This dissertation analyzes a selection of novels by four postcolonial authors, Ama Ata Aidoo, Arundhati Roy, Shani Mootoo, and Zadie Smith, and theorizes "queering" as an ethical literary procedure in which experimentation with narrative form challenges the norms of narrative that uphold heteronormative and liberal individualist models of the human. Each author's experimental engagement with the novel form effects a transformation in the form and function of the novel itself, thus reinventing the ethical potential of the novel and revising understandings of the human. In these novels, the literary practice of queering challenges the norms of narrative realism, including its limited construction of the human as the heteronormative liberal individual subject, so as to articulate an ethical stance in narrative and reinvent the form of the global novel in English in the contemporary world. Contextualizing my theoretical approach with recent work in postcolonial studies, this dissertation engages in current debates about the purpose and aims of postcolonial literary studies in the contemporary, globalized world. Drawing upon the work of Dipesh Chakrabarty, Gayatri Spivak, Aamir Mufti, Paul Jay, Sankaran Krishna, and Sanjay Krishnan, as well as Martha Nussbaum and Nancy Armstrong, this study argues for the value and significance of the ethical potential of the literary. My intervention suggests that queer experimental practice in narrative challenges normative ways of understanding and being in the world, including the values upheld by narratives of globalization, consumer capitalism, progress, and development. While the novel has, since the eighteenth century, been one of the primary forms for consolidating the liberal individual subject as the dominant model of the human, the novels in this study imagine the human as inherently interconnected, a shift in understanding that aligns with the current planetary realities of climate change. In light of planetary shifts caused by global warming, the science of climate change, and the recognition of human beings as a geological force, the ethics of queer experimentation in the global novel form offers a site in which to imagine the human otherwise--as planetary, futural, and connected

Intrauterine growth retardation (IUGR) is associated with neurological deficits including cerebral palsy and cognitive and behavioral disabilities. The pathogenesis involves oxidative stress that leads to periventricular white matter injury with a paucity of mature oligodendrocytes and hypomyelination. The molecular mechanisms underlying this damage remain poorly understood. We used a rat model of IUGR created by bilateral ligation of the uterine artery at embryonic Day 19 that results in fetal growth retardation and oxidative stress in the developing brain. The IUGR rat pups showed significant delays in oligodendrocyte differentiation and myelination that resolved by 8 weeks. Bone morphogenetic protein 4 (BMP4), which inhibits oligodendrocyte maturation, was elevated in IUGR brains at postnatal time points and returned to near normal by adulthood. Despite the apparent recovery, behavioral deficiencies were found in 8-week-old female animals, suggesting that the early transient myelination defects have permanent effects. In support of these in vivo data, oligodendrocyte precursor cells cultured from postnatal IUGR rats retained increased BMP4 expression and impaired differentiation that was reversed with the BMP inhibitor noggin. Oxidants in oligodendrocyte cultures increased BMP expression, which decreased differentiation; however, abrogating BMP signaling with noggin in vitro and in BMP-deficient mice prevented these effects. Together, these findings suggest that IUGR results in delayed myelination through the generation of oxidative stress that leads to BMP4 upregulation.

Background

Delirium is a frequent and detrimental complication of inpatient hospitalization. Multicomponent intervention in selected groups has been shown to prevent and treat delirium, though little data exists on the effect of intervention in neurological patients. We studied the efficacy of a multicomponent delirium care pathway implemented on a largely neurology and neurosurgery hospital ward among unselected patients.

Methods

We incorporated a multicomponent delirium care pathway into the workflow of a university hospital for patients older than 50 years. The pathway involved risk-stratification for development of delirium, delirium screening, and non-pharmacologic behavioral prevention and intervention. We then retrospectively reviewed admissions before and after implementation of the care pathway. Our primary endpoint was incidence of delirium; secondary endpoints included delirium days, length of stay, restraint use, readmission rates, and discharge disposition.

Results

Seven hundred ninety eight admissions from before the delirium care pathway went into effect and 797 admissions from afterwards were reviewed. Baseline characteristics between groups were similar. Delirium incidence between the two groups did not change (7.0% before vs 7.2% after, p = 0.89). Length of stay among delirious patients significantly decreased after implementation of the delirium care pathway (9.60 before vs 7.06 after, β = - 0.16, adjusted p-value = 0.001).

Conclusion

Implementation of a delirium care pathway on a neurosciences ward was not associated with changes in the rate of delirium development, though length of stay among delirious patients decreased. In a largely neurologic population, multicomponent intervention to prevent and treat delirium may not change delirium incidence, but may be effective in mitigating delirium complications.

We determined Ar/Ar eruption ages of eight extrusions from the Pleistocene Coso volcanic field, a long-lived series of small volume rhyolitic domes in eastern California. Combined with ion-microprobe dating of crystal ages of zircon and allanite from these lavas and from granophyre geothermal well cuttings, we were able to track the range of magma-production rates over the past 650 ka at Coso. In ≤230 ka rhyolites we find no evidence of protracted magma residence or recycled zircon (or allanite) from Pleistocene predecessors. A significant subset of zircon in the ~85 ka rhyolites yielded ages between ~100 and 200 Ma, requiring that generation of at least some rhyolites involves material from Mesozoic basement. Similar zircon xenocrysts are found in an ~200 ka granophyre. The new age constraints imply that magma evolution at Coso can occur rapidly as demonstrated by significant changes in rhyolite composition over short time intervals (≤10’s to 100’s ka). In conjunction with radioisotopic age constraints from other young silicic volcanic fields, dating of Coso rhyolites highlights the fact that at least some (and often the more voluminous) rhyolites are produced relatively rapidly, but that many small-volume rhyolites likely represent separation from long-lived mushy magma bodies.

Background:To what extent steroid hormones contribute to lung cancer in male and female never smokers and smokers is unclear. We examined expression of hormone receptors in lung tumors by sex and smoking. Methods:Patients with primary non-small cell lung cancer were recruited into an Intergroup study in the United States and Canada, led by SWOG (S0424). Tumors from 813 cases (450 women and 363 men) were assayed using immunohistochemistry for estrogen receptor (ER)-α, ER-β, progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Linear regression was used to examine differences in expression by sex and smoking status. Cox proportional hazard models were used to estimate survival associated with the receptors. All statistical tests were two-sided. Results:In ever smokers, postmenopause and oral contraceptive use were associated with lower nuclear ER-β (P = .02) and total (nuclear + cytoplasmic) PR expression (P = .02), respectively. Women had lower cytoplasmic ER-α (regression coefficient [β], or differences in H-scores = -15.8, P = .003) and nuclear ER-β (β = -12.8, P = .04) expression than men, adjusting for age, race, and smoking. Ever smokers had both higher cytoplasmic ER-α (β = 45.0, P < .001) and ER-β (β = 25.9, P < .001) but lower total PR (β = -42.1, P < .001) than never smokers. Higher cytoplasmic ER-α and ER-β were associated with worse survival (hazard ratio = 1.73, 95% confidence interval [CI] = 1.15 to 2.58, and HR = 1.59, 95% CI = 1.08 to 2.33, respectively; quartiles 4 vs 1). Conclusions:Lower expression of nuclear ER-β in women supports the estrogen hypothesis in lung cancer etiology. Increasing cytoplasmic ER-α and ER-β and decreasing PR protein expression may be mechanisms whereby smoking disrupts hormone pathways.

Bronchial premalignant lesions (PMLs) are precursors of lung squamous cell carcinoma, but have variable outcome, and we lack tools to identify and treat PMLs at risk for progression to cancer. Here we report the identification of four molecular subtypes of PMLs with distinct differences in epithelial and immune processes based on RNA-Seq profiling of endobronchial biopsies from high-risk smokers. The Proliferative subtype is enriched with bronchial dysplasia and exhibits up-regulation of metabolic and cell cycle pathways. A Proliferative subtype-associated gene signature identifies subjects with Proliferative PMLs from normal-appearing uninvolved large airway brushings with high specificity. In progressive/persistent Proliferative lesions expression of interferon signaling and antigen processing/presentation pathways decrease and immunofluorescence indicates a depletion of innate and adaptive immune cells compared with regressive lesions. Molecular biomarkers measured in PMLs or the uninvolved airway can enhance histopathological grading and suggest immunoprevention strategies for intercepting the progression of PMLs to lung cancer.