stratification. While these analyses were limited by the low number of deaths, LOS insights were of great interest. Accumulating more data will be interesting to further phenotype patients undergo ng urgent colectomy, or to personalize risk stratification for other surgeries. (Table Presented).

17.
Anesthesia and Analgesia ; 134(4 SUPPL):59, 2022.
Article in English | EMBASE | ID: covidwho-1820565

ABSTRACT

Introduction: The COVID-19 pandemic has advanced market awareness of the benefits of remote-controlled ventilators to reduce the exposure of healthcare workers to patients with COVID-19, enable more rapid and frequent ventilator setting adjustment, and preserve limited personal protective equipment. The US FDA permitted manufacturers to add remote monitoring and control capabilities to ventilators and infusion pumps through immediate in effect guidance [1,2]. When integrated with tele-critical care systems, remote control of medical devices allows distant clinical experts to collaborate with local clinicians to “virtually” manage the therapy of patients at hotspots. Core remote control capabilities can also be used by software applications to implement medical device control algorithms for Software as a Medical Device (SaMD). The US Army /TATRC launched the National Tele-Critical Care Network (NETCCN) to rapidly develop and deploy a platform to support COVID-19 disaster response [3]. We are investigating technical solutions, communication protocols, and safety assurance measures for integrating remote control of medical devices to the NETCCN systems. Methods: We developed an architecture and a prototype system (Figure 1) to investigate safety, security, and interoperability requirements for integration of remote control of medical devices with tele-critical care systems. The prototype system is based on OpenICE [4], an open-source interoperability platform developed by our program to transmit data and control medical devices at the patient's bedside. Customized interfaces (hardware and software) translate device proprietary protocols to ISO/IEEE 11073-10101 terminology over DDS middleware. Remote control applications of devices connected to OpenICE are implemented as either stand-alone OpenICE apps, which can be deployed inside or immediately outside the patient's room, or as web-based apps, which can be launched from any location to communicate with the OpenICE system. We refer to the former as “nearpatient remote control”, which may be at the bedside or co-located outside the room, and the latter as “far remote” control where the operator does not have physical access to the patient or medical equipment. Our prototype system uses the RTI Web Integration Service [5] to enable web-based control applications to communicate with the connected devices. Results: The generic architecture in Figure 1 is device agnostic: it can be used with critical care ventilators, IV infusion pumps, and other devices, provided that the device interfaces support remote control. As a proof of concept, we applied this architecture to a Q Core Sapphire IV infusion pump using a non-clinical control interface, and confirmed that the infusion rate could be adjusted by both near-patient and far remote (web) control applications with generally acceptable delays (3∼8 seconds from remote control action until the pump executes the change). This prototype system allows the exploration and validation of risks associated with medical device remote control in the tele-critical care context. An example of a risk identified in our study relates contention between near and far “loci of control”. Unexpected device behavior can occur if there is no mechanism to 1) explicitly prioritize loci of control that may occur simultaneously (e.g., always prioritize local control over far control to enable the local provider to regain control or prevent remote control);and 2) clearly indicate where the locus of control resides. Other risks may arise due to issues related to cybersecurity, network QoS, permission for remote control, and usability (e.g., use errors associated with far remote control due to the lack of a real-time view of the patient). We are collaborating with the AAMI InterOperability Working Group (IOWG) to share the experience and lessons learned in this effort to develop a safety standard for medical device remote control, and with other performers in the NETCCN portfolio. (Figure Presented).

18.
Anesthesia and Analgesia ; 134(4 SUPPL):30, 2022.
Article in English | EMBASE | ID: covidwho-1820560

ABSTRACT

Introduction: Social determinants of health (SDOH) have a significant impact on access to health. Low socioeconomic status (SES) has been associated with delayed care and missed appointments. Telehealth services provides an opportunity to deliver health care by reducing physical barriers. During the COVID-19 pandemic, telehealth services were expanded by many health systems to continue providing socially distant care. While telehealth has the potential to bridge physical gaps in care, technology can be an additional barrier to accessing care and exacerbate existing health disparities. Understanding the impact of telehealth in the context of SDOH risk factors may be an important component toward studying and achieving health equity. Unfortunately, there is a limited amount of SES factors available to study in the electronic health record (EHR). The goal of our study was to use an innovative method to better understand the SES and location risk factors that are associated with the utilization of telehealth services in a pediatric pain clinic at an academic children's hospital. Methods: Following IRB approval, we conducted a retrospective study of all pediatric pain clinic patients seen by telehealth at a freestanding academic children's hospital from 4/2020 to 5/2021. Patient demographic details and telehealth utilization data were ed from the EHR and the enterprise data lake. Administrative outcomes of interest were telehealth appointment no-show or cancellations within 24 hours. Patient EHR addresses were geocoded and geospatial analytic techniques, including spatial linkage of EHR data with US Census-American Community Survey 2019 Data (5-Year) was conducted. Analysis was at the patient-level and neighborhood block-group level for SDOH measures. Specific neighborhood level measures used included the percent of households that have no computer. Analysis was conducted utilizing SAS, R, and ArcGIS Pro. Results: Our study included 550 pediatric pain patients, and all were successfully geocoded at the street level address. There were 309 patients (56.2%) who had their initial follow-up appointment using telehealth and 241 (43.8%) who were seen as a new patient visit. Most patients had government insurance (61.6%) as compared to commercial (38.4%). Overall, 14.9% of appointments were cancelled <24 hours or did not show up for their telehealth appointment. New appointments were more likely to be cancelled <24 hours or not show up (21.2%) as compared to follow-up appointments where 10% were cancelled/no show. A large percentage of patients self-reported their race as “Other” (51.8%) or were unknown (14.2%). Patient residential addresses came from a variety of locations in the state of California with a small number of patients from Nevada and Arizona. Patients who cancelled <24 hours or did not show up were more likely to come from neighborhoods (defined as Census Block Groups) of lower socioeconomic status. In addition, census block groups that had more “households with no computers” were more likely to cancel/no show for their telehealth appointment. Digital maps demonstrating geographic variation and disparities in access to telehealth utilization were created for exploration and descriptive purposes. Discussion: We successfully identified patient level and neighborhood level socioeconomic risk factors that are associated with cancelling (<24 hours) or not showing up for their telehealth appointment. Leveraging EHR data with geospatial analytics can augment our understanding of the SDOH that may impact the delivery of telehealth services in a pediatric population. Future steps include using these spatial risk factors to risk stratify and improve care delivery pathways to reduce disparities in telehealth utilization. (Figure Presented).

19.
Insights into Imaging ; 13(SUPPL 1):8, 2022.
Article in English | EMBASE | ID: covidwho-1817265

ABSTRACT

An artificial intelligence (AI) tool designed to detect COVID-19 on chest CT can be used as a screening tool with high sensitivity but with low specificity. Additional training with supplementary artifact datasets should further improve diagnostic accuracy. Purpose/objectives: To evaluate the performance of an AI tool, for Covid-19 detection and lung injury quantification, on chest CT during a real-time clinical workflow. Materials & methods: We retrospectively collected a consecutive dataset of 264 Chest CTs performed to screen for Covid-19 at hospital admission. All axial images were pseudo-anonymized and sent to the AI tool Quibim Precision platform (QUIBIM S.L) to be analyzed by the Imaging COVID-19 Analyzer. The AI tool provided a probability score for COVID-19 infection. RT-PCR was considered the gold standard for COVID-19 diagnosis. Results: When the COVID-19 probability score cut-off value is set at 0.41 there is a sensitivity of 90.48% (95%CI: 82.09% to 95.80%), specificity of 30.00% (95%CI: 23.42% to 37.26%), PPV of 13.65% (95%CI: 12.32% to 15.11%) and NPV of 96.26 (95%CI: 92.77% to 98.10%) and an AUC of 0.75. Regarding the probabilities we suggest the following ranges with 95% sensitivity to exclude the disease and 95% specificity to include the disease: < 0.38: almost certain negative;0.39 - 0.62: indeterminate;> 0.63: almost certain positive. We chose a relatively low cut-off value in order to have a high sensitivity so it could be used as a screening test. However, this reduced the specificity and diagnostic accuracy. When using the suggested probability ranges, a substantial number of cases (69%) were labeled as indeterminate. False positive cases were partly explained by mislabeling of breathing artifacts, hypoventilation in dependent lung areas or linear atelectasis as ground glass opacities. Also, some clear-cut diagnoses for the radiologists (e.g., heart failure, bacterial pneumonia, interstitial lung disease, .) were often given a high probability by the AI tool. Conclusion: The AI tool can be used as a screening tool with a sensitivity of 90% when the cut-off value is set relatively low. Due to low specificity the AI tool on its own cannot be used as a diagnostic test but has the potential to serve as an adjunct for COVID-19 detection. Training with supplementary artifact datasets should further improve the AI accuracy.

20.
Allergy, Asthma and Clinical Immunology ; 18(SUPPL 1), 2022.
Article in English | EMBASE | ID: covidwho-1817263

ABSTRACT

Background: With increasing uptake of COVID-19 vaccines and media focus on adverse reactions, questions and anxiety surrounding vaccinations intensified. The potential relationship between patient anxiety and adverse reactions risks vaccine hesitancy and the possibility of increased COVID-19 infections. The need for allergy consultation for adverse reactions to COVID-19 vaccines is essential in ensuring completion of vaccination protocols, especially in patients identified as having adverse reactions from first vaccinations. Methods: Two patients with reactions to their first dose of the Pfizer- BioNTech COVID-19 vaccine were assessed for potential allergy. Symptoms included throat tightness, dyspnea, tingling, and dizziness immediately after vaccination. One of the patients required treatment with epinephrine with subsequent need for emergency room visit. A two-step approach was taken to assess these patients for a potential allergic cause and exclude anxiety-induced reactions. Patients were blinded and initially skin tested to saline, observed for 15 minutes, and then assessed prior to skin testing to polyethylene glycol (PEG) as a suspected IgE mediated allergic trigger in the Pfizer-BioNTech vaccine. Results: Both patients tested negative to saline. However, both experienced similar or worse symptoms as their initial reaction to Pfizer-BioNTech vaccination with dyspnea, pruritus, coughing, chest tightness, and dizziness during their allergy assessment. Notably, urticaria was absent. One of the patients then went on to receive skin testing to PEG and tested negative. Both patients later received their second vaccination without issue. Conclusions: Two patients experienced “allergic-type” reactions after their first COVID-19 vaccine, not felt to be IgE mediated. Testing to saline elicited similar allergic-type symptoms, likely due to anxiety presenting as pseudo allergic reactions. Benefits of allergy consult and blinded testing to saline facilitated completion of vaccination.

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