HMOX1 Gene Promoter Alleles and High HO-1 Levels Are Associated with Severe Malaria in Gambian Children

Heme oxygenase 1 (HO-1) is an essential enzyme induced by heme and multiple stimuli associated with critical illness. In humans, polymorphisms in the HMOX1 gene promoter may influence the magnitude of HO-1 expression. In many diseases including murine malaria, HO-1 induction produces protective anti-inflammatory effects, but observations from patients suggest these may be limited to a narrow range of HO-1 induction, prompting us to investigate the role of HO-1 in malaria infection. In 307 Gambian children with either severe or uncomplicated P. falciparum malaria, we characterized the associations of HMOX1 promoter polymorphisms, HMOX1 mRNA inducibility, HO-1 protein levels in leucocytes (flow cytometry), and plasma (ELISA) with disease severity. The (GT)n repeat polymorphism in the HMOX1 promoter was associated with HMOX1 mRNA expression in white blood cells in vitro, and with severe disease and death, while high HO-1 levels were associated with severe disease. Neutrophils were the main HO-1-expressing cells in peripheral blood, and HMOX1 mRNA expression was upregulated by heme-moieties of lysed erythrocytes. We provide mechanistic evidence that induction of HMOX1 expression in neutrophils potentiates the respiratory burst, and propose this may be part of the causal pathway explaining the association between short (GT)n repeats and increased disease severity in malaria and other critical illnesses. Our findings suggest a genetic predisposition to higher levels of HO-1 is associated with severe illness, and enhances the neutrophil burst leading to oxidative damage of endothelial cells. These add important information to the discussion about possible therapeutic manipulation of HO-1 in critically ill patients

Playing in Ten Thousand Places: Sacramental Imagination and Mystagogical Praxis for Education in Faith

Thesis advisor: Thomas H. GroomeThe central proposal of this dissertation is that recovering the sacramentalprinciple and sacramentality—as a deep structure to all of life—is essential to Christian life, and thus to Catholic education for faith. The sacramental worldview takes seriously the material and historical reality of finite creaturely existence as the place of encounter with Holy Mystery. The seeds of an approach to cultivating this worldview lie in the ancient church practice of mystagogy. Chapter One surveys the epistemological and anthropological facets of the modern and postmodern contexts which posit a desacramentalized cosmos. Many find themselves confined to the limit and flatness of an instrumental, rationalistic, and data driven day to day existence within a commodity culture. This engenders a resistance to the depth of a sacramental cosmos undergirded by the love of the Creator. Furthermore, sacramental ritual and communal worship are no longer a primary place of formation or celebration for fewer and fewer people. Chapter Two traces the historical contours of the sacramental principle as a deep structure to Catholic Christian faith in particular, and indeed, to all of reality. This is placed in conversation with Charles Taylor’s philosophical diagnosis of the secular age and the sacramental theology of Louis-Marie Chauvet. It is into a “world already spoken” by the Logos that the symbolic order acts as a set of building blocks to construct our reality and is therefore the way in which we experience God’s self-communication in God’s transcendence. Chapter Three explores the anthropology and epistemological category of experience in the work of Karl Rahner. Rahner helps us to understand that experience is a necessary epistemological category—constitutive of human knowing. Second, experience is existentiell, meaning that all experience is active and lived, grounded in freedom. Chapter Four maintains that mystagogy was an essential interpretive frame of reference for discerning Christian mystery in the ancient church. The exploration of origins leads to a four-movement model—recollection, recognition, reorientation, and relation—that emerges as a constitutive pattern in early mystagogy. Chapter Five is constructive employing the work of John Dewey, Maxine Greene, Paulo Freire, bell hooks, and Thomas Groome who emphasize the importance the epistemological category of experience in education. Moreover, the four-movement pattern mentioned above is discernible in the spectacular resurrection narrative of the Road to Emmaus and a model for education in faith, prefigured by Jesus’ earthly pedagogy. Consequently, I propose a more extended, broader sense of a mystagogical approach for contemporary praxis to enable the reclamation of an essential sacramental imagination for our time. The telos of these four movements of mystagogy is to enable an anagnorisis—a re-cognition and response to the presence of Holy Mystery within everyday experience. Finally, Chapter Six engages the implications of the foregoing. Mystagogy is an indexical praxis which invites us to be life-long apprentices to becoming alert to God’s hidden presence in our lived experience. It is the rehearsal of a disposition that understands reality as saturated by grace, and learning to accept it as both gift and obligation.Thesis (PhD) — Boston College, 2021.Submitted to: Boston College. School of Theology and Ministry.Discipline: Sacred Theology

Performance of universal early warning scores in different patient subgroups and clinical settings: a systematic review

Objective To assess predictive performance of universal early warning scores (EWS) in disease subgroups and clinical settings.Design Systematic review.Data sources Medline, CINAHL, Embase and Cochrane database of systematic reviews from 1997 to 2019.Inclusion criteria Randomised trials and observational studies of internal or external validation of EWS to predict deterioration (mortality, intensive care unit (ICU) transfer and cardiac arrest) in disease subgroups or clinical settings.Results We identified 770 studies, of which 103 were included. Study designs and methods were inconsistent, with significant risk of bias (high: n=16 and unclear: n=64 and low risk: n=28). There were only two randomised trials. There was a high degree of heterogeneity in all subgroups and in national early warning score (I2=72%–99%). Predictive accuracy (mean area under the curve; 95% CI) was highest in medical (0.74; 0.74 to 0.75) and surgical (0.77; 0.75 to 0.80) settings and respiratory diseases (0.77; 0.75 to 0.80). Few studies evaluated EWS in specific diseases, for example, cardiology (n=1) and respiratory (n=7). Mortality and ICU transfer were most frequently studied outcomes, and cardiac arrest was least examined (n=8). Integration with electronic health records was uncommon (n=9).Conclusion Methodology and quality of validation studies of EWS are insufficient to recommend their use in all diseases and all clinical settings despite good performance of EWS in some subgroups. There is urgent need for consistency in methods and study design, following consensus guidelines for predictive risk scores. Further research should consider specific diseases and settings, using electronic health record data, prior to large-scale implementation.PROSPERO registration number PROSPERO CRD42019143141