bluuebunny/crossref_metadata_2025 huggingface dataset:
Introduction: Framing Exclusion from Social Relations
Authors: Burholt Vanessa , Aartsen Marja
Published: March 2021

In this part we focus on the domain of exclusion from social relations where social relations can be defined as comprising social resources, social connections and social networks. Other types of social engagement with formal civic, political and voluntary groups and organisations are not included in this part, but instead are incorporated in the domain of civic exclusion [see Part VI]. Theorising on exclusion from social relations is facilitated by the ROSEnet Cost Action, which brought together experts in the field and led to the publication of a critical review and development of a conceptual model of exclusion from social relations for older people (Burholt et al. 2019). The model captured the complexity of exclusion from social relations through a subjective interpretation of the literature and took into account the inter-relationships between systems in the critical human ecology framework (Fig. 6.1). The synthesis of the findings was endorsed by the working group on social relations comprising 45 members from 25 countries. The purpose of this introduction is to outline what exclusion from social relations involves, and to frame the three contributions within this part in the broader research debates and scholarship on this topic.
Conflicting Relations, Abuse and Discrimination Experienced by Older Adults
Authors: Waldegrave Charles , Aartsen Marja , Lowenstein Ariela , Seppänen Marjaana , Niemi Mia , Melchiorre Maria Gabriella , Lamura Giovanni
Published: March 2021

This chapter brings together three dimensions of negative social relations as they impinge on and are experienced by older people, which have not been addressed together in previous studies. Each dimension, conflictual relationships, abuse and discrimination, is characterised by demeaning social interactions that are important to address when considering social exclusion in ageing societies. Five national studies were carried out in Norway, Finland, Israel, Italy and New Zealand. The studies in each dimension confirmed many of the findings of earlier research that have identified the negative health and social relations associations with each dimension. The three dimensions that are usually studied within their own boundaries are brought together to demonstrate the similar way each reduces the quality of life and social inclusion of older people. They function as exclusionary mechanisms in comparable ways within the social relations domain and have an important place in a conceptual framework of old-age social exclusion. While previous research has focussed on each dimension separately, this lens on the similarities and interrelationships of the three dimensions has enabled a broader understanding of exclusionary mechanisms. It also enables more comprehensive and effective policy formation, than a focus on one dimension at a time.
Towards a Natural Social Contract
Authors: Huntjens Patrick
Published: March 2021

In this chapter I will explain why and how the sustainability transition is humankind’s search for a new social contract: a Natural Social Contract (conceptualization by author). I will start with a brief introduction on the origins of the social contract (Sect. 3.1), followed by a debate on the question whether there can be human progress without economic growth (Sect. 3.2) and a section on redesigning economics based on ecology, including circular and regenerative economies and cultures (Sect. 3.3). This chapter includes a debate on the role and scope of the free market (Sect. 3.4), as well as an examination of how the Anglo-Saxon and Rhineland models fare in this debate (Sect. 3.5). This chapter will also describe why we need a new social contract and what it should entail (Sect. 3.6). In doing so, I will embark on a quest for a Natural Social Contract (Sect. 3.7) and its theoretical foundations with multiple dimensions and crossovers (Sect. 3.8). This section concludes with an overview of fundamentals and design principles for a societal transformation towards a Natural Social Contract (see Table 3.4), which is a summary of Sect. 3.8 shaped as a course of action and is intended to help readers to grasp the core rationale of this book. For a better understanding of, and advancing the process towards, a Natural Social Contract this chapter presents a conceptual framework for Transformative Social-Ecological Innovation (Sect. 3.9), and how this will play out at various governance levels (Sect. 3.10).
Conceptual Background of Transformative Social-Ecological Innovation
Authors: Huntjens Patrick
Published: March 2021

In this chapter I survey key theories and concepts that provide substance to the workings of Transformative Social-Ecological Innovation (TSEI). A number of relevant theories and concept have already been mentioned in the previous chapters, such as Social Contract theory (Sect.3.1), and in Sects.3.8and3.9, including resilience theory and social-ecological systems (Sect.3.8), quintuple helix innovation model (Sect.3.9), as well as institutional change and the structure-agency debate (Sect.3.9), and several economic theories (Sects.3.2and3.3). In this chapter I will start with providing a conceptual discussion and definition on Transformative Social-Ecological Innovation (Sect. 4.1), and devote more attention to various theories and approaches that are relevant for TSEI, such as transition studies (Sect. 4.2), institutional design principles for governing the commons (Sect. 4.3), design principles from nature (Sect. 4.4), complex adaptive systems (Sect. 4.5), adaptive, reflexive, and deliberative approaches to governance, management, and planning (Sect. 4.6), social learning, policy learning, and transformational learning (Sect. 4.7), shared value, multiple value creation, and mutual gains approach (Sect. 4.8), effective cooperation (Sect. 4.9), transdisciplinary cooperation, living labs, and citizen science (Sect. 4.10), and the art of co-creation: approaches, principles and pitfalls (Sect. 4.11).
Governance of Urban Sustainability Transitions
Authors: Huntjens Patrick
Published: March 2021

My research group is involved in collaborations with the dynamic ‘Amsterdam Metropolitan Region (MRA)’ and ‘Rotterdam-The Hague Metropolitan Region (MRDH)’, with the objective to investigate the complex governance challenges and opportunities related to urban sustainability transitions, mainly through transdisciplinary collaboration. The resulting knowledge and skills are used to support and engage with Transformative Social-Ecological Innovation (TSEI) in-the-making, which in turn will generate new knowledge and skills (i.e. in iterative learning cycles). This chapter starts with a brief overview of urban sustainability challenges (Sect. 7.1). Research activities are centred around the transition to climate-resilient and healthy cities (Sect. 7.2), feeding and greening megacities (Sect. 7.3), as well as the transition from linear to circular and regenerative economies and cultures in (mega) cities (Sect. 7.4). In parallel, a new transdisciplinary Minor is developed, called ‘Collaboration for the City of the Future’ (Sect. 7.4).
Neurogenic substance P—influences on action potential production in afferent neurons of the kidney?
Authors: Rodionova Kristina , Hilgers Karl F. , Linz Peter , Schätzl Johannes , Raschke Giulia , Ott Christian , Schmieder Roland E. , Schiffer Mario , Amann Kerstin , Veelken Roland , Ditting Tilmann
Published: March 2021

We recently showed that a substance P (SP)–dependent sympatho-inhibitory mechanism via afferent renal nerves is impaired in mesangioproliferative nephritis. Therefore, we tested the hypothesis that SP released from renal afferents inhibits the action potential (AP) production in their dorsal root ganglion (DRG) neurons. Cultured DRG neurons (Th11-L2) were investigated in current clamp mode to assess AP generation during both TRPV1 stimulation by protons (pH 6) and current injections with and without exposure to SP (0.5 µmol) or CGRP (0.5 µmol). Neurons were classified as tonic (sustained AP generation) or phasic (≤ 4 APs) upon current injection; voltage clamp experiments were performed for the investigation of TRPV1-mediated inward currents due to proton stimulation. Superfusion of renal neurons with protons and SP increased the number of action potentials in tonic neurons (9.6 ± 5 APs/10 s vs. 16.9 ± 6.1 APs/10 s, P < 0.05, mean ± SD, n = 7), while current injections with SP decreased it (15.2 ± 6 APs/600 ms vs. 10.2 ± 8 APs/600 ms, P < 0.05, mean ± SD, n = 29). Addition of SP significantly reduced acid-induced TRPV1-mediated currents in renal tonic neurons (− 518 ± 743 pA due to pH 6 superfusion vs. − 82 ± 50 pA due to pH 6 with SP superfusion). In conclusion, SP increased action potential production via a TRPV1-dependent mechanism in acid-sensitive renal neurons. On the other hand, current injection in the presence of SP led to decreased action potential production. Thus, the peptide SP modulates signaling pathways in renal neurons in an unexpected manner leading to both stimulation and inhibition of renal neuronal activity in different (e.g., acidic) environmental contexts.
Multichannel environmental sound segmentation
Authors: Sudo Yui , Itoyama Katsutoshi , Nishida Kenji , Nakadai Kazuhiro
Published: March 2021

This paper proposes a multichannel environmental sound segmentation method. Environmental sound segmentation is an integrated method to achieve sound source localization, sound source separation and classification, simultaneously. When multiple microphones are available, spatial features can be used to improve the localization and separation accuracy of sounds from different directions; however, conventional methods have three drawbacks: (a) Sound source localization and sound source separation methods using spatial features and classification using spectral features trained in the same neural network, may overfit to the relationship between the direction of arrival and the class of a sound, thereby reducing their reliability to deal with novel events. (b) Although permutation invariant training used in autonomous speech recognition could be extended, it is impractical for environmental sounds that include an unlimited number of sound sources. (c) Various features, such as complex values of short time Fourier transform and interchannel phase differences have been used as spatial features, but no study has compared them. This paper proposes a multichannel environmental sound segmentation method comprising two discrete blocks, a sound source localization and separation block and a sound source separation and classification block. By separating the blocks, overfitting to the relationship between the direction of arrival and the class is avoided. Simulation experiments using created datasets including 75-class environmental sounds showed the root mean squared error of the proposed method was lower than that of conventional methods.
Comorbidity Between Depression and Anxiety in Adolescents: Bridge Symptoms and Relevance of Risk and Protective Factors
Authors: Konac Deniz , Young Katherine S. , Lau Jennifer , Barker Edward D.
Published: March 2021

Depression and anxiety are highly prevalent and comorbid in adolescents, and this co-occurrence leads to worse prognosis and additional difficulties. The relationship between depression and anxiety must be delineated to, in turn, reduce and prevent the comorbidity, however our knowledge is still limited. We used network analysis to investigate bridge symptoms; symptoms that connect individual depression and anxiety symptoms and thus can help explain the comorbidity. We also examined the role of relevant risk and protective factors in explaining these symptom-level associations between these disorders. We analyzed data from the Avon Longitudinal Study of Children and Parents (n = 3670). Depression and anxiety symptoms, peer victimization, bullying, peer relational problems, prosocial behavior, and parental monitoring were assessed at a single time point around age 13 years. Stressful life events (SLEs) were assessed at age 11 years. We identified the most prominent bridge symptoms among depression (“feeling unhappy”, “feeling lonely”) and anxiety symptoms (“worrying about past”, “worrying about future”). Peer relational difficulties and SLEs were strongly associated with several depression and anxiety symptoms, such that these two risk factors created a link between individual depression and anxiety symptoms. Prosocial behavior had several negative associations with symptoms of both disorders, suggesting it can be an important protective factor.
Models of overpressure build-up in shallow sediments by glacial deposition and glacial loading with respect to chimney formation
Authors: Wangen Magnus
Published: March 2021

Chimneys and pipe structures have been observed in the caprock above the Utsira Aquifer in the North Sea. The caprock is of Pleistocene age and the chimneys appear to have been formed by natural hydraulic fracturing towards the end of the last glaciation. We study six different models for the pressure build-up in the Utsira Aquifer with respect to chimney formation. The first two models produce overpressure by a rapid deposition of glacial sediments. Using these two models, we show that the caprock permeability must be as low as 100 nD for sufficiently strong overpressure to develop. This value seems to be one order of magnitude lower than the measured permeabilities of the caprock. The four remaining models produce overpressure by a glacial loading of the caprock and the aquifer. This study shows that a 1-D model of a caprock with soil properties cannot produce conditions for chimney formation unless the least horizontal compressive stress is much less than the overburden. Furthermore, a 1-D poroelastic model of glacial loading of an aquifer and a caprock cannot produce conditions for chimney formation based on available geomechanical data. However, we demonstrate that a 2-D poroelastic model can produce conditions for chimney formation with glacial loads that partially cover the surface.
A Comparison of Genetic Representations and Initialisation Methods for the Multi-objective Shortest Path Problem on Multigraphs
Authors: Beke Lilla , Weiszer Michal , Chen Jun
Published: March 2021

This paper compares different solution approaches for the multi-objective shortest path problem (MSPP) on multigraphs. Multigraphs as a modelling tool are able to capture different available trade-offs between objectives for a given section of a route. For this reason, they are increasingly popular in modelling transportation problems with multiple conflicting objectives (e.g., travel time and fuel consumption), such as time-dependent vehicle routing, multi-modal transportation planning, energy-efficient driving, and airport operations. The multigraph MSPP is more complex than the NP-hard simple graph MSPP. Therefore, approximate solution methods are often needed to find a good approximation of the true Pareto front in a given time budget. Evolutionary algorithms have been successfully applied for the simple graph MSPP. However, there has been limited investigation of their applications to the multigraph MSPP. Here, we extend the most popular genetic representations to the multigraph case and compare the achieved solution qualities. Two heuristic initialisation methods are also considered to improve the convergence properties of the algorithms. The comparison is based on a diverse set of problem instances, including both bi-objective and triple objective problems. We found that the metaheuristic approach with heuristic initialisation provides good solutions in shorter running times compared to an exact algorithm. The representations were all found to be competitive. The results are encouraging for future application to the time-constrained multigraph MSPP.
Development and validation of an Arabic pediatric sensorimotor development test
Authors: Alabdulkarim Lamya
Published: March 2021

Aim:

The main concern of Arab rehabilitation therapists is the paucity of a valid clinical assessment tool that fits the demographic and cultural specificities of the pediatric population. This study aimed to describe and validate a localized evidence-based instrument for assessing sensorimotor development in Saudi Arabian children.

Methods:

The Arabic Pediatric Sensorimotor Development Test (A-P-SMDT) designed for Saudi Arabian preschoolers was used for 110 children (3–6 years) in this prospective cross-sectional study. The instrument has two constructs: sensorimotor integration and visual perception and visuomotor integration, with 10 themes and 52 items. Face, content and construct validity and internal consistency were calculated. Cronbach's α was used to test internal consistency. A Kaiser–Meyer–Olkin test and Bartlett's test of sphericity were used to test sampling adequacy.

Results:

Five clinicians and 25 senior clinicians reported good face validity. The content validity index was 3.45, indicating the degree to which the content of the test matches a content domain. The Cronbach's α coefficient was 0.95, indicating excellent internal consistency. The Kaiser–Meyer–Olkin measure for sampling adequacy was 0.80. Bartlett's test of sphericity was significant (chi-square = 3400.43, df = 122, p = .00), indicating that the 10 test domains had a good level of correlation.

Conclusion:

The preliminary results on the Arabic Pediatric Sensorimotor Development Test showed acceptable reliability and validity, which could be useful for identifying children at risk of sensorimotor disorders and delays in a mainstream non-clinical population.
Global prevalence and predictors of postoperative delirium among non-cardiac surgical patients: A systematic review and meta-analysis
Authors: Abate Semagn Mekonnen , Checkole Yigrem Ali , Mantedafro Bahiru , Basu Bivash , Aynalem Alem Eskeziya
Published: March 2021

ABSTRACT

Background:

Postoperative delirium is a recent health problem among the elderly which is associated with delayed functional recovery, longer hospital stays, increased morbidity and mortality, and incurs a significant financial cost. Body of evidence is lacking on the global prevalence of postoperative delirium and its determinants. Therefore, this study aimed to provide evidence on the prevalence of postoperative delirium.

Methods:

A comprehensive search was conducted in PubMed/Medline; Science direct and LILACS from December 2010 to August 2020 without language restriction. The Heterogeneity among the included studies was checked with forest plot, χ2 test, I2 test, and the p-values. All observational studies reporting the prevalence of postoperative delirium were included.

Results:

A total of 930 articles were identified from different databases and 70 articles were selected for evaluation after the successive screening. Forty-three articles with 13,179 participants were included. The Meta-Analysis revealed that the global prevalence of postoperative delirium was 20% (95% confidence interval (CI):17 to 24). The systematic review showed that postoperative delirium was approximately 3 times more likely in patients undergoing surgery under general anesthesia, OR = 2.68 (95% confidence interval (CI): 1.10 to 6.54).

Conclusion:

The Meta-Analysis revealed that postoperative delirium among surgical patients is strongly associated with different modifiable risk factors. Therefore, the perioperative mitigating strategic protocol should be employed to prevent postoperative delirium and its undesirable outcomes.

Registration:

This systematic review and meta-analysis was registered research registry with the registration number (UIN: reviewregistry979).

Highlights
36344 Effect of CHRNA5 genetic variation and smoking on alcohol related phenotypes in healthy adult drinkers
Authors: Venkatesh Shyamala K. , Stangl Bethany L. , Quijano Cardé Natalia A. , De Biasi Mariella , Ramchandani Vijay A.
Published: March 2021

ABSTRACT IMPACT: Understanding the influence of genetic variation and smoking on alcohol consumption helps in improving the treatment strategies for alcohol addiction OBJECTIVES/GOALS: Variation in the nicotinic receptor gene CHRNA5 (rs16969968) is associated with nicotine use and dependence, however its role in alcohol consumption is unclear. This study examined the effects of rs16969968 and smoking on alcohol related phenotypes in people without alcohol use disorder (AUD). METHODS/STUDY POPULATION: The study included 1,037 healthy adult drinkers without AUD (201 smokers, 836 non-smokers). A subset (n=161) participated in an Intravenous Alcohol Self-Administration (IV-ASA) laboratory session. Alcohol-related measures included Timeline Followback (TLFB), which measures drinking quantity and frequency in the past 90 days, and the Alcohol Use Disorders Identification Test (AUDIT), which measures alcohol use and consequences. IV-ASA measures included average and peak breath alcohol concentration (BrAC). The effect of rs16969968 was tested using a dominant model based on the presence of the A allele, and the influence of the rs16969968 polymorphism and smoking on alcohol phenotypes was assessed using t-tests and two-way ANOVA. RESULTS/ANTICIPATED RESULTS: There was a main effect of rs16969968 genotype with A-allele carriers (AA/AG) showing higher AUDIT-Dependence scores compared to the GG group. A main effect of smoking was observed on all the TLFB and AUDIT measures, with smokers showing greater alcohol consumption and problems compared to non-smokers. In the rs16969968 AA/AG group, smokers reported significantly more drinking days (p<0.0001), and greater number of drinks (p<0.0001), as well as higher AUDIT scores than non-smokers. IV-ASA measures did not show any difference between genotype groups or between smokers and non-smokers. DISCUSSION/SIGNIFICANCE OF FINDINGS: This study identifies both independent and interactive effects of CHRNA5 gene variation and smoking on alcohol drinking measures and provides strong evidence for the effect of smoking on alcohol drinking and its consequences.
63438 Differential chromatin accessibility at dorsal root ganglia enhancers is associated with nerve injury
Authors: Stephens Kimberly E. , Zhou Weiqiang , Ji Zhicheng , Ji Hongkai , Guan Yun , Taverna Sean D.
Published: March 2021

ABSTRACT IMPACT: Our improved understanding of the changes in chromatin accessibility that occur in persistent pain states may identify regulatory genomic elements that play essential roles in modulating gene expression in the DRG. OBJECTIVES/GOALS: Efforts to understand genetic variability involved in an individual’s susceptibility to persistent pain support a role for upstream regulation by epigenetic mechanisms. Our objective was to examine the transcriptomic and epigenetic basis of persistent pain following nerve injury. METHODS/STUDY POPULATION: We used a multiomic approach to identify novel molecular pathways associated with nerve injury-induced pain hypersensitivity. Adult Sprague Dawley rats were randomized to Chronic Constriction Injury (CCI) to the sciatic nerve or no treatment (naive). The ipsilateral L4-L6 dorsal root ganglia (DRG)s were removed on Day 14 and used for ChIP-seq for H3K4me1, ATAC-seq, and RNA-seq. We assessed for differential chromatin accessibility, transcription factor motifs, and enrichment for biological processes in chromatin accessible regions associated with cis-regulatory regions identified by ATAC-seq and H3K4me1 enrichment. Luciferase assays determined the functional significance of these sequences. RESULTS/ANTICIPATED RESULTS: We identified 58,446 genomic regions where H3K4me1 enrichment overlapped with chromatin accessibility. Differential analysis identified 2145 of these 58,446 regions that had changes in accessibility after CCI. The majority of these regions were located in introns or intergenic regions. Functional annotation of the differentially accessible regions identified disparate molecular functions enriched following nerve injury which suggests that altered chromatin structure plays a role in the development of mechanical hypersensitivity. Motif analysis identified specific transcription factor families whose binding sequences were enriched in regions of increased or decreased accessibility. Luciferase assays showed significant enhancement or repression of gene transcription. DISCUSSION/SIGNIFICANCE OF FINDINGS: Our data provides a comprehensive map of chromatin accessibility changes in the DRG after CCI and emphasizes the importance of chromatin structure in the development and maintenance of chronic pain.
77232 The role of the bromodomain and extra-terminal motif (BET) family of proteins in head and neck cancer tumorigenic phenotype
Authors: Sample Reilly A. , Paolini Rachel
Published: March 2021

ABSTRACT IMPACT: Understanding the biology underpinning head and neck cancer invasion and metastasis could lead to novel targeted therapies that are both effective and tolerable for patients with this debilitating disease. OBJECTIVES/GOALS: The bromodomain and extra-terminal (BET) family of epigenetic regulators has been implicated in the tumorigenesis of various cancers. In head and neck squamous cell carcinoma (HNSCC), the majority of morbidity is due to invasion and metastasis, so there is special interest in understanding the development of these phenotypes in HNSCC cells. METHODS/STUDY POPULATION: Stable SCC9 knockdown cell lines were generated by infecting cells with a lentivirus encoding Cas9-KRAB and a lentivirus encoding gRNA targeting each of the candidate BET proteins: BRD2, BRD3, BRD4, and BRDT. Knockdown was confirmed by qRT-PCR. Next, standard assays for proliferation (CellTiter-glo), invasion (Matrigel), and migration (scratch-wound healing assay) were performed for all candidate knockdowns and compared to a non-target control. RESULTS/ANTICIPATED RESULTS: Proliferation assay results revealed that BRD4 knockdown had a significant negative effect on the proliferative capacity of SCC9 cells in vitro. Similarly, BRD4 knockdown SCC9 cell lines were less invasive and less migratory. Interestingly, knockdown of BRD2, BRD3, and BRDT had no effect on proliferation, invasiveness, or migration. DISCUSSION/SIGNIFICANCE OF FINDINGS: We have identified BRD4 as a key driver of the HNSCC tumorigenic phenotype. In the future, we plan to investigate the role of JQ1, a pan-BET inhibitor, on HNSCC cell phenotypes. Additionally, we will identify the downstream targets of BRD4, which may serve as potential therapeutic targets for both HNSCC as well as other cancers more broadly.
25380 Cholecystokinin-B Receptor -Mediates Growth of Hepatocellular Carcinoma
Authors: Gay Martha Dee , Safronenka Anita , Cao Hong , Tucker Robin , Shivapurkar Narayan , Smith Jill P.
Published: March 2021

ABSTRACT IMPACT: Cholecystokinin-B Receptor -Mediates Growth of Hepatocellular Carcinoma with the use proglumide. Proglumide is a non-selective antagonistic drug therefore, strategies that block signaling at the CCK-BR may provide to be a novel therapeutic option for Hepatocellular Carcinoma treatment OBJECTIVES/GOALS: Cholecystokinin (CCK)and gastrin mediate the growth of Hepatocellular Carcinoma (HCC) through CCK-R and interruption of this signaling pathway could decrease HCC. CCK-Receptors are overexpressed in HCC and proliferation may be mediated through CCK-B. Blockade of the CCK-BR with proglumide decreased both growth in vitro and tumor growth in vivo. METHODS/STUDY POPULATION: RNA was extracted from murine Hepa1-6, RIL-175 and human HepG2 cells and was evaluated by qRT-PCR for expression of CCK-AR, CCK-BR and gastrin. CCK-R protein expression was analyzed by flow cytometry. HCC cells were treated in vitro with CCK peptide, the CCK-AR antagonist or the CCK-BR antagonist. Proliferation of selective CCK-R KO cells was compared to that of wild-type cells. To determine the effect of a CCK-R antagonist on tumor growth in vivo two cohorts of mice bearing subcutaneous Hepa1-6 or RIL-175 HCC tumors were treated with an oral bioavailable CCK-R antagonist proglumide or untreated water for 3-4 weeks. The mice bearing Hepa1-6 tumors were placed on a high-fat diet to raise blood CCK levels. Mice bearing RIL-175 tumors were fed standard chow to determine if proglumide could block autocrine growth by gastrin. RESULTS/ANTICIPATED RESULTS: The mRNA expression of CCK-AR, CCK-BR and gastrin were increased 80-90-fold in all HCC cell lines compared to that of normal liver. CCK-BRs were detected on >85% of the cells by flow cytometry. CCK peptide (1nM) stimulated HCC growth in vitro in both wild-type cells and in CCK-AR KO cells but not in CCK-BR KO cells. CCK-BR antagonist blocked CCK-stimulated growth in vitro but the CCK-AR antagonist did not, suggesting that the CCK-BR was responsible for mediating proliferation. In vivo tumor growth was significantly reduced with proglumide treatment by 70% (p<0.05) in Hepa1-6 and by 73% (p<0.001) in RIL-75 tumors, respectively. DISCUSSION/SIGNIFICANCE OF FINDINGS: CCK-Rs are overexpressed in HCC and proliferation appears to be mediated through the CCK-BR. Downregulation with CRISPR Cas9 or blockade of the CCK-BR with an antagonist decreases growth in vitro and proglumide therapy decreases tumor growth in vivo. Strategies that block signaling at the CCK-BR maybe a novel therapeutic option for HCC treatment.
55270 The Histone Methyltransferase SETDB2 Regulates Inflammation in Normal and Diabetic Wound Repair
Authors: denDekker Aaron , Davis Frank , Kimball Andrew , Schaller Matthew , Joshi Amrita , Allen Ronald , Gallagher Katherine
Published: March 2021

ABSTRACT IMPACT: Our data reveal a histone modifying enzyme involved in regulating inflammation that may be a novel target for treating non-healing diabetic wounds. OBJECTIVES/GOALS: We investigate molecular mechanisms that regulate the inflammatory phenotype of macrophages in normal and diabetic wound healing. Our goal is to identify novel pathways that may be used to better treat diabetic patients with non-healing wounds. METHODS/STUDY POPULATION: We utilize normal and transgenic murine models on standard chow or high-diet to identify chromatin modifying enzymes involved in regulating macrophage function during wound healing. We validate our murine studies with human blood monocytes or wound macrophages from diabetic patients undergoing limb amputation surgery. RESULTS/ANTICIPATED RESULTS: We have identified the histone methyltransferase SETDB2 as a regulator inflammation in normal and diabetic wound macrophages. We found that SETDB2 was dependent on IFNβ singaling and that both IFNβ and Setdb2 expression were impaired in diabetic wound macrophages. Further, we show that SETDB2 regulates inflammatory response and immune cell trafficking pathways. We also show that SETDB2 genomic localization is dependent on *NFÎºÎ’ deposition of the promoter. DISCUSSION/SIGNIFICANCE OF FINDINGS: Our results indicate that SETDB2 is a regulator of macrophage plasticity and that SETDB2 expression is impaired in diabetic wound macrophages leading to hyper-inflammatory response and delayed wound healing. These data provide a novel potential therapeutic pathway for treating non-healing diabetic wounds.
68477 Pancreatic cancer cell extracellular vesicles drive the unfolded protein response in recipient normal pancreatic cells.
Authors: Hinzman Charles , Bansal Shivani , Li Yaoxiang , Trevino Jose , Banerjee Partha , Cheema Amrita
Published: March 2021

ABSTRACT IMPACT: This study advances our understanding of potentially key drivers in the early formation of pancreatic cancer, a disease with few treatment options and poor patient outcomes. OBJECTIVES/GOALS: Patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) have a 5-year survival rate of ˜9%. A key driver of poor patient outcomes is late-stage diagnosis. A better understanding of PDAC onset is needed. This study was developed to understand how extracellular vesicles may be involved in the early formation of PDAC. METHODS/STUDY POPULATION: Extracellular vesicles (EVs) were isolated from several human PDAC and normal pancreatic cell lines, using ultracentrifugation with filtration or size exclusion chromatography. We next treated normal pancreatic cell lines with cancer cell EVs (cEVs). Next generation sequencing was used to measure global gene expression changes after treatment. Validations were performed using qPCR and luciferase activity assays. Multi-omics characterization of EVs was accomplished using mass spectrometry based proteomics, metabolomics and lipidomics analysis. RESULTS/ANTICIPATED RESULTS: We found that normal cells upregulated a variety of stress response pathways in response to cEVs. Lipid synthesis was also severely downregulated in these cells. We further validated activation of the unfolded protein response (UPR) in normal cells treated with cEVs. Multi-omics characterization of cEVs identified several enriched proteins, lipids and metabolites which may play a role in the activation of the UPR. DISCUSSION/SIGNIFICANCE OF FINDINGS: Our results indicate that cEVs induce stress, and in particular the UPR, in normal pancreatic cells. Long-term UPR can impact a variety of cancer hallmarks. The UPR can mediate progression of pancreatic intraepithelial neoplasia (PanIN) to PDAC. Our results highlight a potential role for cEVs to alter the function of normal cells, aiding disease onset.
70759 Jaw-specific control of Msx1-dependent odontogenesis by Dkk2 and Sostdc1
Authors: Kwon Hyuk-Jae Edward
Published: March 2021

ABSTRACT IMPACT: Our proposed jaw-specific control mechanism of tooth development is expected to address the site-specific prevalence of tooth agenesis in humans. OBJECTIVES/GOALS: To determine the molecular mechanisms that control jaw-specific tooth development. To identify the molecular basis of the site-specific prevalence of humans tooth agenesis cases. METHODS/STUDY POPULATION: We used three different genetically engineered mouse lines: Msx1 ^’/ ^’, Dkk2 ^’/ ^’, and Sostdc1 ^’/ ^’ mice. We used developmental mouse genetics approaches, basically generating different combinations of compound mutant mice. We examined their tooth development by using gross, histology, and mRNA expression analyses. RESULTS/ANTICIPATED RESULTS: We identified that Sostdc1, a secreted Wnt inhibitor, also plays an important role in regulating the Msx1-dependent odontogenic pathway. Sostdc1 mRNA showed similar expression patterns in the developing tooth germs between control and Msx1-null molar buds. Remarkably, by deleting the Sostdc1 gene, as well as the Dkk2 gene, in the Msx1-null background mouse, molar tooth development was rescued in the maxillary jaw, but not in the mandibular jaw. Furthermore, tooth developmental rescue could be achieved in both the maxillary and mandibular molars by combinedly deleting Dkk2 and Sostdc1 in Msx1-null mice. DISCUSSION/SIGNIFICANCE OF FINDINGS: Our study demonstrates that secreted Wnt inhibitors Dkk2 and Sostdc1 synergistically regulate the Msx1-dependent odontogenic pathway and further control early tooth morphogenesis. These mouse model will be used to further address the site-specific prevalence of tooth agenesis in humans.
92418 Molecular imaging of the tumor microenvironment to predict response to combination treatment with immunotherapy in triple negative breast cancer
Authors: Napier Tiara S. , Hunter Chanelle L. , Song Patrick N. , Larimer Benjamin M. , Sorace Anna G.
Published: March 2021

ABSTRACT IMPACT: Insights from this project will provide clinical guidance in treatment of immunotherapy in triple negative breast cancer and identify early imaging biomarkers of treatment response. OBJECTIVES/GOALS: Significant research that addresses monitoring and predicting patient response of triple negative breast cancer (TNBC) to immunotherapy is needed. Using positron emission tomography (PET) imaging to probe the tumor microenvironment (hypoxia, T-cell activation), we aim to predict early response to immunotherapy for in mouse models of TNBC tumors. METHODS/STUDY POPULATION: Female Balb/c mice with 4T1-luciferase mammary carcinoma cell tumors were administered paclitaxel (PTX; 10 mg/kg), anti-PD1 (200 µg), both, or vehicle (saline) intraperitoneally. Treatment was given on days 0, 2, and 5 for cohort 1 (n=16) who underwent granzyme B specific (GZP) PET imaging (T-cell activation) and days 0, 2, 5, and 8 for cohort 2 (n=12) who underwent [18F]-fluoromisonidazole (FMISO)-PET imaging (hypoxia). Bioluminescence (BLI) imaging and caliper measurements were performed to track tumor size changes at multiple timepoints and tumors were collected for histological validation on day 20. Mean standard uptake value (SUVmean) was calculated as percent of day 0, and statistical analyses were performed with unpaired t-tests and Wilcoxon-rank sum tests. RESULTS/ANTICIPATED RESULTS: Non-responders to treatment had a significantly higher tumor volume compared to responders starting on day 6 (p<0.05). Although no significant differences in BLI between control and single-agent therapies were found, BLI data revealed that treatment with combination PTX and anti-PD1 significantly decreased viability signal between days 3 and 6 (p=0.04). SUVmean from GZP-PET was over 250% higher in responders compared to non-responders by day 6 (p=0.03). SUVmean from FMISO-PET was 80% less in responders compared to nonresponders, indicating less tumor hypoxia (p=0.04). DISCUSSION/SIGNIFICANCE OF FINDINGS: Non-invasive PET imaging of the tumor microenvironment can provide data on T cell activation and hypoxic response predicting response to combination immunotherapy and chemotherapy. Utilizing advanced imaging to understand biologically distinct features of the TNBC tumor microenvironment can aid in personalizing anti-cancer therapies.
83649 Modeling COVID-19 infection dynamics and program interventions for K-12 school re-opening
Authors: Morrison Douglas E. , Nianogo Roch , Manuel Vladimir G. , Arah Onyebuchi A. , Anderson Nathaniel , Kuo Tony , Inkelas Moira
Published: March 2021

ABSTRACT IMPACT: This study provides public health and K-12 school districts with a pragmatic, flexible, adaptable model showing COVID-19 transmission dynamics, using local data and program elements that are modifiable and with an online model for easy use, to enable safe and equitable re-opening and maintenance of in-person learning. OBJECTIVES/GOALS: School closures resulting from the COVID-19 pandemic disrupt student education and health and exacerbate inequities. Public health agencies and school districts currently lack pragmatic models to assess the effects of potential strategies for resuming and maintaining in-person learning on outcomes such as transmission and attendance. METHODS/STUDY POPULATION: This study explored how various combinations of transmission-mitigating interventions affect health and learning outcomes in a range of underlying epidemiological conditions. The CTSA science team developed a conceptual framework and an agent-based simulation model with parameters including prevalence, transmission, testing, preventive and responsive actions, infection control, population behavior and awareness, and the potential impact of vaccine adoption and exemption policies. The team partnered with a large school district to ensure relevance of the program components to decision-making. RESULTS/ANTICIPATED RESULTS: The model shows that no single program element or condition ensures safety. Combining interventions can result in synergy in the mitigation efforts. Even without testing, an efficient health screening process with forthcoming risk reporting, combined with on-campus infection control, can reduce on-campus transmission. The resulting model is accessible online to enable exploration of likely scenarios. It is adaptable as COVID-19 science evolves, including for testing and vaccines. DISCUSSION/SIGNIFICANCE OF FINDINGS: This research provides public health agencies and school districts with a model that couples local conditions with programmatic elements to help inform the local COVID-19 response, recognizing that decisions about the school community are often complex politically, technically, and operationally when it comes to addressing a health crisis.
00001 Demographic disparities in proximity to stroke care in the United States
Authors: Yu Cathy Y. , Blaine Timothy , Panagos Peter , Kansagra Akash P.
Published: March 2021

ABSTRACT IMPACT: Given the association between lower time to treatment and better clinical outcomes in stroke patients, identifying factors correlated with reduced proximity and thus greater time to stroke care can aid efforts to reduce disparities in stroke outcomes. OBJECTIVES/GOALS: The objective of this study is to quantify the relationship between distance to the nearest certified stroke hospital and census-derived demographics of age, race/ethnicity, income, and insurance status. METHODS/STUDY POPULATION: This is a cross-sectional study. Population data for all census tracts in the contiguous United States were obtained from the US Census Bureau’s 2014-2018 American Community Survey. Stroke hospitals were identified from national or state level certification databases and were required to offer at least IV tPA. The main outcome is driving distance in kilometers from each census tract to the nearest certified stroke center, which was calculated using OSMnx, a Python package to retrieve, model and analyze real-world street networks. Quantile regression analysis was used to compare relationships between distances and tract-level demographics of age, race/ethnicity, income, and insurance status. RESULTS/ANTICIPATED RESULTS: 2,423 stroke centers and 71,929 census tracts containing 316,995,649 individuals were included. 49,918 (69%) tracts were urban. Demographic disparities in proximity to certified stroke care were greater in non-urban areas than in urban areas. Higher representation of individuals with age ≤65 years were associated with increased median distance to a certified stroke center in non-urban areas, but not urban areas. Median distance was greater with greater representation of American Indian or uninsured populations in urban and non-urban census tracts. Higher median income was associated with decreased median distance in non-urban census tracts and greater median distance in urban census tracts. DISCUSSION/SIGNIFICANCE OF FINDINGS: Reduced proximity to stroke care exists in areas with greater representation of elderly, American Indian, or uninsured persons; and low median income. These disparities are magnified in non-urban settings. Such knowledge can aid efforts to address and reduce disparities in stroke outcomes.
40339 Characterizing the impact of social and structural determinants of health on racial and ethnic disparities in COVID-19 outcomes using electronic health record (EHR) data
Authors: Heery Lauren , Erlandson Kristine , Suresh Krithika , Albright Karen , Schilling Lisa
Published: March 2021

ABSTRACT IMPACT: This study will help to characterize the root causes of racial and ethnic disparities in viral respiratory outbreaks and determine the extent to which this is unique to the COVID-19 pandemic, so that preventative interventions can be designed for future pandemics and epidemics. OBJECTIVES/GOALS: The causes of racial and ethnic disparities in COVID-19 clinical outcomes are multifactorial but include social inequity driven by structural racism. This study seeks to characterize the patterns of these disparities by linking patient-level EHR data with population-level sociodemographic measures. METHODS/STUDY POPULATION: This retrospective review of adult patients tested for SARS-CoV-2 in the UCHealth System will compare rates of COVID-19 infection, hospitalization, in-hospital mortality and 30-day mortality across racial and ethnic groups. Race and ethnicity are determined by patient self-report in the EHR. Univariable and multivariable regression analyses will be used to assess the association of these outcomes with sociodemographic factors. Potential confounders that will be adjusted for include Charlson Co-morbidity Index, disease severity and likelihood of readmission. Using chi-square tests, we will assess differences in the race/ethnicity distributions between this cohort and those from the 2009 H1N1 Pandemic and the 2018-19 influenza season. RESULTS/ANTICIPATED RESULTS: Of the first 459 patients hospitalized for COVID-19 in March and April 2020, race/ethnicity were: 194 Hispanic (42.3%), 104 non-Hispanic Black (22.6%), 83 non-Hispanic white (18.1%), 43 Asian (9.4%), and 35 other or unknown race (7.6%). There were significant differences in the race/ethnicity distribution compared to the cohort of patients hospitalized for viral respiratory infection during the 2018-19 influenza season (n=254, p <0.001): 58 Hispanic (22.8%), 52 non-Hispanic black (20.4%), 116 non-Hispanic white (45.7%), 15 Asian (6%), and 13 other or unknown race (5.1%). Our anticipated results include further adjusted analyses and comparisons to the 2009 pandemic. We will compare COVID-19 prevalence and outcomes by race/ethnicity with other viral infection outbreaks, adjusting for confounders. DISCUSSION/SIGNIFICANCE OF FINDINGS: Initial hospitalizations for COVID-19 at our institution are notable for a high proportion of Hispanic patients and smaller proportion of non-Hispanic whites, in contrast to the prior year. Our study will demonstrate the extent to which racial and ethnic disparities are typical in viral respiratory outbreaks, which can guide future interventions.
15017 Monoclonal antibody use in rheumatoid arthritis: an evaluation of medical expenditure
Authors: Kelly Robert A. , Ceacareanu Alice C. , Wintrob Zachary A.P.
Published: March 2021

ABSTRACT IMPACT: Younger patients receiving biologics for rheumatoid arthritis have higher medical expenditure. OBJECTIVES/GOALS: TNF inhibiting biologic disease modifying antirheumatic drugs are among the most highly regarded treatment options for rheumatoid arthritis (RA). We aimed at evaluating the medical and prescription costs associated with monoclonal antibody use vs. other RA treatment options in subjects diagnosed with RA. METHODS/STUDY POPULATION: Records from the Medical Panels Expenditure Survey (MEPS) database made available by the Agency for Healthcare Research and Quality were used to identify all RA subjects (n=_____). Demographics and MEPS-provided flags for RA were abstracted from the medical condition files for all the subjects surveyed (2008-2018). Prescribed biologics were identified based on generic and brand names following a manual review to detect any misspellings. Total medical expenses and prescription expenses were abstracted for all identified RA subjects. Subject were surveyed for two consecutive years, thus expenses were assessed for each of the two surveyed years. Costs were adjusted for inflation and expressed in 2018 dollars. The relationship between biologics use, cost and age or gender was evaluated by Fisher’s exact test. RESULTS/ANTICIPATED RESULTS: Most RA subjects did not use biologics. RA was more prevalent in women than in men with no significant correlation between sex and the use of biologics in year 1, year 2, or the combined years (p=.44, p=.63, and p=.65, respectively). Biologics users were found to be significantly younger (p<.001), with a mean of 52.8 years compared to 59 years in those who did not use biologics. The 95% confidence interval was 3.7 to 8.6 years younger than non-users. Total medical and prescription costs were higher for biologics users (p<.001) in all analyses. The mean prescription cost difference was $24,038 more per year for biologics users, and $26,296 more total medical expenses, CI $20,502-$27,230 and CI $21,947-$30,646, respectively. There was a trend for biologics users to have higher non-prescription medical expenses (p=.05). DISCUSSION/SIGNIFICANCE OF FINDINGS: Interestingly, biologics non-users had some extreme outliers with expenses far higher than any biologics users, possibly due to poorly controlled RA due to age and/or comorbidities. Yet, our most interesting findings are the higher use of biologics among younger RA subjects and the elevated costs of care being driven mainly by prescriptions cost.