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"Harris, Sean"
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Group B streptococcus induces cellular senescence in human amnion epithelial cells through a partial interleukin-1-mediated mechanism
Group B streptococcus (GBS) infection is a significant public health concern associated with adverse pregnancy complications and increased neonatal mortality and morbidity. However, the mechanisms underlying the impact of GBS on the fetal membrane, the first line of defense against pathogens, are not fully understood. Here, we propose that GBS induces senescence and inflammatory factors (IL-6 and IL-8) in the fetal membrane through interleukin-1 (IL-1). Utilizing the existing transcriptomic data on GBS-exposed human fetal membrane, we showed that GBS affects senescence-related pathways and genes. Next, we treated primary amnion epithelial cells with conditioned medium from the choriodecidual layer of human fetal membrane exposed to GBS (GBS collected choriodecidual [CD] conditioned medium) in the absence or presence of an IL-1 receptor antagonist (IL-1Ra). GBS CD conditioned medium significantly increased β-galactosidase activity, IL-6 and IL-8 release from the amnion epithelial cells. Cotreatment with IL1Ra reduced GBS-induced β-galactosidase activity and IL-6 and IL-8 secretion. Direct treatment with IL-1α or IL-1β confirmed the role of IL-1 signaling in the regulation of senescence in the fetal membrane. We further showed that GBS CD conditioned medium and IL-1 decreased cell proliferation in amnion epithelial cells. In summary, for the first time, we demonstrate GBS-induced senescence in the fetal membrane and present evidence of IL-1 pathway signaling between the choriodecidua and amnion layer of fetal membrane in a paracrine manner. Further studies will be warranted to understand the pathogenesis of adverse pregnancy outcomes associated with GBS infection and develop therapeutic interventions to mitigate these complications. Summary Sentence Role of IL-1 in GBS-induced senescence of human primary amnion epithelial cells. Graphical Abstract
Journal Article
Coevolving Defender Strategies Within Adversarial Ground Station Transit Time Games via Competitive Coevolution
Emerging Proliferated Low Earth Orbit (P-LEO) constellations may be susceptible to attacks launched by malevolent actors capable of compromising orbiting satellites. We introduce and investigate an adversarial ground station transit time game as a proxy to study the ability to rapidly detect and respond to satellite attacks. Investigation of this problem allows us to study more complex real-world dynamics involving threats to satellite systems. Unfortunately, the problem proves to be daunting to solve due to the high-dimensionality of the solution space and the difficulty of predicting action consequences in dynamic adversarial settings. For this reason, an effective method to identify successful strategies as solutions to the problem is necessary. In this work, an artificial intelligence approach called competitive coevolution is employed to solve scenarios featuring an attacker evolving strategic locations to degrade the performance of a constellation, while a defender evolves intelligent strategies to counter the attacker’s action. The proposed solution outperforms both minimal and complex strategies, while showing versatility and robustness over a variety of scenarios.
Journal Article
Evaluating impacts of the trichloroethylene metabolite S -(1,2-dichlorovyinyl)-L-cysteine on transcriptomic responses and cytokine release in a macrophage model: implications for pregnancy outcomes
Trichloroethylene (TCE) is a volatile synthetic chemical used in various industrial processes like metal degreasing. Large amounts of TCE have been released into the environment. Exposure to TCE can occur through routes, such as inhalation for workers using TCE or ingestion of drinking water in contaminated areas. Macrophages are key immune cells in virtually all tissues in the human body, including the fetal membranes, making them a plausible target for DCVC-induced immunotoxicity. Macrophages are critical for maintaining anti-microbial defenses during pregnancy, but little data exists on TCE immunotoxicity during pregnancy. We previously showed that the TCE metabolite,
-(1,2-dichlorovinyl)-L-cysteine (DCVC), down-regulates immune functions in fetal membranes. To gain insight into immune functions impacted by DCVC, we treated a macrophage cell model (THP-1 cells) with DCVC followed by stimulation with bacterial or fungal toxins relevant for intrauterine infections: lipopolysaccharide (LPS), lipoteichoic acid (LTA), or zymosan. DCVC inhibited toxin-stimulated release of cytokines (e.g. TNFα and IL-1β) for all three microbial toxins. We then conducted benchmark dose modeling and compared benchmark doses for DCVC cytotoxicity
cytokine suppression and determined that inhibition of cytokine release was the more potent endpoint compared to cytotoxicity. Finally, we analyzed a previously generated transcriptomic dataset from THP-1 cells stimulated with LPS, with or without DCVC treatment. We identified transcription factors that were enriched with DCVC and/or LPS treatment, including NF-kB and Vitamin D receptor (VDR). Our findings show that DCVC potently alters cellular and molecular macrophage immune responses involved in defense against intrauterine pathogens.
Journal Article
Group B streptococcus activates transcriptomic pathways related to premature birth in human extraplacental membranes in vitro
Streptococcus agalactiae (group B streptococcus [GBS]) infection in pregnant women is the leading cause of infectious neonatal morbidity and mortality in the United States. Although inflammation during infection has been associated with preterm birth, the contribution of GBS to preterm birth is less certain. Moreover, the early mechanisms by which GBS interacts with the gestational tissue to affect adverse pregnancy outcomes are poorly understood. We hypothesized that short-term GBS inoculation activates pathways related to inflammation and premature birth in human extraplacental membranes. We tested this hypothesis using GBS-inoculated human extraplacental membranes in vitro. In agreement with our hypothesis, a microarray-based transcriptomics analysis of gene expression changes in GBS-inoculated membranes revealed that GBS activated pathways related to inflammation and preterm birth with significant gene expression changes occurring as early as 4 h postinoculation. In addition, pathways related to DNA replication and repair were downregulated with GBS treatment. Conclusions based on our transcriptomics data were further supported by responses of prostaglandin E2 (PGE2), and matrix metalloproteinases 1 (MMP1) and 3 (MMP3), all of which are known to be involved in parturition and premature rupture of membranes. These results support our initial hypothesis and provide new information on molecular targets of GBS infection in human extraplacental membranes. Summary Sentence Group B Streptococcus (GBS) activates premature birth and inflammation pathways in human extraplacental membranes in vitro, providing insight into early molecular responses underpinning GBS contributions to adverse birth outcomes.
Journal Article
Pharmaceutical modulation of canonical Wnt signaling in multipotent stromal cells for improved osteoinductive therapy
Human mesenchymal stem cells (hMSCs) from bone marrow are regarded as putative osteoblast progenitors in vivo and differentiate into osteoblasts in vitro. Positive signaling by the canonical wingless (Wnt) pathway is critical for the differentiation of MSCs into osteoblasts. In contrast, activation of the peroxisome proliferator-activated receptor-γ (PPARγ)-mediated pathway results in adipogenesis. We therefore compared the effect of glycogen-synthetase-kinase-3β (GSK3β) inhibitors and PPARγ inhibitors on osteogenesis by hMSCs. Both compounds altered the intracellular distribution of β-catenin and GSK3β in a manner consistent with activation of Wnt signaling. With osteogenic supplements, the GSK3β inhibitor 6-bromo-indirubin-3'-oxime (BIO) and the PPARγ inhibitor GW9662 (GW) enhanced early osteogenic markers, alkaline phosphatase (ALP), and osteoprotegerin (OPG) by hMSCs and transcriptome analysis demonstrated up-regulation of genes encoding bone-related structural proteins. At higher doses of the inhibitors, ALP levels were attenuated, but dexamethasone-induced biomineralization was accelerated. When hMSCs were pretreated with BIO or GW and implanted into experimentally induced nonself healing calvarial defects, GW treatment substantially increased the capacity of the cells to repair the bone lesion, whereas BIO treatment had no significant effect. Further investigation indicated that unlike GW, BIO induced cell cycle inhibition in vitro. Furthermore, we found that GW treatment significantly reduced expression of chemokines that may exacerbate neutrophil- and macrophage-mediated cell rejection. These data suggest that use of PPARγ inhibitors during the preparation of hMSCs may enhance the capacity of the cells for osteogenic cytotherapy, whereas adenine analogs such as BIO can adversely affect the viability of hMSC preparations in vitro and in vivo.
Journal Article
Current Trends in Operating Room Scheduling 2015 to 2020: a Literature Review
The operating room scheduling problem is a popular research topic due to its complexity and relevance. Previous literature reviews established a useful classification system for categorizing technical operating room scheduling articles through 2014. The increasing number of technical operating room scheduling articles published per year necessitates another literature review to allow researchers to react more quickly to emerging trends. This review builds upon previous classification schemes and categorizes 246 technical operating room scheduling articles from 2015 to 2020. Current trends and areas for future research are identified. Most notably, two major themes emerge. First, researchers continue to develop and innovate across each category. Second, the lack of real-life model implementation remains the greatest challenge facing the field.
Journal Article
An Enhanced Kaizen Event in a Sterile Processing Department of a Rural Hospital: A Case Study
Operating Rooms (ORs) generate the largest revenues and losses in a hospital. Without the prompt supply of sterile surgical trays from the Sterile Processing Department (SPD), the OR would not be able to perform surgeries to its busy schedule. Nevertheless, little emphasis has been brought in the medical literature to research on surgical instrument processing in the medical literature. The present study was done applies an Enhanced Kaizen Event (EKE) in the SPD of a rural hospital to identify sources of waste and minimize non-value-added steps in the SPD processes. The EKE consisted of three successive Plan-Do-Check-Act (PDCA) cycles, which focused on improvements at the departmental level first, then at an area level, and finally at the station level. The EKE yielded an improved streamlined workflow and a new design for the SPD layout, one of its areas, and a workstation. This paper aims at building a methodology, including identified steps. Results exhibited a 35% reduction in travel distance by the staff, eliminating non-value-added processes, reducing errors in the sterilization process, and eliminating cross-contamination for sterilized materials.
Journal Article
2715 The ten second triage tool – A multi-discipline field test to determine its feasibility
Aims and ObjectivesTriage is a key principle in the effective management of major incidents. The speed that it is possible to perform triage is important, along with the speed at which key life-saving interventions (LSIs) be performed, e.g., management of external haemorrhage and airway opening manoeuvres. In 2023, an NHS England working group developed the Ten Second Triage (TST) tool. We describe the field-testing process that was undertaken prior to its introduction.Method and DesignA simulated major incident exercise with 37 casualties (33 live ‘patients’, 4 mannequins) was conducted at the NARU Education Centre, Salisbury. Both specialist and non-specialist responders from Police, Ambulance and Fire Services took part. A total of eight ‘runs’ were conducted (table 1), each ‘run’ consisting of ten responders from each emergency service plus a team leader. Quantitative assessments of overall accuracy of triage and time taken from entry on scene through to completion of necessary LSIs for all casualties were conducted. Qualitative assessment was conducted independently by the Health Security Agency.Abstract 2715 Table 1Run NoParticipant GroupTriage Tool UsedTime to Complete Primary Triage (mins)Time to Complete Secondary Triage (mins)1AmbulanceMITT202Ambulance (Team B)TST63Police (Team A)TST74FireTST65Police (Team B)TST56Ambulance (Team A)TST87Police/Fire/Amb,Ambulance Team ATSTMITT5158Police/Fire/Amb,Ambulance Team BTSTMITT717Results and ConclusionAmbulance personnel utilising the new NHS Major Incident Triage Tool (MITT) completed the scenario in 20minutes. ‘Runs’ two to six with TST took a mean time of 6mins 24secs. For ‘runs’ seven and eight, were the TST was performed prior to the MITT, the time taken to complete the MITT reduced to 10minutes (table 1).The TST had an overall accuracy of 78% across all runs, with a corresponding over and under-triage rate of 18% and 4% respectively.Conclusion: The TST is a rapid and accurate method of triaging patients requiring LSI, and delivery by all emergency services personnel is feasible. This study supports its adoption by NHS England.
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