Browsing by Author "Leigh, Richard A."

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    Effectiveness of a standardized electronic admission order set for acute exacerbation of chronic obstructive pulmonary disease
    (BMC Pulmonary Medicine, 2018-05-30) Pendharkar, Sachin R.; Ospina, Maria B.; Gadotti, D. A.; Hirani, Naushad; Graham, Jim Allen; Faris, Peter D.; Bhutani, Mohit; Leigh, Richard A.; Mody, Christopher H.; Strickland, Michael K.
    Background: Variation in hospital management of patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) may prolong length of stay, increasing the risk of hospital-acquired complications and worsening quality of life. We sought to determine whether an evidence-based computerized AECOPD admission order set could improve quality and reduce length of stay. Methods: The order set was designed by a provincial COPD working group and implemented voluntarily among three physician groups in a Canadian tertiary-care teaching hospital. The primary outcome was length of stay for patients admitted during order set implementation period, compared to the previous 12 months. Secondary outcomes included length of stay of patients admitted with and without order set after implementation, all-cause readmissions, and emergency department visits. Results: There were 556 admissions prior to and 857 admissions after order set implementation, for which the order set was used in 47%. There was no difference in overall length of stay after implementation (median 6.37 days (95% confidence interval 5.94, 6.81) pre-implementation vs. 6.02 days (95% confidence interval 5.59, 6.46) post-implementation, p = 0.26). In the post-implementation period, order set use was associated with a 1.15-day reduction in length of stay (95% confidence interval − 0.5, − 1.81, p = 0.001) compared to patients admitted without the order set. There was no difference in readmissions. Conclusions: Use of a computerized guidelines-based admission order set for COPD exacerbations reduced hospital length of stay without increasing readmissions. Interventions to increase order set use could lead to greater improvements in length of stay and quality of care. Keywords: Length of stay, Clinical decision support, Chronic obstructive pulmonary disease, Quality improvement
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    Mechanisms of vaccine protection in pneumococcal pneumonia
    (2018-06-13) Schubert, Courtney Lynn; Yipp, Bryan G.; Leigh, Richard A.; Peters, Nathan C.
    Despite the overwhelming success of vaccination in reducing mortality due to infectious diseases, it is unknown what makes some vaccines protective while others are not. Multiple vaccine candidates have failed clinical trial regardless of the production of neutralizing antibodies, therefore there is a need to establish correlates of protection that are not antibody production. We began investigating the Pnuemovax-23 vaccine which provides well characterized protection in both mice and humans, in an attempt to determine the mechanism of vaccine protection. Instead of finding that Pneumovax-23 vaccination induces disease resistance against Streptococcus pneumoniae pneumonia through eradication of the bacteria, we found that vaccinated mice survive the pneumococcal infection via disease tolerance. Therefore, we began investigating how the survival of vaccinated mice is independent of bacterial clearance from the lungs and the spleen. The role of neutrophils was first explored since there was still robust neutrophil recruitment during infection in vaccinated mice, and neutrophils are known to regulate B cells in the spleen and produce B cell growth factors. Ultimately, we determined that despite ample neutrophil recruitment during infection, neutrophils are not mediating this disease tolerance to infection in vaccinated mice. Instead, we turned to investigate whether B cells were required for disease tolerance, where we found B1 innate B cells to be required for vaccinated mice to survive the infection. CD19-/- mice are deficient in innate cells, however still have conventional B cells and neutrophil recruitment during infection. Therefore, we have found a novel mechanism of how vaccination protects against infection, through disease tolerance of the bacterial infection. With further research into the exact mechanism of B1 cells, these findings can potentially alter the future of vaccine development for bacterial pathogens that do not yet have a protective vaccine.
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    Modulation of TGFβ1-induced Fibroblast-to-Myofibroblast Transition in response to Prostaglandin E2 Production by Human Rhinovirus-Infected Airway Epithelial Cells
    (2020-05-08) Pham, Diana Minh; Leigh, Richard A.; Proud, David G.; Kelly, Margaret Mary; Giembycz, Mark A.
    One of the cardinal features of asthma is the presence of airway remodeling, the structural changes that contribute to exaggerated narrowing of the airway. Fibroblast-to-myofibroblast transition (FMT) is an airway remodeling phenomenon whereby fibroblasts develop phenotypic characteristics of myofibroblasts. This increase in myofibroblasts leads to the excessive deposition of extracellular matrix proteins, leading to the thickening of the airway walls. Transforming growth factor beta-1 (TGFβ1) is highly expressed in asthmatics and is known to upregulate fibroblast alpha-smooth muscle actin (α-SMA) expression, a characteristic marker of myofibroblasts. Given that human rhinovirus (HRV) infections are postulated to be involved in the pathogenesis of airway remodeling in asthma, we originally hypothesized that human airway epithelial cells promoted TGFβ1-induced FMT based on α-SMA expression by secreting mediator(s) upon HRV infection. Interestingly, our data consistently demonstrated that supernatants from HRV-infected epithelial cells inhibited TGFβ1-induced α-SMA in fibroblasts compared to supernatants from non-infected epithelial cells. This led us to hypothesize that HRV-infected airway epithelial cells released PGE2 which acts via EP1-4 receptors on fibroblasts to suppress TGFβ1-induced α-SMA expression. Using an in vitro cell culture model, we confirmed HRV-infection of epithelial cells result in the upregulation of PGE2 and validated that PGE2 inhibits TGFβ1-induced α-SMA protein in fibroblasts. Furthermore, supernatants from epithelial cells treated with diclofenac, a non-selective cyclooxygenase inhibitor, prior to HRV infection had reduced ability to inhibit TGFβ1-induced α-SMA expression in fibroblasts. Finally, we demonstrated that PGE2 acts on the fibroblast EP2 receptor to downregulate TGFβ1-induced FMT. In conclusion, our research findings may account for why healthy, non-asthmatic individuals are prevented from developing TGFβ1-induced FMT following repeated rhinovirus infections. This thesis instigates future investigation on whether well-characterized asthmatic cells behave differently to render it vulnerable to TGFβ1-induced FMT following rhinovirus infections.