Showing papers by "University of Colorado Denver published in 2022"

Engineering Knowledge Graph From Patent Database

Abstract: We propose a large, scalable engineering knowledge graph, comprising sets of (entity, relationship, entity) triples that are real-world engineering facts found in the patent database. We apply a set of rules based on the syntactic and lexical properties of claims in a patent document to extract facts. We aggregate these facts within each patent document and integrate the aggregated sets of facts across the patent database to obtain the engineering knowledge graph. Such a knowledge graph is expected to support inference, reasoning, and recalling in various engineering tasks. The knowledge graph has a greater size and coverage in comparison with the previously used knowledge graphs and semantic networks in the engineering literature.

Impact of Venetoclax and Azacitidine in Treatment-Naïve Patients with Acute Myeloid Leukemia and <i>IDH1/2</i> Mutations

Abstract: To evaluate efficacy and safety of venetoclax + azacitidine among treatment-naïve patients with IDH1/2-mutant (mut) acute myeloid leukemia (AML).Data were pooled from patients enrolled in a phase III study (NCT02993523) that compared patients treated with venetoclax + azacitidine or placebo + azacitidine and a prior phase Ib study (NCT02203773) where patients were treated with venetoclax + azacitidine. Enrolled patients were ineligible for intensive therapy due to age ≥75 years and/or comorbidities. Patients on venetoclax + azacitidine received venetoclax 400 mg orally (days 1-28) and azacitidine (75 mg/m2; days 1-7/28-day cycle).In the biomarker-evaluable population, IDH1/2mut was detected in 81 (26%) and 28 (22%) patients in the venetoclax + azacitidine and azacitidine groups. Composite complete remission [CRc, complete remission (CR)+CR with incomplete hematologic recovery (CRi)] rates (venetoclax + azacitidine/azacitidine) among patients with IDH1/2mut were 79%/11%, median duration of remission (mDoR) was 29.5/9.5 months, and median overall survival (mOS) was 24.5/6.2 months. CRc rates among patients with IDH1/2 wild-type (WT) were 63%/31%, mDoR 17.5/10.3 months, and mOS 12.3/10.1 months. In patients with IDH1mut, CRc rates (venetoclax + azacitidine/azacitidine) were 66.7%/9.1% and mOS 15.2/2.2 months. In patients with IDH2mut, CRc rates were 86.0%/11.1% and mOS not reached (NR)/13.0 months. Patients with IDH1/2 WT AML treated with venetoclax + azacitidine with poor-risk cytogenetics had inferior outcomes compared with patients with IDH1/2mut, who had superior outcomes regardless of cytogenetic risk (mOS, IDH1/2mut: intermediate-risk, 24.5 months; poor-risk, NR; IDH1/2 WT: intermediate, 19.2 and poor, 7.4 months). There were no unexpected toxicities in the venetoclax + azacitidine group.Patients with IDH1/2mut who received venetoclax + azacitidine had high response rates, durable remissions, and significant OS; cytogenetic risk did not mitigate the favorable outcomes seen from this regimen for IDH1/2mut. See related commentary by Perl and Vyas, p. 2719.

Galectin-3 as a potential prognostic biomarker of severe COVID-19 in SARS-CoV-2 infected patients

Abstract: Severe COVID-19 is associated with a systemic hyperinflammatory response leading to acute respiratory distress syndrome (ARDS), multi-organ failure, and death. Galectin-3 is a ß-galactoside binding lectin known to drive neutrophil infiltration and the release of pro-inflammatory cytokines contributing to airway inflammation. Thus, we aimed to investigate the potential of galectin-3 as a biomarker of severe COVID-19 outcomes. We prospectively included 156 patients with RT-PCR confirmed COVID-19. A severe outcome was defined as the requirement of invasive mechanical ventilation (IMV) and/or in-hospital death. A non-severe outcome was defined as discharge without IMV requirement. We used receiver operating characteristic (ROC) and multivariable logistic regression analysis to determine the prognostic ability of serum galectin-3 for a severe outcome. Galectin-3 levels discriminated well between severe and non-severe outcomes and correlated with markers of COVID-19 severity, (CRP, NLR, D-dimer, and neutrophil count). Using a forward-stepwise logistic regression analysis we identified galectin-3 [odds ratio (OR) 3.68 (95% CI 1.47-9.20), p < 0.01] to be an independent predictor of severe outcome. Furthermore, galectin-3 in combination with CRP, albumin and CT pulmonary affection > 50%, had significantly improved ability to predict severe outcomes [AUC 0.85 (95% CI 0.79-0.91, p < 0.0001)]. Based on the evidence presented here, we recommend clinicians measure galectin-3 levels upon admission to facilitate allocation of appropriate resources in a timely manner to COVID-19 patients at highest risk of severe outcome.

Data-Driven Design-by-Analogy: State of the Art and Future Directions

Abstract: Design-by-Analogy (DbA) is a design methodology wherein new solutions, opportunities or designs are generated in a target domain based on inspiration drawn from a source domain; it can benefit designers in mitigating design fixation and improving design ideation outcomes. Recently, the increasingly available design databases and rapidly advancing data science and artificial intelligence technologies have presented new opportunities for developing data-driven methods and tools for DbA support. In this study, we survey existing data-driven DbA studies and categorize individual studies according to the data, methods, and applications in four categories, namely, analogy encoding, retrieval, mapping, and evaluation. Based on both nuanced organic review and structured analysis, this paper elucidates the state of the art of data-driven DbA research to date and benchmarks it with the frontier of data science and AI research to identify promising research opportunities and directions for the field. Finally, we propose a future conceptual data-driven DbA system that integrates all propositions.

A Two-Tier Distributed Market Clearing Scheme for Peer-to-Peer Energy Sharing in Smart Grid

Abstract: This article presents a novel two-tier peer-to-peer (P2P) market paradigm for energy sharing between multiregional proactive prosumers (producer+consumer) in transactive energy systems. In the proposed approach, interactions between prosumers can be achieved in inter-area markets as well as intra-area markets. A dual decomposition based and a consensus-based distributed market-clearing approaches are designed for the proposed double-layered hierarchical intra- and inter-area markets. The proposed approach preserves prosumers’ privacy by sharing only partial information with the fellow prosumers while settling the trade. Compared to the conventional P2P approaches, the proposed two-tier market-clearing scheme allows more prosumer participation in energy trading and significantly enhances their economic benefits in certain situations. The effectiveness of the proposed approach is validated through software simulations.

Outcomes in Patients with Poor-Risk Cytogenetics with or without <i>TP53</i> Mutations Treated with Venetoclax and Azacitidine

Abstract: To evaluate efficacy and safety of venetoclax + azacitidine in treatment-naïve patients with acute myeloid leukemia harboring poor-risk cytogenetics and TP53mut or TP53wt.We analyzed data from a phase III study (NCT02993523) comparing venetoclax (400 mg orally days 1-28) + azacitidine (75 mg/m2 days 1-7) or placebo + azacitidine, and from a phase Ib study (NCT02203773) of venetoclax + azacitidine. Patients were ineligible for intensive therapy. TP53 status was analyzed centrally; cytogenetic studies were performed locally.Patients (n = 127) with poor-risk cytogenetics receiving venetoclax + azacitidine (TP53wt = 50; TP53mut = 54) were compared with patients with poor-risk cytogenetics (n = 56) receiving azacitidine alone (TP53wt = 22; TP53mut = 18).For poor-risk cytogenetics + TP53wt patients, venetoclax + azacitidine versus azacitidine alone resulted in composite remission rates (CRc) of 70% versus 23%, median duration of remission (DoR) of 18.4 versus 8.5 months, and median overall survival (OS) of 23.4 versus 11.3 months, respectively. Outcomes with venetoclax + azacitidine were comparable with similarly treated patients with intermediate-risk cytogenetics and TP53wt.For poor-risk cytogenetics + TP53mut patients, venetoclax + azacitidine versus azacitidine alone resulted in CRc of 41% versus 17%, median DoR of 6.5 versus 6.7 months, and median OS of 5.2 versus 4.9 months, respectively.For poor-risk cytogenetics + TP53mut patients, predominant grade ≥3 adverse events (AE) for venetoclax + azacitidine versus azacitidine were febrile neutropenia (55%/39%), thrombocytopenia (28%/28%), neutropenia (26%/17%), anemia (13%/6%), and pneumonia (28%/33%). AEs were comparable between TP53mut and TP53wt patients.In poor-risk cytogenetics + TP53mut patients, venetoclax + azacitidine improved remission rates but not DoR or OS compared with azacitidine alone. However, in poor-risk cytogenetics + TP53wt patients, venetoclax + azacitidine resulted in higher remission rates and longer DoR and OS than azacitidine alone, with outcomes comparable with similarly treated patients with intermediate-risk cytogenetics. Toxicities were similar in TP53mut and TP53wt patients. See related commentary by Green and Zeidner, p. 5235.

Mitochondria and Inflammatory Bowel Diseases: Toward a Stratified Therapeutic Intervention.

Abstract: Mitochondria serve numerous critical cellular functions, rapidly responding to extracellular stimuli and cellular demands while dynamically communicating with other organelles. Mitochondrial function in the gastrointestinal epithelium plays a critical role in maintaining intestinal health. Emerging studies implicate the involvement of mitochondrial dysfunction in inflammatory bowel disease (IBD). This review presents mitochondrial metabolism, function, and quality control that converge in intestinal epithelial stemness, differentiation programs, barrier integrity, and innate immunity to influence intestinal inflammation. Intestinal and disease characteristics that set the stage for mitochondrial dysfunction being a key factor in IBD, and in turn, pathogenic mitochondrial mechanisms influencing and potentiating the development of IBD, are discussed. These findings establish the basis for potential mitochondrial-targeted interventions for IBD therapy. Expected final online publication date for the Annual Review of Physiology, Volume 84 is February 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Limitations to Propagule Dispersal Will Constrain Postfire Recovery of Plants and Fungi in Western Coniferous Forests

Abstract: Abstract Many forest species are adapted to long-interval, high-severity fires, but the intervals between severe fires are decreasing with changes in climate, land use, and biological invasions. Although the effects of changing fire regimes on some important recovery processes have previously been considered, the consequences for the dispersal of propagules (plant seeds and fungal spores) in forest communities have not. We characterize three mechanisms by which changing fire regimes disrupt propagule dispersal in mesic temperate, boreal, and high-elevation forests: reduced abundance and altered spatial distributions of propagule source populations, less effective dispersal of propagules by wind, and altered behavior of animal dispersers and propagule predators. We consider how disruptions to propagule dispersal may interact with other factors that are also influenced by fire regime change, potentially increasing risk of forest conversion. Finally, we highlight urgent research topics regarding how dispersal limitation may shape twenty-first century forest recovery after stand-replacing fire.

Predicting drug polypharmacology from cell morphology readouts using variational autoencoder latent space arithmetic

Abstract: A variational autoencoder (VAE) is a machine learning algorithm, useful for generating a compressed and interpretable latent space. These representations have been generated from various biomedical data types and can be used to produce realistic-looking simulated data. However, standard vanilla VAEs suffer from entangled and uninformative latent spaces, which can be mitigated using other types of VAEs such as β-VAE and MMD-VAE. In this project, we evaluated the ability of VAEs to learn cell morphology characteristics derived from cell images. We trained and evaluated these three VAE variants-Vanilla VAE, β-VAE, and MMD-VAE-on cell morphology readouts and explored the generative capacity of each model to predict compound polypharmacology (the interactions of a drug with more than one target) using an approach called latent space arithmetic (LSA). To test the generalizability of the strategy, we also trained these VAEs using gene expression data of the same compound perturbations and found that gene expression provides complementary information. We found that the β-VAE and MMD-VAE disentangle morphology signals and reveal a more interpretable latent space. We reliably simulated morphology and gene expression readouts from certain compounds thereby predicting cell states perturbed with compounds of known polypharmacology. Inferring cell state for specific drug mechanisms could aid researchers in developing and identifying targeted therapeutics and categorizing off-target effects in the future.

Antenatal mesenchymal stromal cell extracellular vesicle treatment preserves lung development in a model of bronchopulmonary dysplasia due to chorioamnionitis

Abstract: Antenatal stressors such as chorioamnionitis (CA) increase the risk for bronchopulmonary dysplasia (BPD). Studies have shown that experimental BPD can be ameliorated by postnatal treatment with mesenchymal stromal cell-derived extracellular vesicles (MEx). However, the antenatal efficacy of MEx to prevent BPD is unknown. To determine whether antenatal MEx therapy attenuates intrauterine inflammation and preserves lung growth in a rat model of CA-induced BPD. At embryonic day ( E) 20, rat litters were treated with intra-amniotic injections of saline, endotoxin (ETX) to model chorioamnionitis, MEx, or ETX plus MEx followed by cesarean section delivery with placental harvest at E22. Placental and lung evaluations were conducted at day 0 and day 14, respectively. To assess the effects of ETX and MEx on lung growth in vitro, E15 lung explants were imaged for distal branching. Placental tissues from ETX-exposed pregnancies showed increased expression of inflammatory markers NLRP-3 and IL-1ß and altered spiral artery morphology. In addition, infant rats exposed to intrauterine ETX had reduced alveolarization and pulmonary vessel density (PVD), increased right ventricular hypertrophy (RVH), and decreased lung mechanics. Intrauterine MEx therapy of ETX-exposed pups reduced inflammatory cytokines, normalized spiral artery architecture, and preserved distal lung growth and mechanics. In vitro studies showed that MEx treatment enhanced distal lung branching and increased VEGF and SPC gene expression. Antenatal MEx treatment preserved distal lung growth and reduced intrauterine inflammation in a model of CA-induced BPD. We speculate that MEx may provide a novel therapeutic strategy to prevent BPD due to antenatal inflammation.

Examining linguistic shifts between preprints and publications

Abstract: Preprints allow researchers to make their findings available to the scientific community before they have undergone peer review. Studies on preprints within bioRxiv have been largely focused on article metadata and how often these preprints are downloaded, cited, published, and discussed online. A missing element that has yet to be examined is the language contained within the bioRxiv preprint repository. We sought to compare and contrast linguistic features within bioRxiv preprints to published biomedical text as a whole as this is an excellent opportunity to examine how peer review changes these documents. The most prevalent features that changed appear to be associated with typesetting and mentions of supporting information sections or additional files. In addition to text comparison, we created document embeddings derived from a preprint-trained word2vec model. We found that these embeddings are able to parse out different scientific approaches and concepts, link unannotated preprint-peer-reviewed article pairs, and identify journals that publish linguistically similar papers to a given preprint. We also used these embeddings to examine factors associated with the time elapsed between the posting of a first preprint and the appearance of a peer-reviewed publication. We found that preprints with more versions posted and more textual changes took longer to publish. Lastly, we constructed a web application (https://greenelab.github.io/preprint-similarity-search/) that allows users to identify which journals and articles that are most linguistically similar to a bioRxiv or medRxiv preprint as well as observe where the preprint would be positioned within a published article landscape.

The Everted Acetabular Labrum: Patho-anatomy, Magnetic Resonance Imaging and Arthroscopic Findings of a Native Variant

Abstract: The purpose of this study was to introduce a native labral variant, the everted acetabular labrum, and to describe the patho-anatomy, magnetic resonance imaging and magnetic resonance arthrogram (MRI/MRA) characteristics and the arthroscopic findings in this condition.All primary hip arthroscopy procedures performed by the senior author between June 2013 and January 2020 were reviewed retrospectively. An everted acetabular labrum was identified as a segment of labrum that lacked apposition to the femoral head with the hip off traction. All everted labra were treated with labral advancement and repair with or without augmentation or reconstruction. The labrum-to-femoral head distance was measured in 3T MRI/MRA at the 1-2 o'clock position. A random selection of 38 hips without an everted labrum served as controls to compare radiographic parameters.A total of 68 hips were identified as having an everted labrum during the study period (mean age, 29.1 years), and 55 hips had advanced imaging available for review. MRI/MRA scans revealed the everted labrum to have a triangular shape in 17 hips (31%) and a blunted/round shape in 38 hips (69%), which differed significantly from controls (triangular 25/38 [66%], blunted 13/38 [34%], P < 0.001). The average labrum-to-femoral head distance was 1.4 mm for everted labra versus 0.0 mm for controls (P < 0.0001) and the mean labral lengths and widths were significantly shorter than those of controls (both P < 0.01). Of the hips, 8 underwent labral reconstruction or augmentation, and 61 underwent labral advancement/repair.The everted acetabular labrum is a native variant that is identifiable during hip arthroscopy by assessing the labral seal off traction. Preoperative MRI/MRA findings can be highly predictive of an everted labrum. Surgical treatment includes labral advancement and repair or reconstruction to restore contact between the labrum and the femoral head.III, retrospective comparative study.

Esophageal remodeling in eosinophilic esophagitis: Relationships to luminal captured biomarkers of inflammation and periostin

Abstract: Esophageal remodeling is a factor in disease progression and symptom severity for patients with eosinophilic esophagitis (EoE). Remodeling can begin early in children, resulting in stricture and food impaction. Detection of esophageal remodeling often depends on endoscopy and is appreciated only in its later stages.We sought to determine whether luminal eosinophil-associated and remodeling proteins captured by the esophageal string test (EST) correlate with measures of esophageal remodeling and biomarkers of the epithelial-mesenchymal transition (EMT).Patients with EoE (7-18 years old) were enrolled from 2 pediatric hospitals. Participants performed the EST and underwent endoscopy. Histology, distensibility measured by endoluminal functional lumen imaging probe, and symptoms were assessed. Protein quantitation by ELISA was performed on mucosal biopsy and EST samples. Tissue sections were evaluated for EMT. Outcome measures were summarized, and Spearman ρ was used to assess bivariate correlations.Forty patients (68% male) were enrolled (mean age, 12.5 years). Twenty-four (60%) had active disease (≥15 eosinophils per high-power field). EST-captured eotaxin-3, major basic protein 1, EDN, eosinophil peroxidase, and Charcot-Leyden crystal protein/galectin-10 showed significant correlations with peak eosinophils per high-power field (ρ 0.53-0.68, P < .001). Luminal proteins positively correlated with endoscopic features and markers of EMT, and negatively with esophageal distensibility. Periostin was captured by the EST and correlated with eosinophil density, basal zone hyperplasia, endoscopic appearance, and markers of EMT.Luminal markers of esophageal remodeling in addition to biomarkers of eosinophilic inflammation correlate with epithelial and functional remodeling in EoE.

Unstable minimally displaced lateral compression type 1 (LC1) pelvic ring injuries have a similar hospital course as intertrochanteric femur fractures

Abstract: The purpose of this study was to evaluate how the hospital course of minimally displaced LC1 fractures, with and without occult instability, compares with that of intertrochanteric femur fractures.Retrospective comparative cohort analysis at an urban level one trauma center of 40 consecutive patients with an isolated LC1 pelvic ring injury and 40 age/sex matched patients with an isolated intertrochanteric femur fracture was performed. Medical records and radiographs were reviewed for patient and injury characteristics, including demographics, displacement, time to surgery, ambulation, physical therapy (PT) clearance, hospital length of stay (LOS), and inpatient morphine milligram equivalents (MME).The LC1 pelvic ring injury group included 26 (65%) patients with ≥ 10 mm of displacement on lateral stress radiographs. The unstable LC1 group, compared to the stable LC1 group, had a greater LOS (median difference (MD): 2 days, 95% confidence interval (CI): 1 to 4, p = 0.0004), longer time to ambulate 15 feet (MD: 1 day, CI: 1 to 2, p = 0.0002), longer time to clear PT (MD: 2 days, CI: 1 to 3, p = 0.0003), and more inpatient MMEs (MD: 386 MME, CI: 225.8 to 546.7, p = 0.0002). The unstable LC1 and intertrochanteric fracture groups had no detectable differences in LOS (p = 0.24), days to ambulate 15 feet (p = 0.46), days to clear PT (p = 0.95), and inpatient MMEs (p = 0.06).Patients with minimally displaced unstable LC1 injuries had worse hospital courses than stable LC1 injuries and similar hospital courses as intertrochanteric femur fractures. These findings emphasize the associated morbidity of unstable LC1 injuries.Level III, Retrospective cohort study.

Prehospital triage tools across the world: a scoping review of the published literature

Abstract: Accurate triage of the undifferentiated patient is a critical task in prehospital emergency care. However, there is a paucity of literature synthesizing currently available prehospital triage tools. This scoping review aims to identify published tools used for prehospital triage globally and describe their performance characteristics.A comprehensive search was performed of primary literature in English-language journals from 2009 to 2019. Papers included focused on emergency medical services (EMS) triage of single patients. Two blinded reviewers and a third adjudicator performed independent title and abstract screening and subsequent full-text reviews.Of 1521 unique articles, 55 (3.6%) were included in the final synthesis. The majority of prehospital triage tools focused on stroke (n = 19; 35%), trauma (19; 35%), and general undifferentiated patients (15; 27%). All studies were performed in high income countries, with the majority in North America (23, 42%) and Europe (22, 40%). 4 (7%) articles focused on the pediatric population. General triage tools aggregate prehospital vital signs, mental status assessments, history, exam, and anticipated resource need, to categorize patients by level of acuity. Studies assessed the tools' ability to accurately predict emergency department triage assignment, hospitalization and short-term mortality. Stroke triage tools promote rapid identification of patients with acute large vessel occlusion ischemic stroke to trigger timely transport to diagnostically- and therapeutically-capable hospitals. Studies evaluated tools' diagnostic performance, impact on tissue plasminogen activator administration rates, and correlation with in-hospital stroke scales. Trauma triage tools identify patients that require immediate transport to trauma centers with emergency surgery capability. Studies evaluated tools' prediction of trauma center need, under-triage and over-triage rates for major trauma, and survival to discharge.The published literature on prehospital triage tools predominantly derive from high-income health systems and mostly focus on adult stroke and trauma populations. Most studies sought to further simplify existing triage tools without sacrificing triage accuracy, or assessed the predictive capability of the triage tool. There was no clear 'gold-standard' singular prehospital triage tool for acute undifferentiated patients.Not applicable.

Systemic Chemotherapies Retain Antitumor Activity in Desmoid Tumors Independent of Specific Mutations in <i>CTNNB1</i> or <i>APC</i>: A Multi-institutional Retrospective Study

Abstract: Abstract Purpose: Determine whether specific CTNNB1 or APC mutations in patients with desmoid tumor were associated with differences in clinical responses to systemic treatments. Experimental Design: We established a multi-institutional dataset of previously treated patients with desmoid tumor across four U.S. sarcoma centers, including demographic and clinicopathologic characteristics, treatment regimens, and clinical and radiographic responses. CTNNB1 or APC mutation status was determined from prior pathology records, or archival tissue was requested and analyzed by Sanger sequencing and/or next-generation sequencing. Evaluable patients with mutation results were analyzed to determine clinical progression-free survival (cPFS), RECIST 1.1 PFS (rPFS), time to next treatment (TTNT), and overall survival (OS). Kaplan–Meier analysis and Cox proportional hazards regression were performed to identify differences in cPFS, rPFS, TTNT, and OS by mutation subtype, desmoid tumor location, and treatment regimen. Results: A total of 259 evaluable patients were analyzed for at least one of the survival outcomes, with 177 patients having mutation data. First- and second-line cPFS, rPFS, and TTNT were not significantly affected by mutation subtype; however, APC-mutant desmoid tumors demonstrated nonstatistically significant inferior outcomes. Extremity/trunk desmoid tumor location and treatment with doxorubicin-based, methotrexate/vinca alkaloids and sorafenib regimens were associated with better clinical outcomes compared with surgery or “other” therapies, including estrogen-receptor blockade and imatinib. OS was significantly worse with APC or CTNNB1 negative/other mutations. Conclusions: Mutation subtype did not affect responses to specific systemic therapies. APC mutations and nonextremity desmoid tumor locations remain prognostic for worse outcomes, and earlier initiation of systemic therapy for these higher-risk desmoid tumors should be prospectively evaluated. See related commentary by Greene and Van Tine, p. 3911