Predictive risk of radiation induced cerebral necrosis in pediatric brain cancer patients after VMAT versus proton therapy

Cancer of the brain and central nervous system (CNS) is the second most common of all pediatric cancers. Treatment of many of these cancers includes radiation therapy of which radiation induced cerebral necrosis (RICN) can be a severe and potentially devastating side effect. Risk factors for RICN include brain volume irradiated, the dose given per fraction and total dose. Thirteen pediatric patients were selected for this study to determine the difference in predicted risk of RICN when treating with volumetric modulated arc therapy (VMAT) compared to passively scattered proton therapy (PSPT) and intensity modulated proton therapy (IMPT). Plans were compared on the basis of dosimetric endpoints in the planned treatment volume (PTV) and brain and a radiobiological endpoint of RICN calculated using the Lyman-Kutcher-Burman probit model. Uncertainty tests were performed to determine if the predicted risk of necrosis was sensitive to positional errors, proton range errors and selection of risk models. Both PSPT and IMPT plans resulted in a significant increase in the maximum dose to the brain, a significant reduction in the total brain volume irradiated to low doses, and a significant lower predicted risk of necrosis compared with the VMAT plans. The findings of this study were upheld by the uncertainty analysis

In Situ Small Scale Mechanical Characterization of Materials Under Environmental

This research investigates the mechanical properties and performance of structural materials at a small volume scale. In situ observation was made possible through the Small Punch Test (SPT) method as well as tribological testing. Experimentally, aluminum and titanium alloys were examined using those two techniques. Analysis of their behavior in comparison with their published mechanical properties made it possible to establish connections between test parameters and conventional uniaxial tensile test properties. Connections were generated between SPT parameters and tribological performance. This research used experimental approaches to develop an understanding of the material behaviors during small punch testing and apply them to hydrogen embrittlement. The SPT for such alloys were highly repeatable and specimen surface roughness did not have visible impacts on repeatability. Analysis indicated that there is a link between the SPT and conventional mechanical properties. The relationship between the applied force and the slop of the FvE curve is associated with the tensile strength and elastic modulus. It was found that the SPT can be used to qualitatively gage wear resistance. The SPT was used to analyze hydrogen effects, and no significant effects were seen on 3003-H14 and 2618-T61 aluminum alloys; however, effects were seen on a Ti-6Al-4V alloy. It was also found that hydrogen showed no visible effects on friction and wear. The SPT can now be applied more accurately to the testing of aluminum alloys and new doors for the potential of small punch testing in the application of hydrogen embrittlement and surface characterization have been opened. This thesis consists of six chapters. The first chapter serves as an introduction to the background necessary to understand the rational and motivation for the present research. The second chapter will go into detail about the motivation and the objects of the research while the third chapter will explain the experimental procedures that were conducted to fulfill these objectives. The fourth chapter will present the results of these experiments, and they will be discussed in the fifth chapter. Finally, in the sixth chapter, conclusions will be stated and future work will be discussed

Mechanisms of resistance of normal cells to TRAIL induced apoptosis vary between different cell types

AbstractResistance of normal cells to tumour necrosis factor related apoptosis inducing ligand (TRAIL) induced apoptosis is believed to be mediated by expression of two decoy receptors. Here we show that the expression and localisation of TRAIL receptors (TRAIL-Rs) vary between different cells and that resistance to TRAIL is mediated by different mechanisms. The decoy receptor, TRAIL-R3, appeared important in protection of endothelial cells, whereas lack of surface death receptor expression and as yet unknown intracellular inhibitor(s) of apoptosis downstream of caspase-3 may play a major role in protection of melanocytes and fibroblasts from TRAIL induced apoptosis, respectively. Differential subcellular location of decoy receptors may be an important determinant of their effectiveness in different types of normal cells

The subendothelial extracellular matrix modulates NF-κB activation by flow: a potential role in atherosclerosis

Atherosclerotic plaque forms in regions of the vasculature exposed to disturbed flow. NF-κB activation by fluid flow, leading to expression of target genes such as E-selectin, ICAM-1, and VCAM-1, may regulate early monocyte recruitment and fatty streak formation. Flow-induced NF-κB activation is downstream of conformational activation of integrins, resulting in new integrin binding to the subendothelial extracellular matrix and signaling. Therefore, we examined the involvement of the extracellular matrix in this process. Whereas endothelial cells plated on fibronectin or fibrinogen activate NF-κB in response to flow, cells on collagen or laminin do not. In vivo, fibronectin and fibrinogen are deposited at atherosclerosis-prone sites before other signs of atherosclerosis. Ligation of integrin α2β1 on collagen prevents flow-induced NF-κB activation through a p38-dependent pathway that is activated locally at adhesion sites. Furthermore, altering the extracellular matrix to promote p38 activation in cells on fibronectin suppresses NF-κB activation, suggesting a novel therapeutic strategy for treating atherosclerosis

A baseline assessment of emerging organic contaminants in New Zealand groundwater

Emerging organic contaminants (EOCs) are manufactured compounds, used for a range of purposes, that are a rising concern for freshwater quality, human and aquatic health. Their occurrence in groundwater has been demonstrated in several international surveys. We conducted the first baseline survey on EOC occurrence in New Zealand groundwater, using a wide-screening approach (723 compounds) and a novel stratified to mean residence time (MRT) randomised design to inform future monitoring. A total of 61 sites were sampled: 51 baseline sites from the State of the Environment (SOE) network in the Waikato region and 10 targeted sites located in the vicinity of known EOC sources for comparison. EOCs were detected at 91% of the baseline sites at concentrations ranging from 0.1 to 11,000 ng·L−1. Multiple groups of EOCs were encountered: pesticides (48 compounds), pharmaceuticals (11), industrial (10), preservatives/food additives (3) and personal care products (1). Similar diversity and concentration range of EOCs were observed at the targeted sites, with the addition of drugs of abuse and life-style compounds. EOC detections occurred across young (1–11 yrs. MRT), intermediate (11–50 yrs. MRT) and old (50–250 yrs. MRT) groundwaters with higher concentrations and more types of EOCs detected at sites in the youngest age category. Concentrations of the 73 compounds detected at baseline sites were comparable to those found in overseas groundwaters with 28 compounds measured at concentrations greater than the EU maximum admissible concentration for pesticides. We used the survey results to: review current pesticide monitoring; propose complementary monitoring; identify potential EOC groundwater tracers and identify compounds for which cost-effective national laboratory capability is needed. The Waikato survey results demonstrated ubiquitous occurrence of unmonitored, unregulated EOCs in groundwater and limitations in using targeted approaches to establish monitorin

Incidence of cognitively defined late-onset Alzheimer's dementia subgroups from a prospective cohort study

INTRODUCTION: There may be biologically relevant heterogeneity within typical late-onset Alzheimer's dementia. METHODS: We analyzed cognitive data from people with incident late-onset Alzheimer's dementia from a prospective cohort study. We determined individual averages across memory, visuospatial functioning, language, and executive functioning. We identified domains with substantial impairments relative to that average. We compared demographic, neuropathology, and genetic findings across groups defined by relative impairments. RESULTS: During 32,286 person-years of follow-up, 869 people developed Alzheimer's dementia. There were 393 (48%) with no domain with substantial relative impairments. Some participants had isolated relative impairments in memory (148, 18%), visuospatial functioning (117, 14%), language (71, 9%), and executive functioning (66, 8%). The group with isolated relative memory impairments had higher proportions with ≥ APOE ε4 allele, more extensive Alzheimer's-related neuropathology, and higher proportions with other Alzheimer's dementia genetic risk variants. DISCUSSION: A cognitive subgrouping strategy may identify biologically distinct subsets of people with Alzheimer's dementia

Incidence of cognitively defined late-onset Alzheimer\u27s dementia subgroups from a prospective cohort study.

INTRODUCTION: There may be biologically relevant heterogeneity within typical late-onset Alzheimer\u27s dementia. METHODS: We analyzed cognitive data from people with incident late-onset Alzheimer\u27s dementia from a prospective cohort study. We determined individual averages across memory, visuospatial functioning, language, and executive functioning. We identified domains with substantial impairments relative to that average. We compared demographic, neuropathology, and genetic findings across groups defined by relative impairments. RESULTS: During 32,286 person-years of follow-up, 869 people developed Alzheimer\u27s dementia. There were 393 (48%) with no domain with substantial relative impairments. Some participants had isolated relative impairments in memory (148, 18%), visuospatial functioning (117, 14%), language (71, 9%), and executive functioning (66, 8%). The group with isolated relative memory impairments had higher proportions with ≥ APOE ε4 allele, more extensive Alzheimer\u27s-related neuropathology, and higher proportions with other Alzheimer\u27s dementia genetic risk variants. DISCUSSION: A cognitive subgrouping strategy may identify biologically distinct subsets of people with Alzheimer\u27s dementia

Oral antibiotic prescribing patterns for treatment of pulmonary exacerbations in two large pediatric CF centers

Introduction: Oral antibiotics are frequently prescribed for outpatient pulmonary exacerbations (PEx) in children with cystic fibrosis (CF). This study aimed to characterize oral antibiotic use for PEx and treatment outcomes at two large US CF centers. Methods: Retrospective, descriptive study of oral antibiotic prescribing practices among children with CF ages 6–17 years over 1 year. The care setting for antibiotic initiation (clinic or phone encounter) was determined and outcomes were compared. Results: A total of 763 oral antibiotic courses were prescribed to 312 patients aged 6–17 years (77% of 403 eligible patients) with a median of two courses per year (range: 1–10). Fifty‐eight percent of prescriptions were provided over the phone. Penicillin was the most commonly prescribed antibiotic class (36% of prescriptions) but differences in antibiotic class prescriptions were noted between the two centers. Hospitalizations occurred within 3 months following 19% of oral antibiotic courses. Forced expiratory volume in 1 s (FEV1) recovered to within 90% of prior baseline within 6 months in 87% of encounters; the mean (SD) % recovery was 99.6% (12.1%) of baseline. Outcomes did not differ between phone and clinic prescriptions. Conclusions: Phone prescriptions, commonly excluded in studies of PEx, made up more than half of all oral antibiotic courses. Heterogeneity in prescribing patterns was observed between the two centers. Most patients had improvement in FEV1 returning to near their prior baseline, but hospitalizations occurred in one‐fifth following oral antibiotic treatment. Efforts to optimize PEx treatment must consider care that occurs over the phone; this is particularly important as the use of telemedicine increases.This work was supported by the Cystic Fibrosis Foundation (SANDERS18A1, HOPPE16A0)

Predictors of pulmonary exacerbation treatment in cystic fibrosis

Background: Most studies of pulmonary exacerbations (PEx) in cystic fibrosis (CF) focus on intravenous (IV)-treated PEx, though most PEx are treated with oral antibiotics. Our objectives were to describe predictors of antibiotic choice and outcomes for PEx initially identified in clinic. Methods: For each patient in the U.S. CF Foundation Patient Registry, we selected the first PEx recorded at a clinic visit in 2013-14 following a clinic visit without a PEx. We used multivariable logistic regression to determine associations between clinical characteristics and antibiotic treatment choice. We determined outcomes in the 90 days after the first PEx. Results: Among 14,265 patients with a PEx initially identified in clinic, 21.4% received no antibiotics, 61.5% received new oral and/or inhaled antibiotics, and 17.0% had IV antibiotics within 14 days. Compared to IV antibiotics, patients more likely to receive new oral and/or inhaled antibiotics: were male, 10th percentile or 18.5 kg/m2, >90 days between clinic visits, FEV1 > 70% predicted at the PEx, no prior-year IV-treated PEx, FEV1 decline <10% predicted, and private insurance. Following the PEx, 30.3% of patients had no clinical encounters within 90 days. Treatment with IV antibiotics within 90 days occurred for 23.7% treated without antibiotics, 22.8% of new oral and/or inhaled antibiotics, and 27.1% of IV antibiotics. Conclusion: Most PEx identified in clinic are treated with new oral and/or inhaled antibiotics. Markers of disease severity are associated with antibiotic treatment choice. Many patients had no follow-up evaluation within 90 days of treatment