Systems Toxicology: Mining chemical-toxicity signaling paths to enable network medicine

Systems toxicology, a branch of toxicology that studies chemical effects on biological systems, presents exciting knowledge discovery challenges for the information researcher. The exponential increase in availability of genomic and proteomic data in this domain needs to be matched with increasingly sophisticated network analysis approaches. Improved ability to mine complex gene and protein interaction networks may eventually lead to discovery of drugs that target biological sub-networks (‘network medicine’) instead of individual proteins. In this thesis, we have proposed and investigated the use of a maximal edge centrality criterion to discover drug-toxicity signaling paths inside a human protein interaction network. The signaling path detection approach utilizes drug and toxicity information along with two novel edge weighting measures, one based on edge centrality for detected paths and another using differential gene expression between tissues treated with toxicity-inducing drugs and a control set. Drugs known to induce non-immune Neutropenia were analyzed as a test case and common path proteins on discovered signaling paths were evaluated for toxicological significance. In addition to investigating the value of topological connectivity for identification of toxicity biomarkers, the gene expression-based measure led to identification of a proposed biomarker panel for screening new drug candidates. Comparative evaluation of findings from the DTSP approach with standard microarray analysis method showed clear improvements in various performance measures including true positive rate, positive predictive value, negative predictive value and overall accuracy. Comparison of non-immune Neutropenia signaling paths with those discovered for a control set showed increased transcript-level activation of discovered signaling paths for toxicity-inducing drugs. We have demonstrated the scientific value from a systems-based approach for identifying toxicity-related proteins inside complex biological networks. The algorithm should be useful for biomarker identification for any toxicity assuming availability of relevant drug and drug-induced toxicity information.Ph.D., Information Studies -- Drexel University, 201

A Mixed-Methods Refugee Community Health Needs and Assets Assessment

Introduction: Many factors may negatively affect the experience of refugees navigating the healthcare system in Philadelphia. These factors include, but are not limited to, lack of familiarity with the healthcare system, language and cultural barriers, limited health literacy, physical and transportation barriers, and fear and/or distrust of the healthcare system. In addition, there are a large proportion of United States refugees in Pennsylvania. According to usnews.com, Pennsylvania was ranked the top 6th state for taking in the most refugees in the year 2017. Objective: The primary objective is to assess the experiences of refugees within the healthcare system since resettlement in Philadelphia. The secondary objective is to use the information gained from our study to implement interventions that may improve navigation of the healthcare system for refugees in Philadelphia. Methods: Quantitative and qualitative survey questions will be administered to participants. These questions will cover experiences directly associated with the healthcare system, as well as participant perceptions of social determinants of health that impact physical and behavioral/mental health such as education, community cohesion/support and employment, community-based services related to food security, housing, and transportation. Quantitative questions will be asked through translated surveys. Qualitative questions are will be administered through 1-on-1 interviews with the assistance of interpreters. The analysis will include a mixed methods approach. Quantitative survey data will use descriptive statistics including frequencies, percentages, and mean values. Data will be entered into EXCEL and analysis will be done through EXCEL and SPSS. Qualitative data will undergo content analysis. Interviews will be taped, transcribed/translated, and coded vis NVIVO software. Results: Pending Conclusion: Pendin

Classification of rheumatoid arthritis status with candidate gene and genome-wide single-nucleotide polymorphisms using random forests

Abstract Using the North American Rheumatoid Arthritis Consortium (NARAC) candidate gene and genome-wide single-nucleotide polymorphism (SNP) data sets, we applied regression methods and tree-based random forests to identify genetic associations with rheumatoid arthritis (RA) and to predict RA disease status. Several genes were consistently identified as weakly associated with RA without a significant interaction or combinatorial effect with other candidate genes. Using random forests, the tested candidate gene SNPs were not sufficient to predict RA patients and normal subjects with high accuracy. However, using the top 500 SNPs, ranked by the importance score, from the genome-wide linkage panel of 5742 SNPs, we were able to accurately predict RA patients and normal subjects with sensitivity of approximately 90% and specificity of approximately 80%, which was confirmed by five-fold cross-validation. However, in a complete training-testing framework, replication of genetic predictors was less satisfactory; thus, further evaluation of existing methodology and development of new methods are warranted.http://deepblue.lib.umich.edu/bitstream/2027.42/117372/1/12919_2007_Article_2426.pd

Normalized Healthcare Utilization Among Refugees Resettled in Philadelphia, 2007-2016

Background/Purpose: About 70,000 new refugees are resettled in the United States each year, of which approximately 600 are resettled in Philadelphia. This project seeks to better understand the patterns of healthcare utilization, including primary care, emergency, and hospitalization, among refugees resettled in Philadelphia, PA, between 2007 and 2016. Methods: Demographic and healthcare utilization data for 1,144 refugees seen at Jefferson Family Medical Associates were compiled from the Jefferson Longitudinal Refugee Health Registry. Descriptive statistics were used to describe the demographic characteristics of the refugee population. Negative binomial count regressions were used to test for significant correlations between major demographic variables and healthcare utilization. Results: Refugees had an average of 7.24 (SD = 9.35) and a median of 4 primary care visits. Visits rates were highest during the first eight months post resettlement and declined significantly after expiration of Refugee Medical Assistance. Country of origin and year of arrival were significantly associated with differing rates of healthcare utilization. Discussion: Overall, refugees utilized primary healthcare services at a slightly higher rate than the U.S. average. There are differences in utilization among various sub-populations within the refugee community. Future studies should further explore these differences in healthcare utilization patterns among recently resettled refugees

Impact of updated clinical practice guidelines on outpatient treatment for Clostridioides difficile infection and associated clinical outcomes

BACKGROUND: The 2017 Infectious Diseases Society of America/Society for Healthcare Epidemiology of America (IDSA/SHEA) METHODS: A pre-post study design was employed using Medicare data. CDI treatment utilization and clinical outcomes (4- and 8-week sustained response, CDI recurrence) were compared between patients indexed from April-September 2017 (preguideline period) and those indexed from April-September 2018 (postguideline period). Clinical outcomes associated with fidaxomicin versus vancomycin were compared using propensity score-matched analyses. RESULTS: From the pre- to postguideline period, metronidazole use decreased (initial CDI: 81.2% to 53.5%; recurrent CDI: 49.7% to 27.6%) while vancomycin (initial CDI: 17.9% to 44.9%; recurrent CDI: 48.1% to 66.4%) and fidaxomicin (initial CDI: 0.87% to 1.63%; recurrent CDI: 2.2% to 6.0%) use increased significantly ( CONCLUSIONS: Vancomycin use increased and metronidazole use decreased after the 2017 guideline update. Fidaxomicin use increased but remained low. Improved outcomes associated with fidaxomicin relative to vancomycin suggest benefits from its greater use in Medicare patients

Physiologic compliance in engineered small-diameter arterial constructs based on an elastomeric substrate.

Compliance mismatch is a significant challenge to long-term patency in small-diameter bypass grafts because it causes intimal hyperplasia and ultimately graft occlusion. Current engineered grafts are typically stiff with high burst pressure but low compliance and low elastin expression. We postulated that engineering small arteries on elastomeric scaffolds under dynamic mechanical stimulation would result in strong and compliant arterial constructs. This study compares properties of engineered arterial constructs based on biodegradable polyester scaffolds composed of either rigid poly(lactide-co-glycolide) (PLGA) or elastomeric poly(glycerol sebacate) (PGS). Adult baboon arterial smooth muscle cells (SMCs) were cultured in vitro for 10 days in tubular, porous scaffolds. Scaffolds were significantly stronger after culture regardless of material, but the elastic modulus of PLGA constructs was an order of magnitude greater than that of porcine carotid arteries and PGS constructs. Deformation was elastic in PGS constructs and carotid arteries but plastic in PLGA constructs. Compliance of arteries and PGS constructs were equivalent at pressures tested. Altering scaffold material from PLGA to PGS significantly decreased collagen content and significantly increased insoluble elastin content in constructs without affecting soluble elastin concentration in the culture medium. PLGA constructs contained no appreciable insoluble elastin. This research demonstrates that: (1) substrate stiffness directly affects in vitro tissue development and mechanical properties; (2) rigid materials likely inhibit elastin incorporation into the extracellular matrix of engineered arterial tissues; and (3) grafts with physiologic compliance and significant elastin content can be engineered in vitro after only days of cell culture

Powder Compaction: Compression Properties of Cellulose Ethers

Effective development of matrix tablets requires a comprehensive understanding of different raw material attributes and their impact on process parameters. Cellulose ethers (CE) are the most commonly used pharmaceutical excipients in the fabrication of hydrophilic matrices. The innate good compression and binding properties of CE enable matrices to be prepared using economical direct compression (DC) techniques. However, DC is sensitive to raw material attributes, thus, impacting the compaction process. This article critically reviews prior knowledge on the mechanism of powder compaction and the compression properties of cellulose ethers, giving timely insight into new developments in this field

An inter-site study of biofouling recruitment on static immersion panels in major ports of South East Asia and India

Limited knowledge of native marine biodiversity hinders effective biodiversity management to safeguard South and Southeast Asia’s marine coastal environment against the threat of invasive species transfer through shipping. In particular, sessile marine biofouling organisms in South East Asian ports are poorly known. Through the support of the ASEAN-India Cooperation Project on the Extent of Transfer of Alien Invasive Organisms in South/South East Asia Region by Shipping, a coordinated effort to examine diversity of biofouling organisms in major port areas in Southeast Asia and India was made using polyvinylchloride (PVC) panels as recruitment surfaces in a static immersion study for a period of 12 months. Not surprisingly, the study revealed that fouling patterns differed between ports possibly as a result of dissimilar hydrographic conditions. However, there were also underlying similarities that reflected a regional uniformity in the composition of fouling communities. At the same time, the alien Caribbean bivalve Mytilopsis sallei was detected in Manila Bay (Philippines), Songkhla Port (Thailand) and Singapore. This is a first simultaneous biofouling survey involving scientists and government stakeholders from India and ASEAN nations of Brunei Darussalam, Indonesia, Lao PDR, Malaysia, Myanmar, Singapore, Thailand, Philippines and Vietnam